[Federal Register Volume 86, Number 190 (Tuesday, October 5, 2021)]
[Rules and Regulations]
[Pages 55300-55439]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-21011]



  Federal Register / Vol. 86, No. 190 / Tuesday, October 5, 2021 / 
Rules and Regulations  
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 1100, 1107 and 1114

[Docket No. FDA-2019-N-2854]
RIN 0910-AH44


Premarket Tobacco Product Applications and Recordkeeping 
Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, us, or we) 
is issuing a final rule that sets forth requirements for premarket 
tobacco product applications (PMTAs) and requires manufacturers to 
maintain records establishing that their tobacco products are legally 
marketed. The rule will help ensure that PMTAs contain sufficient 
information for FDA to determine whether a marketing granted order 
should be issued for a new tobacco product. The rule codifies the 
general procedures FDA will follow when evaluating PMTAs and creates 
postmarket reporting requirements for applicants that receive marketing 
granted orders. The rule also requires tobacco product manufacturers to 
keep records establishing that their tobacco products are legally 
marketed, such as documents showing that a tobacco product is not 
required to undergo premarket review or has received premarket 
authorization.

DATES: This rule is effective November 4, 2021.

FOR FURTHER INFORMATION CONTACT: Paul Hart, Office of Regulations, 
Center for Tobacco Products (CTP), Food and Drug Administration, 
Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G335, 
Silver Spring, MD 20993, 877-287-1373, AskCTP@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary
    A. Purpose of the Regulatory Action
    B. Legal Authority
    C. Summary of Major Provisions
    D. Costs and Benefits
Table of Abbreviations/Commonly Used Acronyms
I. Background
II. Legal Authority
III. General Description of Comments on the Proposed Rule
IV. Description of the Final Regulations for, and the Comments on 
and FDA's Responses Regarding, the Maintenance of Records 
Demonstrating That a Tobacco Product Was Commercially Marketed in 
the United States as of February 15, 2007 (Part 1100, Subpart C)
    A. Purpose and Scope (Sec.  1100.200)
    B. Definitions (Sec.  1100.202)
    C. Recordkeeping Requirements (Sec.  1100.204)
V. Description of the Final Regulations for, and the Comments and 
FDA's Responses Regarding, the Maintenance of Records Relating to 
Exemptions From the Requirements of Demonstrating Substantial 
Equivalence (Sec.  1107.3)
    A. Definition
    B. Record Maintenance
    C. Record Quality
    D. Record Retention
VI. Description of the Final Regulations for, and the Comments and 
FDA's Responses Regarding, Premarket Tobacco Product Applications 
(Part 1114)
VII. General (Part 1114, Subpart A)
    A. Scope (Sec.  1114.1)
    B. Definitions (Sec.  1114.3)
VIII. Premarket Tobacco Product Applications (Part 1114, Subpart B)
    A. Application Submission (Sec.  1114.5)
    B. Required Content and Format (Sec.  1114.7)
    C. Amendments (Sec.  1114.9)
    D. Withdrawal by Applicant (Sec.  1114.11)
    E. Change in Ownership of an Application (Sec.  1114.13)
    F. Supplemental Application Submission (Sec.  1114.15)
    G. Resubmissions (Sec.  1114.17)
IX. FDA Review (Part 1114, Subpart C)
    A. Communications Between FDA and Applicants (Sec.  1114.25)
    B. Review Procedure (Sec.  1114.27)
    C. FDA Action on an Application (Sec.  1114.29)
    D. Issuance of a Marketing Granted Order (Sec.  1114.31)

[[Page 55301]]

    E. Issuance of a Marketing Denial Order (Sec.  1114.33)
    F. Withdrawal of a Marketing Granted Order (Sec.  1114.35)
    G. Temporary Suspension of a Marketing Granted Order (Sec.  
1114.37)
X. Postmarket Requirements (Part 1114, Subpart D)
    A. Postmarket Changes (Sec.  1114.39)
    B. Reporting Requirements (Sec.  1114.41)
    C. Requirements for Periodic Reports
    D. Serious and Unexpected Adverse Experience Reporting
    E. Submission of Additional Information
XI. Miscellaneous (Part 1114, Subpart E)
    A. Record Retention (Sec.  1114.45)
    B. Confidentiality (Sec.  1114.47)
    C. Electronic Submission (Sec.  1114.49)
XII. Paperwork Reduction Act of 1995
XIII. Federalism: Executive Order 13132
XIV. Congressional Review Act
XV. Consultation and Coordination with Indian Tribal Governments
XVI. Analysis of Environmental Impact
XVII. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
XVIII. Effective Date
XIX. References

Executive Summary

A. Purpose of the Regulatory Action

    FDA is issuing this final rule to improve the efficiency of the 
submission and review of PMTAs. We are finalizing this rule after 
reviewing comments to the proposed rule (84 FR 50566, September 25, 
2019) (hereinafter referred to as the proposed rule) and are basing 
this rule on the experience the Agency has gained by reviewing several 
types of premarket applications submitted by industry, including 
substantial equivalence (SE) reports, requests for exemptions from the 
SE requirements, modified risk tobacco product applications (MRTPAs), 
and PMTAs. As described in the proposed rule, FDA has received 
thousands of premarket applications that range widely in the level of 
detail they contain. This rule describes and sets forth requirements 
related to the content and format of PMTAs and will provide applicants 
with a better understanding of the information a PMTA must contain. The 
rule requires an applicant to submit detailed information regarding the 
physical aspects of its new tobacco product and full reports of 
information regarding investigations that may show the health risks of 
the new tobacco product and whether it presents the same or different 
risks compared to other tobacco products. FDA is requiring the 
submission of these health risk investigations to ensure it understands 
the full scope of what is known about the potential health risks of a 
new tobacco product.
    The rule also addresses issues such as the procedures by which FDA 
reviews a PMTA, retention of records related to a PMTA, confidentiality 
of application information, electronic submission of the PMTA and 
amendments, and postmarket reporting requirements. FDA will announce 
the withdrawal of its September 2011 draft guidance entitled 
``Applications for Premarket Review of New Tobacco Products'' in the 
Federal Register. Additionally, FDA will update the guidance for 
industry entitled ``Premarket Tobacco Product Applications for 
Electronic Nicotine Delivery Systems'' (the ENDS PMTA Guidance) \1\ to 
ensure the product-specific recommendations on preparing and submitting 
PMTAs for ENDS are consistent with the requirements of this rule.
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    \1\ Available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
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    Additionally, the rule creates requirements for the maintenance of 
records demonstrating the legal marketing status of Pre-Existing 
Tobacco Products (i.e., tobacco products, including those products in 
test markets) that were commercially marketed in the United States as 
of February 15, 2007) and products that are exempt from the 
requirements of demonstrating substantial equivalence. These 
recordkeeping requirements will allow FDA to more efficiently determine 
the legal marketing status of a tobacco product.

B. Legal Authority

    This rule is being issued under FDA's authority to require 
premarket review of new tobacco products under section 910 of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 387j), FDA's 
authority to require records and reports under section 909(a) of the 
FD&C Act (21 U.S.C. 387i(a)), FDA's authorities related to adulterated 
and misbranded tobacco products under sections 902 and 903 (21 U.S.C. 
387b and 387c), as well as FDA's rulemaking and inspection authorities 
under sections 701(a) and 704 of the FD&C Act (21 U.S.C. 371(a) and 
374).

C. Summary of Major Provisions

    This rule describes and sets forth content and format requirements 
for PMTAs and includes FDA's interpretations of various provisions in 
section 910 of the FD&C Act. Under the rule, a PMTA must contain 
information necessary for FDA to determine whether it should issue a 
marketing granted order for a new tobacco product under section 
910(c)(1)(A) of the FD&C Act. Specifically, the PMTA must enable FDA to 
find whether: (1) There is a showing that permitting the marketing of 
the new tobacco product would be appropriate for the protection of the 
public health; (2) the methods used in, or the facilities and controls 
used for, the manufacture, processing, or packing of the product 
conform to the requirements of section 906(e) of the FD&C Act (21 
U.S.C. 387f(e)); (3) the product labeling is not false or misleading in 
any particular; and (4) the product complies with any applicable 
product standard in effect under section 907 of the FD&C Act (21 U.S.C. 
387g) or there is adequate information to justify a deviation from such 
standard. The rule will also allow applicants to submit a supplemental 
PMTA or a resubmission, which will improve the efficiency of submitting 
and reviewing an application in certain instances. A supplemental PMTA 
can be submitted in situations where an applicant is seeking 
authorization for a new tobacco product that is a modified version of a 
tobacco product for which they have already received a marketing 
granted order. A resubmission can be submitted to address application 
deficiencies following the issuance of a marketing denial order.
    In addition, the rule explains how an applicant can amend or 
withdraw a PMTA and how an applicant may transfer ownership of a PMTA 
to a new owner. The rule also addresses FDA communications with 
applicants and identifies the actions that FDA may take after receipt 
of a PMTA. Where an applicant receives a marketing granted order, the 
rule requires the submission of postmarket reports, addresses when FDA 
may withdraw a marketing granted order, and explains how long an 
applicant will be required to maintain the records related to the PMTA 
and postmarket reports. The rule also sets forth FDA's disclosure 
procedures regarding PMTAs and requires the electronic submission of 
PMTAs, unless the applicant requests and obtains a waiver. 
Additionally, the rule requires tobacco product manufacturers to 
maintain records related to the legal marketing of Pre-Existing Tobacco 
Products and products that are exempt from the requirements of 
demonstrating substantial equivalence.

D. Costs and Benefits

    The final rule will require manufacturers of Pre-Existing Tobacco 
Products and manufacturers of products that are exempt from the 
requirements of demonstrating SE to maintain records to demonstrate 
that they can legally market their products. For products that receive 
a PMTA marketing granted

[[Page 55302]]

order, the final rule will require certain postmarket reporting, 
including periodic reporting and adverse experience reporting. The 
final rule will also implement and set forth requirements for the 
content and format of PMTAs and the general procedures we intend to 
follow in reviewing and communicating with applicants.
    The final rule will make the review of PMTAs more efficient. As a 
result, the final rule will create cost savings for FDA related to the 
review of some PMTAs. The final rule will also create cost savings for 
FDA and for PMTA applicants by reducing the number of PMTAs submitted. 
We estimate that annualized benefits over 20 years will equal $2.04 
million at a 7 percent discount rate, with a low estimate of $1.36 
million and a high estimate of $2.85 million. We estimate that 
annualized benefits over 20 years will equal $2.08 million at a 3 
percent discount rate, with a low estimate of $1.43 million and a high 
estimate of $2.84 million.
    This is the first regulation to address the costs of PMTA 
requirements for new, originally regulated tobacco products. While we 
already included the costs to submit and review PMTAs for deemed 
tobacco products \2\ in the final regulatory impact analysis (RIA) for 
the deeming final rule, no RIA includes the costs to submit and review 
PMTAs for originally regulated tobacco products. Therefore, we include 
the costs to prepare and review PMTAs for these tobacco products in 
this analysis.
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    \2\ Note that for the purposes of this final rule, ``deemed 
tobacco products'' are those tobacco products subject to Chapter IX 
of the FD&C Act as a result of regulations enacted by FDA (Deeming 
Tobacco Products To Be Subject to the Federal Food, Drug, and 
Cosmetic Act, as Amended by the Family Smoking Prevention and 
Tobacco Control Act; Restrictions on the Sale and Distribution of 
Tobacco Products and Required Warning Statements for Tobacco 
Products, 81 FR 28974, May 10, 2016 (``deeming final rule'')). These 
products include cigars, pipe tobacco, waterpipe tobacco, electronic 
nicotine delivery systems (ENDS), and other novel tobacco products.
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    The final rule will increase the cost for applicants to prepare a 
PMTA. As a result, the final rule will generate incremental costs 
related to the preparation of PMTAs for ENDS products. Firms will incur 
costs to maintain and submit postmarket reports and we will incur costs 
to review these reports. Finally, firms will incur costs to read and 
understand the rule and costs to maintain records for some Pre-Existing 
Tobacco Products. We estimate that annualized costs over 20 years will 
equal $4.73 million at a 7 percent discount rate, with a low estimate 
of $2.63 million and a high estimate of $7.45 million. We estimate that 
annualized costs over 20 years will equal $4.86 million at a 3 percent 
discount rate, with a low estimate of $2.50 million and a high estimate 
of $7.95 million.

              Table of Abbreviations/Commonly Used Acronyms
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        Abbreviation acronym                     What it means
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APPH................................  Appropriate for the protection of
                                       public health
CAS.................................  Chemical Abstracts Service
CCI.................................  Confidential commercial
                                       information
CCS.................................  Container Closure System
CGMP................................  Current good manufacturing
                                       practices
CORESTA.............................  Cooperation Centre for Scientific
                                       Research Relative to Tobacco
CTP.................................  Center for Tobacco Products
DPF.................................  Denier per filament
EA..................................  Environmental assessment
ENDS................................  Electronic nicotine delivery
                                       systems
FDA.................................  Food and Drug Administration
FD&C Act............................  Federal Food, Drug, and Cosmetic
                                       Act
FEI.................................  Facility Establishment Identifier
FOIA................................  Freedom of Information Act
GLP.................................  Good laboratory practice
HACCP...............................  Hazard analysis and critical
                                       control point
HCI.................................  Health Canada Intense
HHS.................................  Department of Health and Human
                                       Services
HPHC................................  Harmful or potentially harmful
                                       constituent
HTP.................................  Heated tobacco products
IUPAC...............................  International Union of Pure and
                                       Applied Chemistry
ICH.................................  International Council for
                                       Harmonization
IRB.................................  Institutional Review Board
ISO.................................  International Organization for
                                       Standardization
MDSS................................  Manufacturing Data Sheet
                                       Specification
mL..................................  Milliliters
mm..................................  Minimum and maximum diameter
MRTP................................  Modified risk tobacco product
MRTPA...............................  Modified risk tobacco product
                                       application
NCI.................................  National Cancer Institute
NEPA................................  National Environmental Policy Act
                                       of 1969
NNK.................................  4-(methylnitrosamino)-1-(3-
                                       pyridyl)-1-butanone
NNN.................................  N-nitrosonornicotine
NTRM................................  Nontobacco related material
NYTS................................  National Youth Tobacco Survey
OMB.................................  Office of Management and Budget
OTDN................................  Oral tobacco-derived nicotine
OV..................................  Oven volatiles
PDU.................................  Power delivery unit
PK..................................  Pharmacokinetic
PM..................................  Particulate matter
PMTA................................  Premarket tobacco product
                                       application
RIA.................................  Regulatory Impact Analysis
RTA.................................  Refuse to accept
RTF.................................  Refuse to file
RYO.................................  Roll-your-own
SAS.................................  Statistical Analysis Software
SE..................................  Substantial equivalence
Secretary...........................  Secretary of Health and Human
                                       Services
SES.................................  Socioeconomic status
STN.................................  Submission tracking number
TAMC................................  Total aerobic microbial count
TPMF................................  Tobacco product master file
TSNA................................  Tobacco specific nitrosamine
TYMC................................  Total yeast and mold count
TPSAC...............................  Tobacco Products Scientific
                                       Advisory Committee
UNII................................  Unique ingredients identifier
aw..................................  Water activity
------------------------------------------------------------------------

I. Background

    The Family Smoking Prevention and Tobacco Control Act (Tobacco 
Control Act) (Pub. L. 111-31) provides FDA with the authority to 
regulate tobacco products under the FD&C Act. The FD&C Act, as amended 
by the Tobacco Control Act, generally requires that a new tobacco 
product undergo premarket review by FDA before it may be introduced or 
delivered for introduction into interstate commerce. Section 910(a)(1) 
of the FD&C Act defines a ``new tobacco product'' as: (1) Any tobacco 
product (including those products in test markets) that was not 
commercially marketed in the United States as of February 15, 2007, or 
(2) any modification (including a change in design, any component, any 
part, or any constituent, including a smoke constituent, or in the 
content, delivery or form of nicotine, or any other additive or 
ingredient) of a tobacco product where the modified product was 
commercially marketed in the United States after February 15, 2007 (21 
U.S.C. 387j(a)(1)).
    The FD&C Act establishes three premarket review pathways for a new 
tobacco product:
     Submission of a PMTA under section 910(b);
     submission of a report intended to demonstrate that the 
new tobacco product is substantially equivalent to a predicate tobacco 
product under section 905(j)(1)(A) (21 U.S.C. 387e(j)(1)(A)) (SE 
Report); \3\ and
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    \3\ Additionally, section 910(a)(2)(B) of the FD&C Act also 
allows for the continued marketing of new tobacco products first 
introduced or delivered for introduction into interstate commerce 
for commercial distribution after February 15, 2007, and prior to 
March 22, 2011, for which a manufacturer submitted an SE Report 
prior to March 23, 2011 (``provisional tobacco products''), unless 
FDA issues an order that the tobacco product is not substantially 
equivalent.
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     submission of a request for an exemption under section 
905(j)(3) (implemented at 21 CFR 1107.1) (exemption request).
    Generally, if a new tobacco product is marketed without either a 
marketing granted order (for PMTAs), a

[[Page 55303]]

substantially equivalent order (for SE reports), or a finding of 
exemption from SE (for exemption requests), it is adulterated under 
section 902 of the FD&C Act and misbranded under section 903 of the 
FD&C Act and subject to enforcement action.
    Since 2010, FDA has received a large volume of premarket 
applications for tobacco products, thousands of which have been PMTAs. 
Of these PMTAs, FDA has completed its full substantive review and acted 
on several sets of bundled PMTAs, which are single submissions 
containing PMTAs for a number of similar or related tobacco products. 
To assist manufacturers in preparing PMTAs, FDA has issued guidance, 
conducted webinars, met with manufacturers, hosted public meetings 
regarding premarket submissions, and posted the technical project lead 
reviews (which describe the reviews completed on specific PMTAs) and 
marketing granted orders issued to date. FDA has also completed review 
and issued decisions on hundreds of exemption requests, thousands of SE 
reports, and thousands of voluntarily submitted requests for Pre-
Existing Tobacco Product status review, which has provided FDA with 
information and experience to use when implementing the PMTA program 
and establishing recordkeeping requirements.
    FDA issued the proposed rule on September 25, 2019, to set forth 
proposed requirements related to the PMTA premarket pathway and outline 
the information needed for FDA to determine whether it will issue a 
marketing granted order under the pathway. FDA received about 1,000 
comments to the docket for the proposed rule, including comments from 
individuals, academia, healthcare professionals, consumer advocacy 
groups, industry, public health groups, and trade associations. We 
summarize and respond to these comments in section III of this rule. 
After considering these comments, FDA developed this final rule, which 
includes changes made in response to the comments.

II. Legal Authority

    As described in the following paragraphs, FDA is describing and 
setting forth requirements for the content, format, submission, and 
review of PMTAs, as well as other requirements related to PMTAs, 
including recordkeeping requirements, and postmarket reporting. FDA is 
also creating recordkeeping requirements regarding the legal marketing 
of Pre-Existing Tobacco Products and products that are exempt from the 
requirements of demonstrating substantial equivalence. In accordance 
with section 5 of the Tobacco Control Act, FDA intends that the 
requirements that are established by this rule be severable and that 
the invalidation of any provision of this rule would not affect the 
validity of any other part of this rule.
    Section 910(a)(2) of the FD&C Act requires that a new tobacco 
product be the subject of a marketing granted order unless FDA has 
issued an order finding it to be substantially equivalent to a 
predicate product, or exempt from the requirements of demonstrating 
substantial equivalence.\4\ A manufacturer may choose to submit a PMTA 
under section 910(b) of the FD&C Act to satisfy the requirements of 
premarket review. Section 910(b)(1) describes the required contents of 
a PMTA and, in addition to the items specified in section 910(b)(1)(A) 
through (F), allows FDA to require applicants to submit other 
information relevant to the subject matter of the application under 
section 910(b)(1)(G). Section 910(c)(2) of the FD&C Act requires FDA to 
issue an order denying a PMTA if it finds that the applicant has not 
made a showing that permitting the marketing of the new tobacco product 
would be appropriate for the protection of the public health; the 
methods used in, or the facilities or controls used for, the 
manufacture, processing, or packing of the product do not conform to 
the requirements of section 906(e) of the FD&C Act; the proposed 
labeling is false or misleading in any particular; or the product has 
not been shown to meet the requirements of a product standard in effect 
and there is a lack of adequate information to justify a deviation from 
the standard, if applicable.
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    \4\ See section I for a discussion of provisional tobacco 
products and their relation to the premarket review requirements.
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    Section 909(a) of the FD&C Act authorizes FDA to issue regulations 
requiring tobacco product manufacturers or importers to maintain 
records, make reports, and provide information as may be reasonably 
required to assure that their tobacco products are not adulterated or 
misbranded and to otherwise protect public health. Section 910(f) of 
the FD&C Act allows FDA to require that applicants who receive 
marketing granted orders establish and maintain records, and submit 
reports to enable FDA to determine, or facilitate a determination of, 
whether there are or may be grounds for withdrawing or temporarily 
suspending an order.
    Section 910(d)(1) of the FD&C Act grants FDA authority to issue an 
order withdrawing a marketing granted order if FDA finds:
     That the continued marketing of such tobacco product no 
longer is appropriate for the protection of the public health;
     that the application contained or was accompanied by an 
untrue statement of a material fact;
     that the applicant:
    [cir] Has failed to establish a system for maintaining records, or 
has repeatedly or deliberately failed to maintain records or to make 
reports, required by an applicable regulation under section 909 of the 
FD&C Act;
    [cir] has refused to permit access to, or copying or verification 
of, such records as required by section 704 of the FD&C Act; or
    [cir] has not complied with the requirements of section 905 of the 
FD&C Act;
     on the basis of new information before the Secretary of 
Health and Human Services (the Secretary) with respect to such tobacco 
product, evaluated together with the evidence before the Secretary when 
the application was reviewed, that the methods used in, or the 
facilities and controls used for, the manufacture, processing, packing, 
or installation of such tobacco product do not conform with the 
requirements of section 906(e) of the FD&C Act and were not brought 
into conformity with such requirements within a reasonable time after 
receipt of written notice from the Secretary of nonconformity;
     on the basis of new information before the Secretary, 
evaluated together with the evidence before the Secretary when the 
application was reviewed, that the labeling of such tobacco product, 
based on a fair evaluation of all material facts, is false or 
misleading in any particular and was not corrected within a reasonable 
time after receipt of written notice from the Secretary of such fact; 
or
     on the basis of new information before the Secretary, 
evaluated together with the evidence before the Secretary when such 
order was issued, that such tobacco product is not shown to conform in 
all respects to a tobacco product standard which is in effect under 
section 907 of the FD&C Act, compliance with which was a condition to 
the issuance of an order relating to the application, and that there is 
a lack of adequate information to justify the deviation from such 
standard, if applicable.
    Under section 902(6) of the FD&C Act, a tobacco product is 
adulterated if it is required to have premarket review and does not 
have an order in effect under

[[Page 55304]]

section 910(c)(1)(A)(i), or if it is in violation of an order under 
section 910(c)(1)(A) of the FD&C Act. Under section 903(a)(6) of the 
FD&C Act, a tobacco product is misbranded if a notice or other 
information respecting it was not provided as required by section 
905(j) of the FD&C Act. In addition, a tobacco product is misbranded if 
there is a failure or refusal to furnish any material or information 
required under section 909 (section 903(a)(10)(B) of the FD&C Act). 
Section 701(a) of the FD&C Act also gives FDA general rulemaking 
authority to issue regulations for the efficient enforcement of the 
FD&C Act and section 704 of the FD&C Act provides FDA with general 
inspection authority.

III. General Description of Comments on the Proposed Rule

    FDA received over 1,000 comments on the proposed rule. The comments 
came from individuals, academia, healthcare professionals, consumer 
advocacy groups, industry, public health groups, and trade 
associations. In addition to the comments specific to this rulemaking 
that we address in sections IV through XVIII, we received many general 
comments expressing support or opposition to the rule. Some of these 
comments express broad policy views and do not address specific points 
related to this rulemaking. Therefore, these general comments do not 
require a response. Other comments addressed topics outside the scope 
of this rulemaking, such as requests for product standards under 
section 907 of the FD&C Act, recommendations regarding the compliance 
date for manufacturers of deemed tobacco products to submit premarket 
applications, statements that ENDS and pipes should not be regulated as 
tobacco products, and that pipes should not be subject to the 
requirements of premarket review.
    We describe and respond to comments in the description of the final 
rule in sections IV through XVIII. To make it easier to identify 
comments and our responses, the word ``Comment,'' in parentheses, will 
appear before each comment, and the word ``Response,'' in parentheses, 
will appear before each response. We have numbered the comments to make 
it easier to distinguish between comments; the numbers are for 
organizational purposes only and do not reflect the order in which we 
received the comments or any value associated with the comment. We have 
combined similar comments, or comments on similar topics that can be 
addressed by a single response, under one numbered comment.

IV. Description of the Final Regulations for, and Comments and FDA's 
Responses Regarding, the Maintenance of Records Demonstrating That a 
Tobacco Product Was Commercially Marketed in the United States as of 
February 15, 2007 (Part 1100, Subpart C)

    The rule adds subpart C regarding records to part 1100 of 
subchapter K of Title 21. Other than the comments and changes described 
in this section regarding the proposed definition of the term 
``grandfathered tobacco product,'' (now referred to as a ``Pre-Existing 
Tobacco Product''), FDA received no comments regarding proposed part 
1100 and FDA is finalizing the requirements as proposed without 
additional changes.

A. Purpose and Scope (Sec.  1100.200)

    Subpart C of part 1100 establishes requirements for the maintenance 
of records by tobacco product manufacturers who introduce a Pre-
Existing Tobacco Product, or deliver it for introduction, into 
interstate commerce. These requirements are created under the authority 
of section 909 of the FD&C Act, which authorizes FDA to require tobacco 
product manufacturers to establish and maintain records to assure that 
a tobacco product is not adulterated or misbranded and to otherwise 
protect public health. Under section 902(6)(A), a tobacco product is 
adulterated if it is required by section 910(a) of the FD&C Act to have 
premarket review and does not have an order in effect under section 
910(c)(1)(A)(i). In addition, under section 903(a)(6) of the FD&C Act, 
a tobacco product is misbranded if a notice or other information 
respecting it was not provided as required by section 905(j) of the 
FD&C Act. The records that are required under this subpart demonstrate 
that a tobacco product is a Pre-Existing Tobacco Product and, 
therefore, not required by section 910(a) to have premarket review and 
not adulterated or misbranded if marketed without an FDA order. FDA is 
basing these requirements on its experience gained by performing 
thousands of Pre-Existing Tobacco Product status reviews conducted 
during its review of SE reports and at manufacturers' voluntary 
requests. These requirements are needed because currently manufacturers 
do not always maintain sufficient documentation to demonstrate that 
their tobacco product is a Pre-Existing Tobacco Product. The records 
that are required under this rule will allow FDA to more quickly and 
efficiently determine whether a tobacco product is a Pre-Existing 
Tobacco Product.

B. Definitions (Sec.  1100.202)

    Section 1100.202 sets forth the meaning of terms as they apply to 
part 1100:
1. Tobacco Product
    The rule defines the term ``tobacco product'' consistent with 
section 201(rr)(1) of the FD&C Act (21 U.S.C. 321(rr)(1))
2. Tobacco Product Manufacturer
    The rule defines the term ``tobacco product manufacturer'' 
consistent with section 900(20) of the FD&C Act (21 U.S.C. 387(20)). 
FDA interprets the phrase ``manufactures, fabricates, assembles, 
processes, or labels'' in the definition as including, but not being 
limited to: (1) Repackaging or otherwise changing the container, 
wrapper, or labeling of any tobacco product package; (2) reconstituting 
tobacco leaves; or (3) applying any chemical, additive, or substance to 
the tobacco leaf other than potable water in the form of steam or mist. 
For the purposes of the definition, ``finished tobacco product'' means 
a tobacco product, including all components and parts, sealed in final 
packaging (e.g., filters or filter tubes sold to consumers separately 
or as part of kits) or in the final form in which it is intended to be 
sold to consumers.
3. Commercially Marketed
    In the proposed rule, FDA proposed to define ``commercially 
marketed'' as ``selling or offering a tobacco product for sale to 
consumers in all or in parts of the United States.''
    (Comment 1) Several comments discussed specific changes to the 
proposed definition of the term ``commercially marketed.'' One comment 
stated that the proposed definition of commercially marketed departs 
from the plain meaning of the statutory language and FDA's historical 
approach to evaluating whether a product is a Pre-Existing Tobacco 
Product. Specifically, comments raised concerns that inclusion of ``in 
all or in parts of the United States'' seems to depart from the plain 
meaning of the statutory phrase ``commercially marketed in the United 
States'' and requires that firms demonstrate that a product was offered 
nationwide, in multiple regions, or even across State lines. The 
comments also argue that, for example, the statutory definition of 
``new tobacco product'' does not state or imply that a product offered 
for sale within a particular State cannot qualify as ``commercially 
marketed in the United States.'' The comments state that FDA should 
define ``commercially marketed'' as ``offered for sale in the

[[Page 55305]]

United States to any individual or entity by advertising or by any 
other manner used to communicate that the tobacco product is available 
for purchase.'' Another comment expressed similar concerns, stating 
that the definition seems to require the selling or marketing of 
products directly to consumers as well as offering it for sale 
nationwide.
    (Response 1) After reviewing the comments related to commercially 
marketed, we have added a definition of this term to the final rule, 
which reflects the input we received. Given the wide variety of input 
we have received on this term as well as the dictionary definition, we 
do not believe that the term ``commercially marketed'' has a plain 
meaning. Instead, we have added a definition stating that 
``commercially marketed'' means selling or offering for sale a tobacco 
product in the United States to consumers or to any person for the 
eventual purchase by consumers in the United States. This definition 
clarifies that tobacco products that are not sold or offered for sale 
in order to reach consumers within the United States, such as tobacco 
products sold solely for export, fall outside of the definition of 
commercial marketing. Examples of products that may not be covered by 
the definition of commercially marketed include investigational tobacco 
products and free samples. Examples of documentation of commercial 
marketing may include the following items listed in Sec.  1100.204(a): 
dated bills of lading, dated freight bills, dated waybills, dated 
invoices, dated purchase orders, dated advertisements, dated catalog 
pages, dated promotional material, dated trade publications, dated 
manufacturing documents, inventory lists, or any other document 
demonstrating that the product was commercially marketed in the United 
States as of February 15, 2007.
    (Comment 2) One comment requested clarification as to whether 
limited edition products would be considered test marketed products or 
commercially marketed products.
    (Response 2) ``Limited edition'' products are considered 
commercially marketed if they were sold or offered for sale in the 
United States to consumers or to any person for the eventual purchase 
by consumers in the United States--regardless of whether they were 
solely sold or offered for sale in a test market. Therefore, if a 
``limited edition'' product was commercially marketed--even if only in 
a test market--as of February 15, 2007, it would be a Pre-Existing 
Tobacco Product. We note that considering test marketed products to be 
commercially marketed is a change in FDA's interpretation of section 
910(a)(1)(A) of the FD&C Act, which is discussed further in the 
response to comment 3. However, a product that was solely in a test 
market as of February 15, 2007, cannot serve as a predicate product 
under section 905(j) of the FD&C Act. Test marketed products may 
include, for example, products that were sold or offered for sale to 
determine the commercial viability of a product through the collection 
of consumer reaction data.
4. Pre-Existing Tobacco Product
    In the proposed rule, we proposed to define the term 
``grandfathered tobacco product'' as ``a tobacco product that was 
commercially marketed in the United States as of February 15, 2007'' 
and does not include a tobacco product exclusively in test markets as 
of that date. A grandfathered tobacco product is not subject to the 
premarket requirements of section 910 of the FD&C Act.'' In the final 
rule, we have changed this term from ``grandfathered tobacco product'' 
to ``Pre-Existing Tobacco Product'' because it more appropriately 
describes these products by using the more precise ``Pre-Existing'' in 
place of ``grandfathered.'' FDA received many comments regarding the 
definition of ``Pre-Existing Tobacco Product,'' \5\ which are discussed 
as follows.
---------------------------------------------------------------------------

    \5\ Although comments were submitted regarding the term 
``grandfathered tobacco product,'' we describe them using the new 
term, ``Pre-Existing Tobacco Product,'' throughout this document for 
clarity.
---------------------------------------------------------------------------

    (Comment 3) Multiple comments discussed the proposed definition of 
the term ``commercially marketed'' as well as the definition of the 
term ``test marketing'' set forth in the preamble of the proposed rule 
as used in, or to inform, the definitions of ``Pre-Existing Tobacco 
Product'' and ``new tobacco product'' in the proposed rule. Some 
comments argued that Congress was intentional in its use of test 
markets in the definition of new tobacco product and, as such, a 
product in test market as of February 15, 2007 (if not subsequently 
modified within the meaning of section 910(a)(1)(B)), of the FD&C Act 
is not a new tobacco product and is not subject to premarket review. 
These comments also stated that because section 905(j)(1)(A)(i) of the 
FD&C Act explicitly excludes test marketed products from the 
commercially marketed products that may serve as valid predicate 
products, it demonstrates that the term ``commercially marketed'' 
encompasses products that are test marketed (i.e., if test marketed 
products did not constitute commercially marketed products, there would 
have been no need for Congress to exclude them from the types of 
commercially marketed products that may qualify for use as predicate 
products under the substantial equivalence premarket pathway). Some 
comments requested FDA include the definitions as they were defined in 
the proposed rule, including as they relate to the definition of the 
term ``new tobacco product'' in proposed part 1114 (21 CFR part 1114). 
Other comments stated that the proposed definitions should not be 
included in the final rule because they are unnecessary, confusing, 
conflicting, and not useful. Specifically, some comments argued that 
FDA did not provide a workable or rational basis to distinguish ``test 
marketing'' from ``commercially marketed'' and the proposed definitions 
do not reflect industry realities.
    (Response 3) Following our consideration of these comments, we have 
revised the definitions related to ``Pre-Existing Tobacco Product'' to 
remove language related to ``exclusively'' test marketed.
    Upon reviewing comments received, we reassessed our interpretation 
of section 910(a)(1)(A) of the FD&C Act, and we agree with the comment 
indicating that a tobacco product test marketed in the United States as 
of February 15, 2007, is not a new tobacco product. Section 
910(a)(1)(A) defines a ``new tobacco product'' to include ``any tobacco 
product (including those in test markets) that was not commercially 
marketed in the United States as of February 15, 2007.'' The 
parenthetical ``including those in test markets'' in section 
910(a)(1)(A) of the FD&C Act modifies the phrase directly before it--
``any tobacco product''--and is intended to clarify that tobacco 
products commercially marketed in test markets in the United States as 
of February 15, 2007, should be treated the same way as any other 
tobacco product that was commercially marketed as of February 15, 2007, 
i.e., they are not ``new tobacco products.'' We also agree that section 
905 of the FD&C Act provides additional context that supports this 
interpretation. Section 905(j)(1)(A)(i) of the FD&C Act describes 
products that can serve as valid predicate tobacco products: A tobacco 
product commercially marketed (other than for test marketing) in the 
United States as of February 15, 2007, or a tobacco product that the 
Secretary by delegation to FDA has previously determined, pursuant to 
section 910(a)(3), is substantially equivalent. Here, Congress' 
inclusion of the parenthetical ``(other than for test marketing)'' 
supports a reading of the term ``commercially marketed'' as

[[Page 55306]]

including products that were test marketed; otherwise, there would not 
be the need to specifically carve out test marketed products from the 
commercially marketed products that can serve as valid predicate 
products.
    In addition, in the preamble to the proposed rule, we explained 
that FDA was considering whether to add the following definition of 
test marketing: ``test marketing'' means distributing or offering for 
sale (which may be shown by advertisements, etc.) a tobacco product in 
the United States for the purpose of determining consumer response or 
other consumer reaction to the tobacco product, with or without the 
user knowing it is a test product, in which any of the following 
criteria apply: (1) Offered in a limited number of regions; (2) offered 
for a limited time; or (3) offered to a chosen set of the population or 
specific demographic group (84 FR 50566 at 50571).
    We agree with the commenter that further discussion of the term, 
test marketing, is needed to more accurately capture the scope of this 
term; accordingly, we are not including a definition of test marketing 
in the final rule.
    After reviewing these comments and for the purposes of consistency, 
FDA is finalizing the definition of ``Pre-Existing Tobacco Product'' 
with changes to better align with the statute, first, by adding 
``(including those products in test markets)'', and, second, by 
removing ``and does not include a tobacco product exclusively in test 
markets as of that date.'' Specifically, FDA defines a ``Pre-Existing 
Tobacco Product'' to mean a tobacco product (including those products 
in test markets) that was commercially marketed in the United States as 
of February 15, 2007. The definition of ``Pre-Existing Tobacco 
Product'' in this rule reflects FDA's interpretation that ``as of'' 
means ``on'', which has been included as part of previously issued 
regulations and guidance.\6\ For more information on this topic, see 
the response to comment 5 explaining FDA's interpretation that ``as 
of'' means ``on.'' A Pre-Existing Tobacco Product is not subject to the 
premarket review requirements of section 910 of the FD&C Act.
---------------------------------------------------------------------------

    \6\ See the final rule entitled ``Deeming Tobacco Products To Be 
Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by 
the Family Smoking Prevention and Tobacco Control Act; Restrictions 
on the Sale and Distribution of Tobacco Products and Required 
Warning Statements for Tobacco Products'' (81 FR 28973 at 28978, May 
10, 2016) and the guidance entitled ``Establishing That a Tobacco 
Product Was Commercially Marketed in the United States as of 
February 15, 2007'' (79 FR 58358, September 29, 2014). Available at 
https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
---------------------------------------------------------------------------

C. Recordkeeping Requirements (Sec.  1100.204)

1. Required Records
    Consistent with the authority to require recordkeeping under 
section 909 of the FD&C Act, Sec.  1100.204(a) requires any tobacco 
product manufacturer that introduces a Pre-Existing Tobacco Product, or 
delivers it for introduction, into interstate commerce to maintain 
records and information necessary to adequately demonstrate that the 
tobacco product was commercially marketed in the United States as of 
February 15, 2007. This requirement will ensure, among other things, 
that records are available to FDA during an inspection. The rule does 
not require tobacco product manufacturers to maintain records for all 
of the types of information listed in Sec.  1100.204(a); rather, the 
list provides examples of the types of records that may be used to 
demonstrate that a tobacco product was commercially marketed in the 
United States as of February 15, 2007.
2. Record Maintenance
    Section 1100.204(b) requires that all records maintained under this 
part be legible, in the English language, and available for inspection 
and copying by officers or employees duly designated by the Secretary. 
This section also requires documents that have been translated from 
another language into English to be accompanied by: (1) The original 
language version of the document; (2) a signed statement by an 
authorized representative of the manufacturer certifying that the 
English language translation is complete and accurate; and (3) a brief 
statement of the qualifications of the person who made the translation 
(e.g., education and experience). This information will help FDA ensure 
that the English language translations of documents are complete and 
accurately reflect the content of the original documents.
3. Record Retention
    Section 1100.204(c) requires that the records and documents 
demonstrating that the tobacco product was commercially marketed as of 
February 15, 2007, be retained for a period of at least 4 years from 
the date that either FDA makes a Pre-Existing Tobacco Product 
determination or the tobacco product manufacturer permanently ceases 
the introduction or delivery for introduction into interstate commerce 
of the tobacco product, whichever occurs sooner. FDA has selected 4 
years to help ensure that the records will be available for at least 
one biennial FDA inspection under sections 704 and 905(g) of the FD&C 
Act. FDA's biennial inspections under section 905(g) of the FD&C Act 
are required to occur at least once in every 2-year period after a 
manufacturer registers an establishment with FDA, which could result in 
inspections occurring nearly 4 years apart. Retaining records for 4 
years after a manufacturer permanently ceases introduction or delivery 
for introduction into interstate commerce of the tobacco product will 
allow FDA to verify the Pre-Existing Tobacco Product status of the 
product during the time period in which it is offered for sale to 
consumers. Manufacturers that only temporarily cease the introduction 
or delivery for introduction into interstate commerce of the tobacco 
product must retain the records to allow FDA to verify the Pre-Existing 
Tobacco Product status of the product when they resume marketing the 
product. Additionally, manufacturers might want to retain records for 
longer than 4 years to help establish their product is a Pre-Existing 
Tobacco Product and may be eligible as a predicate product in an SE 
Report if it was commercially marketed (other than for test marketing) 
in the United States as of February 15, 2007.

V. Description of the Final Regulations for, and the Comments and FDA's 
Responses Regarding, the Maintenance of Records Relating to Exemptions 
From the Requirements of Demonstrating Substantial Equivalence (Sec.  
1107.3)

    The rule adds Sec.  1107.3 to part 1107 of subchapter K of Title 
21. Other than the comments and changes described in this section 
regarding the proposed definition of the term ``grandfathered tobacco 
product'' (now referred to as a ``Pre-Existing Tobacco Product''), FDA 
received no comments regarding proposed Sec.  1107.3, FDA is finalizing 
the requirements as proposed with one other change; we have removed the 
proposed requirement to maintain product labeling a part of Sec.  
1107.3 because it is not necessary to support an abbreviated report.
    Section 1107.3 establishes recordkeeping requirements related to 
tobacco products that are exempt from the requirements of demonstrating 
SE under section 910(a)(2)(A)(ii) of the FD&C Act. Consistent with the 
authority to require recordkeeping under section 909 of the FD&C Act, 
Sec.  1107.3 requires applicants that submitted an abbreviated report 
under section 905(j)(1)(A)(ii) of the FD&C Act, and received a letter 
from FDA

[[Page 55307]]

acknowledging the receipt of an abbreviated report, to maintain all 
records necessary to support the exemption for at least 4 years from 
the date FDA issues an acknowledgement letter in response to an 
abbreviated report. The rule requires the applicant to maintain records 
that are legible, written in English, and available for inspection and 
copying by officers or employees designated by the Secretary. 
Applicants may want to retain the records for a longer period if, for 
example they intend to submit a subsequent exemption request for a 
modification to the tobacco product.

A. Definition

    Section 1107.3(a) defines ``Pre-Existing Tobacco Product'' \7\ as a 
tobacco product (including those products in test markets) that was 
commercially marketed in the United States as of February 15, 2007. FDA 
has considered the comments described in section IV and revised this 
term as described in the responses in that section. As described in 
section IV.B.4., FDA interprets the phrase ``as of February 15, 2007,'' 
as meaning that the tobacco product was commercially marketed in the 
United States ``on February 15, 2007.'' See the response to comment 5 
explaining FDA's interpretation that ``as of'' means ``on.''
---------------------------------------------------------------------------

    \7\ As described in section IV.B, we have changed the term 
``grandfathered tobacco product'' to ``Pre-Existing Tobacco 
Product.''
---------------------------------------------------------------------------

B. Record Maintenance

    The rule requires applicants to maintain all documents that support 
their abbreviated report, which includes the documents listed in Sec.  
1107.3(b)(1). The rule does not require an applicant to create new or 
additional records; rather, it requires an applicant to maintain the 
records it has, obtains, or creates (including those created on its 
behalf, such as by a contract research organization) that support its 
abbreviated report. This includes documents that an applicant creates 
under other regulatory or statutory sections such as the submission of 
exemption requests under Sec.  1107.1, PMTAs under part 1114, SE 
Reports under section 905(j) of the FD&C Act, and tobacco product 
manufacturing practice requirements issued under section 906(e) of the 
FD&C Act. The records an applicant is required to maintain include, but 
are not limited to:
     A copy of the abbreviated report and, if applicable, the 
exemption request and all amendments thereto;
     a copy of the acknowledgement letter issued in response to 
an abbreviated report and, if applicable, a copy of the exemption order 
issued by FDA;
     documents related to formulation of product, product 
specifications, packaging, and related items. Product formulation 
includes, for example, items such as the types of information described 
in Sec.  1114.7(i) as described in section VIII.B.;
     documents showing that design specifications are 
consistently met. This could include, for example, information about 
testing procedures that are carried out before the product is released 
to market, such as the information described in Sec.  1114.7(j) as 
described in section VIII.B.;
     documents related to product packing and storage 
conditions;
     analytical test method records, including:
    [cir] Performance criteria;
    [cir] validation or verification documentation; and
    [cir] reports/results from these test methods; and
     source data and related summaries.
    In addition to the documents specified in Sec.  1107.3(b)(1), 
paragraphs (b)(2) through (b)(4) require tobacco product manufacturers 
to maintain records that support a determination that their exemption 
request meets the requirements of section 905(j)(3)(A)(i) of the FD&C 
Act that the modification to a product additive described in the 
exemption request was a minor modification made to a tobacco product 
that can be sold under the FD&C Act. This means that applicants need to 
maintain records demonstrating that the modification is being made to 
either a Pre-Existing Tobacco Product or a new tobacco product that has 
satisfied the premarket review requirements of section 910(a)(2) of the 
FD&C Act. For abbreviated reports based on a modification to a Pre-
Existing Tobacco Product, Sec.  1107.3(b)(2) requires applicants to 
maintain the documentation in Sec.  1100.204 to demonstrate that the 
product that is being modified is legally marketed. For abbreviated 
reports based on a modification to a tobacco product that has 
previously received an exemption order in response to a request under 
Sec.  1107.1 (and for which the applicant has submitted an abbreviated 
report under 905(j)(1)(A)(ii)), or a substantially equivalent order or 
a marketing granted order from FDA, Sec.  1107.3(b)(3) requires 
applicants to maintain a copy of the exemption order, substantially 
equivalent order, or marketing granted order to demonstrate the product 
being modified is legally marketed. For abbreviated reports based on a 
modification to a tobacco product that is being marketed pursuant to 
section 910(a)(2)(B) of the FD&C Act for which FDA has not issued a 
substantially equivalent order, an applicant must maintain all 
communications to and from FDA relating to the pending SE Report, such 
as a letter acknowledging receipt of the report.

C. Record Quality

    Section 1107.3(c) requires the records to be legible, in the 
English language, and available for inspection and copying by officers 
or employees duly designated by the Secretary. FDA also requires 
documents that have been translated from another language into English 
be accompanied by: (1) The original language version of the document, 
(2) a signed statement by an authorized representative of the 
manufacturer certifying that the English language translation is 
complete and accurate, and (3) a brief statement of the qualifications 
of the person who made the translation (e.g., education and 
experience). This information helps FDA ensure that the English 
language translations of documents are complete and accurately reflect 
the content of the original documents.

D. Record Retention

    Section 1107.3(d) requires the records described in Sec.  1107.3(b) 
to be maintained for a period of not less than 4 years from the date on 
which FDA issues an acknowledgement letter in response to an 
abbreviated report. FDA has selected 4 years as a means to help ensure 
that the records are available for at least one biennial FDA inspection 
under sections 704 and 905(g) of the FD&C Act. FDA's biennial 
inspections under section 905(g) of the FD&C Act are required to occur 
at least once in every 2-year period after a manufacturer registers an 
establishment with FDA, which could result in inspections occurring 
nearly 4 years apart.

VI. Description of the Final Regulations for, and the Comments and 
FDA's Responses Regarding, Premarket Tobacco Product Applications (Part 
1114)

    The rule adds part 1114 to subchapter K of Title 21. The 
requirements set forth in this part apply to PMTAs for new tobacco 
products. Subpart A sets out the scope and definitions that apply to 
this part. Subpart B sets out the criteria for PMTA submission, content 
and format of PMTAs, application amendments, withdrawal of an 
application by an applicant, supplemental PMTAs, resubmissions, and 
change in ownership or contact information for a

[[Page 55308]]

PMTA. Subpart C describes FDA review and actions on applications, 
including provisions for withdrawal and temporary suspension of orders. 
Subpart D describes postmarket restrictions and reporting requirements. 
Subpart E sets miscellaneous requirements such as record retention, 
confidentiality, and electronic submission.

VII. General (Part 1114, Subpart A)

A. Scope (Sec.  1114.1)

    Section 1114.1 describes the scope of part 1114 and its 
applicability to the submission and review of, and postmarket 
requirements related to, PMTAs. Section 1114.1 provides that part 1114 
does not apply to MRTPAs, except instances where a single application 
is submitted to seek both a marketing granted order and a modified risk 
order instead of a separate PMTA and MRTPA. Under the rule, a single 
application seeking both a marketing granted order and a modified risk 
order under section 911(g) of the FD&C Act needs to meet the content 
and format requirements of both part 1114 and section 911 of the FD&C 
Act (21 U.S.C. 387k) (and any implementing regulations). This section 
also notes that references in the rule to regulatory sections of the 
Code of Federal Regulations (CFR) are to chapter I of Title 21, unless 
otherwise noted. Therefore, any CFR reference that begins with 
``part,'' ``section,'' or the section symbol (Sec.  ) should be read as 
if it were preceded by ``21 CFR'' (e.g., Sec.  1114.1 refers to 21 CFR 
1114.1, part 58 refers to 21 CFR part 58), unless another source is 
cited (e.g., the FD&C Act).
    (Comment 4) Some comments requested that ``premium'' cigars be 
exempt from the PMTA premarket pathway or that a different premarket 
pathway be created for them. Several comments describe the difference 
between ``premium'' cigars and other products, such as cigarettes or 
ENDS, and argue that these differences make it more difficult for 
``premium'' cigars to comply with PMTA requirements. These comments 
request that FDA exempt ``premium'' cigars from premarket requirements, 
create a different premarket pathway for ``premium'' cigars, or delay 
the effective date for submitting premarket applications.
    (Response 4) FDA received a range of comments related to 
``premium'' cigars. A recent court decision ``remand[ed] the [deeming 
final rule] to the FDA to consider developing a streamlined substantial 
equivalence process for premium cigars'' and ``enjoin[ed] the FDA from 
enforcing the premarket review requirements against premium cigars . . 
. until the agency has completed its review.'' \8\ Under the terms of 
the court's order, a ``premium'' cigar is defined as a cigar that meets 
all of the following eight criteria:
---------------------------------------------------------------------------

    \8\ Cigar Ass'n of Am., et al. v. Food and Drug Admin., et al., 
Case No. 1:16-cv-01460 (APM), (D.D.C. August 19, 2020), Dkt. No. 214 
(Cigar Ass'n of Am.).
---------------------------------------------------------------------------

     Is wrapped in whole tobacco leaf;
     contains a 100 percent leaf tobacco binder;
     contains at least 50 percent (of the filler by weight) 
long filler tobacco (i.e., whole tobacco leaves that run the length of 
the cigar);
     is handmade or hand rolled; \9\
---------------------------------------------------------------------------

    \9\ A product is ``handmade or hand rolled'' if no machinery was 
used apart from simple tools, such as a scissors to cut the tobacco 
prior to rolling.
---------------------------------------------------------------------------

     has no filter, nontobacco tip, or nontobacco mouthpiece;
     does not have a characterizing flavor other than tobacco;
     contains only tobacco, water, and vegetable gum with no 
other ingredients or additives; and
     weighs more than 6 pounds per 1,000 units.
    As directed by the court in the Cigar Ass'n of Am. decision, FDA is 
further considering the comments submitted to the deeming final rule 
docket that requested FDA create a streamlined SE process for 
``premium'' cigars. Additionally, FDA notes that a Committee of the 
National Academies of Science, Engineering, and Medicine is conducting 
a study on such products. FDA intends to consider the findings of that 
Committee as well as any additional research specific to ``premium'' 
cigars (as defined in the preceding paragraph) and their health 
effects, patterns of use (such as frequency of use and usage patterns 
among underage persons), and other factors. Such information will 
inform the Agency's regulatory policy with respect to premarket review 
of ``premium'' cigars. Although the court opinion specifically 
discusses considering comments on the SE pathway, FDA's research 
efforts may also inform issues related to the review of applications 
for premium cigars under the PMTA pathway. Because these are ongoing 
efforts, at this time, FDA is not finalizing the proposed PMTA rule 
with respect to ``premium'' cigars. Rather, FDA will take appropriate 
action once it has further considered this matter, including the 
results from additional research. As such, the codified language has 
been revised to exclude ``premium'' cigars from the scope of this final 
rule, and the Cigar Ass'n of Am. court's definition of ``premium'' 
cigars has been added to section Sec.  1114.3.

B. Definitions (Sec.  1114.3)

    Section 1114.3 provides the meaning of terms as they apply to part 
1114:
1. Additive
    As defined in section 900(1) of the FD&C Act, ``additive'' means 
any substance the intended use of which results or may reasonably be 
expected to result, directly or indirectly, in its becoming a component 
or otherwise affecting the characteristic of any tobacco product 
(including any substances intended for use as a flavoring or coloring 
or in producing, manufacturing, packing, processing, preparing, 
treating, packaging, transporting, or holding), except that such term 
does not include tobacco, or a pesticide chemical residue in or on raw 
tobacco, or a pesticide chemical.
    An additive can be a type of ingredient in a tobacco product; an 
example is methyl salicylate in smokeless tobacco, which can serve as 
an absorption enhancer and affect the characteristics of the tobacco 
product by changing the rate of absorption into the body. Tobacco is 
not an additive.
2. Brand
    As defined in section 900(2) of the FD&C Act, ``brand'' means a 
variety of tobacco product distinguished by the tobacco used, tar 
content, nicotine content, flavoring used, size, filtration, packaging, 
logo, registered trademark, brand name(s), identifiable pattern of 
colors, or any combination of such attributes.
3. Characteristics
    As defined in section 910(a)(3)(B) of the FD&C Act, 
``characteristics'' means the materials, ingredients, design, 
composition, heating source, or other features of a tobacco product. 
The terms used in the definition of characteristic (materials, 
ingredients, design, etc.) are defined in Sec.  1114.3.
4. Label
    As defined in section 201(k) of the FD&C Act, ``label'' means a 
display of written, printed, or graphic matter upon the immediate 
container of any article; and a requirement made by or under authority 
of the FD&C Act that any word, statement, or other information appear 
on the label shall not be considered to be complied with unless such 
word, statement, or other information also appears on the outside 
container or wrapper, if any there be, of the retail package of such 
article, or is

[[Page 55309]]

easily legible through the outside container or wrapper.
5. Labeling
    As defined in section 201(m) of the FD&C Act, ``labeling'' means 
all labels and other written, printed, or graphic matter: (1) Upon any 
article or any of its containers or wrappers or (2) accompanying such 
article.
6. New Tobacco Product
    As defined in section 910(a)(1) of the FD&C Act, ``new tobacco 
product'' means: (1) Any tobacco product (including those products in 
test markets) that was not commercially marketed in the United States 
as of February 15, 2007, or (2) any modification (including a change in 
design, any component, any part, or any constituent, including a smoke 
constituent, or in the content, delivery or form of nicotine, or any 
other additive or ingredient) of a tobacco product where the modified 
product was commercially marketed in the United States after February 
15, 2007.
    FDA received many comments regarding the proposed definition of 
``new tobacco product,'' as discussed below.
    (Comment 5) Multiple comments questioned FDA's interpretation of 
the phrase ``as of February 15, 2007'' as used in the definition of the 
terms ``Pre-Existing Tobacco Product'' and ``new tobacco product'' and 
stated that there is a lack of rationale for its interpretation. 
Comments argue that the plain meaning of the term ``as of'' support the 
interpretation that ``as of'' means ``on or before'' rather than 
``on''. As such, a tobacco product must qualify as a Pre-Existing 
Tobacco Product if it was commercially marketed in the United States at 
any time on or before February 15, 2007.
    (Response 5) As previously stated, FDA's longstanding 
interpretation is that the statutory phrase ``as of February 15, 
2007,'' means that the tobacco product was commercially marketed in the 
United States ``on February 15, 2007'' (see the final guidance entitled 
``Establishing That a Tobacco Product Was Commercially Marketed in the 
United States as of February 15, 2007'' (79 FR 58358, September 29, 
2014)). Contrary to the comments, the term ``as of '' does not have a 
clear plain meaning. The dictionary definitions of ``as of'' include: 
``on; at'' (Webster's II New Riverside University Dictionary, 1988); 
``beginning on; on and after'' (Webster's Unabridged Dictionary Random 
House 1997); ``from, at, or until a given time'' (The American Heritage 
Dictionary of Idioms 2003); ``on, at, from--used to indicate a time or 
date at which something begins or ends'' (Merriam Webster's Online 
Dictionary). As evidenced from these varying definitions (e.g., compare 
``until'' with ``from''), the term is ambiguous. Even assuming ``as 
of'' could be interpreted as ``at any time prior to and not necessarily 
including on the particular date'' (in short referred to as the ``on or 
before'' interpretation), interpreting ``as of '' to mean ``on'' gives 
a firm line of demarcation that provides clarity. Additionally, reading 
``as of'' to mean ``on or before'' would mean that obsolete, abandoned, 
or discontinued tobacco products could return to the market without any 
premarket review and could serve as predicates under the SE provision. 
It is reasonable to conclude that Congress did not intend to allow an 
immeasurable number of obsolete, abandoned, or discontinued products 
that were marketed before February 15, 2007, to return to the market 
without any premarket review or serve as predicates under the SE 
provision, but rather intended to confine this number to those products 
that were commercially marketed in the United States on February 15, 
2007. Thus, we decline to adopt the interpretation the comments 
suggest.
    Under section 910(a)(1) of the FD&C Act, and as reflected in the 
definition, new tobacco products include those that are new because 
they have been rendered new through any modification (including a 
change in design, any component, any part, or any constituent, 
including a smoke constituent, or in the content, delivery or form of 
nicotine, or any other additive or ingredient) of a tobacco product 
where the modified product was commercially marketed in the United 
States after February 15, 2007 (21 U.S.C. 387j(a)(1)(B)). For example, 
modifications to cigarette paper, container closure systems (e.g., 
change from glass to plastic e-liquid vials or from plastic to tin 
container closures), product quantity, or tobacco cut size would result 
in a new tobacco product.
    (Comment 6) One comment stated that the term ``co-packaging,'' 
which is included in the discussion of the definition of the term ``new 
tobacco product,'' is confusing and does not provide a basis for 
regulating co-packaged products as part of premarket review.
    (Response 6) Manufacturers sometimes co-package tobacco products, 
and FDA seeks to clarify what effect co-packaging tobacco products may 
have on whether those products are required to undergo premarket 
review. If there has been a change to the packaging of co-packaged 
tobacco products that is intended or reasonably expected to affect or 
alter the performance, composition, constituents, or characteristics of 
the tobacco product, then it is a change to the container closure 
system and, therefore, is a new tobacco product. Under section 
910(a)(1)(B) of the FD&C Act, new tobacco products include those that 
are new because they have been rendered new through any modification 
(including a change in design, any component, any part, or any 
constituent, including a smoke constituent, or in the content, delivery 
or form of nicotine, or any other additive or ingredient) of a tobacco 
product where the modified product was commercially marketed in the 
United States after February 15, 2007. Therefore, if two or more 
products are co-packaged together within a container closure system, it 
results in a new tobacco product requiring premarket authorization. 
However, co-packaging two or more legally marketed tobacco products, 
where there are no changes, including no change to the container 
closure system(s), does not result in a new tobacco product.
    In addition, for purposes of determining whether a tobacco product 
is new under section 910 of the FD&C Act, and therefore requires 
premarket authorization prior to marketing, a ``tobacco product'' 
encompasses the whole product (e.g., a pack of cigarettes or a tin of 
loose tobacco), and is not limited to a single unit or portion of the 
whole product (e.g., a single cigarette or a single snus pouch). See 
Philip Morris USA Inc. v. U.S. Food & Drug Admin., 202 F. Supp. 3d 31, 
55-57 (D.D.C. 2016). If a premarket application includes information on 
only a portion of a new tobacco product, FDA would have an incomplete 
understanding of the tobacco product (e.g., FDA may not get information 
on the container closure system, which could impact the consumable 
product) and would not be able to determine, for example, potential 
impacts on initiation and cessation of tobacco.
7. Package or Packaging
    As defined in section 900(13) of the FD&C Act, the term 
``package,'' also referred to in the rule as ``packaging,'' means a 
pack, box, carton, or container of any kind or, if no other container, 
any wrapping (including cellophane), in which a tobacco product is 
offered for sale, sold, or otherwise distributed to consumers. A subset 
of package is the container closure system (also defined in this rule). 
For example, the carton holding multiple soft packs of cigarettes is 
considered the package, and each soft

[[Page 55310]]

pack with surrounding cellophane is considered the container closure 
system. Packaging that constitutes the container closure system is 
intended or reasonably expected to affect or alter the performance, 
composition, constituents, or characteristics of the tobacco product 
(e.g., leaching substances that are then incorporated into a consumable 
tobacco product), but packaging that is not the container closure 
system is not intended or reasonably expected to affect or alter the 
performance, composition, constituents, or characteristics of the 
tobacco product and is, therefore, not a component or part of a tobacco 
product.
8. Tobacco Product
    As defined in section 201(rr) of the FD&C Act, the term ``tobacco 
product'' means any product that is made or derived from tobacco that 
is intended for human consumption, including any component, part, or 
accessory of a tobacco product (except for raw materials other than 
tobacco used in manufacturing a component, part, or accessory of a 
tobacco product). The term ``tobacco product'' does not mean an article 
that is a drug under section 201(g)(1), a device under section 201(h), 
or a combination product described in section 503(g) of the FD&C Act 
(21 U.S.C. 353(g)).
9. Tobacco Product Manufacturer
    As defined in section 900(20) of the FD&C Act, the term ``tobacco 
product manufacturer'' means any person, including any repacker or 
relabeler, who: (1) Manufactures, fabricates, assembles, processes, or 
labels a tobacco product or (2) imports a finished tobacco product for 
sale or distribution in the United States. FDA interprets 
``manufactures, fabricates, assembles, processes, or labels'' as 
including, but not being limited to, (1) repackaging or otherwise 
changing the container, wrapper, or labeling of any tobacco product 
package; (2) reconstituting tobacco leaves; or (3) applying any 
chemical, additive, or substance to the tobacco leaf other than potable 
water in the form of steam or mist. A definition for the term 
``finished tobacco product'' is also included in the rule.
10. Accessory
    FDA defines ``accessory'' as any product that is intended or 
reasonably expected to be used with or for the human consumption of a 
tobacco product; does not contain tobacco and is not made or derived 
from tobacco; and meets either of the following:
     Is not intended or reasonably expected to affect or alter 
the performance, composition, constituents, or characteristics of a 
tobacco product or
     is intended or reasonably expected to affect or maintain 
the performance, composition, constituents, or characteristics of a 
tobacco product, but:
    [cir] Solely controls moisture and/or temperature of a stored 
product or
    [cir] solely provides an external heat source to initiate but not 
maintain combustion of a tobacco product.
    This matches the definition of accessory set forth in Sec.  1100.3. 
Examples of accessories are ashtrays and spittoons because they do not 
contain tobacco, are not derived from tobacco, and do not affect or 
alter the performance, composition, constituents, or characteristics of 
a tobacco product. Examples of accessories also include humidors or 
refrigerators that solely control the moisture and/or temperature of a 
stored product and conventional matches and lighters that solely 
provide an external heat source to initiate but not maintain combustion 
of a tobacco product.
11. Adverse Experience
    FDA defines ``adverse experience'' as any unfavorable physical or 
psychological effect in a person that is temporally associated with the 
use of or exposure to a tobacco product, whether or not the person uses 
the tobacco product, and whether or not the effect is considered to be 
related to the use of or exposure to the tobacco product. FDA received 
many comments regarding this definition, as discussed below.
    (Comment 7) Multiple comments requested changes to the definition 
of what constitutes an adverse experience. One comment requested FDA 
amend the definition to explicitly include increased use by youth or 
young adults. Another comment stated that the definition of adverse 
experience is too broad and subjective, and should be revised to refer 
to a health-related event associated with the use of or exposure to 
(intended or incidental) a tobacco product.
    (Response 7) FDA declines to change the definition of adverse 
experience because this widely understood definition is generally 
consistent with language used throughout the Agency and is designed to 
capture a broad swath of information related to health effects from FDA 
regulated products. Due to the fact that the experience may not relate 
to the individual user but could also affect the general public or 
bystander, it is FDA's intent that the definition remain broad to 
ensure we receive the potential wide variety of voluntary reports of 
adverse experiences involving tobacco products from investigators, 
consumers, healthcare professionals and concerned members of the 
public. Additionally, FDA declines to revise the definition to include 
use by youth and young adults because it constitutes a behavior, not a 
health effect related to an adverse experience. Increases in use by 
individuals under the minimum age of sale will be monitored through the 
review of periodic reports submitted under Sec.  1114.41, among other 
means.
    FDA notes that it is important to also include information 
regarding adverse experiences associated with use of or exposure to a 
product where the individual suffering the adverse experience did not 
use the product because it can help FDA determine health risks for 
nonusers, such as the effects of second-hand exposure or accidental 
exposure (e.g., skin burns from accidental exposure to liquid nicotine, 
harmful effects resulting from a child drinking an e-liquid, 
respiratory difficulties from second-hand exposure to an e-cigarette). 
Additionally, reporting information regarding all adverse experiences 
that are temporally associated with the use of or exposure to the 
product will help the applicant avoid self-selection bias of what is 
reported to FDA and help identify harmful effects that are not 
obviously attributable to the product.
12. Applicant
    FDA defines ``applicant'' as any person that submits a PMTA to 
receive a marketing granted order for a new tobacco product.
13. Commercially Marketed
    In the proposed rule, FDA proposed to define ``commercially 
marketed'' as ``selling or offering a tobacco product for sale to 
consumers in all or in parts of the United States.'' After reviewing 
comments described in section IV, FDA has decided to finalize the 
definition of ``commercially marketed'' to mean selling or offering for 
sale a tobacco product in the United States to consumers or to any 
person for the eventual purchase by consumers in the United States. 
Examples of products that may not be covered by the definition of 
commercially marketed include investigational tobacco products and free 
samples. Examples of documentation of commercial marketing may include 
dated bills of lading, dated freight bills, dated waybills, dated 
invoices, dated purchase orders, dated advertisements, dated catalog 
pages, dated promotional material, dated trade publications, dated 
manufacturing documents, inventory lists, or any other document 
demonstrating that the

[[Page 55311]]

product was commercially marketed in the United States as of February 
15, 2007. See discussion in section IV.B.3.
14. Component or Part
    FDA defines ``component or part'' as any software or assembly of 
materials intended or reasonably expected: (1) To alter or affect the 
tobacco product's performance, composition, constituents, or 
characteristics or (2) to be used with or for the human consumption of 
a tobacco product. Component or part excludes anything that is an 
accessory of a tobacco product. A container closure system (which is 
also defined in this section) is considered a component or part. With 
respect to these definitions, FDA notes that ``component'' and ``part'' 
are separate and distinct terms within chapter IX of the FD&C Act. 
However, for purposes of this rule, FDA is using the terms 
``component'' and ``part'' interchangeably and without emphasizing a 
distinction between the terms. FDA may clarify the distinctions between 
``component'' and ``part'' in the future. This definition matches the 
definition in Sec.  1100.3.
15. Composition
    FDA defines ``composition'' as the materials in a tobacco product, 
including ingredients, additives, and biological organisms. The term 
includes the manner in which the materials, for example, ingredients, 
additives, and biological organisms, are arranged and integrated to 
produce a tobacco product. Composition refers primarily to the chemical 
and biological properties of a tobacco product, whereas design refers 
to the physical properties of a tobacco product. A biological organism 
refers to any living biological entity, such as an animal, plant, 
fungus, or bacterium.
16. Constituent
    In this final rule, we have updated the definition of constituent 
on our own initiative to clarify the meaning. FDA defines 
``constituent'' as any chemical or chemical compound in a tobacco 
product that is or potentially is inhaled, ingested, or absorbed into 
the body, any chemical or chemical compound in an emission (e.g., 
smoke, aerosol, droplets) from a tobacco product, that either transfers 
from any component or part of the tobacco product to the emission or 
that is formed by the product, including through combustion or heating 
of tobacco, additives, or other components of the tobacco product.
17. Container Closure System
    FDA defines ``container closure system'' as any packaging materials 
that are a component or part of a tobacco product. FDA received several 
comments regarding the proposed definition, as discussed below.
    (Comment 8) A few comments suggested related revisions to both the 
definitions of the terms ``container closure system'' (CCS), 
``packaging,'' and ``component or part,'' as well as what modifications 
to a CCS FDA considers to result in a new tobacco product. The comments 
requested that the definition of CCS be limited to only the product 
packaging that is designed or reasonably expected to alter the product 
characteristics after the time of manufacture. Comments stated that 
failure to make such a change would be inconsistent with the court's 
decision in Philip Morris v. FDA, 202 F. Supp. 3d 31, 51 (D.D.C. 2016). 
Citing this case, which in the course of distinguishing between a 
product and its labeling, referenced ``the physical attributes of the 
product itself, as distinct from its label or the package in which it 
is contained,'' the comments argue that the law's requirements for new 
tobacco products apply only when there are changes in ``the physical 
attributes of a tobacco product--not its labeling or packaging.'' Id. 
Likewise, the comments stated that modifications to the CCS should 
result in a new tobacco product only if modifications are intended or 
reasonably expected to alter the characteristics of the product. The 
comments maintained that if the packaging's purpose is merely to 
maintain or preserve the characteristics of the product, it should only 
be considered packaging, not a CCS.
    (Response 8) As described in the rule, FDA defines ``component or 
part'' as any software or assembly of materials intended or reasonably 
expected: (1) To alter or affect the tobacco product's performance, 
composition, constituents, or characteristics or (2) to be used with or 
for the human consumption of a tobacco product. Contrary to the 
commenter's assertion, packaging that constitutes the container closure 
system is intended or reasonably expected to affect or alter the 
performance, composition, constituents, or characteristics of the 
tobacco product (e.g., leaching substances that are then incorporated 
into a tobacco product), and is thus a component or part of a tobacco 
product. This is consistent with the holding of Philip Morris, 202 F. 
Supp. at 51, as is its converse: Packaging that is not the container 
closure system and is not intended or reasonably expected to affect or 
alter the performance, composition, constituents, or characteristics of 
the tobacco product is, therefore, not a component or part of a tobacco 
product. As such, packaging that is, for example, the packaging around 
a blister pack is not part of the PMTA review process if it is not 
intended or reasonably expected to alter or affect the performance, 
composition, constituents, or characteristics of the tobacco product 
within the blister pack. However, where a change in the container 
closure system could affect the chemistry of the product, FDA requires 
the applicant, where it submits a PMTA, to demonstrate that permitting 
marketing of the product with the change in the container closure 
system is appropriate for the protection of public health.
    For example, packaging materials constitute a container closure 
system if substances within that packaging are intended or reasonably 
expected to affect product moisture, e.g., when the manufacturer 
changes the package of a moist snuff from plastic to fiberboard, which 
can affect microbial stability and tobacco-specific nitrosamine (TSNA) 
formation during storage. Another example of this is when menthol or 
other ingredients are applied to the inner foil to become incorporated 
into the consumed product (Ref. 1). Packaging materials may also be 
intended or reasonably expected to affect the characteristics of a 
tobacco product by impacting the rate of leaching into, and ultimately, 
the amount of substances found in, the consumable tobacco product. In 
fact, it has been demonstrated that compounds in packaging materials 
may diffuse into snuff and affect its characteristics (Ref. 2). Thus, 
packaging material that affects the characteristics of a tobacco 
product by impacting the moisture level or shelf life of a tobacco 
product is a container closure system (e.g., a plastic versus a metal 
container of smokeless tobacco). A difference in tobacco moisture is 
reasonably expected to affect microbial growth in the product, 
extraction efficiency, and total exposure to nicotine or the 
carcinogens N-nitrosonornicotine (NNN) or 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK) (Ref. 3).
    Considering a distinct subset of packaging (i.e., container closure 
system) to be a component or part is consistent with the FD&C Act and 
furthers the fundamental purpose of the Tobacco Control Act to protect 
the public health. For example, section 900(1) of the FD&C Act defines 
an ``additive'' as any substance the intended use of which results or 
may reasonably be expected to result, directly or indirectly, in its 
becoming a component or otherwise affecting the characteristic of any 
tobacco product

[[Page 55312]]

(including any substance intended for use as a flavoring or coloring or 
in producing, manufacturing, packing, processing, preparing, treating, 
packaging, transporting, or holding), except that such term does not 
include tobacco or a pesticide chemical residue in or on raw tobacco or 
a pesticide chemical. Congress specifically included a broad definition 
of ``additive'' that encompasses not just substances that do in fact 
have such effects but also those that may reasonably be expected to 
have such effects. Similarly, if FDA were to adopt a narrow 
construction of ``tobacco product'' to exclude these materials, the 
Agency's ability to evaluate whether permitting the marketing of the 
new tobacco product was appropriate for the protection of public health 
(APPH) would be impeded, thereby leaving the Agency unable to fully 
execute its mission to protect the public health. The definition of 
``package'' in section 900(13) of the FD&C Act does not dictate a 
contrary result and can be reasonably interpreted to mean that a 
distinct subset of packaging is also a component or part of a tobacco 
product.
18. Design
    FDA defines ``design'' to mean the form and structure concerning, 
and the manner in which components or parts, ingredients, software, and 
materials are integrated to produce a tobacco product. This term refers 
to the physical properties of a tobacco product. Examples of design 
parameters include ventilation, paper porosity, filter efficiency, 
battery voltage and current operating range, and electrical heater coil 
resistance. FDA received one comment on this definition, as discussed 
below.
    (Comment 9) One comment stated that the definition of the term 
``design'' does not take into account the inherent variability that can 
occur in tobacco crops over the years. The comment stated that such 
variability may require manufacturers to alter, in a limited capacity, 
certain characteristics of the product, in order to minimize 
variability of constituent levels in its final aerosol. The comment 
concluded that the proposed definition was rather narrow and did not 
allow for the control of emission levels through design adjustments. 
The comment recommended that the definition be amended to allow 
applicants to adjust design features for the sole purpose of 
accommodating natural variability of tobacco plants, without requiring 
the submission of a new PMTA or a supplemental PMTA.
    (Response 9) FDA declines to make changes as a result of this 
comment. At this time, FDA does not intend to enforce the requirement 
of premarket review in section 910 for tobacco blending changes 
required to address the natural variation of tobacco (e.g., blending 
changes due to variation in growing conditions) to maintain a 
consistent product.\10\ Where an applicant changes other 
characteristics of a tobacco product (i.e., characteristics other than 
tobacco blend) to minimize variability of the product, FDA intends to 
enforce the premarket authorization requirements, and the PMTA must 
contain all appropriate information for the distinct new tobacco 
product that would result from such changes.
---------------------------------------------------------------------------

    \10\ For more information on FDA's enforcement of premarket 
review for tobacco blending changes, see the guidance entitled 
``Demonstrating the Substantial Equivalence of a New Tobacco 
Product: Responses to Frequently Asked Questions'' available at 
https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
---------------------------------------------------------------------------

19. Finished Tobacco Product
    FDA defines ``finished tobacco product'' to mean a tobacco product, 
including all components and parts, sealed in final packaging (e.g., 
filters or filter tubes sold to consumers separately or as part of 
kits, or e-liquids sealed in final packaging sold to consumers either 
separately or as part of kits) or in the final form in which it is 
intended to be sold to consumers. FDA received one comment on this 
definition, as discussed below.
    (Comment 10) One comment stated that the definition of the term 
``finished tobacco product'' should conform to the definition 
previously used in the registration and listing guidance, which 
included the phrase ``intended for consumer use.''
    (Response 10) FDA has edited the definition of the term ``finished 
tobacco product'' to include the phrase ``or in the final form in which 
it is intended to be sold to consumers'' to help clarify the meaning of 
the term ``finished.'' We believe that by including products sold in 
the final form in which it is intended to be sold to consumers, we are 
capturing a variety of products including those intended for consumer 
use as requested by the commenter.
20. Harmful or Potentially Harmful Constituent (HPHC)
    FDA defines ``harmful or potentially harmful constituent'' as any 
chemical or chemical compound in a tobacco product or tobacco smoke or 
emission that: (1) Is or potentially is inhaled, ingested, or absorbed 
into the body, including as an aerosol or any other emission and (2) 
causes or has the potential to cause direct or indirect harm to users 
or nonusers of tobacco products. This definition aligns with the 
definition provided for in the guidance for industry entitled 
```Harmful and Potentially Harmful Constituents' in Tobacco Products as 
Used in Section 904(e) of the FD&C Act.''
    The established list of HPHCs can be found on FDA's website at 
https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/harmful-and-potentially-harmful-constituents-tobacco-products-and-tobacco-smoke-established-list (77 FR 20034, April 3, 2012). FDA issued 
a notice in the Federal Register of August 5, 2019 (84 FR 38032), 
seeking public comment on the proposed addition of 19 constituents to 
the established list of HPHCs. FDA is proposing these additions to 
reflect the range of tobacco products now subject to FDA's tobacco 
product authorities, including deemed tobacco products such as ENDS. 
FDA will finalize the addition of these HPHCs to the established list, 
as appropriate, after reviewing public comment and generally intends to 
make any future updates to the established list of HPHCs through a 
similar notice and comment process.
    FDA received one comment on this definition, as discussed below.
    (Comment 11) One comment stated that FDA should either change the 
definition of the term ``harmful or potentially harmful constituent'' 
(HPHC) to include a list of all HPHCs for which testing results must be 
submitted in a PMTA or include a list of all such HPHCs elsewhere in 
the rule.
    (Response 11) FDA declines to revise the definition of HPHC. In 
defining this term, FDA is describing criteria for what constitutes an 
HPHC and is not attempting to identify specific constituents. In 
contrast, section 904 of the FD&C Act requires FDA to establish, and 
periodically revise, a list of HPHCs. More importantly for PMTA 
content, as discussed in section VIII.B.9.a.v., an application would 
not be required to contain testing for all HPHCs; rather, it would be 
required to contain testing for constituents, including HPHCs, that are 
contained within and can be delivered by the type of product and 
contain a description of why the HPHCs that were tested are appropriate 
for the type of product.
    FDA similarly declines to set forth a list of constituents that 
must be tested because it would be overly broad as it pertains to most 
tobacco products. It is FDA's understanding that manufacturers have 
information concerning what constituents might be

[[Page 55313]]

emitted from their specific tobacco products. FDA believes that 
allowing applicants to use this knowledge in selecting the appropriate 
constituents for testing would result in a more efficient process for 
preparing PMTAs than requiring manufacturers to test for each 
constituent in a broad list, including HPHCs that might not pertain to 
the applicant's specific product.
21. Heating Source
    FDA defines ``heating source'' as the source of energy used to burn 
or heat the tobacco product. Examples of a heating source include a 
flame or a rechargeable battery.
22. Ingredient
    FDA defines ``ingredient'' as tobacco, substances, compounds, or 
additives added to the tobacco, paper, filter, or any other component 
or part of a tobacco product, including substances and compounds 
reasonably expected to be formed through a chemical reaction during 
tobacco product manufacturing. For example, an ingredient may be a 
single chemical substance, leaf tobacco, or the product of a reaction, 
such as a chemical reaction, in manufacturing. Examples of substances 
and compounds (ingredients) reasonably expected to be formed through a 
chemical reaction during tobacco product manufacturing include the 
following:
     The reaction of sugars with amines to form families of 
compounds with new carbon-nitrogen bonds, including Maillard reaction 
products and Amadori compounds;
     the reaction of sodium hydroxide with citric acid to form 
sodium citrate;
     the production of ethyl alcohol, a residual solvent, from 
ethyl acetate during production of tipping paper adhesive;
     products of thermolytic reactions, such as the production 
of carboxylic acids from sugar esters;
     products of enzymatically or nonenzymatically catalyzed 
reactions, such as the hydrolytic production of flavor or aroma 
precursors from nonvolatile glucosides; and
     products of acid-base reactions, such as removal of a 
proton from protonated nicotine to generate the basic form of nicotine 
(``free'' nicotine).
23. Line Data
    FDA defines ``line data'' to mean an analyzable dataset of 
observations for each individual study participant, laboratory animal, 
or test replicate. Line data typically provides information that is 
more useful to FDA's review of an application than data in its more 
``raw'' forms because it allows information about time, people, and 
places involved in investigations to be organized and reviewed quickly, 
and it facilitates tracking of different categories of cases. FDA is 
requiring an applicant to submit line data rather than source data 
(also referred to as raw data) to allow for a more efficient review 
process. As described in Sec.  1114.45, applicants are required to 
retain all source data in the event that FDA needs to inspect the data 
as part of its application review.
24. Material
    FDA defines ``material'' to mean an assembly of ingredients. 
Materials are assembled to form a tobacco product, or components or 
parts of tobacco product. For example, material includes the glue or 
paper pulp for a cigarette where the paper pulp includes multiple 
ingredients (e.g., multiple types of tobacco, water, and flavors) 
assembled into the paper (or pulp depending on the water content). 
Another example of a material is a plastic composed of chemical 
substances that houses electrical components.
25. Marketing Granted Order
    FDA defines ``marketing granted order'' to mean the order described 
in section 910(c)(1)(A)(i) of the FD&C Act that authorizes the new 
tobacco product to be introduced or delivered for introduction into 
interstate commerce.
26. Marketing Denial Order
    FDA defines ``marketing denial order'' to mean the order described 
in section 910(c)(1)(A)(ii) of the FD&C Act that the product may not be 
introduced or delivered for introduction into interstate commerce.
27. Other Features
    FDA defines ``other features'' to mean any distinguishing qualities 
of a tobacco product similar to those specifically enumerated in 
section 910(a)(3)(B) of the FD&C Act. The definition includes: (1) 
HPHCs (the definition of new tobacco product includes any modification 
to any constituents, including smoke constituents; section 910(a)(1)(B) 
of the FD&C Act) and (2) any other product characteristics that relate 
to the chemical, biological, or physical properties of the tobacco 
product. The term ``other features'' also encompasses other product 
characteristics that relate to the chemical, biological, and physical 
properties of the product that would not be included as a material, 
ingredient, design, composition, or heating source.
28. Premarket Tobacco Product Application or PMTA
    FDA defines ``premarket tobacco product application'' or ``PMTA'' 
to mean the application described in section 910(b) of the FD&C Act. 
This term includes the initial premarket tobacco product application 
and all subsequent amendments.
29. ``Premium'' Cigar
    As discussed in section VI.A., we are adding the Cigar Ass'n of Am. 
court's definition of ``premium'' cigars to Sec.  1114.3. ``Premium'' 
cigars means a type of cigar that: (1) Is wrapped in whole tobacco 
leaf; (2) contains a 100 percent leaf tobacco binder; (3) contains at 
least 50 percent (of the filler by weight) long filler tobacco (i.e., 
whole tobacco leaves that run the length of the cigar); (4) is handmade 
or hand rolled (i.e., no machinery was used apart from simple tools, 
such as scissors to cut the tobacco prior to rolling); (5) has no 
filter, nontobacco tip, or nontobacco mouthpiece; (6) does not have a 
characterizing flavor other than tobacco; (7) contains only tobacco, 
water, and vegetable gum with no other ingredients or additives; and 
(8) weighs more than 6 pounds per 1,000 units.
30. Serious Adverse Experience
    FDA defines ``serious adverse experience'' to mean an adverse 
experience that results in any of the following outcomes: (1) Death; 
(2) a life-threatening condition or illness; (3) inpatient 
hospitalization or prolongation of existing hospitalization; (4) a 
persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (e.g., seizures that do not 
result in hospitalization, burns that result in damage to a limb or 
nerve damage); (5) a congenital anomaly/birth defect; or (6) any other 
adverse experience that, based upon appropriate medical judgment, may 
jeopardize the health of a person and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this 
definition. This could include, for example, carbon monoxide poisoning, 
which if left untreated, could result in long term and possibly delayed 
brain damage or heart damage.
    FDA received one comment on this definition, as discussed below.
    (Comment 12) One comment stated that the definition of the term 
``serious adverse experience'' needs to be clarified, recommending that 
it be aligned with a similar definition used by FDA for drugs. 
Specifically, the comment requested that FDA further

[[Page 55314]]

define the term ``life-threatening condition or illness'' in paragraph 
(b) of the definition to mean, as it does in the drug context, any 
adverse experience that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse experience as it 
occurred, i.e., it does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. The comment 
also requested that FDA restrict the ``catch-all'' in paragraph (f) of 
the definition so that it focuses on ``important medical events,'' 
similar to the definition for drugs, rather than ``adverse 
experiences'' as the definition currently does.
    (Response 12) FDA declines to revise the definition of serious 
adverse experience because it captures the events for which FDA would 
need prompt notification once a product is on the market. Through 
paragraph (b) of the definition of ``serious adverse experience,'' FDA 
is seeking information about adverse experiences carrying an immediate 
risk of death. In contrast, through paragraph (f) of the definition of 
``serious adverse experience,'' FDA is interested in receiving prompt 
notification of a condition that could have delayed consequences, for 
example, one that that could cause death or severe organ damage if left 
untreated, or immediate death had it occurred in a more severe form so 
we can investigate whether the condition could occur in a more severe 
form and cause death in different individuals. We believe that having 
paragraph (f) focus on adverse experiences appropriately captures this 
scope. Applicants with questions regarding whether an adverse 
experience qualifies as a serious adverse experience are encouraged to 
promptly contact FDA.
31. Submission Tracking Number or STN
    FDA defines ``submission tracking number'' or ``STN'' to mean the 
number that FDA assigns to submissions that are received from an 
applicant, such as a PMTA and a supplemental PMTA. FDA has added this 
definition to the final rule on its own initiative to help clarify 
requirements to specify submission tracking numbers.
32. Unexpected Adverse Experience
    FDA defines ``unexpected adverse experience'' to mean an adverse 
experience occurring in one or more persons in which the nature, 
severity, or frequency of the experience is not consistent with: (1) 
The known or foreseeable risks associated with the use or exposure to 
the tobacco product as described in the PMTA (including the results of 
human subject investigations) and other relevant sources of 
information, such as the product labeling and postmarket reports; (2) 
the expected natural progression of any underlying disease, disorder, 
or condition of the persons(s) experiencing the adverse experience and 
the person's predisposing risk factor profile for the adverse 
experience; or (3) the results of nonclinical investigations.
    FDA received one comment regarding this definition, as discussed 
below.
    (Comment 13) One comment stated that the definition of unexpected 
adverse experience is unnecessarily complex and would likely lead to 
unduly burdensome reporting. The comment noted potential difficulties 
with assessing what constitutes a ``foreseeable'' risk and expressed a 
belief that the definition should be aligned with those found in other 
product groups that focus on unexpected adverse experiences being those 
that are not currently listed on product packaging and not previously 
observed.
    (Response 13) FDA declines to revise the definition of unexpected 
adverse experience because it captures the events and information that 
should be disclosed. This information is important to FDA's ongoing 
monitoring of a tobacco product because it would alert the Agency to 
the potential scope and frequency for health risks that were not 
previously considered as part of application review and may inform a 
determination of whether the marketing granted order should be 
withdrawn or temporarily suspended. Foreseeable risks are harms that 
could reasonably be predicted based upon the content of the PMTA and 
other available sources of information and is largely based on 
mechanism of action or composition of the tobacco product.
33. Vulnerable populations
    The proposed rule did not expressly discuss vulnerable populations. 
However, FDA received several comments regarding this issue, as 
discussed below.
    (Comment 14) Multiple comments raised concerns related to the lack 
of reference to vulnerable populations in the proposed rule. One 
comment stated that the tobacco industry has a history of marketing its 
products to individuals with specific characteristics, including, but 
not limited to veterans, individuals with a low socioeconomic status 
(SES), and vulnerable populations. The comment requested that FDA 
require applicants to specify detailed demographic information in their 
marketing plans, including the targeting of its marketing by SES as 
part of a PMTA. Another comment stated that a definition of vulnerable 
populations should be included in the final rule. In addition, multiple 
comments requested FDA require PMTAs to contain a consideration of the 
effects of permitting the marketing of the new tobacco product on 
vulnerable or sensitive subpopulations (e.g., individuals whose health 
has been compromised).
    (Response 14) FDA agrees that consideration of vulnerable 
populations is an important part of determining whether permitting the 
marketing of a new tobacco product would be APPH. As discussed in 
section IX.D.1., FDA considers many factors when making its APPH 
determination, including the likelihood that existing users of tobacco 
products will stop using such products and the likelihood that nonusers 
of tobacco products will start using. This could include information 
regarding the marketing of a new tobacco product that may produce a 
positive effect for some subpopulations while producing differential 
effects for other subpopulations. For example, a non-combusted tobacco 
product that may help current adult smokers transition away from 
cigarettes may appeal to and lead to tobacco product initiation among 
youth and young adults who have never used tobacco products.
    To ensure FDA understands the full health impact of the product, it 
is important for FDA to consider vulnerable populations and how the 
marketing of the new tobacco product can impact the likelihood that 
existing users of tobacco products will stop using such products and 
the likelihood that nonusers will start using the product. FDA has 
revised the rule to emphasize the importance of considering the effect 
of marketing a new tobacco product would have on vulnerable populations 
as well defined the term ``vulnerable populations'' in Sec.  1114.3 to 
mean groups that are susceptible to tobacco product risk and harm due 
to disproportionate rates of tobacco product initiation, use, burden of 
tobacco-related diseases, or decreased cessation. Relevant vulnerable 
populations will vary depending on the type of tobacco product and may 
change over time, and can include, but are not limited to, youth and 
young adults, those who are of low SES, certain racial or ethnic 
populations, underserved rural populations, people with co-morbid 
mental health conditions or substance use disorders, military or 
veteran populations, people who are pregnant or are trying to become 
pregnant, and sexual or gender minorities (Refs. 4-9).

[[Page 55315]]

Also note that section VIII.B.6.b. includes SES as an example 
demographic characteristic to clarify the range of potential 
characteristics that may be included in descriptions of marketing 
plans.

VIII. Premarket Tobacco Product Applications (Part 1114, Subpart B)

A. Application Submission (Sec.  1114.5)

    As described in Sec.  1114.5, if an applicant seeks a marketing 
granted order under the PMTA pathway for its new tobacco product, it 
would be required to submit a PMTA to FDA and receive a marketing 
granted order before the tobacco product may be introduced or delivered 
for introduction into interstate commerce. An applicant submitting a 
PMTA to FDA should include all information required to be in a PMTA as 
part of its initial submission, including all sections specified in 
Sec.  1114.7(a), except for product samples which, if required, must be 
submitted after a PMTA is accepted for review as described in the 
discussion Sec.  1114.7(e) in section VII.B.5. Submitting a complete 
application as part of an initial submission is important because, as 
explained in the discussion of Sec.  1114.27 in section VIII.B, FDA may 
refuse to accept or file an incomplete application for review.
    FDA received several comments regarding the scope of products 
required to submit a PMTA.
    (Comment 15) Some comments request that certain tobacco products, 
such as ENDS and oral tobacco derived nicotine, be exempt from the PMTA 
premarket pathway or that a different premarket pathway be created for 
them. The comments described certain products as significantly less 
harmful than other products, which they contended justifies either an 
exemption from the requirements of the PMTA pathway or a creation of a 
streamlined pathway under which products can be authorized based upon a 
few approaches, such as the submission of significantly less 
information that would be required under this rule. Other comments 
requested a similar streamlined pathway for small businesses due to the 
cost of preparing a PMTA.
    (Response 15) As described in detail throughout this rule, the 
information required by part 1114 is necessary to ensure FDA has 
sufficient information to consider, as required by section 910(c) of 
the FD&C Act, the potential risks and benefits of a new tobacco product 
to the health of the population as a whole in determining whether the 
marketing of that product would be appropriate for the protection of 
public health. FDA declines to create a streamlined pathway for certain 
tobacco product categories or manufacturers that permits the submission 
of significantly less information than required by this rule because it 
would result in FDA having insufficient information to make its 
statutorily required determinations under section 910(c) of the FD&C 
Act. Consistent with the deeming final rule,\11\ we also decline the 
request to exempt products from the requirements of PMTA or from 
premarket review more broadly. Section 910 of the FD&C Act establishes 
the procedures that must be followed before a new tobacco product can 
be authorized for marketing and it applies to all new tobacco products.
---------------------------------------------------------------------------

    \11\ See the deeming final rule (81 FR 28974) for responses to 
similar comments requesting alternative or abbreviated PMTA pathways 
and exemptions from the requirements of premarket review.
---------------------------------------------------------------------------

B. Required Content and Format (Sec.  1114.7)

1. General
    As explained in Sec.  1114.7(a), the rule requires each PMTA to 
contain sufficient information necessary for FDA to determine whether 
the grounds for denial of an application listed in section 910(c)(2) of 
the FD&C Act apply to the PMTA, which includes the following sections:
     General information (as described in Sec.  1114.7(c));
     descriptive information (as described in Sec.  1114.7(d));
     product samples (as described in Sec.  1114.7(e));
     labeling (as described in Sec.  1114.7(f));
     statement of compliance with part 25 (21 CFR part 25) (as 
described in Sec.  1114.7(g));
     summary (as described in Sec.  1114.7(h));
     product formulation (as described in Sec.  1114.7(i));
     manufacturing (as described in Sec.  1114.7(j));
     health risk investigations (as described in Sec.  
1114.7(k));
     the effect on the population as a whole (as described in 
Sec.  1114.7(l)); and
     certification statement (as described in Sec.  1114.7(m)).
    As described in section VIII.B, if the application does not appear 
to contain these sections and the information required therein (except 
for product samples), the Agency may refuse to accept the application 
for review under Sec.  1114.27(a)(1). As described in section VIII.B, 
if a PMTA does not contain sufficient information required by these 
sections to permit a substantive review, including substantive 
information regarding broad areas of scientific information noted where 
appropriate in this document, FDA may refuse to file the application 
under Sec.  1114.27(b)(1).
2. Format
    Section 1114.7(b) provides the general requirements for the format 
of the application and would require the applicant to submit the 
application with the appropriate FDA form(s) (i.e., Form FDA 4057 (Ref. 
10) and Form FDA 4057b (Ref. 11)). Section Sec.  1114.7(b)(1) would 
require the application and any amendments to contain a comprehensive 
index and table of contents and be well organized, legible, and written 
in the English language. The comprehensive index would include the 
listing of files and data associated with those files (e.g., for an 
application that is electronically submitted, the comprehensive index 
would include the listing of files and associated metadata). FDA is 
also requiring that documents that have been translated from another 
language into English must be accompanied by the original language 
version of the document, a signed statement by an authorized 
representative of the manufacturer certifying that the English language 
translation is complete and accurate, and a brief statement of the 
qualifications of the person who made the translation (e.g., education 
and experience). This information would help FDA ensure that the 
English language translations of documents are complete and accurately 
reflect the content of the original documents.
    As described in Sec.  1114.49, FDA is requiring that the PMTA and 
all supporting documents be submitted to FDA in an electronic format 
that the Agency can process, review, and archive, unless the Agency has 
previously granted a waiver from these requirements. An application 
would not be considered received until CTP's Document Control Center 
has received an application that the Agency can process, review, and 
archive. Applicants that are unable to submit their applications in 
electronic format may seek a waiver from the electronic filing 
requirement, in accordance with Sec.  1114.49.
    FDA received several comments regarding PMTA format, as discussed 
below.
    (Comment 16) One comment stated that FDA must address 
inconsistencies between the ENDS PMTA Guidance and the PMTA Proposed 
Rule, citing

[[Page 55316]]

differences such as marketing plans and application organization.
    (Response 16) FDA will update the ENDS PMTA Guidance to ensure it 
is consistent with the requirements and recommendations in this 
rulemaking. When updated, the ENDS PMTA Guidance will provide updated 
important product-specific recommendations for applicants submitting 
PMTAs for ENDS. In addition, if applicants wish to discuss the 
development of a PMTA, the applicant may request a meeting as set forth 
in the guidance for industry and investigators entitled ``Meetings with 
Industry and Investigators on the Research and Development of Tobacco 
Products.'' \12\
---------------------------------------------------------------------------

    \12\ Available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance
---------------------------------------------------------------------------

    (Comment 17) One commenter stated that while the proposed rule 
notes FDA's intent to provide information regarding acceptable 
technical specifications for electronic submissions, it was not aware 
of FDA having done so and requested that the final rule contain clear 
and consistent expectations for electronic submissions so that industry 
can properly plan and prepare applications in advance of submission.
    (Response 17) Applicants can visit FDA's web page for more 
information on electronic submission, including electronic submission 
file formats and specifications. As of the date of the publication of 
this rule, this information is located at: https://www.fda.gov/industry/fda-esubmitter/using-esubmitter-prepare-tobacco-product-submissions. This web page also contains a link to the document 
``Electronic Submission File Formats and Specifications,'' which 
provides additional helpful information. As mentioned in the proposed 
rule, FDA intends to update this information as needed to accommodate 
changes in technology.
    FDA has created these format requirements using its authority under 
sections 701 and 910 of the FD&C Act to efficiently enforce premarket 
review requirements. The requirements in Sec.  1114.7(b) are intended 
to address some of the problems we have seen with applications to date. 
For example, some applications have been submitted to FDA in a 
proprietary or password protected format without providing FDA access 
or password information. Following up with an applicant to obtain 
access or password information takes time and contributes to delays. In 
addition, some electronic submission files have not been of a static 
format, and thus, the pages reformat, repaginate, rebullet, or redate 
each time the document is accessed. For example, Microsoft Word files 
can change upon opening by FDA reviewers, while PDF files remain as the 
applicant intended. Receiving applications with these issues affects 
our ability to cross-reference, share (internally), and efficiently 
evaluate information. Also, FDA is required under regulations governing 
Federal records to maintain many files long-term, and in a 
``sustainable'' format (for more information on sustainable formats, 
please refer to National Archives and Records Administration Bulletin 
2014-04, https://www.archives.gov/records-mgmt/bulletins/2014/2014-04.html), Sec.  1114.7(b) will ensure that these files can be managed, 
opened, and read by the Agency for the duration of the retention 
period.
    Finally, Sec.  1114.7(b)(2) will allow an applicant to include 
content in a PMTA by cross-reference to a tobacco product master file 
(TPMF) or a pending MRTPA for the same tobacco product submitted under 
section 911 of the FD&C Act. A TPMF is a file that is voluntarily 
submitted to CTP that contains trade secret and/or confidential 
commercial information about a tobacco product or component that the 
owner does not want to share with other persons. TPMFs are a beneficial 
tool for manufacturers, component suppliers, and ingredient suppliers, 
and can assist the tobacco product submission process. TPMFs allow 
individuals to rely on the information contained in a TPMF in a 
submission to FDA without the TPMF owner having to disclose the 
information to those individuals. TPMFs are typically used to prevent 
the disclosure of information that contains trade secrets or 
confidential commercial information. One situation in which TPMFs might 
be useful in submitting a PMTA is where an applicant is seeking 
marketing authorization for a new tobacco product that is made using a 
component or part, or ingredient that is purchased from another tobacco 
product manufacturer (e.g., blended tobacco or an e-liquid). Applicants 
must demonstrate they have the right to reference the TPMF to be able 
to include content by cross-reference, such as by having the master 
file holder provide a letter of authorization. Applicants must specify 
the master file number and clearly identify the specific content that 
it is incorporating into its PMTA. For FDA's current thinking on the 
use of TPMFs, please consult the guidance for industry entitled 
``Tobacco Product Master Files.'' \13\
---------------------------------------------------------------------------

    \13\ Available at: https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
---------------------------------------------------------------------------

    (Comment 18) A number of comments submitted similar concerns about 
the lack of data standardization, stating that FDA should standardize 
the data required to be submitted and allow companies to rely on the 
same pool of standardized data where it applies to similar aspects of 
their new tobacco product, such as submitting the same ingredients, to 
improve the efficiency for both application submission and review.
    (Response 18) When companies want to rely on the same pool of data, 
FDA encourages the use of shared resources, such as tobacco product 
master files, where appropriate.
    Applicants may also include content in a PMTA by cross-reference to 
a pending MRTPA for the same tobacco product.\14\ FDA recommends that 
applicants seeking to market a new tobacco product that has not 
previously received marketing authorization as a modified risk tobacco 
product (MRTP) submit a single application to seek both a marketing 
granted order and a modified risk granted order (i.e., a combined PMTA 
and MRTPA); however, where an applicant chooses to submit a separate 
PMTA and MRTPA, FDA recommends that an applicant submit the full text 
of any common content (e.g., the manufacturing or product formulation 
sections) in a PMTA and include it in the MRTPA by cross-reference. 
This approach would prevent any transcription errors and would allow 
for a more effective review by FDA because the content would only need 
to be reviewed once to be considered as part of both applications.
---------------------------------------------------------------------------

    \14\ FDA has not included MRTPAs that resulted in a modified 
risk order in the list of documents that an applicant may cross-
reference as part of a PMTA. Because a new tobacco product must 
receive premarket authorization under section 910 of the FD&C to be 
introduced or delivered for introduction into interstate commerce, 
FDA does not intend to act on a MRTPA unless the product has a 
pending application seeking, or has already received, marketing 
authorization under section 910, or is a Pre-Existing Tobacco 
Product. Such an approach will allow FDA to efficiently enforce 
section 911 of the FD&C Act by focusing its efforts on only those 
applications that could potentially result in a tobacco product 
being introduced to the market.
---------------------------------------------------------------------------

    Under this rule, except as described in subpart B, FDA will not 
consider content included by cross-reference to any other sources of 
information outside of a submission. An applicant may use internal 
cross-references for any content that would need to be referenced in 
multiple sections of a PMTA (i.e., include the full text of the content 
in one section and use cross-references to

[[Page 55317]]

the content in other sections), rather than including the full text of 
the same information multiple times. If an applicant wishes to include 
information it has previously submitted to FDA other than a master file 
or a pending MRTPA (e.g., portions of an SE Report or previously 
submitted PMTA for a different product), the applicant must include the 
full text of such information in its PMTA. FDA is implementing this 
restriction because cross-referencing information from other types of 
applications (e.g., SE Reports, previously submitted PMTAs for 
different products) can make review difficult and contribute to delays 
in the review process.
    (Comment 19) One comment stated that FDA should amend the 
application format requirements so that it allows PMTAs to include 
information by cross-reference to parts of previously filed PMTAs for 
different products that contain studies applicable to the new tobacco 
product.
    (Response 19) The format requirements of Sec.  1114.7(b) permit an 
applicant to cross-reference a tobacco product master file or a pending 
MRTPA for the same tobacco product. FDA declines to revise Sec.  
1114.7(b) to broadly allow an applicant to cross-reference information 
contained in any previously filed PMTA because it could result in a 
process in which FDA would have to pull information from a variety of 
sources to have a complete PMTA for review, which would increase the 
potential for error and decrease the efficiency of FDA's review. 
Additionally, permitting an applicant to broadly cross-reference 
information presented for different products would not necessarily 
result in a more efficient review process. FDA is limiting the ability 
of applicants to cross-reference content from previously reviewed PMTAs 
to specific circumstances set forth in Sec. Sec.  1114.15 and 1114.17 
where it would facilitate application review. Where an applicant 
intends to submit the same information in multiple applications 
submitted at different periods in time, FDA recommends establishing a 
TPMF containing the information so that it could be included by cross-
reference in each application.
    An applicant may also submit a single premarket submission for 
multiple products (i.e., a bundled PMTA) and a single, combined cover 
letter and table of contents across all products; however, when FDA 
receives a premarket submission that covers multiple new tobacco 
products, we intend to consider information on each product as a 
separate, individual PMTA and it is important to identify the content 
that pertains to each product.
    (Comment 20) Multiple comments requested additional information 
regarding how they should bundle multiple PMTAs for related or similar 
tobacco products into a single submission. One comment requested that 
FDA formally clarify whether e-liquid manufacturers and manufacturers 
of closed-system devices may bundle applications for multiple flavors 
of e-liquid that share common nicotine strengths, package sizes, 
propylene glycol/vegetable glycerin ratios, or other characteristics. 
Another comment requested information regarding how a manufacturer 
should submit PMTAs for products that are used together but may be sold 
separately (e.g., closed e-liquids, such as cartridges or pods that are 
not intended to be refillable, and the e-cigarette with which the e-
liquids would be used).
    (Response 20) FDA recommends that an applicant group PMTAs for 
products in the same subcategory (see Sec.  1114.7(c)) that are 
produced by the same manufacturer into a single submission because they 
will likely share a significant amount of application content. An 
applicant grouping PMTAs together by subcategory would be required to 
use Form FDA 4057b to identify the products that are contained in the 
grouped submission. Additionally, FDA recommends an applicant group 
PMTAs for a new tobacco product and its components or parts into a 
single submission where an applicant seeks to sell the components or 
parts separately. As discussed in section VIII.B.3., FDA generally 
considers an open e-cigarette, also referred to as a refillable e-
cigarette, to be an e-cigarette that includes a reservoir that a user 
can refill with an e-liquid of their choosing. A closed e-cigarette is 
an e-cigarette that includes an e-liquid reservoir that is not 
refillable, such as a disposable cigalike, or that uses e-liquid 
contained in replaceable cartridges or pods that are not intended to be 
refillable. For example, if a manufacturer wanted to sell a closed e-
cigarette and the closed e-liquids (e.g., nonrefillable cartridges or 
pods) that could be used with the e-cigarette separately, it should 
group a PMTA for the e-cigarette and PMTAs for each of the e-liquids 
into a single submission. FDA does not recommend grouping open e-
liquids and open ENDS devices that will be sold separately in a single 
submission except for instances where the applicant is seeking a 
marketing granted order for the e-liquids that have been designed by 
the manufacturer to be used solely in a particular open ENDS device. 
FDA reminds applicants that we intend to consider information on each 
product as a separate, individual PMTA, so it is important to identify 
the content that pertains to each product. If an applicant does not 
clearly identify the content in the submission that makes up the PMTA 
for each product, FDA may refuse to accept or refuse to file the 
submission.
3. General Information
    Section 1114.7(c), including table 1, lists the information that 
must be included in the general information section of the PMTA. This 
information consists of general administrative information that 
includes the type of submission, the new tobacco product with unique 
identifiers, and contact information. Specifically, table 1 to Sec.  
1114.7(c)(3)(iii) provides for the information needed to help ensure 
that we are able to identify and evaluate each product more accurately 
and efficiently. This table includes, among other categories, 
requirements to submit general information related to ENDS product 
category and several subcategories of ENDS. FDA generally considers 
ENDS to be electronic nicotine delivery systems that deliver 
aerosolized e-liquid when inhaled. The term ``e-cigarette'' refers to 
an electronic device that delivers e-liquid in aerosol form into the 
mouth and lungs when inhaled; it is also sometimes referred to as an 
aerosolizing apparatus. An open e-cigarette, also referred to as a 
refillable e-cigarette, is an e-cigarette that includes a reservoir 
that a user can refill with an e-liquid of their choosing. A closed e-
cigarette is an e-cigarette that includes an e-liquid reservoir that is 
not refillable, such as a disposable cigalike, or that uses e-liquid 
contained in replaceable cartridges or pods that are not intended to be 
refillable. For additional information on ENDS, consult the ENDS PMTA 
Guidance.
    In this final rule, we have revised table 1 to Sec.  
1114.7(c)(3)(iii) to help ensure that FDA is able to identify and 
evaluate each product more accurately and efficiently. For example, the 
table includes a waterpipe head as a subcategory of waterpipe. A 
waterpipe head is a container that is typically made of materials like 
clay, marble, or glass and is used to contain coal and tobacco during a 
waterpipe smoking session.
    Additionally, the cigarette product category no longer lists 
noncombusted cigarettes as a subcategory. Instead, for purposes of PMTA 
review, a ``heated tobacco product'' category has been added to the 
identification tables. Under this revised taxonomy, some tobacco

[[Page 55318]]

products may fit under more than one category. This PMTA review 
category should be used for (among others) tobacco products that meet 
the definition of a cigarette but are not combusted (products that do 
not exceed 350[deg] C). Heated tobacco products (HTP) can be used with 
e-liquids, other types of tobacco filler, or consumable (e.g., wax, 
oils). If, however, a tobacco product can only be used with e-liquids, 
it should be captured under ``ENDS'' and not the HTP category. To 
ensure we have all the information we need to efficiently and 
effectively review your application, if the product that is the subject 
of your application is a heated tobacco product and is not an ENDS 
product, you should submit information under Sec.  1114.7(c)(3)(iii) 
under the heated tobacco product category and comply with the design 
parameter requirements for HTPs in table 22 to Sec.  
1114.7(i)(2)(ii).\15\ FDA believes these product categorizations will 
help ensure that applications include the most relevant information for 
their product, which in turn will facilitate FDA's review and ability 
to reach an authorization decision.
---------------------------------------------------------------------------

    \15\ Note that the purpose of the unique identification tables 
in Sec.  1114.7(c)(3)(iii) is to explain what information we need to 
identify and evaluate different types of products, and Sec.  
1114.7(i)(2)(ii) explains the design parameters needed for product 
characterization (see discussion below). The categorization of HTPs 
in Sec.  1114.7(c)(3)(iii) and (i)(2)(ii) does not extend to other 
legal requirements beyond those associated with unique 
identification and product characterization for premarket review.
---------------------------------------------------------------------------

    Other changes to table 1 to Sec.  1114.7(c)(3)(iii) include FDA's 
clarification under the ``cigar'' category to designate ``leaf-
wrapped'' cigars as unfiltered to more accurately describe the product 
category, as ``leaf-wrapped'' cigars typically do not include filters; 
under the ``waterpipe'' category, ``waterpipe'' diameter has been added 
to distinguish between waterpipes of different sizes (width/diameter 
and height) where all other uniquely identifying information is the 
same; and under the ``pipe tobacco filler'' category, ``tobacco cut 
style'' has been added to distinguish between different cut pipe 
tobacco filler, e.g., standard cut, such as shag cut, bugler cut, loose 
cut, etc.; or a pressed cut, such as flake, cube cut, roll cake, etc. 
or a mixture. Additionally, FDA has removed the requirement to provide 
tobacco cut size from the unique identification requirements for 
smokeless tobacco and cigar tobacco filler. A specific numerical value 
for this field is not necessary to uniquely identify the specific 
product to which the PMTA pertains, as it can be described further 
through identification of additional properties (e.g., fine cut, long 
cut). However, to fully characterize the tobacco product and evaluate 
its health effects, information to determine tobacco cut size is 
required under Sec.  1114.7(i)(2)(ii) for the product categories 
specified in that section.
    Additionally, across all product categories, the subcategory of 
``co-package'' has been removed from Sec.  1114.7(c). If an applicant 
submits a PMTA for a co-packaged tobacco product, the unique 
identification of this co-packaged product would require the specific 
items needed to identify each product within the co-package. For 
example, if the co-package is a pouch of roll-your-own (RYO) tobacco 
filler that contains rolling papers inside the pouch, the applicant 
would identify the tobacco product as a co-packaged product and provide 
the unique identification for both the RYO tobacco filler and the 
rolling papers.
    The PMTA must contain the following information using the FDA-
provided form(s) (i.e., Form FDA 4057 (Ref. 10) and Form FDA 4057b 
(Ref. 11)), as appropriate:
     Applicant name, address, and contact information;
     the name, address, and contact information for the 
authorized representative or U.S. agent (for a foreign applicant). As 
required by Sec.  1105.10(a)(5) for application acceptance, a foreign 
applicant must identify a U.S. agent (i.e., an individual located in 
the United States who is authorized to act on behalf of the applicant 
for the submission) to help FDA ensure adequate notice is provided to 
applicants for official Agency communications, assist FDA in 
communicating with the foreign applicant, and help the Agency to 
efficiently process applications and avoid delays; and
     information to uniquely identify the product. Providing 
unique identifying information is important to aid in FDA's review 
because it ensures FDA has information readily available to distinguish 
the tobacco product from other tobacco products, including additional 
new tobacco products in a bundled submission (i.e., more than one 
application contained in a single submission), and assists FDA in 
performing its acceptance and filing reviews. The required unique 
identifying information includes:
    [cir] The manufacturer;
    [cir] product name(s), including the brand and subbrand (or other 
commercial name(s) used in commercial distribution); and
    [cir] product category; product subcategory; and product 
properties, as provided by the table in Sec.  1114.7(c). The applicant 
must select and provide the appropriate category, subcategory, and 
product properties for the new tobacco product. As discussed 
previously, if an applicant submits a PMTA for a co-packaged tobacco 
product, the unique identification of this co-packaged product must 
include the specific items needed to identify each product within the 
co-package. For example, if the co-package is a pouch of RYO tobacco 
filler that contains rolling papers inside the pouch, the applicant 
must identify the tobacco product as a co-packaged product and provide 
the unique identification for both the RYO tobacco filler and the 
rolling papers. This product-specific information is required under 
sections 910(b)(1)(B) and (G) of the FD&C Act and this rule requires 
its inclusion in the general information section of the submission to 
help FDA quickly check whether the product is within CTP's purview and 
identify the specific product that is the subject of the submission. 
For more information regarding product properties and why specific 
properties are a required part of an application, see the discussion of 
Sec.  1114.7(i)(1) in section VIII.B.9. It is important to note that 
for the characterizing flavor product property, the applicant must 
state ``none'' if it does not consider the product to have a 
characterizing flavor. FDA encourages applicants that have questions 
regarding how to describe their product's characterizing flavor to 
contact FDA prior to submission.
    For each type of tobacco product, the applicant should also include 
any additional properties to fully identify the tobacco product, if 
applicable. For example, use of product descriptors such as ``extra-
long'' should be identified. While failure to include such additional 
properties to help uniquely identify the tobacco product would not 
serve as the basis for FDA refusing to accept an application under 
Sec.  1114.27(a)(1), it would likely slow down the substantive review 
process.
    FDA received a few comments regarding Sec.  1114.7(c)(3), as 
discussed below.
    (Comment 21) One comment stated that Sec.  1114.7(c)(3)(iii) should 
be amended to require disclosure of all flavoring agents regardless of 
whether they constitute characterizing flavors and all solvents rather 
than just propylene glycol and glycerin in all new tobacco products.
    (Response 21) We decline to make this proposed edit, because such 
information is already required as part of the full listing of all of 
the product's ingredients, additives, and constituents

[[Page 55319]]

in Sec.  1114.7(i)(1)(ii). Section 1114.7(c)(3)(iii), entitled 
``general information,'' is intended to allow FDA to quickly determine 
whether the product is under CTP's jurisdiction and readily identify 
the specific product that is the subject of the application. A complete 
listing of all flavoring agents and solvents in this section would not 
further the purpose of this section.
    (Comment 22) One comment requested that FDA amend Sec.  
1114.7(c)(3)(iii) to remove the ``dissolvable'' tobacco product 
subcategory and replace it with design parameters for an ``oral 
tobacco-derived nicotine (OTDN)'' subcategory. The comment stated that 
not only does ``dissolvable'' more appropriately describe a product 
trait, dissolvable products are less prevalent on the market today than 
OTDN products.
    (Response 22) FDA declines to remove the ``dissolvable'' tobacco 
product subcategory and replace it with ``oral tobacco-derived nicotine 
(OTDN).'' In 2009, the Family Smoking Prevention and Tobacco Control 
Act authorized FDA to regulate, among other things, smokeless tobacco 
products, the definition of which includes some dissolvables that 
contain finely ground tobacco. While design parameters of the 
dissolvable tobacco products may resemble those of OTDN, the OTDN 
subcategory could imply that such products only contain nicotine that 
is derived from tobacco, and not finely ground tobacco. This narrow 
definition would exclude dissolvable tobacco products that contain 
finely ground tobacco. As discussed in section VIII.B.3., applicants 
are required to identify the product category and subcategory in a PMTA 
to help FDA quickly check whether the product is within CTP's purview 
and identify the specific product that is the subject of the 
submission. Where an applicant believes its new tobacco product, such 
as OTDN, does not fit within a product category set forth in the rule, 
it should identify the product category as ``other.''
    (Comment 23) One comment stated that FDA should remove the 
requirement to identify the category and subcategory of the tobacco 
product in Sec.  1114.7(c)(3), because applications should compare 
their products to all other tobacco products and product categories are 
not contemplated under section 910(b) of the FD&C Act. The comment also 
stated that there is no justification to support the potential for 
users to switch between products within categories when real-world 
evidence shows that current users may switch to products from different 
categories.
    (Response 23) FDA declines to remove the requirement to identify a 
product's category and subcategory. Not only does this information 
allow FDA to identify the product, it provides important context for 
information contained in the application, including but not limited to 
health risks associated with product design and its constituents, 
product and packaging design risks and misuse hazards, principles of 
operation, and warning statement requirements. Specifically, 
identifying a product's category and subcategory ensures that FDA is 
able to distinguish between products that have the same brand and 
subbrand, but a different category or subcategory, which may be 
associated with different health risks, design risks or even have 
different warning statement requirements. For example, if an applicant 
submits a PMTA for a product that has the same brand and subbrand as 
another product but has been identified as smokeless tobacco, FDA will 
review the product labeling to ensure it complies with category 
specific applicable requirements such as the Comprehensive Smokeless 
Tobacco Health and Education Act. Additionally, understanding the 
category will allow FDA to determine whether the application meets the 
requirement in Sec.  1114.27(b)(1)(ii)(B) to compare the health risks 
of the new tobacco product to the health risks of products in the same 
product category and products in at least one different product 
category.
    Section 1114.7(c) also includes the following requirements:
     The type of PMTA. The applicant is required to state the 
type of PMTA the applicant is submitting (i.e., PMTA, supplemental 
PMTA, or resubmission);
     whether the applicant requests that FDA refer the PMTA to 
the Tobacco Products Scientific Advisory Committee (TPSAC). An 
applicant should briefly describe its justification for a request to 
refer the PMTA to TPSAC. FDA retains the discretion to refer an 
application to TPSAC but will consider an applicant's request as part 
of its determination;
     identifying information regarding any prior submissions 
relating to the new tobacco product, including STNs, where applicable. 
The types of prior submissions include premarket applications, such as 
PMTAs, SE Reports, and exemption requests, as well as other submissions 
to FDA including MRTPAs and submissions related to investigational 
tobacco products. The regulatory history of a tobacco product can 
provide useful context for FDA's review of a submission;
     dates and purpose of any prior meetings with FDA regarding 
the new tobacco product;
     if the tobacco product has previously been commercially 
marketed \16\ in the U.S., the dates during which the tobacco product 
was marketed;
---------------------------------------------------------------------------

    \16\ As described in Section IV.B.4., this includes products 
that were commercially marketed in test markets.
---------------------------------------------------------------------------

     address and the Facility Establishment Identifier (FEI) 
number(s), if available, of the establishment(s) involved in the 
manufacturer of the new tobacco product. This information will assist 
the Agency with environmental impact considerations and determinations 
under part 25 by helping FDA understand the location of manufacturing 
and scale of products that would be manufactured. Additionally, it 
helps FDA schedule and conduct facility inspections;
     a brief statement regarding how the PMTA satisfies the 
content requirements of section 910(b)(1) of the FD&C Act. This could 
consist of a table reproducing the section 910(b)(1) requirements and 
listing the sections or page numbers of the PMTA that satisfy the 
requirements. FDA is requiring this brief statement under authority of 
sections 701(a) and 910(b)(1)(G) of the FD&C Act, which will allow FDA 
to more quickly locate application content necessary to determine 
whether a PMTA should be accepted and filed for further review under 
Sec.  1114.27;
     a brief description of how permitting the marketing of the 
new tobacco product is expected to be appropriate for the APPH. This 
description should be no more than a sentence or two that highlights 
the key product characteristics and study results the applicant 
believes would make the marketing of the product APPH (e.g., the 
product delivers significantly lower levels of a specific HPHCs to 
users than the tobacco products they are currently consuming, which 
studies indicate may result in decreased morbidity and mortality); and
     a list identifying all enclosures, labels, and labeling 
being submitted with the application. This list will help FDA identify 
application content and ensure a PMTA contains all the information the 
applicant intended to submit.
    FDA received several comments regarding these requirements (Sec.  
1114.7(c)(4) through (12)), as discussed below:
    (Comment 24) One comment stated that FDA should refer all PMTAs to

[[Page 55320]]

TPSAC and should make all PMTAs available for public comment. The 
comment stated that if referring all applications to TPSAC is 
unfeasible, FDA should at least refer applications from major tobacco 
companies and representative applications from smaller companies.
    (Response 24) We decline to take the comment's suggestion. Under 
section 910(b)(2) of the FD&C Act, FDA has the discretion, on its own 
initiative or upon the request of an applicant, to refer a PMTA to 
TPSAC for reference and for submission of a report and recommendation 
respecting the application. Referring an application to TPSAC is a 
lengthy process that requires extensive time and resources, including 
the significant back-and-forth process with an applicant to redact 
trade secrets and confidential commercial information in an application 
before it can be made publicly available. Receiving and reviewing 
public comments also requires significant time and resources. It would 
not be feasible to redact all PMTAs, receive and consider public 
comments, and receive and consider TPSAC's report and recommendations 
prior to acting on the expected high volume of applications the comment 
is suggesting go to TPSAC within the 180-day review period required by 
section 910(c) of the FD&C Act.
    (Comment 25) Multiple comments stated that FDA should require 
applicants to specify whether the new tobacco product is a deemed 
tobacco product that has been on the market prior to the deadline for 
submitting a PMTA and, if so, require the submission of information 
regarding the marketing of the product prior to application submission, 
including items such as prior sales, labeling, advertising, and 
marketing strategy. One comment also requested that FDA require an 
applicant describe whether the prior marketing of its product has been 
APPH and deny applications where this has not been the case.
    (Response 25) FDA has amended the rule to require a PMTA to specify 
the prior dates, if any, during which the tobacco product was initially 
marketed. Additionally, the requirement in Sec.  1114.7(k) to submit 
full reports of investigations that are published or known to, or which 
should reasonably be known to, an applicant includes the time period 
during which an applicant previously marketed a deemed tobacco product. 
While information relating to the prior marketing of a tobacco product 
may inform FDA review of a PMTA, FDA declines to require an applicant 
to describe whether it believed its prior marketing of a product was 
APPH, or necessarily deny an application where prior marketing was not 
APPH. FDA will make its own determination as to whether permitting the 
marketing of the new tobacco product is APPH based on all of the 
contents of the application. In addition, FDA has authority to include 
postmarket requirements to help ensure that marketing of the product 
after authorization continues to be APPH.
4. Descriptive Information
    Section 1114.7(d) requires applicants to provide descriptive 
information that outlines the major aspects of the new tobacco product, 
which is required to be submitted under section 910(b)(1)(A), (D), and 
(G) of the FD&C Act. This information includes:
     A concise description of the new tobacco product (e.g., 
the product is a portioned smokeless tobacco product made using a blend 
of burley and bright tobacco);
     a statement identifying all tobacco product standards 
issued under section 907 of the FD&C Act that are applicable to the new 
tobacco product and a brief description of how the new tobacco product 
fully meets the identified tobacco product standard(s). If the new 
tobacco product deviates from such standard(s), if applicable, the rule 
requires the application to include adequate information to identify 
and justify those deviations;
     the product name(s) as designated on the product's label;
     a description of problems identified in prototypes that 
are the subject of studies contained in the application, or previous or 
similar versions of the new tobacco product that were marketed, if any. 
This includes information regarding any health risks such as 
overheating, fires, or explosions as well any information regarding 
manufacturing issues related to the product, such as packaging defects 
that could pose a health risk. If there are previous or similar 
versions that were marketed or that are the subject of studies in the 
application, the rule requires the applicant to include a bibliography 
of all reports regarding the previous or similar version of the 
product, whether adverse or supportive. FDA requires this information 
under section 910(b)(1)(A) and (G) of the FD&C Act to assess whether 
any known issues with a predecessor product that could affect the 
health risks of the new tobacco product have been addressed; and
     any restrictions on the sale, distribution, advertising, 
or promotion of the new tobacco product (as described in section 
910(c)(1)(B) of the FD&C Act) that the applicant proposes to be 
included as part of a marketing granted order, if issued. The applicant 
may choose to propose restrictions on the sales and distribution of the 
tobacco product to help support a showing that the marketing of the 
product is appropriate for the protection of the public health (e.g., a 
restriction that decreases the likelihood that those who do not 
currently use tobacco products will initiate tobacco product use with 
the new tobacco product). If an applicant does not wish to propose any 
additional restrictions, it must explicitly state that it proposes no 
restrictions. As described in Sec.  1114.31, FDA may consider these 
proposed restrictions during its review of the PMTA and, where 
appropriate, include applicant proposed restrictions in the marketing 
granted order for the product together with any additional restrictions 
FDA may require.
    FDA received many comments regarding the descriptive information 
requirements, as discussed below.
    (Comment 26) Multiple comments requested that FDA revise the 
requirement in Sec.  1114.7(d)(4). One comment stated that section 
910(b)(1)(B) of the FD&C Act limits review to the new tobacco product 
that is the subject of the application and does not permit review of 
other products. The comments also stated that the terms ``previous or 
similar version,'' ``prototype,'' and ``problem'' are so vague that 
they would leave applicants guessing at what information must be 
included. The comments concluded by stating that a product's effects on 
public health should be determined based on data about the product in 
its current form.
    (Response 26) FDA disagrees with the comments statement that FDA 
cannot require this information or consider it during product review. 
FDA is requiring the submission of information regarding prototypes and 
previous or similar versions of the tobacco product to assess whether 
an applicant has addressed any known issues with a predecessor product 
that could affect the health risks of the new tobacco product. The 
terms ``previous or similar version,'' or ``prototype,'' mean any 
previous generation, model, or version of a tobacco product that has 
undergone testing or was on the market in other countries, such as 
first-generation ENDS products that underwent aerosols or battery 
testing, and was subsequently modified as a result of testing, adverse 
experiences, or other design concerns that could impact the public 
health. Rather than using section 910(b)(1)(B) of the FD&C Act, as 
cited by the comments as authority for this requirement, FDA

[[Page 55321]]

bases its authority for this provision on section 910(b)(1)(G) of the 
FD&C Act, which requires applicants to submit other information 
relevant to the subject matter of the application as the Secretary may 
require.
    The information required in Sec.  1114.7(d)(4) will allow FDA to 
review information regarding risks present in closely related products 
and determine whether the applicant has addressed such risks in the 
development of the product that is the subject of the PMTA. FDA 
declines to adopt the comments' proposed approach that would require 
FDA to ignore information about known problems and related health risks 
that could be present in the tobacco product under review. We note that 
information about known problems and related health risks (e.g., 
product class effects such as mouth ulcers in moist tobacco) would be 
informative and could be used to bridge health effect information. 
Specifically, this information could help FDA to determine the validity 
and applicability of the studies that relied on a prototype.
5. Samples of New Tobacco Products and Components or Parts
    Section 910(b)(1)(E) of the FD&C Act requires an applicant to 
submit samples of a tobacco product and its components as FDA may 
reasonably require. After FDA accepts a submission, FDA will determine 
whether it will require product samples and, if so, issue instructions 
on how and where to submit the samples, and the number of samples that 
are required. Section 1114.7(e) requires an applicant to submit samples 
of the finished tobacco product and its components in accordance with 
instructions issued to the applicant after a PMTA is accepted for 
review, as well as to submit additional samples if required by FDA 
during application review. FDA generally expects that product samples 
will be a required part of a PMTA and that an applicant should be 
prepared to submit them in accordance with FDA instructions within 30 
days after submitting a PMTA. There may be situations in which sample 
submission may not be necessary, including, in some circumstances, 
PMTAs that are resubmitted for the same product after a marketing 
denial order (such as resubmissions as described in Sec.  1114.17) or 
PMTAs submitted for modifications to an authorized product where the 
modifications do not require review of new samples as part of the PMTA 
evaluation process. Presubmission meetings with FDA may help provide 
additional information about whether product samples will need to be 
included in a PMTA; however, in most situations, FDA will only be able 
to determine the need for product samples after a PMTA is accepted for 
review.
    FDA received many comments regarding product samples, as discussed 
below.
    (Comment 27) One comment agreed that requesting samples after a 
PMTA submission has been accepted makes sense; however, it stated that 
providing information regarding the quantity and type of samples that 
will be required for submission in advance is important to ensure that 
the samples FDA requires are actually available at the time of request.
    (Response 27) As described in section VIII.B.5, FDA generally 
expects that product samples will be a required part of a PMTA and that 
an applicant should be prepared to submit them in accordance with FDA 
instructions within 30 days after submitting a PMTA. Because the 
quantity and type of samples need for testing may vary based upon a 
number of factors including product category and specific product 
characteristics, FDA intends to determine the quantity and type that 
will be required after application acceptance. However, as noted in 
section VIII.B.5., presubmission meetings with FDA may help provide 
additional information about whether product samples will need to be 
included in a PMTA.
    (Comment 28) We received multiple comments regarding FDA's proposal 
to require an applicant to submit product samples only after an 
application is accepted for review. One comment stated that the start 
of FDA's 180-day review period should not be postponed until samples 
are received and should instead begin at the time the application is 
otherwise complete except for samples. Another comment requested that 
FDA amend the rule to allow applicants to submit product samples as 
part of its initial PMTA to avoid delays. The comment stated that the 
costs of the delaying the start of substantive review outweigh any 
minor savings gained by postponing inevitable product sample 
submission. The comment also noted that under FDA's proposed approach, 
FDA could indefinitely delay filing an application for review by not 
requesting product samples after application acceptance.
    (Response 28) We decline to make the requested revisions. FDA will 
have applicants submit samples (if required by FDA) after acceptance of 
an application rather than as part of an initial submission. This 
timing will help FDA to determine the need for samples, allow the 
samples to be tracked and identified as part of the correct 
application, and facilitate the submission of samples to testing 
facilities that are adequately prepared to accept them (e.g., one that 
has a refrigerated unit if the product needs to be stored at a certain 
temperature). Additionally, by having applicants submit samples after 
FDA accepts an application, applicants will be able to avoid the effort 
and expense of submitting samples if the application is not accepted 
for review or if samples are not required. It will also allow FDA to 
avoid similar concerns with respect to storage and the return of 
samples for applications where FDA refuses to accept a PMTA. As 
described in Sec.  1114.27, if required by FDA, product samples will be 
necessary for application filing and FDA intends to refuse to file a 
PMTA for a lack of product samples if the applicant has not submitted 
samples in accordance with FDA's instructions by the time FDA is 
prepared to make its filing determination.
    FDA intends to notify an applicant if it determines after PMTA 
acceptance that product samples are not required for PMTA filing; 
however, even in such a situation, FDA may request product samples 
during substantive review after an application is filed, as needed. FDA 
generally expects that, where required, samples will be requested 
within 30 days after application submission. Applicants may discuss the 
need for product samples during a presubmission meeting with FDA, which 
may speed up the sample submission process.
6. Labeling and Description of Marketing Plans
    Section 1114.7(f) of the rule requires that a PMTA contain 
specimens of labeling and describe the applicant's marketing plans for 
the new tobacco product.
    a. Labeling. Section 910(b)(1)(F) of the FD&C Act requires that a 
PMTA contain specimens of the proposed labeling to be used for the 
tobacco product. Section 1114.7(f)(1) elaborates on this requirement 
and requires the application to contain specimens of all proposed 
labeling for the new tobacco product, including labels, inserts, 
onserts, instructions, and other accompanying information.
    FDA received comments regarding the submission of labeling, as 
described below.
    (Comment 29) One comment stated that FDA's proposal to require 
``specimens of all proposed labeling'' in Sec.  1114.7(f)(1) is outside 
the scope of its authority under section 910 of the FD&C

[[Page 55322]]

Act and requested that FDA remove the word ``all'' from the 
requirement. The comment stated that the statute requires the 
submission of specimens proposed to be used, which connotes a typical 
example of a larger whole and, as such, is not compatible with the 
requirement to provide ``all'' proposed labeling.
    (Response 29) FDA disagrees with the assertion that Sec.  
1114.7(f)(1) is outside of its authority and declines to interpret the 
term ``specimens'' as used in section 910(b)(1)(F) of the FD&C Act to 
mean a representative sample. FDA's interpretation of section 
910(b)(1)(F) in Sec.  1114.7(f)(1) is consistent with how it interprets 
similar statutory requirements to submit specimens of labeling for both 
new drug applications and premarket approval applications for medical 
devices.\17\ Not only did FDA's interpretation of these requirements 
for drugs and devices exist when Congress enacted the same requirement 
in the Tobacco Control Act, section 905(i)(1)(B) of the FD&C Act 
demonstrates Congress understands how to require a representative 
sample when it intends to do so. It did not do so here. Furthermore, 
requiring specimens of all proposed labeling is important to FDA's 
review of an application, because FDA must deny a PMTA under section 
910(c)(2)(C) of the FD&C Act where it finds, based on a fair evaluation 
of all material facts, the proposed labeling is false or misleading in 
any particular. This requirement to deny a PMTA based upon any 
particular of the proposed labeling is at odds with the comment's 
suggestion that Congress intended FDA to review only a general 
representation of what an applicant proposes to use.
---------------------------------------------------------------------------

    \17\ See the interpretation of section 505(b)(1)(F) of the FD&C 
Act (21 U.S.C. 355(b)(1)) in 21 CFR 314.50(e)(2)(ii) (50 FR 7493, 
February 22, 1985) for new drug application, and the interpretation 
of 515(c)(1)(F) (21 U.S.C. 360e(c)(1)(F)) in 21 CFR 814.20(b)(10) 
for premarket approval applications for medical devices.
---------------------------------------------------------------------------

    The labeling specimens are required to include all panels and 
reflect the actual size and color proposed to be used for such tobacco 
product. The labels must include any warning statements required by 
statute or regulation, such as the Federal Cigarette Labeling and 
Advertising Act, the Comprehensive Smokeless Tobacco Health and 
Education Act, or the minimum required warning statements contained in 
21 CFR part 1143. For products that are required to provide rotational 
warning statements, the applicant should submit labeling with each of 
the required warnings in the rotation.\18\
---------------------------------------------------------------------------

    \18\ For more information on rotational warning statement 
requirements, see https://www.fda.gov/tobacco-products/products-guidance-regulations/labeling-and-warning-statements-tobacco-products.
---------------------------------------------------------------------------

    As described in Sec.  1114.33, product labeling is an important 
part of FDA's review of an application, because FDA must deny a PMTA 
under section 910(c)(2)(C) of the FD&C Act where it finds, based on a 
fair evaluation of all material facts, the proposed labeling is false 
or misleading in any particular. Additionally, product labeling can be 
an important part of FDA's determination under section 910(c)(2)(A) of 
the FD&C Act of whether there is a showing that permitting the 
marketing of the product would be APPH because it can be used to help 
show perception of the risks of the product and the ability of 
individuals to understand the labeling, including any instructions for 
use, as described in Sec.  1114.7(k)(1)(iv).
    b. Description of Marketing Plans.--i. General. In the proposed 
rule, the marketing plans provision in proposed Sec.  1114.7(f)(2) 
would have required an applicant to submit detailed information about 
all plans it had developed to market its new tobacco product. In 
response to comments and on FDA's own initiative, we have revised the 
requirement to submit information concerning the applicant's plans to 
market the new tobacco product. Rather than requiring all of the 
detailed information required in proposed Sec.  1114.7(f)(2), FDA has 
revised this section to require only a high-level description of 
several key aspects of these plans that directly inform FDA's APPH 
determination. FDA notes that, pursuant to Section 910(b)(1)(G) of the 
FD&C Act, the Agency may require additional information related to 
marketing plans on a case-by-case basis, if the agency determines 
during review that additional information is needed to help determine 
if a product is appropriate for the protection of the public health. 
FDA's discussion of the comments is included below.
    (Comment 30) One comment stated that FDA should clarify the scope 
of marketing information it expects to see in a PMTA and explain how it 
plans to engage in a science-based review of labeling and marketing 
plans, noting that the rule provides little detail as to what specific 
marketing information the Agency expects to see. The comment stated 
that it is unclear whether FDA is proposing to require submission of 
information about top-line product messaging or specific pieces of the 
advertising and marketing strategies for their use. The comment noted 
that it is also unclear to what extent FDA expects to see results of 
consumer research. In addition, the comment stated that it remains 
unknown how the Agency plans to review labeling and marketing plans and 
what specific considerations or methodologies will guide assessment of 
consumer risk perception, comprehension, and use intentions.
    (Response 30) FDA has revised Sec.  1114.7(f)(2) to require only 
high-level marketing plan information that it generally expects 
applicants will have developed prior to seeking marketing authorization 
for their products. The description of marketing plans now required by 
Sec.  1114.7(f)(2)--including intended audience, how the applicant 
would target the intended audience and what other groups would 
foreseeably be exposed, and how exposure would be limited for 
individuals below the minimum age of sale--seeks information necessary 
for FDA to properly evaluate the extent of youth exposure to marketing 
materials for the product and youth access to the product. Discussion 
of these items will not require applicants to conduct consumer 
research; however, where an applicant had undertaken such research, the 
results of such research will be required by Sec.  1114.7(f)(2) or 
(k)(1)(iv). As discussed in section VIII.B.6.b., this information will 
allow FDA to consider whether an applicant has addressed potential 
concerns about the marketing of its product, such as tobacco product 
use initiation by individuals under the minimum age of sale, and will 
help FDA to assess whether the plans to market the product are 
consistent with the applicant's discussion of the likelihood of changes 
in tobacco product use behavior in the application. These 
considerations will help FDA to determine whether there is a showing 
that permitting the tobacco product to be marketed is appropriate for 
the protection of public health.
    (Comment 31) One comment stated that the marketing plan 
requirements seem to be based on the premise that companies will have 
developed marketing plans by the time of application submission, which 
fails to account for the small vape shops that currently serve as both 
retailers and manufacturers who are unlikely to have undertaken 
consumer research. The comment requested that FDA edit the marketing 
plan requirements to apply only ``as applicable'' to companies that 
have conducted such research.
    (Response 31) The requirement to provide descriptions of marketing 
plans does not require applicants to undertake market or consumer 
research. Rather,

[[Page 55323]]

Sec.  1114.7(f)(2) requires PMTAs to contain a discussion of several 
key high-level aspects of the applicant's plans to market the product. 
The discussion of these items will not require consumer research; 
however, be aware that Sec.  1114.7(k)(1)(iv) requires applicants to 
submit reports of all information published or known to, or which 
should reasonably be known to, the applicant concerning investigations 
regarding the impact of the product and its label, labeling, and 
advertising, to the extent that advertising has been studied, on 
individuals' perception of the product and use intentions. This will 
include any consumer research that the applicant has undertaken or used 
to develop the aspects of its marketing plan identified in Sec.  
1114.7(f)(2).
    (Comment 32) One comment stated that FDA should amend the marketing 
plan requirements in Sec.  1114.7(f)(2) to include specific language 
about dual use because the reality is that most adult users of tobacco 
products become dual users.
    (Response 32) We have edited Sec.  1114.7(f)(2) to include polyuse 
as an example tobacco use behavior that descriptions of marketing plans 
may address in describing target audiences. FDA requires descriptions 
of marketing plans to inform our determination of whether the new 
product is appropriate for the protection of public health. As part of 
FDA's determination of the risks and benefits to the health of the 
population as a whole (which includes youth, young adults, and other 
vulnerable populations), FDA will consider the potential for long-term 
dual use among current users. FDA reviews the descriptions of marketing 
plans in conjunction with the other submitted information, which can 
include tobacco product perception and use intention studies and actual 
use studies to assess the likelihood that current users will switch 
completely to the new product or become a dual or polyuser of tobacco 
products. To the extent that the description of marketing plans 
contains information about the target audience by psychographic 
characteristics including tobacco use patterns, FDA will consider 
whether dual use is likely given the description of the marketing plans 
and the other submitted information.
    (Comment 33) One commenter stated that the marketing plan 
requirements are outside of what the FD&C Act allows FDA to review as 
part of a PMTA. The commenter stated that the structure of the FD&C Act 
shows that Congress did not intend for FDA to review marketing plan 
information as part of a PMTA because where Congress found such 
information to be relevant to FDA's analysis, it expressly added such a 
requirement to the statute (e.g., section 905(i)(1) of the FD&C Act). 
The commenter stated that in contrast, in section 910 of the FD&C Act 
Congress required that PMTAs must contain only ``specimens of the 
proposed labeling to be used for [the] tobacco product.'' The commenter 
concluded that the fact that Congress omitted a broader requirement for 
advertisements in section 910 of the FD&C Act but included the 
requirement for only ``specimens'' of labeling shows that Congress did 
not consider broader information relevant to FDA's evaluation of a 
PMTA. The commenter also states that FDA's claim of authority under 
section 910(b)(1)(G) is ineffective because it does not grant FDA the 
limitless authority to require content; rather, FDA only has the 
authority to require information under 910(b)(1)(G) of the FD&C Act 
that is reasonable and reasonably explained, which the commenter 
maintains that FDA has failed to do here.
    (Response 33) As discussed in Response 30, FDA has revised Sec.  
1114.7(f)(2) to require only high-level marketing plan information that 
it generally expects applicants will have developed prior to seeking 
marketing authorization for their products. But even so, we disagree 
with the commenter's position that FDA lacks statutory authority to 
require marketing plans as part of a PMTA. In describing the required 
contents of a PMTA in section 910(b)(1)(G), Congress explicitly 
authorized FDA to require ``such other information relevant to the 
subject matter of the application.'' This provision demonstrates that 
Congress intended for FDA to apply its expertise with respect to review 
of scientific applications and the overall administration of the 
Tobacco Control Act to determine what additional information would be 
``relevant'' to whether the application meets the requirements to 
receive marketing authorization.
    We have determined that the description of marketing plans required 
by Sec.  1114.7(f)(2) is relevant to the subject matter of a PMTA. To 
issue a marketing granted order for a new tobacco product, FDA must 
determine that permitting such tobacco product to be marketed would be 
APPH, which requires FDA to consider the likelihood that those who do 
not use tobacco products, including youth, will start using them. 
Determining the extent to which youth will be exposed to marketing 
materials for the product is critical to that consideration. As 
explained by Congress in enacting the Tobacco Control Act, tobacco 
advertising, marketing, and promotion substantially contribute to youth 
trial and uptake of tobacco use. See, e.g., Tobacco Control Act section 
2(5) (tobacco advertising and marketing contribute significantly to the 
use of tobacco products by adolescents.); id. section 2(15) 
(advertising, marketing and promotion of tobacco products have resulted 
in increased use of such products by youth.); id. section 2(20) 
(children are exposed to substantial and unavoidable tobacco 
advertising that increases the number of young people who begin to use 
tobacco); id. section 2(22) (tobacco advertising expands the size of 
the tobacco market by increasing consumption of tobacco products 
including tobacco use by young people). Congress enacted the Tobacco 
Control Act against the backdrop of years of litigation exposing 
previous tobacco product marketing campaigns in which companies 
successfully targeted and recruited new youth smokers. See, e.g., 
United States v. Philip Morris USA, Inc., 449 F. Supp. 2d 1, 616 
(D.D.C. 2006) (``As the following evidence demonstrates, Defendants 
have utilized the vast amount of research and tracking data they 
accumulated on youth smoking initiation, tastes and preferences by 
employing themes which resonate with youth in their marketing 
campaigns. Defendants have focused their attention on young people 
under the age of twenty-one in order to recruit replacement smokers and 
have emphasized the popularity, physical attractiveness, and `coolness' 
of their youth brands. Above all, Defendants have burnished the image 
of their youth brands to convey rugged independence, rebelliousness, 
love of life, adventurousness, confidence, self-assurance, and 
belonging to the `in' crowd.'' (internal citation omitted)), aff'd in 
part, rev'd in part on other grounds, 566 F.3d 1095 (D.C. Cir. 2009); 
see also 449 F. Supp. 2d at 616-39.
    A well-established body of scientific evidence confirms the 
continuing impact of tobacco product marketing on initiation and use by 
individuals under the minimum age of sale. See, e.g., Dep't of Health & 
Human Servs., E-Cigarette Use Among Youth and Young Adults: A Report of 
the Surgeon General 170 (2016) (``An analysis of the 2011 National 
Youth Tobacco Survey found that adolescents who reported frequent 
exposure to protobacco advertising at the point of sale and on the 
internet (e.g., seeing ads most of the time or always) had 
significantly higher odds of ever using e-cigarettes, and there was a 
dose-response association between the number of marketing channels to 
which

[[Page 55324]]

they were exposed and ever use[.]''); Dep't of Health & Human Servs., 
Preventing Tobacco Use Among Youth and Young Adults: A Report of the 
Surgeon General 598 (2012) (``[T]here is strong empirical evidence, 
along with the tobacco industry's own internal documents and trial 
testimony, as well as widely accepted principles of advertising and 
marketing that support the conclusion that tobacco manufacturers' 
advertising, marketing, and promotions recruit new users as youth and 
continue to reinforce use among young adults[.]''). Companies marketing 
newer forms of tobacco products have employed some of the same 
techniques, as well as newer innovations, to attract the youth market. 
For example, ENDS manufacturers have used social media, including 
influencers, to help create an image for their products as being cool 
and having sex appeal, sponsored music festivals, and created products 
with youth-appealing cartoon images (see, e.g., Refs. 12 through 15).
    The descriptions of marketing plans required by Sec.  
1114.7(f)(2)--including intended audience, how the applicant would 
target the intended audience and what other groups would foreseeably be 
exposed, and how exposure would be limited for individuals below the 
minimum age of sale (e.g., avoiding online social media without access 
restrictions)--seeks information necessary for FDA to properly evaluate 
the extent of youth exposure to marketing materials for the product and 
youth access to the product. Accordingly, this information is directly 
relevant to the subject matter of a PMTA, including FDA's consideration 
of the likelihood that youth will use the tobacco product and its 
determination that permitting the product to be marketed would be APPH.
    Because Congress clearly and unambiguously authorized FDA to 
require additional relevant information, that should be ``the end of 
[the] analysis.'' Zuni Pub. Sch. Dist. No. 89 v. Dep't of Educ., 550 
U.S. 81, 93 (2007) (citing Chevron, U.S.A., Inc. v. Natural Res. Def. 
Council, Inc., 467 U.S. 837 (1984)). But even if Congress has not 
``directly'' addressed ``the precise question at issue,'' FDA's 
interpretation is a ``permissible construction of the statute,'' 
Chevron, 467 U.S. 837 at 843, on a matter where the Agency's expertise 
plays a significant role in resolving important questions related to 
the administration of the statute. Barnhart v. Walton, 535 U.S. 212, 
222 (2002).
    In determining to require the submission of descriptions of 
marketing plans as part of a PMTA, FDA considered the information it 
needed to be able to evaluate whether the statutory requirements for 
PMTA authorization are met, as well as the context and purpose of the 
PMTA requirement. As discussed above, a well-established body of 
historical and scientific evidence and Congress's own findings in 
enacting the Tobacco Control Act support FDA's reasonable conclusion 
that potential exposure to tobacco product advertising, marketing, and 
promotion is relevant to, and indeed a critical factor in, FDA's 
statutorily required determination of the likelihood that nonusers, 
including youth, will use a new tobacco product. Moreover, based on 
this evidence, as well as the expertise it has developed regarding 
tobacco product marketing over more than a decade of administering the 
Tobacco Control Act, FDA has rationally concluded that the required 
descriptions of marketing plans will directly inform its assessment of 
who may be exposed to the applicant's labeling, advertising, marketing, 
and promotion and, as a result, its consideration of the potential 
impact on youth initiation and use. FDA's assessment of who may be 
exposed to tobacco product marketing materials and activities will 
include individuals below the minimum age of sale, recently raised from 
18 to 21 years. For example, information regarding how the applicant 
will target the intended audience, such as the marketing channels and 
tactics an applicant expects to use, will permit FDA to determine the 
extent to which youth would be exposed to and influenced by marketing 
for the product. (See, e.g., Refs. 13, 16, and 17) As another example, 
a description of the ways in which an applicant would limit exposure to 
tobacco product marketing materials and activities for individuals 
below the minimum age of sale will inform FDA's assessment of the 
potential for youth exposure to these materials and activities.
    Submission of descriptions of marketing plans also supports the 
Tobacco Control Act's mandate that FDA protect youth from the dangers 
of tobacco use. See, e.g., Tobacco Control Act section 3(2), (7) 
(purposes of the Tobacco Control Act include to ensure that FDA has 
authority to address issues of particular concern to public health 
officials, especially the use of tobacco by young people, and to ensure 
that tobacco products are not sold or accessible to underage 
purchasers). In enacting the Tobacco Control Act and giving FDA this 
mandate, Congress recognized the substantial impact of exposure to 
tobacco product advertising, marketing, and promotion on youth tobacco 
use. See, e.g., Tobacco Control Act section 2(15) (advertising, 
marketing and promotion of tobacco products have resulted in increased 
use of such products by youth.). Based on this context and the ample 
scientific evidence supporting the powerful impact of marketing on 
youth tobacco use, FDA reasonably concluded that determining the extent 
to which youth may be exposed to marketing materials for a new tobacco 
product is critical to its evaluation of the potential for youth to use 
the new tobacco product and to its ability to fulfill its mandate to 
protect youth from the dangers of tobacco use. To that end, the 
requirement for descriptions of marketing plans seeks information that 
directly informs FDA's assessment of the extent to which youth may be 
exposed to marketing materials for the new tobacco product, as well as 
information to help FDA determine whether any concerns about youth use 
of the product and the corresponding increases in health risks would be 
mitigated, such as information regarding the extent to which an 
applicant would restrict access to the tobacco product for individuals 
below the minimum age of sale.
    Contrary to the comment, Congress's inclusion of an advertising 
requirement in non-PMTA-related sections of the FD&C Act, such as 
section 905(i)(1), and omission of the requirement in section 
910(b)(1)(F) of the FD&C Act, does not demonstrate Congress's intent to 
exclude description of marketing plans from PMTAs. Congress's explicit 
authorization in 910(b)(1)(G) of the FD&C Act that FDA may require 
``such other information relevant to the subject matter of the 
application'' defeats the commenter's inference by omission argument. 
See Adirondack Med. Ctr. v. Sebelius, 740 F.3d 692, 697 (D.C. Cir. 
2014) (the ``expressio unius canon'' is a ``poor indicator of Congress' 
intent'' where there is a ``broad grant of authority'' to the Agency; 
instead, `` `Congress is presumed to have left to reasonable agency 
discretion questions that it has not directly resolved' '' (quoting 
Cheney R.R. Co. v. I.C.C., 902 F.2d 66, 68-69 (D.C. Cir. 1990)). 
Indeed, Congress did not ``omit'' an advertising requirement from 
section 910(b)(1) but rather left its inclusion to FDA's discretion and 
judgment. As explained above, FDA has reasonably exercised its 
discretion in construing section 910(b)(1)(G) of the FD&C Act to 
require descriptions of marketing plans based on the Tobacco Control 
Act's context and purpose, ample scientific evidence,

[[Page 55325]]

and the Agency's own expertise developed over a decade of administering 
the statute.
    (Comment 34) The commenter also stated that the marketing plans 
requirement potentially limits speech, raising First Amendment 
concerns. The commenter stated that the requirement places more than an 
incidental burden on protected expression, and the government cannot 
show it directly advances a substantial government interest that is 
drawn narrowly to achieve that interest. In terms of the alleged 
burden, the commenter stated that the requirement would distract and 
deter manufacturers from the focused development and implementation of 
robust marketing plans--ultimately burdening the right of consumers to 
receive, and manufacturers to provide, information about products 
determined by FDA to be appropriate for the protection of the public 
health. Additionally, the commenter asserted that the requirement would 
significantly chill protected speech due to the threat that FDA might 
disclose information about applicants' marketing plans to TPSAC or the 
public and thereby compromise an applicant's competitive strategy.
    The commenter also asserted that the proposed requirement for 
manufacturers to report ``total dollar amount(s) of media buys and 
marketing and promotional activities'' would have been particularly 
burdensome and lacked justification. It stated that there was no 
evidence in the record that reporting such information for truthful 
advertising and marketing of a product with a PMTA order would directly 
advance the government's interest. The commenter also asserted that 
FDA's proposed request for marketing plans would not yield meaningful 
information given the amount of time it could take for FDA to review an 
application, the evolving tobacco product landscape, and the likelihood 
that the applicant's marketing plans would change.
    In arguing that the government has not justified these burdens, the 
commenter asserts that the marketing plans requirement is a content-
based burden on speech in that it applies only to applicants who wish 
to engage in the marketing of tobacco products, and therefore the 
government's justification is subject to strict scrutiny under Reed v. 
Town of Gilbert, 135 S. Ct. 2218, 2226 (2015), or at least heightened 
scrutiny under Sorrell v. IMS Health Inc., 564 U.S. 552 (2011). The 
commenter states that FDA's required marketing disclosures are not 
narrowly tailored nor do they directly advance a compelling government 
interest, so they cannot meet the higher standard for content-based 
restrictions.
    (Response 34) As discussed in Response 30, FDA has revised Sec.  
1114.7(f)(2) to require only high-level marketing plan information that 
it generally expects applicants will have developed prior to seeking 
marketing authorization for their products. That noted, we do not agree 
that the requirement for descriptions of marketing plans raises First 
Amendment concerns for several reasons. First, we disagree that the 
requirement to submit descriptions of marketing plans burdens speech. 
Federal Agencies routinely require regulated industry to disclose 
information to the government. The FD&C Act contains several premarket 
authorization requirements, including for drugs and devices, which have 
existed for decades, and whose constitutionality is not seriously 
questioned. Indeed, in the proliferation of lawsuits challenging 
various aspects of the Tobacco Control Act, there have been few direct 
challenges to the PMTA requirements, and any related challenges have 
been resolved in the government's favor. See Nicopure Labs., LLC v. 
FDA, 266 F. Supp. 3d 360, 391-95, 409 (D.D.C. 2017) (upholding FDA's 
decision to apply PMTA requirements to deemed tobacco products as 
permissible under the Administrative Procedure Act, and upholding the 
statutory PMTA requirement under the Due Process clause of the 
Constitution), aff'd on other grounds, 944 F.3d 267 (D.C. Cir. 2019) 
(PMTA rulings were not appealed); see also, e.g., Nicopure Labs., 944 
F.3d at 284-90 (D.C. Cir. 2019) (rejecting First Amendment challenge to 
the Tobacco Control Act requirement that manufacturers obtain premarket 
review of MRTPs).
    To the extent that the commenter contends that the requirement to 
provide a description of its marketing plans to FDA would impinge on an 
applicant's ability to market its tobacco products, FDA is not aware of 
any evidence to support that contention (and the commenter cites none). 
The comment's assertion that the requirement would distract and deter 
manufacturers from the focused development and implementation of robust 
marketing plans strains credulity given tobacco manufacturers' 
incentives to market their products and the significant resources 
tobacco product manufacturers commit to marketing their products each 
year. See Edenfield v. Fane, 507 U.S. 761, 766 (1993) (``A seller has a 
strong financial incentive to educate the market and stimulate demand 
for his product or service.''). The Federal Trade Commission reported 
that advertising and promotional expenditures by major cigarette 
manufacturers totaled $8.401 billion in 2018 (Ref. 18).
    FDA has considered the comment's position regarding the proposed 
Sec.  1114.7(f)(2) requirement that applicants provide ``total dollar 
amount(s) of media buys and marketing and promotional activities.'' FDA 
has revised Sec.  1114.7(f)(2) to no longer require total dollar 
amounts of media buys and marketing and promotional activities. In 
addition, FDA has revised this section to require only high-level 
information that it expects applicants will generally have developed 
prior to seeking marketing authorization for their products. For 
example, revised Sec.  1114.7(f)(2)(i) and (ii) require an applicant to 
provide a discussion of the intended audience for the marketing 
materials and activities for the tobacco product and how the applicant 
would target those marketing materials and activities to the intended 
audience. Based on its experience, FDA expects that an applicant will 
generally have considered its intended audience and how it will target 
its marketing materials and activities to that audience by the time it 
submits its PMTA. Discussion of these items will not require applicants 
to conduct consumer research; however, where an applicant has 
undertaken such research, such as conducting tobacco product perception 
and intention studies, it will be required to be included in the PMTA 
as set forth in Sec.  1114.7(k)(1)(iii), where applicable. Applicants 
will be required to provide the descriptions of marketing plans 
identified in this section based on the plans they have developed as of 
the time of submitting their PMTA, and where an applicant has not 
developed plans relating to one or more items in Sec.  1114.7(f)(2), 
they would be required to state that in their application.
    The comment's concern that commercial speech would be chilled due 
to the perceived risk that FDA would disclose an applicant's 
description of its marketing plans to TPSAC or the public and thereby 
compromise confidential commercial information (CCI) in those marketing 
plans is unwarranted. FDA generally may not make information in an 
application publicly available to the extent that the information 
constitutes trade secrets or CCI. See 5 U.S.C. 552(b)(4); 18 U.S.C. 
1905; 21 U.S.C. 387f(c); 21 CFR 20.61(c); id. Sec.  1114.47(a) (FDA 
will determine the public availability of any part of a PMTA under this 
section and part 20 (21 CFR part 20)). The Tobacco Control Act does not 
require FDA to refer PMTAs (or any

[[Page 55326]]

information contained therein) to TPSAC, instead committing that 
decision to the Secretary's discretion. See 21 U.S.C. 387j(b)(2) 
(providing that the Secretary ``may'' refer PMTAs to TPSAC ``on the 
Secretary's own initiative; or . . . upon the request of an 
applicant''). If the Secretary finds it appropriate to consult the 
TPSAC on an issue that requires consideration of CCI contained in the 
description of marketing plans, FDA may share that information only 
with TPSAC members who are subject to the same restrictions with 
respect to disclosure of CCI as any other FDA employee. See 21 CFR 
20.84; id. 21 CFR 14.86(a)(2). Additionally, if the Secretary refers a 
PMTA to TPSAC, Sec.  1114.47(b)(4) of this rule provides that CCI 
contained in the application generally will not be available for public 
disclosure. FDA may close a portion of a TPSAC meeting to allow 
discussion of an applicant's CCI to take place without disclosing the 
CCI to the public. See 21 CFR 14.27(b)(3) (allowing portions of an 
advisory committee meeting to be closed if they concern the review of 
trade secrets and CCI).
    FDA also disagrees with the commenter's assertion that FDA's 
requirement for marketing plans as originally proposed would not yield 
meaningful information given the amount of time it might take for FDA 
to review an application, the evolving tobacco product landscape, and 
the likelihood that the applicant's marketing plans would change. 
Because we have revised Sec.  1114.7(f)(2) to require a discussion of 
high-level items, rather than the submission of details that are more 
subject to change (e.g., media buys, dollar amount, specific tactics), 
we generally do not expect the information contained in the applicant's 
description of marketing plans to change significantly after the 
submission of the application. However, under Sec.  1114.9, FDA may 
request, or an applicant may submit on its own initiative, an amendment 
to its PMTA containing information that is necessary for FDA to 
complete its review of the application, including information regarding 
any alterations or updates to the required description of marketing 
plans. As described in section VIII.C., so long as such an amendment 
does not require significant review time, it will not be considered a 
major amendment for which the review period will be extended by up to 
180 days and even where such an amendment is major amendment, FDA 
anticipates it would generally take less than 180 days to complete 
review thereof.
    Second, even if the requirements of Sec.  1114.7(f)(2) restricted 
speech, they would readily pass muster under the intermediate scrutiny 
test for commercial speech articulated in Central Hudson Gas & Elec. 
Corp. v. Pub. Serv. Comm'n, 447 U.S. 557 (1980). Under that test, 
Agencies may regulate speech where the regulation advances a 
substantial government interest and the regulation is no more extensive 
than necessary to serve that interest.
    It is well established that FDA has a substantial interest in 
protecting youth from tobacco products. See Lorillard Tobacco Co. v. 
Reilly, 533 U.S. 525, 564-66 (2001); see also Discount Tobacco City & 
Lottery, Inc. v. United States, 674 F.3d 509, 519-20, 541 (6th Cir. 
2012). Youth are a significant population of concern for reasons that 
have been extensively documented in scientific research and in the 
Tobacco Control Act. For example, youth are especially susceptible to 
addiction due to their ongoing and incomplete brain development. See 
2012 Surgeon General's Report. In addition, most tobacco use is 
established in adolescence and age of initiation plays a significant 
role in the progression from tobacco experimentation to regular use. 
See id.; see also, e.g., Tobacco Control Act section 2(1) (``The use of 
tobacco products by the Nation's children is a pediatric disease of 
considerable proportions that results in new generations of tobacco-
dependent children and adults.''); id. section 2(4) (``Virtually all 
new users of tobacco products are under the minimum legal age to 
purchase such products.''). FDA has a statutory mandate to protect 
youth from these dangers of tobacco product use. See, e.g., Tobacco 
Control Act section 3(2), (7) (purposes of the Tobacco Control Act 
include to ensure that FDA has authority to address issues of 
particular concern to public health officials, especially the use of 
tobacco by young people, and to ensure that (tobacco products) are not 
sold or accessible to underage purchasers).
    The requirement for applications to contain descriptions of 
marketing plans clearly and directly advances FDA's substantial 
interest in protecting youth from the dangers of tobacco product use. 
As explained in section VIII.B.6.b, it is well established that 
exposure to tobacco product labeling, advertising, marketing, and 
promotion has a direct and powerful impact on youth trial and uptake of 
tobacco product use. See, e.g., Tobacco Control Act section 2(5) 
(``Tobacco advertising and marketing contribute significantly to the 
use of nicotine-containing tobacco products by adolescents.''); 2016 
Surgeon General's Report at 170 (``An analysis of the 2011 National 
Youth Tobacco Survey found that adolescents who reported frequent 
exposure to protobacco advertising at the point of sale and on the 
internet (e.g., seeing ads most of the time or always) had 
significantly higher odds of ever using e-cigarettes, and there was a 
dose-response association between the number of marketing channels to 
which they were exposed and ever use[.]''); 2012 Surgeon General's 
Report at 598 (``[T]here is strong empirical evidence, along with the 
tobacco industry's own internal documents and trial testimony, as well 
as widely accepted principles of advertising and marketing that support 
the conclusion that tobacco manufacturers' advertising, marketing, and 
promotions recruit new users as youth and continue to reinforce use 
among young adults[.]'').
    Accordingly, determining the extent to which youth may be exposed 
to marketing materials for a new tobacco product is critical to FDA's 
evaluation of the potential for youth use of the new tobacco product. 
The requirement for descriptions of marketing plans seeks information 
that directly informs the extent to which youth may be exposed to these 
marketing materials, including information regarding the intended 
audience for the materials, how the applicant plans to target the 
materials to that audience and what other groups would foreseeably be 
exposed to those materials, and how the applicant plans to limit youth 
exposure to the materials. In addition, the requirement seeks 
information to help FDA determine whether any concerns about youth use 
of the product and the corresponding increases in health risks may be 
mitigated, such as information regarding how the applicant plans to 
limit youth access to the product. Moreover, the requirement for 
descriptions of marketing plans is no more extensive than necessary to 
permit FDA to make these determinations, as it requires minimal, high-
level information that FDA expects an applicant to have at the time of 
submitting its application.
    In addition, the requirement for descriptions of marketing plans 
clearly and directly advances FDA's substantial government interest in 
ensuring that permitting the marketing of new tobacco products would be 
APPH. Under section 910(c)(2)(4) of the FD&C Act, a key consideration 
of the APPH determination is whether permitting the marketing of the 
product would increase or decrease the likelihood that those who do not 
use tobacco products, including youth, will start using them. Among 
nonusers, youth are a significant population of concern for the reasons 
already explained above. Determining the extent to which youth would be

[[Page 55327]]

exposed to marketing materials for the product is therefore critical to 
FDA's evaluation of the likelihood that youth will initiate tobacco use 
with the new tobacco product. Accordingly, by providing FDA with 
certain high-level information necessary to help determine potential 
youth exposure to marketing materials for a new tobacco product, the 
requirement for descriptions of marketing plans directly advances and 
is reasonably tailored to FDA's substantial interest in ensuring that 
permitting the marketing of the new tobacco product is APPH.
    Finally, we disagree with the commenter's assertion that Sec.  
1114.7(f)(2)'s disclosure requirements are subject to strict scrutiny 
under Reed v. Town of Gilbert, 135 S. Ct. 2218, 2226 (2015), or at 
least heightened scrutiny under Sorrell v. IMS Health Inc., 564 U.S. 
552 (2011). In Reed v. Town of Gilbert, the Court applied strict 
scrutiny to content-based restrictions on noncommercial speech in 
public fora. Reed had nothing to do with commercial speech doctrines, 
see 135 S. Ct. at 2224-25, and it has not been understood to alter the 
applicability of Central Hudson. Likewise, Sorrell ``did not mark a 
fundamental departure from Central Hudson's four-factor test, and 
Central Hudson continues to apply'' to regulations of commercial 
speech, regardless of whether they are content based. Retail Digital 
Network, LLC v. Prieto, 861 F.3d 839, 846 (9th Cir. 2017) (en banc); 
accord Vugo, Inc. v. City of New York, 931 F.3d 42, 50 (2d Cir. 2019), 
cert. denied, 140 S. Ct. 2717 (2020) (``No Court of Appeals has 
concluded that Sorrell overturned Central Hudson. We agree with our 
sister circuits that have held that Sorrell leaves the Central Hudson 
regime in place, and accordingly we assess the constitutionality of the 
City's ban under the Central Hudson standard.''); Missouri Broad. Ass'n 
v. Lacy, 846 F.3d 295, 300 n.5 (8th Cir. 2017) (``The upshot [of 
Sorrell] is that when a court determines commercial speech restrictions 
are content- or speaker-based, it should then assess their 
constitutionality under Central Hudson.'') (quotation marks omitted; 
alteration in original); Nicopure Labs., LLC v. FDA, 266 F. Supp. 3d 
360, 411 (D.D.C. 2017) (``[T]he Sorrell opinion did not alter or 
replace the Central Hudson intermediate scrutiny standard to be applied 
to commercial speech.''), aff'd, 944 F.3d 267, 290 (D.C. Cir. 2019) 
(``Sorrell's concerns about suppression of advertising messages in the 
marketplace of ideas are inapposite here.'').
    (Comment 35) Multiple comments expressed concerns about the 
difficulty of creating marketing plans for the first year of product 
marketing given that the time it has taken FDA to review PMTAs to date 
has been unpredictable. Specifically, comments stated that the 
requirement for marketing plans in proposed Sec.  1114.7(f)(2) did not 
take into account the considerable external variables that inform 
marketing plan decisions including competitor activities, FDA actions 
and State or Federal legislation. Comments noted that FDA's evaluation 
of the IQOS PMTA, for example, stretched over 2 years. The comments 
requested more flexibility in their marketing plans, including the 
potential to amend their plans during application review, to avoid 
being locked into outdated plans that do not account for the use of new 
technology or to allow for adjustment.
    (Response 35) FDA has revised and narrowed the scope of Sec.  
1114.7(f)(2) to require an applicant's description of its marketing 
plans to discuss certain key, high-level aspects of its plans to market 
the product for the first year after receiving a marketing granted 
order. FDA notes that the applicant's description of its marketing 
plans does not by itself create rigid requirements regarding the way in 
which an applicant must market its new tobacco product; however, where 
an applicant proposes a specific restriction on its marketing of the 
new tobacco product to support an APPH finding as part of its 
description of its marketing plans (e.g., avoiding online social media 
without access restrictions), FDA might incorporate such proposals into 
the restrictions on the sales and distribution of a new tobacco product 
in a marketing granted order as set forth in Sec.  1114.31(b). 
Additionally, FDA will monitor an applicant's implementation of its 
marketing plans as described in the application to ensure the marketing 
of the new tobacco product continues to be APPH. Applicants are 
required to report information about the marketing of their product 
under Sec.  1114.41(a)(1)(xi), and FDA may require submission of 
marketing plan changes in advance of implementation under Sec.  
1114.31(b)(3).
    An applicant may alter or update its description of its marketing 
plans during the course of application review by submitting an 
amendment; however, as described in the response to comment 34, we 
generally do not expect an applicant's approach to the high-level items 
in Sec.  1114.7(f)(2) to change significantly after the submission of 
an application. As described in section VIII.C., where such an 
amendment requires significant review time (e.g., significant changes 
to the intended audience(s) and how the marketing material and tactics 
would be targeted thereto), it will be considered a major amendment for 
which the review period will be extended by up to 180 days; however, 
FDA will review such amendments promptly and generally expects review 
of such changes will require fewer than 180 days.
    ii. Requirements for description of marketing plans. Section 
1114.7(f)(2) requires a PMTA to contain a description of the 
applicant's plans to market the new tobacco product, for at least the 
first year the product would be marketed after receiving a marketing 
granted order, in a way that permits FDA to determine whether this 
information is consistent with the applicant's discussion of the 
increased or decreased likelihood of changes in tobacco product use 
behavior, including switching (i.e., complete transition to a different 
tobacco product), initiation, cessation, and polyuse (i.e., using the 
new tobacco product in conjunction with one or more other tobacco 
products), under Sec.  1114.7(l), and whether permitting the new 
tobacco product to be marketed would be APPH. This section requires 
descriptions of actions to market the new tobacco product that would be 
taken by the applicant, on behalf of the applicant, or at the 
applicant's direction, and of any restrictions on the sales and 
distribution of the new tobacco product that the applicant is proposing 
to be included in the marketing granted order under section 
910(c)(1)(B) of the FD&C Act. As set forth below, the description of an 
applicant's plans to market a product will contain information that is 
important to FDA's consideration of the likelihood of changes in 
tobacco product use behavior (including initiation and cessation) under 
section 910(c)(4) of the FD&C Act. The described changes in tobacco 
product use behavior, when considered as part of FDA's determination of 
the risks and benefits of the new tobacco product to the population as 
a whole under section 910(c)(4) of the FD&C Act, form part of the basis 
upon which FDA must make its finding of whether there is a showing that 
permitting the marketing of the new tobacco product would be APPH under 
section 910(c)(2)(A) of the FD&C Act. While the criteria for FDA to 
accept and file the application in Sec.  1114.27 can be satisfied with 
only some discussion of the four items in Sec.  1114.7(f)(2)(i) through 
(iv), FDA encourages applicants to provide more detailed information to 
help inform FDA's substantive APPH determination.

[[Page 55328]]

    An understanding of how an applicant plans to market a new tobacco 
product for at least an initial period of time will help FDA determine 
the potential for increases in health risks related to marketing of the 
new tobacco product, such as the potential for youth initiation. If FDA 
determines that the potential increases in health risks outweigh the 
potential benefits, FDA would not be able to determine that the 
marketing of the new tobacco product would be APPH and would issue a 
marketing denial order.
    Section 1114.7(f)(2)(i) requires a PMTA to contain a description of 
the specific group(s) to which the labeling, advertising, marketing, 
promotion, and other consumer-directed activities for the new tobacco 
product would be targeted (i.e., the intended audience(s)). As used in 
Sec.  1114.7(f)(2), the term ``other consumer-directed activities'' 
includes any other types of action regarding the new tobacco product 
taken by the applicant, on behalf of the applicant, or at the 
applicant's direction that may directly or indirectly impact 
information about the tobacco product that reaches consumers (e.g., use 
of third parties or social media influencers to reach consumers). 
Additionally, the labeling, advertising, marketing, promotion, and 
other consumer-directed activities for a new tobacco product are 
collectively referred to as ``marketing materials and activities'' in 
this document for ease of reference. An applicant would need to provide 
the characteristics it has used to identify the specific group(s) to 
which its marketing materials and activities would be targeted, such as 
age-range(s) (including young adult audiences ages 21 to 24 years, if 
applicable) and other demographic characteristics, details of tobacco 
use behaviors (e.g., dual use), and psychographic characteristics. 
Examples of other demographic characteristics include, but are not 
limited to, race, ethnicity, socioeconomic status and geographic 
location (e.g., urban, rural). Such information will be informative to 
FDA in identifying potential impacts of marketing on specific 
populations, including vulnerable populations. Examples of types of 
psychographic characteristics include, but are not limited to, hobbies, 
interests, risk-taking behaviors, purchase behaviors, and online search 
behaviors. Based on our experience, FDA generally expects that 
applicants will have conducted or otherwise obtained market or consumer 
research to determine its intended audience(s). Where an applicant has 
conducted such research and has used the results to determine its 
intended audience, FDA recommends an applicant discuss such information 
in this section.
    As a general example, the description of the intended audience(s) 
could include, for example, a statement that the applicant would target 
its marketing materials and activities for the new tobacco product to 
all current adult cigarette smokers, with a focus on cigarette smokers 
aged 26 to 54 years who are seeking alternatives to combustible 
cigarettes.
    Section 1114.7(f)(2)(ii) requires the applicant's description of 
its marketing plans to contain a discussion of the ways in which the 
applicant would target its marketing materials and activities for the 
new tobacco product to reach the intended audience(s) described in 
paragraph (i) and what other group(s) would foreseeably be exposed to 
the marketing materials and activities as a result. A discussion of 
these aspects of the plans can provide information that is important to 
FDA's evaluation of the increased or decreased likelihood of changes in 
tobacco product use behavior under section 910(c)(4) of the FD&C Act. 
Describing how an applicant would target the marketing materials and 
activities for the new tobacco product to intended audiences could help 
FDA determine whether the applicant's descriptions of its marketing 
plans are consistent with information in the application regarding the 
likelihood of changes in tobacco product use behaviors, such as current 
tobacco product users switching to the new tobacco product.
    A discussion of the ways in which the applicant would target the 
marketing materials and activities for a new tobacco product to reach 
the intended audience(s) can include items such as: how the applicant 
would use key insights about its intended audience(s) to tailor its 
marketing approach; the types and sources of data, technologies, and 
methodologies the applicant would use to develop, implement, and track 
targeted paid media plans (e.g., first and second-party age-verified 
data, public records, industry-standard syndicated research services, 
and embedded tracking pixels in digital advertising); and the marketing 
channels and tactics an applicant expects to use.
    Additionally, this information will help FDA determine whether the 
identified audiences and not other audiences, such as individuals below 
the minimum age of sale, would be exposed to the marketing materials 
and activities for the new tobacco product. Describing the other groups 
that would foreseeably be exposed to the marketing materials and 
activities for the new tobacco product will help FDA understand the 
potential for other groups to be affected by the plans to market the 
new tobacco product. For example, where an applicant's plans to target 
its marketing materials and activities to an intended audience of adult 
consumers has the potential to reach individuals below the minimum age 
of sale, an applicant would have to note that potential and describe 
whether the potential would be limited under paragraph (iii). FDA is 
requiring a discussion of an applicant's plans to target its marketing 
materials and activities to the intended audience(s) and the other 
groups that could foreseeably be exposed to those materials as a result 
of such targeting because, as discussed in the following paragraphs, 
there is a well-established body of scientific evidence regarding the 
effect of advertising and marketing on tobacco product behavior (see 
e.g., Refs. 19-22).
    Section 1114.7(f)(2)(iii) requires the applicant's description of 
its marketing plans to contain a discussion of the ways in which, for 
individuals below the minimum age of sale, access to the new tobacco 
product would be restricted and exposure to the marketing materials and 
activities for the new tobacco product would be limited. Describing the 
ways in which an applicant would restrict access to the new tobacco 
product by individuals below the minimum age of sale would be an 
important part of FDA's consideration under section 910(c)(4) of the 
FD&C Act regarding the increased or decreased likelihood that persons 
who do not use tobacco products will start using the tobacco product 
that is the subject of the application. Limiting the potential for 
youth to access the new tobacco product is one way to help mitigate the 
potential for youth initiation with the new tobacco product (Refs. 23 
and 24). For example, an applicant could propose to restrict the sale 
and distribution of its new tobacco product to adult-only facilities 
and limit the quantity of its product that an adult customer (other 
than scientific researchers or research institutions) may purchase 
within a given period of time to limit the potential for resale to 
youth.
    Describing the ways in which an applicant would plan to limit the 
exposure of individuals below the minimum age of sale to the marketing 
materials and activities for the new tobacco product would also help 
FDA assess the potential for initiation with the new tobacco product by 
this group. Examples of how applicants could limit the exposure of 
individuals below the

[[Page 55329]]

minimum age of sale to the marketing materials and activities could 
include actions such as utilizing services that compare consumer 
information against independent, competent, and reliable data sources, 
such as public records, before granting users access to the applicant's 
tobacco product website(s), using only first- or second-party age-
verified data to target paid digital advertising, and limiting sales to 
adult-only stores. Applicants could also restrict or avoid the use of 
marketing practices that are not or cannot be targeted in ways that 
would limit exposure of individuals below the minimum age of sale and 
choose tactics more narrowly targeted to current adult users of tobacco 
products, such as avoiding online social media without access 
restrictions to promote the tobacco product and, instead, choose 
actions such as paper or electronic mail directed only to current 
smokers at or above the minimum age of sale.
    FDA is requiring the description of an applicant's plans to market 
the new tobacco product to contain a discussion of an applicant's plans 
to target the marketing materials and activities to reach the intended 
audience(s) and limit the exposure of individuals below the minimum age 
of sale to such materials and activities, because there is a well-
established body of scientific evidence regarding their effect on 
tobacco product use behavior (see e.g., Refs. 19-22). The impact of 
tobacco marketing tactics on youth and young adult tobacco use behavior 
in particular has been well documented. The 2012 Surgeon General's 
report entitled ``Preventing Tobacco Use Among Youth and Young 
Adults,'' (the 2012 SGR) synthesizes more than 30 years of research on 
the topic and outlines the findings demonstrating that product 
labeling, advertising, marketing, and promotion influence youth tobacco 
use by shaping attitudes, beliefs, and risk perceptions, and promoting 
pro-tobacco social and cultural norms (Ref. 9). The 2012 SGR states 
that the strong empirical evidence, along with the tobacco industry's 
own internal documents and trial testimony, as well as widely accepted 
principles of advertising and marketing, support the conclusion that 
tobacco manufacturers' advertising, marketing, and promotions recruit 
new users as youth and continue to reinforce use among young adults 
(Ref. 9). The 2012 SGR states that this evidence is sufficient to 
conclude that marketing efforts and promotion by tobacco companies show 
a consistent dose-response relationship in the initiation and 
progression of tobacco use among young people (Ref. 9). The 2012 SGR 
also states that research conducted by the tobacco industry 
consistently demonstrates that the brand imagery portrayed on packages 
is particularly influential during youth and young adulthood--the 
period in which smoking behavior and brand preferences develop. The 
2016 Surgeon General's report entitled, ``E-Cigarette Use Among Youth 
and Young Adults,'' similarly synthesizes research on e-cigarettes and 
concluded that e-cigarette manufacturers used tactics similar to those 
used to market conventional cigarettes to youth and young adults (Ref. 
15).
    The National Cancer Institute (NCI) made a similar conclusion in 
its monograph, ``The Role of the Media in Promoting and Reducing 
Tobacco Use,'' that the total weight of evidence--from multiple types 
of studies, conducted by investigators from different disciplines, and 
using data from many countries--demonstrates a causal relationship 
between tobacco advertising and promotion and increased tobacco use 
(Ref. 20). As such, the direct role of tobacco product marketing and 
related activities in increasing tobacco use in the United States, 
especially among youth, and the high rates of youth-exposure to tobacco 
marketing due to its ubiquity, are two key rationales cited by NCI for 
restricting tobacco product marketing and related activities (Ref. 20). 
A variety of research has found that exposure to advertising is 
associated with susceptibility to use tobacco products and the actual 
use of tobacco products (see e.g., Refs. 25-33). For example, research 
has found that the use of certain kinds of imagery, such as logos and 
cartoons, have an impact on youth tobacco initiation (see, e.g., Refs. 
34-36) and that a key tactic of tobacco companies seeking to attract 
and recruit youth users is to use advertising and marketing with 
aspirational imagery and themes known to resonate with younger 
audiences, such as independence, popularity, rebelliousness, 
attractiveness, and being cool (Ref. 9).
    An analysis of the 2011 National Youth Tobacco Survey (NYTS) found 
that adolescents who reported frequent exposure to tobacco advertising 
at the point of sale and on the internet had significantly higher odds 
of ever using e-cigarettes and that there was a dose-response 
association between the number of marketing channels to which they were 
exposed and whether they used tobacco products (Refs. 15 and 33). An 
analysis of 2014 NYTS data assessing exposure to e-cigarette 
advertising in different channels (i.e., internet, print, television 
and movies, retail stores) found that as the number of channels of e-
cigarette marketing exposure increased, the likelihood of use and 
susceptibility also increased (Refs. 15, 37, and 38). Thus, providing 
information regarding the ways in which an applicant would target the 
marketing materials and activities for the new tobacco product to reach 
the intended audience(s) and limit the exposure of individuals below 
the minimum age of sale to such items can provide valuable insight into 
the potential that youth would initiate tobacco product use.
    Finally, Sec.  1114.7(f)(2)(iv) requires the description of an 
applicant's marketing plans to contain a concluding summary discussing 
how the applicant's plans for marketing the new tobacco product are 
consistent with the applicant's discussion regarding the increased or 
decreased likelihood of changes in tobacco product use behavior 
(including switching, initiation, cessation, and polyuse) under Sec.  
1114.7(l) and permits FDA to determine whether permitting the marketing 
of the new tobacco product would be APPH. This section requires an 
application to contain a discussion of how each of the items in Sec.  
1114.7(f)(2)(i) through (iii) are consistent with the applicant's 
discussion regarding the increased or decreased likelihood of changes 
in tobacco product use behavior by both current users and nonusers of 
tobacco products. This includes, but is not limited to: How the planned 
targeting of intended audience(s) is consistent with discussions 
regarding the likelihood of changes in tobacco product use behavior 
such as by current adult users, including switching, quitting, and 
polyuse; and how, for individuals below the minimum age of sale, 
restrictions on access to the new tobacco product and limitations on 
exposure to the marketing materials and activities for the new tobacco 
product are consistent with discussions regarding the likelihood of 
tobacco product use initiation, including among youth. For example, 
where an applicant expects current adult cigarette smokers to use its 
new tobacco product, the applicant would be required to explain its 
basis for concluding that its planned marketing is consistent with that 
expectation, such as providing an explanation of how the applicant 
determined its selected marketing channels and tactics would reasonably 
reach its intended users. Similarly, if an applicant claims its 
marketing plans would adequately prevent or reduce youth initiation, 
the applicant would be required to explain its basis for such a 
conclusion by

[[Page 55330]]

providing explanations of any measures or controls the applicant would 
use to restrict youth access to the product (e.g., selling the product 
only in brick-mortar retail locations), using competent and reliable 
third-party services to verify the age and identity of product 
purchasers, implementing purchase quantity limits) and limit youth 
exposure to the product's marketing materials and activities (e.g., 
restricting its marketing to channels and tactics where it is possible 
to target delivery of advertising to only age-verified adults).
    An applicant can use this portion of the summary as an opportunity 
to help show the description of its marketing plans are consistent with 
its expectations for the potential initiation by current nonusers of 
tobacco products. For example, where conclusions drawn from tobacco 
product perception and use intention studies contained in a PMTA show 
the potential for current nonusers to initiate tobacco product use with 
the new tobacco product, an applicant could discuss how its plans to 
market the tobacco product, such as advertising at only point-of-sale 
locations for tobacco products or sending direct mail marketing to 
individuals of legal purchasing age who have opted-in to such 
communications, would mitigate the potential for initiation by nonusers 
and aligns with the applicant's discussion of such potential under 
Sec.  1114.7(l).
    In addition to the basic requirements of Sec.  1114.7(f)(2), to 
help inform FDA's APPH determination, applicants may develop and submit 
more detailed plans to implement specific marketing campaigns. Not only 
would this provide an applicant the opportunity to further address any 
concerns about the potential for youth to initiate tobacco product use 
with the new tobacco product, it would be an opportunity for an 
applicant to more concretely show how it would target its marketing 
materials and activities to reach the intended audience(s).
    The types of more detailed marketing plan information an applicant 
could develop and submit as part of a PMTA include materials such as 
strategic creative briefs, media and distribution channels, specific 
tactics, and the intended scope of each marketing activity (e.g., 
information such as the expected reach and frequency of audience 
exposures to the marketing, and timing and duration of the marketing 
activities), and the information described in the items listed below. 
These details, if provided, should be provided as part of the 
appropriate discussion under Sec.  1114.7(f)(2) (if applicable) and can 
include:
     A description of specific insights about the intended 
audience(s) (e.g., findings from consumer research) that have informed 
the applicant's marketing plans, including its strategic approach, key 
messages and themes, creative direction, and potential tactics or 
marketing channels. This could include product-specific insights (e.g., 
an audience's impressions of one product being just as harmful as 
another, preference of a certain brand), as well as other beliefs, 
interests, motivations, or behaviors that can be used to tailor an 
applicant's approach to marketing the product. This could also include 
information regarding where the intended audience(s) tends to consume 
marketing and advertising (e.g., television programs the intended 
audience(s) watches, social media influencers the intended audience(s) 
follows, websites and retail locations the intended audience(s) 
frequents) that can be used to tailor an applicant's approach, select 
relevant marketing tactics, and use relevant marketing channels. The 
applicant should describe such insights in either paragraph (i) or 
(ii), as appropriate, and state the source of such data;
     plans to use owned, earned, shared, or paid media to 
create labeling for, advertise, market, or promote the tobacco product. 
While media categories overlap, owned media typically consists of a 
company's own media properties and content they control, such as the 
company's product-branded website or mobile application. Earned media 
typically consists of unpaid media publicity or coverage of a company's 
brand or product that the company did not commission or pay for, such 
as a news article about the product or an influencer talking about a 
company's product without compensation. Examples of plans to use earned 
media can include, but are not limited to, pitching articles to news 
outlets, using unsolicited consumer reviews or testimonials to promote 
the product, and inviting influencers or reporters to attend a product 
launch event. Shared media typically consists of social media 
properties, such as a company's social media accounts and content, 
including interactions with other social media users and their content, 
such as comments, ``likes,'' and responses to comments. Paid media 
typically consists of content that a company pays to place and promote 
in media properties it does not own, such as advertising appearing on 
television and radio, in and around retail stores, and in digital 
media, including content shared by a celebrity who a company pays to 
promote the tobacco product;
     plans to use (or not use) partners, influencers (e.g., 
celebrities, cultural icons, individuals with substantial followers on 
social media), bloggers, or brand ambassadors to create labeling for, 
advertise, market, or promote the tobacco product;
     plans to conduct (or not conduct) consumer engagements, 
including events at which the tobacco product will be demonstrated; and
     plans to use public relations or other communications 
outreach to promote the tobacco product. Public relations could consist 
of actions such as using a public relations firm to promote the tobacco 
product. Other communications to promote the product could consist of 
actions such as direct mail to consumers.
7. Statement of Compliance With Part 25
    A PMTA must contain an environmental assessment (EA) prepared in 
accordance with Sec.  25.40 or a valid claim of a categorical 
exclusion, if applicable. Pursuant to Sec.  25.15(a), all submissions 
requesting FDA action require the submission of either a claim of 
categorical exclusion or an EA. In accordance with Sec.  25.40(a), an 
EA must include, at a minimum, brief discussions of: The need for the 
proposed action; alternatives to the proposed action as required by 
section 102(2)(E) of the National Environmental Policy Act of 1969 
(NEPA); the environmental impacts of the proposed action and 
alternatives; the Agencies and persons consulted during the preparation 
of the EA; and the relevant environmental issues relating to the use 
and disposal of the tobacco product. Although applicants may wish to 
review the categorical exclusions specific to tobacco product 
applications at Sec.  25.35, the only categorical exclusion currently 
available for a marketing order is for provisional SE reports that 
receive an SE order in the SE premarket pathway, not for PMTAs. If the 
applicant believes the action would qualify for an available 
categorical exclusion, the applicant must state under Sec.  25.15(a) 
and (d) that the action qualifies for a categorical exclusion, cite to 
the claimed exclusion, and state that to the applicant's knowledge no 
extraordinary circumstances exist under Sec.  25.21.
    Failure to include an EA in a PMTA is grounds for FDA to refuse to 
accept an application and failure to include an adequate EA is 
sufficient grounds under Sec.  25.15 for FDA to refuse to file the PMTA 
or refuse to issue a marketing

[[Page 55331]]

granted order. (See the discussion of Sec. Sec.  1114.27 and 1114.29 in 
section IX.)
8. Summary
    Section 1114.7(h) requires the application to contain a summary of 
the application contents in sufficient detail to provide FDA with an 
adequate understanding of the data and information in the application. 
FDA requires the summary under authority of sections 701(a) and 
910(b)(1)(G) of the FD&C Act because it provides FDA with an 
understanding of the information contained in the PMTA and allows FDA 
to plan and conduct a more efficient review of the detailed technical 
information the summary describes. The summary also helps reviewers 
understand the product and the accompanying scientific data more 
quickly and allows applicants to highlight information they believe 
demonstrates their product should receive a marketing granted order.
    The summary should discuss all aspects of the PMTA and synthesize 
the application in a well-structured, unified manner. The summary 
should serve as a briefing document that highlights the most important 
aspects of the application, with each section of the summary consisting 
of a brief explanation of information that the applicant believes 
contributes to a finding that permitting the marketing of the product 
would be APPH. The applicant must summarize the content included in the 
PMTA in a manner that describes the operation of the product, the 
health risks of the new tobacco product, the product's effect on 
tobacco use behavior of current users, the product's effect on tobacco 
use initiation by nonusers, and the product's effect on the population 
as a whole. The summary must describe the new tobacco product's 
potential effects on youth, young adults, and other relevant vulnerable 
populations. After reviewing comments on the proposed rule, FDA has 
added vulnerable populations to this requirement in the final rule to 
ensure the summary specifically accounts for those groups that may be 
disproportionately affected or more likely to use the new tobacco 
product. The summary must contain the following items, where 
applicable:
     A summary of the product formulation section of the 
application. This section should provide a high-level description of 
the product formulation section of the application, highlighting 
information such as key ingredients, constituent levels, and design 
aspects of the product. See the discussion of Sec.  1114.7(i) in 
section VIII.B.9;
     a summary of the manufacturing section of the application. 
This section should provide an overview of the manufacturing section of 
the application, including activities at each facility, and highlight 
information such as major aspects of the manufacturing and controls, 
especially those that the applicant believes contribute to a finding 
that permitting the marketing of the product would be APPH (e.g., an 
aspect of the manufacturing process that results in lower levels of 
HPHCs than other tobacco products in the same category). See the 
discussion of Sec.  1114.7(j) in section VIII.B.12;
     a summary of the health risk investigations section of the 
application. This section should briefly describe and synthesize the 
findings of each investigation describing the following items, and 
explicitly identify areas in which there is a lack of information, if 
any:
    [cir] The health risks of the tobacco product to both users and 
nonusers of the product (including youth, young adults, and other 
relevant vulnerable populations) and whether the tobacco product 
presents less health risk than other tobacco products, such as the risk 
of cancers (e.g., lung, mouth, pancreatic), heart disease, stroke, or 
lung disease, compared to other categories of tobacco products and 
other tobacco products within the category, if known. See the 
discussion of Sec.  1114.7(k)(1)(i) in section VIII.B.13.a.iii.;
    [cir] The impact the product and its marketing will have on the 
likelihood of changes in tobacco use behavior of tobacco product users 
(including youth, young adults, and other relevant vulnerable 
populations), including cessation, switching (i.e., to a different 
tobacco product), and polyuse (i.e., using the new tobacco product in 
conjunction with one or more other tobacco products). See the 
discussion of Sec.  1114.7(k)(1)(ii) in section VIII.B.13.a.iv.;
    [cir] the impact the product and its marketing will have on the 
likelihood of tobacco use initiation by tobacco products nonusers, 
especially youth, young adults, and other relevant vulnerable 
populations, including among never users and former users, and the 
likelihood of polyuse and switching behaviors. See the discussion of 
Sec.  1114.7(k)(1)(iii) in section VIII.B.13.a.v.;
    [cir] How users and nonusers perceive the risk of the tobacco 
product based upon label, labeling, and advertising (if any has been 
studied). This includes how the label, labeling, and advertising affect 
use intentions. See the discussion of Sec.  1114.7(k)(1)(iv) in section 
VIII.B.13.a.vi.;
    [cir] whether users are able to understand the labeling and 
instructions for use, and use the product in accordance with those 
instructions. See the discussion of Sec.  1114.7(k)(1)(iv) in section 
VIII.B.13.a.vi.; and
    [cir] the impact of human factors on the health risks to product 
users and nonusers including, for example, how various use and misuse 
scenarios may impact the health risks posed by the product. See the 
discussion of Sec.  1114.7(k)(1)(v)) in section VIII.B.13.a.vii..
    The rule also requires the summary to contain a concluding 
discussion demonstrating how the data and information contained in the 
PMTA both constitute valid scientific evidence and establish that 
permitting the marketing of the new tobacco product would be APPH as 
determined with respect to the risks and benefits to the population as 
a whole, including users and nonusers of the tobacco product. The rule 
also requires the summary to identify any key or pivotal studies on 
which an applicant is relying to establish that permitting the 
marketing of the new tobacco product would be APPH. FDA recommends that 
this discussion include estimates of the effect that the new tobacco 
product may have on the health of the population as a whole, such as 
effects on tobacco use initiation switching and cessation, and 
reductions in premature mortality, or increases in life-years lived. 
The estimates should integrate all of the information in the PMTA 
regarding the product and its potential effects on health, including, 
but not limited to adverse experiences, tobacco use behavior, and 
tobacco use initiation to provide an overall assessment of the 
potential effect that permitting the product to be marketed has or may 
have on overall tobacco-related morbidity and mortality.
    As an illustration, an applicant may make an overall assessment of 
whether the product will likely have a net benefit on population health 
by accounting for potential reductions in disease risk (compared to 
other tobacco products) and the potential for current tobacco users to 
switch to the new tobacco product, and weighing that against the 
potential for nontobacco users to use the tobacco product and the 
accompanying potential increases in disease risks among those new 
tobacco product users. An applicant should provide quantitative 
assessments in the concluding discussion wherever possible; however, an 
applicant may provide qualitative assessments where

[[Page 55332]]

appropriate for the type of investigation(s) on which the assessment is 
based (e.g., focus group or interview-type studies).
    The summary's concluding discussion must also briefly describe why 
the data and scientific information on which the applicant relies in 
concluding that permitting the marketing of the product would be APPH 
constitute valid scientific evidence. Section 910(c)(5)(A) of the FD&C 
Act requires FDA to make its determination of whether permitting the 
marketing of a new tobacco product would be APPH, where appropriate, on 
the basis of well-controlled investigations; however, under section 
910(c)(5)(B) of the FD&C Act, where FDA determines that there exists 
valid scientific evidence other than well-controlled investigations 
that is sufficient to evaluate the product, FDA may use such evidence. 
As discussed in more detail in section IX.D regarding Sec.  1114.31, 
FDA considers valid scientific evidence to be evidence gathered using 
well-established or standardized methodologies from which it can be 
concluded by qualified experts that there is reasonable assurance of 
the reliability of its findings. Thus, if an application contains 
information regarding another tobacco product (e.g., published 
literature, marketing information) with appropriate bridging studies 
and describes the relationship to the product that is the subject of 
the application, FDA will review that information to determine whether 
it is valid scientific evidence sufficient to demonstrate that 
permitting the marketing of a product would be APPH.
9. Product Formulation
    Section 910(b)(1)(B) of the FD&C Act requires that a PMTA contain a 
full statement of the components, ingredients, additives, and 
properties, and of the principle or principles of operation, of such 
tobacco product. Section 1114.7(i) implements FDA's interpretation of 
this statutory requirement, together with its authority under section 
910(b)(1)(G) of the FD&C Act, by requiring a PMTA to contain the 
following information:
    a. Components or parts, materials, ingredients, additives, and 
constituents. Under the rule, the application is required to contain a 
full statement (i.e., a listing) of the product components or parts, 
materials, ingredients other than tobacco, tobacco ingredients, HPHCs, 
and the container closure system.
    i. Components or parts. Section 1114.7(i)(1)(i) requires the 
application to state the quantity, function, and purpose of, and where 
applicable, target specifications of each component or part in the 
product. This information should also include an explanation of how 
each component or part is, or can be, integrated into the product 
design, and the purpose and function of each component or part. Where 
the tobacco product contains software components, the rule requires:
     A description of the software or technology (e.g., 
Bluetooth);
     a description of the purpose of the software or 
technology, such as monitoring where the tobacco product is located, 
activated, or used;
     a description of the data collected by the software and 
how this information will be used by the applicant.
    FDA received comments regarding this section, as discussed below.
    (Comment 36) One comment stated that the rule should be amended to 
state that FDA will issue a marketing denial order if the application 
does not include specific assurances and evidence that there will be no 
communication between the device and any external source, and that the 
software would not be programmed to increase consumption.
    (Response 36) We agree that understanding how any software in a 
product may function is important to the review of an application. For 
example, software used in or with some consumer products may have 
functions and purposes that are not immediately clear, such as use 
monitoring and location tracking functions, and may be able to function 
in conjunction with other electronic devices, such as a smart phone. We 
decline to prohibit all communication between a new tobacco product and 
external sources as part of this rulemaking because product standards 
are outside the scope of this rulemaking; however, we will consider 
information regarding software (if applicable) as part of substantive 
review. For example, if the product has software features that could 
help prevent youth use of the tobacco product, FDA would review this 
information as part of the determination of whether permitting the 
marketing of the new tobacco product would be APPH. This information is 
especially important as it may not be readily apparent from a component 
or part's identity what function and purpose it may serve.
    (Comment 37) One comment stated that FDA should amend Sec.  
1114.7(i)(3)(ii) to also require specification of software or other 
controls in an e-cigarette to limit the intensity of use, including 
minimum inter-puff interval and maximum number of puffs per hour that 
the device will deliver because, unlike with combusted cigarettes, 
there are no obvious indicators for consumers of how quickly they are 
consuming the product.
    (Response 37) As discussed in section VIII.B.10., FDA requires the 
PMTA to contain a full narrative description of the way in which a 
typical consumer will use the new tobacco product. This includes, for 
example, a description of how a consumer operates the product, where 
applicable, whether and how a consumer can change the product design 
and add or subtract ingredients, the length of time it takes for a user 
to consume a single unit of the product, and whether the product 
incorporates a heating source and, if it does, a description of the 
heating source. As described above, the presence of software or other 
controls in an e-cigarette to limit the intensity of use would be 
relevant to FDA's review of an application and a required part of a 
PMTA submission under Sec.  1114.7.(i)(1)(i); however, FDA declines to 
require such controls in all e-cigarettes as part of this rule because 
it would constitute a product standard that is outside the scope of 
this rule.
    ii. Materials. Section 1114.7(i)(1)(ii) requires the application to 
contain information for each material in the product because materials 
can affect the performance of the product. FDA considers materials to 
be part of ``components'' under section 910(b)(1)(B) and the required 
materials information is relevant to the subject matter of a PMTA under 
section 910(b)(1)(G) because it is needed to fully characterize the 
tobacco product and understand its health risks. For example, in 
portioned smokeless tobacco products, the materials used in the pouch 
can affect the rate at which nicotine is released and specifications 
such as pouch fabric air permeability can provide information about how 
quickly nicotine can be delivered to the consumer. For ENDS, the 
material used in the construction of an electrical heater coil 
influences its resistance and the temperature reached by the coil, 
which in turn may affect the type and amount of HPHCs produced in 
aerosol. The rule requires a PMTA to contain:
     The material name and common name (if applicable);
     the component or part of the tobacco product where the 
material is located;
     the subcomponent or subpart where the material is located 
(if applicable);
     the function of the material;
     quantities (including ranges or means and acceptance 
limits) of the materials(s) in the new tobacco product;

[[Page 55333]]

     specifications (including quality, grades, and suppliers) 
of the materials used for the new tobacco product (including any 
specification variations, if applicable); and
     any other material properties that fully characterize the 
new tobacco product, such as pouch material porosity or air 
permeability for portioned smokeless products. While failure to include 
additional material properties to fully characterize the tobacco 
product would not serve as the basis for FDA refusing to accept or file 
an application under Sec.  1114.27(a)(1), it may slow down the 
substantive review process.
    FDA received comments regarding this section, as described below.
    (Comment 38) One comment requested that FDA clarify the scope of 
the materials that an applicant would have to describe in a PMTA, 
specifically requesting that FDA require PMTAs for e-cigarettes to 
contain information on only those materials that are reasonably 
expected to have contact with the e-liquid and not materials found in 
items such as the exterior plastic casing, electronic circuitry, and 
batteries. The comment stated that this would align with FDA's current 
approach set forth in the guidance entitled ``Listing of Ingredients in 
Tobacco Products.'' \19\
---------------------------------------------------------------------------

    \19\ Available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
---------------------------------------------------------------------------

    (Response 38) FDA declines to limit the scope of the materials in 
an ENDS for which an applicant would have to provide information in a 
PMTA to only those materials that are reasonably expected to have 
contact with the e-liquid. As discussed in section Sec.  1114.3, FDA 
defines material to mean an assembly of ingredients. Materials are 
assembled to form the tobacco product, or components or parts of the 
tobacco product. This includes both those materials that are in contact 
with the e-liquid as well as any other materials in the product, such 
as those used in the exterior plastic casing, electronic circuitry, and 
batteries. FDA declines to limit the scope of materials for ENDS 
because they are components or parts with the potential to introduce, 
diffuse, leach or extract to become part of the e-liquid formulation or 
constituents during storage and use. For example, batteries and solder 
joints of the product have been shown to be the potential source of 
metals contamination in e-liquid or aerosol (Ref. 39). Furthermore, 
defective or damaged batteries on their own may lead to battery failure 
or overheating, resulting in thermal runaway; thermal runaway has been 
identified as an immediate threat in e-cigarettes, particularly due to 
the metal enclosure of the e-cigarette batteries that allow the 
dangerous build-up of gasses (Ref. 40). In addition, the guidance for 
industry, entitled ``Listing of Ingredients in Tobacco Products,'' 
discusses FDA's current enforcement policy for ingredient listing 
submission requirements under section 904(a)(1) of the FD&C Act. While 
FDA does not intend to enforce ingredient listing requirements for 
component and parts such as electrical components, batteries, and 
electronic circuitry, FDA recognizes that the ingredients of these 
other components and parts can also be important in determining the 
public health impact of tobacco products. As the guidance states, FDA 
will receive ingredient information for these other components and 
parts during our premarket review of new tobacco products. This is 
consistent with the rule's requirement to include information on 
materials in a PMTA.
    iii. Ingredients other than tobacco. Section 1114.7(i)(1)(iii) 
requires that the application contain information on ingredients other 
than tobacco (tobacco ingredients are addressed in Sec.  
1114.7(i)(1)(iv)). The application must contain:
     International Union of Pure and Applied Chemistry (IUPAC) 
chemical name and common name (if applicable);
     Chemical Abstracts Service (CAS) number or FDA Unique 
Ingredients Identifier (UNII). Both the IUPAC and CAS or UNII are 
required to ensure FDA has the relevant information associated with 
each identifier and to allow FDA to efficiently differentiate between 
similar ingredients;
     the function of the ingredient;
     the quantity of the ingredient in the tobacco product, 
with the unit of measure (including ranges or means, and acceptance 
limits) reported as mass per gram of tobacco for nonportioned tobacco 
products and as mass per portion for portioned tobacco products (with 
any specification variation, if applicable);
     the specifications (including purity or grade and 
supplier); and
     for complex purchased ingredients, each single chemical 
substance reported separately.
    Additionally, FDA recommends that an application contain any other 
ingredient information to fully characterize the new tobacco product, 
as applicable. While failure to include other ingredient information to 
fully characterize the tobacco product would not serve as the basis for 
FDA refusing to accept or file an application under Sec.  
1114.27(a)(1), it may slow down the substantive review process.
    iv. Tobacco ingredients. Section 1114.7(i)(1)(iv) requires 
information regarding tobacco ingredients, including:
     The type(s) of tobacco (e.g., Bright, Burley, 
reconstituted). This information is important to determining the public 
health impact of the products because different types of tobacco have 
different constituent profiles. In the proposed rule, we also included 
a requirement to specify the grade(s) of the tobacco and we have 
removed this due to the general lack of standardized grading systems.
     the quantity, with the unit of measure (including ranges 
or means, and acceptance limits), of each tobacco ingredient in the new 
tobacco product reported as mass per gram of tobacco for nonportioned 
tobacco products and as mass per portion for portioned tobacco products 
(with any specification variation, if applicable);
     the specification(s) of tobacco used for the new tobacco 
product (with any specification variation, if applicable); and
     a description of any genetic engineering that impacts 
characteristics of the tobacco product, such as the constituent 
profile.
    Additionally, FDA recommends a PMTA contain any other information 
about tobacco ingredients to fully characterize the new tobacco 
product, as applicable, such as country of origin, which can reflect 
different constituent levels (Ref. 41). While failure to include other 
information about tobacco ingredients to fully characterize the tobacco 
product would not serve as the basis for FDA refusing to accept or file 
an application under Sec.  1114.27(a)(1), it may slow down the 
substantive review process. If the new tobacco product does not contain 
tobacco (e.g., rolling paper or tipping paper), this section of the 
application must specifically state that the product does not contain 
tobacco.
    FDA requires in Sec.  1114.7(i)(1) that ingredient quantities be 
reported as mass per gram of tobacco for nonportioned tobacco products 
and as mass per portion for portioned tobacco products. These specific 
measurements provide consistent, complete information that allows FDA 
to understand the ingredient quantities. In contrast, if ingredient 
quantities were reported as percentages, FDA would have to make 
assumptions about the denominator used to calculate the percentage. For 
example, if xylitol were reported as 10 percent of a portioned moist 
snuff, FDA would not able to determine if xylitol was 10 percent of the 
mass of the tobacco filler or of the entire product (containing filler, 
paper, etc.). For more information on uniquely

[[Page 55334]]

identifying components, ingredients, and additives and reporting their 
quantities, please refer to FDA's guidance for industry entitled 
``Listing of Ingredients in Tobacco Products.''
    v. Constituents. Section 1114.7(i)(1)(v) requires a full statement 
of the constituents, including HPHCs and other constituents, contained 
within, or emitted from (including its smoke or aerosol), the product, 
including any reaction products from leaching or aging. FDA considers 
constituents to be properties of the new tobacco product, a full 
statement of which is required to be in a PMTA by section 910(b)(1)(B) 
of the FD&C Act. The constituents contained within, and delivered from, 
the product can be detected through constituent testing on the product. 
The constituent testing should reflect the various conditions under 
which consumers may use the product (e.g., light use, typical use, and 
heavy use) and the types of products that consumers are likely to use 
in conjunction with the product. For example, an open (refillable) e-
cigarette should be tested with a variety of e-liquids that consumers 
are likely to consume using the e-cigarette. The reports of constituent 
testing must be conducted in the manner required by, and include all 
information that is specified in, Sec.  1114.7(i)(1)(v), including the 
full test data.
    FDA published an initial list of the constituents that it has 
identified as HPHCs in the Federal Register of April 3, 2012, which it 
intends to update periodically by providing the public with notice and 
the opportunity to submit comments. FDA recently proposed the addition 
of 19 constituents to the established list of HPHCs.\20\
---------------------------------------------------------------------------

    \20\ 84 FR 38032 (August 5, 2019).
---------------------------------------------------------------------------

    The constituent testing data FDA requires for all products include:
     The constituent names in alphabetical order;
     the common name(s);
     the CAS number;
     the mean quantity and variance with unit of measure;
     the number of samples and measurement replicates for each 
sample. As stated in Sec.  1114.7(i)(4)(iv), the testing must be 
conducted using a sufficient sample size and number of replicates to 
substantiate the results of the type of testing conducted;
     a description of method procedure, method validation 
information, and rationale for selecting each test method (as required 
by Sec.  1114.7(i)(4)(v));
     the name and location of the testing laboratory or 
laboratories and documentation showing that the laboratory or 
laboratories is (or are) accredited by a nationally or internationally 
recognized external accreditation organization (as required by Sec.  
1114.7(i)(4)(i));
     the length of time between dates of manufacture and 
date(s) of testing (as required by Sec.  1114.7(i)(4)(ii));
     storage conditions of the tobacco product before it was 
tested. It is important for FDA to understand the storage conditions 
before testing because they could affect the quantity of volatile 
organic compounds or promote microbial growth in the tobacco product 
(as required by Sec.  1114.7(i)(4)(iii));
     reports of constituent testing that include test 
protocols, any deviation(s) from the test protocols, quantitative 
acceptance (pass/fail) criteria, line data, and a summary of the 
results, for each applicable parameter (as required by Sec.  
1114.7(i)(4)(vi)); and
     complete descriptions of any smoking or aerosol generating 
regimens used for analytical testing that are not standardized or 
widely accepted by the scientific community, if applicable (as required 
by Sec.  1114.7(i)(4)(vii)).
    Multiple comments provided feedback or requested clarification 
related to these provisions, as discussed below.
    (Comment 39) One comment requested additional clarification 
regarding the HPHCs for which an applicant must conduct testing when 
submitting a PMTA for an ENDS. The comment noted the proposed addition 
of 19 constituents to the established list of HPHCs and sought further 
information regarding what must be submitted in a PMTA.
    (Response 39) The rule requires each applicant to submit 
information regarding all constituents contained in and emitted from 
the product, which could include both constituents that are contained 
within the established list of HPHCs and those that are not on the 
list. FDA's recommendations regarding constituents in an ENDS for which 
a prospective applicant might want to consider testing, as appropriate 
for its specific product, are discussed elsewhere in this document (see 
Response 35).
    (Comment 40) One comment stated that while consideration of the 
constituents on FDA's list of HPHCs is important, FDA should not give 
it undue emphasis because there are other toxins in tobacco products 
that are not on this list. The comment stated an application's exposure 
assessment should cover the full range of exposures generated by the 
new product and that FDA should revise the rule to clearly state that 
evidence of biological and clinical effects of the product will be 
given more weight than measures of exposure.
    Another comment stated that the definitions of the terms 
``constituent'' and ``HPHC'' are so broad that the requirement in Sec.  
1114.7(i)(1)(v) to report all constituents contained within or emitted 
from the product could be difficult for applicants. The comment stated 
that there are practical constraints on the number, capacity, and 
capability of laboratories equipped to conduct the testing. The comment 
also expressed concern that FDA could potentially refuse to file an 
application in which an applicant omitted a constituent. The comment 
suggested that FDA revise the rule so that an application would be 
required to contain only information for ``relevant'' constituents and 
HPHCs, rather than all constituents. Specifically, the comment 
recommended that the inclusion of constituent and HPHC information 
should be based on a comprehensive risk assessment of the particular 
product.
    (Response 40) FDA declines to make revisions in response to these 
comments. An application is not required to contain testing for all 
HPHCs on the initial list; rather, it must contain testing for HPHCs 
that are contained within and can be delivered by the type of product 
and contain a description of why the HPHCs that were tested are 
appropriate for the type of product. FDA declines to limit the scope of 
the constituents that must be reported in a PMTA to only those that an 
applicant considers to be relevant because it may impair FDA's ability 
to determine the health risks of a new tobacco product. As discussed in 
the rule, the constituents contained within and delivered from a 
tobacco product directly relate to its health risks. The HPHC list can 
be helpful to applicants in preparing a description of why the HPHCs 
for which it tested are appropriate for the product type, including, 
where appropriate, why an applicant did not test for certain HPHCs. For 
example, a PMTA for a smokeless tobacco product would not be required 
to contain testing results for HPHCs that are a byproduct of combustion 
(e.g., carbon monoxide) where the product does not contain or deliver 
such constituents. However, a PMTA for an inhaled tobacco product that 
an applicant claims aerosolizes a substance but does not combust it, 
such as an e-cigarette or heated tobacco product, should provide 
evidence, such as testing for HPHCs that result from complete or 
incomplete combustion, to demonstrate that the product is not 
combusted. For recommendations on constituent testing

[[Page 55335]]

for ENDS products, please see the ENDS PMTA Guidance.
    Additionally, FDA declines to revise the rule to assign weight to 
different types of evidence. Finding that there is a showing that 
permitting the marketing of a new tobacco product would be APPH is a 
complex determination that must be made with respect to risks and 
benefits to the population as a whole, considering the likelihood of 
changes in tobacco product use behavior (including initiation and 
cessation) caused by the marketing of the new tobacco product. When 
determining whether the marketing of a particular new tobacco product 
would be APPH, FDA will evaluate the factors in light of available 
information regarding the existing tobacco product market, tobacco use 
behaviors, and the associated health risks at the time of review.
    (Comment 41) One comment requested FDA provide greater detail 
regarding the ranges of constituents that would be acceptable in a 
PMTA.
    (Response 41) FDA does not set limits for what constitutes 
acceptable ranges for constituents as a part of this rulemaking. FDA's 
APPH determination will include a consideration of constituent levels 
and their resulting health risks; however, FDA must also consider of a 
variety of information related to health risk and tobacco product use 
behaviors. FDA recommends that applicants take all the necessary steps 
in controlling and mitigating any circumstances that may affect the 
constituent yields generated from a new tobacco product as this may 
impact the risks and benefits associated with the new tobacco product 
on the population health as a whole, when compared to other products on 
the market.
    (Comment 42) One comment stated the final rule must provide greater 
detail regarding the appropriate validated methodologies or regimens 
required for testing.
    (Response 42) As discussed in Sec.  1114.7(i)(1)(v), for combusted 
or inhaled tobacco products, constituent smoke or aerosol yields from 
the new product must be determined using intense and nonintense smoking 
or aerosol-generating regimens, where established. Two smoking or 
aerosol-generating regimens are required, where established, to 
understand the way that constituent yields delivered by a tobacco 
product can change over a range of different smoking conditions. If 
constituent yields were only reported from a single smoking or aerosol-
generating regimen, FDA would have limited and potentially misleading 
information about constituent yields produced by a given tobacco 
product. Many studies demonstrate that different smoking regimens 
result in different constituent yields from the same product (Refs. 42 
and 43). By requiring both an intense and a nonintense smoking or 
aerosol generating regimen, where established, FDA will have a better 
understanding of quantities of each constituent that may be produced by 
the tobacco product when used under different conditions. If no intense 
and nonintense smoking or aerosol-generating regimens (e.g., 
International Organization for Standardization (ISO) and Health Canada 
Intense (HCI) regimens for cigarettes, Cooperation Centre for 
Scientific Research Relative to Tobacco (CORESTA) regimens for cigars) 
have been established and an applicant must use an alternative regimen, 
an applicant should provide an explanation as to why the alternative 
regimen provides comparable results. For ENDS products, for example, 
where intense and nonintense regimens may have not been established, 
the application must contain an explanation of why the alternative 
regimen provides comparable results to the intense and nonintense 
regimens.
    (Comment 43) One comment stated that manufacturers of premium 
cigars should not be required to submit information regarding HPHCs and 
other constituents. The comment stated that not only is there a lack of 
testing standards, the variability inherent in premium cigars would 
render the results of any constituent testing worthless for assessing a 
product.
    (Response 43) As stated in Sec.  1114.1(d) and described in section 
VII.A., this rule does not apply to ``premium'' cigars. To the extent 
this comment is applicable to products other than ``premium'' cigars, 
such as large cigars that do not meet the definition of ``premium'' 
cigar, FDA disagrees with this comment. Each applicant that submits a 
PMTA is required by Sec.  1114.7(i)(1)(v) to conduct constituent 
testing and submit the results as part of their application. 
Understanding the constituents contained within and emitted from a 
tobacco product is a crucial component of being able to determine its 
health effects, which is why FDA will refuse to accept a PMTA (under 
Sec.  1114.27(a)(1)), as appropriate, where it lacks constituent 
testing information required by Sec.  1114.7(i)(1)(v). Where a 
product's ingredients have natural variability that could affect 
constituent testing results, FDA recommends an applicant submit 
scientific evidence justifying why the results reflect the natural 
variability of the ingredients in the new tobacco product. This 
evidence could include items such as scientific literature establishing 
the variability of the product, information related to international or 
national testing standards, or data from an investigation with 
sufficient sample size to demonstrate attributes affecting variability 
of the test results (e.g., weight, smoke efficiency, crop year to crop 
year, region to region). Additionally, CORESTA \21\ have established 
and published methods on how to generate cigar smoke to quantitatively 
compare HPHCs found in cigar smoke.
---------------------------------------------------------------------------

    \21\ CORESTA standards that applicants might consider include 
CORESTA Reference Method (CRM) 46: Atmosphere for Conditioning and 
Testing Cigars of all Sizes and Shapes; CRM 47: Cigars--Sampling; 
CRM 64: Routine Analytical Cigar-Smoking Machine--Specifications, 
Definitions and Standard Conditions; CRM 65: Determination of Total 
and Nicotine-Free Dry Particulate Matter using a Routine Analytical 
Cigar-Smoking Machine--Determination of Total Particulate Matter and 
Preparation for Water and Nicotine Measurements; CRM 66: 
Determination of Nicotine in the Mainstream Smoke of Cigars by Gas 
Chromatographic Analysis; CRM 67: Determination of Water in the 
Mainstream Smoke of Cigars by Gas Chromatographic Analysis; CRM 68: 
Determination of Carbon Monoxide in the Mainstream Smoke of Cigars 
by Non-Dispersive Infrared Analysis.
---------------------------------------------------------------------------

    vi. Container closure system. Section 1114.7(i)(1)(vi) requires 
that the application contain a description of the container closure 
system for the new tobacco product, if applicable, including 
information describing how the container closure system protects and 
preserves the product from damage during transport, environmental 
contaminants, and leaching and migration of constituents into the new 
tobacco product. The description must also contain information 
describing design features developed to prevent the risk of accidental 
exposure, if any (e.g., child resistant packaging for e-liquids). These 
descriptions are important to FDA's review of the product because they 
help demonstrate that the product used by consumers is in the same 
condition as that described in the application and manufactured by the 
applicant and provide information regarding whether the container 
closure system has any features that could prevent accidental exposure.
    Additionally, evidence demonstrates that the container closure 
system used can change the characteristics of the product. For example, 
substances within the packaging materials can affect product moisture 
(e.g., when the manufacturer changes the container closure system of a 
moist snuff from plastic to fiberboard), which can affect microbial 
stability and TSNA formation during storage (Ref. 44). Another example 
is when menthol or other

[[Page 55336]]

ingredients are applied to the inner foil of a cigarette package to 
become incorporated into the consumed product (Ref. 1). The container 
closure system may also be intended or reasonably expected to affect 
the characteristics of a tobacco product by impacting the rate of 
leaching into, and ultimately, the amount of substances found in, the 
consumable tobacco product. In fact, it has been demonstrated that 
compounds in the container closure system may diffuse into snuff and 
affect its characteristics (Ref. 2). Thus, for example, packaging 
material that affects the characteristics of a tobacco product by 
impacting the moisture level or shelf life of a tobacco product is a 
container closure system (e.g., a plastic container compared to a metal 
container of smokeless tobacco) because a difference in tobacco 
moisture is reasonably expected to affect microbial growth in the 
product, extraction efficiency, and total exposure to nicotine or the 
carcinogens NNN or NNK. For additional examples of container closure 
systems, see the ENDS PMTA Guidance.
    vii. Statement of tobacco blending, reconstitution, and 
manipulation. Finally, the rule requires a PMTA to contain a full 
statement of the tobacco blending, reconstitution, or manipulation, 
where applicable. This may include manufacturer specifications, and 
tobacco types, and quantities. This information is important because it 
helps FDA understand the characteristics of the tobacco product. 
Information on tobacco types and quantities used by an applicant (where 
applicable) will help FDA understand the composition of tobacco used, 
which can provide important information since the tobacco types and 
quantities may impact the tobacco chemistry (e.g., the nicotine 
content) and, thereby, the chemical composition of the tobacco product 
(Ref. 45).
    b. Other properties. Section 1114.7(i)(2) describes additional 
parts of FDA's interpretation of the requirement in section 
910(b)(1)(B) of the FD&C Act to provide a full statement of the product 
properties and, together with FDA's authority under section 
910(b)(1)(G), requires the applicant to provide a full description of 
the properties of the tobacco product that includes:
    i. Product dimensions and construction. The product dimensions and 
the overall construction of the product using a diagram or schematic 
drawing that clearly depicts the finished product and its components 
with dimensions, operating parameters, and materials. Under the 
definition of finished tobacco product (which includes all components 
and parts, sealed in final packaging), the dimensions and schematic 
drawings are required to include the final packaging. The diagram or 
schematic is an annotated graphical representation that will help FDA 
understand the applicant's nomenclature, how the components and parts 
function together, and the overall principles of operation of the 
finished tobacco product.
    ii. Design parameters and test data. All design parameters of the 
product and test data, specifying nominal values or the explicit range 
of values as well as the design tolerance (i.e., upper and lower range 
limits), where appropriate. Changes in design parameters can change the 
health impact of the tobacco product by affecting the level of 
constituents that reach the user or nonuser and are also necessary to 
fully characterize a tobacco product. Given the potential health 
impacts associated with changes in design parameters as well as the 
importance of design parameters in fully characterizing a product, the 
PMTA review process does not simply note or link these parameters to 
the product and any associated constituents. Instead, during PMTA 
review, FDA evaluates how products are manufactured, and the controls 
put in place during production. For the PMTA pathway, FDA reviews 
whether each design parameter meets its specification through test 
data, determining whether each parameter is adequately controlled via 
documented processes, determining whether safeguards are in place 
against hazards and foreseeable misuse, and assessing how the applicant 
deals with nonconforming products. FDA believes it is necessary to 
review sufficient information to ensure that products marketed under 
the PMTA pathway have the necessary manufacturing and control processes 
in place. Tables 1 through 22 in Sec.  1114.7(i)(2)(ii)(B) provide the 
parameters that are required for different categories of tobacco 
products. As part of the full description of the properties of the 
tobacco product, the rule also requires, as included in the tables, a 
quantitative description of the performance criteria, including test 
protocols, test data, and a summary of the results, for each applicable 
design parameter and manufacturing step. The test data is a required 
part of the PMTA to demonstrate the product consistently meets the 
nominal values or range of values as well as the design tolerance. 
While test data is a required part of the PMTA, FDA does not require 
test data for all the parameters for which it requires target and 
range. For example, for parameters that are observational (e.g., number 
of waterpipe holes), FDA would not seek test data on that parameter. 
Also, some design parameters are machine settings (e.g., tobacco cut 
size), calculated (e.g., denier per filament (DPF)), provided by 
suppliers (e.g., certificate of analysis for base paper porosity), or 
can be extrapolated from other design parameter test data (e.g., filter 
pressure drop test data is more informative than filter length test 
data). Test data would not be needed for such parameters. In addition, 
in tables 1 through 22, FDA has clarified alternative terminology for 
``porosity'' understanding that applicants may refer to this term as 
``permeability'' for several design parameters as well as adding units 
of measure for several design parameters. The design parameters, their 
importance to understanding their impact on public health, and methods 
for applicants to provide this information are described below.
    One way an applicant can provide the information needed for a 
product's required design parameters is with a Manufacturing Data Sheet 
Specification (MDSS) document. The MDSS is a document typically 
maintained by manufacturers, describing all the parameters that are 
controlled by the manufacturer during manufacture of their tobacco 
products. There will be cases where the design parameters on the MDSS 
will not directly translate into one of the product-specific design 
parameters in section 1114.7(i)(2)(ii). In these cases, additional 
information would need to be submitted to provide the complete 
characterization necessary. There may also be instances (e.g., for 
novel tobacco products in one of the categories described in table 1 to 
Sec.  1114.7(c)(3)(iii)) where one or more of the required design 
parameters do not apply to the tobacco product described in the PMTA. 
In these instances, an applicant must justify why the required design 
parameter does not apply or how an alternative design parameter(s) 
would satisfy one or more of the required design parameters. Similarly, 
for test data, an applicant must justify why the required test data 
does not apply or how alternative test data should be considered by FDA 
in lieu of the required test data. Further, there may be instances 
where the tobacco product may not fit into any of the categories 
described in table 1 to Sec.  1114.7(c)(3)(iii). In these instances, 
the applicant must provide design parameters that would fully 
characterize their product. Additionally, if there are

[[Page 55337]]

design parameters beyond what FDA is requiring that would characterize 
the tobacco product, applicants should provide those to aid in FDA's 
scientific review. While failure to include additional design 
parameters to fully characterize the tobacco product beyond what FDA is 
requiring under this rule would not serve as the basis for FDA refusing 
to accept or file an application under Sec.  1114.27(a)(1), it may slow 
down the substantive review process.
    Applicants should also state whether the ranges or tolerances 
associated with each design parameter correspond to product or process 
controls, and what actions the applicant takes when test data falls 
outside of these specified ranges. As an example of product and process 
controls, a smokeless tobacco product may have set design parameters 
(also known as product specifications) for pH and oven volatiles (OV). 
The applicant may establish process controls for the fermentation 
process by setting lower and upper temperature and humidity limits for 
specified time durations. At the end of the fermentation process, a 
sample may be tested to verify that the tobacco product meets the 
established pH and OV design parameter limits. For any design 
parameters that are provided that are not included in the tables to 
Sec.  1114.7(i)(2)(ii)(B), applicants must provide test data or process 
information to demonstrate that these parameters or their associated 
processes are adequately controlled.
    Table 1 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for cigarettes. In this final rule we have revised 
table 1 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to 
identify and evaluate each product more accurately and efficiently. 
These changes include: (1) Removal of the proposed requirement for 
applicants to provide cigarette draw resistance, as FDA determined that 
requiring this parameter was unnecessary and not as informative as 
pressure drop as draw resistance could be modified by the user by 
puffing more or less intensely; (2) removal of cigarette paper base 
paper basis weight and tipping paper basis weight, as they are not as 
informative as other design parameters, such as cigarette paper base 
paper porosity; (3) removal of plug wrap parameters, as the effects of 
plug wrap are not as informative as cigarette paper parameters; (4) 
removal of cigarette mass, paper width, filter diameter, tipping paper 
width, and tobacco rod length, as these parameters can be either 
calculated from other required design parameters or are not as 
informative as other required parameters; (5) removal of filter mass 
and filter tow crimp index, as these parameters have less of an impact 
on the filter efficiency than other required design parameters that 
will affect the smoke constituents that are exposed to users and 
nonusers; (6) removal of filter ventilation position of holes, filter 
ventilation number of holes, and filter ventilation number of rows as 
filter ventilation, which is still required, is affected by these 
parameters; (7) the inclusion of filter efficiency as an alternative to 
DPF, total denier, or filter density, if available, as these parameter 
have a direct effect on filter efficiency and vice versa; (8) the 
option to provide cigarette diameter as an alternative to cigarette 
circumference as FDA is able to calculate the necessary information 
based on either one; and (9) the option for the applicant to provide 
cigarette paper band diffusivity in lieu of cigarette paper band 
porosity, if applicable (also described as permeability). FDA has 
clarified terminology for cigarette paper band porosity, as applicants 
may refer to this term as permeability, and also provided an 
alternative to providing cigarette paper band porosity or 
permeability--band diffusivity, while not preferred, is an acceptable 
alternative if it is currently not part of an applicant's practice to 
specify cigarette paper band porosity. While there are minor 
differences (porosity is more relevant during active puffing, whereas 
diffusivity is more relevant during smoldering), the addition of 
diffusivity as an alternative parameter allows flexibility to 
applicants who do not directly measure porosity or permeability (see 
Ref. 46).
    Additionally, FDA has revised certain proposed parameters for test 
data, which includes: (1) Removal of puff count as this was duplicative 
of information that an applicant would submit with smoke constituent 
data since puff count is determined in a smoking machine using either 
the ISO or HCI smoking regimen or other applicable regimen; (2) removal 
of cigarette draw resistance, as explained above; (3) removal of 
cigarette mass, cigarette paper base paper and tipping paper basis 
weight, as explained above; (4) removal of plug wrap parameters, as 
explained above; (5) removal of tipping paper width and tipping paper 
perforation, as explained above; (6) removal of tipping paper length 
and width, tobacco rod length, cigarette paper length and width, 
cigarette length, cigarette diameter, cigarette paper band width, 
cigarette paper band space, filter diameter and length as these are 
measured parameters, that are not needed as test data; (7) removal of 
filter tow crimping index and filter mass, as explained above. The 
finalized parameters listed in table 1 to Sec.  1114.7(i)(2)(ii)(B) are 
a necessary part of the application because they are needed to fully 
characterize the product and changes in these parameters may affect the 
cigarette's impact on the public health, as described below:
     Cigarette length may alter tobacco biomarker levels (Ref. 
47);
     cigarette circumference or diameter may affect filter 
efficiency and, in turn, smoke constituent yields (Ref. 48); puff count 
can directly affect smoke constituent yields (Ref. 49);
     tobacco filler mass may affect smoke constituent yields 
(Ref. 50);
     tobacco rod density may modify burn properties and smoke 
constituent yields (Refs. 51 and 52);
     tobacco cut size alters the size of the tobacco pieces, 
which may result in more particulate matter (Ref. 53);
     tobacco moisture may affect puff count (Ref. 54);
     cigarette paper base paper basis weight may affect puff 
count and smoke constituent yields (Ref. 55);
     cigarette paper base paper porosity or permeability may 
affect smoke constituent yields (Ref. 55);
     cigarette paper band porosity or permeability may affect 
smoke constituent yields because band porosity allows for the overall 
assessment of the weighted change in air flow through the cigarette 
paper during active puffing (Ref. 56);
     cigarette paper band diffusivity may affect smoke 
constituent yields because it mimics air flow during smoldering (Ref. 
57);
     cigarette paper band width may affect ventilation and, in 
turn, smoke constituent yields (Ref. 58);
     cigarette paper band space may affect ignition propensity 
and, in turn, puff count (Ref. 59);
     filter efficiency may affect smoke constituent yields 
(Ref. 58);
     filter DPF, total denier, filter density, and filter 
length may affect filter efficiency and, in turn, smoke constituent 
yields (Ref. 60);
     filter pressure drop may affect smoke constituent yields 
(Ref. 61);
     tipping paper, including length, may affect smoke 
constituent yields (Ref. 62); and
     filter ventilation may affect smoke constituent yields 
(Ref. 48).
    Table 2 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for

[[Page 55338]]

portioned and nonportioned smokeless tobacco products. We have revised 
table 2 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to 
identify and evaluate each product more accurately and efficiently. 
These changes include: (1) Removal of portion thickness, as it is an 
unnecessary parameter because it is the pouch effective area that may 
result in an increase of the release level of nicotine, unprotonated 
nicotine, and could affect TSNA levels, and the pouch effective area 
can be calculated from other required design parameters, i.e., pouch 
length and pouch width; (2) removal of pouch material nicotine 
dissolution extent, as nicotine dissolution rate provides the nicotine 
exposure to the user over time, and therefore was considered redundant 
and unnecessary; (3) addition of pouch material thickness as this 
parameter influences the release level of nicotine and can affect TSNA 
levels; \22\ (4) option to provide tobacco particle size in lieu of 
tobacco cut size, as tobacco particle size can impact the use profile 
of the product and thereby affect the rate and total delivery of HPHCs 
similar to tobacco cut size. FDA has revised certain proposed 
parameters for test data, which includes the removal the portion 
length, width, portion thickness, and material thickness, as these are 
measured design parameters that can be obtained from the supplier of 
the portion or pouch, and (5) clarification of requiring certain 
parameters ``if applicable'' for portioned product properties. While 
these parameters are needed for all portioned smokeless products, not 
all portioned products are pouched, so the pouch-specific properties 
should only be reported if applicable, and thus FDA has added ``if 
applicable'' to pouch material porosity or permeability and pouch 
material basis weight.
---------------------------------------------------------------------------

    \22\ See, e.g., Gale, N., G. Errington, and K. McAdam, Group 
Research & Development, British American Tobacco, ``Effects of 
Product Format on Nicotine and TSNA Extraction from Snus Pouches,'' 
Presentation at the 67th Tobacco Science Research Conference, 
Williamsburg, VA, September 15-18, 2013. Available at: https://www.researchgate.net/publication/299854728_Effects_of_Product_Format_on_Nicotine_and_TSNA_Extraction_from_Snus_Pouches.
---------------------------------------------------------------------------

    The finalized parameters in table 2 to Sec.  1114.7(i)(2)(ii)(B) 
are a necessary part of the applications because they are needed to 
fully characterize the product and changes in these parameters may 
affect the smokeless tobacco product's impact on public health, as 
described below:
     Tobacco cut size may alter the particle surface area and 
accessibility of saliva to get to the surfaces of the tobacco, thereby 
affecting the amount and rate of constituents released from the product 
(Ref. 63);
     tobacco moisture may affect microbial growth in the 
product, extraction efficiency, and total exposure to nicotine, NNN, 
and NNK (Refs. 3 and 64);
     portion mass may affect user exposure to a tobacco product 
and, in turn, HPHCs contained in each portion (Ref. 65);
     portion length may affect the constituents in each portion 
(Ref. 65);
     portion width may result in a surface area difference, 
which is proportional to the amount and rate of constituents released 
from the product (Ref. 66);
     pouch material basis weight, pouch material air 
permeability, and pouch material thickness influences the interactions 
between the tobacco and oral cavity, thereby potentially affecting the 
amount and rate of constituents released from the product (Refs. 67, 
141, and 142; \23\) and
---------------------------------------------------------------------------

    \23\ See response 45 for additional information.
---------------------------------------------------------------------------

     nicotine dissolution rate is a function of tobacco cut 
size and pouch materials, thereby potentially affecting the amount and 
rate of constituents released from the product (Ref. 68).
    Table 3 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for RYO tobacco rolling paper products. In this 
final rule, we have revised table 3 to Sec.  1114.7(i)(2)(ii)(B) to 
help ensure that FDA is able to identify and evaluate each product more 
accurately and efficiently. These changes include the option to provide 
RYO paper band diffusivity in lieu of RYO paper band porosity (also 
described as permeability). FDA has clarified terminology for RYO paper 
band porosity, as applicants may refer to this term as permeability, 
and also provided an alternative to providing cigarette paper band 
porosity or permeability--band diffusivity, while not preferred, is an 
acceptable alternative if it is currently not part of an applicant's 
practice to specify cigarette paper band porosity. While there are 
minor differences (porosity is more relevant during active puffing, 
whereas diffusivity is more relevant during smoldering), the addition 
of diffusivity as an alternative parameter allows flexibility to 
applicants who do not directly measure porosity or permeability (see 
Ref. 46). Additionally, FDA has revised certain proposed parameters for 
test data, which includes the removal the paper length, width, band 
space, and band width as these are measured design parameters that are 
not needed as test data.
    The finalized parameters listed in table 3 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes in these 
parameters may affect the rolling paper's impact on public health, as 
described below:
     RYO paper length and RYO paper width may alter the surface 
area that is available for tobacco packing, thereby affecting the smoke 
constituent yields (Ref. 61);
     RYO mass per paper may be a result of a surface area or 
basis weight difference and, in turn, may affect puff count and smoke 
constituent yields (Refs. 55 and 61);
     RYO paper base paper basis weight may affect puff count 
and smoke constituent yields (Ref. 55);
     RYO paper base paper porosity may affect smoke constituent 
yields (Ref. 55);
     RYO paper band porosity may affect smoke constituent 
yields because band porosity allows for the overall assessment of the 
weighted change in air flow through the cigarette paper during active 
puffing (Ref. 56);
     RYO paper band diffusivity may affect smoke constituent 
yields because it mimics air flow during smoldering (Ref. 57);
     RYO paper band width may affect ventilation and, in turn, 
smoke constituent yields (Ref. 58); and
     RYO paper band space may affect ignition propensity and, 
in turn, puff count (Ref. 59).
    Table 4 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for RYO tobacco tubes. We have revised table 4 to 
Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to identify 
and evaluate each product more accurately and efficiently. These 
changes include the addition of: (1) The option to provide tube 
diameter as an alternative to tube circumference, as FDA is able to 
calculate the information necessary based on either one and (2) the 
option for the applicant to provide tube paper band diffusivity in lieu 
of tube paper band porosity or permeability, if applicable. FDA has 
clarified terminology for RYO paper band porosity, as applicants may 
refer to this term as permeability, and also provided an alternative to 
providing cigarette paper band porosity or permeability--band 
diffusivity, while not preferred, is an acceptable alternative if it is 
currently not part of an applicant's practice to specify cigarette 
paper band porosity. While there are minor

[[Page 55339]]

differences (porosity is more relevant during active puffing, whereas 
diffusivity is more relevant during smoldering), the addition of 
diffusivity as an alternative parameter allows flexibility to 
applicants who do not directly measure porosity or permeability (see 
Ref. 46). FDA has revised certain proposed parameters for test data, 
which includes the removal of tube length, tube paper width, tube 
circumference, tube paper band width, and tube paper band space, as 
these are measured design parameters.
    The finalized parameters listed in table 4 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes in these 
parameters may affect the RYO tube's impact on public health, as 
described below:
     Tube mass may affect smoke constituent yields (Ref. 50);
     tube length may alter tobacco biomarker levels (Ref. 47);
     tube circumference or diameter may affect filter 
efficiency and, in turn, smoke constituent yields (Ref. 48);
     tube paper width may affect smoke constituent yields (Ref. 
50);
     tube paper base paper basis weight may affect puff count 
and smoke constituent yields (Ref. 55);
     tube paper base paper porosity may affect smoke 
constituent yields (Ref. 55);
     tube paper band porosity may affect smoke constituent 
yields since band porosity allows for the overall assessment of the 
weighted change in air flow through the cigarette paper during active 
puffing (Ref. 56);
     tube paper band diffusivity may affect smoke constituent 
yields because it mimics air flow during smoldering (Ref. 57);
     tube paper band width may affect ventilation and, in turn, 
smoke constituent yields (Ref. 58); and
     tube paper band space may affect ignition propensity and, 
in turn, puff count (Ref. 59).
    Table 5 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for RYO tobacco filtered tubes. In this final rule 
we have revised table 5 to Sec.  1114.7(i)(2)(ii)(B) to help ensure 
that FDA is able to identify and evaluate each product more accurately 
and efficiently. These changes include: (1) The option to provide tube 
diameter as an alternative to tube circumference, as FDA is able to 
obtain the information necessary from calculations based on what the 
applicant submits; (2) the option for the applicant to provide filter 
efficiency as an alternative to DPF, total denier, or filter density 
(Ref. 60); (3) the option for the applicant to provide diffusivity in 
lieu of paper band porosity or permeability, as described in previous 
design parameter sections, is an acceptable alternative if it is 
currently not part of an applicant's practice to specify paper band 
porosity; (4) removal of filter mass, filter diameter, and filter tow 
crimping index as these parameters are considered as not as important 
as other parameters such as DPF and total denier, and therefore deemed 
unnecessary; (5) removal of plug wrap length, width, basis weight, and 
porosity as plug wrap parameters contribute to ventilation; however, 
filter ventilation and paper porosity have more of an effect on 
ventilation and therefore, plug wrap parameters were considered 
unnecessary; (6) removal of tipping paper width, basis weight, and 
perforation are considered unnecessary because they have little effect 
on the airflow and are not combusted during use; and (7) removal of 
filter ventilation position of holes, filter ventilation number of 
holes, and filter ventilation number of rows as these parameters are 
considered redundant because the filter ventilation is affected by 
these parameters. The alternatives (filter efficiency and diffusivity) 
are also provided under test data for this product category. Further, 
FDA has revised certain parameters for test data that were previously 
proposed in the PMTA rule, which include: (1) Removal of the tube mass, 
tube length, tube diameter, tube paper length, nonfilter tube length, 
tube width, tube paper band width and space, filter length, filter 
mass, and filter diameter as these are measured design parameters and 
(2) removal of filter tow index, plug wrap length, plug wrap width, and 
tipping paper basis weight for reasons described above.
    The finalized parameters listed in table 5 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes in these 
parameters may affect the filtered tube's impact on public health, as 
described below:
     Tube mass may affect smoke constituent yields (Ref. 50);
     tube length may alter tobacco biomarker levels (Ref. 47);
     tube circumference or diameter may affect filter 
efficiency and, in turn, smoke constituent yields (Ref. 48);
     tube paper length directly correlates to non-filter tube 
length, which may affect smoke constituent yields (Ref. 50);
     tube paper width may affect smoke constituent yields (Ref. 
50);
     tube paper base paper basis weight may affect puff count 
and smoke constituent yields (Ref. 55);
     tube paper base paper porosity may affect smoke 
constituent yields (Ref. 55);
     tube paper band porosity may affect smoke constituent 
yields since band porosity allows for the overall assessment of the 
weighted change in air flow through the cigarette paper during active 
puffing (Ref. 56);
     tube paper band diffusivity may affect smoke constituent 
yields because it mimics air flow during smoldering (Ref. 57);
     tube paper band width may affect ventilation and, in turn, 
smoke constituent yields (Ref. 58);
     tube paper band space may affect ignition propensity and, 
in turn, puff count (Ref. 59);
     filter efficiency may affect smoke constituent yields 
(Ref. 58);
     filter DPF may affect filter efficiency and, in turn, 
smoke constituent yields (Ref. 60);
     total denier, filter density, and filter length may affect 
filter efficiency and, in turn, smoke constituent yields (Ref. 43);
     filter pressure drop may affect smoke constituent yields 
(Ref. 61);
     tipping paper length may affect smoke constituent yields 
(Ref. 62); and
     filter ventilation may affect smoke constituent yields 
(Ref. 48).
    Table 6 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for RYO tobacco. In this final rule, we have 
revised table 6 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is 
able to identify and evaluate each product more accurately and 
efficiently. This change includes the removal of the requirement for 
the applicant to provide filler mass as this is provided as part of 
unique identification of the tobacco product under Sec.  1114.7(c).
    The finalized parameters listed in table 6 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes in these 
parameters may affect the RYO tobacco's impact on public health, as 
described below:
     Tobacco cut size alters the size of the tobacco pieces, 
which may result in more particulate matter (Ref. 53) and
     tobacco moisture may affect puff count when used with 
rolling paper (Ref. 54).
    Table 7 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for RYO tobacco paper tips. In this final rule, we 
have revised table 7 to

[[Page 55340]]

Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to identify 
and evaluate each product more accurately and efficiently. This 
includes the replacement of the requirement for the applicant to 
provide RYO paper base paper perforation, and instead provide RYO paper 
porosity. RYO porosity was found to directly convey the smoke 
constituent exposure to users, while paper perforation was less 
indicative of the exposure of smoke constituents when accounting for 
additional design parameters. FDA has also revised certain parameters 
for test data that were proposed previously in the PMTA rule, which 
include: (1) Removal of the tip length and width and tip mass as these 
are measured design parameters; and (2) replacement of paper 
perforation to paper porosity, as described above.
    The finalized parameters listed in table 7 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect the paper tip's impact on public health, as described below:
     RYO paper tip length and RYO paper tip width may alter the 
surface area that is available for tobacco packing, thereby affecting 
the smoke constituent yields (Ref. 61);
     RYO paper tip mass may be a result of a surface area or 
basis weight difference and, in turn, may affect puff count and smoke 
constituent yields (Refs. 55 and 61);
     RYO paper base paper basis weight may affect puff count 
and smoke constituent yields (Ref. 55);
     RYO paper base paper porosity may affect smoke constituent 
yields (Ref. 55); and
     RYO paper tip ventilation may affect smoke constituent 
yields (Ref. 48).
    Tables 8 through 12 to Sec.  1114.7(i)(2)(ii)(B) describe the 
design parameters and information on performance criteria that must be 
contained in a PMTA for products categorized as cigars. Cigarettes 
(outside the category of heated tobacco products) and cigars are 
similar, as they are both cylinders filled with a blend of processed 
tobacco that is generally smoked. Both are generally lit with a fire 
source, which burns the tobacco as the user inhales at one end; thus, 
they are consumed and deliver nicotine in a similar manner. A main 
difference between cigarettes and cigars is that cigars are either 
wrapped in a tobacco leaf (wrapper and binder) or a material containing 
tobacco, whereas non-HTP cigarettes are wrapped in paper (cigarette 
paper) or a material that does not contain tobacco. Additionally, 
cigars come in a wider variety of sizes and some types of cigars may be 
thicker in diameter and contain more tobacco filler than cigarettes. 
Despite these differences, for both types of tobacco products, no 
matter the size, air is pulled through the tobacco column, which aids 
in tobacco combustion and nicotine delivery. Cigarette paper commonly 
has an established porosity (permeability), that is set during 
manufacturing, while cigar wrapper properties are based on the tobacco 
used as the wrapper. Although cigars and cigarettes are wrapped in 
different materials, both cigar wrappers and binders, as well as 
cigarette papers, have inherent permeabilities/porosities, which may 
affect smoke constituent yields. Cigars may be filtered (containing 
filter tow or other materials), unfiltered, or unfiltered with tips 
made of wood or plastic, while most cigarettes have filters (containing 
filter tow) and do not contain tips. If a cigar does contain a filter, 
it will be similar to cigarette filters and contain tow. Based on FDA's 
experience with cigarettes under the SE pathway, as well as the 
similarities between the two products, FDA has used established design 
parameter information from cigarettes to develop some of the design 
parameter requirements for cigars. Tables 8 through 12 to Sec.  
1114.7(i)(2)(ii)(B) describe in more detail the parameters for each 
subcategory of cigars.
    Table 8 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
contained in a PMTA for filtered, sheet-wrapped cigars. In this final 
rule we have revised table 8 to Sec.  1114.7(i)(2)(ii)(B) to help 
ensure that FDA is able to identify and evaluate each product more 
accurately and efficiently. These changes include (1) the addition of 
cigar wrapper and binder band space, as these parameters affect smoke 
constituents; (2) the addition of cigar minimum and maximum diameter 
(mm), as the shape of cigars can differ, with the tips being narrower 
than the center of the cigar, affecting the rod density, which in turn 
modifies the burn properties and smoke yields; (3) providing applicants 
the option to provide oven volatiles as an alternative to tobacco 
moisture, as well as the option to provide oven volatiles instead of 
moisture, as this provides similar information to FDA \24\ and allows 
the applicant flexibility to provide either parameter based on the 
specific manufacturing processes they employ; and (4) removing cigar 
length, cigar diameter, filter diameter, filter length as requirements 
for test data as these are measured design parameters that are not 
needed as test data.
---------------------------------------------------------------------------

    \24\ Please note that the term ``moisture,'' has widely varying 
and conflicting definitions and terminology in use within the 
tobacco industry. It is common for ``moisture'' or ``moisture 
content'' to be used to refer to water content of a material but in 
relation to the tobacco industry it is necessary to differentiate 
between ``moisture'' as water content and ``moisture'' as oven 
volatiles. https://www.coresta.org/sites/default/files/technical_documents/main/PTM-CTR_MoistureWaterOvenVolatiles_July2014%282%29.pdf.
---------------------------------------------------------------------------

    Additionally, based on FDA's understanding of machine-made cigars 
and their similarity to cigarettes, we have also included design 
requirements previously recommended in the proposed PMTA rule. These 
design parameters include (1) cigar mass, wrapper and binder basis 
weight, cigar binder and wrapper length and width, cigar wrapper and 
binder band porosity, and cigar wrapper and binder width, as these 
design parameters may affect smoke constituent yields and (2) the 
option for the applicant to provide filter efficiency, if available, as 
an alternative to DPF, total denier, or filter density. We have also 
included test data requirements for cigar mass, puff count, wrapper and 
binder basis weight, and cigar minimum and maximum diameter for reasons 
previously discussed.
    The finalized parameters listed in table 8 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect the cigar's impact on public health, as described below:
     Cigar mass reflects the amount of tobacco in a cigar, 
which may affect smoke constituent yields (Ref. 69);
     cigar puff count can directly affect smoke constituent 
yields (Ref. 69);
     cigar length and diameter can directly affect the amount 
of tobacco that is burned and, in turn, affect smoke constituent yields 
(Ref. 70);
     tobacco filler mass may affect smoke constituent yields 
(Ref. 71);
     for cigarettes, the cigarette paper basis weight may 
affect puff count and smoke constituents (Ref. 71). Similarly, for 
cigars, the cigar wrapper and binder basis weight may affect puff count 
and smoke constituent yields;
     for cigarettes, the paper length and width may affect puff 
count and smoke constituents (Ref. 71). Similarly, for cigars, the 
cigar wrapper and binder length and width may directly influence the 
area through which air is permitted to enter the tobacco column, which, 
in turn, may affect puff count and smoke constituent yields;
     cigar wrapper porosity may affect smoke constituent yields 
(Refs. 72 and 73);

[[Page 55341]]

     for cigarettes, tobacco rod density may modify burn 
properties and smoke constituent yields (Refs. 51 and 52). Similarly, 
for cigars, tobacco rod density may modify burn properties and smoke 
constituent yields;
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for cigars, the tobacco 
moisture may affect puff count (Ref. 54);
     for cigarettes, the tobacco cut size may result in more 
particulate matter (Ref. 53). Similarly, for cigars, the tobacco cut 
size alters the size of the tobacco pieces, which may result in more 
particulate matter;
     for cigarettes, the band porosity may affect smoke 
constituent yields (Ref. 56). Similarly, for cigars, the band porosity 
or permeability may affect smoke constituent yields because band 
porosity allows for the overall assessment of the weighted change in 
air flow through the cigarette paper during active puffing;
     for cigarettes, the band width may affect smoke yields 
(Ref. 58). Similarly, for cigars, the wrapper band width and binder 
band width may affect ventilation and, in turn, smoke constituent 
yield;
     for cigarettes, the band space may affect puff count (Ref. 
59). Similarly, for cigars, the wrapper band space and binder space may 
affect ignition propensity and, in turn, puff count;
     for cigarettes, the filter parameters can impact smoke 
yields (Ref. 60). Similarly, for cigars, the filter diameter, filter 
mass, filter tow crimping index, DPF, total denier, filter density, and 
filter length may affect filter efficiency and, in turn, smoke 
constituent yields;
     For cigarettes, the filter pressure drop affects smoke 
yields (Ref. 61). Similarly, for cigars, the filter pressure drop may 
affect smoke constituent yields.
     for cigarettes, tipping paper length may affect smoke 
constituent yields (Ref. 62). Similarly, for cigars, the tipping paper, 
including width, and basis weight, may affect smoke constituent yields; 
and
     ventilation may affect smoke constituent yields (Ref. 69).
    Table 9 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for unfiltered, sheet-wrapped cigars. In this final rule, we 
have revised table 9 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that 
FDA is able to identify and evaluate each product more accurately and 
efficiently. These changes include: (1) The addition of overall 
diameter because cigar diameter can directly affect the amount of 
tobacco that is burned and, in turn, affect smoke constituent yields; 
(2) the removal of cigar tip width (mm); (3) the option for applicants 
to provide oven volatiles in lieu of tobacco moisture, as this provides 
similar information to FDA \25\ and allows the applicant flexibility to 
provide either parameter based on the specific manufacturing processes 
they employ. In addition, as compared to the proposed PMTA rule, FDA 
has removed certain parameters for test data, including the removal of 
cigar length, cigar tip length, cigar tip diameter, and cigar tip 
width, as FDA has determined that these parameters are not necessary as 
test data. Additionally, based on FDA's understanding of cigars and 
their similarity to cigarettes, we have also included all the design 
requirements previously recommended in the proposed PMTA rule except 
cigar burn rate and cigar draw resistance. We have also included the 
following test data: Puff count, tobacco rod density, tobacco cut size, 
cigar wrapper and binder basis weight, binder porosity, and cigar tip 
mass.
---------------------------------------------------------------------------

    \25\ See footnote 21.
---------------------------------------------------------------------------

    The finalized parameters listed in table 9 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect the cigar's impact on public health, as described below:
     Cigar mass reflects the amount of tobacco in a cigar, 
which may affect smoke constituent yields (Ref. 69);
     cigar puff count can directly affect smoke constituent 
yields (Ref. 69);
     cigar length and diameter can directly affect the amount 
of tobacco that is burned and, in turn, affect smoke constituent yields 
(Ref. 70);
     tobacco filler mass may affect smoke constituent yields 
(Ref. 69);
     for cigarettes, the cigarette paper basis weight may 
affect puff count and smoke constituents (Ref. 71). Similarly, for 
cigars, the cigar wrapper and binder basis weight may affect puff count 
and smoke constituent yields;
     for cigarettes, the paper length and width may affect puff 
count and smoke constituents (Ref. 71). Similarly, for cigars, the 
cigar wrapper length and width and binder width may directly influence 
the area through which air is permitted to enter the tobacco column, 
which, in turn, may affect puff count and smoke constituent yields;
     cigar wrapper porosity may affect smoke constituent yields 
(Refs. 72 and 73).
     for cigarettes, tobacco rod density may modify burn 
properties and smoke constituent yields (Refs. 51 and 52). Similarly, 
for cigars, the tobacco rod density may modify burn properties and 
smoke constituent yields;
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for cigars, the tobacco 
moisture may affect puff count;
     for cigarettes, the tobacco cut size may result in more 
particulate matter (Ref. 53). Similarly, for cigars, the tobacco cut 
size alters the size of the tobacco pieces, which may result in more 
particulate matter;
     for cigarettes, the band porosity may affect smoke 
constituent yields (Ref. 56). Similarly, for cigars, the wrapper and 
binder band porosity or permeability may affect smoke constituent 
yields because band porosity allows for the overall assessment of the 
weighted change in air flow through the cigarette paper during active 
puffing;
     for cigarettes, the band width may affect smoke yields 
(Ref. 58). Similarly, for cigars, the wrapper and binder band width may 
affect ventilation and, in turn, smoke constituent yields;
     for cigarettes, the band space may affect puff count (Ref. 
59). Similarly, for cigars, the wrapper and binder band space may 
affect ignition propensity and, in turn, puff count; and
     cigar tip dimensions directly influence the overall cigar 
draw resistance and in turn, puff count (Ref. 74).
    Table 10 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for leaf-wrapped cigars. In this final rule, we have revised 
table 10 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able 
to identify and evaluate each product more accurately and efficiently. 
These changes include the option to provide oven volatiles instead of 
moisture, as this provides similar information to FDA \26\ and allows 
the applicant flexibility to provide either parameter based on the 
specific manufacturing processes they employ. FDA has also revised 
certain parameters for test data previously discussed in the proposed 
PMTA rule. Specifically, FDA has removed cigar length as this is a 
measured design parameter for which we do not need test data. 
Additionally, based on FDA's understanding of leaf-wrapped cigars and 
their similarity to cigarettes, we have included the design 
requirements that were previously recommended in the proposed PMTA rule 
except cigar draw resistance, wrapper and binder porosity, and cigar 
burn rate. We have

[[Page 55342]]

also included the following parameters for test data that were 
previously recommended in the proposed PMTA rule: Puff count, tobacco 
rod density, tobacco filler mass, tobacco cut size, and wrapper and 
binder basis weight.
---------------------------------------------------------------------------

    \26\ See footnote 21.
---------------------------------------------------------------------------

    FDA has also included: (1) The overall diameter as a design 
parameter because cigar diameter can directly affect the amount of 
tobacco that is burned and, in turn, affect smoke constituent yields 
and (2) tobacco cut size as a design parameter as it can alter the size 
of tobacco pieces, which may result in more particulate matter.
    The finalized parameters listed in table 10 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect the cigar's impact on public health, as described below:
     Cigar mass reflects the amount of tobacco in a cigar, 
which may affect smoke constituent yields (Ref. 69);
     cigar puff count can directly affect smoke constituent 
yields (Ref. 69);
     for cigarettes, the paper length and width may affect puff 
count and smoke constituents (Ref. 71). Similarly, for cigars, the 
cigar wrapper length and width and binder width may directly influence 
the area through which air is permitted to enter the tobacco column, 
which, in turn, may affect puff count and smoke constituent yields;
     cigar length and diameter can directly affect the amount 
of tobacco that is burned and, in turn, affect smoke constituent yields 
(Ref. 70);
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for cigars, the tobacco 
moisture may affect puff count;
     for cigarettes, the cigarette paper basis weight may 
affect puff count and smoke constituents (Ref. 71). Similarly, for 
cigars, the cigar wrapper and binder basis weight may affect puff count 
and smoke constituent yields;
     for cigarettes, tobacco rod density may modify burn 
properties and smoke constituent yields (Refs. 51 and 52). Similarly, 
for cigars the tobacco rod density may modify burn properties and smoke 
constituent yields; and
     for cigarettes, the tobacco cut size may result in more 
particulate matter (Ref. 53). Similarly, for cigars, the tobacco cut 
size alters the size of the tobacco pieces, which may result in more 
particulate matter.
    Table 11 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for cigar tobacco. In this final rule, we have revised table 
11 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to 
identify and evaluate each product more accurately and efficiently. 
These changes include the option to provide oven volatiles instead of 
moisture, as this provides similar information to FDA \27\ and allows 
the applicant flexibility to provide either parameter based on the 
specific manufacturing processes they employ. FDA has also revised 
certain proposed parameters for test data, which includes the option to 
provide oven volatiles instead of moisture, as described above. In the 
proposed rule, we proposed a recommended design parameter for cigar 
tobacco, filler mass. Based on FDA's understanding of cigar tobacco, we 
have decided not to include filler mass (mg) as a required design 
parameter. FDA has concluded that the amount of tobacco added to a 
cigar is generally user-dependent and so, the filler mass of the cigar 
tobacco as packaged does not have a direct effect on the smoke 
constituents.
---------------------------------------------------------------------------

    \27\ See footnote 21.
---------------------------------------------------------------------------

    The finalized parameters listed in table 11 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect its impact on public health, as described below:
     For cigarettes, the tobacco cut size may result in more 
particulate matter (Ref. 53). Similarly, for cigars, the tobacco cut 
size alters the size of the tobacco pieces, which may result in more 
particulate matter and
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for cigars, the tobacco 
moisture may affect puff count.
    Table 12 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for a cigar wrapper. In this final rule, we have revised table 
12 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to 
identify and evaluate each product more accurately and efficiently. 
These changes include, for both target specification and test data, the 
replacement of cigar maximum and minimum width with wrapper width, as 
not all cigar wrappers have a maximum and minimum width; additionally, 
in the proposed rule, we discussed recommended design parameters for 
cigar wrappers. Based on FDA's understanding of cigar wrappers, and 
because cigar wrapper basis weight affects smoke constituents as well 
as puff count, we have included cigar wrapper basis weight in the final 
rule. For test data that was previously recommended in the proposed 
rule, FDA has included cigar wrapper basis weight as a requirement and 
replaced cigar minimum and maximum wrapper width with wrapper width for 
the reasons discussed previously.
    The finalized parameters listed in table 12 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect its impact on public health, as described below:
     For cigarettes, the paper length and width may affect puff 
count and smoke constituents (Ref. 71). Similarly, for cigars, the 
cigar wrapper length and width may directly influence the area through 
which air is permitted to enter the tobacco column, which, in turn, may 
affect puff count and smoke constituent yields and
     for cigarettes, the cigarette paper basis weight may 
affect puff count and smoke constituents (Refs. 71 and 72). Similarly, 
for cigars, the cigar wrapper and binder basis weight may affect puff 
count and smoke constituent yields.
    Table 13 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for a waterpipe. Cigarette tobacco and waterpipe tobacco are 
similar, as they are both processed tobacco that is cut, milled, and 
sifted before ingredients are added to control for tobacco moisture and 
taste. Therefore, tobacco parameters for a cigarette can be 
extrapolated to tobacco parameters for a waterpipe. Additionally, the 
waterpipe length of the waterpipe stem causes affects the pressure drop 
in the waterpipe in a similar way as to the length of the cigarette 
filter and filter tow causes a filter pressure drop in a cigarette: 
Both determines the amount of suction a smoker needs to apply to the 
tobacco product to draw smoke through. Therefore, filter pressure drop 
for a cigarette can be extrapolated to the pressure drop of a 
waterpipe. The parameters included in table 13 apply to waterpipes 
generally. For products that contain a heating source or waterpipe 
tobacco, applications should specify information regarding the heating 
source and waterpipe tobacco as described in tables 14 and 15.
    In this final rule, we have revised table 13 to Sec.  
1114.7(i)(2)(ii)(B) to help ensure that FDA is able to identify and 
evaluate each product more accurately and efficiently. These changes 
include: (1) The removal of number of hoses as the number of hoses can 
vary during smoking session and (2) the change in terminology from 
``bowl'' to ``base.'' Additionally, in the proposed rule, we 
recommended design parameters for waterpipes. Based on FDA's 
understanding of waterpipes, we have

[[Page 55343]]

required the following design parameters: (1) Hose length, hose 
material, and hose internal diameter, which are directly proportional 
to air infiltration and affects toxicant yields; (2) stem length and 
stem internal diameter, which impacts puffing behavior and toxicant 
exposure; (3) pressure drop, which affects smoke constituent yields; 
(4) water filter efficiency, which is directly proportional to 
mainstream smoke and can increase exposure to HPHCs; and (5) hose air 
permeability and heating source type, as theses parameters have a 
direct correlation with toxicants and smoke constituents exposed to 
users and nonusers. For test data that was previously recommended in 
the proposed rule, FDA is requiring all the parameters except foil 
length, foil width, and ventilation.
    Further, based on FDA's understanding of waterpipes, we have also 
included the following required design parameters: Base diameter, base 
volume, base shape, head height, head top diameter, head bottom 
diameter, number of holes, head volume, and head material. The shape 
and size of the base can affect the pressure drop or difficulty of 
pulling air through the waterpipe hose, while the head dimensions 
affect how long a smoke session lasts by controlling how much tobacco 
can be used during a session. Head dimensions can also affect airflow 
beneath and through the tobacco to make heat transfer more effective, 
prolonging smoking sessions. FDA has also included the following 
required parameter for test data: Head height, head top diameter, head 
bottom diameter, and head volume.
    The finalized parameters listed in table 13 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect its impact on public health, as described below:
     Hose dimensions (length and diameter) are directly 
proportional to air infiltration and affects toxicant yields (Ref. 75);
     hose material may affect hose permeability, which may 
affect smoke constituent yields (Ref. 75);
     stem length influences draw resistance, which can in turn 
impact nicotine and other toxicant delivery to the user (Ref. 76);
     stem internal diameter can impact puffing behavior and 
toxicant exposure, and in turn, smoke constituent yields (Ref. 76);
     for cigarettes, the pressure drop effect smoke constituent 
yields (Ref. 71). For waterpipes the base diameter and base volume 
impact how much water the base can hold and how much water the user can 
add to the base and the volume of water impacts the pressure drop or 
the difficulty of pulling air through the waterpipe hose. Similarly, 
for waterpipes, the pressure drop may result in differences in the 
difficulty of pulling air through the waterpipe and, in turn, affect 
smoke constituent yields (Ref. 71);
     head dimensions affect how long a smoke session lasts by 
controlling how much tobacco can be used during a session. Head 
dimensions can also affect airflow beneath and through the tobacco to 
make heat transfer more effective, prolonging smoking sessions. With a 
wider surface area, there is more room for the head to more evenly 
distribute heat to the tobacco. A shallower bowl makes tobacco at the 
bottom of the head more accessible to heat and allows for heat to be 
more evenly distributed to the tobacco. The more holes in the head, the 
more airflow, which affects the tobacco temperature. All of this causes 
the tobacco to reach different temperatures that affects smoke yields 
(Ref. 75);
     water filtering efficiency is directly proportional to 
mainstream smoke and can increase exposure to HPHCs (Ref. 77);
     for cigarettes, the filter pressure drop affects smoke 
yields (Ref. 71). Similarly, for waterpipes, the pressure drop may 
result in differences in the difficulty of pulling air through the 
waterpipe and, in turn, affect smoke constituent yields;
     heating source type affects tobacco temperature, which in 
turn, may affect smoke constituent yields (Ref. 78); and
     head material could aid in heat transfer, prolonging the 
heating of the tobacco and causing the tobacco to reach temperatures 
that affect smoke yields.
    Table 14 in Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for waterpipe tobacco. In this final rule, we have revised 
table 14 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able 
to identify and evaluate each product more accurately and efficiently. 
These changes include the option for the applicant to provide oven 
volatiles as an alternative to tobacco filler moisture. We have 
provided this alternative because it will allow the applicant to 
provide information needed to evaluate the product without conducting 
additional testing as this alternative may satisfy these requirements. 
Additionally, in the proposed rule, we recommended a design parameter 
for waterpipe tobacco, filler mass. Based on FDA's understanding of 
waterpipe tobacco, we have decided not to include filler mass as a 
required design parameter for waterpipe tobacco. FDA concluded that the 
amount of tobacco added during a given smoking session is user-
dependent and so, filler mass of the waterpipe tobacco as packaged does 
not have a direct impact on smoke constituents.
    The finalized parameters listed in table 14 to Sec.  
1114.7(i)(2)(ii)(B) are necessary to fully characterize the product and 
changes may affect its impact on public health as follows:
     For cigarettes, the tobacco cut size may result in more 
particulate matter (Refs. 53 and 54). Similarly, for waterpipe tobacco, 
the tobacco cut size alters the size of the tobacco pieces, which may 
result in more particulate matter. Finer tobacco cut size may result in 
a decrease in filling power and in turn, a larger amount of tobacco in 
the bowl (Refs. 53 and 54) and
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for waterpipe tobacco, the 
tobacco moisture may affect puff count. Moisture contributes to packing 
density, thus decreasing void volume (Ref. 54).
    Table 15 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for a waterpipe heating source. In this final rule, we have 
revised table 15 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA 
is able to identify and evaluate each product more accurately and 
efficiently. These changes include: (1) The removal of heating source 
type. As there are multiple types of heating source for waterpipe, 
instead of asking for the source type, FDA has changed the terminology 
and considered all heating sources as the heating element and (2) the 
removal of charcoal temperature and coil temperature range, as 
described above, FDA considers all heating sources the heating element; 
therefore, the charcoal and coil temperature have been removed and 
replaced with ``heating element temperature.'' FDA has also revised the 
test data and removed test data for charcoal temperature range and coil 
temperature range, for reasons previously described.
    Additionally, in the proposed rule, we recommended design 
parameters for waterpipe heating source. Based on FDA's understanding 
of waterpipe heating sources, we have included some of these design 
parameters, including those related to batteries and power delivery 
units (PDU). The finalized parameters listed in table 15 to

[[Page 55344]]

Sec.  1114.7(i)(2)(ii)(B) are necessary to fully characterize the 
product and changes may affect its impact on public health as follows:
     When combusted, heating sources such as charcoal or wood 
cinders expose the user to high yields of toxicants such as carbon 
monoxide and polycyclic aromatic hydrocarbons. Therefore, the heating 
source mass, density, and temperature may affect smoke constituent 
yields (Ref. 78);
     for ENDS, the number of elements affects resistance and 
distribution of heat dissipation (Ref. 79). Similarly, for waterpipe 
heating source, the number of heating elements can affect resistance 
and distribution of heat dissipation;
     for ENDS, the heating element configuration effect affect 
toxicant emissions and nicotine delivery (Refs. 80-84). Similarly, for 
waterpipe heating source, the eating element configuration may affect 
overall heating element resistance, thereby influencing heating element 
temperature. The heating element temperature may affect toxicant 
emissions and nicotine delivery;
     for ENDS, the heating element diameter may affect toxicant 
emissions and nicotine delivery (Refs. 80-84). Similarly, for waterpipe 
heating source, the diameter of the heating element affects its 
resistance. Heating element resistance may influence heating element 
temperature, which in turn affects toxicant emissions and nicotine 
delivery;
     for ENDS, an increase in battery capacity (mAh rating) can 
increase the number of puffs the e-cigarette can deliver per vaping 
session. Longer vaping sessions may lead to greater exposure to 
toxicant emissions (Ref. 83). Similarly, for waterpipe heating source 
the battery mAh ratings is a measure of the average amount of current 
the battery releases over time under normal. Current may influence the 
heating element temperature, which in turn affects toxicant emissions 
and nicotine delivery. In addition, provides understanding how long a 
battery will last and thus the product stability;
     for ENDS, the battery and PDU voltage impacts the amount 
of e-liquid consumed, the vapor temperature, and the total emissions of 
volatile aldehydes (Ref. 85). Similarly for waterpipe heating sources, 
the battery voltage operating range and PDU voltage operating range 
(volts) impact the amount of e-liquid consumed, the vapor temperature, 
and the total emissions of volatile aldehydes;
     for ENDS, the battery type, battery current operating 
range, battery failure safety features, battery conformance to 
standards, and PDU current operating range are necessary for evaluating 
battery and PDU safety. Risks of e-cigarette battery explosion, 
leakage, fire, or overheating are a safety concern (Refs. 58 and 86). 
Similarly, for waterpipe heating source, the battery current operating 
range is a measure of the current batteries put out to heat the heating 
element of the product. The battery should have a normal operating 
range as to not overheat the product and cause it to become a hazard to 
the user. In addition, this current range has a direct impact on the 
heating element, which in turn affects the smoke constituent yields;
     for ENDS, the battery and PDU voltage impacts the amount 
of e-liquid consumed, the vapor temperature, and the total emissions of 
volatile aldehydes (Ref. 85). Similarly for waterpipe heating source 
the PDU voltage operating range impacts the amount of e-liquid 
consumed, the vapor temperature, and the total emissions of volatile 
aldehydes;
     for ENDS, the battery type, battery current operating 
range, battery failure safety features, battery conformance to 
standards, and PDU current operating range are necessary for evaluating 
battery and PDU safety. Risks of e-cigarette battery explosion, 
leakage, fire, or overheating are a safety concern (Refs. 58 and 86). 
Similarly for waterpipe heating source, the PDU current operating range 
is a measure of the current output to heat the heating element of the 
product, which, if not adequately controlled can lead to overheating 
the product subsequently may harm the user. In addition, this current 
range has a direct impact on the heating element, which in turn affects 
the smoke constituent yields; and
     for ENDS, PDU current operating range and wattage range 
are necessary for evaluating battery and PDU safety. Risks of e-
cigarette battery explosion, leakage, fire, or overheating are a safety 
concern (Refs. 80 and 86). Similarly, for waterpipe heating source the 
PDU wattage operating range determines the amount of heat produced. PDU 
wattage or wattage operating range may affect the heating element 
temperature, thereby affecting toxicant emissions.
    Table 16 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for waterpipe foil. In this final rule, we have revised table 
16 to Sec.  1114.7(i)(2)(ii)(B) to help ensure that FDA is able to 
identify and evaluate each product more accurately and efficiently. 
Specifically, in the proposed rule, we recommended design parameters 
for waterpipe foil. Based on FDA's understanding of waterpipe foil, we 
have included the following design parameter requirements: Foil 
diameter, foil thickness, number of holes, and diameter of holes. We 
have added these parameters because foil parameters affect smoke 
constituent yields, and ultimately, the user's exposure to toxicants 
and HPHCs. FDA has also revised the required test data to include the 
following parameters for the reasons detailed previously: Foil 
diameter, foil thickness, and diameter of the holes. Waterpipe foil 
length and width were erroneously listed both as required parameters 
(in table 16) and as recommended parameters in table 16a. FDA notes 
that waterpipe foil length and width are included in the final rule 
required parameters.
    The finalized parameters listed in table 16 to Sec.  
1114.7(i)(2)(ii)(B) are necessary to fully characterize the product and 
changes may affect its impact on public health as follows.
     Waterpipe foil length, diameter, and width are necessary 
because they impact the user's puffing behavior and toxicant exposure. 
Therefore, the foil dimensions may affect smoke constituent yields 
(Ref. 76);
     waterpipe foil thickness influences the distribution of 
heat to the tobacco, affecting tobacco temperatures and therefore smoke 
constituent yields (Ref. 76); and
     the number and diameter of holes impacts the path of hot 
gases through the tobacco mixture, which may affect smoke constituent 
yields (Ref. 76).
    Table 17 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for a waterpipe head. These parameters are a necessary part of 
the application because they are needed to fully characterize the 
product and changes may affect the waterpipe head's impact on public 
health, as described below:
     Head dimensions (height, top diameter, bottom diameter), 
including number of holes, and head volume, affect how long a smoke 
session lasts, as well as how much tobacco is used. Head dimensions can 
also affect airflow beneath and through the tobacco in the head, 
affecting heat transfer to the tobacco. The temperatures reached during 
smoking affect smoke yields, and user exposure to these smoke yields 
and
     the head material could aid in heat transfer, prolonging 
the heating of the tobacco and causing the tobacco to reach 
temperatures that affect smoke yields.
    Table 18 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for a pipe. The design

[[Page 55345]]

parameters described in table 18 to Sec.  1114.7(i)(2)(ii)(B) are a 
necessary part of the application because they are needed to fully 
characterize the product and changes that may affect the pipe's impact 
on public health. In this final rule, we have revised the design 
parameters related to pipes to help ensure that FDA is able to identify 
and evaluate each product more accurately and efficiently. These 
changes include the removal of: Bore minimum diameter, bore maximum 
diameter, bit length, and bit diameter. We have removed these 
parameters because they were found to be equal to the stem and shank 
diameter should be equal to the bore diameter, and in addition, the 
length of the bit can vary and have little effect on the user's 
exposure to toxicants. FDA has also revised the parameters for test 
data to include the removal of: Bore minimum diameter, bore maximum 
diameter, bit length, and bit diameter for the reasons described 
previously. Additionally, in the proposed rule, we recommended design 
parameters for pipes. Based on FDA's understanding of pipes, we have 
added design parameters related to the bowl chamber (bowl chamber cover 
outer diameter, bowl chamber cover inner diameter, bowl chamber hole 
shape, and bowl chamber volume), shank (length and diameter), draught 
hole (draught hole diameter, draught hole shape, draught hole location, 
and draught hole dimension), screen, airway and pressure drop, and 
filter (filter efficiency, pressure drop, and length). These parameters 
are a necessary part of the application because they are needed to 
fully characterize the product and changes may affect the pipe's impact 
on public health, as described below:
     Pipe screens are used in pipes to filter and stop hot 
embers and tobacco from traveling up the pipe to the user;
     the bowl chamber inner and outer diameters allow FDA to 
calculate the chamber wall thickness. A thicker wall will lead to a 
cooler smoke and makes it less likely the user will burn themselves 
when holding the chamber. Additionally, the chamber inner diameter will 
affect temperature and tobacco capacity, meaning the greater the pipe 
surface area, the more leaf can be burned at once, and with increased 
temperature, this will affect smoke constituents;
     the bowl chamber hole shape is important to characterize 
the pipe as this may affect the airflow and tobacco temperatures, which 
in turn affects the burn rate and smoke constituents delivered;
     the bowl chamber volume affects the burn rate and 
temperature, which in turn, dictates the smoke constituents delivered 
to users.
     the draught hole allows the user to pull air through the 
tobacco to their mouth. The diameter of the draught holes affects the 
resistance to draw, which can impact nicotine and other toxicant 
delivery to the user;
     the draught hole dimensions and geometry may affect the 
airflow and oxygen available at the burning tobacco for the chemical 
reaction and thus affect smoke constituent yields;
     the draught hole location should enter the bowl directly 
centered and at the very bottom of the bowl. The location can affect 
airflow and tobacco temperatures, which in turn, affects the burn rate 
and smoke constituents delivered;
     the stem of a pipe delivers smoke from the bowl to the 
user's mouth. The length of the stem may affect the smoke temperature, 
which may affect how the product is consumed, while the diameter of the 
stem may affect resistance to draw which can impact nicotine and other 
toxicant delivery to the user;
     the shank of a pipe may affect the smoke temperature 
(length) and resistance to draw (diameter);
     for cigarettes, the filter pressure drop affects smoke 
yields (Ref. 62). Similarly, for pipes, the pressure drop through the 
air valve can affect nicotine and other toxicant delivery to the user. 
Air flow through an air valve can affect tobacco burn rate and tobacco 
temperatures which in turn, may affect smoke constituent delivery to 
the user. Some pipes may come with a filter; and
     for cigarettes, filter diameter, DPF, total denier, filter 
density, and filter length may affect filter efficiency and, in turn, 
smoke constituent yields (Ref. 60). Similarly, for pipes, the filter 
efficiency, filter pressure drop, and filter length may affect smoke 
constituent yields.
    Table 19 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for pipe tobacco. In this final rule, we have revised table 19 
(formerly table 18 in the proposed PMTA rule) to Sec.  
1114.7(i)(2)(ii)(B) to help ensure that FDA is able to identify and 
evaluate each product more accurately and efficiently. These changes 
include allowing applicants to provide oven volatiles (%) as an 
alternative for tobacco moisture. We have provided these alternatives 
because it will allow the applicant to provide information needed to 
evaluate the product without conducting additional testing as these 
alternatives may satisfy the requirements. Additionally, in the 
proposed rule, we recommended design parameters for pipe tobacco. Based 
on FDA's understanding of pipe tobacco, we have decided not to include 
filler mass (mg) as a design parameter.
    The finalized parameters listed in table 19 to Sec.  
1114.7(i)(2)(ii)(B) are required as part of the application because 
they are necessary to fully characterize the product and changes may 
affect its impact on public health:
     for cigarettes, the tobacco cut size may result in more 
particulate matter (Ref. 53). Similarly, for pipes, the tobacco cut 
size alters the size of the tobacco pieces, which may result in more 
particulate matter and
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for pipes, the tobacco moisture 
or oven volatiles may affect puff count.
    While demonstrating compliance with voluntary standards can provide 
information that is important to FDA's review, this alone would neither 
fulfill the reporting requirements for battery design parameters under 
Sec.  1114.7(i)(2)(ii) nor render further of the battery review 
superfluous. As described elsewhere in this section, FDA needs a full 
characterization of the tobacco product--including the battery, where 
applicable--to complete its review. FDA provides information regarding 
the health impacts for each design parameter for products categorized 
as ENDS, as discussed elsewhere in this section.
    Table 20 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for an ENDS. In this final rule, we have revised table 20 
(formerly table 19 in the proposed PMTA rule) to Sec.  
1114.7(i)(2)(ii)(B) to help ensure that FDA is able to identify and 
evaluate each product more accurately and efficiently. These changes 
include (1) the removal of overall atomizer resistance (ohms), wick 
ignition temperature, coil temperature cut-off, and coil temperature 
range. We have removed these parameters because, current cut-off and 
heating element temperature range are now required; as such, the 
inclusion of these parameters would be considered redundant. We have 
removed wicking ignition because not all wicking materials have an 
ignition temperature, nor do all ENDS products have an overall atomizer 
resistance; (2) change in language instead of ``coil'' the phrase 
``heating element'' is used to include all heating elements that may 
not be considered a coil; and (3) the inclusion of ventilation. 
Additionally, in the proposed rule, we recommended design parameters 
for

[[Page 55346]]

ENDS. Based on FDA's evolving understanding of ENDS products, we have 
included the following previously recommended design parameters, as 
required: Draw resistance puff count, atomizer tank/cartridge volume, 
number of heating elements, heating elements length and diameter, 
heating element configuration, battery voltage operating range, battery 
current operating range, battery nominal voltage, battery current 
rating, battery charging temperature limits, battery discharge 
temperature limits, battery end of discharge voltage, battery maximum 
charging current, battery maximum discharging current, battery upper 
limits charging voltage, PDU voltage operating range, and PDU current 
operating range. FDA has also revised the test data to include these 
parameters, as these parameters affect the heating element temperature 
which in turn effects the smoke constituents exposed to the users and 
nonusers.
    The finalized parameters listed in table 20 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes may 
affect its impact on public health, as described below.
     The air flow rate of the ENDS can affect the coil/heating 
element temperature, e-liquid consumption, and aerosol characteristics 
such as particle number concentration, count median diameter, and 
PM2.5, which impact aerosol exposure (Ref. 87);
     coil/heating element resistance may affect overall heating 
element resistance, thereby influencing heating element temperature. 
The coil/heating element's resistance, material and the voltage \28\ 
determine the current flow and heating element temperature. The heating 
element temperature and temperature duration may affect toxicant 
emissions and nicotine delivery (Refs. 80-84);
---------------------------------------------------------------------------

    \28\ Voltage, current, and resistance are used to ensure the 
battery and the ENDS are operating within the ``normal operating 
range.'' The battery manufacturer sets the normal range of the 
voltage and current. Understanding the resistance allows FDA to 
assess whether the coil is drawing more current than the battery is 
designed for.
---------------------------------------------------------------------------

     coil/heating element resistance and battery output voltage 
determine PDU wattage. PDU wattage determines the amount of heat 
produced by the atomizer. PDU wattage or wattage operating range may 
affect the heating element temperature, thereby affecting toxicant 
emissions and nicotine delivery (Refs. 82 and 84);
     an increase in battery capacity (mAh rating) can increase 
the number of puffs the e-cigarette can deliver per vaping session. 
Longer vaping sessions may lead to greater exposure to toxicant 
emissions (Ref. 83);
     the temperature of the coil/heating element can affect the 
chemical and physical characteristics of the aerosol delivered to the 
user. An increase in coil/heating element temperature can increase HPHC 
levels in the aerosol, therefore, maximum coil/heating element 
temperature and temperature control deviation from this maximum coil/
heating element temperature can affect toxicant emissions and nicotine 
delivery (Refs. 80-84);
     number of coils/heating element present can affect overall 
atomizer resistance and distribution of heat dissipation (Ref. 79);
     the position of the coil/heating element can increase the 
possibility of dry puff conditions and subsequent increased toxicant 
emissions (Ref. 82);
     atomizer and cartridge components of e-cigarettes may be 
heated repeatedly and aerosolized and can contribute to increased 
toxicant emissions (Ref. 80);
     puff count can differ depending on other puff topography 
(e.g., puff duration and puff flow rate), e-cigarette and atomizer 
design, and e-liquid parameters. Puff count can also affect total puff 
volume, which in turn can affect total toxicant emissions (Ref. 88). In 
addition, information on the puff count of ENDS can help FDA assess the 
health risks of the product, including how it compares to other 
products;
     e-liquid capacity of the atomizer tank/cartridge can 
affect total puff volume, which in turn can affect total toxicant 
emissions (Refs. 88 and 89);
     battery/PDU voltage or voltage operating range may affect 
the heating element temperature, thereby affecting toxicant emissions 
and nicotine delivery (Refs. 81-84);
     battery wattage or wattage operating range may affect the 
heating element temperature, thereby affecting toxicant emissions 
(Refs. 82 and 84);
     coil/heating element resistance and battery output voltage 
determine PDU wattage. PDU wattage determines the amount of heat 
produced by the atomizer. PDU wattage or wattage operating range may 
affect the heating element temperature, thereby affecting toxicant 
emissions (Refs. 82 and 84);
     PDU wattage deviation may influence heating element 
temperature, thereby affecting toxicant emissions (Refs. 82 and 84).
     the temperature of the coil/heating element can affect the 
chemical and physical characteristics of the aerosol delivered to the 
user. An increase in coil/heating element temperature can increase HPHC 
levels in the aerosol, therefore, maximum coil/heating element 
temperature and temperature control deviation from this maximum coil/
heating element temperature can affect toxicant emissions and nicotine 
delivery (Refs. 81-84);
     coil/heating element resistance, number of coils/heating 
element, coil/heating element gauge, and coil/heating element 
configuration may affect overall heating element resistance, thereby 
influencing heating element temperature. The heating element 
temperature may affect toxicant emissions and nicotine delivery (Refs. 
81-84);
     battery type, battery current operating range, battery 
failure safety features, battery conformance to standards, and PDU 
current operating range are necessary for evaluating battery and PDU 
safety. Risks of e-cigarette battery explosion, leakage, fire, or 
overheating are a safety concern (Refs. 80 and 86);
     battery power impacts the delivery of nicotine and the 
total emissions of volatile aldehydes (Refs. 85 and 90);
     battery and PDU voltage impact the amount of e-liquid 
consumed, the vapor temperature, and the total emissions of volatile 
aldehydes (Ref. 85);
     the draw resistance of the ENDS impacts the ease of 
drawing air into the ENDS to produce aerosol, which can affect nicotine 
and other toxicant delivery to the user (Ref. 91). For cigarettes, we 
evaluate filter pressure drop since it is more informative than draw 
resistance; however, for ENDS, there is no filter pressure drop or 
other similar parameter that could be used in place of draw resistance;
     inhaled aerosol temperatures can be damaging or 
uncomfortable to users who inhale aerosol above a certain temperature 
(Ref. 92); and
     ventilation may affect smoke constituent yields (Ref. 69).
    Table 21 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for an e-liquid. In this final rule, we have revised Table 21 
(formerly Table 20 in the proposed PMTA rule) to Sec.  
1114.7(i)(2)(ii)(B) to help ensure that FDA is able to identify and 
evaluate each product more accurately and efficiently. Specifically, we 
removed the requirement to provide the e-liquid boiling point as a 
required design parameter because the information it would provide is 
sufficiently captured by coil temperature and e-liquid composition.
    The finalized parameters listed in table 21 to Sec.  
1114.7(i)(2)(ii)(B) are a necessary part of the application because 
they are needed to fully characterize the product and changes

[[Page 55347]]

may affect its impact on public health, as described below:
     The e-liquid volume can affect the delivery of nicotine 
and other toxicants to the user (Refs. 88 and 89);
     aerosol parameters such as particle number concentration, 
count median diameter, and PM2.5 are used to characterize 
the amount and size of particles to which the user is exposed. 
Epidemiological and clinical studies have shown that exposure to large 
amounts of small particles can impair lung function and is correlated 
with cardiovascular disease (Refs. 93 and 94);
     e-liquid viscosity impact the proportion of nicotine that 
is aerosolized (Ref. 95). Also, the e-liquid viscosity can affect the 
electronic cigarette nicotine and other toxicant delivery to the user 
(Refs. 79 and 88); and
     the e-liquid volume can affect the delivery of nicotine 
and other toxicants to the user (Refs. 88 and 89).
    Table 22 to Sec.  1114.7(i)(2)(ii)(B) describes the design 
parameters and information on performance criteria that must be 
provided for heated tobacco products (HTPs). HTPs currently sold in 
global markets can function in ways that are similar to products in 
other product categories. For example, some HTPs can function like ENDS 
products by aerosolizing e-liquids or using a battery and PDU to power 
the product. Other HTPs can contain tobacco filler, like a cigarette or 
cigar, but are heated instead of combusted. For these reasons, the 
properties of HTPs vary widely, but are comparable to the properties of 
other tobacco product categories. As such, based on FDA's experience 
with other similarly characterized tobacco products, the information 
needed from a design parameter standpoint perspective for HTPs overlaps 
with that of products in other categories. The parameters listed in 
table 22 to Sec.  1114.7(i)(2)(ii)(B) are a necessary part of the 
application because they are needed to fully characterize the product 
and changes may affect its impact on public health, as described below:
     For cigarettes, the length, diameter, and mass can affect 
smoke constituent yields (Ref. 70). Similarly, for HTPs, dimensions 
(mass, length, width, height, and diameter) can directly affect the 
amount of tobacco that is heated and, in turn, affect smoke constituent 
yields;
     for ENDS products, the draw resistance can affect nicotine 
and other toxicant delivery to the user (Ref. 91). Similarly, for HTPs, 
the draw resistance can impact the ease of drawing air into the product 
to produce aerosol, which can affect smoke constituent yields;
     for ENDS, puff count can affect total toxicants emissions 
(Refs. 88). Similarly, for HTPs, the puff count can affect puff volume, 
which in turn can affect total toxicant emissions;
     for ENDS, e-liquid capacity of the atomizer tank/cartridge 
can affect total toxicant emissions (Refs. 88 and 89). Similarly, for 
HTPs, the product volume (capacity of the cartridge) can affect total 
puff volume, which in turn can affect total toxicant emissions;
     for ENDS, airflow rate can impact aerosol exposure (Ref. 
87). Similarly, for HTPs, the airflow rate allows air to flow from the 
heating element to the user's mouth; some products allow the user to 
manually change the airflow while others have a minimum airflow that 
activates the product;
     for cigars, ventilation may affect smoke constituents 
yields. Similarly, for HTPs, ventilation may affect smoke constituent 
yields (Ref. 69);
     for ENDS, the battery and PDU voltage may affect the 
heating element, thereby affecting toxicant emissions and nicotine 
delivery (Refs. 81-84). Similarly, for HTPs, the battery and PDU 
voltage impact the amount of e-liquid consumed, the vapor temperature, 
and the total emissions of volatile aldehydes (Ref. 85). In addition, 
it gives an idea of the temperature users will encounter;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 60 and 86). Similarly, for 
HTPs the temperature sensor is a safety feature that allows the product 
power to be cut off to ensure the product does not get too hot, causing 
the battery to vent or harm the user;
     for cigarettes, wrapper length and width may affect puff 
count and smoke constituents yields (Ref. 71). Similarly, for HTPS 
material wrapper length and width may directly influence the area 
through which the air is permitted to enter the tobacco column, which, 
in turn, may affect puff count and smoke constituent yields (Ref. 71);
     for cigarettes, wrapper basis weight may affect puff count 
and smoke constituents (Ref. 71 and 72). Similarly, for HTPs, the 
material wrapper basis weight may affect puff count and smoke 
constituent yields;
     for cigars, the cigar wrapper porosity may affect smoke 
constituent yields (Refs. 72 and 73). Similarly, for HTPs, the material 
porosity may affect smoke constituent yields;
     for waterpipe, the heating source may affect smoke 
constituent yields. Similarly for HTPs, the heating element source (or 
a description of the type or approach) provides information on the type 
of heated tobacco product, such as a coil applied to the product;
     for ENDS, the temperature of the heating element can 
affect the chemical and physical characteristics of the aerosol 
delivered to the user (Refs. 81-84). Similarly for HTPs, the 
temperature of the heating element (heating element temperature range, 
operational temperature, maximum temperature) can affect the chemical 
and physical characteristics of the aerosol delivered to the user. An 
increase in heating element temperature can increase HPHC levels in the 
aerosol; therefore, maximum heating element temperature and temperature 
control deviation from this maximum heating element temperature can 
affect toxicant emissions and nicotine delivery;
     for ENDS, the heating element temperature may affect 
toxicant emissions and nicotine delivery (Ref. 84). Similarly, for 
HTPs, the heating element material can have a direct effect on the heat 
transfer to the e-liquid or tobacco, and in turn, affect the smoke 
constituent yields;
     for ENDS, the heating element configuration may affect 
toxicant emissions and nicotine delivery (Refs. 80-84). Similarly, for 
HTPs, the heating element configuration may affect overall heating 
element resistance, thereby influencing heating element temperature. 
The heating element temperature may affect toxicant emissions and 
nicotine delivery;
     for ENDS, the heating element dimensions may affect 
toxicant emissions and nicotine delivery (Refs. 80-84). Similarly, for 
HTPs, the heating element dimensions such as length influences the 
overall surface area, which affects heating element resistance, which 
influences the heating element temperature;
     for ENDS, the heating element mass may affect toxicant 
emissions and nicotine delivery (Refs. 80-84). Similarly, for HTPs, the 
heating element mass influences the power delivery of the battery, and 
in turn, the heat applied to the e-liquid or tobacco, which affects the 
smoke constituent yields and in turn, affects the smoke constituent 
yields;
     for ENDS, the heating element location may affect toxicant 
emissions and nicotine delivery (Refs. 80-84). Similarly, for HTPs, the 
heating element location can affect nicotine emissions;
     for ENDS, the number of heating elements may influence the 
heating element temperature thereby affecting toxicant exposure and 
nicotine delivery

[[Page 55348]]

(Ref. 79). Similarly, for HTPs, the number of coils/heating element 
present can affect overall resistance and distribution of heat 
dissipation;
     for ENDS, the heating element diameter or gauge may affect 
toxicant emissions and nicotine delivery (Refs. 80-84). Similarly, for 
HTPs, the bigger the diameter of the heating element, the lower its 
resistance, and vice versa. Heating element resistance may influence 
heating element temperature. The heating element temperature may affect 
toxicant emissions and nicotine delivery;
     for ENDS, the heating element resistance may affect 
toxicant emissions and nicotine delivery (Refs. 80-84). Similarly, for 
HTPs, the heating element resistance may affect overall heating element 
resistance, thereby influencing heating element temperature. The 
heating element temperature may affect toxicant emissions and nicotine 
delivery;
     for cigars, tobacco filler mass may affect smoke 
constituent yields (Ref. 69). Similarly, for HTPs, the tobacco filler 
mass may affect smoke constituent yields;
     for cigarettes, tobacco rod density may modify burn 
properties and smoke constituent yields (Refs. 51 and 52). Similarly, 
for HTPs, the tobacco rod density may modify burn properties and smoke 
constituent yields;
     for cigarettes, the tobacco moisture or oven volatiles may 
affect puff count (Ref. 54). Similarly, for HTPs, tobacco moisture or 
oven volatiles may affect puff count.
     for cigarettes, tobacco cut size alters the size of the 
tobacco pieces, which may result in more particulate matter (Ref. 53). 
Similarly, for HTPs, tobacco cut size alters the size of the tobacco 
pieces, which may result in more particulate matter (Ref. 53);
     for e-liquids, the e-liquid volume can affect the delivery 
of nicotine and other toxicants to the user (Refs. 88 and 89). 
Similarly, for HTPs, the e-liquid volume can affect the delivery of 
nicotine and other toxicants to the user;
     for e-liquids, the e-liquid viscosity can affect the 
electronic cigarette nicotine and other toxicant delivery to the user 
(Refs. 79 and 88). Similarly, for HTPs e-liquid viscosity impact the 
proportion of nicotine that is aerosolized. The e-liquid viscosity can 
affect the nicotine and other toxicant delivery to the user (Refs. 79 
and 88);
     for ENDS, an increase in battery capacity (mAh rating) can 
increase the number of puffs the e-cigarette can deliver per vaping 
session. Longer vaping sessions may lead to greater exposure to 
toxicant emissions (Ref. 83). Similarly, for HTPs the battery capacity 
is a measure of the charge stored by the battery. The higher the mAh 
rating, the higher the capacity of the battery and the longer it will 
last between charges. The longer the battery lasts, the more the user 
can inhale smoke constituents;
     for ENDS, the battery voltage operating range and PDU 
voltage operating range impact the amount of e-liquid consumed, the 
vapor temperature, and the total emissions of volatile aldehydes (Ref. 
85). Similarly, for HTPs, the battery and PDU voltage operating range 
or wattage impact the amount of e-liquid consumed, the vapor 
temperature, and the total emissions of volatile aldehydes;
     for ENDS, the battery type, battery current operating 
range, battery failure safety features, battery conformance to 
standards, and PDU current operating range are necessary for evaluating 
battery and PDU safety. Risks of e-cigarette battery explosion, 
leakage, fire, or overheating are a safety concern (Refs. 58 and 86). 
Similarly, for HTPs, the battery current range gives an indication of 
the safe zone for the battery to charge and what is considered its 
normal operating region; if the battery levels go beyond the safe zone 
while charging, the battery could be damaged, which could cause harm to 
the user;
     for ENDS, the battery and PDU voltage impacts the amount 
of e-liquid consumed, the vapor temperature, and the total emissions of 
volatile aldehydes (Ref. 85). Similarly for HTPs, the battery nominal 
voltage indicates how much current the battery can send out to the 
heating element. For the same resistance, a higher voltage will send 
more current (and more watts) to the heating element and it will 
produce more vapor. There is a link between voltage and capacity 
because vaping at a higher wattage will produce a higher current and 
that will reduce the amount of time you can vape between charges;
     for ENDS, an increase in battery capacity (mAh rating) can 
increase the number of puffs the e-cigarette can deliver per vaping 
session. Longer vaping sessions may lead to greater exposure to 
toxicant emissions (Ref. 83). Similarly, for HTPs, the battery rating 
is a measure of the average amount of current the battery releases over 
time under normal use. Current may influence the heating element 
temperature, which in turn affects toxicant emissions and nicotine 
delivery. In addition, battery mAh rating provides an understanding of 
how long a battery will last and thus the product stability;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly for 
HTPs, the battery charging temperature limits gives insight on the safe 
range for battery charging temperatures and testing will show if the 
software of the battery can keep the battery in the safe zone;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly, for 
HTPs, battery discharge temperature limits give insight on the safe 
range for battery discharging temperatures and testing will show if the 
software of the battery can keep the battery in the safe zone;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly, for 
HTPs, the end of discharge voltage is the level to which the battery 
voltage or cell voltage can fall to before affecting the load. This 
helps to establish the life cycle of the battery;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly, for 
HTPs, the battery maximum charging current at which the battery can be 
charged continuously is usually defined by the battery manufacturer in 
order to prevent excessive charge rates that would damage the battery 
or reduce its capacity. Damage to batteries is a hazard to users;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly, for 
HTPs, the battery maximum discharge current at which the battery can be 
discharged continuously is usually defined by the battery manufacturer 
in order to prevent excessive discharge rates that would damage the 
battery or reduce its capacity. Damage to batteries is a hazard to 
users;
     for ENDS, the battery type, failure safety features, and 
battery conformance

[[Page 55349]]

to standards are necessary for evaluating battery and PDU safety. Risks 
of e-cigarette battery explosion, leakage, fire, or overheating are a 
safety concern (Refs. 58 and 86). Similarly, for HTPs, the battery 
upper limits charging voltage is important to limit the maximum battery 
voltage during charging to prevent damage to the battery, which is a 
hazard to users;
     for ENDS, battery and PDU voltage can impact the total 
emissions of volatile aldehydes (Ref. 85). Similarly, for HTPs, the 
battery and PDU voltage impact the amount of e-liquid consumed, the 
vapor temperature, and the total emissions of volatile aldehydes (Ref. 
85);
     for ENDS, PDU current operating range and wattage range 
are necessary for evaluating battery and PDU safety. Risks of e-
cigarette battery explosion, leakage, fire, or overheating are a safety 
concern (Refs. 80 and 86). Similarly, for HTPS, PDU current operating 
range and wattage operating range may influence the heating element 
temperature thereby affecting toxicant emissions;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly, for 
HTPs, the PDU temperature cutoff is an electrical safety product that 
interrupts electric current when heated to a specific temperature to 
protect the user;
     for ENDS, the battery type, failure safety features, and 
battery conformance to standards are necessary for evaluating battery 
and PDU safety. Risks of e-cigarette battery explosion, leakage, fire, 
or overheating are a safety concern (Refs. 58 and 86). Similarly, for 
HTPs, the current cutoff is an electrical cutoff, which is an 
electrical safety product that interrupts electric current when a 
specific condition is met (i.e., temperature, current, etc.) to protect 
the user;
     for ENDS, the battery and PDU current operating range may 
influence the toxicant emissions (Refs. 82 and 84). Similarly, for 
HTPs, the batteries and PDU should have a normal current operating 
range so as to not overheat the product and cause it to become a hazard 
to the user. In addition, this current range has a direct impact on the 
heating element, which in turn affects the smoke constituent yields;
     inhaled aerosol temperatures can be damaging or 
uncomfortable to users who inhale aerosol above a certain temperature;
     for e-liquids, aerosol parameters such as particle number 
concentration, count median diameter, and particulate matter 
(PM)2.5 are used to characterize the amount and size of 
particles to which the user is exposed (Refs. 93 and 94). Similarly, 
for HTPs, aerosol parameters such as particle number concentration, 
count median diameter, and PM2.5 are used to characterize 
the amount and size of particles to which the user is exposed. Clinical 
studies have shown that exposure to large amounts of small particles 
can impair lung function and is correlated with cardiovascular disease;
     for cigarettes, filter efficiency may affect smoke 
constituent yields (Ref. 60). Similarly, for HTPs, filter efficiency 
effect smoke constituent yields;
     for cigarettes, filter pressure drop may affect smoke 
constituent yields (Ref. 61). Similarly, for HTPs, filter pressure drop 
may affect smoke constituent yields; and
     for cigarettes, filter diameter, DPF, total denier, filter 
density, and filter length may affect filter efficiency and, in turn, 
smoke constituent yields (Ref. 60). Similarly, for the HTPs, the filter 
diameter, DPF, total denier, filter density, and filter length, may 
affect filter efficiency and, in turn, smoke constituent yields (Ref. 
60).
    FDA received comments regarding design parameters and test data, as 
required by Sec.  1114.7(i)(2)(ii) and associated tables, as discussed 
below.
    (Comment 44) One comment stated that the lists of product design 
parameters in Sec.  1114.7(i)(2)(ii) do not reflect the subcategories 
of innovative tobacco products or nicotine delivery systems that exist 
in some of the product categories and that by requiring all parameters, 
FDA would have some applicants generate parameters that are not 
relevant to their particular subcategory. The comment suggested that 
FDA make the design parameters in these tables recommendations rather 
than required parameters.
    (Response 44) FDA declines to make this change to the rule. FDA 
believes that design parameters are necessary to fully characterize a 
tobacco product and are an important consideration in determining its 
health effects. FDA agrees that the required lists of product design 
parameters in Sec.  1114.7(i)(2)(ii) are not necessarily reflective of 
all subcategories of innovative tobacco products or nicotine delivery 
systems. However, table 1 to Sec.  1114.7(c)(3)(iii) includes a list of 
tobacco product categories and subcategories, which should help the 
applicant to determine whether the rule includes an appropriate 
category and subcategory for its new tobacco product and the 
corresponding design parameters that must be submitted, where 
applicable.
    (Comment 45) One comment stated that FDA should not require testing 
for nicotine dissolution in portioned smokeless tobacco because it does 
not represent the potential rate or amount of exposure. The comment 
also stated that because the pouch material for smokeless tobacco does 
not have nicotine, applicants should not be required to provide pouch 
material information.
    (Response 45) FDA believes that nicotine dissolution testing is an 
effective mechanism for FDA to gain insight into product performance 
and relative differences in the likely experience of users. In 
addition, changes in pouch materials of portioned smokeless tobacco 
products may change the permeability of the pouch and the rate at which 
nicotine is released, which can affect the overall performance of the 
product, including the rate at which nicotine is released to consumers 
(Ref. 67). Additionally, a study using nicotine tablets with different 
polymer content shows that nicotine release can be affected by 
thickness and pore size of the material that encloses nicotine (Ref. 
67). In this study, upon hydration, polymer in tablet formulations 
swells, forming a polymer gel layer and effectively acting as a 
permeable membrane. The tablets released nicotine at a rate controlled 
by swelling of the polymer followed by the diffusion through the 
swollen polymer gel layer. Polymer network gel swelling can affect 
material layer thickness (Ref. 141) and pore size (Ref. 142) which in 
turn can affect diffusion across the layer. Pouch materials are 
characterized by basis weight, air permeability, and thickness. 
Therefore, pouch material properties such as basis weight, air 
permeability and thickness are required to evaluate nicotine release 
from pouched smokeless tobacco products. Given the important 
information that nicotine dissolution testing and pouch material 
provide to FDA's review, FDA declines to remove the requirements for 
reporting pouch material information and nicotine dissolution testing 
in this PMTA rule.
    (Comment 46) One comment stated that FDA needs to remove the 
proposed design parameters for cigars in Sec.  1114.7(i)(2)(ii) from 
the rule and reassess its thinking as to the design parameters it 
requires and recommends for premarket review for cigars. The comment 
stated that the current proposed parameters for each type of cigar 
specified do not correspond to the actual design parameters that cigar 
manufacturers can or do use or test for

[[Page 55350]]

and, therefore, it would be impossible for applicants to provide the 
proposed parameters to FDA. The comment recommended that FDA require 
the reporting of design parameters only for cigar length, ring gauge, 
weight, and filter ventilation.
    (Response 46) FDA declines to remove the design parameters for 
cigars. As described below, design parameters are needed to fully 
characterize the product and assess its impact on public health. 
Because these design parameters are an important component of being 
able to determine a product's health effects, FDA may refuse to accept 
or refuse to file a PMTA if it lacks design parameters information 
required by Sec.  1114.7(i)(2)(ii). To ensure that FDA is able to fully 
determine the precise product being reviewed, FDA requires applicants 
provide all design parameters specific to the new product tobacco 
category. In an event that an applicant is unable to provide a design 
parameter listed in Sec.  1114.7(i)(2)(ii) for the new tobacco product, 
the applicant must provide a justification and scientific evidence for 
why those design parameters are not relevant and do not raise public 
health concerns.
    (Comment 47) One comment stated that it would be arbitrary and 
capricious to require manufacturers to submit the design parameters for 
pipes because the terms used are ones that pipe manufacturers neither 
know nor could they test for in pipes.
    (Response 47) FDA disagrees with the suggestion that requiring pipe 
manufacturers to submit design parameters for their new tobacco 
products in PMTAs would be arbitrary and capricious. FDA believes that 
these design parameters are needed to fully characterize the product 
and assess its impact on public health. Because these design parameters 
are an important component of being able to determine a product's 
health effects, FDA may refuse to accept or refuse to file a PMTA if it 
lacks design parameters information required by Sec.  1114.7(i)(2)(ii). 
For FDA to fully determine the precise product being reviewed and 
understand the potential health effects associated with the product, we 
are requiring that applicants provide all design parameters specific to 
the new product tobacco category. The design parameters required for 
pipes are measurable, and therefore test data should be easily 
obtained. Even if the design parameter names were not familiar to 
manufacturers, the manufacturers could supplement design parameter 
information by providing labeled images of their product that associate 
each component with the design parameter name used by the applicant or 
as discussed above, provide the information needed is with an MDSS 
document. FDA believes with the information provided in this rule, 
manufacturers should now be familiar with the required design 
parameters and can provide the necessary data. If FDA did not have the 
design parameters for the product it was reviewing, it would be unable 
to determine the precise product being reviewed, let alone whether the 
data and information contained in a PMTA are applicable.
    (Comment 48) One comment stated that many of the items listed in 
the ENDS design parameters section apply to components or parts that do 
not provide a direct correlation to aerosol emissions when evaluated 
independently or individually. The comment suggested that measuring 
HPHCs is a better way to assess the product than by reviewing these 
design parameters.
    (Response 48) Sections 1114.7(i)(1)(v) and (i)(2)(ii) require a 
PMTA to include both a full statement of the constituents, including 
HPHCs and other constituents, and of the design parameters for the new 
tobacco product because both provide information that is important for 
FDA's review. The design parameters are necessary to fully characterize 
the new tobacco product, which is important to FDA's accurately 
identifying and understanding of the product under review. As described 
elsewhere in this document, these design parameters can also affect the 
health risks of the new tobacco product. Information regarding the 
constituents contained in and delivered from the new tobacco product is 
also important because, as described in section VIII.B.13.a.iii, it 
directly correlates to the health risks of the new tobacco product.
    (Comment 49) One comment stated that the costs associated with 
generating design parameter data exceeds the potential marginal benefit 
of the data to FDA's overall determination of whether permitting the 
marketing of the new tobacco product would be APPH. The comment stated 
that rather than providing information regarding a product's battery, 
it should just be able to provide a certificate of compliance with the 
Underwriters Laboratories 8139 standard, which would render further 
review of the battery by FDA superfluous. The comment also stated that 
even though information regarding the particles in the aerosol produced 
by e-cigarettes is relevant to lung and cardiovascular function, FDA 
does not need it to determine whether permitting the marketing of e-
cigarettes would be APPH because they are far less harmful than 
combusted cigarettes.
    (Response 49) FDA disagrees with the comment's suggestion that FDA 
should not require design parameters for ENDS. While FDA acknowledges 
there is cost associated with generating design parameter data, the 
design parameters of the product can change the health impact of the 
tobacco product by affecting the level of constituents that reach 
tobacco product users or nonusers and as such are an important part of 
the APPH determination. This information is also necessary to fully 
characterize a tobacco product. The differences in health risks that a 
new tobacco product may present compared to one other product category 
such as cigarettes is not, by itself, sufficient to demonstrate that 
permitting the marketing of a new tobacco product would be APPH. As 
explained in section IX.D., FDA interprets the APPH standard in 
910(c)(2)(A) to require a showing that permitting the marketing of a 
new tobacco product would likely have at least a net benefit to public 
health based upon the risks and benefits to the population as a whole 
(which includes youth, young adults, and other vulnerable populations). 
Comparative health risk information is just one factor FDA may consider 
in making this determination. Additionally, a comparison to just one 
other product category may not be sufficient when current users of more 
than one product category may begin using the new tobacco product.
    iii. Function. The rule requires the application to contain a 
description of how the product is intended to function. For example, 
this could include a description of how the energy or heating source is 
used in or with the product, and how the delivery of the product's 
output (e.g., smoke, aerosol, nicotine) is controlled. This information 
can be critical to FDA's review of a tobacco product, including whether 
the product functions as intended and whether the application contains 
data and information that is relevant to the way in which it is 
intended to function. For example, if an applicant states that a 
product heats or aerosolizes, but does not combust tobacco or an e-
liquid, it would assist FDA in determining whether the information in 
the PMTA shows the product functions as intended and whether the 
application contains appropriate information regarding this function 
(e.g., data regarding relevant HPHCs).
    iv. pH of product and nicotine formulation. The rule requires the 
PMTA to specify the pH of the product. The pH of the product is 
important for

[[Page 55351]]

FDA to review as part of a PMTA because it can affect the amount of 
unprotonated nicotine delivered to the user (Refs. 96 and 97).
    The rule also requires the PMTA to specify the formulation of the 
nicotine in the product. The nicotine formulation information is 
required to state the type(s) and quantity of nicotine in the product. 
Type(s) of nicotine include, but are not limited to, unprotonated 
nicotine and nicotine salts (e.g., nicotine lactate, nicotine benzoate, 
nicotine pyruvate). The quantity of unprotonated nicotine is important 
for FDA to review because the amount and speed of nicotine delivered by 
a tobacco product is related to the proportion of nicotine in a tobacco 
product that is unprotonated (Refs. 98 and 99). The types and 
quantities of nicotine salts in the product are important for FDA to 
review because nicotine salt complexes can substantially increase 
nicotine delivery relative to free-base nicotine in ENDS products 
(Refs. 100-102).
    v. Fermentation process. For smokeless tobacco products and tobacco 
products that contain fermented tobacco (including naturally fermented 
tobacco), the rule requires an application to contain information on 
the fermentation process. The rule requires this information because 
the fermentation process can result in different degrees of change in 
the chemical constituents of the tobacco (Refs. 103-105) and affect the 
type and number of microorganisms in the final tobacco product, (Refs. 
106-108) which could potentially affect the levels of TSNAs and 
stability of the tobacco products during storage. In addition, the type 
and amount of the fermentation inoculum can change the product as a 
result of directed fermentation (Ref. 109). Therefore, the application 
must contain the following information regarding the fermentation 
process:
     A description of the fermentation process;
     composition of the inoculum (starter culture) with genus 
and species name(s) and concentration(s) (if applicable);
     any step(s) taken to reduce microbes already present 
during product processing (e.g., cleaning of product contact surfaces);
     specifications and test data for pH, temperature, and 
moisture content, or water activity;
     frequency of aeration or turning (if applicable);
     duration of fermentation;
     added ingredients;
     method used to stabilize or stop fermentation. If the 
applicant uses heat treatment, then it must provide the information 
specified in the following subsection. If an applicant uses a method 
other than heat treatment, it must provide the parameters of the method 
(e.g., length of treatment, temperature) and method validation data; 
and
     storage conditions of the fermented tobacco prior to 
further processing or packaging and duration of storage (if 
applicable).
    vi. Heat treatment process. In final rule, we have added a 
requirement for information on the heat treatment process, if 
applicable. For tobacco products that are heat treated, the rule 
requires an application to contain information on the heat treatment 
process. We have included this requirement for information because the 
heat treatment process can potentially reduce the microbial load, 
resulting in lower levels of carcinogenic TSNAs thereby altering 
product composition (i.e., product characteristics) (Refs. 110-112). 
Therefore, the application must contain the following information 
regarding the heat treatment process:
     A description of the heat treatment process;
     the type of heat treatment;
     the conditions of heat treatment, including time, 
temperature, and moisture; and
     method validation data, including microbial loads 
(including bacteria, spores, yeast, and fungi) and TSNAs before and 
after heat treatment.
    vii. Shelf life and stability information. In the proposed rule, 
Sec.  1114.7(i)(2)(vii) would have required a PMTA for any category of 
tobacco product to contain tobacco product storage and stability 
information that establishes the microbial and chemical stability of 
the tobacco product throughout the stated shelf life. Upon review of 
public comments and further consideration, we are finalizing these 
requirements (with specified changes) for products other than 
cigarettes and RYO tobacco as explained in this section.
    Shelf life and stability information is important for FDA's review 
of many tobacco products because bacterial communities and constituents 
in tobacco products can change over time (Refs. 107, 108, 113 and 114). 
Stability information is a particular concern with smokeless tobacco 
products and other tobacco products that contain fermented tobacco 
(including naturally fermented tobacco) because the characteristics of 
these products can be affected by the manufacturing process, storage 
conditions, and length of time on a shelf. Carcinogenic TSNA production 
is critically influenced by the microbial communities associated with 
the tobacco (Refs. 113 and 105). TSNA content in the finished tobacco 
products is greatly affected by a variety of factors, such as tobacco 
processing method(s) (e.g., curing, aging, sweating, fermentation, and 
heat treatment), chemical additives added to control microbial activity 
(e.g., humectants or preservatives), water activity (aw) of 
the product, container closure system, and product storage conditions 
(e.g., temperature, humidity), all of which could potentially alter 
microbial activity and, in turn, affect the stability of the tobacco 
products over the shelf life (Refs. 107, 108, 110, 113, 114, 115-120). 
Furthermore, some tobacco products such as smokeless tobacco products 
and e-liquids, have been shown to contain microbial cell wall 
constituents ([1[rarr]3]-[beta]-D-glucan) and/or microbial toxins, such 
as aflatoxins and endotoxins (Refs. 121 and 122). These microbial 
components or toxins may result in increased risk to public health 
because they are either carcinogenic in nature or associated with the 
development of respiratory symptoms, reduced lung function, 
inflammation and asthma (Refs. 121 and 122). In addition, based on our 
experience, HTPs can contain high levels of humectants, which can 
affect product stability; therefore shelf life and stability 
information is required to support an application for HTPs. Humectants 
function to keep a product moist, thereby impacting the moisture 
content and water activity of the product, which in turn may impact 
microbial growth and product stability (Ref. 116). Thus, for many 
tobacco products, information obtained through stability testing and 
shelf life is important for FDA to consider during its review to ensure 
that the tobacco products are microbiologically and chemically stable 
during the storage and do not result in an increased risk to public 
health as the product sits in storage.
    Under the final rule, applicants submitting a PMTA for cigarettes 
\29\ and RYO tobacco products do not need to provide the shelf life and 
stability information under Sec.  1114.7(i)(2)(vii). In our review 
experience, we have found that since the vast majority of cigarettes 
and RYO tobacco products do not contain fermented tobacco, these 
products generally do not present the same stability concerns as other 
tobacco products. Thus, after further consideration, FDA is not 
finalizing the shelf life and stability information

[[Page 55352]]

requirements for these products based upon its review experience with 
the product categories under the SE pathway. However, since we lack 
similar experience with novel tobacco products, such as ENDS and HTPs, 
we need stability information for these types of products to determine 
whether there is a difference in microbial factors or HPHC quantities 
over time. Given the Agency's lack of experience reviewing applications 
for novel tobacco products, at this time FDA believes information 
regarding these products' shelf life and stability over time is needed 
to ensure FDA fully understands the microbial and chemical stability of 
the tobacco products throughout their stated shelf life.
---------------------------------------------------------------------------

    \29\ See the discussion in section VIII.B.3. about how products 
should be categorized for purposes of PMTA review.
---------------------------------------------------------------------------

    In addition, after review of available scientific information 
regarding stability testing as well as consideration of comments 
received in responses to the proposed rule, the stability testing 
requirements have been updated including changes such as the removal of 
identification of microbiological organisms by genus and species and 
removal of testing for pH, moisture content, nitrate and nitrite 
levels, and preservatives and microbial metabolic inhibitors. 
Specifically, the final rule requires an application to contain the 
following shelf life and stability information:
     The length of the shelf life, a description of how the 
shelf life is determined and a description of how shelf life is 
indicated on the tobacco product, if applicable. The rule would not 
require a tobacco product to indicate the product's shelf life; 
however, if it is indicated on the product, the PMTA must describe how 
it is determined. For example, if the tobacco product labeling has a 
``use by,'' ``best by,'' or expiration date, a PMTA must contain a 
description of how the date is determined (e.g., a certain number of 
days after packaging);
     stability date assessed at the beginning (zero time), 
middle, and end of the expected shelf life. If a tobacco product does 
not have a defined shelf life, provide stability data over a specified 
amount of time and a justification for why that time period is 
appropriate. For example, if an applicant believes that 2 years after 
the date of product manufacture is an appropriate shelf life, the 
applicant should provide clear justification to support this time. 
Stability testing must be performed for the chemical and microbial 
endpoints for the following items:
    [cir] Microbial content data, including total aerobic microbial 
count and total yeast and mold count;
    [cir] water activity (aw);
    [cir] TSNA yields (total N-nitrosonornicotine [NNN], and 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK]); and
    [cir] preservative content (if applicable).
    If microbial activity during the product shelf life is detected, 
further information, such as endotoxin or aflatoxin levels, should be 
included in the PMTA.
    Accelerated studies for chemical endpoints, combined with basic 
stability information on the components or parts and container closure 
system (separately), or the tobacco product (as a whole) may be used to 
support chemical stability of the tobacco product provided full shelf 
life studies are not available and are being conducted. Where data from 
accelerated studies are used to project a tentative shelf life that is 
beyond a date supported by actual shelf life studies, stability studies 
must be conducted under nonaccelerated conditions at appropriate 
intervals, until the tentative expiration date is verified or the 
appropriate expiration date is determined.
    As required by Sec.  1114.7(i)(4), the reported stability testing 
must be performed on test samples that reflect the final tobacco 
product composition and design (including the container closure system) 
and be conducted using a sufficient sample size and number of 
replicates to substantiate the results of the type of testing 
conducted. Section 1114.7(i)(4) also requires the application to 
contain the following information regarding stability testing:
     The mean quantity and variance with unit of measure;
     the number of samples and measurement replicates for each 
sample;
     the methods used, including a deviation(s) from the 
methods, associated reference(s), and full validation reports for each 
method;
     the name and location of the testing laboratory or 
laboratories and documentation showing that the laboratory or 
laboratories is (or are) accredited by a nationally or internationally 
recognized external accreditation organization;
     the length of time between dates of tobacco product 
manufacture and date(s) of testing;
     the length of time between date of tobacco product 
manufacture and date(s) of testing;
     the storage conditions of the tobacco product before it 
was tested;
     a statement that the testing was performed on a tobacco 
product in the same container closure system in which the tobacco 
product is intended to be marketed; and
     full test data (including quantitative acceptance (pass/
fail) criteria, complete data sets, and a summary of the results) for 
all stability testing performed.
    FDA received several comments regarding shelf life and stability 
information, as discussed below.
    (Comment 50) One comment requested that FDA clarify, with regard to 
shelf life and stability testing, whether changes to the product over 
time will form the basis of FDA's decision to issue a marketing denial 
order for a new tobacco product.
    (Response 50) Product stability information is important for FDA to 
consider during its review because if a product changes over time, it 
may affect the health risks presented by the new tobacco product. As 
described in section IX.D, the health risks of a new tobacco product 
forms part of the basis for FDA's determination of whether it should 
issue a marketing granted order for the new tobacco product. This may 
include the health risks of a new tobacco product as it changes over 
time. For example, a product with a 24-month expiration date whose 
stability testing data demonstrates that the product may be unstable 
after manufacturing, with the levels of TSNAs (NNN and NNK) increasing 
significantly over the 24-month period shelf life above what is 
reasonably expected for similar products on the market, may raise 
additional health risks. Because NNN and NNK are carcinogenic to humans 
with no safe level of exposure, the increased levels of TSNAs may 
increase the health risks to the users. Therefore, this type of 
stability testing information is important for FDA to consider during 
its review to ensure that the tobacco products are microbiologically 
and chemically stable, and the product remains APPH, over the product's 
shelf life.
    (Comment 51) One comment stated that where a product does not have 
an established shelf life, the rule should require an applicant to 
report stability data using the upper bound length of time the product 
will remain in storage, such as the upper 95 percent confidence 
interval, rather than relying on the typical period of time in which a 
product is sold to consumers, which it interprets to be the median 
time. The comment also stated that the rule should be amended to 
require applicants to provide regular postmarket reports on how much 
product has been removed because it was in storage for too long and how 
that product was disposed of.

[[Page 55353]]

    (Response 51) FDA disagrees with this comment. As discussed 
elsewhere in this document, a PMTA is required to contain product 
storage and stability information that establishes the microbial and 
chemical stability of the product throughout the product's shelf life. 
For tobacco products with no established or defined shelf life, FDA 
recommends that applicants provide details of stability over a 
specified amount of time and justify why that time period is 
appropriate. This time period should correspond to the expected storage 
time of the tobacco product after the date of manufacture of the 
product until it is sold to consumers, as determined by the applicant. 
This information is product-specific, and the burden is on the 
applicant to show that the product is stable for the entire duration 
determined by the applicant. Since the expected storage time is 
product-specific, FDA declines to establish requirements for postmarket 
reports regarding product removal or disposal for all products. FDA 
will monitor the marketing of the product, including review of periodic 
reports required under Sec.  1114.41, to determine whether there are 
product stability issues that were not addressed in the PMTA.
    (Comment 52) One comment stated that FDA's approach for stability 
testing for microbiological endpoints in the form of total aerobic 
microbial count (TAMC), total yeast and mold count (TYMC), and testing 
for specific microbial organisms is not aligned with current scientific 
approaches. The comment also noted that the proposed testing 
requirements are not aligned with the current scientific approaches in 
addressing microbiological quality in various industries (e.g., 
pharmaceuticals), which take into consideration the importance of water 
for microbiological proliferation. The comment suggested that 
applicants should be allowed to adopt a risk-impact assessment-based 
approach, whereby results of a toxicological assessment of the product 
taking into account its composition, manufacturing process, and typical 
supply chain conditions shall be used by the applicant to define and 
execute a stability program appropriate for the product category. The 
comment stated that in particular, with regards to risks associated 
with potential microbiological activity, scientifically justified 
surrogate factors can be employed such as water activity 
(aw). The comment concluded by stating that FDA should not 
employ a one-size fits all approach for different categories of tobacco 
products.
    (Response 52) FDA disagrees with this comment. During review of a 
PMTA, FDA evaluates stability of the finished tobacco product during 
storage. To determine the microbial and chemical stability of a tobacco 
product during the expected storage period, FDA evaluates the 
cumulative effect of all factors, such as tobacco processing (e.g., 
fermentation, heat-treatment, curing), product composition (e.g., 
humectants, preservatives, certain flavor compounds, metabolic 
inhibitors), aw of the finished tobacco product, container 
closure system, and product storage conditions (e.g., temperature, 
humidity), that could potentially affect the stability of the product 
during storage. Aw is a measure of the amount of water that 
is available for microbial growth in a product. Therefore, it only 
provides information on the potential of a product to support growth of 
microbes present in the product. Fresh tobacco leaves are colonized by 
a variety of microorganisms. Additionally, microbial contamination 
could potentially occur during tobacco processing, finished tobacco 
product manufacture, and/or storage. Some tobacco products such as 
smokeless tobacco products and e-liquids, have been shown to contain 
microbial cell wall constituents ([1[rarr]3]-[beta]-D-glucan) or 
microbial toxins, such as aflatoxins and endotoxins (Refs. 121 and 
122). These microbial components or toxins may result in increased risk 
to public health because they are either carcinogenic in nature or 
associated with the development of respiratory symptoms, reduced lung 
function, inflammation and asthma. Therefore, TAMC and TYMC data 
provide crucial information on the microbial load in the finished 
tobacco product and serve as an indicator for the potential of presence 
or absence of microbial toxins in the product. Additionally, 
aw levels are influenced by several factors (e.g., humectant 
levels, container closure system, storage conditions) and could 
potentially change during storage. TAMC and TYMC data are important to 
corroborate changes in aw during storage and therefore 
crucial in evaluating the stability of the finished tobacco product 
during storage. FDA will evaluate shelf life and stability information 
of each tobacco product as part of its APPH determination.
    (Comment 53) Two comments expressed additional concerns about the 
breadth of information required to be submitted regarding the stability 
of smokeless tobacco products. One comment disagreed with the proposed 
requirement to include analytical measurements of pH, moisture content, 
aw, TAMC, TYMC, nitrate, nitrite, preservatives, and 
microbial metabolic inhibitors in stability studies for new smokeless 
tobacco products. The comment stated that because the ultimate endpoint 
of stability testing is to determine whether TSNA formation occurs over 
time, assessment of these additional parameters is burdensome, resource 
intensive, and unnecessary. The comment noted that not only would they 
have to develop validated methodologies and find laboratories to 
conduct the testing, the analysis of the proposed parameters would only 
indicate favorable conditions for increases of TSNAs and would not 
yield a change in total TSNAs, which are also being measured. Another 
comment expressed similar concerns and disagreed with the requirement 
to provide microbial content data that identifies detected 
microbiological organisms by genus and species names because it would 
be costly and time intensive, yield highly variable results depending 
on the method used, and would not alter the presence of TSNAs in the 
tobacco product as measured at each stability timepoint.
    (Response 53) FDA has revised section Sec.  1114.7(i)(2)(vii) of 
the codified to include aw, preservative content, TSNAs 
(reported as separate amounts for the total TSNAs, NNN, NNK) and 
microbial content data including TAMC and TYMC along with 
identification of microbiological organisms by genus and species names. 
FDA disagrees with the statement that the parameters would only 
indicate favorable conditions for increases of TSNAs and would not 
yield a change in total TSNAs. Microbial-mediated reduction of nitrate 
results in production of nitrite, which further reacts with alkaloids 
present in tobacco to produce carcinogenic TSNAs (Refs. 107 and 113). 
Microbial-mediated nitrite production is a key determinant of TSNA 
levels in the final tobacco product. Several nitrate-reducing bacterial 
species (e.g., Bacillus, Enterobacter, Staphylococcus, Corynebacterium, 
Escherichia) and fungal species (e.g., Candida, Fusarium, Aspergillus, 
Alternaria) that are active across a wide temperature and pH range have 
been identified in smokeless tobacco products (Refs. 107, 113, and 
123). During tobacco processing and storage, these nitrate-reducing 
microbial species could potentially convert nitrate to nitrite 
resulting in increases in TSNA levels thereby affecting product 
stability during storage. It is important for FDA to evaluate all of 
the factors that affect

[[Page 55354]]

microbial growth and determine if any increases in TSNAs over tobacco 
product storage are microbial-mediated. This information ensures that 
the tobacco product is microbiologically and chemically stable during 
the expected storage period and does not result in an increased risk to 
public health as the product sits in storage.
    viii. Product and packaging design risks and misuse hazards. This 
section of an applicant's PMTA is required to contain a review and 
assessment of reasonably foreseeable risks associated with the design 
of the tobacco product and its packaging that may occur during normal 
use of the tobacco product or during any foreseeable misuse of the 
product, including user error, which may cause illness, injury, or 
death not normally associated with the use of the tobacco product. The 
review and assessment must identify the measures taken to reduce or 
eliminate each risk associated with the design of the tobacco product 
and packaging. Examples of these design risks include, but are not 
limited to: (1) Defects in the air permeability of fire standards 
compliant banding on cigarette paper that is intended to allow 
cigarettes to self-extinguish when left unattended; (2) software errors 
or flaws (i.e., bugs) that occasionally result in the product 
performing differently than designed; (3) failure of a safety switch to 
shutoff a product if it exceeds a certain temperature; and (4) the 
failure of a battery design feature to prevent battery from 
overcharging. The PMTA must contain a review and assessment of each 
defect, describing the potential to cause illness, injury, or death and 
the measures taken to reduce or eliminate the defects and their 
potential impact. FDA is requiring this information under section 
910(b)(1)(G) of the FD&C Act, because the potential for the product 
design or foreseeable misuse to cause illness, injury, or death 
provides information that informs FDA's determination of whether 
permitting the marketing of the product would be APPH.
    FDA received one comment regarding product and packaging design 
risks and misuse hazards, as discussed below.
    (Comment 54) One comment stated that applicants should not be 
required to report or assess the ways in which a tobacco product could 
be misused because requiring companies to do so would require judgments 
that are so wildly subjective that the results are unlikely to be valid 
or relevant.
    (Response 54) FDA disagrees with this comment. As discussed above, 
a PMTA would not be required to contain information regarding all 
potential misuses; rather it would be required to contain an 
identification and assessment of foreseeable misuses. Prospective 
applicants should review section VII.13.a, which explains the ways in 
which applicants can include this type of information, including 
information bridged from investigations on similar products.
10. Principles of Operation
    Section 1114.7(i)(3) describes FDA's interpretation of the full 
statement of the principle or principles of operation required by 
section 910(b)(1)(B) of the FD&C Act and requires the PMTA to contain 
full narrative descriptions of:
     The way in which a typical consumer will use the new 
tobacco product. This includes a description of how a consumer operates 
the product, how long a single unit of the product is expected to last 
(e.g., total length of time of use to consume a unit, number of use 
sessions expected per unit), and where applicable, whether and how a 
consumer can change the product design and add or subtract ingredients, 
such as:
    [cir] E-cigarettes that allow users to change performance features, 
such as the temperature, voltage, or wattage;
    [cir] e-cigarettes that allow users to add or subtract e-liquid 
ingredients, such as liquid nicotine and flavoring, including instances 
where such manipulation is not intended by the manufacturer (e.g., ways 
to misuse the product);
    [cir] e-cigarettes that allow users to add, subtract, or substitute 
components or parts other than identical replacement parts; and
    [cir] waterpipes that allow users to add, subtract, or substitute 
components or parts other than identical replacement parts, such as 
stems and hoses;
     a justification for an applicant's determination of what 
constitutes a single unit of product as described in the PMTA; and
     whether the product incorporates a heating source and, if 
it does, a description of the heating source.
    FDA received several comments regarding these provisions, as 
discussed below.
    (Comment 55) FDA received multiple comments in response to its 
request for comment regarding how the rule should require measurement 
of the length of time it takes a user to consume a single unit of the 
product. One comment stated that FDA should not require any such 
measurements with respect to e-cigarettes because it is the overall 
exposures to HPHCs from repeated use of a product that informs health 
risks, not the use of a single unit. Another comment had specific 
suggestions as they relate to ENDS, stating that for a closed ENDS, a 
single unit should be the amount of e-liquid in the closed ENDS; for an 
open ENDS, a single unit should be the amount of liquid required to 
fill the reservoir; and for open e-liquids, a single unit should be 2 
milliliters (mL) of e-liquid regardless of the container size.
    (Response 55) FDA agrees that the overall exposures to HPHCs from 
repeated use of a product provide the most relevant information about 
health risk. However, because the overall exposures come from an 
accumulation of individual use sessions over time, it is important for 
FDA to understand how the new tobacco product is likely to be used by a 
typical consumer in an individual use session as well as how frequently 
they use the product (including variable use behaviors within sessions 
and over time). It is also important to fully characterize the product 
so that FDA can determine the differences in health risks between the 
new tobacco product and other similar products on the market. 
Therefore, FDA declines to exempt e-cigarettes from reporting the 
length of time it takes for a user to consume a single unit of product.
    In terms of what should constitute a single unit for an ENDS, FDA 
agrees with the comment's suggestions and recommends that applicants 
consider a closed e-cigarette, such as a prefilled disposable cigalike, 
or closed e-liquids, like cartridges or pods that are not intended to 
be refillable, to constitute a single unit. For an open e-cigarette, 
applicants consider a single unit to be the amount of e-liquid required 
to fill the reservoir. FDA believes these measurements of a single unit 
are appropriate because they are a consistent unit of measure set by 
the manufacturer that could be useful in providing meaningful 
information about product use; however, for open e-liquids, differences 
in how consumers use the product may make a different unit of measure 
more appropriate. Therefore, for open e-liquids, it may be more 
appropriate to consider the volume of e-liquid required to fill the 
container to be a single unit, rather than 2 mL of e-liquids. Due to 
product variability and associated differences on what may be 
appropriate as a single unit of a tobacco product, FDA declines to set 
a required unit size and requires applicants to provide a scientific 
justification for why the single unit used for the new tobacco product 
is appropriate.

[[Page 55355]]

11. Product Testing and Analysis Information
    Section 1114.7(i)(4) requires that all testing and analyses of the 
tobacco product required in Sec.  1114.7(i) be performed on test 
samples that reflect the final tobacco product composition and design, 
and that they be conducted using a sufficient sample size and number of 
replicates to substantiate the results of the type of testing 
conducted. This is required under FDA's authority in section 
910(b)(1)(G), because the testing requirements are relevant to the 
subject matter of the application in that they help FDA determine 
whether the product testing and analyses are accurate and reliable. If 
the product that is the subject of the PMTA is a component or part, 
testing and analyses of the product should be performed with a range of 
other components or parts with which a consumer is expected to use the 
product (e.g., an e-liquid should be tested in a representative sample 
of e-cigarettes in which it is may be used).
    Additionally, the applicant must provide the following information 
about the testing and analysis:
     The name and location of the testing laboratory or 
laboratories and documentation showing that the laboratory is (or 
laboratories are) accredited by a nationally or internationally 
recognized external accreditation organization;
     the length of time between dates of manufacture and 
date(s) of testing;
     the storage conditions of the tobacco product before it 
was tested;
     the number of samples and measurement replicates for each 
sample;
     description of method procedure, method validation 
information and rationale for selecting each test method, including 
relevant voluntary testing standards;
     reports of all product formulation testing, including line 
data, test protocols, quantitative acceptance criteria, and a summary 
of the results, for each applicable parameter. Please note that an 
applicant must retain source data under Sec.  1114.45; and
     complete descriptions of any smoking or aerosol-generating 
regimens used for analytical testing that are not standardized or 
widely accepted by the scientific community, if applicable. Where the 
applicant is not using a widely recognized and standardized regimen, 
such as the ISO or HCI regimens, the PMTA must contain a complete 
description of the regimen.
    FDA received one comment regarding constituents and stability 
testing, as discussed below.
    (Comment 56) One comment stated that the final rule must provide 
greater detail regarding method validation and the number of samples 
and measurement replicates required for constituent and stability 
testing.
    (Response 56) FDA declines to set requirements for a specific 
number of samples and replicates because the type of product and 
methodology of testing will vary for a PMTA and the sample size and 
number of replicates necessary to substantiate the type of testing may 
vary. Thus, FDA does not find it appropriate to establish specific 
requirements for testing in terms of validation methodologies, and the 
number of samples and replicates at this time. While FDA generally 
recommends testing across three batches with seven replicates per batch 
as advised in the ENDS PMTA Guidance, varying numbers of batches and 
replicates may be required to substantiate the results of testing. FDA 
recommends that the validation report include sufficient information to 
demonstrate method efficiency, specificity, sensitivity, accuracy, and 
precision needed for the intended purpose. In addition, FDA recommends 
that a PMTA contain an explanation of why the information used for 
testing is sufficient to support the reliability of the results, 
representative of their products, and does not cause public health 
concerns.
12. Manufacturing
    Section 910(b)(1)(C) of the FD&C Act requires a PMTA to contain 
full descriptions of the methods used in, and the facilities and 
controls used for, the manufacture, processing, and, when relevant, 
packing and installation of, the tobacco product. Section 1114.7(j) 
provides FDA's interpretation of this requirement, together with its 
authority under section 910(b)(1)(G) of the FD&C Act, stating that 
these descriptions must include information regarding all manufacturing 
facilities, include descriptions of design controls, and be 
sufficiently detailed to demonstrate that the product meets 
manufacturing specifications and can be manufactured in a manner 
consistent with the information submitted in the PMTA.
    Additionally, because FDA must, under section 910(c)(2)(B) of the 
FD&C Act, deny a PMTA that does not demonstrate compliance with 
regulations issued under section 906(e) of the FD&C Act, the 
descriptions contained in the manufacturing section must demonstrate 
the means by which the processes comply with any applicable tobacco 
product manufacturing practices regulation issued under section 906(e). 
FDA has not yet issued a regulation under section 906(e) of the FD&C 
Act, so demonstrating compliance with such regulations is not currently 
required; however, FDA intends to issue regulations under section 
906(e), and once such regulations are effective, applicants must 
demonstrate that their methods, facilities, and controls comply with 
that rule to receive a marketing granted order under section 
910(c)(1)(i)(A) of the FD&C Act.\30\ Until a final rule issued under 
section 906(e) of the FD&C Act is effective, FDA will evaluate the 
manufacturing process information and consider whether the product can 
be manufactured in a manner consistent with the information submitted 
within the application as part of its determination of whether the 
marketing of the new tobacco product would be APPH. As part of this 
evaluation, FDA may conduct inspections as described in Sec.  1114.27 
to verify the information and data submitted in the application.
---------------------------------------------------------------------------

    \30\ In establishing the effective date of a regulation under 
section 906 of the FD&C Act, FDA must provide for a ``reasonable 
period of time for . . . manufacturers to conform to good 
manufacturing practices,'' and small tobacco product manufacturers 
will have at least 4 additional years to comply. See section 
906(e)(1)(B) of the FD&C Act. FDA anticipates that manufacturers 
preparing PMTA applications before any regulation under 906(e) is 
finalized will have sufficient time to prepare applications that 
demonstrate that their methods, facilities, and controls comply with 
such a rule before the applicable effective date. For PMTA 
applications submitted before any regulation under 906(e) is 
finalized, FDA generally expects the review of such applications 
will be concluded prior to the effective date.
---------------------------------------------------------------------------

    FDA received one comment regarding this issue, as discussed below.
    (Comment 57) One comment stated that the proposed manufacturing 
information requirements in Sec.  1114.7(j) exceed FDA's statutory 
authority because they constitute the equivalent of a current good 
manufacturing practice that must be issued in accordance with the 
process specified in section 906(e) of the FD&C Act. The comment 
further stated that FDA would, in effect, be requiring that applicants 
demonstrate to its satisfaction that a new tobacco product conforms 
with manufacturing criteria as precondition to placing that product on 
the market. The comment requested that FDA significantly revise Sec.  
1114.7(j) and establish regulations in accordance with section 906(e) 
of the FD&C Act.
    (Response 57) FDA disagrees with the comment's conclusory assertion 
that requiring the submission of information regarding whether an 
applicant can manufacture the product described in its application 
constitutes manufacturing practice requirements.

[[Page 55356]]

Section 906(e) requires that FDA, in applying manufacturing 
restrictions to tobacco, follow a prescribed process to require 
manufacturers to conform to current good manufacturing practices (CGMP) 
or hazard analysis and critical control point (HACCP) methodology. In 
issuing section Sec.  1114.7(j), FDA has neither created a requirement 
to conform to a CGMP or HACCP methodology, nor set forth any 
manufacturing practice requirements; rather, FDA has created a 
requirement to submit information about the manufacturing process and 
has identified the level of detail of such information that must be 
submitted in the application. Drawing upon its experience with CGMP and 
HACCP regulations for other regulated products, such as medical 
devices, FDA has embraced a similar flexible approach that does not 
prescribe in detail how a manufacturer must produce a specific tobacco 
product but rather provides a framework to provide detailed information 
regarding the manufacturing of a specific product.\31\ As described in 
the following paragraphs, the process by which a tobacco product is 
manufactured is important to FDA's determination of whether a new 
tobacco product is APPH because it demonstrates the likelihood that the 
tobacco product that will ultimately be used by consumers meets the 
specifications set forth in the PMTA.
---------------------------------------------------------------------------

    \31\ See e.g., Medical Devices; Current Good Manufacturing 
Practice (CGMP); Final Rule, 61 FR 52601 (October 7, 1996).
---------------------------------------------------------------------------

    The information required under Sec.  1114.7(j) is based on FDA's 
interpretation of the manufacturing information required by section 
910(b)(1)(C) of the FD&C Act as supplemented by FDA's section 
910(b)(1)(G) authority. The statutory requirement to submit 
manufacturing information under section 910(b)(1)(C) of the FD&C Act 
exists independently of the requirements in section 906(e) of the FD&C 
Act and FDA is in no way required to create a rule under section 906(e) 
before requiring the submission of manufacturing information and 
reviewing it as part of a PMTA. Only once FDA issues a regulation under 
section 906(e) of the FD&C Act would an applicant have to demonstrate 
it complies with any manufacturing practice requirements established by 
FDA.
    The process by which a tobacco product is manufactured is important 
to FDA's determination of whether a new tobacco product is APPH because 
it demonstrates the likelihood that a tobacco product will be 
manufactured in accordance with the specifications set forth in the 
PMTA. A tobacco product that fails to conform to the PMTA's 
specifications, referred to as a ``nonconforming tobacco product,'' 
could result in a defective product and increase the product's risk 
compared to what would normally be expected from use of the product as 
characterized in the PMTA. Additionally, a nonconforming tobacco 
product constitutes a different tobacco product than the one authorized 
in the marketing granted order, which would render a nonconforming 
tobacco product adulterated under section 902(6)(B) of the FD&C Act. A 
nonconforming tobacco product can be the result of a number of issues, 
including design defects, failures of or problems with purchasing 
controls, inadequate process controls, improper facilities or 
equipment, inadequate training, inadequate manufacturing methods and 
procedures, or improper handling of the tobacco product.
    Nonconforming tobacco products have been highlighted in the news. 
For example, in 2017, a manufacturer of smokeless tobacco products 
issued a voluntary recall of certain products after receiving 
complaints of foreign metal material, including sharp metal objects, in 
its smokeless tobacco products. After the recall, the manufacturer 
investigated whether the contamination was a result of the 
manufacturing practice or a deliberate act by an individual to 
contaminate the product. FDA is also aware of other instances where 
smokeless tobacco products contained rocks or metal shavings as well as 
other nontobacco related materials (NTRMs) (e.g., glass, nails, pins, 
wood, dirt, sand, fabric, cloth, and plastics) in finished tobacco 
products. These NTRMs can cause cuts or lacerations to the lips and 
gums or result in broken teeth.
    FDA also has observed during inspections that tobacco product 
manufacturers have received complaints regarding nonconforming tobacco 
products that contain contaminants and hazards such as biological 
materials (e.g., mold, mildew, hair, fingernails) and chemical hazards 
(e.g., ammonia, cleaning agents, and kerosene). Caustic cleaning 
chemicals may cause the consumer to experience adverse health effects 
not normally associated with tobacco use, such as vomiting, nausea, 
allergic reactions, dizziness, numbness, or headaches.
    Nonconforming tobacco products may also contain higher levels of a 
constituent than the consumer is expecting and that the product is 
supposed to have as characterized by the PMTA, which may result in 
increased risks to health. For example, FDA is aware of the variability 
of nicotine among certain ENDS products and that the labeling may not 
accurately reflect the actual levels of nicotine in those products. In 
one study, researchers found that actual nicotine amounts differed from 
labeled amounts by more than 20 percent in 9 out of 20 original e-
cigarette cartridges tested, and in 3 out of 15 refill cartridges 
tested (Ref. 124). FDA has observed on inspections that some e-liquid 
manufacturers do not have established procedures to conduct activities 
or maintain records of their manufacturing processes, including but not 
limited to calibration of equipment, documenting the identity or purity 
of their ingredients, and testing final product to confirm that it 
meets established specifications such as the concentration of nicotine. 
A finished ENDS product that contains a nicotine concentration higher 
than the established specification can be more addictive (Refs. 125 and 
126). Similarly, a cigarette that does not conform to its pH 
specification can deliver nicotine in a different speed and amount to 
the user which can impact the tobacco product's toxicity and 
addictiveness (Ref. 59). Exposure to nonconforming products in this 
circumstance can result in user exposure to increased levels of 
nicotine, which can lead to increased addictiveness.
    Nonconforming products may also contain defects that can cause the 
tobacco product to be more harmful. For example, an ENDS product may 
have a defect that contributes to an increased risk of fire and/or 
explosion. The ENDS product, during use or foreseeable misuse, can 
expose consumers to increased harm if the device catches fire or 
explodes resulting in serious burns that would not be expected from use 
of the product (e.g., Ref. 127).
    Given the dangers associated with nonconforming (including 
contaminated) tobacco products, FDA will evaluate an applicant's 
manufacturing process information to help determine whether the 
marketing of a new tobacco product would be APPH, specifically 
considering whether the manufacturer explains controls it would 
establish and maintain to prevent the manufacture and distribution of 
nonconforming products that may have an adverse effect on public 
health.
    The manufacturing section of a PMTA must contain the following 
information in the manufacturing section to meet the requirements of 
Sec.  1114.7(j) and to help FDA determine if it conforms to the 
requirements of section 906(e) of the

[[Page 55357]]

FD&C Act, when regulations are in effect:
     A listing of all manufacturing, packaging, storage, and 
control facilities for the product, including the name, address, and 
FEI number for each facility, if applicable, and a contact name and 
telephone number for a representative from each facility;
     a narrative description, accompanied by a list and summary 
of all standard operating procedures (SOPs) and examples of relevant 
forms and records for the following categories of information for all 
manufacturing, design controls, packing, and storage for the tobacco 
product:
    [cir] Manufacturing and production process activities at each 
establishment, including a description of each establishment, all 
production steps, process controls, process specifications with 
relevant acceptance criteria, and monitoring and acceptance activities;
    [cir] managerial oversight and employee training related to the 
manufacture, processing, packing, and installation of the tobacco 
product, as applicable;
    [cir] monitoring procedures and manufacturing controls for product 
design, product characteristics, and changes in products, 
specifications, methods, processes, or procedures, including a hazard 
analysis that details the correlation of the product design attributes 
with public health risk, as well as any mitigation strategies 
implemented;
    [cir] activities related to identifying and monitoring suppliers 
and the products supplied (including, for example, purchase controls 
and product acceptance activities);
    [cir] handling of complaints, nonconforming products and processes, 
and corrective and preventative actions;
    [cir] testing procedures carried out before the product is released 
to market, including:
     A list and summary of any standards used for all testing 
methods;
     validation or verification activities for all test methods 
used to ensure that the tobacco product meets specifications;
     documentation of accreditation information for all testing 
laboratories;
     complete description of smoking or aerosol-generating 
regimes used for analytical testing, if any;
     tobacco product specifications (including any physical, 
chemical, and biological specifications) and acceptance criteria for 
those specifications; and
     reports of release testing performed on finished products 
to demonstrate conformity with established specifications, including 
test protocols, line data, and a summary of the results for each 
applicable testing.
13. Health Risk Investigations
    Under section 910(b)(1)(A) of the FD&C Act, a PMTA must contain 
full reports of all information, published or known to, or which should 
be reasonably known to, the applicant concerning investigations which 
have been made to show the health risks of the tobacco product and 
whether the tobacco products present less risk than other tobacco 
products. Section 1114.7(k) sets forth FDA's interpretation of this 
requirement, together with its authority in section 910(b)(1)(G), in 
three parts: (1) The types of investigations that are considered 
investigations into the health risks of the product and whether the 
tobacco product presents less risk than other products; (2) the 
documentation an application must contain to demonstrate that the 
application contains all published investigations; and (3) the 
information that constitutes a full report of an investigation.
a. Types of Investigations and Analyses
    i. Interpretation of statutory language. FDA interprets the 
information required under section 910(b)(1)(A) of the FD&C Act, 
together with its authority under section 910(b)(1)(G) of the FD&C Act, 
to include the health risk investigations specified in Sec.  
1114.7(k)(1). Under the rule, applicants must submit full reports (as 
described in Sec.  1114.7(k)(3)) of all information, both favorable and 
unfavorable, published or known to, or which should reasonably be known 
to, the applicant regarding the types of investigations described in 
Sec.  1114.7(k)(1). Applicants are required to submit full reports of 
these investigations, regardless of whether they support or are adverse 
to the application, or are conducted within or outside the United 
States.
    Section 1114.7(k)(1) requires an application to contain health risk 
investigations that are published, known to, or should reasonably be 
known to an applicant. This requirement ensures that FDA understands 
the full scope of the health risk investigations for a new tobacco 
product.
    Section 1114.7(k) interprets section 910(b)(1)(A) of the FD&C Act 
broadly to ensure FDA has a complete understanding of the existing 
information about a new tobacco product; it does not set requirements 
for specific studies that must be contained in every single PMTA. The 
description of the issuance of marketing denial orders (Sec.  1114.33), 
discussed in section VIII.E, describes circumstances where FDA intends 
to issue a marketing denial order. The description of the issuance of 
marketing order (Sec.  1114.31) in section VIII.D contains information 
regarding FDA's determination of whether there is a showing that the 
marketing of a new tobacco product would be APPH.
    FDA received many comments regarding this provision, as discussed 
below.
    (Comment 58) Multiple comments expressed concerns about what they 
consider to be the breadth of the information required by proposed 
Sec.  1114.7(k)(1). One comment stated that FDA should define the scope 
of health risk investigations that must be submitted in every PMTA so 
that applicants know exactly what to present in a PMTA and to reduce 
potential burdens on both applicants and FDA. Another comment 
interpreted the proposed rule as requiring information regarding 
investigations for each of the topics described in Sec.  1114.7(k)(1) 
and requested that FDA provide information about the expected design of 
these studies as well as details regarding the ranges of acceptable 
approaches to provide consistency and reliability to the PMTA review 
process.
    (Response 58) FDA has made edits to the codified to further clarify 
that FDA is not requiring an applicant to conduct an investigation into 
each individual topic in Sec.  1114.7(k)(1). As described throughout 
this document, a PMTA must contain at least some amount of substantive 
information regarding each of the topic areas in Sec.  
1114.27(b)(1)(ii) to be filed for substantive review. Additionally, a 
PMTA must contain full reports of all investigations that are published 
or known to, or which should reasonably be known to an applicant, 
concerning the topics in Sec.  1114.7(k)(1) to be filed for substantive 
review. FDA generally expects that applicants will be able to meet the 
substantive information requirement in Sec.  1114.27(b)(1)(ii) by 
submitting investigations that are published or known to, or which 
should reasonably be known to, an applicant under Sec.  1114.7(k)(1); 
however, in the event an application is lacking required substantive 
information, an applicant may need to conduct its own investigation to 
meet the filing requirements.
    (Comment 59) Other comments stated that FDA is providing too much 
flexibility for applicants and should instead require applicants 
conduct specific types of studies, allowing for exceptions only where 
an applicant can demonstrate that a specific type of information is not 
applicable.

[[Page 55358]]

    (Response 59) We decline to require that an applicant conduct a 
list of new studies as part of every application under this rule 
because there may be other ways in which an applicant can provide 
scientific information to inform FDA's review (e.g., bridging, 
published literature). Additionally, while a PMTA must contain 
substantive information regarding certain categories of information set 
forth in Sec.  1114.27(b)(i)(ii) to be filed by FDA as described in 
section VIII.B, an applicant has some flexibility in determining how to 
use existing information to support a PMTA for their product and what 
types of additional investigations it may need to conduct to provide 
FDA with information that demonstrates that permitting the marketing of 
its new tobacco product would be APPH. For example, information about 
known problems and risks related to mouth ulcers in moist tobacco 
products would be informative and could be used to extrapolate known 
health risk information for a related type of product that is the 
subject of the PMTA submitted to FDA. Applicants may want to review the 
areas of scientific investigation listed in Sec.  1114.31 to determine 
whether there are gaps in the existing scientific information regarding 
its product that it may need to fill by conducting a new study 
regarding its tobacco product. As discussed in the description of Sec.  
1114.31 in section VIII.D, acceptance and filing of a PMTA does not 
mean that it has sufficient scientific information necessary to obtain 
a marketing granted order.
    (Comment 60) Another comment stated that FDA's interpretation of 
section 910(b)(1)(A) of the FD&C Act set forth in Sec.  1114.7(k) is 
both unclear and is potentially limitless in scope. The comment noted 
that the requirements in Sec.  1114.7(k)(1) go far beyond the 
information that is required to be submitted for other products 
regulated by FDA, such as the requirements for new drug applications. 
The comment recommended that rather than requiring information 
concerning the product under the range of conditions under which the 
product might be used, FDA should revise the rule to focus on normal, 
customary, and ordinary conditions of use and permit the use of 
customary scientific methods, such as bracketing and dose response 
curves, to provide such information to FDA.
    (Response 60) FDA declines to revise Sec.  1114.7(k) in response to 
the comment and disagrees with the claim that it is potentially 
limitless in scope. Unlike the premarket approval standard for drugs or 
devices, which requires the submission of information to show whether a 
drug or device is safe and effective, section 910(b)(1)(A) of the FD&C 
Act requires applications to include information regarding the health 
risk of the tobacco product and whether the product presents less risk 
than other tobacco products. As discussed in section VIII.B.13.a, FDA 
interprets the information required under section 910(b)(1)(A) of the 
FD&C Act, together with its authority under section 910(b)(1)(G) of the 
FD&C Act, to include the health risk investigations specified in Sec.  
1114.7(k)(1). This requirement ensures that FDA understands the full 
scope of the health risk investigations for a new tobacco product as 
well as provides FDA with crucial information when determining whether 
permitting the marketing of the new tobacco product is APPH.
    FDA also declines to limit the required submission of information 
to just what the applicant considers to be normal, customary, and 
ordinary conditions of use because understanding the full range of 
conditions under which a product may be used, including the potential 
for misuse, is important to determining the health risks posed by a new 
tobacco product. For example, in ENDS products, the heating element 
configurations and the number of heating elements have been known to be 
modified. Another misuse that has occurred includes modifying the 
wicking materials and the amount of wicking materials in the ENDS 
product. Information such as whether an applicant's product design 
reduces the possibility that the product will be misused or used 
outside of ordinary conditions of use are an important part of 
demonstrating that the new tobacco product would be APPH.
    (Comment 61) Another comment requested clarification regarding what 
constitutes information that is ``known to or which should reasonably 
be known to an applicant,'' suggesting that documentation of a search 
of its own files and a survey of its scientific staff should be 
sufficient. Multiple comments also requested that FDA amend Sec.  
1114.7(k)(2) to require that an applicant impose a reasonable time 
limit on searches of its own files and available literature, such as a 
limitation to what is currently available or what has recently been 
published (e.g., within a specified time period).
    (Response 61) FDA declines to adopt an interpretation of documents 
that should reasonably be known to an applicant as part of this 
rulemaking because it is likely to be a fact specific determination. 
FDA also declines to set a time limit for the literature search 
requirement because there is no such limitation in the statutory 
requirement to submit full reports of published investigations. Under 
Sec.  1114.7(k)(2), the application must contain a description of the 
literature search performed, including the databases searched and the 
date searched, search terms, reasons for inclusion or exclusion of 
documents, and the strategy for study quality assessment. If, for 
example, an applicant limits the literature search to a certain time 
period, the applicant must include the reason for such limitation in 
their description of the literature search.
    ii. General recommendations related to health investigations. The 
rule does not require an applicant to conduct any of its own studies 
for the purposes of the application acceptance and filing requirements 
in Sec.  1114.27, except as necessary to meet the filing requirements 
of Sec.  1114.27(b)(2)(ii). Should an applicant choose to do so, FDA is 
providing recommendations for consideration throughout this section of 
the preamble. In addition to recommendations for specific types of 
studies that follow, FDA is making recommendations for three general 
topics related to health risk investigations that may help an applicant 
prepare a PMTA in some instances: (1) Bridging data from an 
investigation conducted using a different product to the product that 
is the subject of the application; (2) choosing appropriate comparison 
products; and (3) using foreign data.
    (Comment 62) One comment stated that because FDA is acknowledging 
the acceptability of ``bridging,'' ``comparison products,'' and 
``foreign data,'' it should define these terms in the final rule, 
stating that it is not sufficient to just mention these terms in 
passing.
    (Response 62) FDA declines to define the terms in the final rule. 
We believe the discussion of these topics and the associated 
recommendations that follow provide sufficient information to be useful 
to applicants in preparing PMTAs.
 Bridging
    FDA recognizes that in preparing the health risk investigations 
section of a PMTA, an applicant may choose to use data from a study 
conducted using a different tobacco product in an attempt to 
demonstrate the health risks of the product that is the subject of the 
application. The submission of studies using different products is 
optional. Ideally, a PMTA will contain studies conducted with respect 
to the new tobacco product itself, but the bridging of data from a 
different product to the

[[Page 55359]]

new tobacco product that is the subject of the application may be 
feasible for a subset of products or for certain types of studies. If 
an applicant lacks data on the product from one or more of the types of 
studies listed in this section, the applicant could bridge data 
regarding another product, or an earlier version of the product where 
appropriate. For example, ``X-flavor'' e-liquids with nicotine 
concentrations ranging from 1 milligram per milliliter (mg/mL) to 24 
mg/mL may be able to show the health risks of each of the e-liquids 
without having to conduct a unique study for each nicotine 
concentration of the ``X-flavor'' product if data from a subset of 
nicotine concentrations (e.g., low, middle, high) of ``X-flavor'' 
products may be bridged to other nicotine concentrations of ``X-
flavor'' products. Other examples where data from studies on a smaller 
number of products could potentially be bridged to a larger number of 
products include smokeless tobacco products available in various pouch 
sizes or e-liquids available in various container volumes.
    FDA received multiple comments regarding bridging information in a 
PMTA, as discussed below.
    (Comment 63) Multiple comments expressed concerns related to the 
use of bridging in a PMTA. One comment requested that FDA prohibit the 
use of bridging information from an investigation conducted using a 
different tobacco product to the new tobacco product that is the 
subject of the PMTA. The comment stated that specifically with regard 
to ENDS, even minor variations in e-liquids and battery outputs affect 
the production of toxicants. Another comment stated that the health 
effects of a given product can differ dramatically because of 
individual differences among consumers. Both comments suggested instead 
that FDA require applicants to conduct product-specific research. 
Another comment stated that FDA should issue a marketing granted order 
for a PMTA based on bridged data only where FDA concludes that there is 
compelling evidence that the differences between the product studied 
and the new tobacco product that is the subject of the application are 
immaterial to FDA's review of the application.
    (Response 63) FDA declines to prohibit the use of bridging in a 
PMTA because it can be used to provide information that is relevant to 
FDA's review of a PMTA. Where an applicant chooses to bridge to data 
from a general study or a study conducted using a different tobacco 
product, it would need to provide a scientific rationale to justify why 
the study findings apply to its new tobacco product and any study 
limitations that may be relevant. Failure to provide a sufficient 
justification that such data can be used to evaluate the new tobacco 
product would result in FDA being unable to rely upon it in evaluating 
the PMTA. There may be circumstances when an applicant would need to 
submit additional substantive information, including bridging studies, 
as appropriate, to justify that the results of a general study or a 
study using a different tobacco product is relevant to evaluation of 
its new tobacco product. Where an applicant seeks to use information 
from a study conducted using a different tobacco product in the same 
product category, it may need to provide comparative product 
information or potentially a bridging study to show the results apply 
to its specific new tobacco product. For instance, if an applicant 
wants to use the results of an abuse liability study that was conducted 
on a different product, an applicant should justify how key 
similarities between the products (e.g., product design, nicotine 
formulation and content) demonstrate the results of the study apply to 
its tobacco product. As another example, national surveys, such as the 
NYTS, provide information about trends in tobacco product use by youth 
and typically do so for product categories as a whole, rather than 
specific products. If an applicant intends to use such survey data to 
help show the likelihood of youth initiation with its product, it would 
need to explain why results about a product category in general apply 
to its specific product.
    Another example of when a justification or a bridging study may be 
needed is when the location or region of a study differs from the 
intended locations or regions where the product will be used, which is 
further described in the foreign data section.
 Comparison Products
    As part of FDA's consideration under 910(c)(4) of the FD&C Act of 
the risks and benefits of permitting the marketing of the new tobacco 
product to the population as a whole, including users and nonusers of 
tobacco products, FDA reviews the health risks associated with changes 
in tobacco product use behavior (e.g., initiation, switching, polyuse, 
cessation) that may occur with the marketing of the new tobacco 
product. Applicants must compare the health risks of its product to 
both products within the same category and subcategory, as well as 
products in different categories as appropriate. Additionally, as 
likely users of a new tobacco product will vary dependent on the type 
of product, and product use patterns vary across different populations, 
the appropriate comparison product(s) may vary. When identifying the 
likely users of the product and appropriate comparator products, FDA 
recommends that applicants specifically consider product use patterns, 
including abuse liability and unintended use, among youth, young 
adults, and other relevant vulnerable populations. It is helpful for 
FDA to understand the applicant's rationale and justification for 
comparators chosen whether within the same category or different 
categories of tobacco products. This comparative health risk data is an 
important part of the evaluation of the health effects of product 
switching. As set forth in Sec.  1114.27(b)(1)(ii), a PMTA must contain 
substantive information regarding comparative health risks to be filed 
for review.
    Information about tobacco products in the same category or 
subcategory is important to FDA's evaluation of a tobacco product's 
potential effect on public health because current users may switch to 
other products within the same category. When determining an 
appropriate comparison product within the same category or subcategory 
of product, FDA recommends applicants consider products consumers are 
most likely to consider interchangeable with the new tobacco product 
and other similar products. For example, for a PMTA for an e-liquid, 
FDA recommends the product be compared to other e-liquids used in a 
similar manner. This comparison is not meant to be a 1 to 1 comparison 
as in a SE report under section 905(j); rather, it is meant to 
demonstrate how the new tobacco product may be evaluated in relation to 
similar products.
    Information about tobacco products in different categories is 
important to FDA's evaluations because it can help demonstrate the 
changes in health risks current tobacco users could face if they 
switched to the new tobacco product or use it in conjunction with their 
current tobacco product. For tobacco products that are not in the same 
tobacco product category, but that may be appropriate for examining 
health risk, FDA recommends determining the likely users of the new 
tobacco product to justify appropriate comparison products. For 
example, if an applicant submitting a PMTA for an ENDS believes that 
current users of cigarettes and ENDS will use its product, it would be 
appropriate to compare the health risks of the ENDS to both cigarettes 
and other similar ENDS products.

[[Page 55360]]

Polytobacco use risks should also be considered.
    FDA received many comments regarding comparison products, as 
discussed below.
    (Comments 64) Multiple comments discussed comparison products. One 
comment stated that the rule should specifically require PMTAs to 
compare the health risks of new tobacco products to the health risks of 
all other tobacco products on the market. Another comment stated that 
Sec.  1114.7(k)(1)(i) is unclear regarding the tobacco products to 
which an applicant must compare the new tobacco product that is the 
subject of an application and stated that requiring a comparison to 
just cigarettes could disincentivize the development of new, lower risk 
e-cigarettes, not just to combustible cigarettes.
    (Responses 64) As described in the preceding paragraphs, 
comparative health risk information is an important part of FDA's 
review of a PMTA because it can demonstrate the potential risks and 
benefits that current tobacco users could face if they switched to the 
new tobacco product or used it in conjunction with their current 
tobacco product. As required by Sec.  1114.27(b)(1)(ii)(B), applicants 
must compare the health risks of its product to both products within 
the same category and subcategory, as well as products in at least one 
different category that are used by the consumers an applicant expects 
will use its new tobacco product. FDA declines to require comparisons 
to all other products in every instance because not every application 
will necessarily require comparisons to all other categories and the 
determination of which comparison products are necessary to consider in 
determining the risks and benefits to the health of the population as a 
whole is more appropriately considered during substantive review. We 
also disagree with the suggestion that the comparative health risk 
information requirements in the rule would disincentivize development 
of lower risk products because FDA requires each PMTA to compare the 
health risk of its product to other tobacco products in the same 
product category. Because FDA's APPH determination considers changes in 
health risks to users of other products in the same category that 
switch to the new tobacco product, applicants have an incentive to 
ensure its product does not pose greater health risks than other 
products in the same category.
    (Comment 65) One comment stated that section 910 of the FD&C Act 
does not permit FDA to require a PMTA to contain a comparison to other 
products in the same product category and, as a result, FDA should 
remove the requirement to do so in Sec.  1114.27(b)(2)(ii)(B). The 
comment stated that interpreting the phrase ``other tobacco products'' 
in section 910(b)(1)(A) to include products in the same category would 
defeat the congressional intent of the APPH standard, which the 
comment, citing a statement from a 1998 Senate committee report, argues 
is to ensure FDA issues PMTA marketing orders for only those products 
that do not introduce more risk than conventional tobacco products.
    (Response 65) FDA disagrees with this comment. The determination of 
whether the marketing of a new product would be APPH under section 
910(c) of the FD&C Act is required to be based on the risks and 
benefits to the health of the population as a whole, and not limited to 
a determination of on whether a new tobacco product presents less risk 
than conventional tobacco products. As described in this section, 
information about tobacco products in the same category or subcategory 
is important to FDA's evaluation of a tobacco product's potential 
effect on public health because current users may switch to other 
products within the same category. Not only does this constitute 
information regarding ``other tobacco product'' that falls under 
section 910(b)(1)(A), it is relevant to the subject matter under 
910(b)(1)(G) of the FD&C Act because it informs FDA's consideration of 
the risks and benefits of the product to the health of the population 
as a whole.
 Foreign Data
    Foreign clinical studies should be performed by clinical 
investigators so that the rights, safety, and welfare of human subjects 
are protected in accordance with ethical principles acceptable to the 
international community, such as those reflected in the International 
Council for Harmonisation (ICH) Good Clinical Practice standards.
    An application may be required to contain full reports of foreign 
investigations even if they do not meet these criteria because of the 
requirements of Sec.  1114.7(k) that an application contain all 
published studies regarding the health risks of a new tobacco product 
and other topics. This could include, for example, a published health 
risk investigation regarding the product conducted outside the United 
States by someone other than the applicant. Where data do not meet the 
recommendations described in the preceding paragraph, an application 
should contain a description of the ways in which the foreign data 
fails to meet those criteria and, if applicable, describe whether FDA 
should still consider the data to be valid.
    FDA received one comment regarding foreign data, as discussed 
below.
    (Comment 66) One comment stated that FDA should be required to 
provide its own rationale as to why any foreign data in an application 
are relevant to the U.S. population and why FDA concluded that specific 
data from U.S. studies are not required. The comment stated that FDA 
should not assume that consumers in the U.S. market will respond the 
same way as consumers in a different country.
    (Response 66) FDA declines to make the requested revision. An 
application may contain health risk investigations conducted outside of 
the United States. If the study data concern a demographic that is 
different from the United States, the burden is on the applicant to 
provide a scientific rationale for why the results of the study can be 
generalized to other demographic groups that are representative of the 
U.S. population as whole.\32\ This could include a discussion of the 
factors that would be expected to influence study findings and whether 
they vary significantly across the U.S. population. The applicant 
should also clearly describe any reasons why study findings may not be 
generalized to the broader U.S. population.
---------------------------------------------------------------------------

    \32\ For a discussion of both intrinsic and extrinsic factors in 
foreign data that might need to be addressed, please see the 
International Council for Harmonisation (ICH) E5 guidance: ``Ethnic 
Factors in the Acceptability of Foreign Clinical Data.''
---------------------------------------------------------------------------

    iii. Health risks of the product. Section 1114.7(k)(1)(i) requires 
a PMTA to contain full reports of all investigations, published or 
known to, or which should reasonably be known to, the applicant 
regarding the potential health effects of their product. This includes 
full reports of investigations on the constituents, including HPHCs, in 
the specific product or formed during use of the product, and at the 
quantitative levels that would be delivered to both users and nonusers 
under the range of conditions under which the specific product may be 
used. FDA includes these investigations under its interpretation of the 
requirements of section 910(b)(1)(A) of the FD&C Act, because the 
health effects of constituents at the levels delivered to both users 
and nonusers help demonstrate the overall health risks of the product. 
Types of investigations into the health effects of constituents that 
applicants must submit as part of a PMTA if published or known to, or 
which should reasonably be known to

[[Page 55361]]

an applicant include human exposure studies, in silico computational 
toxicology techniques, risk assessments, in vitro toxicology studies, 
published reports of in vivo toxicology studies, and, if necessary, new 
in vivo toxicology studies.
    As set forth in Sec.  1114.27(b)(1)(ii) and described in section 
VIII.B, an application must contain substantive information regarding 
the health risks of the new tobacco product as described in either 
Sec.  1114.7(k)(1)(i)(A), (B), or (C) as well as substantive 
information regarding the health risks of the new tobacco product 
compared to the health risks generally presented by products in the 
same category as described in Sec.  1114.7(1)(i)(D). While the rule 
does not require an applicant to conduct any particular type of studies 
regarding the health risks of the constituents for the purposes of 
application acceptance and filing, the applicant would be required to 
do so where it is not aware of existing studies that could be used to 
support the application or where additional information is necessary to 
ensure the application contains substantive information regarding the 
health risks of the new tobacco product. Where an applicant chooses to, 
or must, conduct its own investigations, FDA is providing the following 
discussion of nonbinding recommendations for consideration. The 
adequacy of the studies provided and whether they help demonstrate that 
a product is APPH will be determined during FDA's review of the 
application. The study recommendations, provided here and throughout 
this document, are intended to help an applicant develop a more robust 
application, which would facilitate FDA making a determination as to 
whether the product is APPH.
    The health effect evaluation of tobacco constituents, including 
HPHCs, in a PMTA should begin with an assessment of human exposure. For 
tobacco product users, this assessment should include direct 
measurements of exposure, estimates of exposure from analytical studies 
of the tobacco product and its smoke or aerosol, or investigations that 
combine both approaches. For nonusers of the tobacco product, exposure 
estimates would include analytical studies. One source of this 
information can be the HPHC data required by Sec.  1114.7(i)(1)(v). FDA 
recommends that these investigations specifically assess the levels of 
each HPHC to which users and nonusers could be exposed and that direct 
measurements or estimates of exposure use the same route of 
administration (e.g., inhalation, ingestion, dermal contact) as the 
tobacco product they evaluate. Other aspects of the exposure that FDA 
recommends applicants define in the tobacco constituent exposure 
assessment include exposure duration, inhalation rate, consumption 
rate, body mass, and other similar relevant measures.
    Study reports regarding the health effects of product constituents 
at both the exposure ranges estimated for user and nonuser exposure and 
higher exposures are important in the toxicological evaluation of a 
PMTA because it allows for a more thorough dose-response assessment. 
Higher exposures may provide indication of toxicity potential from 
lower exposure levels over longer exposure times. FDA recommends 
including dose-response assessments across a range of exposures. For 
noncarcinogenic constituents, FDA recommends including study reports 
that define the threshold of toxicity, especially those that identify 
the no-observable-adverse effect level and lowest-observable-adverse-
effects-level. For carcinogenic constituents, if only high-exposure 
studies are available, an assumption of linearity should be made for 
low-dose extrapolation. For both carcinogenic and noncarcinogenic 
constituents, user and nonuser exposures should be compared to 
available dose response information.
    FDA received several comments regarding this issue, as discussed 
below.
    (Comment 67) One comment stated that because FDA notes that 
clinical studies would typically be a necessary part of a PMTA, FDA 
should not allow applicants to conduct animal studies, which the 
comment states are unethical.
    (Response 67) Restrictions on the types of investigations that an 
applicant is allowed to conduct are outside the scope of this rule. FDA 
supports reducing the reliance on animal testing where adequate and 
scientifically valid nonanimal alternatives can be substituted. FDA 
encourages sponsors to meet with CTP early in the development process 
to discuss what, if any, animal testing is appropriate and the 
suitability and acceptability of nonanimal tests for their specific new 
tobacco product. When animal-based nonclinical laboratory studies are 
conducted, investigators should use appropriate animal models and 
adhere to the best practices of refinement, reduction, and replacement 
of animals in research and to applicable laws, regulations, and 
policies governing animal testing, such as the Animal Welfare Act (7 
U.S.C. 2131 et seq.) and the Public Health Service Policy of Humane 
Care and Use of Laboratory Animals (available at https://olaw.nih.gov/policies-laws/phs-policy.htm).
    Under Sec.  1114.7(k)(1)(i)(B), a PMTA must contain all 
investigations, published or known to, or which should reasonably be 
known to, the applicant regarding the toxicological profile of the new 
tobacco product related to the route of administration, including, but 
not limited to, the genotoxicity, carcinogenicity, respiratory 
toxicity, cardiac toxicity, reproductive and developmental toxicity, 
and chronic (repeat dose) toxicity of the new tobacco product relative 
to other tobacco products.
    (Comment 68) One comment stated that FDA should revise all of the 
PMTA requirements to give more prominence to heart and lung disease 
effects and in particular, Sec.  1114.7(k)(1)(i)(B) should be amended 
to require applicants to prioritize submission of information regarding 
the cardiovascular and respiratory effects of the new tobacco product, 
and additionally include effects on blood and intergenerational health 
effects caused by epigenetic changes.
    (Response 68) FDA agrees that heart and lung disease effects are 
important considerations, which is why they are part of the information 
required by Sec.  1114.7(k)(1)(i)(B). However, the rule does not set 
forth requirements in order of importance and moving a particular item 
would not affect the importance of any requirements.
    The toxicological profile also includes information regarding the 
ingredients, additives, and HPHCs, relative to the route of 
administration and the range of the potential levels of exposure 
resulting from the use of or other exposure to the product. While FDA 
is aware of the risk of harm posed by HPHCs generally, understanding 
the toxicological effects of HPHCs in the product is important to FDA's 
review because the levels and combinations of HPHCs to which a consumer 
may be exposed can determine whether, and the severity with which, a 
user may experience harm. For example, some constituents may only cause 
harm above certain levels of exposure, while others may have no safe 
level of exposure. Additionally, since there are potential complex 
interactions between HPHCs and each tobacco product can produce a 
different mixture of these HPHCs, FDA needs to determine the toxicity 
of the specific mixture of HPHCs in a tobacco product in order to 
compare that tobacco product to other similar products on the market 
and to use this comparison in its determination of whether permitting 
the marketing of the product would be APPH. The toxicological profile 
investigations covered by the rule also includes

[[Page 55362]]

studies that discuss the toxicological effects of any leachables and 
extractables from the container closure system and the ingredient 
mixture, such as additive or synergistic effects.
    FDA includes the toxicological profile of the tobacco product as 
part of its interpretation of the health risk investigations required 
under section 910(b)(1)(A) of the FD&C Act, where published, known to, 
or which should reasonably be known to an applicant, because it 
identifies the hazardous or harmful effects of product constituents and 
allows for product comparisons that estimate the impact of the assessed 
tobacco product on the health of both users and nonusers of the tobacco 
product.
    The types of toxicological information or data regarding a tobacco 
product that a PMTA must contain if published or known to, or should 
reasonably be known to, an applicant generally include the 
characterization of toxic effects of HPHCs to which users and nonusers 
may be exposed. This evaluation can include identification of the 
organs affected by constituents; the cancer and noncancer effects of 
the constituents; dose response relationships between exposure to 
constituents and health effects; and, when appropriate, threshold 
levels of exposure above which noncancer effects occur. The 
toxicological assessment of the product that is the subject of a PMTA 
should focus on the HPHCs reported in Sec.  1114.7(i)(1)(v), the 
constituent reporting section. The types of studies or information 
required by the rule, if published or known to, or should reasonably be 
known to an applicant, include toxicological assessments conducted in 
terms of both the whole tobacco product and the individual HPHCs that 
the product contains or delivers to users and nonusers.
    Because different tobacco products contain different ingredients 
and additives, they may also have different HPHC yields. A tobacco 
product that would result in increased exposure to a potent HPHC or set 
of HPHCs, for example, may present higher health risks to users. 
However, important aspects such as dose-response and whether the end 
organ toxicity is carcinogenic or noncarcinogenic in nature could 
affect whether this higher exposure results in an estimate of increased 
risk. The information generated from the toxicological assessment of 
tobacco products is part of the information that the applicant should 
use in product comparisons to estimate the impact of the assessed 
tobacco product on the public health.
    The types of toxicological information that the applicant must 
include in a PMTA if published or known to, or should reasonably be 
known to, the applicant include information about, or investigations 
into, the potential for a tobacco product or its constituents to cause 
toxicity. For the specific toxicological profile of a new tobacco 
product or constituents in or formed during use of the new tobacco 
product, the applicant should address known tobacco target organs of 
toxicity, as appropriate for the product and/or route of 
administration. The profile should include data and thorough literature 
reviews of the following health effects known to be caused by tobacco 
products as applicable such as:
     Genotoxicity (the ability of a chemical agent to damage 
DNA within a cell, causing mutations that may lead to cancer);
     carcinogenicity (the ability of a chemical agent to 
directly cause cancer in humans or animals after exposure);
     cardiovascular toxicity (the ability of a chemical agent 
to cause adverse effects on the cardiovascular system (i.e., heart and 
blood vessels));
     respiratory toxicity (the ability of a chemical agent to 
cause adverse effects on the respiratory system, which comprises the 
nasal passages, pharynx, trachea, bronchi, and lungs);
     reproductive toxicity (the ability of a chemical agent to 
cause adverse effects on the male or female reproductive systems such 
that normal reproduction is impaired);
     developmental toxicity (the ability of a chemical agent to 
interfere with the development of the embryo or fetus); and
     other diseases associated with use.
    While not required for application acceptance or filing under Sec.  
1114.27, FDA recommends that an application contain a discussion of the 
toxicological potential for the tobacco product to cause additional 
chronic toxicities, other than those listed above, such as any end-
organ toxicity or route of administration effects. These end-organ 
toxicities include, but are not limited to, the potential toxicity on 
the liver, kidneys, immune system, digestive system, and neurological 
system. An example of route of administration effects that FDA 
recommends be addressed is the toxic potential of a smokeless tobacco 
product to the oral cavity, including teeth.
    FDA also recommends the application address acute toxicity, which 
concerns the ability of a chemical agent to cause adverse effects after 
either a single exposure or multiple exposures in a short period of 
time (usually less than 24 hours). If there are known acute toxicities 
for product constituents at the levels to which an individual may be 
exposed (e.g., carbon monoxide poisoning from waterpipe use, the 
ingestion of nicotine contained in e-liquids) including through 
accidental or unintended exposures, an applicant should justify how the 
product could contain such constituents and how permitting its 
marketing would be APPH. This could include a description of the design 
features, such as child-resistant packaging for e-liquids, that would 
prevent exposures to constituents that could result in acute toxicity 
as part of Sec.  1114.7(i)(1)(vi)(B). See the discussion in section 
VII.B.9.a.vi. for more information about protective packaging.
    FDA recommends that an applicant compare the toxicity of its 
product to the toxicity of other products in the same product category 
or subcategory. Additionally, FDA recommends that applicants consider 
use exposure in conjunction with the hazards posed by a particular 
product to determine the most appropriate group of comparator products.
    While applicants are not required to conduct toxicological analyses 
under the rule, if an application does not contain substantive 
information regarding either the health risks of the new tobacco 
product or a comparison of the health risks compared to other tobacco 
product categories, FDA intends to refuse to file a PMTA as set forth 
in Sec.  1114.27(b)(1)(ii) and described in section VIII.B. Information 
about the product's toxicity and a comparison of its toxicity to other 
tobacco products could satisfy this substantive information requirement 
for filing; however, it should be noted that information from 
nonclinical studies alone, including a product's toxicological profile, 
is generally not sufficient to support a determination that permitting 
the marketing of the product would be APPH. An applicant should also 
consider the existing valid scientific evidence regarding its new 
tobacco product to determine whether it would need to conduct and 
submit a full report of toxicological analyses to demonstrate the 
potential health risks of the new tobacco product as part of its PMTA. 
If an application does not contain sufficient information about the 
health risks of the new tobacco product to allow FDA to make a 
determination regarding the potential risks and benefits to the 
population as a whole under section 910(c)(4) of the FD&C Act, FDA will 
issue a marketing denial order for the new tobacco product.

[[Page 55363]]

    Under Sec.  1114.7(k)(1)(i)(C), a PMTA must contain all studies 
concerning the pharmacological profile of the new tobacco product that 
are published or known to, or which should reasonably be known to, the 
applicant, including investigations into the pharmacokinetics, 
pharmacodynamics, metabolism, and elimination profile, of each of the 
ingredients, additives, and HPHCs for the range of potential levels of 
exposure resulting from the use of or exposure to the product relative 
to other tobacco products. The applicant also must specify whether the 
studies were conducted in vitro, in vivo, ex vivo, or in silico. The 
pharmacological profile of the product and its constituents are 
important for FDA to consider when evaluating the relationship between 
the dose of the product and the body's response. As such, where 
published or known to, or which should reasonably be known to the 
applicant, the pharmacological profile of the tobacco product is part 
of the information required under section 910(b)(1)(A) of the FD&C Act 
because it provides important information regarding how the product 
constituents and human body interact with each other, which directly 
impacts whether and what health impacts the constituents can have on 
users and nonusers of the product.
    The types of pharmacological information that the applicant must 
include in a PMTA if published or known to, or which should reasonably 
be known to, the applicant include pharmacokinetics and 
pharmacodynamics. Pharmacokinetics concern the movement of a 
constituent into, through, and out of the body. Types of 
pharmacokinetic information that an application must contain if 
published or known to, or which should reasonably be known to, the 
applicant include absorption (the rate and movement of a constituent 
into the bloodstream after administration), bioavailability (the extent 
to which the constituent reaches the site of action), distribution (the 
transfer of a constituent from one location in the body to another), 
metabolism (the breaking down of a constituent), and excretion (the 
elimination of a constituent). Pharmacodynamics refers to the effects 
of the constituent on the body including physiological (e.g., changes 
in blood pressure and heart rate) and subjective effects (e.g., whether 
the product is ``liked'' or produces other changes in affect). Types of 
pharmacodynamic information that an applicant must submit in a PMTA if 
published or known to, or which should reasonably be known to, the 
applicant include physiological and subjective effects data and 
information regarding drug-receptor interactions, chemical 
interactions, and dose-response relationships.
    FDA received several comments regarding toxicological information, 
as discussed below.
    (Comment 69) One comment stated that the pharmacological profile of 
many of the ingredients or constituents in a tobacco product might not 
be helpful to FDA's determination of health risks and that FDA should 
recommend inclusion of this information rather than require it. The 
comment noted that some constituents, such as nicotine, have already 
had their pharmacological profile established in literature and that 
other constituents are delivered at such low levels that they would not 
permit evaluation of their pharmacological profile.
    (Response 69) FDA declines to revise the rule as a result of this 
comment. The pharmacological profile of the product and its 
constituents provide important information about the health risks of 
the product as well as its risk relative to other products. 
Specifically, this information is important for FDA to consider when 
evaluating the relationship between the dose of the product and the 
body's response. While the pharmacological profile of some ingredients 
and constituents, such as the nicotine pharmacokinetic (PK) profile, is 
well characterized for some general classes of tobacco products, slight 
changes in product features (e.g., cigarette ventilation (Ref. 128), 
tobacco pH and nicotine absorption site (Ref. 68), ENDS voltage (Refs. 
129-133)) affect the nicotine PK profile. In general, the abuse 
potential of nicotine increases when absorption is rapid because the 
rewarding properties of the compound increase, and suppression of 
withdrawal symptoms occurs more quickly. Nicotine's pharmacological 
profile impacts use behavior that can then affect the overall exposure 
of the user to HPHCs and other constituents in the product. Changes in 
use behavior may result from the pharmacokinetic properties of the 
nicotine and can result in increased or decreased exposure to the 
constituents within a product (Refs. 4 and 132-134). Because this 
profile directly impacts use behaviors and abuse liability, it remains 
a critical piece to understanding a tobacco product's impact on public 
health.
    (Comment 70) One comment stated that in addition to describing the 
health risks of the tobacco products contained within the new tobacco 
product, FDA should require applicants to present evidence that the 
product does not interfere with the pharmaceutical drugs that expected 
users of the new tobacco product may be taking.
    (Response 70) As required under Sec.  1114.7(k), a full report of 
each health risk investigation that is published or known to, or which 
should reasonably be known to, an applicant concerning the potential 
for interaction between drugs and the new tobacco product must be 
included as part of a PMTA in order for it to be filed for review. FDA 
intends to consider the implications of such health risk information, 
or a lack thereof, during substantive review, as appropriate.
    Under Sec.  1114.7(k)(1)(i)(D), a PMTA must contain full reports of 
all investigations published or known to, or which should reasonably be 
known to the applicant concerning the health risks of the tobacco 
product compared to other tobacco products on the market, never using 
tobacco products, quitting tobacco product use, and using the tobacco 
product in conjunction with other tobacco products. Under section 
910(b)(1)(A) of the FD&C Act, an applicant must submit investigations 
that have been made to show whether the tobacco product presents less 
risks than other tobacco products. Under section 910(b)(1)(G) of the 
FD&C Act, FDA requires applicants to submit investigations that have 
been made to show whether the tobacco product has the same or different 
potential health risks (not just less potential health risks) than 
other tobacco products to capture investigations that could potentially 
show a range of risks compared to other tobacco products. FDA requires 
applicants to include comparisons between the health risks of the 
tobacco product and never using tobacco product under the authority of 
section 910(b)(1)(A) and (G) of the FD&C Act because this information 
is relevant to determining the health risks faced by nonusers who 
initiate tobacco use with the tobacco product.
    FDA also requires that an application contain, if published, known 
to, or which should be reasonably known to the applicant, comparisons 
between the health risks of the tobacco product and using the tobacco 
product in conjunction with other tobacco products because existing 
data indicates that a significant number (approximately 40 percent or 
more by some estimates) of both adults and youth who currently use 
tobacco products use more than one type of tobacco product (Refs. 135 
and 136). This information is important in determining the health risks 
faced by individuals that may use the new tobacco product in 
conjunction with other tobacco products because research

[[Page 55364]]

indicates that individuals who use a tobacco product with lower health 
risks in conjunction with a tobacco product with potentially higher 
health risks may continue to face the potentially higher health risks 
of the more dangerous product above a certain threshold of usage (Refs. 
137 and 138).
    The types of investigations that a PMTA must contain if published 
or known to, or which should reasonably be known to the applicant, in 
this section include, for example:
     Cross-sectional and longitudinal surveys (such as market 
analyses or publicly available national surveys such as NYTS);
     epidemiologic studies that are descriptive (which describe 
the occurrence of a prespecified or unknown outcome), such as case 
reports and case series; and
     analytic studies (which describe the association between 
exposure and outcome) such as randomized controlled clinical trials, 
cohort studies, and case control studies.
    Additionally, clinical studies that employ surrogate endpoints 
(e.g., biomarker studies) may be used to draw conclusions regarding the 
effects of the product on a clinical benefit endpoint and patient 
reported outcome data (i.e., report of the status of health that comes 
directly from the subject without interpretation of the subject's 
response by a clinician) may be used as supportive evidence for health 
outcomes or effects.
    For determining the health risks that are posed to a typical user 
of a tobacco product for the purposes of comparison, FDA recommends 
using an average of light, moderate, and heavy users. FDA also 
recommends including evidence and a description supporting the range of 
light, moderate, and heavy use an applicant includes in its PMTA, 
including how they relate to the exposures in the submitted toxicology 
studies. Where an applicant does not have data regarding light, 
moderate, or heavy product use because the product has not been 
commercially marketed, including outside the United States, an 
applicant could, where applicable, bridge to data regarding a similar 
tobacco product or conduct clinical studies under ad libitum (i.e., 
unrestricted use) conditions.
    As set forth in Sec.  1114.27(b)(1)(ii) and described in section 
VIII.B, for an application to be filed it must contain substantive 
information comparing the new tobacco product's health risks to those 
generally presented by the same product category and at least one 
different product category that is used by the consumers an applicant 
expects to use their new tobacco product.
    (Comment 71) One comment stated that Sec.  1114.7(k)(1)(i) is 
unclear regarding the tobacco products to which an applicant must 
compare the new tobacco product that is the subject of an application. 
The comment stated requiring a comparison to just cigarettes could 
disincentivize the development of new, lower risk e-cigarettes.
    (Response 71) FDA disagrees with the suggestion that the rule 
requires a comparison to cigarettes in each application. Section 
1114.27(b)(1)(ii) requires a PMTA to contain substantive information 
regarding the health risks of the new tobacco product compared to the 
health risks generally presented by both products in the same product 
category and products in at least one different category that are used 
by the consumers an applicant expects will use its new tobacco product. 
While this could require a comparison to cigarettes for at least some 
applications, it would not be required in all applications. For the 
comparison to other products in the same category, this could include, 
for example, comparing an e-liquid to other e-liquids used in a similar 
manner. We also disagree with the suggestion that the comparative 
health risk information requirements in the rule would disincentivize 
development of lower risk products because FDA also requires each PMTA 
to compare the health risk of its product to other tobacco products in 
the same product category. Because FDA's APPH determination considers 
changes in health risks to users of other products in the same category 
that switch to the new tobacco product, applicants have an incentive to 
ensure its product does not pose greater health risks than other 
products in the same category.
    An applicant should consider the appropriate comparative health 
information a PMTA may need beyond the minimum requirement for 
substantive information to provide FDA with a full understanding of the 
potential risk and benefits to current tobacco users. If a PMTA lacks 
sufficient information to demonstrate the changes in risk to which 
current users of tobacco products would potentially be exposed if they 
switched to the new tobacco product or began using it in conjunction 
with their current product, FDA intends to issue a marketing denial 
order for the new tobacco product.
    For demonstrating the health risks that are posed by the product in 
comparison to using other tobacco products, a PMTA must contain, under 
Sec.  1114.27(b)(1)(ii), comparison to both products that are within 
the same category or subcategory of tobacco product and also to other 
categories of tobacco products currently on the market, as appropriate. 
As described in section VII.B.13.a, when determining an appropriate 
comparison product within the same category or subcategory of product, 
FDA recommends applicants consider products that consumers are most 
likely to consider interchangeable with the new tobacco product and 
other similar products. For example, for a PMTA for an e-liquid, FDA 
recommends the product be compared to other e-liquids likely to be used 
in the same manner. When determining appropriate comparator products 
that are not in the same tobacco product category, FDA recommends, in 
addition to the requirements of Sec.  1114.27(b)(1)(ii), comparing the 
health risks of the product to categories of products that users are 
likely to switch to. Applicants may compare to comparator products that 
have a substantial market share (e.g., cigarettes, smokeless tobacco, 
cigars); however, such comparisons may only be appropriate if users are 
likely to switch to the comparator products. Because it is expected 
that current consumers of products that are in the same category may 
switch products and consumers of different categories of tobacco 
product may also switch products or use a new product in conjunction 
with their current product, this comparative health risk data is an 
important part of the evaluation of whether switching could potentially 
result in a lower or higher population health risks.
    iv. Impacts on tobacco use behavior of tobacco product users. FDA 
interprets the health risk investigations that must be provided under 
section 910(b)(1)(A) of the FD&C Act (where published or known to, or 
which should reasonably be known to the applicant) to include the 
effect of either the product or its label, labeling, or advertising, to 
the extent that advertising has been studied, on tobacco use behavior 
and tobacco use topography because use behavior and topography are 
directly related to levels of exposure to HPHCs, which, in turn, 
impacts health risks. For example, changes in tobacco product use 
behavior and topography that result in more frequent or intense use of 
the product will result in greater exposure to HPHCs and may result in 
increased health risks. Aspects of a product that could result in more 
frequent or intense use compared to currently marketed products can 
include differences in the appeal and design of the product, including 
ingredients; flavors; alteration in the

[[Page 55365]]

amount or delivery of nicotine; physical differences such as changes in 
the velocity of the inhaled particles, the effort required to inhale, 
or the density of the smoke, vapor, or aerosol; or other changes which 
similarly affect user behavior (e.g., ventilation, filter density).
    (1). Abuse liability. Section 1114.7(k)(1)(ii)(A) requires a PMTA 
to contain full reports of investigations into the abuse liability of 
the new tobacco product that are published or known to, or which should 
reasonably be known to the applicant. However, as set forth in Sec.  
1114.27(b)(1)(ii) and described in section VIII.B, if a PMTA does not 
contain substantive information regarding the abuse liability of a new 
tobacco product, FDA may refuse to file the application. This means 
where there is no published information regarding the abuse liability 
or information that is otherwise known to the applicant or should 
reasonably be known to an applicant, including information from 
investigations using other products that an applicant could bridge to 
its product, an applicant would need to conduct its own investigation 
and include a full report of the results in its PMTA for filing.
    Abuse liability refers to the potential of a substance to result in 
addiction and be used repeatedly or even sporadically resulting in 
undesirable effects. The abuse liability of a new tobacco product is 
important for FDA to evaluate because it indicates the degree to which 
users of the tobacco product are likely to use and develop an addiction 
to the product. Abuse liability may result in craving of the product 
and compulsive and continued use despite harm or risk of harm. FDA 
requires the submission of abuse liability information under its 
interpretation of section 910(b)(1)(A) and (G) of the FD&C Act because 
it indicates the likelihood of users to become addicted to the product 
and face the health risks posed by product use over the long term, and 
provides insight into the use and adoption of the product, which is an 
important part of FDA's assessment of the health risks of the new 
tobacco product as part of its determination of the risks and benefits 
to the population as a whole under section 910(c)(4) of the FD&C Act. 
If FDA lacks sufficient information regarding the potential abuse 
liability of the new tobacco product, it intends to issue a marketing 
denial order for the new tobacco product.
    The types of investigations that inform an evaluation of a 
product's abuse liability can be wide ranging and are likely to overlap 
with data submitted elsewhere as part of the PMTA, including data 
regarding product chemistry, pharmacology, and pharmacokinetic 
characteristics. Where the data are included elsewhere in a PMTA, FDA 
recommends including content in this section by cross-reference to the 
full reports of relevant investigations in other sections. Applicants 
should analyze the results of all investigations included in the 
application that impact the abuse liability of the product and 
synthesize the findings in this section.
    While applications need to contain some amount of substantive 
information concerning abuse liability under Sec.  1114.27(b)(2)(ii) to 
be filed, the abuse liability of a tobacco product is an important part 
of FDA's finding of whether permitting the marketing of the new tobacco 
product would be APPH and applicants should consider conducting an 
abuse liability study if they do not believe there is sufficient 
existing data regarding their product. The ``standard'' abuse liability 
study is a double-blind, placebo-controlled, within-subject study 
comparing several doses of a new product to a comparator product with a 
known abuse liability. Generally, the primary outcome measure is peak 
``liking'' (Emax) as reported via a visual analog scale. Applicants 
that wish to conduct abuse liability studies examining tobacco products 
may utilize a similar framework with additional assessments, although 
evaluating multiple doses may not be applicable to some tobacco 
products. These assessments may include use topography, and 
pharmacokinetics and pharmacodynamics assessments under both prescribed 
and ad libitum (i.e., unrestricted) use conditions. Real world, actual 
use data may also provide outcomes relevant to the products' abuse 
liability, including misuse. Abuse liability conclusions should be 
considered as an integral assessment of all outcome measures important 
to understanding the abuse liability of the new tobacco product both 
independently and relative to other tobacco products with a known abuse 
liability. FDA generally expects abuse liability studies to contain a 
comparison to one or more tobacco products and applicants seeking to 
market a new tobacco product for which little abuse liability data has 
been established should ensure FDA has sufficient information to 
understand how the abuse liability of such a product compares to other 
relevant categories of tobacco products.
    FDA received comments regarding abuse liability, as discussed 
below.
    (Comment 72) One comment objected to the inclusion of a statement 
in numerous places throughout the preamble to the proposed rule 
indicating that an applicant would be required to conduct 
investigations in certain circumstances. The comment stated that the 
requirement should appear in the codified, rather than the preamble, 
and requested additional information regarding how a company that does 
not have a product on the market could meet such requirements.
    (Response 72) FDA disagrees with the characterization that it is 
creating a requirement for the submission of information in the 
preamble rather than in the codified. The instances identified by the 
comment in which FDA references the potential need for applicants to 
conduct their own investigations for submission in a PMTA are each a 
part of a discussion regarding the substantive information required by 
Sec.  1114.27(b)(1)(ii) for application filing. These portions of the 
preamble identified by the comment, make it clear that where there is 
no existing substantive information regarding these topics that an 
applicant could include in its PMTA, including published investigations 
or investigations it could bridge to its new tobacco product, the 
applicant would need to conduct its own investigation to generate such 
substantive information for inclusion in its application or have FDA 
refuse to file its application for failing to meet the requirement of 
Sec.  1114.27(b)(1)(ii).
    (Comment 73) One comment stated that the rule is overly broad in 
that it requires the submission of information regarding abuse 
liability and also contains recommendations concerning abuse liability 
studies that align with how FDA assesses abuse liability for drugs. The 
comment stated that because tobacco products are legal, there are no 
defined parameters regarding abuse or misuse. The comment also noted 
that there are a number of factors concerning individual users that 
affect whether they will develop dependence and that a number of social 
factors drive individual's decisions to start using and continue to 
regularly use tobacco products and these factors cannot be simulated in 
a premarket setting. The comment recommended that FDA use the term 
``dependence potential'' and that FDA should limit the scope of 
required information only to the product that is the subject of the 
application and a comparator.
    (Response 73) As described in the preceding paragraphs, the abuse 
liability of a new tobacco product is important for FDA to evaluate 
because it indicates

[[Page 55366]]

the degree to which users of the tobacco product are likely to use or 
develop an addiction to the product. Despite tobacco products being 
marketed legally in the United States, nicotine is an addictive drug 
and there are diagnostic criteria for tobacco use disorder in the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 
There are a number of factors that contribute to the abuse liability of 
a substance and there are methodologies widely accepted to evaluate 
abuse liability in a research setting. These methodologies can be used 
to inform FDA about the abuse liability of product described in a PMTA. 
FDA requires the submission of abuse liability information because it 
indicates the likelihood of users to become addicted to the product and 
face the health risks posed by product use over the long term and may 
provide insight into the use and adoption of the product, which is an 
important part of FDA's assessment of the health risks of the new 
product. Given the importance of this information in FDA's 
understanding of the abuse liability of the new product both 
independently and relative to other products with a known abuse 
liability, FDA declines to use the term ``dependence potential'' or 
limit the scope of required information to only the product that is 
subject of the application and a comparator product. FDA generally 
expects abuse liability studies to contain a comparison to one or more 
tobacco products to ensure that FDA has sufficient information to 
understand how the abuse liability of a product compares to other 
relevant categories of tobacco products.
    (Comment 74) One comment stated that FDA should prioritize evidence 
about real-world actual use over clinical trials or laboratory studies 
and proposed revisions that appear to require the submission of actual 
use data that is relevant to the abuse liability of the new tobacco 
product.
    (Response 74) We agree that information regarding actual use of a 
product and its abuse liability are important to FDA's review of an 
application, which is why, under Sec.  1114.27(b)(1)(ii), FDA may 
refuse to file a PMTA that does not contain substantive information 
regarding those topics. We decline to require ``real-world actual use 
data'' concerning abuse liability as part of FDA's acceptance and 
filing requirements, because a determination of whether the data in an 
application adequately demonstrate the abuse liability of a product is 
more appropriately considered during substantive review on a case-by-
case basis.
    (2). Use Topography, Frequency, and Trends. Section 
1114.7(k)(1)(ii)(B) of the rule requires a PMTA to contain 
investigations published or known to, or which should reasonably be 
known to the applicant into how consumers actually use the product, 
including use topography, the product use frequency, use trends over 
time, and how such use affects the health risks of the product to 
individual users. FDA requires this information because the ways in 
which consumers actually use the product, instead of relying only on 
how manufacturers intend the product to be used, help to demonstrate 
the levels of constituents to which the users will be exposed.
    An actual use study can include the use of actual product in either 
a simulated use setting or in a real use environment. Actual use 
studies are important to the evaluation of a PMTA because they provide 
information regarding whether consumers will use the product as 
intended. In addition, actual use studies help demonstrate whether 
consumers are likely to misuse the product, including in ways that may 
change the health risks that the product poses to users and nonusers. 
For example, ENDS users have applied e-liquid directly onto an exposed 
heater coil, a process known as dripping, which can lead to greater 
exposure to volatile aldehyde and a resulting change in the health 
risks of using the product (Ref. 83). Actual use studies may be 
conducted using outpatient protocols so that results are as close to 
actual use as possible. The format of the study should reflect the 
goals of the study and how the applicant believes the information will 
inform FDA's decision.
    Use topography measures the way in which users consume a product. 
Use topography is an important measure to consider in assessing a 
product's health risk and abuse liability because the volume, 
frequency, and duration of product use determines the amount of, and 
manner in which, a user is exposed to HPHCs in a product and, 
consequently, affects the health risks of the product. For combusted or 
inhaled products, use topography could include measurements of the 
number of puffs taken, puff duration, puff volume, duration of use, and 
other relevant measures. For smokeless tobacco, use topography could 
include measures such as the number of smokeless tobacco tins used per 
week, the total dips per day, and the dip duration.
    FDA received one comment regarding this issue, as described below.
    (Comment 75) One comment requested that FDA clarify what 
information an applicant would be required to submit under Sec.  
1114.7(k)(1)(2)(ii)(B) to demonstrate how consumers actually use the 
product, including use topography, the product use frequency, use 
trends over time, and how such use affects the health risks of the 
product to individual users. The comment noted that the rule seemed to 
require actual use studies and requested that FDA clarify whether this 
needs to be real-world studies or they could be in a simulated setting.
    (Response 75) Under Sec.  1114.27(b)(1)(ii), FDA may refuse to file 
a PMTA that does not contain substantive information regarding how 
consumers actually use the product, including use topography, product 
use frequency, use trends over time, or how such use affects the health 
risks of the product to individual users. Thus, where there is no 
published information regarding actual use or information that is 
otherwise known to the applicant, including information from 
investigations using other products that an applicant could bridge to 
its product, an applicant would need to conduct its own investigation 
and include a full report of the results in its PMTA for filing. 
However, FDA does not require a particular type of actual use study. 
For example, applicants may conduct and submit results from an actual 
use study in a real or simulated setting. The types of studies that may 
provide this information on current tobacco use behavior can include, 
but are not limited to, actual use studies and national survey 
databases that could be used to bridge general data to the specific 
product. Ideally, the studies would look at the past, present, and 
likely future behaviors of tobacco product users. As described in the 
following paragraphs, FDA requires this information because the ways in 
which consumers actually use the product, instead of relying only on 
how manufacturers intend the product to be used, helps to demonstrate 
the levels of constituents to which the users will be exposed.
    (3). Polyuse. Section 1114.7(k)(1)(ii)(C) of the rule also requires 
the PMTA to contain full reports of all investigations, published or 
known to, or which should reasonably be known to the applicant, 
regarding the likelihood that users will use the product in conjunction 
with other tobacco products (i.e., polyuse).
    FDA received on comment regarding polyuse, as discussed below.
    (Comment 76) One comment stated that to assess the health impacts 
of dual use, proposed rule Sec.  1114.7(k)(1)(i)(D) should be 
strengthened to require submission of meaningful estimates of

[[Page 55367]]

true levels of dual and polyuse based on research for the proposed 
product or comparable products.
    (Response 76) FDA agrees that consideration of dual and polyuse are 
important to determining whether permitting the marketing of a new 
tobacco product would be APPH, which is why FDA is finalizing Sec.  
1114.7(k)(1)(ii)(C). Data indicate that a substantial number of tobacco 
product users are polyusers of tobacco products (Refs. 135 and 136). 
FDA requires information regarding the likelihood of dual or polyuse 
because such use may increase or decrease known health risks and may 
pose risks that are not currently known (Refs. 137 and 138). The 
likelihood of tobacco product users using the new tobacco product in 
conjunction with another tobacco product, when considered with the 
health effects resulting from such polyuse, will help FDA determine the 
health risks that polyusers may encounter. However, because the main 
purpose of the rule is to set requirements for application acceptance 
and filing that ensure that a PMTA contains sufficient information for 
FDA to conduct substantive review of the application, FDA declines to 
make the requested revisions. Questions about whether data regarding 
the potential for polyuse of other tobacco products along with the new 
tobacco product is meaningful, valid, or applicable are more 
appropriate to consider during substantive review, rather than at 
filing review, because it requires an in-depth, scientific evaluation 
to make such a determination.
    (4). Start or continue use of product. Section 1114.7(k)(1)(ii)(D) 
through (F) of the rule also requires the PMTA to contain full reports 
of investigations published or known to, or which should reasonably be 
known to the applicant, regarding the likelihood that current tobacco 
product users:
     Will start using the product;
     will starting using the product exclusively and then 
switch to other tobacco products that may present increased risks to 
individual health; and
     will start or continue to use the product when they 
otherwise would have quit using tobacco products.
    While Sec.  1114.7(k)(1)(ii)(a) through (f) requires a PMTA to 
contain only information published or known to, or which should 
reasonably be known to the applicant, as set forth in Sec.  
1114.27(b)(1)(ii), if a PMTA does not contain a substantive information 
regarding likelihood of changes to tobacco use behavior of current 
tobacco users, FDA intends to refuse to file the application. This 
means where there is no published information regarding the likelihood 
of changes in tobacco use behavior by current users of tobacco products 
or information that is otherwise known to the applicant, including 
information from investigations using other products that an applicant 
could bridge to its product, an applicant would need to conduct its own 
investigations and include a full report of the results in its PMTA to 
meet this requirement for application filing. Although the rule would 
not require an applicant address each potential change in tobacco 
product use behavior for the purposes of filing, FDA must be able to 
determine the potential risks and benefit to the population as a whole, 
including each of the potential risks and benefits associated with 
changes in tobacco product use behavior by current tobacco product 
users in order to issue a marketing granted order. If a PMTA lacks 
sufficient information needed for FDA to make these determinations, FDA 
intends to issue a marketing denial order for the new tobacco product.
    FDA requires information regarding the tobacco use behavior of 
current tobacco product users because these behavior patterns affect 
the health risks posed to those individuals. Current tobacco product 
users who start using the product may be switching from a product that 
may present greater, lower, or equal levels of individual health risk. 
Current tobacco product users that adopt the product may not continue 
use of the product in the future, so FDA seeks information regarding 
whether they are likely to switch back or switch to a product that may 
present higher levels of individual risk. Finally, current tobacco 
product users who would have otherwise quit using tobacco may use the 
new tobacco product instead, exposing them to health risks to which 
they might not have otherwise been exposed.
    FDA received one comment regarding this issue, as discussed below.
    (Comment 77) A comment stated that FDA should require applicants to 
submit all marketing research related to the development of any 
proposed new product, specifically including research considering the 
positioning of the proposed new product as a competitor to quitting. 
FDA also requires information regarding current tobacco product user 
behavior because to determine whether the product is appropriate for 
the protection of public health, FDA must take into account the 
increased or decreased likelihood that current tobacco product users 
will stop using tobacco products under section 910(c)(4)(A). The types 
of studies that will likely fall into this category can include actual 
use studies and national survey databases that could be used to bridge 
general data to the specific product. Ideally, the studies would look 
at past, present, and likely future behaviors of the tobacco product 
users.
    (Response 77) Each PMTA is required by Sec.  1114.7(k)(1)(ii)(F) to 
contain full reports of all investigations that are published, known 
to, or which should reasonably be known to, an applicant concerning the 
likelihood that current tobacco product users who may have otherwise 
quit using tobacco products will instead start or continue to use the 
product. This could include information such as applicant-conducted or 
sponsored marketing research as part of the development of its 
marketing plans. The description of marketing plans required under 
Sec.  1114.7(f)(2) could also provide relevant information concerning 
how an applicant would target the marketing of its new tobacco product 
to specific intended audiences.
    v. Impacts on tobacco use initiation by nonusers, including youth, 
young adults, and other relevant vulnerable populations. The rule also 
requires a PMTA to contain full reports of investigations published or 
known to, or which should reasonably be known to the applicant, 
regarding the likelihood that consumers who have never used tobacco 
products, particularly youth, young adults, and other relevant 
vulnerable populations, will initiate use of the tobacco product and 
the likelihood that consumers who have never used tobacco products and 
adopt use of the tobacco product will switch to other tobacco products 
that may present higher levels of individual health risk; however, as 
set forth in Sec.  1114.27(b)(1)(ii), if a PMTA does not contain 
substantive information regarding the likelihood of initiation of 
tobacco use by current nonusers of tobacco products, FDA intends to 
refuse to file the application. This means that where there is no 
published information or information that is otherwise known to the 
applicant regarding the likelihood of changes in tobacco use behavior 
by current nonusers of tobacco products, including information from 
investigations using other products that an applicant could bridge to 
its product, an applicant would need to conduct its own investigations 
and include a full report of the results in its PMTA for filing. If FDA 
lacks sufficient information to determine the potential risks and 
benefits to the population as a whole, including the potential risks 
and benefits associated with changes in tobacco product use behavior by 
current tobacco product users, it may issue a

[[Page 55368]]

marketing denial order for the new tobacco product.
    The rule also requires a PMTA to contain full reports of 
investigations published or known to, or which should reasonably be 
known to the applicant, regarding the likelihood that former users of 
tobacco products will re-initiate use with the tobacco product. FDA 
include information regarding likelihood of re-initiation by former 
users as part of its interpretation of the requirements of section 
910(b)(1)(A) and under its authority of section 910(b)(1)(G) of the 
FD&C Act because it will help FDA determine the health risks to which 
these former users may be exposed if they begin using the new tobacco 
product. Survey studies are one type of investigation that is likely to 
fall into this category.
    FDA received several comments on initiation information, as 
discussed below.
    (Comment 78) One comment requested clarity regarding a statement in 
the preamble regarding the assessment of current nonusers of tobacco 
products who initiate tobacco product use with the new tobacco product 
and that begin polyuse of tobacco products or switch completely to 
another tobacco product. The comment stated that predicting such 
potential future behaviors that would be made after the potential 
future initiation of tobacco product use would be challenging both in 
terms of reliability and precision.
    (Response 78) FDA does not generally require applicants to conduct 
studies regarding the likelihood that nonusers would initiate tobacco 
product use with the new tobacco product and then transition to polyuse 
or switch to another tobacco product for the purposes of application 
acceptance and filing under the rule. Applicants would only be required 
to submit full reports of such investigations where they are published 
or known to, or which should reasonably be known to an applicant. 
However, such information would be helpful to FDA's determination of 
whether the marketing of the new tobacco product would be APPH, 
specifically FDA's consideration of the likelihood that nonusers of the 
tobacco product will start using the product. Where there is no direct 
information about the new product and its impact on patterns of use 
among those who initiate, it's possible an applicant could use 
historical data on patterns of tobacco use (e.g., rates of switching 
between product categories), to discuss what they anticipate the impact 
of the new product might be. For example, this could be information 
about the proportion of new users of a tobacco product or tobacco 
product category that sustain use for a year and become polyusers of 
the new product or product category and another tobacco product or 
switch entirely to another tobacco product. This information may be 
available from sources such as existing longitudinal and repeated 
cross-sectional datasets available to the public.
    FDA requires information regarding likelihood of tobacco use 
initiation and switching to potentially more harmful tobacco products, 
including among youth and young adults, as part of its interpretation 
of the requirements of section 910(b)(1)(A) of the FD&C Act because it 
will help FDA determine the number of current nonusers who will likely 
be exposed to the health risks presented by the tobacco product, as 
well as the risks posed by potentially more harmful products that 
individuals may go on to use. The information regarding initiation and 
switching by current nonusers of tobacco products is also being 
required under section 910(b)(1)(G) because FDA must take into account 
the increased or decreased likelihood that those who do not use tobacco 
products will start using tobacco products under section 910(c)(4)(A) 
of the FD&C Act. The types of studies that would likely fall into this 
category include survey studies and focus groups. In order to assess 
whether permitting the marketing of a new tobacco product would be 
APPH, FDA will need to understand how individuals below the minimum age 
of sale may use or intend to use the new tobacco product because 
individuals below the minimum age of sale are a population of 
particular concern for initiating tobacco use.
    (Comment 79) One comment supported the requirement to submit 
information regarding the potential health risks of the new product on 
youth and young adults, but it stated that tobacco companies should not 
be permitted to conduct research on youth because applicants could use 
such information to design their marketing campaigns to attract youth. 
In addition, multiple comments stated that FDA needs to be more 
explicit about whether it recommends conducting investigations using 
youth as test subjects. One comment requested explicit direction 
regarding what falls within the narrow scope of research using youth 
subjects that could be appropriate and how applicants should assess 
whether the benefits of the research outweigh its risks. Another 
comment requested more information regarding bridging methods and 
information on how it could be used to extrapolate the impact on youth 
from young adult data in the context of consumer and perception 
studies.
    (Response 79) FDA does not require research to be conducted on 
individuals below the minimum age of sale and does not anticipate that 
will be necessary or an applicant to do so because inferences regarding 
individuals below the minimum age of sale may potentially be 
extrapolated from young adults, as well as derived from existing 
sources of data, reviews of published scientific literature, or 
bridging information obtained from other sources. Providing data from 
the published literature or marketing information in an application 
with appropriate bridging information may be one useful approach. If an 
applicant takes such an approach, FDA recommends a PMTA contain a clear 
explanation of how such data can be extrapolated to the target 
population or populations of interest for the product that is the 
subject of the PMTA. Setting requirements with respect to different 
types of tobacco product research that an applicant may conduct is 
outside the scope of this rulemaking, which is why in the following 
paragraph we highlight some of the laws and ethical considerations 
applicable to research involving subjects below the minimum age of 
sale. If an applicant chooses to conduct a study in the United States 
using minors, it must use appropriate parental consent procedures, as 
well as follow the requirements of the Children's Online Privacy and 
Protection Act (15 U.S.C. 6501-6505), the Pupil Rights Amendment (20 
U.S.C. 1232h), and their implementing regulations (See 16 CFR part 312 
and 34 CFR part 98, respectively). FDA strongly recommends that any 
studies conducted outside of the United States are designed so that the 
rights, safety, and welfare of human subjects, including minors, are 
protected in accordance with ethical principles acceptable to the 
international community, such as those reflected in the ICH Good 
Clinical Practice standards.
    Regardless of where a study is conducted, any studies using 
individuals under the minimum age of sale should have a narrow research 
scope and be as focused as possible given sensitivities around the 
conduct of research in these populations. Specifically, research 
priorities for individuals minimum age of sale should be focused on key 
questions relating to use (e.g., prevalence of use, characteristics of 
users, and patterns of use), risk perception, and intention to 
initiate/susceptibility among non-users.

[[Page 55369]]

Studies conducted among individuals under the minimum age of sale 
focusing on issues beyond these key questions (e.g., exposing youth to 
advertisements or marketing material for tobacco products) would 
necessitate a very strong justification to demonstrate that the risks 
of conducting the research are minimal and do not outweigh the 
potential benefits of collecting such information.
    vi. Perceptions and use intentions. The rule requires a PMTA to 
contain full reports of investigations published or known to, or which 
should reasonably be known to the applicant, regarding tobacco product 
perceptions and use intentions, including the effect of either the 
product or its label, labeling, or advertising, to the extent that 
advertising has been studied, on individuals' perception of the risks 
of the product, use intentions, and the ability of individuals to 
understand the labeling and instructions for use and use the product in 
accordance with those instructions.
    FDA received one comment on this issue, as discussed below.
    (Comment 80) One comment stated that FDA should require testing 
regarding product packaging, labeling, and advertising that shows they 
will not mislead consumers or otherwise encourage any harm-increasing 
uses of the product.
    (Response 80) FDA agrees that information regarding consumer 
perception and use intentions is an important part of an APPH 
determination. Under Sec.  1114.27(b)(1)(ii), FDA intends to refuse to 
file any PMTA that does not contain any substantive information 
regarding the potential impact of either the product or its label, 
labeling, or advertising on individuals' perception of the product, or 
their use intentions. This means where there is no published 
information or information that is otherwise known or should reasonably 
be known to the applicant regarding either the potential impact of the 
product or its label, labeling, or advertising on individuals' 
perception of the product, and their use intentions, including 
information from investigations using other products that an applicant 
could bridge to its product, an applicant would need to conduct its own 
investigation or testing regarding at least one of the topics and 
include a full report of the results in its PMTA for filing. If, based 
upon a fair evaluation of all material facts, FDA determines that the 
proposed labeling is false or misleading in any particular, FDA must 
issue a marketing denial order as required by section 910(c)(2)(C) of 
the FD&C Act. Additionally, as described in section VII.B.6, because 
the advertising, marketing, and promotion of a tobacco product can have 
a significant impact on the potential for tobacco product initiation, 
especially by youth, where FDA is unable to determine the impact that 
the labeling, advertising, marketing, or promotion of the new tobacco 
product may have on consumer perceptions and use intentions, FDA 
intends to issue a marketing denial order for the new tobacco product.
    (Comment 81) One comment stated that FDA should make it clear that 
investigations of perceptions and use intentions are required only for 
prospectively proposed labels, labeling, and advertising. The comment 
stated that because FDA is using section 910(b)(1)(G) of the FD&C Act 
as its authority and that section is limited to information that is 
relevant to the subject matter of the application, FDA should limit 
Sec.  1114.7(k)(1)(iv) to investigations for prospectively proposed 
labels, labeling, and advertising, as this would be the relevant 
information. The comment added that this approach would avoid potential 
burdens on applicants and FDA from having to submit and review past 
materials, especially for products on the market for several years 
before the requirement took effect.
    (Response 81) FDA disagrees with the comment because investigations 
regarding prior labels, labeling, and advertising can provide 
information that is relevant to FDA's review. FDA includes perception 
and use intention studies as part of its interpretation of the 
requirements of section 910(b)(1)(A), and under its authority of 
910(b)(1)(G) of the FD&C Act because perception of the risk of the 
product may influence decisions to use the product and the resultant 
exposure to the health risks presented by the product (Ref. 139). If an 
applicant uses advertising as stimuli in a tobacco product perception 
and use intention study, the PMTA must indicate, as part of the full 
report of the study under Sec.  1114.7(k)(3), whether it is 
representative of advertising that the applicant intends to use in 
marketing the product that is required by Sec.  1114.7(f)(2). If the 
advertising is not representative of the advertising an applicant 
intends to use in marketing the product, the applicant must indicate 
whether the study results are still relevant to the likely impact of 
product advertising on tobacco product perceptions and use intentions.
    Additionally, information about individuals' understanding 
regarding the labeling is relevant to determining whether the labeling 
is misleading, which is a reason for which FDA must deny an application 
under section 910(c)(2)(C) of the FD&C Act, and also may provide 
information on the likelihood of individuals using the product. 
Further, whether consumers understand the instructions for use and use 
the product in accordance with those instructions can help show whether 
consumers will be exposed to potentially greater health risks by using 
the product improperly. Topics that should be examined in tobacco 
product perception and intention investigations overlap with the topics 
identified in the human factors section that follows.
    vii. Human factors. The rule also requires a PMTA to contain full 
reports of investigations, published or known to, or which should 
reasonably be known to, the applicant regarding human factors that 
influence the health risks of the product, which includes use 
conditions, use environments, use related hazards, estimated use error 
risk, potential unintended uses, risk controls to ensure that harms and 
unintended consequences are minimized, and adverse experiences related 
to such uses.
    FDA received comments regarding human factors, as discussed below.
    (Comment 82) One comment stated that the human factors requirements 
in Sec.  1114.7(k)(1)(v) and the corresponding description in the 
preamble did not address the complex nature of human factors or the 
numerous permutations and interactions among subcategories of products. 
Given the complexity of ``human factors'' and unspecified ``threshold 
amount of information'' applicants are required to submit for FDA to 
file an application, the comment requested that FDA clarify how much 
information regarding human factors is required for filing.
    (Response 82) Section 1114.27(b)(2)(ii) requires a PMTA to contain 
substantive information concerning the ways in which human factors can 
affect the health risks of the new tobacco product. This rule does not 
require an applicant to conduct an investigation regarding human 
factors for an application to be filed unless there is no information 
that is published or can otherwise be bridged to the new tobacco 
product that is the subject of the application. As described in section 
IX.B, FDA considers substantive information to be information that is 
relevant to the subject it claims to support and has evidentiary 
support. Any amount of substantive information regarding the ways in 
which human factors can affect the health risks of the new tobacco 
product is sufficient to meet the filing requirements of Sec.  
1114.27(b)(2)(ii).

[[Page 55370]]

    Further, although the rule requires an application to contain some 
amount of substantive information for filing, FDA must be able to 
determine the potential risks and benefits of the new tobacco product 
to the population as a whole, which includes youth, young adults, and 
other vulnerable populations. If FDA lacks sufficient information to 
make this determination, it intends to issue a marketing denial order 
for the new tobacco product. FDA requires human factors information as 
part of its interpretation of the requirements of section 910(b)(1)(A) 
and (G) of the FD&C Act because it provides an assessment of use-
related health hazards for the tobacco product.
    In situations where it is critical for the end user to have 
instructions on how to properly use the product, it is important for 
applicants to demonstrate that the instructions for use are adequate. 
FDA recommends that human factors studies focus on the particular 
aspects of labeling that provide instructions for use. For example, it 
may be appropriate for a human factors study to evaluate the tobacco 
product user's:
     Ability to select the appropriate task from a set of 
instructions that include different options;
     understanding of how to identify a defective or expired 
product;
     awareness and understanding of the safety information 
provided in the instructions for use;
     recognition of any potential harms or dangers that would 
signify the need to seek medical attention, such as shortness of 
breath, allergic reaction, weakness, increased heart rate; and
     understanding of diagrams, if provided as part of the 
product labeling (which may overlap with investigations regarding 
consumer perception and understanding).
    Analyzing use-related risks is a critical step in identifying use 
related hazards associated with the product and in characterizing high-
risk hazards so that they can be mitigated or eliminated. FDA 
recommends that a PMTA contain a use-related risk analysis to help 
identify critical tasks that should be evaluated in human factors 
studies and inform the priority of testing the tasks in a human factors 
study, and determine if there are specific use scenarios to include in 
testing. If an applicant conducts human factors testing to determine 
tobacco product use-related risks, FDA recommends that the test 
considers potential users of the product, use environments, similar 
products used within the environments, and any associated medical 
factors or health conditions that may affect whether users may 
experience serious or unexpected adverse experiences. An applicant may 
also want to include information on known use related problems with 
similar products or previous versions of the product.
    As part of the risk analysis, FDA recommends that an application 
first identify all users and use environments for the product, as well 
as unintended users who are likely to use the product and unintended 
environments, in which the product is likely to be used. For example, 
intended users may be characterized within the application according to 
their respective experience levels, skills, age ranges, and use 
responsibilities. Use environments are an important factor to consider 
because they can have diverse characteristics that affect the users' 
interactions with the product. In some cases, use of the product may be 
prohibited (e.g., laws prohibiting use of a product in the workplace, 
public spaces, airplanes).
    (Comment 83) One comment stated that actual use studies concerning 
human factors are costly and time consuming, and in some cases, they 
are unnecessary. The comment recommended that FDA consider less costly 
alternatives to actual use studies, such as simulated use studies. The 
comment stated that data from the actual use of products that are 
already on the market should also be acceptable. The comment also noted 
that the preamble references a human factors validation study, which is 
referenced nowhere else in the rule, and requested this reference be 
better explained. The comment raised additional concerns with the human 
factor section's discussion of unintended users and unintended use 
environments, stating that there is no logical way for manufacturers to 
address all potential users and environments that fit into those 
categories.
    (Response 83) FDA recommends that human factors investigations be 
conducted in the form of actual use studies, rather than simulated use 
studies. Because it may be difficult in some cases to simulate the 
conditions of use, physical characteristics of the product, or 
environment of use, actual use studies allow for better assessment of 
how users interface with the product. However, the rule does not 
require a specific type of human factors study. As described in this 
section, the rule requires a PMTA to contain at least some amount of 
substantive information concerning the ways in which human factors can 
affect the health risks of the new tobacco product in order for the 
application to be filed for substantive review.
    FDA recommends an applicant conduct human factors validation 
testing because it can demonstrate that the expected users can 
understand and follow the device instructions without serious use 
errors or problems under the expected use conditions. For ENDS, for 
example, the human factors validation study should demonstrate and 
provide evidence that an e-cigarette, as designed, can be used as 
intended by people who are representative of the expected users and 
under normal use conditions. If errors or failures or new findings are 
identified in a human factors validation study, then these problems 
should be evaluated to determine the root cause(s), potential for harm, 
and additional measures to eliminate or mitigate risk.
    b. Literature search. Section 1114.7(k)(2) requires a PMTA to 
describe, and contain the results of, a literature search for each type 
of information described in Sec.  1114.7(k)(1). FDA requires that an 
application contain the bibliography and literature search information 
because section 910(b)(1)(A) of the FD&C Act requires (in part) that a 
PMTA contain full reports of all published health risk investigations. 
FDA is also including these requirements in the rule under authority of 
sections 701(a) and 910(b)(1)(G) of the FD&C Act because they would 
help FDA to determine whether the application contains reports of all 
published investigations in an efficient manner rather than having to 
follow up with the applicant about the inclusion or exclusion of 
specific studies.
    FDA received multiple comments regarding the literature search 
requirement, as discussed below.
    (Comment 84) One comment stated it was unclear how the literature 
search requirement would apply and what level of detail the Agency 
expects to see. The comment noted that in the case of a product not on 
the market, there would be no or limited scientific literature on the 
product.
    (Response 84) Section 1114.7(k)(2) requires a PMTA to contain a 
description of the literature search performed, including the databases 
searched and the date searched, search terms, reasons for inclusion or 
exclusion of documents, and the strategy for study quality assessment. 
The PMTA must also contain a bibliography of all published studies and 
articles referenced in the application. If a literature search was 
performed and resulted in no information found, the application must 
contain a statement to that effect. FDA must determine whether the 
application contains all

[[Page 55371]]

published investigations because the Agency needs to ensure it has all 
relevant health risk data to determine whether permitting the marketing 
of the product would be APPH. The description of the reasons for 
inclusion or exclusion of documents, in particular, will facilitate 
FDA's review of an application because it will explain, if applicable, 
why some investigations that initially appear relevant were excluded 
from the application and why some investigations that do not initially 
appear to be relevant were included in the application. For example, if 
an applicant limits the literature search to a certain time period, the 
applicant must include the reason for such limitations in their 
description of the literature search. For ease of review, FDA 
recommends that an applicant include internal hyperlinks to, or 
otherwise reference, the location of published studies that are 
included in an application. If applicable, it is also recommended that 
an application explain why an investigation that was conducted using a 
product other than the one that is the subject of the PMTA is relevant 
to the application to inform FDA's review of the PMTA.
    It is possible that there may be less information captured by the 
literature search for novel products; however, there may be at least 
some applicable information, such as investigations on constituents 
delivered to users and nonusers under the range of conditions under 
which the product may be used, which may be bridged to the product that 
is the subject of the application.
    c. Study reports. Section 1114.7(k)(3) sets requirements for the 
full report of each investigation that must be included as part of an 
application. An application must contain each type of documentation 
listed in Sec.  1114.7(k)(3) to the extent that it is applicable to the 
type of investigation and to the extent that it is reasonably available 
to the applicant. FDA considers a document to be reasonably available 
unless it does not exist or it would be unduly burdensome to obtain the 
document due to the effort or expense involved. Where an applicant 
considers a document required by this section to not be reasonably 
available, the application must contain an explanation in the full 
report that describes the actions taken to obtain the document and 
specifies why the document is not reasonably available. It is important 
to note that failure to submit documents may affect the extent to which 
FDA is able to rely upon an investigation's findings during substantive 
application review. A full report of the investigation must contain:
    i. Full copies of any published articles and other reference 
materials. FDA requires that an application contain full copies of 
published articles and other reference materials to facilitate the 
review process.
    ii. Documentation of all actions taken to ensure the reliability of 
the study. The requirements for this item would differ based upon 
whether the investigation is a clinical investigation or a nonclinical 
laboratory investigation. For nonclinical laboratory investigations, an 
application must contain documentation demonstrating all actions taken 
to ensure the reliability of the study, including whether the 
investigation was conducted using good laboratory practices (GLPs), 
such as those specified in part 58 (21 CFR part 58). FDA considers GLPs 
to be those that support the quality, reliability, and integrity of 
nonclinical laboratory investigations. This requirement helps FDA 
determine whether the study's findings are accurate and reliable. While 
this rule on its own does not require compliance with the GLP 
regulations found in part 58,\33\ FDA would consider a nonclinical 
laboratory investigation that contains the documentation required by 
part 58 to be one way to satisfy the requirements of Sec.  
1114.7(k)(3)(ii).
---------------------------------------------------------------------------

    \33\ It is important to note that in the Federal Register of 
August 24, 2016 (81 FR 58341), FDA issued a proposed rule that, when 
finalized, would require laboratory investigations regarding tobacco 
products to comply with the requirements of part 58.
---------------------------------------------------------------------------

    FDA recommends that an application contain a final report of each 
nonclinical laboratory investigation that contains the following items, 
at minimum, to show that the study was accurate and reliable:
     Name and address of the facility performing the study and 
the dates on which the study was initiated and completed;
     objectives and procedures stated in the approved protocol, 
including any changes in the original protocol;
     statistical methods employed for analyzing the data;
     the test and control articles identified by name, chemical 
abstracts number or code number, strength, purity, and composition or 
other appropriate characteristics;
     stability of the test and control articles under the 
conditions of administration;
     a description of the methods used;
     a description of the test system used. Where applicable, 
the final report should include the number of animals used, sex, body 
weight range, source of supply, species, strain and substrain, age, and 
procedure used for identification;
     a description of the dosage, dosage regimen, route of 
administration, and duration;
     a description of all circumstances that may have affected 
the quality or integrity of the data;
     the name of the study director, the names of other 
scientists or professionals, and the names of all supervisory 
personnel, involved in the study;
     a description of the transformations, calculations, or 
operations performed on the data, a summary and analysis of the data, 
and a statement of the conclusions drawn from the analysis;
     the signed and dated reports of each of the individual 
scientists or other professionals involved in the study;
     the locations where all specimens, raw data, and the final 
report are stored;
     the statement prepared and signed by the quality assurance 
unit, if any, a description of the quality control review performed and 
its results;
     the study director's signature and date upon completion of 
the final report; and
     any corrections or additions to a final report, clearly 
identifying the part of the final report that is being added to or 
corrected and the reasons for the correction or addition, and bearing 
the dated signature of the person responsible.
    The rule requires full reports of investigations (both clinical and 
nonclinical) to contain, to the extent reasonably available, a 
certification that the investigators do not have, or documentation 
fully disclosing, any potential financial conflicts of interest, such 
as the financial arrangements specified in the financial disclosure by 
clinical investigators regulation in part 54 (21 CFR part 54). While 
FDA does not currently require compliance with part 54 for tobacco 
product investigations, complying with those requirements for both 
clinical and nonclinical investigators would be one way to satisfy the 
financial disclosure requirements of the rule. Financial conflicts 
information is important for FDA to consider because they address a 
potential source of bias in investigations. Applicants would be able to 
use these disclosures as well as appropriate procedures in the design 
and conduct of the study to demonstrate that a potential bias that may 
affect the results of the investigation has been minimized. FDA would 
use the information contained in these disclosures, in conjunction with 
information about the design and purpose of the study, as well as on-
site

[[Page 55372]]

inspections (if necessary) in its assessment of the reliability of the 
data.
    The investigator financial arrangements that the applicant should 
disclose and describe, include:
     Any financial arrangement entered into between the sponsor 
of the study and the investigator involved in the conduct of a clinical 
trial, whereby the value of the compensation to the investigator for 
conducting the study could be influenced by the outcome of the study;
     any significant payments of other sorts from the sponsor 
of the study, such as a grant to fund ongoing research, compensation in 
the form of equipment, retainer for ongoing consultation, or honoraria;
     any proprietary interest in the tested product held by any 
investigator involved in a study;
     any significant equity interest in the sponsor of the 
study held by any investigator involved in any clinical study; and
     any steps taken to minimize the potential for bias 
resulting from any of the disclosed arrangements, interests, or 
payments.
    iii. A copy of all protocols and amendments that were used in the 
study.
    iv. Copies of all investigator instructions, if any were produced 
in addition to the protocol.
    v. The statistical analysis plan. The rule requires that the 
applicant submit a statistical analysis plan, including a detailed 
description of the statistical analyses used (including all variables, 
confounders, and subgroup analyses), the scientific rationale for the 
choice of sample sizes, and any amendments to the plan. FDA requires 
the protocol, investigator instructions, and statistical analysis plan 
to be part of the full report of a study because they would enable FDA 
to understand a study's design, conduct, and analysis in its entirety 
and to evaluate the validity of a study.
    FDA received one comment regarding statistical methods, as 
discussed below.
    (Comment 85) One comment stated that FDA should require that all 
studies submitted in support of a PMTA be adequately powered, and Sec.  
1114.7(k)(3)(v) should be amended to require presentation of power 
data, including study power and minimum detectable effect size, as part 
of the statistical methods used.
    (Response 85) FDA agrees that having adequately powered data is 
important to an applicant's prospects of receiving a marketing granted 
order, but the Agency disagrees with this comment insofar as it 
proposes to restrict the data companies would be required to submit in 
a PMTA. An applicant must submit full reports of health risk 
investigations as described in Sec.  1114.7(k), regardless of whether 
an applicant considers them to be adequately powered. FDA will review 
the information and make its own determination as to whether the data 
are sufficient to support the issuance of a marketing granted order.
    vi. Line data. To facilitate FDA's review, the application should 
contain line data in Statistical Analysis Software (SAS)-transport file 
in .xpt format, created by a procedure that allows the files to be 
readily read by the JMP software. FDA also recommends that an 
application contain data definition files that include the names of the 
variables, codes, and formats used in each dataset, and copies of SAS 
programs and necessary macro programs used to create derived datasets 
and the results reported in the study reports. Such data are important 
for FDA to replicate applicant findings or conduct alternative 
statistical analyses. FDA intends to provide technical specifications 
on its website for submitting information, such as line data, in an 
electronic format that FDA can review, process, and archive (e.g., 
method of transmission, media, file formats, preparation, organization 
of files, accompanying metadata) (https://www.fda.gov/tobacco-products).
    FDA received one comment regarding line data, as discussed below.
    (Comment 86) One comment stated that where an applicant is using a 
published health risk investigation in its application, FDA should not 
require the applicant to obtain and submit underlying data from the 
study sponsor because, in most cases, the source data are unavailable 
and FDA lacks the resources to review, verify, and audit that data.
    (Response 86) Under the rule, the full report of each health risk 
investigation in a PMTA must contain the items specified in Sec.  
1114.7(k)(3) to the extent those items are applicable to the type of 
investigation and to the extent they are reasonably available. For 
additional information on what constitutes a document that is 
reasonably available, please see section VIII.B.13.c. FDA declines to 
amend the rule such that the underlying data from published 
investigations would not need to be submitted where reasonably 
available. Reviewing data from a study can be an important part of 
FDA's assessment of the reliability of its results and where an 
application does not contain data, it may affect the extent to which 
FDA is able to rely upon an investigation's findings during substantive 
application review.
    vii. Sites and clinical investigators. A list of sites and clinical 
investigators that conducted the study, including contact information 
and physical address(es).
    viii. The location of all source data. If the site that conducted 
the study has not maintained all of the source data, indicate where the 
data are located.
    ix. Format. The format of the records and data (e.g., electronic or 
hard copy).
    x. Early termination sites. In the proposed rule, Sec.  
1114.7(k)(3)(x) would have required a PMTA to a list of all sites that 
had early termination, the reason for early termination, and audit 
certificates and inspection results for study sites with early 
terminations. We have revised this provision in response to this 
comment, as discussed below.
    (Comment 87) One comment objected to the proposal to require audit 
certificates and inspection results for study sites that had an early 
termination, stating it contradicts long-standing FDA policy and should 
not be included in the final rule. The comment cited to FDA documents 
concerning the regulation of other products, which state that granting 
FDA access to quality assurance unit inspection reports would tend to 
weaken the inspection system and that confidentiality is necessary for 
inspections to be complete and candid. The comment states that FDA does 
not explain why it would fail to recognize this long-standing practice 
in the tobacco context and that it should not be changed as a part of 
this rule.
    (Response 87) FDA agrees with the comment that the requirement to 
submit audit certificates and inspection results should be removed from 
the rule because of the policy concerns the comment describes and we 
have revised Sec.  1114.7(k)(3)(x) accordingly to require only a list 
of all sites that had early termination and the reason for early 
termination. The rule also now clarifies that FDA may conduct 
inspections of sites that had early terminations. As part of these 
inspections, FDA intends, as appropriate, to review a firm's written 
quality assurance program.
    xi. Contractors. A list of contractors who participated in the 
study, the role of each contractor, and the initiation and termination 
dates of the participation of each contractor.
    xii. Signed report. A signed full report of all findings.
    xiii. Study materials and case report forms. For human subject 
studies, all versions of study materials and case report forms used, 
and all individual case report forms associated with participant 
deaths, other serious and unexpected adverse experiences, withdrawals, 
and discontinuations from

[[Page 55373]]

the study. The rule requires the application to contain one blank copy 
of each version of the study materials (including, but not limited to, 
consent forms, questionnaires, and stimuli) and case report form, and 
only those completed individual case report forms regarding deaths, 
serious and unexpected adverse experiences, withdrawals, and 
discontinuations for individuals that were exposed to the tobacco 
product, or for individuals who were exposed to a similar or related 
product that the applicant is using to help demonstrate the health 
effects of its product. An example of where such case report forms from 
a study regarding a similar product are required is where a clinical 
biomarker study on a product that is similar to the new tobacco product 
in terms of design, ingredients, and HPHCs is used to provide 
information about the anticipated health risks of the new tobacco 
product. As described in Sec.  1114.45, applicants must keep each 
questionnaire and case report form from the study as part of its own 
internal records, which FDA may inspect, as described in Sec.  1114.27, 
or request that the applicant submit to facilitate its review of an 
application. If an applicant fails to keep such records, FDA may be 
unable to rely upon an investigation's findings during substantive 
application review.
    Additionally, while clinical investigations for tobacco products 
are not currently required to be conducted in accordance with the 
requirements for the protocol and procedures implemented to protect 
human subjects in the Institutional Review Boards regulation in part 56 
(21 CFR part 56) and the Protection of Human Subjects regulation in 
part 50 (21 CFR part 50), FDA plans to issue regulations requiring 
compliance with those parts for tobacco products. Until FDA takes such 
action, FDA strongly encourages applicants to follow the requirements 
of parts 50 and 56 or take sufficient actions to ensure that the 
investigation is conducted in a manner that comports with the ethical 
and moral considerations involved with conducting studies using human 
subjects. Each clinical investigation included in the PMTA should have 
been reviewed and approved by an institutional review board (IRB) 
operating to safeguard the rights, safety, and well-being of all trial 
subjects, with special attention being paid to potentially vulnerable 
study subjects including, but not limited to vulnerable populations, 
such as children, incarcerated persons, individuals with impaired 
decision-making capacity, or economically or educationally 
disadvantaged persons. For more information on some of the laws and 
ethical considerations applicable to research involving subjects below 
the minimum age of sale, please see section VIII.B.13.a.(5).
    FDA recommends applicants retain documentation concerning efforts 
related to the protection of human subjects, including documents 
related to the IRB, such as:
     Copies of all research proposals reviewed, scientific 
evaluations, if any, that accompany he proposals, approved sample 
consent documents, progress reports submitted by investigators, and 
reports of injuries to subjects;
     minutes of IRB meetings in sufficient detail to show 
attendance at the meetings; actions taken by the IRB; the vote on these 
actions including the number of members voting for, against, and 
abstaining; the basis for requiring changes in or disapproving 
research; and a written summary of the discussion of controverted 
issues and their resolution;
     records of continuing review activities;
     copies of all correspondence between the IRB and the 
investigators;
     a list of IRB members identified by name; earned degrees; 
representative capacity; indications of experience such as board 
certifications, licenses, etc., sufficient to describe each member's 
chief anticipated contributions to IRB deliberations; and any 
employment or other relationship between each member and the 
institution (e.g., full-time employee, part-time employee, a member of 
governing panel or board, stockholder, paid or unpaid consultant);
     written procedures for the IRB; and
     statements of significant new findings provided to 
subjects, such as those discussed in Sec.  50.25.
    FDA also strongly recommends, but does not currently require, 
maintaining all documentation of the protocol and procedures 
implemented to protect human subjects, such as those set forth in the 
protection of human subjects regulation in part 50. Each clinical 
investigation included in the PMTA should have been conducted using 
only human subjects who gave their informed consent to participate in 
the study. As described in Sec.  50.20, informed consent is consent 
that is obtained from the subject or the subject's authorized 
representative under circumstances that provide the prospective subject 
or representative with sufficient opportunity to consider whether to 
participate and that minimize the possibility of coercion or undue 
influence. The information that is given to the subject or the 
subject's representative should be in language understandable to the 
subject or the representative. The informed consent should not include 
any exculpatory language through which the subject or representative is 
made to waive or appear to waive any of the subject's legal rights, or 
releases or appears to release the investigator, the sponsor, the 
institution, or its agents from liability for negligence.
    xiv. Perception and use intention studies. For perception and use 
intention studies that use a label, labeling, advertising, or other 
materials as stimuli, the rule requires the full report of the study to 
contain a statement regarding whether the label, labeling, or 
advertising used is representative of those the applicant intends to 
use in marketing the product. If the advertising used as stimuli is not 
representative of the advertising an applicant intends to use in 
marketing the product, the applicant must indicate whether and how the 
study findings are still relevant to the likely impact of product 
advertising on consumer tobacco product perceptions and use intentions. 
For more information about tobacco product perception and use intention 
studies, please see the description of Sec.  1114.7(k)(1)(iv) in 
section VII.B.13.a.iv.
14. The Effect on the Population as a Whole
    The rule requires a PMTA to contain an in-depth analysis and 
discussion of how the data and information contained in the application 
establish that permitting the marketing of the new tobacco product 
would be appropriate for the protection of public health. This 
discussion must include the effect that the new tobacco product may 
have on the health of the population as a whole, including youth, young 
adult, and other relevant vulnerable populations with emphasis on the 
populations disproportionately affected by and most likely to use the 
new tobacco product by integrating all of the information (both 
qualitative and quantitative as available) regarding the product, its 
potential effects on health, as well as tobacco use behavior (including 
likelihood of both cessation and initiation), to provide an overall 
assessment of the potential effect that the marketing of the tobacco 
product may have on overall tobacco-related morbidity and mortality. 
Relevant outcomes measures could include reductions in serious medical 
conditions and premature mortality and gains in life-years lived in the 
population. This requirement directly informs FDA's determination under 
section 910(c)(2)(A) of the FD&C Act as

[[Page 55374]]

to whether permitting the marketing of the new tobacco product would be 
APPH.
    FDA received one comment regarding population health analysis, as 
discussed below.
    (Comment 88) One comment stated that FDA should require PMTAs to 
provide reasonable estimates of information regarding the future public 
health impacts from FDA issuing a marketing granted order for the new 
tobacco product, including comparisons to other products and the 
likelihood of changes in tobacco product use behavior. The comment 
suggested that this could include estimates regarding product 
harmfulness, possible harm-increasing consumer uses, mortality impacts 
or impacts on quality adjusted life years.
    (Response 88) FDA agrees that information regarding the potential 
risks and benefits related to the tobacco product, including 
comparisons to other products and the likelihood of changes in tobacco 
product use behavior, is important to the evaluation of a PMTA. 
Accordingly, FDA requires a PMTA under Sec.  1114.7(k) to contain full 
reports of investigations regarding the health risks of the tobacco 
product and to contain an analysis and discussion of all data and 
information under Sec.  1114.7(l) that integrates the information 
regarding the likely effects of the new tobacco product on overall 
health and tobacco use behavior to provide an assessment of the likely 
effect that the marketing of the new tobacco product would have on 
overall tobacco-related morbidity and mortality.
15. Certification Statements
    Section 1114.7(m) requires that the application contain a specific 
statement certifying that the applicant will maintain all records to 
substantiate the accuracy of the application consistent with the record 
retention requirements in Sec.  1114.45, that the information and 
accompanying submission are true and correct, that no material fact has 
been omitted, that the signer is authorized to submit the information 
on the applicant's behalf, and that the signer understands that anyone 
who knowingly and willfully makes a materially false, fictitious, or 
fraudulent statement to the Government of the United States is subject 
to criminal penalties under 18 U.S.C. 1001. This certification will 
help ensure that the applicant understands the responsibilities related 
to the application (including the potential consequences of submitting 
false information to the U.S. Government), the applicant intends to 
submit the PMTA, and the PMTA is ready for review.

C. Amendments (Sec.  1114.9)

    FDA generally expects that when an applicant submits a PMTA, the 
submission will include all information required by section 910(b)(1) 
of the FD&C Act and part 1114 to enable FDA to determine whether it 
should authorize the marketing of a new tobacco product. However, FDA 
recognizes that additional information may be needed to complete the 
review of a PMTA and, therefore, allows the submission of amendments to 
a pending application.
    Section 1114.9 provides that FDA may request, and an applicant may 
submit, an amendment to a pending PMTA together with the appropriate 
form (Ref. 140). Because FDA tracks PMTAs using the STN, an amendment 
must specify the STN that is assigned to the PMTA. An amendment must 
contain the certification statement set forth in Sec.  1114.7(m), with 
the appropriate information inserted, and signed by an authorized 
representative of the applicant. FDA may, at any time after it receives 
and before it acts on an application, request that an applicant submit 
additional information that is necessary to complete the review of a 
PMTA. Similarly, an applicant may submit an amendment on its own 
initiative that is necessary for FDA to complete its review of the 
pending PMTA. These amendments may include information such as newly 
completed or published studies that are relevant to the PMTA, 
clarifications, or a transfer in ownership of the PMTA as described in 
Sec.  1114.13.
    Section 1114.9(b)(2) describes the effect that minor amendments 
have on the 180-day review period. FDA considers minor amendments to be 
any amendments that are not major amendments. Minor amendments can be 
clarifications or other information that FDA needs to complete its 
review of a PMTA, but they will not require substantial review time. 
Examples of minor amendments that FDA has requested include a 
certificate of analysis and administrative information.
    FDA received many comments regarding amendments, as discussed 
below.
    (Comment 89) Multiple comments requested that FDA provide 
additional clarity regarding, and examples of, what constitutes a minor 
amendment or a major amendment.
    (Response 89) Section 1114.9(b) describes how the submission of an 
amendment may affect the time required for the review (as described in 
Sec.  1114.27(c)(1)) of the application. FDA intends to notify 
applicants regarding changes to the review period, including pausing, 
resuming, and resetting the review period for amendments as described 
in this section. If the applicant submits a major amendment to an 
application, either at FDA's request or on its own initiative, FDA will 
restart the 180-day review period. FDA considers major amendments to be 
those that will require substantial FDA review time. Examples of major 
amendments include: Substantial new data from a previously unreported 
study, detailed new analyses of previously submitted data, or 
substantial new manufacturing information (e.g., addition of a new 
manufacturing site for primary and secondary processing, or a change in 
a manufacturing step or process to address a product quality or safety 
issue not initially provided in the application). When an applicant 
submits a major amendment, FDA would consider the applicant to have 
submitted a new PMTA with the review period beginning on the date FDA 
receives the amendment. Therefore, under Sec.  1114.9(b)(1), a new 180-
day review period would begin on the date FDA receives a major 
amendment.
    (Comment 90) One comment stated that FDA should allow applicants to 
submit amendments containing the results of studies that were ongoing 
when the PMTA was submitted and FDA should not automatically restart 
the 180-day review clock when an applicant does so. The comment 
suggested that FDA should instead only add the number of review days 
needed to complete review of the amendment.
    (Response 90) FDA declines to take this suggestion because FDA does 
not expect that it will be able to reliably predict the number of days 
needed to review a major amendment, such as one containing the results 
from a new study, which could require FDA to conduct a potential 
inspection of the study site, at the time when it is received. While 
FDA will restart the 180-day review period after the receipt of a major 
amendment, the Agency intends to promptly act on an amended 
application, which might take fewer than 180 days.
    (Comment 91) One comment stated that the rule implies that 
applicants would be unable to submit minor amendments on their own 
initiative. The comment requested that FDA amend the rule to allow for 
the submission of unsolicited minor amendments and give such amendments 
the same due consideration as solicited amendments.

[[Page 55375]]

    (Response 91) As set forth in Sec.  1114.9, FDA may request, or an 
applicant may submit on its own initiative, an amendment to a PMTA 
containing information that is necessary for FDA complete the review of 
a pending PMTA. This permits the submission of unsolicited minor 
amendments, which FDA will consider in the same manner as solicited 
minor amendments.
    If FDA determines that a minor amendment is necessary to complete 
its review of a pending submission and requests that the applicant 
submit the amendment, FDA may pause the review period on the date that 
it issues the amendment request to the applicant. FDA will resume the 
review period on the date that it receives a written response from the 
applicant either submitting the requested information or declining to 
submit the amendment. For example, if FDA requests a minor amendment on 
day 80 of its review, the date FDA receives the amendment would be day 
81, even though weeks or months may have passed from the date of 
request to receipt. An applicant may notify FDA that it is declining to 
submit an amendment; however, if an applicant declines to submit an 
amendment to FDA, and FDA is not be able to determine whether the PMTA 
meets the requirements to receive a marketing granted order without the 
amendment, it will issue a marketing denial order.
    If FDA requests an amendment, either major or minor, and the 
applicant neither submits the amendment nor notifies FDA that it is 
declining to submit the amendment within the time period specified in 
FDA's request, FDA may, as described in Sec.  1114.9(c), consider the 
applicant to have submitted a request to voluntarily withdraw its PMTA 
and issue an acknowledgement letter stating that the application has 
been withdrawn under Sec.  1114.11. FDA will consider requests for more 
time to submit an amendment and may grant reasonable requests. Section 
1114.9(c) is based on FDA's authority under section 701(a) of the FD&C 
Act to efficiently enforce section 910 of the FD&C Act because it would 
allow FDA to dedicate its resources to reviewing PMTAs that are more 
likely to receive a marketing granted order, rather than continuing to 
review a PMTA submitted by a nonresponsive applicant that is unlikely 
to provide FDA with the information it needs to complete its review.
    If an application has been closed under Sec.  1114.29 or withdrawn 
under Sec.  1114.11, Sec.  1114.9(d) does not allow the application to 
be amended. If an applicant wishes to make changes to an application 
after it is closed or withdrawn, it would have to do so through 
submission of a new application.

D. Withdrawal by Applicant (Sec.  1114.11)

    Section 1114.11 discusses the ability of an applicant to withdraw a 
pending PMTA. At any time prior to FDA acting on the application (i.e., 
taking one of the actions described in Sec.  1114.29), the applicant 
may request to withdraw its application by using the appropriate form 
(Ref. 140) to specify the name of the new tobacco product, the STN of 
the application, and state whether the withdrawal request is related to 
a health concern. If the request is related to a health concern, the 
applicant must describe the concern(s), including the extent, duration, 
and frequency of the health effects, and identify what gave rise to the 
concerns, such as adverse experience reports. FDA requires information 
about health concerns under authority of section 909 of the FD&C Act 
because the information would help FDA protect the public health (e.g., 
identifying a problem that could be present in similar currently 
marketed products) and section 701(a) of the FD&C Act because it allows 
FDA to efficiently enforce provisions of the FD&C Act (e.g., more 
quickly ensure an identified health concern was addressed if an 
application for the same product is submitted again). Once FDA receives 
and processes the withdrawal request, it will issue an acknowledgment 
letter to the applicant, at which time the application will be 
considered withdrawn. Withdrawing an application would not prejudice a 
future submission.
    The application is an Agency record even if withdrawn. Thus, under 
Sec.  1114.11(c), FDA will retain the withdrawn application consistent 
with Agency record retention schedules and policies and will provide a 
copy to the applicant upon request, subject to the Agency's public 
information regulations in part 20 and under the fee schedule in Sec.  
20.45.

E. Change in Ownership of an Application (Sec.  1114.13)

    Section 1114.13 describes the steps that an applicant must take 
when it transfers ownership of a PMTA. This section is intended to 
facilitate transfers of ownership and help ensure that FDA has current 
information regarding the ownership of a PMTA. An applicant may 
transfer ownership of its PMTA at any time prior to FDA taking one of 
the actions described in Sec.  1114.29. Under Sec.  1114.13, at the 
time of the transfer, the new and former applicants (or owners) of the 
PMTA must use the appropriate form (Ref. 140) and submit certain 
information to the Agency. First, the former applicant must submit a 
notice to FDA identifying the new applicant and stating that all rights 
to the PMTA have been transferred to the new applicant. Second, the new 
applicant must submit a signed notice to FDA containing the following 
information:
     To the extent applicable, the new applicant's commitment 
to agreements, promises, and conditions made by the former applicant 
and contained in the PMTA (e.g., certifications, proposed restrictions 
on the sales and distribution of the tobacco product);
     the date that the change in ownership is effective;
     either a statement that the new applicant has a complete 
copy of the PMTA (including any amendments, or any records required to 
be kept under Sec.  1114.45); or a statement of intent to request a 
copy of the PMTA filed with FDA under the Freedom of Information Act 
(FOIA) (FDA's implementing regulations are in part 20); and
     a certification that no modifications have been made to 
the new tobacco product since the PMTA was submitted to FDA.
    Although FDA expects that the new applicant will have a copy of the 
PMTA from the former applicant, if the new applicant requests a copy of 
the PMTA filed with FDA, FDA will provide a copy to the new applicant, 
subject to the public information regulations in part 20 and under the 
fee schedule in Sec.  20.45.
    The new applicant also would be required to make available all 
required records upon inspection by FDA (Sec.  1114.45 would impose a 
recordkeeping requirement).

F. Supplemental Application Submission (Sec.  1114.15)

    Section 1114.15 discusses the availability of supplemental PMTAs. 
Supplemental PMTAs are an alternative format for a PMTA that meets the 
requirements of Sec.  1114.7, which would reduce the burden associated 
with the submission and review of an application. Specifically, 
supplemental PMTAs are a standardized cross-referencing format that FDA 
is implementing under its authority of section 701(a) of the FD&C Act 
to efficiently enforce section 910 of the FD&C Act for submissions that 
are based on a PMTA that FDA has previously reviewed. Applicants that 
have received a marketing granted order would be able to submit a 
supplemental PMTA to seek marketing authorization for a new tobacco 
product that results from a modification or modifications to the

[[Page 55376]]

original tobacco product that received the marketing granted order. An 
applicant can submit a supplemental PMTA only for modifications where 
the submission of limited info can demonstrate that permitting the 
marketing of the modified product would be APPH. FDA is restricting the 
use of supplemental PMTAs to ensure that FDA is able to efficiently 
review the application. An applicant could also submit a supplemental 
PMTA for modifications made to comply with a product standard issued 
under section 907 of the FD&C Act where FDA specifies in that product 
standard rule that the submission of supplemental PMTAs would be 
appropriate.
    Applicants that have questions about whether it would be 
appropriate to submit a supplemental PMTA for the modifications they 
are seeking to implement should contact FDA for more information. To 
further illustrate when a supplemental PMTA could be submitted, FDA has 
prepared the following examples of modifications to ENDS products that 
are likely appropriate to be submitted using the supplemental PMTA 
format and likely not appropriate to be submitted using the 
supplemental PMTA format. After review and consideration of comments 
received in response to the proposed rule, we have added an additional 
example to provide clarity on the product modifications that are likely 
appropriate to be submitted using the supplemental PMTA format.
Potentially Appropriate for Supplemental PMTA Format
     Changes in connection type/thread size (e.g., 510);
     minor Software Changes not affecting device functionality; 
and
    [cir] changes to user interface;
    [cir] changes in recording/data capture properties; and
     certain changes to account for improvements in electronics 
technology or to improve use and convenience (e.g., use of haptics or 
simplification of device functions like cleaning cycle).
     Minor changes in e-liquid volume, viscosity or boiling 
temperature;
     minor changes in draw resistance;
     minor changes in air flow rate;
     changes to coil configuration if number of coils, coil 
gauge, material, and overall coil resistance remain unchanged; and
     changes to amount of wicking material.
Likely Not Appropriate for Supplemental PMTA Format
     Any modification that might increase risk of harm to 
individual health from the product;
     modifications that may alter tobacco product use behavior 
and initiation, such as modifications that have strong youth appeal; 
and
     design modifications that change the category or 
subcategory of the product (e.g., modifying a closed e-cigarette to be 
an open e-cigarette).
    Additionally, there are two other specific limitations on the 
submission of a supplemental PMTA. Under Sec.  1114.15(a), a 
supplemental PMTA could not be submitted where the marketing granted 
order for the original tobacco product has been withdrawn or has been 
temporarily suspended or is the subject of temporary suspension or 
withdrawal proceedings by FDA, except where authorized by FDA in 
writing. FDA restricts the submission of supplemental PMTAs in these 
situations because, for example, withdrawal or suspension may involve 
consideration of whether the marketing of the original product is no 
longer appropriate for the protection of the public health, or the 
application was accompanied by an untrue statement of material fact. If 
the reason for the temporary suspension or withdrawal is unrelated to 
the sufficiency or reliability of information contained in a PMTA, an 
applicant may request, and FDA may grant, authorization to use a 
supplemental PMTA under these circumstances.
    FDA received comments about the use of supplements generally, as 
discussed below.
    (Comment 92) One comment stated that verifying compliance with a 
product standard under section 907 of the FD&C Act should require only 
a certification by the applicant and not a new PMTA, Supplemental or 
otherwise. The comment further stated that in adopting a product 
standard, FDA will have already determined that the standard ``is 
appropriate for the protection of the public health'' for the products 
to which it applies, so product modifications made to comply with an 
applicable new standard thus will not require the same evaluation as a 
standard or supplemental PMTA. The comment asserted that any 
requirement beyond a certification of compliance would be needlessly 
burdensome and would unnecessarily delay consumer access to products 
that satisfy the new product standard.
    (Response 92) The circumstances that would determine the actions a 
manufacturer would need to take to legally market a tobacco product 
after issuance of a product standard are fact-specific and are 
dependent upon the tobacco product, the modifications made (if any), 
and the product standard involved; however, FDA disagrees with the 
suggestion that modifications made to comply with a product standard 
would never need to be the subject of a PMTA or another premarket 
submission to seek marketing authorization. The rule for a future 
product standard would indicate whether an applicant may submit a 
supplemental PMTA, where applicable.
    As discussed in Sec.  1114.15(a), an applicant may not submit a 
supplemental PMTA where the modifications to the original tobacco 
product require the submission of new information or revisions to the 
extent that review of the PMTA for the new tobacco product in the 
supplemental PMTA format would be confusing, cumbersome, or otherwise 
inefficient and submitting a standard PMTA under Sec.  1114.7(b) would 
better facilitate review.
    (Comment 93) One comment requested that FDA make supplemental PMTAs 
available to be submitted for a broader range of modifications to 
reduce the burden on industry.
    (Response 93) FDA declines to allow for broader use of the 
supplemental format because it would likely not result in a more 
efficient review process. Because supplemental PMTAs are based on a 
cross-referencing system that is supposed to reduce the burden of 
preparing and reviewing a PMTA, FDA has created this limitation to 
ensure PMTAs are submitted in the format that is the easiest to review, 
process, and archive. Changes that require multiple, sweeping, or 
difficult-to-trace changes to the PMTA for the original tobacco product 
would be more efficient to review in the full text format of Sec.  
1114.7.
1. Required Format
    Under Sec.  1114.15(b) the supplemental PMTA format is the same as 
the format for standard PMTAs submitted under Sec.  1114.7(b), except 
that applicants must include content in a supplemental PMTA by cross-
referencing content in the PMTA and postmarket reports for the original 
tobacco product. FDA believes that including content in an application 
by cross-referencing to a PMTA for the original tobacco product is 
appropriate for supplemental applications because the referenced 
information will be presented in the proper context and format, and 
will facilitate application review.

[[Page 55377]]

2. Required Content
    The required content for a supplemental PMTA is divided into two 
general categories: New content sections and content sections cross-
referenced from the PMTA for the original tobacco product. The new 
content sections required under Sec.  1114.15(c)(1) must contain the 
full text or a cross-reference to text in a tobacco product master file 
or postmarket reports for the original tobacco product. These sections 
may not include information by cross-reference to the PMTA for the 
original tobacco product. The new content sections that must be 
included under Sec.  1114.15(c)(1) are:
     General information (as described in Sec.  1114.7(c));
     new product information (as described in Sec.  
1114.15(d));
     statement of compliance with part 25 (as described in 
Sec.  1114.7(g));
     labeling (as described in Sec.  1114.7(f)) if the labeling 
is not identical to the labeling submitted in the PMTA or postmarket 
reports for the original tobacco product;
     postmarket information (as described in Sec.  1114.15(e)); 
and
     certification statement (as described in Sec.  
1114.15(f));
    A supplemental PMTA must also contain application sections that 
comprise information included by cross-reference to the PMTA for the 
original tobacco product and contain any additional information that is 
necessary to supplement or update the cross-referenced information. It 
is important to note that these cross-referenced sections must be 
accompanied by the full text of any updates or supplemental information 
that are necessary to tailor this information to the new tobacco 
product. These updates or supplemental information should consist of 
changes to application content that is not otherwise included as part 
of the new content sections required under Sec.  1114.15(c)(1). For 
example, if a new health risk investigation on the product is published 
and it is not contained in the new content sections, the cross-
referenced sections must contain a full report (as described in Sec.  
1114.7(k)(3)) of the investigation in full text with a cross-reference 
to the health risk investigations section in the PMTA for the original 
tobacco product. The cross-referenced sections that must be included 
under Sec.  1114.15(c)(2) are:
     Descriptive information (as described in Sec.  1114.7(d));
     product samples (as described in Sec.  1114.7(e)). Please 
note, however, that FDA may, request the submission of product samples 
after receipt of a supplemental PMTA;
     labeling (as described in Sec.  1114.7(f)) if the labeling 
is identical to the labeling submitted in the PMTA or postmarket 
reports for the original tobacco product;
     summary of all research findings (as described in Sec.  
1114.7(h));
     product formulation (as described in Sec.  1114.7(i));
     manufacturing (as described in Sec.  1114.7(j)); and
     health risk investigations (as described in Sec.  
1114.7(k)).
3. New Product Information
    Under Sec.  1114.15(d), the new product information section 
required under Sec.  1114.15(c)(1)(ii) must contain the following 
information concerning modifications to the original tobacco product, 
including:
     Full descriptions of the modification(s) to the original 
tobacco product and comparisons of such modification(s) to the 
unmodified version(s) described in the PMTA for the original tobacco 
product;
     a statement as to whether the new tobacco product is 
intended to replace the original tobacco product if the new product 
receives a marketing granted order, is intended to be a line extension 
of the original tobacco product, or is intended to be introduced as an 
additional product by the same manufacturer;
     all data and information relating to the modification(s) 
that are required in an application under Sec.  1114.7. This is data 
and information that can span across a number of application sections. 
A change in the connection type or thread size for an ENDS product, for 
example, may require a change in the design parameters and the 
manufacturing sections; and
     a concluding summary of how the new tobacco product meets 
the requirements to receive a marketing granted order. This summary 
must describe how the data and information concerning the product 
modification when viewed together with the information cross-referenced 
from the previously submitted PMTA demonstrate that the new tobacco 
product meets the requirements of section 910(c) of the FD&C Act to 
receive a marketing granted order.
4. Postmarket Information
    Under Sec.  1114.15(c)(1)(v), a supplemental PMTA must contain 
postmarket information as specified in Sec.  1114.15(e). Where an 
applicant has submitted postmarket reports for the original tobacco 
product, it must incorporate those reports by cross-reference. Where an 
applicant has yet to submit a postmarket report for the original 
tobacco product, it must submit a report as part of the supplemental 
application that contains all the information for the original tobacco 
product that would otherwise be required in a report under Sec.  
1114.41, covering the period in time from when it received its 
marketing granted order for the original tobacco product to when it 
submitted the supplemental PMTA. Because information that is contained 
in a postmarket report for the original tobacco product would likely be 
required content of a standard PMTA for the modified tobacco product, 
FDA is allowing applicants to cross-reference this content to avoid the 
burden of resubmitting information that FDA has previously reviewed.
5. Certification Statement
    Under Sec.  1114.15(f), the certification statement required under 
Sec.  1114.15(c)(1)(vi) must be signed by an authorized representative 
and, in addition to the certification required under Sec.  1114.7(m) 
for a standard PMTA, must certify that the modifications identified in 
the certification are the only modification(s) to the original tobacco 
product.

G. Resubmissions (Sec.  1114.17)

    Section 1114.17 describes resubmissions, which are an alternative 
format for submitting an application that meets the requirements of 
Sec.  1114.7(b) or Sec.  1114.15 to seek a marketing granted order, by 
responding to the deficiencies outlined in a marketing denial order. An 
applicant may submit a resubmission for the same tobacco product that 
received a marketing denial order or for a different new tobacco 
product that results from changes necessary to address the deficiencies 
outlined in a marketing denial order. This application format allows an 
applicant to address the deficiencies described in a marketing denial 
order without having to undertake the effort of submitting a standard 
PMTA. The resubmission format is available to resubmit an application 
that received a marketing denial order because FDA has completed its 
review of the PMTAs subject to the marketing denial order and can rely 
on the findings of these reviews to save time when reviewing a 
resubmission. The resubmission format is not available for PMTAs that 
FDA refused to accept, refused to file, cancelled, or administratively 
closed, or that the applicant withdrew, because FDA has not previously 
completed reviews of such applications upon which it can rely, and such 
applications may need significant changes to be

[[Page 55378]]

successfully resubmitted. It is important to note that, as discussed in 
section VIII.E regarding Sec.  1114.33, while FDA will identify 
deficiencies that resulted in the marketing denial order, the 
deficiencies specified in the order might not be an exhaustive listing 
of all deficiencies contained in the PMTA.
    Similar to a supplemental PMTA, an applicant may not submit a 
resubmission to the extent that review would be confusing, cumbersome, 
or otherwise inefficient and submitting a standard PMTA under Sec.  
1114.7 would better facilitate review. Where responding to the 
deficiencies outlined in the marketing denial order requires broad or 
sweeping changes to the original PMTA, an applicant would need to 
submit a standard PMTA under Sec.  1114.7 to better facilitate review. 
Where possible, FDA will specify in the marketing denial order if an 
applicant may not pursue a resubmission to address the identified 
flaws.
    Applicants may request a meeting with FDA prior to submitting a 
resubmission to determine whether it may utilize the resubmission 
format and to discuss any issues related to the application, such as 
application organization and format. For example, applicants that have 
questions about whether it would be appropriate to pursue a 
resubmission for the modifications they are seeking to implement to 
respond to deficiencies identified in a marketing denial order may 
contact FDA for more information.
1. Format
    Under Sec.  1114.17(b) the resubmission format requirements are the 
same as the format in Sec.  1114.7(b) for standard PMTAs, except that 
applicants must include content in a resubmission by cross-referencing 
content in the PMTA. FDA believes that including content in a PMTA by 
cross-referencing to a PMTA for the original tobacco product is 
appropriate for resubmissions because the referenced information will 
be presented in the proper context and format and will facilitate 
application review. In addition, an applicant may include content in a 
resubmission by cross-reference to a TPMF.
2. Content
    The required content for resubmission is divided into two general 
categories: New content sections and cross-referenced content sections. 
The new content sections required under Sec.  1114.17(c)(1) must 
contain the full text or cross-referenced text from a tobacco product 
master file. These sections may not include information by cross-
reference to the PMTA or postmarket reports for the original tobacco 
product. The new content sections that must be included under Sec.  
1114.17(c)(1) are:
     General information (as described in paragraph Sec.  
1114.7(c));
     response to deficiencies (as described in Sec.  
1114.17(d)); and
     certification statement (as described in Sec.  
1114.17(e)).
    A resubmission must also contain application sections that comprise 
information included by cross-reference to the PMTA for the original 
tobacco product and all additional information that is necessary to 
supplement or update the cross-referenced information. It is important 
to note that these cross-referenced sections must be accompanied by the 
full text of any updates or additional information that are necessary 
to tailor this information to the new tobacco product. These updates or 
additional information should consist of changes to application content 
that is not otherwise included as part of the response to deficiencies 
section. This information could include, for example, full reports of 
health risk investigations published after the applicant submitted the 
PMTA that received the marketing denial order. The cross-reference-
based sections that must be included under Sec.  1114.17(c)(2) are:
     Descriptive information (as described in Sec.  1114.7(d));
     product samples (as described in Sec.  1114.7(e)). Please 
note that FDA may require the submission of product samples after it 
has received your application;
     labeling (as described in Sec.  1114.7(f)), together with 
updates to the labeling made by the time of submission, if any;
     statement of compliance with 21 CFR part 25 (as described 
in Sec.  1114.7(g));
     summary of all research findings (as described in Sec.  
1114.7(h));
     product formulation (as described in Sec.  1114.7(i));
     manufacturing (as described in Sec.  1114.7(j)); and
     health risk investigations (as described in Sec.  
1114.7(k)).
3. Response to Deficiencies
    As described in Sec.  1114.17(d), the response to deficiencies 
section required under Sec.  1114.17(c)(1)(ii) must list and provide a 
separate response to each deficiency described by FDA in the marketing 
denial order, including all data and information necessary to complete 
each response, as well as any applicant-identified deficiencies. The 
deficiencies should be addressed in the order in which they are listed 
in the marketing denial order, followed by applicant-identified 
deficiencies. Where an applicant modifies the original tobacco product 
to address the deficiencies outlined in the marketing denial order, the 
applicant must also include: (1) A full description of each 
modification to the product and comparisons of that change to the 
original version described in the PMTA for the original tobacco product 
and (2) all data and information relating to each modification to the 
product that would be required in an application under Sec.  1114.7.
4. Certification Statement
    Under Sec.  1114.17(e), the certification statement required under 
Sec.  1114.17(c)(1)(iii) must be signed by an authorized representative 
and, in addition to the certification required under Sec.  1114.7(l) 
for standard PMTA, must certify either: (1) That the application 
addresses all deficiencies specified in the marketing denial order and 
is being submitted for a tobacco product that is identical to the 
product for which FDA issued a marketing denial order or (2) the 
application addresses all deficiencies and the tobacco product is 
distinct from the original tobacco product, but the only modifications 
to the original tobacco product are those identified in the 
certification.

IX. FDA Review (Part 1114, Subpart C)

A. Communications Between FDA and Applicants (Sec.  1114.25)

    Section 1114.25 sets forth general principles for the 
communications between FDA and applicants and is intended to provide 
more information to applicants about FDA communications. Section 
1114.25 explains that, during the course of FDA's review of an 
application, FDA may seek to communicate with applicants about relevant 
matters including scientific, medical, and procedural issues that arise 
during the review process. Communications regarding human risk issues 
may arise if adverse experience reports exist for the tobacco product.
    FDA received some comments regarding its communications with 
applicants, as discussed below.
    (Comment 94) Some comments mentioned that while FDA states that it 
encourages applicants to meet with FDA, this is not what often happens. 
Instead of face-to-face meetings, the comment noted that FDA often 
provides written responses instead. The comment argued that there is no 
substitute for face-to-face meetings and encourages FDA to include 
provisions in the PMTA

[[Page 55379]]

rule related to presubmission meetings that includes standards for 
face-to-face meetings.
    (Response 94) FDA may use a variety of methods to communicate with 
applicants such as telephone conversation, letters, emails, or face-to-
face meetings depending on the circumstances and issues. Furthermore, 
as discussed in the guidance entitled ``Meetings with Industry and 
Investigators on Research and Development of Tobacco Products,'' while 
an applicant may request a face-to-face presubmission meeting, FDA may 
determine that this type of meeting is unnecessary and instead provide 
a written response to the questions raised in the meeting request. If 
an applicant feels that the written responses are insufficient, it may 
submit a subsequent request for a meeting.
    FDA documents any communications regarding a PMTA in accordance 
with 21 CFR 10.65. While applicants may contact FDA with questions, as 
a general matter, FDA does not provide applicants with predecisional 
details about an ongoing application review, such as whether an initial 
submission is sufficient to receive a marketing granted order or the 
date and time at which FDA will act on an application. For additional 
information on requesting a face-to-face presubmission meeting, please 
consult the guidance for industry and investigators entitled ``Meetings 
with Industry and Investigators on Research and Development of Tobacco 
Products.'' \34\
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    \34\ Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/meetings-industry-and-investigators-research-and-development-tobacco-products.
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B. Review Procedure (Sec.  1114.27)

    Section 1114.27 describes the procedures by which FDA would review 
a PMTA. When an applicant submits a PMTA, FDA performs an acceptance 
review of the submission. Currently, FDA performs its acceptance review 
of all premarket submissions based upon the criteria set forth in Sec.  
1105.10. The rule incorporates and builds upon these general criteria 
to set PMTA-specific acceptance criteria. Under the rule, FDA may 
refuse to accept an application for further review if, upon initial 
review, it:
     Does not comply with the applicable format requirements 
for the type of PMTA (i.e., Sec.  1114.7(b) for a standard PMTA, Sec.  
1114.15 for a supplemental PMTA, Sec.  1114.17 for a resubmission);
     is not administratively complete because it does not 
appear to contain the information required by the applicable 
application content requirements section. This means that the content 
required for the type of PMTA must be readily and easily identifiable 
as part of a cursory review of the application (i.e., a standard PMTA 
must appear to contain information required by Sec.  1114.7, a 
supplemental PMTA must appear to contain information required by Sec.  
1114.15, and a resubmission must appear to contain information required 
by Sec.  1114.17). The acceptance review would assess the facial 
completeness of a submission only, and would not be an in-depth, 
technical review. Examples of submissions that FDA would refuse to 
accept under this rule include, but are not limited to, applications 
that do not appear to contain:
    [cir] Labeling (as required by Sec.  1114.7(f));
    [cir] Design parameter information (as required by Sec.  
1114.7(i)(2)(ii));
    [cir] An EA (as required by Sec.  1114.7(g)); or
    [cir] A literature search (as required by Sec.  1114.7(k)(2)).
     does not pertain to a tobacco product that is subject to 
chapter IX of the FD&C Act, as required by Sec.  1105.10(a)(1). Under 
this provision FDA would refuse to accept the PMTA if it does not 
pertain to a product that is subject to the jurisdiction of CTP. CTP 
has premarket review jurisdiction over products that meet the 
definition of ``tobacco product'' in section 201(rr) of the FD&C Act 
and are subject to chapter IX of the FD&C Act either in section 901(b) 
of the FD&C Act or by regulation. Therefore, FDA will refuse to accept 
submissions for a product that is a drug under the definition in 
section 201(g)(1), a device under section 201(h), a combination product 
as described in section 503(g) of the FD&C Act, or otherwise does not 
meet the definition of a tobacco product; and
     may otherwise be refused under Sec.  1105.10.
    Once FDA has completed its acceptance review under Sec.  
1114.29(a)(1), FDA will issue a letter to the applicant informing it of 
FDA's decision. If FDA accepts the application for further review, it 
will issue an acceptance letter to the applicant that specifies the STN 
for the PMTA. If FDA refuses to accept the application, it will issue a 
letter to the applicant that identifies the reasons, where practicable, 
that prevented FDA from accepting the application. The applicant may, 
after FDA has refused to accept a PMTA, correct the deficiencies and 
submit a new PMTA under Sec.  1114.7. Because FDA is not issuing a 
marketing denial order under Sec.  1114.33 when it refuses to accept a 
submission, an applicant may not utilize the resubmission format 
described in Sec.  1114.17 to address the flaws outlined by FDA.
    FDA implements the acceptance review procedures under authority of 
sections 701(a) and 910 of the FD&C Act. The content, format, and 
jurisdiction requirements that an application must meet to be accepted 
for review will ensure that FDA will be able to efficiently review 
applications and consider only applications that are more complete and 
better prepared for further review. By refusing to accept submissions 
that have clear deficiencies, FDA will be able to focus its resources 
on those submissions that are more likely to be filed for substantive 
review. After FDA accepts a PMTA for review, FDA may request product 
samples as described in Sec.  1114.7(e).
    FDA will also conduct a filing review to determine whether the 
application contains sufficient information to permit a full 
substantive review of the application. FDA may refuse to file a PMTA 
if:
     The PMTA does not include sufficient information required 
by section 910(b)(1) of the FD&C Act and by Sec.  1114.7, 1114.15, or 
1114.17, as applicable, to permit a substantive review of the 
application. These requirements include a sufficient EA for each type 
of PMTA, the absence of which is a reason for which FDA may refuse to 
file an application under Sec.  25.15. The filing requirements also 
include product samples if required by FDA after application 
acceptance. FDA's filing review is an examination of the submission to 
ensure it contains adequate technical information for FDA's substantive 
review of the application to proceed. Unlike the acceptance review, 
which considers whether a submission meets basic content, format, and 
jurisdiction requirements as described above, the filing review is a 
more in-depth review to ensure the application contains sufficient 
information for initiating substantive review. For example, during 
acceptance review, FDA will check whether the PMTA appears to contain 
product design parameters, but during filing review, FDA will review to 
determine whether it contains the correct design parameters for the 
product category and has a value for each design parameter required by 
Sec.  1114.7(i)(2)(ii). FDA implements the filing review requirements 
under authority of section 701 of the FD&C Act to improve the 
efficiency of the PMTA review process. By determining whether a PMTA 
contains sufficient information

[[Page 55380]]

prior to conducting substantive review, FDA can commit the considerable 
resources necessary to conduct substantive review of a PMTA to only 
those submissions that are prepared for review;
     the application does not contain substantive information 
regarding certain specified broad categories of information that must 
be addressed in every PMTA for FDA to determine whether permitting the 
marketing of the new tobacco product would be APPH. FDA considers 
substantive information to be information that is relevant to the 
subject it claims to support and has evidentiary support. Bare 
statements that the marketing of the tobacco product is unlikely to 
result in tobacco product initiation or that it has no abuse liability 
without supporting information do not constitute the types of 
substantive information necessary for application filing. This 
information can come from a variety of sources including investigations 
conducted by the applicant, investigations conducted using a different 
product that the applicant can bridge to its new tobacco product (as 
described in section VII.B.13.a.), or published reports of 
investigations that apply to, or are bridged to, the new tobacco 
product (such as those found in the literature search required by Sec.  
1114.7(k)(2)). Section 1114.27(b)(1)(ii) requires a PMTA to contain 
substantive information regarding certain categories of investigations 
described in Sec.  1114.7(k)(1). While FDA retains discretion to file 
applications as set forth in Sec.  1114.27(b)(1), we generally intend 
to refuse to file each application that does not meet the substantive 
information requirement in paragraph (ii). Where there is no 
substantive information that is published or known to an applicant 
regarding any of the categories of information outlined in this 
section, including information in scientific literature or an 
investigation that an applicant could bridge to its product, an 
applicant would be required to conduct its own investigations and 
include the resulting full report in its PMTA in order to meet the 
requirements for filing. In general, FDA expects that manufacturers 
seeking to market a new product in accordance with the requirements of 
the statute will have access to information to meet these requirements 
for filing.\35\
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    \35\ Information that is available to applicants includes, for 
example, the studies FDA has funded, published, and made available 
to the public, which are consolidated on our website. This database 
includes many ENDS related studies and can be searched by key terms 
(e.g., e-cigarettes): https://www.fda.gov/tobacco-products/research/ctp-supported-tobacco-regulatory-research-projects.
---------------------------------------------------------------------------

    FDA is implementing the application filing requirement under its 
authority in sections 910(b) and 701(a) of the FD&C Act. As described 
in section VIII.D, FDA needs information regarding the potential health 
risks of the new tobacco product, the likelihood of changes in tobacco 
product use behavior, and the potential health consequences associated 
with those changes in behavior to determine the potential risks and 
benefits to the health of the population as a whole under section 
910(c)(4) of the FD&C Act. Refusing to file PMTAs that contain no 
information regarding these broad categories of information allows FDA 
to efficiently enforce the premarket review requirements of section 910 
of the FD&C Act by avoiding the significant expenditure of resources it 
would otherwise commit to the substantive review of applications that 
clearly lack sufficient information to receive a marketing granted 
order. FDA expects that this efficiency will significantly benefit 
those applicants seeking timely consideration of complete, high-quality 
applications.
    Section 1114.27(b)(1)(ii) requires a PMTA to contain at least some 
amount of substantive information regarding each of the following 
topics:
     The health risks of the new tobacco product as described 
in either Sec.  1114.7(k)(1)(i)(A), (B), or (C)). Information regarding 
the health risks of the new tobacco product is a basic piece of 
information that FDA needs to determine the potential risks and 
benefits to the population as a whole associated with changes in 
tobacco use behavior;
     the health risks of the new tobacco product compared to 
the health risks that are generally presented by both tobacco products 
in the same category as well as tobacco products in at least one 
different category that are used by the consumers an applicant expects 
to use their new tobacco product (as described in a portion of Sec.  
1114.7(k)(1)(i)(D)). To demonstrate the health risks that are generally 
presented by the same, or a different, product category, applicants may 
use the health risks generally presented by a product category as a 
whole, or the health risks that are presented by specific products that 
are generally representative of the risks of the product category as a 
whole (e.g., products that represent a significant share of the market 
for the product category). Comparative health risk information is a 
required part of FDA's review of an application because, as described 
in section VII.B.13.a, it can demonstrate the potential risks and 
benefits that current tobacco users could face if they switched to the 
new tobacco product or used it in conjunction with their current 
tobacco product;
     the abuse liability of the new tobacco product (as set 
forth in Sec.  1114.7(k)(1)(ii)(A)). Information regarding abuse 
liability indicates the likelihood of users to become addicted to the 
product and face the health risks posed by product use over the long 
term, and may provide insight into the use and adoption of the product, 
which FDA must consider as part of its determination of the risks and 
the benefits of permitting the marketing of the new tobacco product to 
the population as a whole under section 910(c)(4) of the FD&C Act;
     how consumers actually use the product, including use 
topography, product use frequency, use trends over time, and how such 
use affects the health risks of the product to individual users (as set 
forth in Sec.  1114.7(k)(1)(ii)(B)). Information regarding how 
consumers will actually use the new tobacco product is necessary to 
FDA's review of a PMTA because it helps demonstrate the health risks of 
the new tobacco product by showing the levels, and frequency, of 
exposure to HPHCs and other toxic substances contained in and delivered 
from the new tobacco product;
     the potential impact that the marketing of the new tobacco 
product would have on the likelihood that current tobacco product users 
would start using the new tobacco product, use the product in 
conjunction with other tobacco products, and, after using the product, 
switch to other tobacco products that may present increased risks to 
individual health (i.e., any of the information described in either 
Sec.  1114.7(k)(1)(ii)(C), (D), (E), or (F)). Information regarding 
potential changes to tobacco product use of current tobacco product 
users is a required basis for FDA's findings under 910(c)(4)(A);
     the potential impact of the product and its label, 
labeling, or advertising, to the extent advertising has been studied, 
on tobacco product use behavior of current nonusers of tobacco products 
(i.e., any of the information described in Sec.  1114.7(k)(1)(iii)). 
Information regarding potential impact that the marketing of the new 
tobacco product would have on tobacco product initiation by current 
nonusers of tobacco products is a required basis for FDA's findings 
under 910(c)(4)(B);
     the potential impact of the product and its label, 
labeling, or advertising (to the extent that advertising has been

[[Page 55381]]

studied) on individuals' perception of the product, and individuals' 
use intentions (as described in Sec.  1114.7(k)(1)(iv)). This 
information is important to FDA's review of a PMTA because perceptions 
of the health risk of the product can influence decisions to use the 
product and, as described in section VII.B.6, exposure to advertising 
can have a significant impact on the likelihood that nonusers of 
tobacco products, particularly youth, will initiate tobacco product 
use. Without information regarding perceptions and use intentions, FDA 
will be unable to complete its required determination under section 
910(c)(4)(B) of the FD&C Act of the increased or decreased likelihood 
that nonusers of tobacco products will initiate tobacco product use. It 
is important to note that this substantive information requirement does 
not require an applicant to develop or study advertising for the 
purpose of filing;
     the ways in which human factors can affect the health 
risks of the new tobacco product (i.e., any of the information 
described in Sec.  1114.7(k)(1)(v)). This information is important to 
FDA's review of a PMTA because it provides an assessment of use-related 
health hazards for the tobacco product.
    FDA may also refuse to file a PMTA if:
     The PMTA contains a false statement of material fact; or
     the PMTA is a supplemental PMTA that does not comply with 
Sec.  1114.15 or the PMTA is a resubmission that does not comply with 
Sec.  1114.17. FDA may refuse to file a supplemental PMTA or a 
resubmission that contains all of the required content but does not 
meet the criteria for when a supplemental PMTA or a resubmission may be 
submitted. For both supplemental PMTAs and resubmissions, this could 
occur when, as discussed in Sec. Sec.  1114.15(a) and 1114.17(a), the 
modifications to the original tobacco product are not appropriate to 
review in these formats. As described in Sec.  1114.15(a), FDA may also 
refuse to file a supplemental PMTA where the marketing granted order 
for the original tobacco product has been temporarily suspended (except 
where authorized in writing by FDA) or has been withdrawn. As described 
in Sec.  1114.17(a), FDA will refuse to file a resubmission where the 
marketing denial order for the original tobacco product states that the 
applicant may not use the resubmission format. If FDA refuses to file 
an application, it will send a letter to the applicant identifying, 
where practicable, the deficiencies that prevented FDA from filing the 
application. FDA received many comments regarding review procedures, as 
discussed below.
    (Comment 95) One comment stated that FDA should include clear 
deadlines for the completion of acceptance and filing reviews. The 
comment stated that doing so would allow applicants to schedule the 
submission of PMTA in a way to ensure that the application is accepted 
and filed before the end of FDA's enforcement discretion policy. The 
comment stated that in addition, it is inconsistent with FDA policies 
for other regulated product types such as the deadline of 60 days for 
the filing of new drug applications.
    (Response 95) To the extent that this comment concerns the 
compliance policy for the submission of PMTAs as a result of the 
deeming final rule, it is outside the scope of this rule. As a general 
process matter, FDA declines to set a deadline for acceptance and 
filing reviews both because it would not affect the 180-day review 
period and because FDA wishes to retain some amount of flexibility in 
its review process as it gains more substantial experience in reviewing 
PMTAs. Unlike with new drug applications, FDA's decision to file an 
application does not affect the statutory 180-day review period.\36\ As 
described later in this section of the document, regardless of when in 
the process FDA files a PMTA, the 180-day review period begins when the 
last piece of information necessary to complete a PMTA is received by 
FDA.
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    \36\ Compare section 505(c)(1) of the FD&C Act ``within one 
hundred and eighty days after filing of an application'' to section 
910(c) ``as promptly as possible, but in no event later than 180 
days after a receipt of an application under [910(b)(1)].''
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    (Comment 96) Multiple comments expressed opinions regarding the 
standards for application acceptance and filing. One comment supported 
the filing requirements, urging FDA to apply a standard of review that 
will enable it to distinguish between applications that contain 
scientific information that is arguably sufficient to address the 
issues relevant to determining whether the marketing of a product is 
APPH, and those applications that do not. Another comment requested 
that FDA clarify what an application must contain to be filed for 
review under Sec.  1114.27(b), stating that what constitutes 
``sufficient information'' under the filing standard is not addressed 
in the rule. Another comment stated that FDA has failed to make any 
meaningful distinction between the information that satisfies FDA's 
ability to review a PMTA and the ``sufficient information'' necessary 
for industry to obtain a marketing order. In addition, several comments 
requested that FDA clarify the requirements related to acceptance, 
filing, and substantive review because it was unclear what threshold of 
information must be in a PMTA to meet the requirements of each.
    (Response 96) As described in the rule, FDA may refuse to accept a 
PMTA under Sec.  1114.27(a)(1) where it does not appear to have the 
information required by the rule. This is a cursory check for the 
presence or absence of information at a very high level (e.g., does the 
application contain labeling) and is intended to eliminate low-quality 
submissions. FDA may refuse to file an application where it does not 
contain sufficient information to permit a substantive review by FDA. 
Filing review is a limited examination to determine whether the 
technical elements of the application contain the information required 
by Sec.  1114.7 (or other section as applicable), which FDA considers 
``sufficient information'' at that time that would allow FDA to 
determine whether the application demonstrates the marketing of the 
product would be APPH. The ``sufficient information'' necessary to 
receive a marketing granted order is information that does, in fact, 
demonstrate the marketing of the product would be APPH and the PMTA 
meets the other requirements of section 910(c)(1)(A)(i) of the FD&C 
Act.
    (Comment 97) Multiple comments stated that FDA should permit 
applicants to omit certain required information. One comment referenced 
the regulations for medical devices, in which FDA states that if an 
applicant believes that particular information is not applicable, an 
applicant can identify the omitted information and justify the 
omission. The comment stated that FDA cannot expect each applicant to 
provide information that will satisfy every requirement and that 
justified omissions should not result in marketing denial orders as 
currently stated in the PMTA proposed rule. Another comment requested 
flexibility regarding requirements to submit information it does not 
consider to be dispositive of health risks, such as the pharmacological 
profile.
    (Response 97) FDA declines to make any revisions in response to 
these comments. As discussed throughout the rule, section 910(b)(1) of 
the FD&C Act describes the required contents of a PMTA upon which FDA 
must base its determination under section 910(c)(1)(A) of whether to 
issue a marketing granted order. FDA has carefully described why the 
information required by this rule is important to FDA's determination 
of whether a

[[Page 55382]]

marketing granted order should be issued and specifies where certain 
information would need to be submitted only if applicable to the new 
tobacco product that is the subject of the PMTA.
    (Comment 98) One comment stated that FDA should file PMTAs for 
substantive review where they contain information about the various 
topics discussed in the rule, even where they do not include the final 
results of all referenced studies, so long as the applicant includes 
the study protocol and the expected date by which the applicant would 
submit the final study report to FDA. The comment also requested FDA 
identify application deficiencies before making its filing decision and 
request an amendment containing the specific information necessary for 
the application to be filed and do so under a reasonable timeline for 
the applicants' response before FDA issues a refuse to file decision.
    (Response 98) FDA is establishing the filing requirements in order 
to encourage the submission of applications that contain the 
information FDA needs to determine whether a PMTA meets the 
requirements to receive a marketing granted order. FDA intends to 
refuse to file applications that do not contain the information 
required by Sec.  1114.27(b), regardless of whether the applicant is 
conducting or sponsoring ongoing studies at the time of submission. FDA 
declines to, in every instance, identify application deficiencies 
before making its filing decision. In some circumstances, where the 
PMTA meets the information requirements in Sec.  1114.27(b), the fact 
that a study has not yet been completed might not affect FDA's filing 
decision; however, this is a fact specific determination based on the 
content of each PMTA.
    FDA generally does not intend to submit requests for amendments 
before it makes its decision to file the application for substantive 
review and applicants cannot expect to rely on FDA feedback to complete 
a PMTA after submission. FDA has provided detailed information 
regarding what application content is necessary for filing in this 
rule.
    (Comment 99) Another comment stated that the final rule should be 
amended to clarify that FDA's decisions to refuse to accept (RTA) and 
refuse to file (RTF) PMTAs are subject to judicial review. The comment 
requested that FDA amend the rule to state that RTA and RTF letters 
constitute a denial within the meeting of 910 and 912 of the FD&C Act.
    (Response 99) FDA disagrees with the contention that its decision 
to RTA or RTF constitutes a denial of a PMTA as described in section 
910(a)(2)(A) of the FD&C Act; rather, refusing to accept or refusing to 
file constitutes a determination that the submission is either 
incomplete or does not conform to basic administrative requirements 
and, therefore, is not ready for substantive review. FDA makes its 
determination of whether to grant or deny the applicant a marketing 
authorization order only after conducting substantive review. Refusing 
to accept or refusing to file an application is a decision that is made 
without prejudice to any future submission and, as described in section 
IX.B, FDA intends to provide information regarding how the applicant 
can address the specific issues that led FDA to RTA or RTF the 
submission. It is important to note that section 910(c)(1)(A) requires 
FDA to grant or deny an order within 180 days after receipt of an 
application under section 910(b) and where FDA chooses to RTA or RTF an 
application, it is because it lacks required information and, 
therefore, does not constitute an application under section 910(b) of 
the FD&C Act.
    After FDA files an application, it will begin its substantive 
review of the PMTA. Within 180 days after receipt of an application 
described in section 910(b)(1) of the FD&C Act, FDA intends to complete 
its review of a PMTA and, as described in Sec.  1114.29, act on the 
application, except as described in Sec. Sec.  1114.9 and 1114.27(c)(4) 
through (5).
    (Comment 100) One comment stated that the final rule should be 
amended to clarify that acceptance and filing reviews do not extend the 
180-day review clock.
    (Response 100) FDA's acceptance and filing reviews do not extend 
the 180-day review period. To determine when the 180-day period begins, 
FDA generally relies on the date the last piece of information 
necessary to complete the submission is received by CTP's Document 
Control Center or the FDA laboratory (for product samples), not the 
date that the applicant sent it. It is important to note the event that 
starts the 180-day review clock is the receipt of an application that 
meets the requirements of section 910(b)(1) of the FD&C Act which also 
includes information required by the rule. Given that product samples 
are likely to be required after application acceptance, the review 
period would typically begin, at the earliest, when FDA receives 
product samples. Similarly, if an application is missing other pieces 
of required information, the review period would begin only upon 
receipt of that information. FDA intends to provide applicants with 
notice of the date on which the 180-day review period began, as well as 
notice of when it is paused, resumed, or reset.
    (Comment 101) Multiple comments suggested that because FDA 
acknowledges the supplemental PMTA format will improve the efficiency 
of the review process, FDA should shorten the 180-day review period for 
supplemental PMTAs accordingly. Some comments pointed to the 
application supplement framework used by FDA for other products, such 
as drugs, and urged FDA to adopt a tiered system with different 
notification requirements and timeframes for review corresponding to 
the nature of the modification and the evidence needed to support it. 
In addition, one comment stated that FDA should provide clarity about 
the product modifications for which an applicant would be able to 
submit a supplemental PMTA, stating that the list of examples provided 
is insufficient and the suggestion to request a meeting with FDA to 
discuss supplemental PMTA submission would lengthen what should be an 
abbreviated process.
    (Response 101) FDA agrees that supplemental PMTAs will improve the 
efficiency of the PMTA review process; however, FDA declines to create 
a standard shortened review period because it does not yet have any 
experience in conducting such reviews. In addition, supplemental PMTAs 
could contain substantial information that was not included in the 
original PMTA, such as the addition of Bluetooth capability for ENDS 
which may affect device functionality and, that may affect the review 
time. The application supplement notification procedures and timelines 
for other product types regulated by FDA are not only based on 
different statutory authorities, they are also the result of decades of 
experience in conducting such reviews. In addition, while FDA will have 
a 180-day review period to review a supplemental PMTA application, FDA 
intends to promptly act on the application, which might take fewer than 
180 days.
    There are four instances in which the 180-day review period after 
receipt of a complete PMTA would not be 180 consecutive calendar days. 
First, as described in Sec.  1114.9, the submission of or request for 
amendments may result in changes to the number of calendar days in the 
review period. Where FDA requests a minor amendment, the issuance of 
this request would result in a pause of the review period and receipt 
of the amendment would resume the review period. As described in 
section VIII.C, the submission of a major

[[Page 55383]]

amendment is considered to be the submission of a new PMTA, which 
resets the 180-day review period.
    The second instance in which FDA's 180-day review period would not 
be 180 consecutive calendar days after receipt of a complete PMTA is 
where a new tobacco product, if introduced or delivered for 
introduction into interstate commerce, would be adulterated or 
misbranded due to the domestic manufacturer or importer being in 
violation of the user fee requirements of part 1150 (21 CFR part 
1150).\37\ Situations in which a new tobacco product would be 
adulterated or misbranded for failure to comply with user fee 
requirements are described in Sec.  1150.17(a) and (b), which include 
failure to pay user fee assessments and failure to submit required 
reports. In this situation, FDA intends to pause the 180-day review 
period until any violation of the user fee requirement of part 1150 is 
resolved. FDA implements this provision under its section 701(a) 
authority to issue regulations for the efficient enforcement of the 
FD&C Act. It would be inefficient for FDA to expend the significant 
resources necessary to review an application for a product that could 
not be legally marketed. It would also not be reasonable for FDA to 
complete its review and issue a marketing granted order for a product 
that, if it is put into interstate commerce, would immediately be 
adulterated or misbranded and subject to FDA enforcement action. While 
FDA will not refuse to accept or refuse to file an application on the 
basis that the product would be adulterated for failure to pay user 
fees, FDA will not complete its review of a PMTA until the applicant is 
in compliance with part 1150. FDA will take this action, rather than 
refusing to accept or refusing to file an application, because 
noncompliance with the requirements of part 1150 can often be resolved 
quickly.
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    \37\ Currently, only the manufacturers of cigarettes, cigars, 
snuff, chewing tobacco, pipe tobacco, and RYO tobacco are subject to 
the requirements of part 1150. See the final rule, ``Requirements 
for the Submission of Data Needed to Calculate User Fees for 
Domestic Manufacturers and Importers of Cigars and Pipe Tobacco'' 
(81 FR 28707) (May 10, 2016), for more information.
---------------------------------------------------------------------------

    The third instance in which FDA's 180-day review period would not 
be 180 consecutive calendar days after the receipt of a complete PMTA 
is where FDA is prevented from scheduling or conducting inspections of 
the manufacturing sites or the sites or entities involved with the 
clinical and nonclinical research (including third parties and contract 
research organizations) prevent FDA from completing its review of the 
PMTA in a timely manner. Where this occurs, FDA may pause the 180-day 
review period for the number of days necessary to complete the 
inspection after a delay occurs. FDA has experienced delays in both 
scheduling and conducting inspections, which results in FDA not having 
the information it needs to complete its required review in 180 
consecutive calendar days.
    The fourth instance in which FDA's 180-day review period may not be 
180 consecutive calendar days after the receipt of a complete PMTA is 
where FDA determines after application filing that the applicant has 
not submitted an adequate EA. NEPA and regulations issued by the 
Council on Environmental Quality (CEQ) (42 U.S.C. 4332(2); 40 CFR parts 
1500 to 1508) require FDA to assess, as an integral part of its 
decision-making process, the environmental impacts of any proposed 
Federal action to ascertain the environmental consequences of that 
action on the quality of the human environment and to ensure that the 
interested and affected public is appropriately informed. FDA has 
implemented the NEPA and CEQ requirements in part 25. Under Sec.  
25.15(a), failure to submit an adequate EA is grounds for refusing to 
authorize an application. Consistent with Sec.  25.15(a), FDA may 
refuse to authorize the marketing of a new tobacco product where a PMTA 
contains an inadequate EA.
    As described in Sec.  1114.27(c)(4), FDA may conduct inspections of 
the applicant's manufacturing sites, and sites and entities involved 
with clinical and nonclinical research (including third parties and 
contract research organizations) to support FDA's review of the PMTA. 
Inspecting the facilities and controls described in the application 
will allow FDA to ensure the applicant can manufacture the product in 
accordance with the manufacturing practices described in the 
application and would help FDA determine under section 910(c)(2) of the 
FD&C Act whether such practices conform to an applicable product 
standard issued under section 907 of the FD&C Act or tobacco product 
manufacturing practice requirement issued under section 906(e) of the 
FD&C Act, when in effect. Inspecting sites and entities involved with 
clinical and nonclinical research, including their records (such as 
those required to be kept under Sec.  1114.45), will allow FDA the 
opportunity to verify the study findings and data that the applicant 
relies upon in the PMTA to demonstrate that the new tobacco product 
should receive a marketing granted order. Under Sec.  1114.33, failure 
to grant FDA access at a reasonable time and in a reasonable manner, an 
opportunity to inspect these sites and have access to, copy, and verify 
all records pertinent to the application may result in the issuance of 
a marketing denial order because FDA would not be able to determine 
whether permitting the marketing of the new tobacco product would be 
APPH. During an inspection, an applicant should ensure that:
     All pertinent records can be viewed;
     documents written in a language other than English can be 
translated into English, if requested. Documents that have been 
translated from another language into English should be accompanied by 
a signed statement by an authorized representative of the manufacturer 
certifying that the English language translation is complete and 
accurate, and a brief statement of the qualifications of the person 
that made the translation; and
     if the tobacco product is in production (domestic or 
foreign) and is intended for U.S. commercial distribution, FDA can view 
the product being manufactured.

C. FDA Action on an Application (Sec.  1114.29)

    Section 1114.29 lists six actions that FDA may take after receiving 
an application:
     First, FDA could refuse to accept the application, as 
described in Sec.  1114.27(a);
     second, FDA could issue a letter administratively closing 
the application. This could occur where an applicant fails to respond 
to a request for an amendment within the time period specified in the 
amendment request under Sec.  1114.9(b) or requests to withdraw an 
application under Sec.  1114.11. In the proposed rule, FDA had 
previously stated that ``this could occur where an applicant fails to 
response to a request for an amendment within 180 days.'' FDA changed 
this language in the final rule to be the time period to respond to the 
amendment request to reflect that fact that the time for response might 
vary according to the complexity of the amendment request and thus 
could be a period other than 180 days (e.g., an amendment request for 
relatively simple information might have a shorter response period).
     third, FDA could issue a letter canceling the application 
if FDA finds it mistakenly accepted the application (e.g., the 
application does not pertain to a new tobacco product, or the 
application was submitted in error);

[[Page 55384]]

     fourth, FDA could refuse to file the application as 
described in Sec.  1114.27(b);
     fifth, FDA could issue a marketing granted order as 
described in Sec.  1114.31; or
     sixth, FDA could issue a marketing denial order as 
described in Sec.  1114.33.

D. Issuance of a Marketing Granted Order (Sec.  1114.31)

1. The Requirements To Receive a Marketing Granted Order
    Under section 910(c)(1)(A)(i) of the FD&C Act, FDA will issue a 
marketing granted order for a new tobacco product after its review of a 
PMTA if it finds that none of the grounds for denial specified in 
section 910(c)(2) of the FD&C Act applies to the application. This 
means that in order for FDA to issue a marketing granted order for a 
new tobacco product, FDA must be able to determine the following:
    a. There is a showing that permitting the marketing of the new 
tobacco product would be APPH. Under section 910(c)(4) of the FD&C Act, 
FDA's finding that permitting the marketing of a new tobacco product 
would be APPH must be determined with respect to the risks and benefits 
to the population as a whole, including users and nonusers of tobacco 
products, and taking into account:
     The increased or decreased likelihood that existing users 
of tobacco products will stop using such products and
     the increased or decreased likelihood that those who do 
not use tobacco products (including youth and young adults) will start 
using such products.
    Finding that there is a showing that permitting the marketing of a 
new tobacco product would be APPH is a complex determination that must 
be made with respect to risks and benefits to the population as a 
whole, considering the likelihood of changes in tobacco product use 
behavior (including initiation and cessation) caused by the marketing 
of the new tobacco product. When determining whether the marketing of a 
particular new tobacco product would be APPH, FDA will evaluate the 
factors in light of available information regarding the existing 
tobacco product market, tobacco use behaviors, and the associated 
health risks at the time of review. As described in section 910(c)(5) 
of the FD&C Act, the types of scientific data that FDA will consider in 
making its determination can include well-controlled investigations 
and, where appropriate, other valid scientific evidence that FDA 
determines to be sufficient to evaluate the tobacco product. FDA will 
consider the information supplied in the application together with any 
other relevant sources of information, including a report or 
recommendation from TPSAC, when applicable, in making its 
determination.
    Section 910(c) of the FD&C Act requires FDA to consider an array of 
potential risks and benefits of each new tobacco product with respect 
to the population as a whole when determining whether permitting the 
marketing of a new tobacco product would be APPH. As set forth in the 
criteria for withdrawing a marketing granted order in section 
910(d)(1)(A) of the FD&C Act, FDA must continue to find the product 
meets the APPH standard over time.
    FDA received many comments regarding the requirements to obtain a 
marketing granted order, as discussed below.
    (Comment 102) Several comments stated that FDA has failed to 
explain or justify how it is interpreting and applying the APPH 
standard when evaluating PMTAs and must do so to allow a determination 
of whether its issuance of PMTA marketing orders is arbitrary and 
capricious. In addition, some comments expressed concern that the lack 
of articulated definitions and standards regarding the APPH standard 
would leave applicants guessing at what might satisfy the standard. In 
addition, another comment stated that failing to provide this essential 
direction could increase the likelihood of arbitrary and inconsistent 
decisions.
    (Response 102) FDA disagrees with the assertion that is has failed 
to provide adequate information concerning the APPH standard in section 
910(c)(2) of the FD&C Act. Similar to premarket standards for other 
products, such as medical devices or drugs, FDA does not provide a 
precise definition of the standard but instead provides information 
regarding the types of information that can be used to demonstrate the 
standard has been met. FDA intends to consider the marketing of a new 
tobacco product to be APPH where a PMTA contains sufficient valid 
scientific evidence to demonstrate that the potential risks and 
benefits of the marketing of the new tobacco product would likely have 
a net positive effect on the health of the population as a whole, which 
includes youth, young adults, and other relevant vulnerable 
populations. This could include a variety of different types of 
evidence that may provide FDA with an overall assessment of the 
potential effect permitting the product to be marketed may have on 
tobacco-related morbidity and mortality. For example, FDA may consider 
scientific evidence such as whether levels of HPHCs and other 
constituents in the new tobacco product are similar or lower than 
levels of similar tobacco products currently on the market (see section 
VIII.B.9.a.v), whether the use of the tobacco product has a lower risk 
of disease than the use of a similar product (see section 
VIII.B.13.a.ii), whether consumers are likely to use the product in a 
manner that will lead to possible lower risks (see section 
VIII.B.13.a.iv), and whether the marketing of the new tobacco product 
affects the likelihood of nonuser uptake, ways in which the product may 
be designed to limit or prevent youth access and use, cessation rates 
or other significant shifts in user demographics such that it decreases 
morbidity and mortality from tobacco product use, including youth, 
young adults, and other vulnerable populations (see section 
VIII.B.6.b). As described in this section, the APPH standard requires a 
balancing of product-specific potential risks and benefits. For 
example, an applicant maybe able to demonstrate that their product is 
APPH by providing sufficient valid scientific evidence to show, among 
several key considerations, that the tobacco product reduces morbidity 
and mortality. This could include showing the potential reductions in 
disease risk as compared to other tobacco products and weighing that 
against the potential for nontobacco users to use tobacco product and 
the accompanying potential changes in disease risk among new tobacco 
users. As a result, the factors that could help demonstrate that the 
marketing of a particular new tobacco product would be APPH might not 
support the marketing of a different new tobacco product. As a general 
example, if an application demonstrates that using a new tobacco 
product would present significantly less toxicological risk to 
individual health than cigarettes in a marketplace where many addicted 
users currently smoke cigarettes, it could likely, depending on other 
factors, receive an order where the PMTA demonstrates that the vast 
majority of individuals who would use the product would be current 
users of cigarettes who otherwise would not have quit and would switch 
to using the new product exclusively. This can be seen in FDA's 
determination to authorize the marketing of a tobacco product that 
demonstrated, among several key considerations, that the product 
produced fewer or lower levels of some

[[Page 55385]]

toxins than conventional cigarettes.\38\ On the other hand, where a 
PMTA for a different tobacco product shows that individuals that would 
use the new tobacco product are predominately current users of tobacco 
products that have less toxicological risk to individual health, 
including products within the same product category, the application is 
likely, again depending on other factors, to result in the issuance of 
a marketing denial order because the product is not likely to have a 
net benefit to the population as a whole. As discussed in section 
VIII.B.14, understanding of the effect the new tobacco product may have 
on the health of the population as a whole, which includes youth, young 
adults, and other vulnerable populations, such as effects on tobacco 
use initiation, switching, and cessation, and reductions in premature 
mortality, or increases in life-years lived, directly informs FDA's 
determination as to whether permitting the marketing of the new tobacco 
product would be APPH. The discussion should include all of the 
information in the PMTA regarding the product and its potential effects 
on health, including, but not limited to adverse experiences, tobacco 
use behavior, and tobacco use initiation to provide an overall 
assessment of the potential effect that permitting the product to be 
marketed has or may have on overall tobacco-related morbidity and 
mortality including on youth, young adults, and other vulnerable 
populations.
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    In addition to the information provided throughout this document, 
applicants may obtain information regarding how the APPH standard can 
be met from marketing granted orders and decision memoranda that FDA 
posts on its website.
    (Comment 103) One comment stated that where an applicant proposes a 
restriction on the marketing of its product, such as a limitation on 
sales, FDA should apply that restriction in making its APPH 
determination.
    (Response 103) FDA will consider proposed restrictions on the sales 
and distribution of a tobacco product as part of its review of a PMTA 
and may determine that it should impose such restrictions where FDA 
determines they are APPH. However, FDA's review is not constrained by 
such proposals and FDA intends to consider a variety of factors in 
determining whether it should include those restrictions, including, 
but not limited to, whether it would be feasible or realistic for the 
applicant to implement such restrictions, or the ease with which the 
implementation of the restrictions may be monitored or enforced as they 
pertain to all population groups, including among groups 
disproportionately affected by tobacco product use. FDA will also 
consider and may impose restrictions on sales and distribution 
different from, or in addition to, those proposed by the applicant.
    (Comment 104) One comment stated that FDA should focus its 
evaluation on the population segments most likely to be affected by the 
marketing of the new tobacco product and require applicants to show a 
public health benefit for those specific groups.
    (Response 104) FDA declines to make changes in response to this 
comment. FDA is required by section 910(c)(4) of the FD&C Act to 
determine its APPH finding based upon the risks and the benefits to the 
population as a whole. This includes consideration of all parts of the 
population, including those more likely to be affected by the marketing 
of the new tobacco product, and it is not limited to only the effect on 
specific population segments.
    (Comment 105) One comment requested a clear regulatory definition 
of the APPH standard, with product category-specific guidance about 
what is required to meet the target, noting that it is missing from the 
proposed rule and is crucial for applicants as they develop the data 
needed to substantiate that a new tobacco product meets the APPH 
standard and prepare their applications. The comment recommended that 
FDA provide further clarity in the final rule as to the factors to be 
considered in an APPH analysis and how the Agency will weigh those 
factors. The comment requested that FDA provide clarification as to 
whether a showing of reduced morbidity and mortality is required to 
receive a marketing order, asserting that the structure of the statute 
and congressional intent make clear that Congress intended a marketing 
order under section 910 of the FD&C Act to be a less burdensome 
standard than the standard for a marketing order for a modified risk 
product under section 911of the FD&C Act. The comment also requested 
additional information regarding how FDA will determine whether a 
product has had a net positive effect on the health of the population 
as a whole, including whether each factor has a threshold finding.
    (Response 105) FDA declines to set static requirements that a new 
tobacco product could meet and be considered to meet the APPH standard 
because the tobacco product marketplace and trends in consumer behavior 
that inform FDA's APPH determination are not static. The factors that 
could demonstrate that permitting the marketing of a new tobacco 
product would be APPH at one point in time might not support the same 
determination with respect to a similar product in the future. For 
example, FDA may consider, in conjunction with other available data 
regarding the new tobacco product, information showing that a product 
has reduced morbidity and mortality to help demonstrate that the 
potential risks and benefits of marketing the new tobacco product would 
have a net positive effect on the health of the population as a whole 
(which includes youth, young adults, and other vulnerable populations).
    However, FDA does not make its APPH determination on one static set 
of requirements. FDA makes its APPH determination in consideration of 
the existing market (e.g., the products on the market, tobacco product 
use behaviors) at the time the determination is made. For example, FDA 
has authorized marketing of a product that would, among other things, 
potentially reduce nicotine dependence in adult smokers who may also 
benefit from decreasing nicotine exposure and cigarette consumption. In 
consideration of the existing market and based on the information 
provided by the applicant, FDA was able to determine that nonsmokers, 
including youth, would also be unlikely to start using the product, and 
those who experiment would be less likely to be become addicted than 
people who experiment with conventional cigarettes. \39\ As the tobacco 
product market changes over time, the potential risks and benefits of 
marketing a new tobacco product to the population as a whole might also 
change. A new tobacco product that receives a marketing granted order 
under the current market conditions might not receive an order at a 
future time in which fewer individuals are using products that present 
higher levels of risk to individual health or such products are no 
longer on the market. Due to the nature of the Federal rulemaking 
process, if FDA were to codify what could satisfy the APPH standard 
under market conditions that are current at the time, FDA may not be 
able to update such standards in a timely manner.
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    (Comment 106) Several comments stated that FDA has failed to 
explain or

[[Page 55386]]

justify how it is interpreting and applying the APPH standard when 
evaluating PMTAs and must do so to allow a determination of whether its 
issuance of PMTA marketing orders is arbitrary and capricious. In 
addition, some comments were concerned that the lack of articulated 
definitions and standards regarding the APPH standard would leave 
applicants guessing at what might satisfy the standard. In addition, 
another comment stated that failing to provide this essential direction 
could increase the likelihood of arbitrary and inconsistent decisions.
    (Response 106) FDA disagrees with the assertion that is has failed 
to provide direction concerning the APPH standard in section 910(c)(2) 
of the FD&C Act. FDA describes its interpretation of the APPH standard 
in details in this section, including the statement that FDA intends to 
consider the marketing of a new tobacco product to be APPH where a PMTA 
contains sufficient valid scientific evidence to demonstrate that the 
potential risks and benefits of the marketing of the new tobacco 
product would have a net positive effect on the health of the 
population as a whole.
    (Comment 107) Multiple comments stated that FDA should require that 
PMTAs contain information demonstrating that all available steps have 
been taken to make the product as minimally harmful as possible in 
order for the marketing of a tobacco product to be considered APPH.
    (Response 107) As described in section IX.D, FDA interprets the 
APPH standard in section 910(c)(2)(A) to require a showing that 
permitting the marketing of a new tobacco product would likely have at 
least a net benefit to public health based upon the risks and benefits 
to the population as a whole. Where an applicant meets this standard 
along with the other criteria in section 910(c)(2) of the FD&C Act, FDA 
will issue a marketing granted order.
    (Comment 108) Multiple comments stated that FDA should impose a 
number of conditions that products must meet to receive a marketing 
granted order. One comment stated FDA should apply a more rigorous 
standard than it did in previous PMTA reviews by requiring an applicant 
demonstrate, among other things that its product is significantly less 
harmful than other products current on the market and that any increase 
in health risks is significantly smaller than the likelihood and size 
of the benefits it presents. Another comment stated FDA should impose 
specific requirements that a flavored tobacco product must meet to 
receive a marketing granted order, including requirements such as 
having no appeal to youth, being substantially less harmful than 
smoking, and promoting complete cessation of tobacco products.
    (Response 108) FDA declines to create a series of criteria that 
either all products or a specific subset of products must meet be in 
order for marketing of such products to be considered APPH as part of 
this rule. As described elsewhere in this section, FDA intends to 
consider marketing of a new tobacco product to be APPH where permitting 
its marketing would likely have at least a net benefit to public health 
based upon the risks and benefits to the population as a whole, which 
includes youth, young adults, and other vulnerable populations. While 
this determination would involve consideration of many factors, 
including some of the particular concerns cited by the comments, it 
will be made with respect to the risks and benefits to the health of 
the population as a whole, rather than whether a product meets each 
item in a series of specific criteria.
    (Comment 109) Multiple comments made suggestions regarding how FDA 
should consider the risks and benefits that the marketing of the new 
tobacco product may have on specific groups of the population, with one 
comment emphasizing social justice concerns and highlighting the 
effects that the new tobacco product may have on disadvantaged or 
vulnerable populations. Another comment stated that the FD&C Act does 
not permit FDA to weigh the risks and benefits a product may have on 
one group more strongly than another.
    (Response 109) Section 910(c)(4) of the FD&C Act requires the 
finding of whether the marketing of a new tobacco product would be APPH 
to be determined with respect to the population as a whole. As noted 
elsewhere in this document, FDA has made edits to ensure the rule 
addresses the potential effects of permitting the marketing of a new 
tobacco product to vulnerable populations and FDA will consider the 
potential effects on such groups as part of its assessment of the 
effect on the population as a whole.
    It is important to note that in order for FDA to issue a marketing 
granted order for a new tobacco product, section 910(c)(1)(A)(i) of the 
FD&C Act requires FDA to find there is ``a showing'' that the marketing 
of the new tobacco product would be APPH. FDA interprets this to mean 
that an applicant must submit sufficient information in its PMTA for 
FDA to be able to find whether the marketing of a product would be 
APPH. While FDA may consider outside sources of information during PMTA 
review, an applicant cannot rely on FDA to seek out or create 
additional data to fill information gaps that may exist in a PMTA. As 
discussed in section VIII.E., failure to submit sufficient information 
that FDA needs to make its required findings would result in the 
issuance of a marketing denial order.
    This rule focuses primarily on PMTA review procedures and content 
requirements, particularly with respect to application acceptance and 
filing. An application may meet the acceptance and filing requirements, 
but still lack vital information that FDA needs to determine whether it 
should issue a marketing granted order. The rule creates a requirement 
to submit full reports of all existing health risk investigations; 
however, where there is not sufficient existing evidence that an 
applicant may utilize to demonstrate that the marketing of a new 
tobacco product would be APPH, an applicant would need to conduct its 
own investigations to ensure that FDA has sufficient valid scientific 
evidence it needs to determine whether a marketing granted order should 
be issued for the new tobacco product.
    Although an applicant may submit any type of evidence to FDA in an 
attempt to substantiate that the new tobacco product should receive a 
marketing granted order, FDA relies upon only valid scientific evidence 
to determine whether the marketing of the new tobacco product would be 
APPH.
    (Comment 110) One comment stated that FDA should require the full 
report of each study to identify the source of funding and give less 
weight to the results of industry research than to independent 
scientific research and should explicitly consider bias in industry 
studies.
    (Response 110) FDA declines to make changes as a result of this 
comment FDA's determination of whether there's a showing that 
permitting the marketing of a new tobacco product would be APPH must be 
determined on the basis of valid scientific evidence. FDA assesses all 
scientific evidence with the same rigor to determine whether it is 
valid, regardless of the source.
    (Comment 111) One comment stated that FDA must require long-term 
clinical studies because it impossible to determine the risks and 
benefits of a tobacco product without them.
    (Response 111) Long-term clinical studies can provide information 
that is important to FDA's review; however, the FD&C Act grants FDA the 
authority to consider other valid scientific evidence in making its 
APPH determination. Section 910(c)(5) of the

[[Page 55387]]

FD&C Act explains that APPH ``shall, when appropriate, be determined on 
the basis of well-controlled investigations.'' This section also 
explains that FDA may base its APPH determination on ``valid scientific 
evidence (other than evidence derived from [well-controlled 
investigations]) which is sufficient to evaluate the tobacco product.'' 
As discussed in this section, FDA does not expect that long-term 
clinical studies will need to be conducted for each PMTA; instead, it 
expects that it should be able to rely on other valid scientific 
evidence to evaluate some PMTAs.
    FDA will determine whether the evidence submitted or otherwise 
available to FDA is valid scientific evidence for the purpose of 
determining the new tobacco product's impact on individual and 
population health, and whether the available evidence, when taken as a 
whole, is adequate to support a determination that permitting the new 
tobacco product to be marketed would be APPH.
    Valid scientific evidence includes data from well-controlled 
investigations, as well as other sources upon which FDA may base its 
determinations under section 910(c)(5) of the FD&C Act. Other sources 
may include partially controlled studies, studies and objective trials 
without matched controls, and well-documented case histories conducted 
by qualified experts. The other sources of study data may be considered 
valid scientific evidence if they have been gathered using well-
established or standardized methodologies from which it can fairly and 
responsibly be concluded by qualified experts that there is reasonable 
assurance of the reliability of their findings. The evidence required 
may vary according to the characteristics of the tobacco product, its 
conditions of use, the existence and adequacy of warnings and other 
restrictions, and the extent of consumer experience with its use. 
Isolated case reports, anecdotal experiences, reports lacking 
sufficient details to permit scientific evaluation, and unsubstantiated 
opinions are not considered valid scientific evidence.
    As part of its determination of whether permitting the marketing of 
a new tobacco product would be APPH, FDA must be able to determine the 
likely health risks of the new tobacco product. While this rule does 
not necessarily require applicants to conduct new studies for the 
purposes of application acceptance and filing (beyond the requirements 
of Sec.  1114.27(b)(1)(ii)), FDA expects that it could not issue a 
marketing granted order unless an application contains data from a 
variety of sources, including both clinical and nonclinical 
investigations that give FDA comprehensive information about the 
product's likely health effects in the U.S. market. Where 
epidemiological evidence is available and comes from an investigation 
using a different product or one that was conducted outside the United 
States, FDA would examine whether the PMTA contains sufficient 
information, or the applicant has conducted bridging studies when 
needed, to demonstrate the data is applicable to the product and the 
U.S. population or provides adequate justification for how the 
information is relevant. FDA recognizes that this type of long-term 
epidemiological data is not available for all categories of products 
and does not expect that long-term clinical studies (i.e., those 
lasting approximately 6 months or longer) will need to be conducted for 
each PMTA; however, in the event long-term clinical study data should 
become available for the new product or similar product while the 
application is pending, this information should be submitted to FDA in 
an amendment.
    Where a PMTA contains no long-term epidemiological evidence 
regarding the product or that could be bridged to the product, FDA 
would consider whether there are other sources of scientific evidence 
that sufficiently demonstrate the potential health risks of the 
product, such as actual use studies (e.g., clinical studies that assess 
real-world use conditions and health outcomes, or clinical studies that 
use scientifically valid endpoints as a predictor for potential long-
term health effects). Where a PMTA lacks human subject study data 
regarding the product or that can be bridged to the product, FDA will 
examine how a PMTA attempts to estimate the health effects of the 
product on the U.S. population from the results of nonclinical 
investigations; however, it should be noted that information from 
nonclinical studies alone is generally not sufficient to support a 
determination that permitting the marketing of the product would be 
APPH.
    As part of FDA's consideration of the changes in tobacco product 
use behavior that are likely to be caused by the marketing of the new 
tobacco product, FDA will examine data regarding how the product, its 
label, labeling, and any available advertising, and description of the 
applicant's marketing plans will affect the tobacco use behavior of 
both users and nonusers of tobacco products, including the behaviors 
described in Sec.  1114.7(k)(1)(ii) and (iii). FDA needs sufficient 
information to determine the potential changes in tobacco product use 
behavior and the health risks and benefits associated with the changes 
in user behavior will allow FDA to make a determination of whether 
permitting the marketing of the new tobacco product would be APPH. 
Where a PMTA does not contain sufficient information for FDA to make 
these determinations, FDA will issue a marketing denial order for the 
product because the PMTA lacks information necessary to determine the 
risks and benefits to the population as a whole as required by section 
910(c)(4) of the FD&C Act.
    (Comment 112) Multiple comments stated that a premarket assessment 
of a new tobacco product can neither fully nor precisely predict future 
tobacco use behavior patterns and recommended that FDA modify the rule 
to acknowledge such limitations on premarket research. Another comment 
expressed a similar opinion and noted that FDA has postmarket tools, 
including the ability to withdraw a marketing granted order to address 
unintended consequences.
    (Response 112) FDA disagrees with the implication that it should 
discount the importance of information concerning the likelihood of 
changes in tobacco product use behavior during application review and, 
in essence, shift it to a postmarket determination. As discussed in the 
following paragraphs, the burden is on the applicant to make a showing 
that the marketing of its new tobacco product would be APPH. Section 
910(c)(4) of the FD&C Act requires FDA to consider the likelihood of 
changes in tobacco product use behavior in making its APPH 
determination and if an application lacks sufficient information to 
make this determination, FDA must issue a marketing denial order.
    b. The methods used in and the facilities and controls used for, 
the manufacture, processing, or packing of such tobacco product conform 
to the requirements of section 906(e) of the FD&C Act. As discussed in 
section VII.B.12 regarding Sec.  1114.7(j), FDA has not yet issued a 
regulation under section 906(e) of the FD&C Act, so demonstrating 
compliance with such regulations in a PMTA is not currently required; 
however, FDA plans to issue proposed rulemaking(s) under section 
906(e), and once such regulations are effective, applicants must 
demonstrate that their methods, facilities, and controls are in 
conformance with applicable requirements to receive a marketing granted 
order under section 910(a)(1)(i)(A) of the FD&C Act. Until such a final 
rule issued under section 906(e) of the FD&C Act is effective, FDA

[[Page 55388]]

will evaluate the manufacturing process and consider whether the 
product can be manufactured in a manner consistent with the information 
submitted within the application as part of its determination of 
whether the marketing of the new tobacco product is appropriate for the 
protection of public health. As part of this evaluation, FDA will 
consider whether the applicant would be able to consistently produce 
the new tobacco product as described in the PMTA. The potential for an 
applicant to produce nonconforming tobacco products that have higher 
levels of HPHCs than intended, have dangerous foreign material, or 
otherwise potentially presents a higher risk of harm than the product 
described in the PMTA may affect FDA's determination of whether the 
marketing of a product would be APPH.
    (Comment 113) One comment stated that FDA should amend the rule to 
address how applicants will be able to address evolving requirements, 
such as product standard and manufacturing practice requirements, 
especially if changes become effective during application review.
    (Response 113) The regulatory processes that FDA must follow to 
issue a product standard under section 907 of the FD&C Act or tobacco 
product manufacturing practices under section 906(e) of the FD&C Act 
are lengthy and would provide applicants with notice of proposed 
requirements well in advance of any change becoming effective. FDA 
generally intends to give applicants the opportunity to amend 
previously submitted applications to demonstrate conformance with new 
requirements under sections 906(e) or 907 of the FD&C Act; however, FDA 
may provide directions regarding how to demonstrate conformance in the 
text of any such rulemaking.
    c. Based on a fair evaluation of all material facts, the proposed 
labeling is not false or misleading in any particular.
    d. The tobacco product is shown to conform in all respects to a 
tobacco product standard in effect under section 907 of the FD&C Act or 
there is adequate information to justify a deviation from such 
standard. A PMTA submitted under the rule is required by Sec.  
1114.7(d)(2) to contain a statement identifying all tobacco product 
standards issued under section 907 of the FD&C Act that are applicable 
to the new tobacco product and a brief description of how the new 
tobacco product fully meets the identified tobacco product standard(s) 
or justifies a deviation from such standards, if applicable. FDA must 
be able to locate the data regarding the tobacco product's compliance 
with the product standard and determine that the tobacco product does, 
in fact, meet the requirements of the applicable product standard(s) 
or, if applicable, deviates from such standards in a way that is 
justified. For example, if an applicant submitted a PMTA for a product 
that is subject to a product standard limiting the amount of an HPHC 
that may be delivered to product users, FDA must be able to verify 
though a review of the HPHC testing data contained in the product 
formulation section that the product complies with that product 
standard. Under section 910(c)(2)(D) of the FD&C Act, FDA will not 
issue a marketing granted order for a tobacco product unless a PMTA 
demonstrates that it meets any applicable product standard(s), or an 
applicant has justified the deviation from such standard, if 
applicable.
1. Restriction on the Sale and Distribution of a New Tobacco Product in 
a Marketing Granted Order
    Section 1114.31(b) describes restrictions and additional 
requirements that FDA may include as part of a marketing granted order. 
Under section 910(c)(1)(B) of the FD&C Act, FDA may require the sale 
and distribution of the tobacco product be restricted to the extent 
that the sale and distribution of a tobacco product may be restricted 
under a regulation under section 906(d) of the FD&C Act. Section 
1114.31(b)(1) reiterates this authority as part of the rule and Sec.  
1114.31(b)(2) allows FDA to include restrictions on sales and 
distribution proposed by the applicant in its PMTA as part of a 
marketing granted order.
    A number of comments suggested that FDA impose a number of specific 
restrictions on the sales and distribution of tobacco products under 
the rule, as discussed below.
    (Comment 114) One comment stated that the rule should be amended to 
require age verification for all websites and social media, and to 
prohibit the use of partners, sponsors, influencers, bloggers, or brand 
ambassadors to market or promote the product.
    (Response 114) FDA declines to revise the rule in response to this 
comment because, at this time, FDA intends to consider which 
restrictions on sales and distribution should be included in a 
marketing granted order for a new tobacco product on a case-by-case 
basis.
    (Comment 115) One comment stated that FDA should amend the rule to 
require preauthorization of all advertising and marketing materials 
during an initial 5-year period that a new tobacco product is permitted 
on the market.
    (Response 115) FDA declines to make this revision because it is in 
conflict with section 903(b) of the FD&C Act.
    (Comment 116) One comment stated that FDA should require each 
marketing granted order to include all available restrictions on the 
product packaging, labeling, marketing, sale, including the use of 
restrictions that require products to be sold with additional labeling 
and marketing requirements that would reduce the risk of youth exposure 
to the product or its advertising while also reducing the likelihood of 
increased tobacco-related harms and risks for current users. For 
example, FDA could require revisions to an ENDS product nicotine 
warning statement to include information such as the product is meant 
only as a complete substitute for traditional smoking and any other use 
will increase harms or risks to the user's health. The comment further 
stated that FDA must take advantage of readily accessible means in its 
issuing of marketing granted orders to avoid or reduce any unnecessary 
individual or public health harms or risks. The comment stated the 
belief that FDA's failure to implement or consider these types of 
restrictions to reduce the risk of harm of these products could lead to 
FDA being found arbitrary and capricious under the Administrative 
Procedure Act.
    (Response 116) FDA agrees with the comment's general point that 
restricting the sales and distribution of a new tobacco product is an 
important way in which FDA can potentially limit the health risks of a 
new tobacco product. FDA intends to consider whether and which 
restrictions are appropriate for the marketing of a new tobacco product 
under section 910(c)(1)(B) on a case-by-case basis during substantive 
review. FDA disagrees with the comment's broad assertion, which 
suggests that FDA is required to impose certain restrictions in every 
marketing order, when the FD&C Act does not so require.
    (Comment 117) One comment requested that FDA, in issuing a marketed 
granted order, explicitly prohibit the marketing of a product in any 
way that targets vulnerable populations unless it only reaches users of 
more harmful tobacco products or users of more harmful products who 
have already switched.
    (Response 117) FDA agrees with the general principle that a new 
tobacco product should be marketed in ways that will not increase the 
health risks to vulnerable populations. FDA declines to implement a 
blanket restriction on the scope of permissible advertising as part

[[Page 55389]]

of this final rule and instead will consider restrictions on the sales 
and distribution of a new tobacco product under Sec.  1114.31(b)(2) on 
a case-by-case basis for each new tobacco product that meets the 
requirements to receive a marketing granted order.
2. Requirements for Postmarket Records and Reports in a Marketing 
Granted Order
    Section 1114.31(b)(3) allows FDA, using its authority in section 
910(f) of the FD&C Act, to require an applicant to submit postmarket 
reports in addition to those described in Sec.  1114.41, as 
appropriate. This can include, but is not limited to, requirements that 
an applicant provide information such as labeling, advertising, 
marketing, promotional materials, or marketing plans not previously 
submitted to FDA, and do so at least 30 days prior to the initial 
publication, dissemination to consumers, or use in engaging or 
communicating with consumers of such materials. Similar to what is 
described in section VII.B.6, these items provide information that is 
important to FDA's determination of whether the continued marketing of 
the new tobacco product would be APPH or whether FDA must withdraw the 
marketing granted order under section 910(d)(1)(A) of the FD&C Act 
because the marketing of the new tobacco product is no longer APPH. 
Receiving this information in advance of its first use is not for pre-
approval but will allow FDA to ensure it can appropriately track and 
monitor the impact that the use of such information has on tobacco use 
behavior. In addition, if needed, this information will allow FDA to 
provide applicants with advisory comments, including any concerns about 
possible impact on youth appeal and tobacco use initiation and with 
regard to the finding that the continued marketing of the product is 
appropriate for the protection of public health. FDA anticipates it 
will use this authority on a case-by-case basis, especially as it 
relates to novel tobacco products for which the body of knowledge is 
still growing.

E. Issuance of a Marketing Denial Order (Sec.  1114.33)

    Section 1114.33 describes the circumstances under which FDA would 
issue a marketing denial order for a new tobacco product after PMTA 
review. Section 1114.33(a)(1) specifies that based on the information 
submitted as part of the application and any other information before 
FDA with respect to the new tobacco product, FDA will issue a marketing 
denial order if any of the grounds for denial listed in 910(c)(2) of 
the FD&C Act apply to the application. Any other information before FDA 
may include, for example, information received from a TPSAC report, 
toxicological information regarding a particular ingredient or 
combination of ingredients (e.g., diacetyl) from peer reviewed research 
results that were published after the PMTA was submitted, or 
preliminary results from a study that FDA is aware of (e.g., a Tobacco 
Centers of Regulatory Science study).
    As discussed elsewhere in this document, meeting the requirements 
for application acceptance and filing does not mean that an application 
has sufficient information to receive a marketing granted order. For 
example, while FDA may accept and file an application that contains the 
information in Sec.  1114.7(k), FDA will not issue a marketing granted 
order unless that information also makes a showing that permitting the 
marketing of a new tobacco product would be APPH. While the rule does 
not necessarily require the applicant to conduct studies on its 
product, applicants would need to do so for products for which 
insufficient information exists to demonstrate whether marketing of the 
product is APPH. Similarly, the information required in the 
manufacturing section of the application is required for acceptance and 
filing; however, unless the manufacturing process described ensures a 
product will be consistently produced as described in a PMTA (e.g., 
implementing sufficient controls), an applicant would receive a 
marketing denial order.
    Examples of when FDA would be required to issue a marketing denial 
order for a lack of information necessary to make its required findings 
and determinations under sections 910(c)(2) and (c)(4) of the FD&C Act 
are contained throughout this document and include, but are not limited 
to, a lack of sufficient information regarding:
     The health risks of the new tobacco product;
     a comparison of the new tobacco product to the health 
risks of other tobacco products used by individuals that the applicant 
expects to use the new tobacco product, including products both within 
the same category as the new tobacco product and at least one different 
product category;
     the abuse liability of the new tobacco product;
     potential changes to tobacco product use behavior of 
current tobacco product users;
     the increased or decreased likelihood that those who do 
not use tobacco products will start using tobacco products;
     the impact of the product and its label, labeling, and 
advertising, to the extent that advertising has been developed and 
studied, on individuals' perception of the health risks of the product 
and their use intentions; and
     how human factors can influence the health risks of the 
new tobacco product.
    Section 1114.33(a) also allows FDA to issue a marketing denial 
order where the applicant does not permit an authorized FDA employee, 
at a reasonable time and a reasonable manner, an opportunity to: (1) 
Inspect the facilities and controls, and sites and entities involved 
with clinical and nonclinical research (including third parties and 
contract research organizations) described in the application or (2) 
have access to, copy, and verify all records pertinent to the 
application, where such refusal prevents FDA from making the required 
findings in 910(c) necessary to issue a marketing granted order. FDA 
would issue a marketing denial order where an applicant does not permit 
these inspections because the ability to access and inspect the 
facilities and controls and sites and entities involved with clinical 
and nonclinical research, as well as pertinent records, is important to 
FDA's ability to determine whether any of the denial criteria specified 
in section 910(c)(2) of the FD&C Act and Sec.  1114.33(a)(1) apply to 
the application. Inspecting the facilities and controls described in 
the application will allow FDA to ensure the applicant can manufacture 
the product in accordance with the manufacturing practices described in 
the application. Inspecting records, including those required to be 
kept under Sec.  1114.45, will allow FDA the opportunity to verify the 
study findings and data that the applicant relies upon in the PMTA to 
demonstrate that the new tobacco product should receive a marketing 
granted order. As stated in Sec.  1114.45, the records would be 
required to be legible and written in English.
    If FDA issues a marketing denial order, it will, where practicable, 
identify measures to address the reasons for which the application is 
being denied. While FDA will identify the deficiencies that resulted in 
the marketing denial order, the deficiencies specified in the order 
might not be an exhaustive listing of all deficiencies contained in the 
PMTA.
    FDA received several comments regarding issuance of marketing 
denial order, as discussed below.

[[Page 55390]]

    (Comment 118) One comment stated that Sec.  1114.33(a) should be 
amended to provide that FDA will issue a marketing denial order if, 
after considering outside sources of information during PMTA review, 
FDA finds that the new tobacco product is not appropriate for the 
protection of the public health.
    (Response 118) We have edited Sec.  1114.33 to make it clear that 
FDA's issuance of a marketing denial order will be made, as required by 
section 910(c)(2) of the FD&C Act, on the basis of information 
submitted as part of an application and any other information before 
FDA with respect to the new tobacco product. If, during substantive 
review, FDA considers information outside of a PMTA that leads FDA to 
find that one or more of the grounds for denial in section 910(c)(2) of 
the FD&C Act apply, FDA intends to issue a marketing denial order for 
the new tobacco product.
    (Comment 119) One comment stated that FDA should consider any 
public comments submitted in response to MRTP applications for the same 
new product that is the subject of the PMTA and FDA's assessment of 
these public comments should be explicitly addressed in any PMTA 
marketing order.
    (Response 119) Under section 910(c)(2) of the FD&C Act, FDA will 
determine whether a PMTA should be denied on the basis of the 
information in a PMTA and any other information before FDA with respect 
to such tobacco product. Where public comments on an MRTPA for the same 
product are before FDA during its consideration of a PMTA, FDA 
generally intends to consider those comments where relevant and clearly 
applicable to the marketing of the new tobacco product without modified 
risk information. FDA declines to explicitly address its assessment of 
public comments in a marketing granted order because it would further 
delay FDA's action on an application and a marketing granted order is 
not an appropriate venue to address comments to an MRTPA.
    (Comment 120) One comment stated that Sec.  1114.33 should be 
revised to include dual use and deterrence of complete quitting of all 
tobacco products as factors that FDA must explicitly consider when 
deciding whether to issue a marketing denial order.
    (Response 120) Section 1114.33 incorporates the grounds for denial 
set forth in section 910(c)(2) of the FD&C Act, which FDA interprets to 
require consideration of these tobacco product use behaviors. In 
determining whether permitting the marketing of the new tobacco product 
would be APPH, FDA will consider dual use and potential changes to 
cessation as part of its determination of the risks and benefits to the 
health of the population as a whole.
    (Comment 121) One comment suggested that FDA amend Sec.  1114.33 to 
specifically state that FDA will issue a marketing denial order where 
FDA is unable to determine the impact that the labeling, advertising, 
marketing, and promotion of the new tobacco product may have on 
consumer perceptions and use intentions.
    (Response 121) FDA considers information regarding consumer 
perceptions and use intentions to be an important part of PMTA review. 
If a PMTA does not contain sufficient information for FDA to determine 
that permitting the marketing of the product would be APPH, including 
impact on tobacco product and use intentions, it cannot authorize the 
marketing of the new tobacco product. FDA recently issued a draft 
guidance for public comment regarding scientific issues for applicants 
to consider as they design and conduct tobacco product perception and 
use intention studies to support tobacco product applications. For more 
information, please see the guidance for industry entitled ``Tobacco 
Products: Principles for Designing and Conducting Tobacco Product 
Perception and Intention Studies.'' \40\
---------------------------------------------------------------------------

    \40\ Available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
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    (Comment 122) Several comments requested that FDA issue marketing 
denial orders for all products that meet certain criteria or in certain 
product categories, including flavored tobacco products, hookah, 
cigarillos, and little cigars. The comments asserted that FDA should 
deny all PMTAs for specific products because there is little or no 
evidence of health benefits and they are attractive to youth.
    (Response 122) FDA declines to make revisions in response to these 
comments because the FD&C Act requires FDA to make an individualized 
determination of whether to deny an application based on the risks and 
benefits of a specific tobacco product to the health of the population 
as a whole (which includes youth, young adults, and other vulnerable 
populations).

F. Withdrawal of a Marketing Granted Order (Sec.  1114.35)

    Section 1114.35 describes the grounds and procedures for 
withdrawing a marketing granted order for a new tobacco product. FDA 
will move to withdraw an order in the following situations:
1. Any of the Grounds for Withdrawal Under Section 910(d)(1) of the 
FD&C Act Apply
    These grounds include situations in which FDA finds that the 
continued marketing of the tobacco product is no longer APPH. The 
marketing of a product may no longer be APPH in several situations, 
including, for example, where there are changes to tobacco product use 
behaviors that were not expected in FDA's assessment of the PMTA (e.g., 
more nonusers of tobacco products are initiating use with the product 
than expected and/or fewer users of potentially more harmful products 
are switching to the potentially less harmful new tobacco product). 
Another example is where studies conducted after the issuance of the 
marketing granted order show that the product presents greater risks to 
health than FDA understood during application review and, as a result, 
the product likely has or will have a net negative impact on the health 
of the population as a whole (which includes youth, young adults, and 
other vulnerable populations).
    FDA also interprets section 910(d)(1)(A) of the FD&C Act to provide 
for the withdrawal of a marketing granted order where changes to the 
tobacco product marketplace result in FDA finding that the marketing of 
a product is no longer APPH:
     The application contained or was accompanied by an untrue 
statement of material fact;
     the applicant has failed to establish a system for 
maintaining records, or has repeatedly or deliberately failed to 
maintain records or make reports required by part 1114 or another 
applicable regulation under section 909 of the FD&C Act;
     the applicant has refused to permit access to, or copying 
or verification of, records as required by section 704 of the FD&C Act;
     the applicant has not complied with the requirements of 
section 905 of the FD&C Act;
     on the basis of new information before the Secretary with 
respect to such tobacco product, evaluated together with the evidence 
before the Secretary when the application was reviewed, that the 
methods used in, or the facilities and controls used for, the 
manufacture, processing, packing, or installation of such tobacco 
product do not conform with the requirements of section 906(e) of the 
FD&C Act and were not brought into conformity with such requirements 
within a reasonable time after receipt of

[[Page 55391]]

written notice from the Secretary of nonconformity;
     on the basis of new information before the Secretary, 
evaluated together with the evidence before the Secretary when the 
application was reviewed, that the labeling of such tobacco product, 
based on a fair evaluation of all material facts, is false or 
misleading in any particular and was not corrected within a reasonable 
time after receipt of written notice from the Secretary of such fact; 
or
     on the basis of new information before the Secretary, 
evaluated together with the evidence before the Secretary when such 
order was issued, that such tobacco product is not shown to conform in 
all respects to a tobacco product standard which is in effect under 
section 907 of the FD&C Act, compliance with which was a condition to 
the issuance of an order relating to the application, and that there is 
a lack of adequate information to justify the deviation from such 
standard.
    FDA received comments regarding grounds for withdrawal, as 
discussed below.
    (Comment 123) Multiple comments requested that FDA provide more 
clarity with regard to how the APPH standard may change over time with 
respect to determining whether a marketing granted order should be 
withdrawn. One comment noted concerns regarding the example FDA 
provided in section IX.F of the preamble to the proposed rule that 
appears to contemplate FDA withdrawing marketing orders under section 
910(d)(1)(A) of the FD&C Act based on only the issuance of a product 
standard. The comment also stated that FDA should use the PMTA pathway 
to further the principles of tobacco product harm reduction and the 
potential for marketing orders to be withdrawn after an unduly short 
period of time or on an unpredictable basis may discourage 
manufacturers from investing the significant resources necessary to 
bring harm-reducing products to market.
    Another comment suggested that FDA develop a more systematized 
approach to determining whether the marketing of a product is no longer 
APPH. The comment suggested that because substantial shifts in consumer 
use of tobacco products are unlikely in the short term, FDA should 
determine whether marketing of a product is no longer APPH by comparing 
the product to a single comparator product in the same product class as 
the new tobacco product and that is used by the majority of likely 
users of the new tobacco product. The comment also requested that FDA 
reevaluate its APPH determination no sooner than 5 years after the 
issuance of a marketing granted order, noting that this approach is 
consistent with section 911 of the FD&C Act for the marketing of MRTPs 
and would allow FDA to use its authority to temporarily suspend a 
marketing order if significant health issues needed to be addressed 
before the end of the 5-year period.
    (Response 123) FDA disagrees with the comment's characterization of 
the APPH standard as changing over time. As described in this document, 
FDA interprets the APPH standard in 910(c)(2) of the FD&C Act as 
requiring the marketing of a new tobacco product to likely present a 
net benefit to the health of the population as a whole to receive a 
marketing order. FDA interprets section 910(d)(1)(A) of the FD&C Act 
consistently to require that FDA withdraw a marketing granted order 
where FDA is no longer able to find that the marketing of the new 
tobacco product likely presents a net benefit to public health. Because 
market conditions will change over time, what might be APPH at one 
point in time may no longer be APPH in the future. Examples of changes 
that could affect FDA's determination that the marketing of the product 
is APPH could include the example from the proposed rule mentioned by 
the comment: FDA's implementation of a tobacco product standard 
pursuant to section 907 of the FD&C Act that alters the relative health 
risks presented by other tobacco products. For instance, if FDA issued 
a marketing granted order for a new (non-cigarette) tobacco product, in 
part, because it presented significantly lower risks to individual 
health than cigarettes, and FDA later implemented a product standard 
that significantly lowered the health risks of cigarettes, FDA may 
determine that the continued marketing of the new (non-cigarette) 
tobacco product is no longer APPH. If FDA were to be unable to consider 
changing market conditions when evaluating whether the marketing of a 
new tobacco product continues to be APPH after it is granted a 
marketing granted order, FDA would potentially be unable to address the 
continued marketing of products that have higher levels of relative 
health risks, thus undermining its core statutory mandate to reduce the 
harm caused by tobacco product use. Accordingly, FDA declines to limit 
its consideration of whether a product continues to be APPH to just one 
comparator product in the same product category, as suggested by the 
comment.
    The example regarding the issuance of a product standard that 
changes the health risks to current tobacco product users is a general 
example of a circumstance that could affect whether the marketing of a 
new tobacco product continues to be APPH. This example does not dictate 
that marketing orders for a different category of tobacco products must 
be withdrawn should such a product standard be implemented; rather, the 
determination of whether a marketing order should be withdrawn under 
section 910(d)(1)(A) of the FD&C Act would be made on a fact-specific 
basis for each new tobacco product based on whether its marketing 
continues to be APPH and a change to the health risks presented by a 
tobacco product category an applicant relied on to demonstrate a likely 
net benefit to public health may affect this APPH determination.
    FDA also notes that marketing granted orders do not come with a 
guaranteed time duration. Applicants concerned about the effect of 
tobacco product standards on the PMTA pathway should consider the 
process required under section 907 of the FD&C Act to issue and 
implement product standards and make business decisions accordingly. 
FDA also declines to establish a minimum 5-year period in which 
applicants may market a new tobacco product without having its APPH 
determination reassessed. FDA intends to review new information 
regarding the health risks of tobacco products and changes in tobacco 
product use behavior, including information submitted as part of 
periodic and adverse experience reports, on an ongoing basis and 
consider whether it affects FDA's APPH determination for any new 
tobacco products that have received marketing granted orders. FDA also 
notes that, contrary to the assertion in the comment, waiting 5 years 
before reevaluating the issuance of a marketing granted order is not 
consistent with section 911 of the FD&C Act because 911(j)(1), like 
910(d)(1)(A), provides for withdrawal prior to expiration of the order 
if standard for authorization is no longer met.
2. Any Postmarket Requirement Imposed by the Marketing Granted Order or 
By This Part That Has Not Been Met and Results in FDA Finding That One 
or More of the Grounds for Withdrawal Specified in Section 910(d)(1) of 
the FD&C Act Apply
    This requirement will allow the withdrawal of a marketing granted 
order where an applicant fails to meet requirements imposed by a 
marketing granted order or part 1114, including postmarket restrictions 
on the sales and distribution of the tobacco product as described in 
section VIII.D and results

[[Page 55392]]

in FDA finding one or more of the grounds for withdrawal specified in 
section 910(d)(1) of the FD&C Act apply.
    FDA received multiple comments on this issue, as discussed below.
    (Comment 124) Multiple comments stated that FDA should include 
bright lines or triggers in all marketing orders that would result in 
the automatic withdrawal of marketing authorization. One comment stated 
that FDA should withdraw or temporarily suspend a marketing order if it 
learns from any source that the tobacco product is impacting the health 
of youth and young adults, including increases in the percentages of 
youth and young adults who report use of the product. Another comment 
stated that FDA should set a threshold for problems with nonconforming 
products in the manufacturing process and require an order to be 
withdrawn if these thresholds are exceeded.
    (Response 124) As set forth in Sec.  1114.35(a)(1), FDA will move 
to withdraw a marketing granted order if FDA finds, after due notice 
and opportunity for an informal hearing, that the continued marketing 
of such tobacco product is no longer APPH. As described throughout the 
preamble to the final rule, FDA must make its APPH determination with 
respect to the risks and benefits of the population as a whole. FDA 
agrees that the potential for nonconforming tobacco products and 
underage use of tobacco products are an important consideration in 
making this determination and FDA will give them due consideration as 
part of its ongoing evaluation of whether the marketing of the tobacco 
product is APPH.
    FDA may seek advice on scientific matters from any appropriate FDA 
advisory committee in deciding whether to withdraw a marketing granted 
order and may use information other than that submitted by the 
applicant in deciding whether to withdraw a marketing granted order. 
Prior to withdrawing a marketing granted order, FDA will notify the 
holder of the marketing granted order of the opportunity for an 
informal hearing under 21 CFR part 16. If the holder of the marketing 
granted order does not request an informal hearing or if FDA decides to 
withdraw the marketing granted order after the informal hearing is 
held, FDA will issue an order withdrawing the marketing granted order. 
FDA will notify the public that the marketing granted order for the 
product has been withdrawn and state the basis for the withdrawal.

G. Temporary Suspension of a Marketing Granted Order (Sec.  1114.37)

    Section 1114.37 describes the grounds and procedures by which FDA 
will temporarily suspend a marketing granted order under section 
910(d)(3) of the FD&C Act. FDA is required by section 910(d)(3) to 
initiate a temporary suspension of a marketing granted order when it 
determines that there is a reasonable probability that the continued 
distribution of the product will cause serious, adverse health 
consequences or death, that is greater than what is ordinarily caused 
by tobacco products on the market. FDA interprets this language to mean 
serious, adverse health consequences at a rate or of a severity, or 
death at a rate, that is greater than what is ordinarily caused by 
tobacco product currently on the market. Under the rule, FDA will 
notify the holder of the marketing granted order of the opportunity to 
hold an informal hearing. If FDA determines after the opportunity for 
the informal hearing that the marketing granted order for the tobacco 
product should be temporarily suspended, the Agency will issue an order 
temporarily suspending the marketing granted order. FDA recommends that 
the applicant submit a plan demonstrating how it intends to comply with 
the temporary suspension, including a description of how the applicant 
will ensure that the tobacco product will not cause or continue to 
cause the serious, adverse health consequences or death (or reasonable 
probability of such events) that resulted in the temporary suspension, 
and the steps the applicant plans to take to ensure that the product is 
not further distributed, imported, sold, marketed, or promoted in the 
United States. Once FDA temporarily suspends a marketing granted order, 
it will proceed expeditiously to withdrawal. Where appropriate, FDA may 
combine the notices and hearings for temporary suspension of a 
marketing granted order and withdrawal of a marketing granted order 
into one notice and hearing. Whether the determinations occur 
separately or in one combined proceeding, the determination regarding 
temporary suspension and the determination regarding withdrawal will be 
made separately by the Agency as the findings are separate and 
distinct.

X. Postmarket Requirements (Part 1114, Subpart D)

A. Postmarket Changes (Sec.  1114.39)

    Section 1114.39 describes the scope of a marketing granted order. 
FDA issues marketing granted orders for the specific new tobacco 
product described in the PMTA.
    FDA received several comments regarding this section, as discussed 
below.
    (Comment 125) One comment stated that FDA should issue marketing 
orders for e-cigarettes that allow for the independent sale of 
components and parts that are identical to the ones contained in the 
authorized e-cigarette for use as replacements. The comment stated that 
because the components and parts would have already been reviewed as 
part of the complete e-cigarette, it would be redundant and unduly 
costly to require a company to submit a separate PMTA for an individual 
component or part.
    (Response 125) FDA declines to make the revisions suggested by this 
comment. Unless an applicant otherwise satisfies the requirements of 
premarket review in section 910(a)(2) of the FD&C Act, it must submit a 
PMTA and receive a marketing granted order prior to introducing a new 
tobacco product, or delivering it for introduction, into interstate 
commerce. This requirement applies to both an entire e-cigarette and 
its components and parts where sold separately. Applicants seeking to 
market an e-cigarette and its components and parts in such a manner 
should consider whether a bundled submission containing the information 
required to support multiple PMTAs would be appropriate.
    An applicant may not make any modification to the specific product 
that is the subject of the order, as any modification to the tobacco 
product results in a new tobacco product under the definition in 
section 910(a)(1) of the FD&C Act. Changes that do not result in a new 
tobacco product, such as manufacturing process changes that do not 
modify the finished tobacco product, must be reported under Sec.  
1114.41.
    (Comment 126) One comment stated that the proposed requirement in 
Sec.  1114.39 is redundant and unnecessary because it is no different 
from the plain meaning of section 910(a)(1)(B) of the FD&C Act and, 
therefore, should not be included in the final rule.
    (Response 126) FDA declines to remove Sec.  1114.39 because it 
serves to emphasize that the requirements of premarket review apply to 
modifications to new tobacco products that have already received a 
marketing granted order.
    (Comment 127) One comment stated that FDA should clarify the 
circumstances in which ``changes'' are considered ``modifications,'' 
and the

[[Page 55393]]

pathways available when modifications are made. The manufacturer stated 
that based on its interpretation of the rule, FDA would not require 
reporting of any changes that do not rise to the level of modifications 
resulting in a new tobacco product, other than the specific types of 
manufacturing-related and labeling changes described in proposed Sec.  
1114.41.
    (Response 127) FDA has provided numerous examples throughout this 
document, and guidance documents,\41\ regarding modifications that 
result in a new tobacco product. Under section 910(a)(1)(B) of the FD&C 
Act, new tobacco products include those that are new because they have 
been rendered new through any modification (including a change in 
design, any component, any part, or any constituent, including a smoke 
constituent, or in the content, delivery or form of nicotine, or any 
other additive or ingredient) of a tobacco product where the modified 
product was commercially marketed in the United States after February 
15, 2007. The discussion of the definition of the term ``new tobacco 
product'' in section VII.B. contains information about what constitutes 
a new tobacco product, including the description of modifications to 
cigarette paper, container closure systems (e.g., change from glass to 
plastic e-liquid vials or from plastic to tin container closures), 
product quantity, or tobacco cut size as some examples of changes that 
result in a new tobacco product.
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    \41\ Please see ENDS PMTA Guidance and the guidance for industry 
entitled ``Demonstrating the Substantial Equivalence of a New 
Tobacco Product: Responses to Frequently Asked Questions,'' both of 
which are available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
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    Where an applicant seeks to modify a new tobacco product that has 
received a PMTA marketing order, it may choose to seek premarket 
authorization through any of the three premarket pathways described in 
section VII.B; however, we note that the requirements of the PMTA 
pathway are distinct from those of the SE pathway. Under the SE 
pathway, an applicant must rely on a tobacco product that was 
commercially marketed (other than for test marketing) in the United 
States as of February 15, 2007, or a tobacco product that FDA has 
previously found substantially equivalent under section 910(a)(2)(A)(i) 
of the FD&C Act; the issuance of a PMTA marketing order would not 
independently create a valid predicate product for use in the SE 
pathway. Therefore, an applicant seeking to modify a new tobacco 
product that has received a PMTA marketing order (and does not have a 
corresponding SE order), has three options to receive premarket 
authorization: (1) It could submit a new PMTA for the product with the 
modifications; (2) depending on the type of modification, it could seek 
authorization through the SE exemption pathway; or (3) it could seek 
authorization through the SE pathway relying on a valid predicate, 
i.e., a product FDA has previously found SE or a product that was 
commercially marketed in the United States (other than for test 
marketing) as of February 15, 2007. The modifications for which an SE 
exemption request may be submitted are set forth in Sec.  1107.1. The 
circumstances under which an applicant may submit a supplemental PMTA 
for a new tobacco product that results from a modification or 
modifications to the original tobacco product that received a marketing 
granted order are described in section VIII.F.
    Marketing a new tobacco product without required premarket 
authorization would render the product adulterated under section 
902(6)(A) of the FD&C Act and misbranded under section 903(a)(6) of the 
FD&C Act and subject to an FDA enforcement action.

B. Reporting Requirements (Sec.  1114.41)

    Section 1114.41 requires applicants that receive a marketing 
granted order to submit postmarket reports. FDA is requiring postmarket 
reports under the authority of section 910(f) of the FD&C Act, which 
requires applicants to establish and maintain records and make reports 
that FDA requires as necessary to determine or facilitate a 
determination of whether there may be grounds to withdraw or 
temporarily suspend a marketing granted order. In addition, under 
section 909 of the FD&C Act, FDA is permitted to require the reporting 
of information to assure that a tobacco product is not adulterated or 
misbranded and to otherwise protect public health. Section Sec.  
1114.41 describes the reports that FDA requires through this 
regulation; however, FDA may require additional reporting in an 
individual applicant's marketing granted order.
    Applicants are required under Sec.  1114.41 to submit two types of 
reports after receiving a marketing granted order: Periodic reports and 
adverse experience reports. Applicants must submit periodic reports 
within 60 calendar days of the reporting date specified in the 
marketing granted order (or potentially sooner if they choose to use 
the application as the basis for a supplemental PMTA under Sec.  
1114.15). FDA anticipates that the reports will be required on an 
annual basis, but FDA may require, by a specific order, that reports be 
made more or less frequently depending upon a number of factors (e.g., 
the novelty of the type of product).

C. Requirements for Periodic Reports

    Applicants must submit the following information electronically 
together with the appropriate form (Ref. 140) as part of each periodic 
report under Sec.  1114.41(a)(1). The materials provided in these 
reports can provide important information regarding whether the 
marketing of the product is no longer APPH under section 910(d)(1)(A) 
of the FD&C Act or whether the marketing granted order should be 
temporarily suspended under section 910(d)(3) of the FD&C Act:
     A cover letter that includes basic identifying 
information, such as the product name(s) (including the original 
product name, if different) and application STN;
     a full description of the changes made to the methods used 
in, and the facilities and controls used for, the manufacture, 
processing, and, when relevant, packing and installation of, such 
tobacco product, if any, during the reporting period. This description, 
which we are requiring under section 909 of the FD&C Act, must include 
sufficient information for FDA to determine whether a change to methods 
used in, and the facilities and controls used for, the manufacture, 
processing, and, when relevant, packing and installation of, such 
tobacco product results in a new tobacco product or do not conform to 
the requirements of section 906(e) and potentially be a basis to 
withdraw or temporarily suspend the marketing granted order. This 
information includes a comparison to the methods used in, and the 
facilities and controls used for, the manufacture, processing, and, 
when relevant, packing and installation of, such tobacco product, 
described in the PMTA, the rationale for making the change, and an 
explanation of why the change does not result in a new tobacco product 
and why there are no grounds for FDA to withdraw or temporarily suspend 
the marketing granted order on the basis of the change (i.e., the 
marketing of product continues to be APPH, the manufacturing process 
complies with the requirements of section 906(e) of the FD&C Act, and 
the product still conforms to any product standards under section 907 
of the FD&C Act);
     An inventory of all ongoing and completed studies about 
the tobacco product conducted by, or on behalf of, the applicant that 
are within the scope of Sec.  1114.7(k) and were not already submitted 
as part of the PMTA or

[[Page 55394]]

previous postmarket reports. These reports can provide important 
information regarding health risks or changes in tobacco product use 
behavior, including initiation, which helps FDA determine whether the 
marketing of the product is no longer APPH under section 910(d)(1)(A) 
of the FD&C Act;
     full reports of information (as described in Sec.  
1114.7(k)(3)) published or known to, or which should reasonably be 
known to, the applicant concerning scientific investigations and 
literature about the tobacco product that would be required in a PMTA 
under Sec.  1114.7(k)(1) not previously submitted as part of the PMTA 
or previous postmarket reports, including significant findings from 
publications not previously reported;
     a summary and analysis of all serious and unexpected 
adverse experiences associated with the tobacco product that have been 
reported to the applicant or that the applicant is aware of, 
accompanied by a statement of any changes to the overall risk 
associated with the tobacco product, including the nature and frequency 
of the adverse experience, and potential risk factors;
     a summary of sales and distribution of the tobacco 
product, to the extent that the applicant collects or receives such 
data, for the reporting period, including:
    [cir] total U.S. sales reported in dollars, units, and volume with 
breakdowns by U.S. census region, major retail markets, and channels in 
which the product is sold. Sales and distribution information may 
constitute confidential commercial information under Sec.  20.61 that 
is exempt from public disclosure. See Sec.  1114.47 and part 20 for 
more information about the confidentiality of information submitted to 
FDA;
    [cir] the Universal Product Code that corresponds to the product(s) 
identified in the PMTA; and
    [cir] Demographic characteristics of product purchasers, such as 
age, gender, race or ethnicity, geographic region, and tobacco use 
status. After reviewing and considering comments received in response 
to the proposed rule, FDA has updated this language here and throughout 
the rule as the consideration of vulnerable populations is an important 
part of determining whether permitting the continued marketing of a new 
tobacco product is APPH;
     a summary of the implementation and effectiveness of 
policies and procedures regarding verification of the age and identity 
of purchasers of the product;
     a summary of all formative consumer research studies 
conducted (if any), among any audiences, in the formation of new 
labeling, advertising, marketing, or promotional materials, not 
previously submitted, including qualitative and quantitative research 
studies used to determine message effectiveness, consumer knowledge, 
attitudes, beliefs, intentions and behaviors toward using the products, 
and including the findings or these studies and copies of the stimuli 
used in testing;
     a summary of all consumer evaluation research studies 
conducted (if any), among any audiences, not previously submitted, to 
determine the effectiveness of labeling, advertising, marketing, or 
promotional materials and shifts in consumer knowledge, attitudes, 
beliefs, intentions, and behaviors toward using the products, and 
including the findings of these studies and copies of the stimuli used 
in testing;
     a summary of the creation and dissemination of the 
products' labeling, advertising, marketing, and promotional materials 
(if any), including a list of all entities involved and a description 
of their involvement, including a description of contractual agreements 
with such entities. For example, a list of entities involved in the 
creation and dissemination of marketing materials might include the 
names of advertising agencies, media companies, public relations firms, 
market research companies, partners, sponsors, bloggers and social 
media influencers;
     specimens of all labeling that has not been previously 
submitted in the PMTA, prior postmarket reports, or under section 
905(i) of the FD&C Act and descriptions of all labeling changes 
including the date the labeling was first disseminated and the date 
when dissemination was completely terminated. This labeling information 
can help FDA determine whether the withdrawal grounds under section 
910(d)(1)(E) of the FD&C Act apply;
     full color copies of all advertising, marketing, and 
promotional materials for the tobacco product that have not been 
previously submitted, the original date the materials were first 
disseminated, and the date when their dissemination was completely 
terminated. FDA is requiring the submission of this information under 
authority of section 910(f) because as discussed in section 
VIII.B.6.b., the way in which a tobacco product is advertised, 
marketed, and promoted can play an important role in FDA's 
determination of whether the marketing of a tobacco product is APPH. A 
substantial body of evidence illuminates the powerful impact of tobacco 
product labeling, advertising, marketing, and promotion on youth 
perceptions of tobacco products, youth appeal of tobacco products, the 
likelihood of youth initiation and use of tobacco products, even when 
said marketing is purportedly targeted or designed to appeal to adults. 
Youth are a significant population of concern as their current stage of 
brain development makes them especially susceptible to nicotine 
addiction. Thus, for FDA to help ensure that the continued marketing of 
a new tobacco product is appropriate for the protection of public 
health, it is critical for FDA to conduct ongoing review and evaluation 
of the product's labeling, advertising, marketing, and promotional 
materials and activities to assess any possible effects on perceptions, 
appeal, intentions, and behaviors among intended and unintended 
audiences, especially youth. The information, together with other 
postmarket information concerning the marketing of the tobacco product, 
will facilitate determination of whether there are or may be grounds to 
withdraw a marketing granted order under section 910(d)(1)(A) of the 
FD&C Act;
     a description of the implementation of all advertising and 
marketing plans, not previously submitted to FDA (whether conducted by 
the applicant, on its behalf, or at its discretion), including 
strategic creative briefs and paid media plans by channel and by 
product, and the dollar amount(s) and flighting of such plans, by 
channel and by product, including a description of any of the following 
activities that an applicant may have engaged in:
    [cir] Use of competent and reliable data sources, methodologies, 
and technologies to establish, maintain, and monitor highly targeted 
advertising and marketing plans and media buys, including a list of all 
data sources used to target advertising and marketing plans and media 
buys;
    [cir] Targeting of specific group(s) by age-range(s), including 
young adults, ages 21-24, and other demographic or psychographic 
characteristics that reflect the intended audience including the source 
of such data;
    [cir] with respect to individuals below the minimum age of sale, 
actions taken to restrict access to the product and limit exposure to 
the product labeling, advertising, marketing, promotion, or other 
consumer-directed activities;
    [cir] use of owned, earned, shared, or paid media to create 
labeling for, advertise, market, or promote the product;
    [cir] use of partners, influencers, bloggers, or brand ambassadors 
to create labeling for, advertise, market, or promote the product;
    [cir] consumer engagements--whether conducted by an applicant, on 
its

[[Page 55395]]

behalf, or at its direction--including events at which the product was 
demonstrated and how access was restricted to individuals at or above 
minimum age of sale; or
    [cir] use of public relations or other communications outreach to 
create labeling for, advertise, market, or promote the products;
     a summary of media tracking and optimization (e.g., 
assessment of marketing campaigns in market, and adjustments to a media 
buy to improve or correct delivery of advertising to the intended 
audience) by channel, by product, and by audience demographics (e.g., 
age, gender, race/ethnicity, geographic region), including a summary of 
any real-time digital media monitoring (e.g., tracking the use of a 
specific hashtag, reviewing audience engagement metrics such as 
``likes'', ``comments'', and ``shares'') and including a summary of 
implementation of any corrective and preventive measures to identify, 
correct, and prevent delivery of advertising to individuals below the 
minimum age of sale, not previously submitted;
     a report or summary of the actual delivery of advertising 
impressions (e.g., instances where the intended audience had the 
opportunity to view or consume the product's advertising and 
marketing), by channel, by product, and by audience demographics (e.g., 
age, gender, race/ethnicity, geographic region), not previously 
submitted. This report or summary must be based on post-launch 
delivery-verification reports submitted to the tobacco product company 
from an accredited source, where applicable;
     additional information required to be reported under the 
terms of a marketing granted order (if applicable); and
     an overall assessment of how the marketing of the tobacco 
product continues to be APPH.
    Postmarket information concerning the marketing of a tobacco 
product is critical to FDA's evaluation of whether the continued 
marketing of the product is APPH under section 910(d)(1)(A) of the FD&C 
Act. Determining whether the continued marketing of the tobacco product 
is APPH requires FDA to consider the likelihood that those who do not 
use tobacco products, including youth, will start using the product. As 
discussed in section VIII.B.6.b., youth exposure to tobacco product 
advertising, marketing, and promotion has a direct and powerful impact 
on youth trial and uptake of tobacco product use, making it directly 
relevant to FDA's determination of the likelihood that nonusers and 
users of other products switching to the new product, including youth 
will use the product. Accordingly, section Sec.  1114.41(a)(1) seeks 
information that directly informs FDA's evaluation of youth exposure to 
marketing materials for the product and youth access to the product. 
Information regarding paid media plans for the product, such as the 
channels used and the dollar amount(s) and flighting of the plans, as 
well as information regarding the use (or nonuse) of competent and 
reliable data sources, methodologies, and technologies to establish, 
maintain, and monitor highly targeted advertising and marketing plans 
and media buys, allows FDA to estimate the scale and potential reach of 
advertising, marketing, and promotion for the product and thereby 
directly informs its determination of the likelihood that youth will be 
exposed to such marketing materials. For example, the use of social 
media platforms known to reach youth, such as Twitter, Instagram, and 
YouTube, without use of methods to restrict and monitor youth access to 
marketing on those platforms may indicate a higher likelihood of youth 
exposure to marketing for the tobacco product and youth use of the 
tobacco product (see, e.g., Refs. 12-14 and 16). Additionally, use of 
partners, influencers, bloggers, or brand ambassadors to create 
labeling for, advertise, market, or promote a tobacco product may also 
indicate a higher likelihood of youth exposure to marketing materials 
for the product and youth use of the product, given studies 
demonstrating that such methods, including the use of ``organic'' 
depictions of tobacco use and endorsements of tobacco products by 
cultural icons and other influencers, are especially effective among 
youth who are particularly susceptible to social influences (Ref. 9). 
Moreover, information regarding actions taken to restrict access to the 
product and limit exposure to the product labeling, advertising, 
marketing, promotion, or other consumer-directed activities for 
individuals below the minimum age of sale directly informs FDA's 
evaluation of youth access to the product.

D. Serious and Unexpected Adverse Experience Reporting

    Applicants must report all serious and unexpected adverse 
experiences associated with the tobacco product that have been reported 
to the applicant or of which the applicant is aware under Sec.  
1114.41(a)(2). The serious and unexpected adverse experience reports 
must be submitted to CTP's Office of Science through the Health and 
Human Services (HHS) Safety Reporting Portal or in another manner 
designated by FDA (if applicable) within 15 calendar days after 
receiving or becoming aware of a serious or unexpected adverse 
experience. FDA notes that the submission of a report under this 
section (and any release by FDA of that report) will not constitute an 
admission that the tobacco product caused or contributed to an adverse 
experience.
    FDA received several comments regarding the requirements for 
periodic reports, as discussed below.
    (Comment 128) One comment stated that section 910 of the FD&C Act 
does not authorize FDA to require postmarket reporting for 
manufacturing changes. The comment stated that if a manufacturing 
change of the nature described by the proposed rule results in a new 
product, then there can be no ``postmarket'' information for FDA to 
evaluate because such a product cannot be placed on the market until a 
new marketing order has been obtained. The comment further stated that, 
if the manufacturing change does not result in a new tobacco product, 
then this change cannot alter FDA's prior determination that the 
marketing of the product is appropriate for the protection of public 
health nor would it enable FDA to determine, or facilitate a 
determination, that there are any other statutory grounds for 
withdrawing or suspending a marketing order. The comment concluded that 
in the future, manufacturing changes may result in a withdrawal or 
suspension but as no manufacturing regulations exist under section 
906(e) of the FD&C Act, this does not seem applicable.
    (Response 128) FDA declines to make any changes as a result of this 
comment. As discussed in the rule, whether the applicant can 
consistently manufacture the new tobacco product described in the PMTA 
is important to FDA's determination of whether a tobacco product is 
APPH, and given the dangers associated with nonconforming tobacco 
products, reviewing manufacturing changes on a postmarket basis is 
necessary for FDA to determine whether the continued marketing of the 
product is APPH. Additionally, reviewing manufacturing changes would 
allow FDA to determine whether they would result in a modification 
(intended or unintended) to the product and is therefore a different 
new tobacco product without premarket authorization, which would render 
that tobacco product adulterated under section 902(6)(A) of the FD&C 
Act and misbranded under section 903 of the FD&C Act. FDA is requiring 
such information, in part, under its section 909 of the FD&C Act 
authority, which

[[Page 55396]]

allows FDA to require the reporting of information to assure that a 
tobacco product is not adulterated or misbranded and to otherwise 
protect public health.
    (Comment 129) One comment stated that section 910 of the FD&C Act 
does not authorize FDA to require postmarket reporting of sales and 
marketing information. The comment noted that while FDA states that 
this information will inform a determination of whether the marketing 
of the new tobacco product continues to be APPH, it claimed that this 
statement does not establish that all of the information required in 
the proposed rule is necessary for FDA to make its determination and, 
as such, many of the postmarket reporting requirements should be 
deleted in the final rule.
    (Response 129) FDA disagrees with the statement that this reporting 
is not authorized by the FD&C Act. As discussed throughout this 
document, this postmarket information is necessary to help inform FDA's 
determination of whether the continued marketing of the tobacco product 
is APPH. FDA requires applicants to submit sales data under its 
authority in section 910(f) of the FD&C Act to help inform its 
determination of whether the continued marketing of the product is 
APPH. Sales data in conjunction with other data such as demographics of 
purchasers and information on retail channels can provide information 
that can help indicate trends in tobacco use behavior across the United 
States and potential changes in tobacco use behaviors among certain 
subsets of the population. For example, if tobacco use of a specific 
product was previously low among a certain demographic and, through the 
postmarket reporting, is now being reported at higher levels of tobacco 
use that also correlates with sales of the new product among the same 
demographic group, this type of information would be important to FDA's 
determination of whether the continued marketing of the tobacco product 
is APPH. In addition, sales of tobacco products by retail channel, 
combined with other required data, can help FDA understand where 
products are being sold as well as help FDA better understand the 
potential for youth access to the products. In particular, the data 
help FDA to assess whether the information regarding likely tobacco 
product use behavior described in the PMTA was consistent with actual 
use after authorization. For example, data that indicate significantly 
higher rates of youth initiation with the tobacco product than among 
other nonusers than anticipated in the PMTA could result in FDA finding 
that continued marketing of the tobacco product is no longer APPH and 
the marketing granted order should be withdrawn under section 
910(d)(1)(A) of the FD&C Act. Furthermore, because youth exposure to 
tobacco product labeling, advertising, marketing, and promotion has a 
direct and powerful impact on youth trial and uptake of tobacco product 
use, information regarding the marketing of the tobacco product and 
potential youth exposure to marketing directly informs FDA's 
consideration of the likelihood that youth will use the product, which 
is relevant to determining whether continued marketing of a product is 
APPH and consistent with its statutory mandate to protect youth from 
the dangers of tobacco use. In addition, as discussed below, 
information regarding the marketing of the product can help FDA 
determine whether the withdrawal grounds under section 910(d)(1)(E) of 
the FD&C Act apply.
    (Comment 130) One comment requested that the rule require the 
submission of postmarket information to demonstrate that all labeling, 
instructions for use, and other communications related to the product 
have been carefully designed and tested to ensure they will provide 
accurate, not misleading, information and guidance to all consumers, 
including those with less education, or weaker or non-existent English 
literacy, and will not encourage harm-increasing uses of the product 
among any subpopulations.
    (Response 130) FDA intends to consider the labeling, advertising, 
and marketing, and promotion for a new tobacco product, including 
labels, instructions for use and other advertising and marketing 
materials, that an applicant uses after receiving a marketing granted 
order as part of FDA's evaluation of whether the continued marketing of 
a new tobacco product is APPH. FDA is not requiring formal testing of 
advertising and marketing materials. However, when determining whether 
the continued marketing of a new tobacco product is APPH, under section 
910(d)(1)(E) of the FD&C Act, FDA is required to consider whether the 
labeling of the tobacco product is false or misleading. In addition, 
FDA will review advertising and marketing materials with consideration 
of the potential for use among nonusers, including youth, as well as 
product misuse and dual use among current tobacco product users (see 
section VII.B.6 regarding Sec.  1114.7(f) for a discussion of the 
impact of advertising).
    (Comment 131) One comment stated that FDA should, similar to 
language FDA uses for other regulated product categories, make it clear 
that submission of required postmarket reports, including adverse 
experience reports, does not reflect a conclusion or admission by the 
applicant or FDA that the product at issue caused or contributed to the 
adverse experience.
    (Response 131) In section X.B., FDA has amended this document to 
clarify that reporting an adverse experience will not constitute an 
admission that the tobacco product caused or contributed to the adverse 
experience.

E. Submission of Additional Information

    As part of its review of a postmarket report, FDA could require the 
applicant to submit additional information to enable it to determine 
whether a change results in a new tobacco product, or to facilitate a 
determination of whether there are or may be grounds to withdraw or 
temporarily suspend the marketing granted order. FDA may notify an 
applicant that FDA has determined that a change described in a periodic 
report made under this section results in a new tobacco product outside 
the scope of the marketing granted order, requiring the submission of a 
new PMTA under Sec.  1114.7 or a supplemental PMTA under Sec.  1114.15 
and issuance of a marketing granted order if the applicant seeks to 
market the new tobacco product, unless the new tobacco product can be 
legally marketed through a different premarket pathway. Failure to 
obtain marketing authorization for a new tobacco product would render 
it adulterated under section 902(6) of the FD&C Act and misbranded 
under section 903(a)(6) of the FD&C Act and could be subject to 
enforcement action.
    FDA received one comment on this issue, as discussed below.
    (Comment 132) One comment stated that they expected some e-liquid 
manufacturers to join controlled distribution networks to show youth 
access to tobacco products would be limited. The comment recommended 
that the rule be amended to allow third party entities (e.g., 
controlled distribution networks or their auditing agents) to submit 
reports directly to the Agency that reference and link to participants' 
approved PMTAs. This would allow applicants or their designated 
distribution networks and auditors to submit to FDA all information 
required.
    (Response 132) We decline to make this change. The rule concerns 
the postmarket reports that applicants are required to make, rather 
than the information that third parties or other entities may submit to 
FDA about a tobacco product; however, note that

[[Page 55397]]

where an applicant obtains sales data about its product from a third 
party, the applicant would need to report it to FDA as required by 
Sec.  1114.41. As noted in section VIII.B.2, applicants have the 
ability to cross-reference third-party owned information through TPMFs, 
including in the submission of postmarket reporting requirements.

XI. Miscellaneous (Part 1114, Subpart E)

    Subpart E describes other procedures and requirements related to 
PMTAs, including record retention, electronic submission requirements, 
and confidentiality considerations.

A. Record Retention (Sec.  1114.45)

    Consistent with the authority to require recordkeeping under 
sections 909 and 910(f) of the FD&C Act, Sec.  1114.45 requires 
applicants receiving a marketing granted order to maintain all records 
necessary to facilitate a determination of whether there are or may be 
grounds to withdraw or temporarily suspend the marketing granted order 
and ensure that such records remain readily available to the Agency 
upon request. The records must be legible, written in English, and 
available for inspection and copying by officers or employees 
designated by the Secretary.
1. Record Retention by the Applicant
    Under Sec.  1114.45(a)(1), an applicant must retain all documents 
submitted to FDA as part of an application and postmarket reports. An 
applicant must also retain any additional documentation supporting the 
application and postmarket reports that was not submitted to FDA. This 
additional documentation includes information that demonstrates:
     Nonclinical laboratory studies were conducted using 
laboratory practices that ensure the reliability and validity of the 
study. This information includes documents that were generated during 
the performance of nonclinical studies, but were not required to be 
submitted as part of a full study report under Sec.  1114.7(k)(3). One 
way that an applicant may satisfy this requirement is to retain all of 
the documentation described in part 58 and
     whether any investigators had financial conflicts of 
interest. One approach to satisfying this requirement is to retain all 
of the documentation described in part 54 for both clinical and 
nonclinical investigations.
    Applicants must also retain all other documents generated during 
the course of a study that are necessary to substantiate the study 
results (e.g., certain communications, case reports) including:
     Communications related to the investigation between the 
investigator and the sponsor, the monitor, or FDA and
     all source data and related summaries, including records 
regarding each study subject's case history and exposure to tobacco 
products used in the investigation, which can include, but is not 
limited to case report forms, progress notes, hospital records, 
clinical charts, x-rays, lab reports, and subject diaries.
    The applicant must also maintain a record of each complaint 
associated with the tobacco product that has been reported to the 
applicant as well as a summary and an analysis of all complaints 
associated with the tobacco product reported to the applicant. The 
records and analysis of complaints should reflect all reports made 
about the product, including those made during clinical investigations. 
FDA is requiring that records and analysis of such complaints be kept 
to demonstrate whether there are any potential issues with the product 
that could present health or safety issues.
    FDA received comments regarding record retention by applicants, as 
discussed below.
    (Comment 133) One comment suggested that the language of the 
proposed rule be amended to allow for either applicants or their third-
party representatives to retain the records required by Sec.  1114.45. 
The applicant stated that this could be more efficient and save costs.
    (Response 133) FDA has amended the language of the preamble to 
clarify that an applicant may utilize a third-party entity to store 
records on their behalf. If an applicant uses a third-party entity to 
store records, it is important to note that the applicant is still 
solely responsible for ensuring that all records necessary to 
facilitate a determination of whether there are or may be grounds to 
withdraw or temporarily suspend the marketing granted order are readily 
available to the Agency upon request. This requirement will ensure that 
records are available to FDA during an inspection.
    Applicants that have stopped marketing a tobacco product may want 
to retain the records for a longer period if the product might be 
reintroduced in order to avoid the time and expense of having to 
generate the information again. FDA may, under the terms of section 
910(f) of the FD&C Act, impose additional recordkeeping and reporting 
requirements as part of a marketing granted order in addition to the 
requirements in the rule.
    (Comment 134) One comment expressed support for the requirement for 
applicants to retain records but suggested the proposed rule should be 
amended to include retention requirements for specific information that 
would enable FDA to track and trace a product from the manufacturing 
source to the shelf.
    (Response 134) FDA declines to make such a change because it is 
outside the scope of this rulemaking. Consistent with sections 909 and 
910(f) of the FD&C Act, the rule (as described in Sec.  1114.45) 
requires applicants to retain all records necessary to facilitate a 
determination of whether there are or may be grounds to withdraw or 
temporarily suspend the marketing order as well as ensure that the 
tobacco product that is the subject of the marketing order is not 
adulterated or misbranded.
2. Record Format and Availability
    The rule requires the applicant to maintain records that are 
legible and in the English language, and make them available for 
inspection and copying by officers or employees duly designated by the 
Secretary.
3. Retention Period
    Applicants must retain the records as described in Sec.  
1114.45(a)(3). Records relating to the PMTA must be retained for a 
period of no less than 4 years from the date the marketing granted 
order is issued. Records relating to the postmarket reports, including 
both periodic reporting and adverse experience reporting must be 
retained for a period of at least 4 years from the date the postmarket 
report was submitted or the date FDA inspects the records, whichever 
occurs sooner. FDA has selected 4 years as a means to help ensure that 
the records would be available for at least one biennial FDA inspection 
under sections 704 and 905(g) of the FD&C Act.

B. Confidentiality (Sec.  1114.47)

    Section 1114.47 states that FDA will determine the public 
availability of any part of any PMTA and other content related to a 
PMTA, including all data and information submitted with or incorporated 
by reference in the application, as provided under this section and 
part 20 (Public Information). FOIA (5 U.S.C. 552), as well as certain 
provisions of the FD&C Act, (e.g., section 301(j) (21 U.S.C. 331(j)) 
and section 906(c)), govern the disclosure of the existence of a 
pending PMTA and the information contained in such a PMTA. Under FOIA, 
the public has broad access to government documents.

[[Page 55398]]

However, FOIA provides certain exemptions from mandatory public 
disclosure. One such provision, 5 U.S.C. 552(b)(4), exempts records 
that are ``trade secrets and commercial or financial information 
obtained from a person and privileged or confidential'' from the 
requirement of mandatory disclosure. Part 20 of FDA's regulations sets 
forth FDA's general regulations concerning public availability of FDA 
records.
    FDA received several comments regarding confidentiality, as 
discussed below.
    (Comment 135) One comment suggested that a public database be 
established that lists the products for which a PMTA has been filed, 
accepted, or is pending substantive review. The comment stated that 
this is important because it would allow other state and federal 
agencies to know whether a product has the ability to remain on the 
shelves of stores. Similarly, another comment stated that by not making 
the application process more public, FDA is not permitting adequate 
participation by stakeholders other than the applicant and is contrary 
to established FDA practice. The comment expressed concern that this 
could result in FDA having access only to research conducted by 
industry or prevent FDA from accessing research not yet published.
    (Response 135) FDA agrees that stakeholder engagement, including 
with federal and state entities as well as members of the public, is 
important to the effective implementation of the law and the PMTA 
process generally. However, the Agency disagrees with the assertion 
that a public database or other measures not included in this rule are 
necessary to ensure adequate public participation or to ensure that FDA 
has access to all potentially relevant information, including research 
not yet published, from sources other than the applicant. As discussed 
in the preamble of the proposed rule, like with drugs and devices, the 
intent to market a tobacco product that is not currently marketed is 
often considered confidential commercial information. This is 
consistent with the recent Supreme Court decision that addressed the 
legal standard for determining whether information is confidential. See 
Food Mktg. Inst. v. Argus Leader Media, 139 S. Ct. 2356, 2366 (2019). 
Therefore, Sec.  1114.47(b) addresses the confidentiality of a PMTA 
prior to the issuance of a marketing granted order. Under the rule, FDA 
will not publicly disclose the existence of a PMTA unless the applicant 
has publicly disclosed or acknowledged that it has submitted the 
application to FDA (as such disclosure is defined in Sec.  20.81), the 
applicant has authorized FDA in writing to publicly disclose or 
acknowledge the submission of the PMTA, or FDA has referred the 
application to TPSAC. Section 1114.47(b)(2) provides that FDA will not 
disclose the fact or contents of an FDA communication with an applicant 
or regarding an application or information contained in the application 
unless the applicant has publicly disclosed, acknowledged, or 
authorized FDA in writing to publicly disclose or acknowledge the 
existence of the FDA communication or information contained in the 
application. However, if the applicant has disclosed information 
contained in the application or that it received a communication from 
FDA regarding the application, FDA may disclose the record of the 
communication after redacting confidential commercial or trade secret 
information. Section 1114.47(b)(3) provides that if FDA refers the 
application to TPSAC, the PMTA will be available for public disclosure 
under part 20 as described in Sec.  14.75 (21 CFR 14.75) (which 
concerns the public disclosure of advisory committee records), except 
information that that is exempt from public disclosure under part 20, 
including trade secrets, confidential commercial information, and 
personal privacy information. This is consistent with FDA's practice 
for tobacco product premarket applications, as well as for premarket 
applications generally.
    (Comment 136) One comment stated that section 910 of the FD&C Act 
does not authorize FDA to make PMTAs publicly available as part of FDA 
or TPSAC review. The comment argued that if Congress intended FDA to 
have the authority to divulge the content of a PMTA, it would have 
stated so in the Tobacco Control Act. Another comment argued that the 
only information that should be referred to TPSAC is a limited summary 
of the relevant portions of the application.
    (Response 136) As stated above, prior to the issuance of a 
marketing granted order, FDA will not publicly disclose the existence 
of a PMTA unless the applicant has publicly disclosed or acknowledged 
that it has submitted the application to FDA, the applicant has 
authorized FDA in writing to publicly disclose or acknowledge the 
submission of the PMTA, or FDA has referred the application to TPSAC. 
Except as described in Sec.  1114.47(b)(4) regarding referral to TPSAC, 
FDA will not disclose information contained in an application unless 
the applicant has publicly disclosed or acknowledged, or authorized FDA 
in writing to publicly disclose or acknowledge, the existence of that 
particular information.
    FDA disagrees with the assertion that it cannot make a PMTA 
publicly available as part of TPSAC review because it is required to do 
so under section 10(b) of the Federal Advisory Committee Act (Pub. L. 
92-463, 5 U.S.C. App) and its implementing regulations. If FDA refers 
the application to TPSAC, the PMTA will be available for public 
disclosure under part 20 as described in Sec.  14.75 (which concerns 
the public disclosure of advisory committee records), except 
information that is exempt from disclosure under part 20, including 
trade secrets, confidential commercial information, and personal 
privacy information
    Section 1114.47(c) describes the information that FDA will make 
available after issuing a marketing granted order. Under Sec.  
1114.47(c), FDA can make available data previously disclosed to the 
public, protocols for a test or study, information and data in the 
application that demonstrate the new tobacco product is appropriate for 
the protection of the public health, any correspondence between FDA and 
the applicant, the EA or request for categorical exclusion, and 
information and data contained in postmarket reports, so long as the 
information listed above is not exempted from disclosure under part 20.
    Even after receipt of a marketing denial order for an application 
for a product that is not currently marketed, the intent to market may 
still constitute confidential commercial information, as the applicant 
may still have the intent to market the new tobacco product that is the 
subject of the PMTA and it is the type of information that is 
customarily and actually treated as private by its owner. Under Sec.  
1114.47(d), FDA may also make certain information available after it 
issues a marketing denial order unless the information is otherwise 
exempt from disclosure under part 20. The information that FDA may 
disclose includes product category, subcategory, package size, and the 
basis for the marketing denial order. FDA notes that where an applicant 
receives a marketing denial order for, or FDA refuses to accept or 
file, a PMTA for a new tobacco product that is currently on the market 
as a result of FDA's compliance policy for deemed tobacco products on 
the market as of August 8, 2016, FDA may disclose additional 
identifying information about the product to help ensure that it is 
taken off of the market. Where a product is marketed, basic identifying 
information regarding the

[[Page 55399]]

product is not a trade secret or confidential commercial information.
    (Comment 137) One comment states that the final rule should be 
amended to state that all aspects of the PMTA, including all data and 
information submitted with or incorporated by reference into the 
application, are confidential information under Sec.  1114.47.
    (Response 137) As explained elsewhere in this section, FDA will 
determine the public availability of any information contained in a 
PMTA under Sec.  1114.47 and part 20. This includes the data and 
information in the application submitted in both full text and 
incorporated by cross-reference. FDA has amended the language in this 
section, to clarify what information would be confidential under the 
rule and part 20.
    (Comment 138) One comment stated that the final rule should be 
amended to state that all data and information received in an ITP 
submission prior to a PMTA being filed with the Agency is also 
confidential. Furthermore, the comment stated that FDA should update 
part 20 to describe the legal standard for FOIA exemption 4 established 
by the Supreme Court in Food Mktg. Inst. v. Argus Leader Media.
    (Response 138) This rulemaking addresses the general process by 
which PMTAs are submitted and reviewed. Any comments concerning the 
investigational tobacco product submission process or FDA's public 
information regulations under part 20 are outside the scope of this 
rule.
    (Comment 139) One comment stated that FDA should publicly disclose 
the existence of PMTAs for which the applicant has previously submitted 
a MRTPA or submits an MRTPA concurrently with the PMTA.
    (Response 139) FDA has amended Sec.  1114.47 to state that it will 
disclose the existence of a PMTA for a new tobacco product for which an 
MRTPA has been made available for public comment under section 911(e) 
of the FD&C Act. Once FDA makes an MRTPA for the new tobacco product 
publicly available, the intent to market the new tobacco product would 
no longer be confidential commercial information. Further, as stated 
previously, the contents of a PMTA that is referred to TPSAC (either as 
a standalone application or concurrently with an MRTPA) will be 
available for public disclosure under part 20 as described in Sec.  
14.75 (which concerns the public disclosure of advisory committee 
records), including withholding information that is trade secrets, 
confidential commercial information, or personal privacy information.
    (Comment 140) One comment stated that it is important for FDA to 
publicly disclose all data and information submitted to demonstrate the 
marketing of a product would be APPH, marketing plans, and postmarket 
reporting for each new tobacco product that is authorized by FDA. The 
comment stated that marketing plans concern the sale and distribution 
of tobacco products, which under section 916 of the FD&C Act (21 U.S.C. 
387p) may also be subject to state and local regulation, even if such 
regulations are different or stricter than Federal regulations. The 
comment further stated that the public health interest in disclosure 
outweighs other interests and should result in marketing plans and 
postmarket reporting being disclosed to the public.
    (Response 140) As described in this section, FDA may make 
information publicly available after the issuance of a marketing 
granted order consistent with Sec.  1114.47(c) and part 20. FDA is 
unable to make any information in an application, including 
descriptions of marketing plans, publicly available to the extent that 
it constitutes trade secrets or confidential commercial information 
unless it is disclosed publicly or authorized to be disclosed publicly 
by the applicant.

C. Electronic Submission (Sec.  1114.49)

    Consistent with FDA's authority to issue regulations for the 
efficient enforcement of the FD&C Act, Sec.  1114.49 requires an 
applicant to submit a PMTA and all supporting and related documents to 
FDA in electronic format that FDA can process, review, and archive 
unless an applicant requests, and FDA grants, a waiver from this 
requirement. Reasons that an applicant might request a waiver would 
include that the applicant has no access to email or a computer. Under 
Sec.  1114.49(c), an applicant that has a waiver would submit a paper 
submission to the address that FDA provides in the letter granting the 
waiver.
    FDA received one comment regarding the proposed electronic 
submission provision, as discussed below.
    (Comment 141) One comment stated that while the submission of 
electronic documents may be a preferred delivery mechanism, it should 
not be a requirement that an applicant submit a PMTA and all supporting 
and related documents in electronic format.
    (Response 141) FDA declines to take this recommendation. FDA is 
implementing Sec.  1114.49 based on FDA's general experience with 
electronic submissions, which FDA has found help facilitate premarket 
reviews because electronic submissions typically enable FDA to receive, 
access, search, and review a submission more efficiently than a paper 
submission. FDA has provided technical specifications on its website 
for submitting information in an electronic format that FDA can review, 
process, and archive (e.g., method of transmission, media, file 
formats, preparation, organization of files, accompanying metadata) 
(https://www.fda.gov/tobacco-products/manufacturing/electronic-submissions-tobacco-products) and update this information as needed to 
accommodate changes in technology. As previously discussed, applicants 
who have limited access to email or a computer may apply for a waiver 
from the electronic submission requirement, which if granted by FDA, 
would allow an applicant to submit a paper submission to the address 
that FDA provides.

XII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The title, 
description, and respondent description of the information collection 
provisions are shown in the following paragraphs with an estimate of 
the annual reporting and recordkeeping burden. Included in the estimate 
is the time for reviewing instructions, searching existing data 
sources, gathering and maintaining the data needed, and completing and 
reviewing each collection of information.
    Title: Premarket Tobacco Product Applications and Recordkeeping 
Requirements, OMB Control Number 0910-0879.
    Description: This rule interprets and codifies requirements related 
to the content and format of PMTAs, the procedure by which FDA reviews 
PMTAs, and the maintenance of records regarding the legal marketing of 
certain tobacco products without PMTAs. The rule also addresses issues 
such as the procedures of retention of records related to the PMTA, 
confidentiality of application information, electronic submission of 
the PMTA and amendments, and postmarket reporting requirements.
    Description of Respondents: This rule applies to tobacco product 
manufacturers. Manufacturer is defined here as any person, including 
any repacker or relabeler, who: (1) Manufactures, fabricates, 
assembles, processes, or labels a tobacco product or (2) imports a 
finished tobacco product

[[Page 55400]]

for sale or distribution in the United States.
    As required by section 3506(c)(2)(B) of the Paperwork Reduction Act 
of 1995 (PRA), FDA provided an opportunity for public comment on the 
information collection requirements of the proposed rule that published 
in the Federal Register of September 25, 2019 (84 FR 50566). In 
response to this rule FDA received two PRA-related comments:
    (Comment 142) One comment made specific comments requesting changes 
to elements in Form 4057.
    (Response 142) FDA has considered these comments and agrees that 
many updates are necessary. The list below details the updates we have 
made to the form in response to the comments.
     FDA has harmonized, as appropriate, terms used within the 
PMTA and other FDA forms.
     FDA has revised the form by adding fields for address and 
contact information for manufacturer information to provide for the 
situation where the manufacturer is different from the Applicant.
     FDA agrees that the form does not collect organization 
information for certain parties. FDA has revised the form by providing 
fields to enter organization information for certain parties, e.g., the 
authorized representative. Additionally, FDA has revised the form by 
providing additional fields to describe the alternate point of contact.
     FDA has revised section III which now contains additional 
fields to identify cross-referenced submissions (ITP, SE, and MRTPA) 
and formal meetings held with FDA that pertain to the PMTA. For 
example, the applicant can now input in the revised form document 
keywords, document filenames, and submission dates for cross-referenced 
content. For formal meetings with FDA, the applicant can now input in 
the revised form the new tobacco product name. These fields would also 
help ensure FDA identify the cross-referenced content or related 
submission.
     Section III of the revised form also contains new fields 
(e.g., ``document keyword'' and ``document filename'') that allow the 
submitter to adequately describe the content they are cross-
referencing. Section III now allows the applicant to indicate if the 
cross-referenced content is relevant to a specific product or to all 
bundled products in the application. Across all product categories, the 
subcategory of ``co-package'' has been removed. However, co-packaged 
items can be grouped within the same submission and the unique 
identification of this co-packaged product would include the specific 
items needed to identify each product within the co-package.
     In section IV, FDA has added a ``Submission Table of 
Contents'' with fields for ``filename,'' ``title,'' ``table of contents 
category,'' and ``keyword'' in order that FDA can easily identify the 
application contents listed in section IV.
    (Comment 143) One comment made specific comments requesting changes 
to elements in Form FDA 4057a.
    (Response 143) FDA has considered these comments and agrees that 
many updates are necessary. The list below details the updates we have 
made to the form in response to the comments.
     FDA has combined sections I and IV to only ask for current 
owner's information once. The current owner's information is now only 
required in section I of the revised form.
     FDA now allows the manufacturer's address and contact 
information to be provided (if a different entity from the applicant) 
contact information is to be provided.
     FDA has revised the form to allow the organization's name 
to be provided (where an organization is an alternate point of 
contact). Additionally, FDA added a field so that organizational 
affiliation of the authorized representative information can be 
provided.
     For a change in authorized representative FDA agrees that 
``Replace'' is the appropriate step and has added this as an option in 
section I, subsection C of the form.
     The form has been edited to allow the submitter to 
indicate the purpose of the amendment (i.e., whether it was for a 
single new tobacco product or for a bundled/grouped submission).
     Section III of the form has been revised to allow the 
submitter to indicate the addition, updating or removal of cross-
referenced content, related submissions, and meetings with FDA. Section 
III now allows the submitter to describe the cross-referenced content, 
related submissions, and meetings, and to indicate the purpose of the 
cross-referenced content, related submissions, and meetings. 
Additionally, section III allows the submitter to indicate whether the 
submitter intends to ``add,'' ``update'' or ``remove'' referenced 
content, related submissions, and meetings.
     Section III of the revised form now contains a 
``submission summary'' field which allows the applicant to be used to 
describe the subject of the amendment.
     Section II of the revised form now allows information for 
``bundled'' or grouped PMTAs to be submitted. Section II now allows 
submitters to submit updated tobacco product information for all new 
tobacco products including co-packaged products. Additionally, section 
II of the revised form enables submitters to describe the subject of 
their correspondence and provide a submission summary describing the 
intended use of the submitted contents.
    Where appropriate, FDA has harmonized the terminology in the form 
with other FDA forms and has harmonized the layout of the Amendment and 
General Correspondence submission form with the layout of the PMTA 
submission form. For example, section I of the revised PMTA form is 
used to describe the applicant, the authorized representative, the 
alternate point of contact and other applicant information. 
Correspondingly, section I of the revised Amendment and General 
Correspondence submission form is used to update applicant information. 
Similarly, section II of the revised PMTA form is used to set out 
tobacco product information. Correspondingly, section II of the revised 
Amendment and General Correspondence submission form is used to update 
tobacco product information.
    FDA received generally supportive comments regarding proposed Form 
FDA 4057b. Comments agreed the form was a positive step towards 
streamlining the current PMTA submission process, as well as promoting 
efficient processing and review of bundled PMTAs.
    (Comment 144) One comment noted that Form FDA 4057b failed to 
include an ``oral tobacco-derived nicotine (OTDN)'' category or 
subcategory designation. The comment argued that OTDN products are both 
distinct, being tobacco-free and non-dissolvable, and one of the 
fastest growing tobacco product segments in the U.S. market. Including 
an OTDN product subcategory would provide clarity for applicants and 
streamline FDA review of these products. The comment also noted that 
Form FDA 4057b requires applicants to include characterizing flavor 
information but does not define this term in Form FDA 4057b or within 
the proposed rule.
    (Response 144) Providing unique identifying information, such as 
product category or subcategory, ensures FDA can identify the new 
tobacco product and distinguish it from other tobacco products, 
including additional new tobacco products in a bundled submission 
submitted using Form FDA 4057b, and assists FDA in performing its 
acceptance and filing reviews. At this

[[Page 55401]]

time, FDA does not yet have the experience necessary to create 
requirements for OTDN as a standalone product category or subcategory. 
Review of OTDN products will be handled on a case-by-case basis and any 
future decision to update or change the requirements of the rule and 
form to include OTDN products will follow appropriate notice and 
comment procedures. While the rule does not specifically include OTDN 
as a category or subcategory, where an applicant believes its new 
tobacco product, such as OTDN, does not fit within a product category 
set forth in the rule, it should identify the product category as 
``other''. Applicants are encouraged to include any properties in 
addition to those required by the ``other'' category or subcategory to 
fully identify the tobacco product, if applicable.
    In addition, the requirement for applicants to include product-
specific information, such as characterizing flavor(s), corresponds to 
the general information requirements of Sec.  1114.7.(c)(3)(iii) that 
will allow FDA to quickly check whether the product is within CTP's 
purview and identify the specific product that is the subject of the 
submission. For the characterizing flavor item, FDA is looking to see 
how the applicant identifies the tobacco product as having no 
characterizing flavor or having a particular characterizing flavor. If 
applicants do not consider the product to have a characterizing flavor, 
applicants must state ``none''. As discussed in the proposed rule, 
applicants that have questions regarding how to describe their 
product's characterizing flavor are encouraged to contact FDA prior to 
submission.
    (Comment 145) Another comment noted that while the use of Form FDA 
4057b would be a positive step, the current PMTA process is 
prohibitively expensive for most individual manufacturers of nicotine 
e-liquids.
    (Response 145) As discussed in the proposed RIA, FDA has considered 
the costs and benefits associated with the rule, if finalized. While 
there are costs associated with the rule, the analysis also noted that 
the rule, would create cost savings for firms and for FDA by reducing 
the number of follow-on submission for PMTAs (i.e., additional PMTAs 
submitted for the same product(s) after FDA refuses to accept or file, 
or issues a marketing denial order in response to, an initial PMTA). 
The analysis also noted small manufacturers who submit ENDS PMTA 
bundles would benefit from the proposed rule, if finalized. Submitted 
bundles, such as those submitted via Form FDA 4057b, would receive 
marketing orders through the PMTA pathway earlier with rulemaking than 
without rulemaking, increasing lifetime profits for the ENDS products 
included in the submitted ENDS bundles.
    FDA is finalizing requirements for the content, format, submission, 
and review of PMTAs, as well as other requirements related to PMTAs, 
including recordkeeping requirements, and postmarket reporting. FDA is 
also finalizing recordkeeping requirements regarding the legal 
marketing of Pre-Existing Tobacco Products and products that are exempt 
from the requirements of demonstrating substantial equivalence.
    Section 910(a)(2) of the FD&C Act generally requires that a new 
tobacco product be the subject of a PMTA marketing order unless FDA has 
issued an order finding it to be substantially equivalent to a 
predicate product or it is exempt from the requirements of 
demonstrating substantial equivalence. A manufacturer may choose to 
submit a PMTA under section 910(b) of the FD&C Act in an attempt to 
satisfy the requirements of premarket review. Section 910(b)(1) 
describes the required contents of a PMTA, which in addition to 
specific items, allows FDA to require applicants to submit other 
information relevant to the subject matter of the application.
    Under Sec.  1114.5 an applicant may submit a PMTA to demonstrate 
that a new tobacco product meets the requirements to receive a 
marketing order. A new tobacco product may not be introduced or 
delivered for introduction into interstate commerce under this part 
until FDA has issued a marketing order for the product. Section Sec.  
1114.7 describes the required content and format of the PMTA. The PMTA 
must contain sufficient information for FDA to determine whether any of 
the grounds for denial specified in section 910(c)(2) of the FD&C Act 
apply. The application must contain the following sections: general 
information, descriptive information, product samples as required by 
FDA, a statement of compliance with part 25, a summary, product 
formulation, manufacturing, health risk investigations, and a 
certification statement.
    Section Sec.  1114.9 provides that FDA may request, and an 
applicant may submit, an amendment to a pending PMTA. FDA generally 
expects that when an applicant submits a PMTA, the submission will 
include all information required by section 910(b)(1) of the FD&C Act 
and part 1114 to enable FDA to determine whether it should authorize 
the marketing of a new tobacco product. However, FDA recognizes that 
additional information may be needed to complete the review of a PMTA 
and, therefore, section Sec.  1114.9 allows the submission of 
amendments to a pending application.
    Section Sec.  1114.13 describes the steps that requires an 
applicant to take when it changes ownership of a PMTA. This section is 
intended to facilitate transfers of ownership and help ensure that FDA 
has current information regarding the ownership of a PMTA. An applicant 
may transfer ownership of its PMTA at any time, including when FDA has 
yet to act on it.
    Section Sec.  1114.15 discusses supplemental PMTAs, which are an 
alternative format for submitting a PMTA. Specifically, supplemental 
PMTAs are a standardized cross-referencing format that FDA would 
implement under its authority of section 701(a) of the FD&C Act to 
efficiently enforce section 910 for submissions that are based on a 
PMTA that FDA has previously reviewed. Applicants that have received a 
marketing order are able to submit a supplemental PMTA to seek 
marketing authorization for a new tobacco product that results from a 
modification or modifications to the original tobacco product that 
received the marketing order. FDA is restricting the use of 
supplemental PMTAs to only changes that require the submission of 
limited information or revisions to ensure that FDA is able to 
efficiently review the application. An applicant is also be able to 
submit a supplemental PMTA for modifications made to comply with a 
product standard issued under section 907 of the FD&C Act where FDA 
specifies that the submission of supplemental PMTAs would be 
appropriate.
    Section Sec.  1114.17 describes resubmissions, which are an 
alternative format for submitting an application that meets the 
requirements of Sec.  1114.7(b) or Sec.  1114.15 to seek a marketing 
order for a tobacco product by responding to the deficiencies outlined 
in a marketing denial order. An applicant may submit a resubmission for 
the same tobacco product that received a marketing denial order or for 
a different new tobacco product that results from changes necessary to 
address the deficiencies outlined in a marketing denial order. This 
application format allows an applicant to address the deficiencies 
described in a marketing denial order without having to submit a 
standard PMTA. The resubmission format is not available for PMTAs that 
FDA refused to accept, refused to file, cancelled, or administratively 
closed, or that the

[[Page 55402]]

applicant withdrew because FDA has not previously completed reviews of 
such applications upon which it can rely, and such applications may 
need significant changes to be successfully resubmitted.
    Section Sec.  1114.41 requires applicants that receive a marketing 
order to submit postmarket reports. FDA requires such reports as 
necessary to determine or facilitate a determination of whether there 
may be grounds to withdraw or temporarily suspend a marketing order. 
Section Sec.  1114.41 describes the reports that FDA would require 
through this regulation; however, FDA may require additional reporting 
in an individual applicant's marketing order. Applicants would be 
required under Sec.  1114.41 to submit two types of reports after 
receiving a marketing order: periodic reports and adverse experience 
reports.
    Applicants need to submit periodic reports within 60 calendar days 
of the reporting date specified in the marketing order. FDA requires 
the submission of these reports on an annual basis, but FDA may require 
in a specific order that reports be made more or less frequently 
depending upon a number of factors. Applicants are also required to 
report all serious and unexpected adverse experiences associated with 
the tobacco product that have been reported to the applicant or of 
which the applicant is aware under section Sec.  1114.41(a)(2). The 
serious and unexpected adverse experience reports must be submitted to 
CTP's Office of Science through the HHS Safety Reporting Portal within 
15 calendar days after receiving or becoming aware of a serious and 
unexpected adverse experience.
    Section Sec.  1114.45 requires applicants receiving a marketing 
order to maintain all records necessary to facilitate a determination 
of whether there are or may be grounds to withdraw or temporarily 
suspend the marketing order, including records related to both the 
application and postmarket reports, and ensure that such records remain 
readily available to the Agency upon request. Under section Sec.  
1114.45(a)(1), an applicant must retain all documents submitted to FDA 
as part of an application and postmarket reports. An applicant must 
also retain any additional documentation supporting the application and 
postmarket reports that was not submitted to FDA.
    Section Sec.  1100.200 states that subpart C of part 1100 
establishes requirements for the maintenance of records by tobacco 
product manufacturers who introduce a Pre-Existing Tobacco Product, or 
deliver it for introduction, into interstate commerce
    Section Sec.  1107.3 describes that each applicant who submits an 
abbreviated report under section 905(j)(1)(A)(ii) of the FD&C Act and 
receives a letter acknowledging the receipt of an abbreviated report 
from FDA must maintain all records to support a determination that 
their exemption request meets the requirements of section 
905(j)(3)(A)(i) of the FD&C Act that the modification to a product 
additive described in the exemption request was a minor modification 
made to a tobacco product that can be sold under the FD&C Act.
    Section Sec.  1114.49 requires an applicant to submit a PMTA and 
all supporting and related documents to FDA in electronic format. Under 
section Sec.  1114.49(c), an applicant that has a waiver would submit a 
paper submission to the address that FDA provides in the letter 
granting the waiver. FDA's section Sec.  1114.49 is based on FDA's 
general experience with electronic submissions, which FDA has found 
help facilitate premarket reviews because electronic submissions 
typically enable FDA to receive, access, search, and review a 
submission more quickly than a submission submitted on paper through 
postal mail.
    FDA estimates the burden of this collection of information as 
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                              Activity                                  Number of      responses per     Total annual    Average burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
PMTA Submission (ENDS).............................................             200             3.75              750            1,713    1,284,750 \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ This total will not be added to the total burden for this rule as its currently approved under a separate OMB control number 0910-0768.


                                 Table 2--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                  Number of
    21 CFR part; activity         Number of     responses per   Total annual     Average burden     Total hours
                                 respondents     respondent       responses       per response
----------------------------------------------------------------------------------------------------------------
1114.5--Submission of                       1               1               1              1,713           1,713
 Standard Bundled PMTAs \2\..
1114.7--Premarket Tobacco                  24               1              24  0.75 (45 minutes)              18
 Product Application (PMTA)
 Submission (Form FDA 4057)..
Premarket FDA Tobacco Product              24              14             336  0.16 (10 minutes)              54
 Application Amendment and
 General Correspondence
 Submission (Form FDA 4057a).
Premarket Tobacco Product                  24               1              24  0.75 (45 minutes)              18
 Unique Identifying
 Information for New Tobacco
 Products Submission (Form
 FDA 4057b)..................
1114.41--Reporting                          3               1               3                 50             150
 Requirements (periodic
 reports)....................
1114.9--Amendments...........              24               2              48                188           9,024
1114.13--Change in Ownership.               1               1               1                  1               1
1114.15--Supplemental                       2               1               2                428             856
 applications................
1114.17--Resubmissions.......               3               1               3                565           1,695
1114.41(a)(2)--Adverse                      3               6              18   0.6 (36 minutes)              11
 Experience Reports..........
1114.49(b) and (c)--Waiver                  1               1               1  0.25 (15 minutes)            0.25
 from Electronic Submission..
                              ----------------------------------------------------------------------------------

[[Page 55403]]

 
    Total....................  ..............  ..............  ..............  .................          13,540
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ FDA anticipates that applicants will submit bundled PMTAs, which are single submissions containing PMTAs for
  a number of similar or related products. We estimate that a bundle will contain on average (between 6 and 11)
  with most submitting 9 distinct products.

    FDA has based these estimates on the full analysis of economic 
impacts and experience with current PMTA submissions. Table 1 describes 
the current estimates for OMB control number 0910-0768 which covers the 
burden for ENDS products PMTA submissions. These estimates were 
originally published in the deeming final rule and recently in the 
Federal Register of April 22, 2019 (84 FR 16673). FDA estimates that it 
will take each respondent approximately 1,500 hours to prepare a PMTA 
seeking an order from FDA allowing the marketing of a new tobacco 
product. FDA also estimates that it would on average take an additional 
213 hours to prepare an EA in accordance with the requirements of Sec.  
25.40, for a total of 1,713 hours per PMTA application.
    Table 1 describes the estimated annual reporting burden per the 
requirements that the rule would create beyond what is covered in the 
existing information collection. For this analysis, FDA assumes that 
firms will submit all applications as PMTA bundles. We also considered 
updated data on market consolidation that has occurred since the 
deeming final rule was published. For originally regulated products we 
expect to receive one full PMTA submission for a total of 1,713 hours.
    FDA conducted a thorough analysis of the current paperwork burden 
associated with the PMTA program and other similar forms and applied 
the most accurate burden to the forms; however, upon further review and 
certain updates made to the form based on comments received and product 
categorization changes, FDA has revised the burden associated with 
entering the data into the form (which includes searching existing data 
sources and gathering and maintaining the data needed) to be 45 minutes 
per individual product (rather than 30 minutes per product) on Form FDA 
4057. For Form FDA 4057a, FDA has revised the burden for this form to 
10 minutes (from 5 minutes). This form serves several purposes from 
changing a point of contact (minimal burden) to providing additional 
substantive information for the purpose of the review of the PMTA 
application (more burdensome).
    FDA developed Form FDA 4057 for use when submitting PMTA single and 
bundled submissions. FDA estimates that 24 respondents will submit PMTA 
bundles using this form at 0.75 (45 minutes) per response. The number 
24 is accounting for the bundles of ENDS products and the 1 bundle we 
expect to receive yearly for originally regulated products. (200 + 1 = 
201/8.5 products on average in a bundle) for a total of 12 hours.
    FDA developed Form FDA 4057a for use when firms are submitting 
amendments and other general correspondence. Our estimate is 0.16 (10 
minutes) per response to fill out this form. We estimate there will be 
at least one amendment per application for a total of 28 hours. With 
most applications being submitted toward the end of our 3-year range, 
we expect fewer amendments during this period. However, FDA expects 
correspondence from earlier applications to be submitted during this 
period.
    FDA developed an additional form (Form FDA 4057b) that will assist 
industry and FDA in identifying the products that are the subject of a 
submission where an applicant groups multiple PMTAs into a single 
submission (referred to as a bundled submission or a grouped 
submission). FDA has previously stated that one approach to submitting 
PMTAs could be to group applications for products that are both from 
the same manufacturer or domestic importer and in the same product 
category and subcategory into a single submission. FDA discussed 
bundled submissions in the proposed rule (84 FR 50566 at 50578) and 
noted that FDA intends to consider information on each tobacco product 
as a separate, individual PMTA. The form will assist applicants in 
providing the unique identifying information for each product in a 
grouped submission of PMTAs that are required Sec.  1114.7(c)(3)(iii). 
By having the identifying information for products contained in a 
submission be more clearly organized, FDA will be able to more 
efficiently process and review the applications contained in a grouped 
submission.
    Based on the Form FDA 4057 for use when submitting PMTA single and 
bundled submissions, a respondent would utilize Form FDA 4057b once for 
each submission containing more than one PMTA. We assume the submitter 
could include from 2 to 2,000 products in each Form FDA 4057b. Entering 
data for up to 2,000 rows can take approximately 4 hours on average per 
Form FDA 4057b for manual data entry. However, FDA's original estimate 
that Form 4057b would estimate 4 hours per response was a high-end 
estimate and not an average. We now reflect the average time of 45 
minutes per response based on the assumption that we expect to receive 
an average of nine bundled products per submission. Assuming 45 minutes 
per Form FDA 4057b for 24 applications, we estimate a total burden of 
18 hours for this activity.
    FDA estimates under Sec.  1114.41 that three respondents will 
submit a periodic report. This number is based on the average number of 
periodic report submissions expected between 2020-2022. The RIA 
estimates that periodic reports will take between 20 and 80 hours per 
submission. For this estimate, we use the average of 50 per response 
for a total of 150 hours.
    Under Sec.  1114.9 firms will prepare amendments to PMTA bundles in 
response to deficiency letters. These amendments contain additional 
information that we need to complete substantive review. In the RIA we 
state in our limited history reviewing PMTAs, we on average issue two 
deficiency letters. Based on this, we would anticipate two responses 
back per bundle. Therefore, we estimate that 24 respondents will submit 
48 amendments (24 x 2). Assuming 1,500 hours as the time to prepare and 
submit a full PMTA and amendments may on average take 10 percent to 15 
percent of that time (150-225). We averaged this time out (12.5 percent 
of a full submission preparation time) and arrived at 188 hours per 
response. FDA estimates the total burden hours for preparing amendments 
is 9,024 hours.

[[Page 55404]]

    Section Sec.  1114.13 would allow an applicant to transfer 
ownership of a PMTA to a new owner. FDA believes this will be 
infrequent, so we have assigned 1 token hour acknowledging the 
requirement.
    Section Sec.  1114.15 is an alternative format of submitting a PMTA 
that meets the requirements of Sec.  1114.7 that would reduce the 
burden associated with the submission and review of an application. Our 
estimated number of 2 respondents is based on the number estimated for 
postmarket reports, which is 3 bundles (which is approximately 26 
products). Not all applicants will resubmit modifications to previously 
authorized products, so we estimate 2 bundles (which is approximately 
17 products). FDA estimates further that a supplemental PMTA will take 
25 percent of the time it takes to do an original submission (including 
EA hours) for 428 hours per response. We estimate a total of 856 burden 
hours for this activity.
    Under Sec.  1114.17 an applicant may submit a resubmission for the 
same tobacco product that received a marketing denial order or for a 
different new tobacco product that results from changes necessary to 
address the deficiencies outlined in a marketing denial order. Based on 
the preliminary RIA, we are estimating that out of all bundles received 
in 2020, 2021, and 2022, that an average of three bundles are 
authorized. If we receive 24 bundles yearly, and based on historical 
data, 58 percent fail at acceptance (down to 8 bundles remaining), 17 
percent fail at filing (down to 7 bundles remaining), and 25 percent 
receive marketing orders (5 left). We estimate that 50 percent will try 
to resubmit in a year. Thus, this number of respondents is three 
(rounded up). FDA estimates that a resubmission will take 33 percent of 
the time it takes to complete an original submission (including EA 
hours) at 565 hours per response for a total of 1,695 hours.
    Under Sec.  1114.41(a)(2), firms would also submit adverse 
experience reports for tobacco products with marketing orders. We 
assume the same number of firms submitting periodic reports will submit 
adverse experience reports. Currently, firms may voluntarily submit 
adverse experience reports using Form FDA 3800 under OMB control number 
0910-0645. We have based our estimates on this information collection 
which estimates that it takes 1 hour (for mandatory reporting) to 
complete this form for tobacco products for a total of 18 hours.
    Section Sec.  1114.49 would require an applicant to submit a PMTA 
and all supporting and related documents to FDA in electronic format 
that FDA can process, review, and archive unless an applicant requests, 
and FDA grants, a waiver from this requirement. FDA does not believe we 
will receive many waivers, so we have assigned one respondent to 
acknowledge the option to submit a waiver. Consistent with our other 
application estimates for waivers, we believe it would take .25 hours 
(15 minutes) per waiver for a total of .25 hours.

                               Table 3--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
      21 CFR part; activity          Number of      records per    Total annual         per         Total hours
                                   recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
1114.45--PMTA Records...........              24               1              24               2              48
1100.204--Pre-Existing Tobacco                 1               1               1               2               2
 Product Records................
1107.3--Exemptions from                        1               1               1               2               2
 Substantial Equivalence Records
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............              52
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Table 3 describes the annual recordkeeping burden per the 
requirements in this rule. FDA estimates that 26 recordkeepers will 
maintain records at 2 hours per record. Additionally, the rule requires 
that firms establish and maintain records related to SE Exemption 
Requests and Pre-Existing Tobacco Products. We expect the burden hours 
of this rule to be negligible for SE Exemption Requests. Firms would 
have already established the required records when submitting the SE 
Exemption Request. Similarly, we expect the hours of this rule to be 
negligible for any Pre-Existing Tobacco Products that have already 
submitted Standalone Pre-Existing Tobacco Product Submissions, because 
firms would have established the required records when submitting the 
Standalone Pre-Existing Tobacco Product Submissions. We believe this 
time is usual and customary for these firms. We estimate that it would 
take 2 hours per record to establish the required records for a total 
of 4 hours. Therefore, the total recordkeeping burden hours is 
estimated to be 52 hours.
    The total burden for these new collections of information in this 
rulemaking is 13,540 reporting hours and 52 recordkeeping hours for a 
total of 13,592 hours.
    The information collection provisions in this final rule have been 
submitted to OMB for review as required by section 3507(d) of the 
Paperwork Reduction Act of 1995.
    Before the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

XIII. Federalism: Executive Order 13132

    We have analyzed this rule in accordance with the principles set 
forth in Executive Order 13132. Section 4(a) of the Executive Order 
requires Agencies to ``construe . . . a Federal statute to preempt 
State law only where the statute contains an express preemption 
provision or there is some other clear evidence that the Congress 
intended preemption of State law, or where the exercise of State 
authority conflicts with the exercise of Federal authority under the 
Federal statute.''
    Section 916(a)(2) of the FD&C Act is an express preemption 
provision. Section 916(a)(2) provides that ``no State or political 
subdivision of a State may establish or continue in effect with respect 
to a tobacco product any requirement which is different from, or in 
addition to, any requirement under the provisions of this chapter 
relating to . . . premarket review.'' Thus, the final

[[Page 55405]]

rule creates requirements that fall within the scope of section 
916(a)(2) of the FD&C Act.

XIV. Congressional Review Act

    Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.), 
the Office of Information and Regulatory Affairs designated this rule 
as not a ``major rule,'' as defined by 5 U.S.C. 804(2).

XV. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects on one or 
more Indian Tribes, on the relationship between the Federal Government 
and Indian Tribes, or on the distribution of power and responsibilities 
between the Federal Government and Indian Tribes. Accordingly, we 
conclude that the rule does not contain policies that have tribal 
implications as defined in the Executive Order and, consequently, a 
tribal summary impact statement is not required.

XVI. Analysis of Environmental Impact

    The Agency has determined under Sec.  25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. No extraordinary circumstances exist 
to indicate that the specific proposed action may significantly affect 
the quality of the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

XVII. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). 
This final rule is a significant regulatory action as defined by 
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. We expect that the final rule will generate net benefits or 
negligible net costs for most affected small entities. Therefore, we 
certify that the final rule will not have a significant economic impact 
on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $158 million, using the most current (2020) Implicit 
Price Deflator for the Gross Domestic Product. This final rule will not 
result in an expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    The final rule will require manufacturers of Pre-Existing Tobacco 
Products and manufacturers of products that are exempt from the 
requirements of demonstrating SE to maintain records to demonstrate 
that they can legally market their products. For products that receive 
a PMTA marketing granted order, the final rule will require certain 
postmarket reporting, including periodic reporting and adverse 
experience reporting. The final rule will also implement and set forth 
requirements for the content and format of PMTAs and the general 
procedures we intend to follow in reviewing and communicating with 
applicants.
    The final rule will make the review of PMTAs more efficient. As a 
result, the final rule will create cost savings for FDA related to the 
review of some PMTAs. The final rule will also create cost savings for 
FDA and for PMTA applicants by reducing the number of PMTAs submitted. 
In table 4, we present the annualized benefits of the final rule. We 
estimate that annualized benefits over 20 years will equal $2.04 
million at a 7 percent discount rate, with a low estimate of $1.36 
million and a high estimate of $2.85 million. We estimate that 
annualized benefits over 20 years will equal $2.08 million at a 3 
percent discount rate, with a low estimate of $1.43 million and a high 
estimate of $2.84 million.
    This is the first regulation to address the costs of PMTA 
requirements for new, originally regulated tobacco products. While we 
already included the costs to submit and review PMTAs for deemed 
tobacco products in the final RIA for the deeming final rule, no RIA 
includes the costs to submit and review PMTAs for originally regulated 
tobacco products. Therefore, we include the costs to prepare and review 
PMTAs for these tobacco products in this analysis.
    The final rule will increase the cost for applicants to prepare a 
PMTA. As a result, the final rule will generate incremental costs 
related to the preparation of PMTAs for ENDS products. Firms will incur 
costs to maintain and submit postmarket reports and we will incur costs 
to review these reports. Finally, firms will incur costs to read and 
understand the rule and costs to maintain records for some Pre-Existing 
Tobacco Products. In table 4, we present the annualized costs of the 
final rule. We estimate that annualized costs over 20 years will equal 
$4.73 million at a 7 percent discount rate, with a low estimate of 
$2.63 million and a high estimate of $7.45 million. We estimate that 
annualized costs over 20 years will equal $4.86 million at a 3 percent 
discount rate, with a low estimate of $2.50 million and a high estimate 
of $7.95 million.

                                    Table 4--Summary of Benefits, Costs, and Distributional Effects of the Final Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                   Units
                                                                                   ------------------------------------
                   Category                       Primary       Low        High                               Period                  Notes
                                                 estimate    estimate    estimate      Year      Discount     covered
                                                                                      dollars     rate  %     (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized ($m/year)............       $2.04       $1.36       $2.85        2019           7          20  All quantified benefits are cost
                                                      2.08        1.43        2.84        2019           3          20   savings.

[[Page 55406]]

 
    Annualized Quantified.....................
                                               ---------------------------------------------------------------------------------------------------------
    Qualitative...............................  Benefits from postmarket surveillance.
-----------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized ($m/year)............        4.73        2.63        7.45        2019           7          20
                                                      4.86        2.50        7.95        2019           3          20
    Annualized Quantified.....................
    Qualitative...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
 
    Federal Annualized Monetized ($m/year)....  From:
                                                To:
                                               ---------------------------------------------------------------------------------------------------------
    Other Annualized Monetized ($m/year)......  From: Currently marketed tobacco
                                                products.
                                                To: New tobacco products with PMTA
                                                marketing orders.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local, or Tribal Government: None............................................................................................................
    Small Business: None................................................................................................................................
    Wages: None.........................................................................................................................................
    Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

XVIII. Effective Date

    This rule will become effective 30 days after it publishes in the 
Federal Register.
    (Comment 146) One comment stated that FDA must not apply any 
requirements from the final rule retroactively to applications that 
have already been submitted because doing so would be fundamentally 
unfair. The comment further stated, for instance, that FDA should not 
discount the results of a study on the basis that it does not contain 
the newly required statements or documentation regarding financial 
conflicts of interest.
    (Response 146) FDA agrees with this comment insofar as it applies 
to the acceptance and filing criteria. FDA does not intend to 
retroactively apply any new acceptance and filing criteria added by 
Sec.  1114.27 to applications that have been submitted before the final 
rule is effective. If an applicant has submitted an application before 
this rule is effective, FDA will not refuse to accept or refuse to file 
the PMTA unless the FD&C Act or other existing regulations require 
information that the application is missing. It is important to note 
that while FDA will not apply acceptance and filing criteria required 
by this rule retroactively, the information required for acceptance and 
filing under this rule remains important to FDA's substantive review of 
an application. The comment's example of information regarding 
financial conflicts of interest is particularly relevant because 
determining the reliability of a study's results is an important part 
of FDA's substantive review of an application, regardless of whether 
it's applied as a filing criteria. Other provisions in this rule, such 
as those regarding application amendments, temporary suspension and 
withdrawal, postmarket changes, postmarket reporting, and 
recordkeeping, will take effect for all PMTAs, as applicable, once the 
rule is effective. In addition, all the requirements in section 910 of 
FD&C Act are in effect.

XIX. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff and are available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they also are available electronically at https://www.regulations.gov. 
References without asterisks are not on public display at https://www.regulations.gov because they have copyright restriction. Some may 
be available at the website address, if listed. References without 
asterisks are available for viewing only at the Dockets Management 
Staff, Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852, 240-402-7500. FDA has verified the website 
addresses, as of the date this document publishes in the Federal 
Register, but websites are subject to change over time.
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6. NCI, ``A Socioecological Approach to Addressing Tobacco-Related 
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Report of the Surgeon General, 2012. Available at: https://www.hhs.gov/surgeongeneral/reports-and-publications/tobacco/index.html.
10. *Form FDA 4057.
11. *Form FDA 4057b.
12. ``4 Marketing Tactics E-Cigarette Companies Use to Target 
Youth,'' Truth Initiative, August 2018, available at: https://truthinitiative.org/research-resources/tobacco-industry-marketing/4-marketing-tactics-e-cigarette-companies-use-target.
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the Extraordinary Growth and Marketing of JUUL transformed the US 
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Advertising Over Its First Three Years on the Market,'' Stanford 
Research into the Impact of Tobacco Advertising White Paper, 2019. 
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Health and Public Health Practice; Institute of Medicine; Bonnie 
R.J., K. Stratton, L.Y. Kwan, editors. ``Public Health Implications 
of Raising the Minimum Age of Legal Access to Tobacco Products.'' 
Washington (DC): National Academies Press (US); July 23, 2015. 
Available at: https://www.ncbi.nlm.nih.gov/books/NBK310412/.
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Retail Licensing and Youth Product Use,'' Pediatrics, 
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25. Weiss, J., S. Cen, D. Shuster, et al., ``Longitudinal Effects of 
Pro-Tobacco and Anti-Tobacco Messages on Adolescent Smoking 
Susceptibility,'' Nicotine and Tobacco Research, 8(3), 455-465, 
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and Promotion in Smoking Initiation,'' National Cancer Institute, 
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List of Subjects

21 CFR Part 1100

    Administrative practice and procedure, Smoke, Smoking, Tobacco, 
Tobacco products.

21 CFR Part 1107

    Administrative practice and procedure, Smoke, Smoking, Tobacco, 
Tobacco products.

21 CFR Part 1114

    Administrative practice and procedure, Smoke, Smoking, Tobacco, 
Tobacco products.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, 
chapter I of title 21 of the Code of Federal Regulations will be 
amended as follows:

PART 1100--GENERAL

0
1. The authority citation for part 1100 is revised to read as follows:

    Authority: 21 U.S.C. 371, 374, 387a(b), 387e, and 387i; Pub. L. 
111-31.

0
2. Revise the part heading to read as set forth above.

Subpart A--Tobacco Products Subject to FDA Authority

0
3. Add subpart A consisting of Sec. Sec.  1100.1, 1100.2, 1100.3, and 
1100.5 to read as set forth above:

Subpart B [Reserved]

0
4. Add and reserve subpart B.

0
5. Add subpart C, consisting of Sec. Sec.  1100.200, 1100.202, and 
1100.204, to read as follows:
Subpart C--Maintenance of Records Demonstrating That a Tobacco Product 
Was Commercially Marketed in the United States as of February 15, 2007
Sec.
1100.200 Purpose and scope.
1100.202 Definitions.
1100.204 Recordkeeping requirements.

Subpart C--Maintenance of Records Demonstrating That a Tobacco 
Product Was Commercially Marketed in the United States as of 
February 15, 2007.


Sec.  1100.200  Purpose and scope.

    This subpart sets out requirements under the Federal Food, Drug, 
and Cosmetic Act for the maintenance of records by tobacco product 
manufacturers that introduce a Pre-Existing Tobacco Product, or deliver 
it for introduction, into interstate commerce.


Sec.  1100.202  Definitions.

    For the purposes of this subpart:
    Commercially marketed means selling or offering for sale a tobacco 
product in the United States to consumers or to any person for the 
eventual purchase by consumers in the United States.
    Pre-Existing Tobacco Product means a tobacco product (including 
those products in test markets) that was commercially marketed in the 
United States as of February 15, 2007. A Pre-Existing Tobacco Product 
is not subject to the premarket requirements of section 910 of the 
Federal Food, Drug, and Cosmetic Act.
    Tobacco product means any product made or derived from tobacco that 
is intended for human consumption, including any component, part, or 
accessory of a tobacco product (except for raw materials other than 
tobacco used in manufacturing a component, part, or accessory of a 
tobacco product). The term ``tobacco product'' does not mean an article 
that under the Federal Food, Drug, and Cosmetic Act is a drug (section 
201(g)(1)), a device (section 201(h)), or a combination product 
(section 503(g)).
    Tobacco product manufacturer means any person, including any 
repacker or relabeler, who--
    (1) Manufactures, fabricates, assembles, processes, or labels a 
tobacco product; or
    (2) Imports a finished tobacco product for sale or distribution in 
the United States.


Sec.  1100.204  Recordkeeping requirements.

    (i) Any tobacco product manufacturer that introduces a Pre-Existing 
Tobacco Product, or delivers it for introduction, into interstate 
commerce must maintain records that demonstrate that the tobacco 
product was commercially marketed in the United States as of February 
15, 2007, as described in this subpart. These records may include items 
such as:

[[Page 55412]]

    (A) Dated copies of advertisements;
    (B) Dated catalog pages;
    (C) Dated promotional material;
    (D) Dated trade publications;
    (E) Dated bills of lading;
    (F) Dated freight bills;
    (G) Dated waybills;
    (H) Dated invoices;
    (I) Dated purchase orders;
    (J) Dated customer receipts;
    (K) Dated manufacturing documents;
    (L) Dated distributor or retailer inventory lists; or
    (M) Any other dated document that demonstrates that the tobacco 
product was commercially marketed in the United States as of February 
15, 2007.
    (ii) All records must be legible, in the English language, and 
available for inspection and copying by officers or employees duly 
designated by the Secretary. Documents that have been translated from 
another language into English (e.g., advertisements written in a 
language other than English) must be accompanied by the original 
language version of the document, a signed statement by an authorized 
representative of the manufacturer certifying that the English language 
translation is complete and accurate, and a brief statement of the 
qualifications of the person that made the translation.
    (iii) All records required by this subpart must be retained for a 
period of not less than 4 years after the date either FDA makes a 
determination that the product is a Pre-Existing Tobacco Product, or 
the tobacco product manufacturer permanently ceases the introduction or 
delivery for introduction into interstate commerce of the tobacco 
product, whichever occurs sooner.

PART 1107--EXEMPTION REQUESTS AND SUBSTANTIAL EQUIVALENCE REPORTS

0
6. The authority citation for part 1107 is revised to read as follows:

    Authority:  21 U.S.C. 371, 374, 387e(j), 387i, 387j.

0
7. Revise the part heading as set forth above.

0
8. Add Sec.  1107.3 to subpart A to read as follows:


Sec.  1107.3  Recordkeeping.

    (a) Definition. The term ``Pre-Existing Tobacco Product'' means a 
tobacco product (including those products in test markets) that was 
commercially marketed in the United States as of February 15, 2007. A 
Pre-Existing Tobacco Product is not subject to the premarket 
requirements of section 910 of the Federal Food, Drug, and Cosmetic 
Act.
    (b) Record maintenance. (1) Each applicant who submits an 
abbreviated report under section 905(j)(1)(A)(ii) of the Federal Food, 
Drug, and Cosmetic Act and receives a letter acknowledging the receipt 
of an abbreviated report from FDA must maintain all records (including 
those created by third parties on the applicant's behalf) that support 
the submission. Such records may include, but are not limited to:
    (i) A copy of the abbreviated report and, if applicable, the 
exemption request and all amendments thereto.
    (ii) A copy of the acknowledgement letter issued in response to an 
abbreviated report and, if applicable, the exemption order issued by 
FDA.
    (iii) Documents related to formulation of product, design 
specifications, packaging, and related items.
    (iv) Documents showing design specifications are consistently met.
    (v) Documents related to product packing and storage conditions.
    (vi) Analytical test method records, including:
    (A) Performance criteria.
    (B) Validation or verification documentation; and
    (C) Reports/results from these test methods.
    (vii) Source data and related summaries.
    (2) An applicant that submits an abbreviated report for a 
modification to a Pre-Existing Tobacco Product must also maintain 
records demonstrating that the Pre-Existing Tobacco Product was 
commercially marketed in the United States as of February 15, 2007, 
such as the records described in Sec.  1100.204 of this chapter.
    (3) An applicant that submits an abbreviated report for a 
modification to a tobacco product that previously received premarket 
authorization (i.e., an exemption (and for which the applicant has 
submitted an abbreviated report under section 905(j)(1)(A)(ii) of the 
Federal Food, Drug, and Cosmetic Act, a substantially equivalent order 
under section 910(a), or a marketing granted order under section 
910(c)) must maintain a copy of the exemption order, substantially 
equivalent order, or marketing granted order.
    (4) An applicant that submits an abbreviated report for a 
modification to a tobacco product that is the subject of a pending SE 
report and is marketed pursuant to section 910(a)(2)(B) of the Federal 
Food, Drug, and Cosmetic Act must maintain all communications to and 
from FDA relating to the pending SE Report (e.g., acknowledgement 
letter, deficiency letters), including the SE Report.
    (c) Record quality. All records must be legible, in the English 
language, and available for inspection and copying by officers or 
employees duly designated by the Secretary. Documents that have been 
translated from another language into English (e.g., advertisements 
written in a language other than English) must be accompanied by the 
original language version of the document, a signed statement by an 
authorized representative of the manufacturer certifying that the 
English language translation is complete and accurate, and a brief 
statement of the qualifications of the person that made the 
translation.
    (d) Record retention. All records required by this subpart must be 
retained for a period of 4 years from the date that an acknowledgement 
letter is issued by FDA.

0
9. Add part 1114 to subchapter K to read as follows:

PART 1114--PREMARKET TOBACCO PRODUCT APPLICATIONS

Subpart A--General Provisions
Sec.
1114.1 Scope.
1114.3 Definitions.
Subpart B--Premarket Tobacco Product Applications
1114.5 Application submission.
1114.7 Required content and format.
1114.9 Amendments.
1114.11 Withdrawal by applicant.
1114.13 Change in ownership of an application.
1114.15 Supplemental applications.
1114.17 Resubmissions.
Subpart C--FDA Review
1114.25 Communication between FDA and applicants.
1114.27 Review procedure.
1114.29 FDA action on an application.
1114.31 Issuance of a marketing granted order.
1114.33 Issuance of a marketing denial order.
1114.35 Withdrawal of a marketing granted order.
1114.37 Temporary suspension of a marketing granted order.
Subpart D--Postmarket Requirements
1114.39 Postmarket changes.
1114.41 Reporting requirements.
Subpart E--Miscellaneous
1114.45 Record retention.
1114.47 Confidentiality.
1114.49 Electronic submission.

    Authority:  21 U.S.C. 371, 374, 387a, 387i, and 387j.

[[Page 55413]]

Subpart A--General Provisions


Sec.  1114.1  Scope.

    (a) This part sets forth the procedures and requirements for 
submitting a premarket tobacco product application (PMTA), the general 
procedures FDA will follow when evaluating a PMTA, and postmarket 
reporting requirements.
    (b) This part does not apply to modified risk tobacco product 
applications, except that single applications seeking both a marketing 
granted order under section 910(c) of the Federal Food, Drug, and 
Cosmetic Act and an order under section 911(g) of the Federal Food, 
Drug, and Cosmetic Act must satisfy the requirements of this part in 
addition to the requirements of section 911 of the Federal Food, Drug, 
and Cosmetic Act.
    (c) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21, unless otherwise 
noted.
    (d) This part does not apply to ``premium'' cigars as defined in 
Sec.  1114.3.


Sec.  1114.3  Definitions.

    For purposes of this part:
    Accessory means any product that is intended or reasonably expected 
to be used with or for the human consumption of a tobacco product; does 
not contain tobacco and is not made or derived from tobacco; and meets 
either of the following:
    (1) Is not intended or reasonably expected to affect or alter the 
performance, composition, constituents, or characteristics of a tobacco 
product; or
    (2) Is intended or reasonably expected to affect or maintain the 
performance, composition, constituents, or characteristics of a tobacco 
product, but:
    (i) Solely controls moisture and/or temperature of a stored tobacco 
product; or
    (ii) Solely provides an external heat source to initiate but not 
maintain combustion of a tobacco product.
    Additive means any substance the intended use of which results or 
may reasonably be expected to result, directly or indirectly, in its 
becoming a component or otherwise affecting the characteristic of any 
tobacco product (including any substances intended for use as a 
flavoring or coloring or in producing, manufacturing, packing, 
processing, preparing, treating, packaging, transporting, or holding), 
except that such term does not include tobacco, or a pesticide chemical 
residue in or on raw tobacco or a pesticide chemical.
    Adverse experience means any unfavorable physical or psychological 
effect in a person that is temporally associated with the use of or 
exposure to a tobacco product, whether or not the person uses the 
tobacco product, and whether or not the effect is considered to be 
related to the use of or exposure to the tobacco product.
    Applicant means any person that submits a premarket tobacco product 
application to receive a marketing granted order for a new tobacco 
product.
    Brand means a variety of tobacco product distinguished by the 
tobacco used, tar content, nicotine content, flavoring used, size, 
filtration, packaging, logo, registered trademark, brand name(s), 
identifiable pattern of colors, or any combination of such attributes.
    Characteristics means the materials, ingredients, design, 
composition, heating source, or other features of a tobacco product.
    Commercially marketed means selling or offering for sale a tobacco 
product in the United States to consumers or to any person for the 
eventual purchase by consumers in the United States.
    Component or part means any software or assembly of materials 
intended or reasonably expected:
    (1) To alter or affect the tobacco product's performance, 
composition, constituents, or characteristics; or
    (2) To be used with or for the human consumption of a tobacco 
product. Component or part excludes anything that is an accessory of a 
tobacco product.
    Composition means the materials in a tobacco product, including 
ingredients, additives, and biological organisms. The term includes the 
manner in which the materials, for example, ingredients, additives, and 
biological organisms, are arranged and integrated to produce a tobacco 
product.
    Constituent means any chemical or chemical compound in a tobacco 
product that is or potentially is inhaled, ingested, or absorbed into 
the body, any chemical or chemical compound in an emission (e.g., 
smoke, aerosol, droplets) from a tobacco product, that either transfers 
from any component or part of the tobacco product to the emission or 
that is formed by the product, including through combustion or heating 
of tobacco, additives, or other components of the tobacco product.
    Container closure system means any packaging materials that are a 
component or part of a tobacco product.
    Design means the form and structure concerning, and the manner in 
which components or parts, ingredients, software, and materials are 
integrated to produce a tobacco product.
    Finished tobacco product means a tobacco product, including all 
components and parts, sealed in final packaging (e.g., filters or 
filter tubes sold to consumers separately or as part of kits, or e-
liquids sealed in final packaging sold to consumers either separately 
or as part of kits) or in the final form in which it is intended to be 
sold to consumers.
    Harmful or potentially harmful constituent or HPHC means any 
chemical or chemical compound in a tobacco product or tobacco smoke or 
emission that:
    (1) Is or potentially is inhaled, ingested, or absorbed into the 
body, including as an aerosol or any other emission; and
    (2) Causes or has the potential to cause direct or indirect harm to 
users or nonusers of tobacco products.
    Heating source means the source of energy used to burn or heat the 
tobacco product.
    Ingredient means tobacco, substances, compounds, or additives 
contained within or added to the tobacco, paper, filter, or any other 
component or part of a tobacco product, including substances and 
compounds reasonably expected to be formed through a chemical reaction 
during tobacco product manufacturing.
    Label means a display of written, printed, or graphic matter upon 
the immediate container of any article.
    Labeling means all labels and other written, printed, or graphic 
matter upon any article or any of its containers or wrappers, or 
accompanying such article.
    Line data means an analyzable dataset of observations for each 
individual study participant, laboratory animal, or test replicate.
    Marketing denial order means the order described in section 
910(c)(1)(A)(ii) of the Federal Food, Drug, and Cosmetic Act stating 
that the product may not be introduced or delivered for introduction 
into interstate commerce.
    Marketing granted order means the order described in section 
910(c)(1)(A)(i) of the Federal Food, Drug, and Cosmetic Act stating 
that the new tobacco product may be introduced or delivered for 
introduction into interstate commerce.
    Material means an assembly of ingredients. Materials are assembled 
to form a tobacco product or components or parts of a tobacco product.
    New tobacco product means:
    (1) Any tobacco product (including those products in test markets) 
that was not commercially marketed in the United States as of February 
15, 2007; or

[[Page 55414]]

    (2) Any modification (including a change in design, any component, 
any part, or any constituent, including a smoke constituent, or in the 
content, delivery or form of nicotine, or any other additive or 
ingredient) of a tobacco product where the modified product was 
commercially marketed in the United States after February 15, 2007.
    Other features means any distinguishing qualities of a tobacco 
product similar to those specifically enumerated in section 
910(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act. Such other 
features include harmful and potentially harmful constituents and any 
other product characteristics that relate to the chemical, biological, 
and physical properties of the tobacco product.
    Package or packaging means a pack, box, carton, or container of any 
kind or, if no other container, any wrapping (including cellophane), in 
which a tobacco product is offered for sale, sold, or otherwise 
distributed to consumers.
    Premarket tobacco product application or PMTA means the application 
described in section 910(b) of the Federal Food, Drug, and Cosmetic 
Act. This term includes the initial premarket tobacco product 
application and all subsequent amendments.
    ``Premium'' cigar means a type of cigar that:
    (1) Is wrapped in whole tobacco leaf;
    (2) Contains a 100 percent leaf tobacco binder;
    (3) Contains at least 50 percent (of the filler by weight) long 
filler tobacco (i.e., whole tobacco leaves that run the length of the 
cigar);
    (4) Is handmade or hand rolled (i.e., no machinery was used apart 
from simple tools, such as scissors to cut the tobacco prior to 
rolling);
    (5) Has no filter, nontobacco tip, or nontobacco mouthpiece;
    (6) Does not have a characterizing flavor other than tobacco;
    (7) Contains only tobacco, water, and vegetable gum with no other 
ingredients or additives; and
    (8) Weighs more than 6 pounds per 1,000 units.
    Serious adverse experience means an adverse experience that results 
in any of the following outcomes:
    (1) Death;
    (2) A life-threatening condition or illness;
    (3) Inpatient hospitalization or prolongation of existing 
hospitalization;
    (4) A persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions;
    (5) A congenital anomaly/birth defect; or
    (6) Any other adverse experience that, based upon appropriate 
medical judgment, may jeopardize the health of a person and may require 
medical or surgical intervention to prevent one of the other outcomes 
listed in this definition.
    Submission tracking number or STN means the number that FDA assigns 
to submissions that are received from an applicant, such as a PMTA and 
a supplemental PMTA.
    Tobacco product means any product made or derived from tobacco that 
is intended for human consumption, including any component, part, or 
accessory of a tobacco product (except for raw materials other than 
tobacco used in manufacturing a component, part, or accessory of a 
tobacco product). The term ``tobacco product'' does not mean an article 
that under the Federal Food, Drug, and Cosmetic Act is a drug (section 
201(g)(1)), a device (section 201(h)), or a combination product 
(section 503(g)).
    Tobacco product manufacturer means any person, including a repacker 
or relabeler, who:
    (1) Manufactures, fabricates, assembles, processes, or labels a 
tobacco product, or
    (2) Imports a finished tobacco product for sale or distribution in 
the United States.
    Unexpected adverse experience means an adverse experience occurring 
in one or more persons in which the nature, severity, or frequency of 
the experience is not consistent with:
    (1) The known or foreseeable risks of adverse experiences 
associated with the use or exposure to the tobacco product as described 
in the PMTA and other relevant sources of information, such as the 
product labeling and postmarket reports;
    (2) The expected natural progression of any underlying disease, 
disorder, or condition of the persons(s) experiencing the adverse 
experience and the person's predisposing risk factor profile for the 
adverse experience; or
    (3) The results of nonclinical investigations.
    Vulnerable populations means groups that are susceptible to tobacco 
product risk and harm due to disproportionate rates of tobacco product 
initiation, use, burden of tobacco-related diseases, or decreased 
cessation. Vulnerable populations can include, but are not limited to, 
youth and young adults, those with lower socioeconomic status, certain 
races or ethnicities, sexual or gender minorities, underserved rural 
populations, those pregnant or trying to become pregnant, those in the 
military or veterans, and those with mental health conditions or 
substance use disorders.

Subpart B--Premarket Tobacco Product Applications


Sec.  1114.5  Application submission.

    An applicant may submit a PMTA to demonstrate that a new tobacco 
product meets the requirements to receive a marketing granted order. A 
new tobacco product may not be introduced or delivered for introduction 
into interstate commerce under this part until FDA has issued a 
marketing granted order for the product.


Sec.  1114.7  Required content and format.

    (a) General. The PMTA must contain sufficient information for FDA 
to determine whether any of the grounds for marketing denial order 
specified in section 910(c)(2) of the Federal Food, Drug, and Cosmetic 
Act apply. The application must contain the following sections:
    (1) General information (as described in paragraph (c) of this 
section);
    (2) Descriptive information (as described in paragraph (d) of this 
section);
    (3) Product samples (as described in paragraph (e) of this 
section);
    (4) Labeling and description of marketing plans (as described in 
paragraph (f) of this section);
    (5) Statement of compliance with 21 CFR part 25 (as described in 
paragraph (g) of this section);
    (6) Summary (as described in paragraph (h) of this section);
    (7) Product formulation (as described in paragraph (i) of this 
section);
    (8) Manufacturing (as described in paragraph (j) of this section);
    (9) Health risk investigations (as described in paragraph (k) of 
this section); and
    (10) The effect on the population as a whole (as described in 
paragraph (l) of this section);
    (11) Certification statement (as described in paragraph (m) of this 
section).
    (b) Format. (1) The application must be submitted using the form(s) 
that FDA provides, contain a comprehensive index (i.e., a listing of 
files and data associated with those files) and table of contents, be 
well-organized and legible, and be written in English. Documents that 
have been translated from another language into English (e.g., original 
study documents written in a language other than English) must be 
accompanied by: The original language version of the document, signed a 
statement by an authorized representative of the manufacturer

[[Page 55415]]

certifying that the English language translation is complete and 
accurate, and a brief statement of the qualifications of the person 
that made the translation. As described in Sec.  1114.49, the applicant 
must submit the application and all information supporting the 
application in an electronic format that FDA can process, read, review, 
and archive, unless FDA has granted a waiver.
    (2) An applicant may include content in a submission by cross-
reference to a tobacco product master file or a pending modified risk 
tobacco product application for the same tobacco product. Applicants 
using a master file must provide documentation of their right of 
reference for the master file and clearly identify the specific content 
being incorporated into the PMTA submission. Except as provided for in 
Sec. Sec.  1114.15 and 1114.17, FDA will not consider content included 
by cross-reference to other sources of information outside of the 
submission.
    (c) General information. The applicant must, by using the form(s) 
FDA provides, specify the following general information:
    (1) Applicant name, address, and contact information;
    (2) Authorized representative or U.S. agent (for a foreign 
applicant), including the name, address, and contact information;
    (3) The following information to uniquely identify the product:
    (i) Manufacturer;
    (ii) Product name(s), including brand and subbrand (or other 
commercial name(s) used in commercial distribution); and
    (iii) The product category, product subcategory, and product 
properties as provided in the following table. If the product does not 
have a listed product property, such as ventilation or characterizing 
flavor, the application must state ``none'' for that property.

                                        Table 1 to Paragraph (c)(3)(iii)
----------------------------------------------------------------------------------------------------------------
                                           Tobacco product
       Tobacco product category              subcategory                       Product properties
----------------------------------------------------------------------------------------------------------------
(A) Cigarettes.......................  (1) Filtered...........  --Package type (e.g., hard pack, soft pack, clam
                                                                 shell).
                                                                --Product quantity (e.g., 20 cigarettes, 25
                                                                 cigarettes).
                                                                --Length (e.g., 89.1 millimeters (mm), 100.0
                                                                 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Ventilation (e.g., none, 10.0%, 25.0%).
                                                                --Characterizing flavor(s) (e.g., none,
                                                                 menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) Non-filtered.......  --Package type (e.g., hard pack, soft pack, clam
                                                                 shell).
                                                                --Product quantity (e.g., 20 cigarettes, 25
                                                                 cigarettes).
                                                                --Length (e.g., 89.1 mm, 100.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Characterizing flavor(s) (e.g., none,
                                                                 menthol).
                                                                -- Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) Other..............  --Package type (e.g., hard pack, soft pack, clam
                                                                 shell).
                                                                --Product quantity (e.g., 20 cigarettes, 25
                                                                 cigarettes).
                                                                --Length (e.g., 89.1 mm, 100.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Ventilation (e.g., none, 10.0%, 25.0%).
                                                                --Characterizing flavor(s) (e.g., none,
                                                                 menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
(B) Roll-Your-Own Tobacco Products...  (1) Roll-Your-Own        --Package type (e.g., bag, pouch).
                                        Tobacco Filler.
                                                                --Product quantity (e.g., 20.1 grams [g], 16.0
                                                                 ounces [oz.]).
                                                                --Characterizing flavor(s) (e.g., none,
                                                                 menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) Rolling Paper......  --Package type (e.g., box, booklet).
                                                                --Product quantity (e.g., 50 sheets, 200
                                                                 papers).
                                                                --Length (e.g., 79.1 mm, 100.0 mm, 110.2 mm).
                                                                --Width (e.g., 28.1 mm, 33.0 mm, 45.2 mm).
                                                                --Characterizing flavor(s) (e.g., none,
                                                                 menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) Cigarette Tube,      --Package type (e.g., bag, box).
                                        Filtered.
                                                                --Product quantity (e.g., 100 tubes, 200 tubes).
                                                                --Length (e.g., 89.1 mm, 100.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Ventilation (e.g., none, 10.0%, 25.0%).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 tobacco).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (4) Cigarette Tube, Non- --Package type (e.g., bag, box).
                                        filtered.
                                                                --Product quantity (e.g., 100 tubes, 200 tubes).
                                                                --Length (e.g., 89.1 mm, 100.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 tobacco).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (5) Filter.............  --Package type (e.g., bag, box).
                                                                --Product quantity (e.g., 100 filters, 200
                                                                 filters).
                                                                --Length (e.g., 8.0 mm, 12.1 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 tobacco).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).

[[Page 55416]]

 
                                       (6) Paper Tip..........  --Package type (e.g., bag, box).
                                                                --Product quantity (e.g., 200 tips, 275 tips).
                                                                --Length (e.g., 12.0 mm, 15.1 mm).
                                                                --Width (e.g., 27.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 tobacco).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (7) Other..............  --Package type (e.g., bag, box).
                                                                --Product quantity (e.g., 200 tips, 100 filters,
                                                                 200 tubes.
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 tobacco).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product.
(C) Smokeless Tobacco Products.......  (1) Moist Snuff, Loose.  --Package type (e.g., plastic can with metal
                                                                 lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 20.0 g, 2.1 oz.).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable,
                                                                 e.g., fine cut, long cut, straight cut).
                                       (2) Moist Snuff,         --Package type (e.g., plastic can with metal
                                        Portioned.               lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 22.5 g, 20.0 g).
                                                                --Portion count (e.g., 15 pouches, 20 pieces).
                                                                --Portion mass (e.g., 1.5 g/pouch, 1.0 g/piece).
                                                                --Portion length (e.g., 15.0 mm, 20.1 mm).
                                                                --Portion width (e.g., 10.0 mm, 15.1 mm).
                                                                --Portion thickness (e.g., 5.0 mm, 7.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) Snus, Loose........  --Package type (e.g., plastic can with metal
                                                                 lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 20.0 g, 2.1 oz.).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (4) Snus, Portioned....  --Package type (e.g., plastic can with metal
                                                                 lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 22.5 g, 20.0 g).
                                                                --Portion count (e.g., 15 pouches, 20 pieces).
                                                                --Portion mass (e.g., 1.5 g/pouch, 1.0 g/piece).
                                                                --Portion length (e.g., 15.0 mm, 20.1 mm).
                                                                --Portion width (e.g., 10.0 mm, 15.1 mm).
                                                                --Portion thickness (e.g., 5.0 mm, 7.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (5) Dry Snuff, Loose...  --Package type (e.g., plastic can with metal
                                                                 lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 20.0 g, 2.1 oz.).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (6) Dissolvable........  --Package type (e.g., plastic can with metal
                                                                 lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 22.5 g, 20.0 g)
                                                                --Portion count (e.g., 15 sticks, 20 pieces).
                                                                --Portion mass (e.g., 1.5 g/strip, 1.0 g/piece).
                                                                --Portion length (e.g., 10.0 mm, 15.1 mm).
                                                                --Portion width (e.g., 5.0 mm, 8.1 mm).
                                                                --Portion thickness (e.g., 3.0 mm, 4.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (7) Chewing Tobacco,     --Package type (e.g., bag, pouch, wrapped).
                                        Loose.
                                                                --Product quantity (e.g., 20.0 g, 3.1 oz).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (8) Chewing Tobacco,     --Package type (e.g., plastic can with metal
                                        Portioned.               lid, plastic can with plastic lid).
                                                                --Product quantity (e.g., 22.5 g, 20.0 g)
                                                                --Portion count (e.g., 10 bits).
                                                                --Portion mass (e.g., 2.1 g/bit).
                                                                --Portion length (e.g., 8.0 mm, 10.1 mm).
                                                                --Portion width (e.g., 6.0 mm, 8.1 mm).
                                                                --Portion thickness (e.g., 5.1 mm, 7.0 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (9) Other..............  --Package type (e.g., bag, box, can).
                                                                --Product quantity (e.g., 20.1 g, 22.5 g, 3.0
                                                                 oz.).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry, wintergreen, tobacco).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product.

[[Page 55417]]

 
(D) Electronic Nicotine Delivery       (1) E-Liquid, Open.....  --Package type (e.g., bottle, box, pod).
 System (ENDS) (Also referred to as
 vapes).
                                                                --Product quantity (e.g., 1 bottle, 5 bottles).
                                                                --E-liquid volume (e.g., 0.5 milliliters [ml]),
                                                                 2.0 ml, 5.1 ml).
                                                                --Nicotine concentration (e.g., 0 milligrams/
                                                                 milliliter [mg/ml], 0.2 mg/ml, 0.4 mg/ml, 1%,
                                                                 0.2 mg/bottle).
                                                                --Propylene glycol (PG)/vegetable glycerin (VG)
                                                                 ratio (e.g., not applicable [N/A], 0/100, 50/
                                                                 50, 100/0).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) E-Liquid, Closed...  --Package type (e.g., cartridge, pod).
                                                                --Product quantity (e.g., 1 cartridge, 5
                                                                 cartridges).
                                                                --E-liquid volume (e.g., 0.5 ml, 2.0 ml, 5.1
                                                                 ml).
                                                                --Nicotine concentration (e.g., 0 mg/ml, 0.2 mg/
                                                                 ml, 0.4 mg/ml, 1%, 2.0 mg/bottle).
                                                                --PG/VG ratio (e.g., N/A, 0/100, 50/50, 100/0).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) E-Cigarette, Closed  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g., 1 e-cigarette, 5 e-
                                                                 cigarettes).
                                                                --Length (e.g., 100.0 mm, 120.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.0 mm).
                                                                --Wattage (e.g., 100 watts [W], 200 W).
                                                                --Battery capacity (e.g., 100 milliampere hours
                                                                 [mAh], 200 mAh).
                                                                --E-liquid volume (e.g., 0.5 ml, 2.0 ml, 5.1
                                                                 ml).
                                                                --Nicotine concentration (e.g., 0 mg/ml, 0.2 mg/
                                                                 ml, 0.4 mg/ml, 1%, 0.2 mg/e-cigarette).
                                                                --PG/VG ratio (e.g., N/A, 0/100, 50/50, 100/0).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product.
                                       (4) E-Cigarette, Open..  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g., 1 e-cigarette, 5 e-
                                                                 cigarettes).
                                                                --Length (e.g., 100.0 mm, 120.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.0 mm).
                                                                --E-liquid volume (e.g., 0.5 ml, 2.0 ml, 5.1
                                                                 ml).
                                                                --Wattage (e.g., 100 W, 200 W).
                                                                --Battery capacity (e.g., 100 mAh, 200 mAh).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (5) ENDS Component.....  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g.,1 coil).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry, wintergreen).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (6) ENDS Other.........  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g., 1 e-cigarette, 5
                                                                 bottles).
                                                                --Characterizing flavor(s) (e.g., none, cherry,
                                                                 wintergreen, tobacco, menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product.
(E) Cigars...........................  (1) Cigar, Filtered      --Package type (e.g., hard pack, soft pack, clam
                                        Sheet-Wrapped.           shell).
                                                                --Product quantity (e.g., 20 filtered cigars, 25
                                                                 filtered cigars).
                                                                --Length (e.g., 89.1 mm, 100.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Ventilation (e.g., none, 0%, 10.0%, 25.0%).
                                                                --Characterizing flavor (e.g., none, menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) Cigar, Unfiltered    --Package type (e.g., box, film sleeve).
                                        Sheet-Wrapped.
                                                                --Product quantity (e.g., 1 cigar, 5
                                                                 cigarillos).
                                                                --Length (e.g., 100.1 mm, 140.0 mm).
                                                                --Diameter (e.g., 8.0 mm, 10.1 mm).
                                                                --Tip (e.g., none, wood tips, plastic tips).
                                                                --Characterizing flavor (e.g., none, menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) Cigar, Unfiltered    --Package type (e.g., box, film, sleeve, none).
                                        Leaf-Wrapped.
                                                                --Product quantity (e.g., 1 cigar, 5 cigars).
                                                                --Length (e.g., 150.1 mm, 200.0 mm).
                                                                --Diameter (e.g., 8.0 mm, 10.1 mm).
                                                                --Wrapper material (e.g., burley tobacco leaf,
                                                                 Connecticut shade grown tobacco leaf).
                                                                --Characterizing flavor (e.g., none, whiskey).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).

[[Page 55418]]

 
                                       (4) Cigar Component....  --Package type (e.g., box, booklet).
                                                                --Product quantity (e.g., 10 wrappers, 20
                                                                 leaves).
                                                                --Characterizing flavor (e.g., none, menthol,
                                                                 cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (5) Cigar Tobacco        --Package type (e.g., bag, pouch).
                                        Filler.
                                                                --Product quantity (e.g., 20.0 g, 16.1 oz.).
                                                                --Characterizing flavor (e.g., none, menthol,
                                                                 cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (6) Other..............  --Package type (e.g., box, booklet).
                                                                --Product quantity (e.g., 1 cigar, 5 cigars, 20
                                                                 leaves, 16 g).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product.
(F) Pipe Tobacco Products............  (1) Pipe...............  --Package type (e.g., box, none).
                                                                --Product quantity (e.g., 1 pipe).
                                                                --Length (e.g., 200.0 mm, 300.1 mm).
                                                                --Diameter (e.g., 25.1 mm).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cavendish, cherry).
                                                                 --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) Pipe Tobacco Filler  --Package type (e.g., bag, none).
                                                                --Product quantity (e.g., 20.0 g, 16.1 oz).
                                                                --Tobacco cut style (e.g., standard cut, such as
                                                                 shag cut, bugler cut, loose cut, etc., or a
                                                                 pressed cut, such as flake, cube cut, roll
                                                                 cake, etc., or a mixture).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cavendish, cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) Pipe Component.....  --Package type (e.g., box, bag, none).
                                                                --Product quantity (e.g., 1 bowl, 1 stem, 100
                                                                 filters).
                                                                --Characterizing flavor(s) (e.g., none, cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (4) Other..............  --Package type (e.g., bag, box, none).
                                                                --Product quantity (e.g., 1 pipe, 1 bowl, 1
                                                                 stem, 100 filters).
                                                                --Characterizing flavor(s) (e.g., none, cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product.
(G) Waterpipe Tobacco Products.......  (1) Waterpipe..........  --Package type (e.g., box, none).
                                                                --Product quantity (e.g., 1 waterpipe).
                                                                --Height (e.g., 200.0 mm, 500.1 mm).
                                                                --Width (e.g., 100.1 mm, 300.0 mm).
                                                                --Diameter (e.g., 100.1 mm, 300.0 mm)--Number of
                                                                 hoses (e.g., 1, 2, 4).
                                                                --Characterizing flavor(s) (e.g., none).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) Waterpipe Tobacco    --Package type (e.g., bag, pouch).
                                        Filler.
                                                                --Product quantity (e.g., 20.0 g, 16.1 oz.).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, apple).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) Waterpipe Heat       --Package type (e.g., box, film sleeve, bag,
                                        Source.                  none).
                                                                --Product quantity (e.g., 150.0 g, 680.0 g).
                                                                --Portion count (e.g., 20 fingers, 10 discs, 1
                                                                 base).
                                                                --Portion mass (e.g., 15.0 g/finger, 10.0g/
                                                                 brick).
                                                                --Portion length (e.g., 40.0 mm, 100.0 mm).
                                                                --Portion width (e.g., 10.0 mm, 40.0 mm).
                                                                --Portion thickness (e.g., 10.0 mm, 40.0 mm).
                                                                --Source of energy (e.g., charcoal, battery,
                                                                 electrical).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 apple).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (4) Waterpipe Component  --Package type (e.g., bag, box, none).
                                                                --Product quantity (e.g., 1 base, 1 bowl, 1
                                                                 hose, 10 mouthpieces).
                                                                --Characterizing flavor(s) (e.g., none, menthol,
                                                                 cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (5) Waterpipe Other....  --Package type (e.g., bag, box, none).
                                                                --Product quantity (e.g., 1 base, 1 bowl, 1
                                                                 hose, 10 mouthpieces).
                                                                --Characterizing flavor(s) (e.g., none, cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
(H) Heated Tobacco Products (HTP)....  (1) Closed HTP.........  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g., 1 device, 1 HTP).
                                                                --Length (e.g., 100.0 mm, 120.0 mm).

[[Page 55419]]

 
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Wattage (e.g., 100 W, 200 W).
                                                                --Battery capacity (e.g., 100 mAh, 200 mAh).
                                                                --Characterizing flavor(s) (e.g., none).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (2) Open HTP...........  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g., 1 device, 1 HTP).
                                                                --Length (e.g., 100.0 mm, 120.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Wattage (e.g., 100 W, 200 W).
                                                                --Battery capacity (e.g., 100 mAh, 200 mAh).
                                                                --Characterizing flavor(s) (e.g., none).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (3) HTP Consumable.....  --Package type (e.g., hard pack, soft pack,
                                                                 plastic clamshell).
                                                                --Product quantity (e.g., 20 sticks, 25
                                                                 cartridges).
                                                                --Length (e.g., 60.0 mm, 82.0 mm).
                                                                --Diameter (e.g., 6.0 mm, 8.1 mm).
                                                                --Ventilation (e.g., none, 10.0%, 25.0%).
                                                                --Characterizing flavor(s) (e.g., none,
                                                                 menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (4) HTP Component......  --Package type (e.g., box, none, plastic
                                                                 clamshell).
                                                                --Product quantity (e.g., 1 mouthpiece, 1
                                                                 spacer).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
                                       (5) Other..............  --Package type (e.g., box, bag, plastic
                                                                 clamshell, none).
                                                                --Product quantity (e.g., 1 base, 5 capsules).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
(I) Other............................  (1) Other..............  --Package type (e.g., box, bag, plastic
                                                                 clamshell, none).
                                                                --Product quantity (e.g., 1 base, 5 capsules).
                                                                --Characterizing flavor(s) (e.g., none, tobacco,
                                                                 menthol, cherry).
                                                                --Additional properties needed to uniquely
                                                                 identify the tobacco product (if applicable).
----------------------------------------------------------------------------------------------------------------

    (4) The type of PMTA (i.e., PMTA, supplemental PMTA, or 
resubmission);
    (5) Whether the applicant requests that FDA refer the PMTA to the 
Tobacco Products Scientific Advisory Committee (TPSAC);
    (6) Identifying information regarding any prior submissions 
regarding the tobacco product (e.g., submissions related to 
investigational tobacco products, substantial equivalence reports, 
PMTAs), including submission tracking numbers (STNs) where applicable;
    (7) Dates and purpose of any prior meetings with FDA regarding the 
new tobacco product;
    (8) If applicable, the dates when the tobacco product was 
commercially marketed in the United States;
    (9) Address and the Facility Establishment Identifier (FEI) 
number(s), if available, of the establishment(s) involved in the 
manufacture of the new tobacco product;
    (10) A brief statement regarding how the PMTA satisfies the content 
requirements of section 910(b)(1) of the Federal Food, Drug, and 
Cosmetic Act;
    (11) A brief description of how marketing of the new tobacco 
product would be appropriate for the protection of the public health; 
and
    (12) A list identifying all enclosures, labels, and labeling being 
submitted with the application.
    (d) Descriptive information. The application must contain 
descriptive information in this section that outlines the major aspects 
of the new tobacco product, including the following items:
    (1) A concise description of the new tobacco product;
    (2) A statement identifying all tobacco product standards issued 
under section 907 of the Federal Food, Drug, and Cosmetic Act that are 
applicable to the new tobacco product and a brief description of how 
the new tobacco product fully meets any identified tobacco product 
standard, or if the new tobacco product deviates from a product 
standard, if applicable, the application must include adequate 
information to identify and justify those deviations;
    (3) The name(s) of the product as designated on the product's 
label;
    (4) A description of problems that were identified in prototypes 
that are the subject of studies in the application and previous or 
similar versions of the new tobacco product that were marketed, if any. 
If there are previous or similar versions that are the subject of 
studies in the application or were marketed, the application must 
contain a bibliography of all reports regarding the previous or similar 
version of the product, whether adverse or supportive; and
    (5) Any restrictions on the sale, distribution, advertising, or 
promotion of the new tobacco product that the applicant proposes to be 
included as part of a marketing granted order under section 
910(c)(1)(B) of the Federal Food, Drug, and Cosmetic Act to help 
support a showing that the marketing of the product is appropriate for 
the protection of the public health. If there are no proposed 
restrictions, the application must contain a statement to that effect.
    (e) Samples of new tobacco products. After FDA accepts a PMTA for 
review, it may require the submission of samples of the new tobacco 
product, including its components and parts. If required, the applicant 
must submit samples of the finished tobacco product or its components 
or parts in accordance with instructions provided by FDA. FDA may also 
require the submission of additional samples to further aid in its 
review.
    (f) Labeling and description of marketing plans--(1) Labeling. The 
application must contain specimens of

[[Page 55420]]

all proposed labeling for the new tobacco product, including labels, 
inserts, onserts, instructions, and other accompanying information. The 
specimens of labeling must include all panels, reflect the actual size 
and color proposed to be used for the tobacco product, and include any 
warning label statements and other information required by regulation 
or statute, as applicable.
    (2) Description of Marketing Plans. A PMTA must contain a 
description of the applicant's plans to market the new tobacco product, 
for at least the first year the product would be marketed after 
receiving a marketing granted order, in way that is both consistent 
with the applicant's discussion of the increased or decreased 
likelihood of changes in tobacco product use behavior, including 
switching, initiation, cessation, and polyuse, under Sec.  1114.7(l), 
and permits FDA to determine permitting the new tobacco product to be 
marketed would be appropriate for the protection of public health. The 
description must include actions to market the product that would be 
taken by the applicant, on behalf of the applicant, or at the 
applicant's direction, and also discuss any restrictions on the sales 
and distribution the applicant proposes to be included in a marketing 
order under section 910(c)(1)(B) of the Federal Food Drug and Cosmetic 
Act. The description of marketing plans must contain, at minimum:
    (i) A description of the specific group(s) to which the labeling, 
advertising, marketing, promotion, and other consumer-directed 
activities for the new tobacco product would be targeted (i.e., the 
intended audience(s));
    (ii) A discussion of how the labeling, advertising, marketing, 
promotion, and other consumer-directed activities for the new tobacco 
product would be targeted to reach the intended audience(s) identified 
in paragraph (i) and what other group(s) would foreseeably be exposed 
to those materials and activities as a result;
    (iii) A discussion of, for individuals below the minimum age of 
sale, how access to the new tobacco product would be restricted and 
exposure to the labeling, advertising, marketing, promotion, and other 
consumer-directed activities would be limited; and
    (iv) A concluding summary describing how the applicant's plans for 
marketing the new tobacco product are consistent with the applicant's 
discussion of the increased or decreased likelihood of changes in 
tobacco product use behavior, including switching, initiation, 
cessation, and polyuse, under Sec.  1114.7(l) and permits FDA to 
determine permitting the new tobacco product to be marketed would be 
appropriate for the protection of public health.
    (g) Statement of compliance with 21 CFR part 25. (1) The 
application must contain an environmental assessment prepared in 
accordance with Sec.  25.40 of this chapter, or a valid claim of 
categorical exclusion, if applicable. If the applicant believes that 
the action qualifies for an available categorical exclusion, the 
applicant must state under Sec.  25.15(a) and (d) of this chapter that 
the action requested qualifies for a categorical exclusion, citing the 
particular exclusion that is claimed, and that to the applicant's 
knowledge, no extraordinary circumstances exist under Sec.  25.21 of 
this chapter.
    (h) Summary. The application must include a summary of all 
information contained in the application. The summary must include the 
following items, highlighting the effects on youth, young adults, and 
other relevant vulnerable populations:
    (1) A summary of the product formulation section of the 
application;
    (2) A summary of the manufacturing section of the application;
    (3) A summary of the health risk investigations section of the 
application, including all information regarding the following items, 
and identify areas in which there is a lack of information, where 
applicable:
    (i) The health risks of the tobacco product to both users and 
nonusers of the product and whether the tobacco product may present 
less health risk than other tobacco products;
    (ii) The impact the product and its marketing will have on the 
likelihood of changes in tobacco use behavior, including cessation, 
switching, and polyuse, of tobacco product users;
    (iii) The impact the product and its marketing will have on the 
likelihood of tobacco use initiation by tobacco product nonusers;
    (iv) How users and nonusers perceive the risk of the tobacco 
product based upon its label, labeling, and advertising, to the extent 
that advertising has been studied;
    (v) Whether users are able to understand the labeling and 
instructions for use, and use the product in accordance with those 
instructions; and
    (vi) The impact of human factors on the health risks to product 
users and nonusers (as described in paragraph (k)(1)(v) of this 
section);
    (4) A concluding discussion describing how the data and information 
contained in the PMTA both constitute valid scientific evidence and 
establish that permitting marketing of the new tobacco product is 
appropriate for the protection of the public health, as determined with 
respect to the risks and benefits to the population as a whole, 
including users and nonusers of the tobacco product. This discussion 
must specifically describe the effects on youth, young adults, and 
other relevant vulnerable populations with an emphasis on populations 
that are most likely to use the new tobacco product. The summary must 
also identify any key or pivotal studies on which an applicant is 
relying to establish that permitting the marketing of the new tobacco 
product would be APPH.
    (i) Product formulation. The application must contain a full 
statement of the components or parts, materials, ingredients, 
additives, constituents, properties, and the principle or principles of 
operation, of the tobacco product, including the following information:
    (1) Components or parts, materials, ingredients, additives, and 
constituents. The applicant must provide a full statement of:
    (i) Components or parts. The quantity, function, and purpose of, 
and, where applicable, target specification(s) of, each component or 
part in the product. Where the tobacco product contains software 
components, the applicant must provide:
    (A) A description of the software or technology (e.g., Bluetooth);
    (B) The purpose of the software or technology, such as monitoring 
where tobacco products are located, activated, or used;
    (C) A description of the data collected by the software and how it 
will be used.
    (ii) Materials. For each material in the product, include:
    (A) The material name and common name(s), if applicable;
    (B) The component or part of the tobacco product where the material 
is located;
    (C) The subcomponent or subpart where the material is located, if 
applicable;
    (D) The function of the material;
    (E) The quantities (including ranges or means and acceptance 
limits) of the material(s) in the new tobacco product (with any 
specification variation, if applicable);
    (F) The specification(s) (including quality/grades and suppliers) 
used for the new tobacco product (including any specification 
variations, if applicable); and
    (G) Any other material properties to fully characterize the new 
tobacco product.

[[Page 55421]]

    (iii) Ingredients other than tobacco. For ingredients other than 
tobacco in each component or part of the product, include:
    (A) The International Union of Pure and Applied Chemistry (IUPAC) 
chemical name and common name, if applicable;
    (B) The Chemical Abstracts Service (CAS) number or FDA Unique 
Ingredient Identifier (UNII), if applicable;
    (C) The function of the ingredient;
    (D) The quantity of the ingredient in the tobacco product, with the 
unit of measure (including ranges or means and acceptance limits) 
reported as mass per gram of tobacco for nonportioned tobacco products 
and as mass per portion for portioned tobacco products (with any 
specification variation, if applicable);
    (E) The specification(s) (including purity or grade and supplier); 
and
    (F) For complex purchased ingredients, each single chemical 
substance reported separately.
    (iv) Tobacco ingredients. For tobacco ingredients in each component 
or part, include the following information or, if applicable, a 
statement that the product does not contain tobacco ingredients:
    (A) The type(s) (e.g., Bright, Burley, reconstituted);
    (B) The quantity with the unit of measure (including ranges or 
means, acceptance limits) of each tobacco ingredient in the tobacco 
product reported as mass per gram of tobacco for nonportioned tobacco 
products and as mass per portion for portioned tobacco products (with 
any specification variation, if applicable);
    (C) The specification of tobacco used for the new tobacco product 
(with any specification variation, if applicable); and
    (D) A description of any genetic engineering of the tobacco that 
impacts product characteristics.
    (v) Constituents. Constituents, including HPHCs and other 
constituents, contained within, or emitted from (including its smoke or 
aerosol), the product, including any reaction product from leaching or 
aging, by providing:
    (A) The constituent names in alphabetical order;
    (B) The common name(s);
    (C) The Chemical Abstract Services number;
    (D) The mean quantity and variance with unit of measure;
    (E) The number of samples and measurement replicates for each 
sample;
    (F) A description of method procedure, method validation 
information and rationale for selecting each test method;
    (G) The name and location of the testing laboratory or laboratories 
and documentation showing that the laboratory or laboratories is (or 
are) accredited by a nationally or internationally recognized external 
accreditation organization;
    (H) Length of time between dates of manufacture and date(s) of 
testing;
    (I) Storage conditions of the tobacco product before it was tested;
    (J) Test data including test protocols, any deviation(s) from the 
test protocols, quantitative acceptance (pass/fail) criteria, and line 
data for all testing performed. Test data for combusted or inhaled 
products must reflect testing conducted using both intense and 
nonintense smoking or aerosol-generating regimens, where established; 
and
    (K) Complete descriptions of any smoking or aerosol-generating 
regimens used for analytical testing that are not standardized or 
widely accepted by the scientific community, if applicable.
    (vi) Container closure system. A description of the container 
closure system, including:
    (A) Information describing how the container closure system 
protects and preserves the product from damage during transport, 
environmental contaminants, and potential leaching and migration of 
packaging constituents into the new tobacco product; and
    (B) Information describing design features developed to prevent the 
risk of accidental exposure, if any.
    (vii) Statement of tobacco blending, reconstitution, or 
manipulation. Information regarding tobacco blending, reconstitution, 
or manipulation, where applicable.
    (2) Other properties. The applicant must provide a full description 
of the additional properties of the tobacco product that includes:
    (i) Product dimensions and construction. The product dimensions and 
the overall construction of the product using a diagram or schematic 
drawing that clearly depicts the finished tobacco product and its 
components with dimensions, operating parameters, and materials.
    (ii) Design parameters and test data. (A) All final design 
parameters of the product, specifying nominal values or the explicit 
range of values as well as the design tolerance (where appropriate), 
including, but not limited to, the parameters specified in tables 1 to 
22 of this paragraph as applicable. If a design parameter specified in 
tables 1 to 22 does not apply to the tobacco product, applicants must 
explain why the required design parameter does not apply or how an 
alternative design parameter would satisfy the required design 
parameter. If the product has additional design parameters that are not 
specified in tables 1 to 22, the application must contain a description 
of the design specifications as well as test data and processes to 
demonstrate that the design parameters and their associated processes 
are adequately controlled; and
    (B) A quantitative description of the performance criteria, 
including test protocols, line data, and a summary of the results, for 
each applicable intermediate and final design parameter and 
manufacturing step, that includes, but is not limited to the test data 
specified in tables 1 to 22 of this paragraph for the product category 
as applicable. If the test data specified in the applicable table does 
not apply to the tobacco product, applicants must explain why the test 
data does not apply or how alternative test data would satisfy this 
requirement. Where tobacco cut size or particle size is a required 
design parameter for a product category or subcategory and the target 
specifications and range limits are not available, the following 
alternative information may be submitted in place of this information: 
a description of the tobacco cutting process (including a complete 
description of the milling, cutting, and sifting process; the control 
parameters of the miller or cutter; and any sift specifications), or 
the measured particle size distribution;

 Table 2 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                             for Cigarettes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigarette length (mm).              Tobacco filler mass
                                             (mg).
 Cigarette circumference or          Tobacco rod density
 diameter (mm).                              (g/cm\3\).
 Tobacco filler mass (mg).           Tobacco cut size
                                             (mm or CPI).
 Tobacco rod density (g/cm\3\).      Tobacco moisture or
                                             oven volatiles (%).

[[Page 55422]]

 
 Tobacco cut size (mm or CPI).       Cigarette paper
                                             base paper porosity
                                             (permeability) (CU).
 Tobacco moisture or oven            Cigarette paper
 volatiles (%).                              band porosity or
                                             permeability (CU) or
                                             Cigarette paper band
                                             diffusivity (cm\2\/s).
 Cigarette paper length (mm).        Filter pressure
                                             drop (mm H2O).
 Cigarette paper base paper
 porosity (permeability) (CU).
 Cigarette paper band porosity       Filter efficiency
 (permeability) (CU) [alternatively, band    (%) (If no filter
 diffusivity (cm\2\/s)] (if applicable).     efficiency data is
                                             available for the products,
                                             include information
                                             sufficient to show that the
                                             cigarette filter is
                                             unchanged (e.g., denier per
                                             filament, total denier, and
                                             filter density)).
 Cigarette paper band width (mm).    Filter ventilation
                                             (%).
 Cigarette paper band space (mm).
 Filter length (mm).
 Filter pressure drop (mm H2O).
 Filter efficiency (%) (If no
 filter efficiency data is available for
 the products, include information
 sufficient to show that the cigarette
 filter is unchanged (e.g., denier per
 filament, total denier, and filter
 density)).
 Tipping paper length (mm).
 Filter ventilation (%).
------------------------------------------------------------------------


 Table 3 to Paragraph (i)(2)(ii)--Required Design Parameter Information
        for Portioned and Nonportioned Smokeless Tobacco Products
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
                  Portioned Smokeless Tobacco Products
------------------------------------------------------------------------
 Tobacco cut size (mm or CPI) or     Tobacco cut size
 tobacco particle size (mm or micron).       (mm or CPI) or tobacco
                                             particle size (mm or
                                             micron).
 Tobacco moisture (%).               Tobacco moisture
                                             (%).
 Portion length (mm).                Portion mass (mg).
 Portion width (mm).                 Pouch material
                                             basis weight (g/m\2\) (if
                                             applicable).
 Portion mass (mg).                  Pouch material
                                             porosity (CU)
                                             (permeability) (L/m\2\/s).
 Portion material thickness (mm)     Nicotine
 (if applicable).                            dissolution rate (%/min).
 Pouch material basis weight (g/
 m\2\) (if applicable).
 Pouch material porosity
 (permeability) (CU or L/m\2\/s) (if
 applicable).
 Nicotine dissolution rate (%/
 min).
------------------------------------------------------------------------
                 Nonportioned Smokeless Tobacco Products
------------------------------------------------------------------------
 Tobacco cut size (mm or CPI) or     Tobacco cut size
 tobacco particle size (mm or micron)        (mm or CPI) or tobacco
                                             particle size (mm or
                                             micron).
 Tobacco moisture (%)                Tobacco moisture
                                             (%).
------------------------------------------------------------------------


 Table 4 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                     for RYO Tobacco Rolling Papers
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Roll-your-own (RYO) paper length    RYO mass per paper
 (mm).                                       (mg).
 RYO paper width (mm).               RYO paper base
                                             paper basis weight (g/
                                             m\2\).
 RYO mass per paper (mg).            RYO paper base
                                             paper porosity
                                             (permeability) (CU).
 RYO paper base paper basis weight   RYO paper band
 (g/m\2\).                                   porosity (permeability)
                                             (CU) or [alternatively, RYO
                                             paper band diffusivity
                                             (cm\2\/s)] (if applicable).
 RYO paper base paper porosity
 (permeability) (CU).
 RYO paper band porosity
 (permeability) (CU) or [alternatively,
 RYO paper band diffusivity (cm\2\/s)] (if
 applicable).
 RYO paper band width (mm) (if
 applicable).
 RYO paper band space (mm) (if
 applicable).
------------------------------------------------------------------------


 Table 5 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                          for RYO Tobacco Tubes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Tube mass (mg).                     Tube mass (mg).
 Tube length (mm).                   Tube paper base
                                             paper basis weight (g/
                                             m\2\).
 Tube circumference or diameter      Tube paper base
 (mm).                                       paper porosity
                                             (permeability) (CU).

[[Page 55423]]

 
 Tube paper width (mm).              Tube paper band
                                             porosity (permeability)
                                             (CU) (if applicable) or
                                             Tube paper band diffusivity
                                             (cm\2\/s) (if applicable).
 Tube paper base paper basis
 weight (g/m\2\).
 Tube paper base paper porosity
 (permeability) (CU).
 Tube paper band porosity
 (permeability) (CU) (if applicable) or
 Tube paper band diffusivity (cm\2\/s) (if
 applicable).
 Tube paper band width (mm) (if
 applicable).
 Tube paper band space (mm) (if
 applicable).
------------------------------------------------------------------------


 Table 6 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                     for RYO Tobacco Filtered Tubes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Tube mass (mg).                     Tube paper base
                                             paper basis weight (g/
                                             m\2\).
 Tube length (mm).                   Tube paper base
                                             paper porosity
                                             (permeability) (CU).
 Tube circumference or diameter      Tube mass (mg).
 (mm).
 Tube paper length (mm).             Tube paper band
                                             porosity (permeability)
                                             (CU) (if applicable) or
                                             Tube paper band diffusivity
                                             (cm\2\/s) (if applicable).
 Nonfilter tube length (mm).         Filter pressure
                                             drop (mm H2O).
 Tube paper width (mm).              Filter efficiency
                                             (%) (If no filter
                                             efficiency data is
                                             available for the products,
                                             include information
                                             sufficient to show that the
                                             cigarette filter is
                                             unchanged (e.g., denier per
                                             filament (DPF), total
                                             denier (g/9000m), and
                                             filter density (g/cm\3\))).
 Tube paper base paper basis         Filter ventilation
 weight (g/m\2\).                            (%).
 Tube paper base paper porosity     ............................
 (permeability) (CU).
 Tube paper band porosity
 (permeability) (CU) (if applicable) or
 Tube paper band diffusivity (cm\2\/s) (if
 applicable).
 Tube paper band width (mm) (if
 applicable).
 Tube paper band space (mm) (if
 applicable).
 Filter length (mm).
 Filter pressure drop (mm H2O).
 Filter efficiency (%) (If no
 filter efficiency data is available for
 the products, include information
 sufficient to show that the cigarette
 filter is unchanged (e.g., denier per
 filament (DPF), total denier (g/9000m),
 and filter density (g/cm\3\))).
 Tipping paper length (mm).
 Filter ventilation (%).
------------------------------------------------------------------------


 Table 7 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                             for RYO Tobacco
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Tobacco cut size (mm or CPI).       Tobacco cut size
                                             (mm or CPI).
 Tobacco moisture or oven            Tobacco moisture or
 volatiles (%).                              oven volatiles (%).
------------------------------------------------------------------------


 Table 8 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                       for RYO Tobacco Paper Tips
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 RYO paper tip length (mm).          RYO paper base
                                             paper basis weight (g/
                                             m\2\).
 RYO paper tip width (mm).           RYO paper porosity
                                             (permeability) (CU).
 RYO paper tip mass (mg).            RYO paper tip
                                             ventilation (%).
 RYO paper base paper basis weight
 (g/m\2\).
 RYO paper porosity (permeability)
 (CU).
 RYO paper tip ventilation (%).
------------------------------------------------------------------------


 Table 9 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                    for Filtered Sheet-Wrapped Cigars
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar mass (mg).                    Cigar mass (mg).
 Cigar wrapper basis weight (g/      Puff count.
 m\2\).
 Cigar binder length (mm).           Cigar wrapper basis
                                             weight (g/m\2\).
 Cigar binder width (mm).            Cigar wrapper
                                             porosity (permeability)
                                             (CU).

[[Page 55424]]

 
 Cigar binder basis weight (g/       Cigar binder
 m\2\)                                       porosity (permeability)
                                             (CU).
 Cigar length (mm).                  Cigar binder basis
                                             weight (g/m\2\).
 Cigar overall diameter (mm).        Tobacco filler mass
                                             (mg).
 Cigar minimum diameter (mm) if      Tobacco rod density
 applicable.                                 (g/cm\3\).
 Cigar maximum diameter (mm) if      Tobacco cut size
 applicable.                                 (CPI or mm).
 Tobacco filler mass (mg).           Tobacco moisture or
                                             oven volatiles (%).
 Tobacco rod density (g/cm\3\).      Cigar wrapper band
                                             porosity (permeability)
                                             (CU) [alternatively, band
                                             diffusivity (cm\2\/s)](if
                                             applicable).
 Tobacco cut size (CPI or mm).       Cigar binder band
                                             porosity (permeability)
                                             (CU) [alternatively, band
                                             diffusivity (cm\2\/s)] (if
                                             applicable).
 Tobacco moisture or oven            Cigar minimum
 volatiles (%).                              diameter (mm) (if
                                             applicable).
 Cigar wrapper porosity              Cigar maximum
 (permeability) (CU).                        diameter (mm) (if
                                             applicable).
 Cigar wrapper length (mm).          Filter pressure
                                             drop (mm H2O).
 Cigar wrapper width (mm).           Filter efficiency
                                             (%) (if no filter
                                             efficiency data is
                                             available for the products,
                                             include information
                                             sufficient to show that the
                                             cigar filter is unchanged
                                             [e.g., denier per filament
                                             (DPF), total denier (g/
                                             9000m), and filter density
                                             (g/cm\3\)]{time} .
 Cigar wrapper band porosity         Filter ventilation
 (permeability) (CU) (if applicable).        (%).
 Cigar wrapper band width (mm) (if
 applicable).
 Cigar wrapper band space (mm) (if
 applicable).
 Cigar binder porosity
 (permeability) (CU).
 Cigar binder band porosity
 (permeability) (CU) (if applicable).
 Cigar binder band width (mm) (if
 applicable).
 Cigar binder band space (mm) (if
 applicable).
 Filter length (mm).
 Filter diameter (mm).
 Filter pressure drop (mm H2O).
 Filter efficiency (%) {If no
 filter efficiency data is available for
 the products, include information
 sufficient to show that the cigar filter
 is unchanged [e.g., denier per filament
 (DPF), total denier (g/9000m), and filter
 density(g/cm\3\)]{time} .
 Tipping paper length (mm).
 Filter ventilation (%).
------------------------------------------------------------------------


 Table 10 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                   for Unfiltered Sheet-Wrapped Cigars
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar mass (mg).                    Puff count.
 Cigar length (mm).                  Cigar mass (mg).
 Cigar overall diameter (mm).        Tobacco rod density
                                             (g/cm\3\).
 Cigar minimum diameter (mm) (if     Tobacco cut size
 applicable).                                (CPI or mm).
 Cigar maximum diameter (mm) (if     Tobacco moisture or
 applicable).                                oven volatiles (%).
 Tobacco rod density (g/cm\3\).      Tobacco filler mass
                                             (mg).
 Tobacco moisture or oven            Cigar minimum
 volatiles (%).                              diameter (mm) (if
                                             applicable).
 Tobacco cut size (CPI or mm).       Cigar maximum
                                             diameter (mm) (if
                                             applicable).
 Tobacco filler mass (mg).           Cigar wrapper
                                             porosity (permeability)
                                             (CU).
 Cigar wrapper porosity              Cigar wrapper basis
 (permeability) (CU).                        weight (g/m\2\).
 Cigar wrapper length (mm).          Cigar binder basis
                                             weight (g/m\2\).
 Cigar wrapper width (mm).           Cigar binder
                                             porosity (permeability)
                                             (CU).
 Cigar wrapper basis weight (g/      Cigar tip mass (mg)
 m\2\).                                      (if applicable).
 Cigar binder porosity               Cigar wrapper band
 (permeability) (CU).                        porosity (permeability)
                                             (CU) [alternately, band
                                             diffusivity (cm2/s)] (if
                                             applicable).
 Cigar binder width (mm)             Cigar binder band
                                             porosity (permeability)
                                             (CU) [alternately, band
                                             diffusivity (cm2/s)] (if
                                             applicable).
 Cigar binder basis weight (g/
 m\2\).
 Cigar tip length (mm) (if
 applicable).
 Cigar tip inner diameter (mm) (if
 applicable).
 Cigar tip mass (mg) (if
 applicable).
 Cigar wrapper band space (mm) (if
 applicable).
 Cigar wrapper band width (mm) (if
 applicable).
 Cigar binder band width (mm) (if
 applicable).
 Cigar binder band space (mm) (if
 applicable).
 Cigar wrapper band porosity or
 permeability (CU) [alternately, band
 diffusivity (cm2/s)] (if applicable).

[[Page 55425]]

 
 Cigar binder band porosity
 (permeability) (CU) [alternately, band
 diffusivity (cm2/s)] (if applicable).
------------------------------------------------------------------------


 Table 11 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                         for Leaf-Wrapped Cigars
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar mass (mg).                    Puff count.
 Cigar length (mm).                  Cigar mass (mg).
 Overall diameter (mm).              Cigar minimum
                                             diameter (mm).
 Cigar minimum diameter (mm).        Cigar maximum
                                             diameter (mm).
 Cigar maximum diameter (mm).        Cigar wrapper basis
                                             weight (g/m\2\).
 Tobacco moisture or oven            Cigar binder basis
 volatiles (%).                              weight (g/m\2\).
 Tobacco filler mass (mg).           Tobacco filler mass
                                             (mg).
 Tobacco rod density (g/cm\3\).      Tobacco rod density
                                             (g/cm\3\).
 Tobacco cut size (CPI or mm).       Tobacco cut size
                                             (CPI or mm).
 Tobacco moisture or oven            Tobacco moisture or
 volatiles (%).                              oven volatiles (%).
 Cigar wrapper length (mm).
 Cigar wrapper width (mm).
 Cigar wrapper basis weight (g/
 m\2\).
 Cigar binder width (mm).
 Cigar binder basis weight (g/
 m\2\).
------------------------------------------------------------------------


 Table 12 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                            for Cigar Tobacco
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Tobacco cut size (CPI or mm)        Tobacco cut size
                                             (CPI or mm).
 Tobacco moisture or oven            Tobacco moisture or
 volatiles (%)                               oven volatiles (%).
------------------------------------------------------------------------


 Table 13 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                           for Cigar Wrappers
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar wrapper length (mm).          Cigar wrapper
                                             length (mm).
 Cigar wrapper width (mm).           Cigar wrapper width
                                             (mm).
 Cigar wrapper basis weight (g/      Cigar wrapper basis
 cm\2\).                                     weight (g/cm\2\).
------------------------------------------------------------------------


 Table 14 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                             for Waterpipes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Hose length (mm).                   Hose length (mm).
 Hose materials.                     Hose internal
                                             diameter (mm).
 Hose internal diameter (mm).        Stem length (mm).
 Stem length (mm).                   Stem internal
                                             diameter (mm).
 Stem internal diameter (mm).        Base diameter (mm).
 Base diameter (mm).                 Base volume
                                             (cm\3\).
 Base volume (cm\3\).                Pressure drop (mm
                                             H2O).
 Base shape.                         Water filter
                                             efficiency (%).
 Pressure drop (mm H2O).             Head height (mm).
 Water filter efficiency (%).        Head top diameter
                                             (mm).
 Hose air permeability (CU).         Head bottom
                                             diameter (mm).
 Head height (mm).                   Head volume
                                             (mm\3\).
 Head top diameter (mm).
 Head bottom diameter (mm).
 Number of holes.
 Head volume (mm\3\).
 Heating source type.
 Head materials.
------------------------------------------------------------------------


[[Page 55426]]


 Table 15 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                          for Waterpipe Tobacco
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Tobacco cut size (CPI or mm).       Tobacco cut size
                                             (CPI or mm).
 Tobacco moisture or oven            Tobacco moisture or
 volatiles (%).                              oven volatiles (%).
------------------------------------------------------------------------


 Table 16 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                      for Waterpipe Heating Sources
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Heating element temperature range   Heating element
 ([deg]C).                                   temperature range ([deg]C).
 Heating element mass (mg).          Heating element
                                             mass (mg).
 Heating element density (g/         Heating element
 cm\3\).                                     density (g/cm\3\).
 Heating element resistance (ohms)   Heating element
 (if applicable).                            resistance (ohms) (if
                                             applicable).
 Number of heating elements.         Heating element
                                             diameter (gauge).
 Heating element configuration.      Battery current
                                             rating (mA) (if
                                             applicable).
 Heating element diameter (gauge)    Battery capacity
 (if applicable).                            (mAh) (if applicable).
 Battery current rating (mA) (if     Battery voltage
 applicable).                                operating range (volts) (if
                                             applicable).
 Battery capacity (mAh) (if          Battery current
 applicable)                                 operating range (amps) (if
                                             applicable).
 Battery voltage operating range     Power delivery unit
 (volts) (if applicable).                    (PDU) temperature cut-off
                                             ([deg]C) (if applicable).
 Battery current operating range     Power delivery unit
 (amps) (if applicable).                     (PDU) voltage operating
                                             range (volts) (if
                                             applicable).
 Power delivery unit (PDU)           PDU current
 temperature cut-off ([deg]C) (if            operating range (amps) (if
 applicable).                                applicable).
 Power delivery unit (PDU) voltage   PDU wattage
 operating range (volts) (if applicable).    operating range (watts) (if
                                             applicable).
 PDU current operating range        ............................
 (amps) (if applicable).
 PDU wattage operating range        ............................
 (watts) (if applicable).
------------------------------------------------------------------------


 Table 17 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                           for Waterpipe Foil
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Foil length (mm) (for square or     Foil length (mm)
 rectangular shape foil).                    (for square or rectangular
                                             shape foil).
 Foil width (mm) (for square or      Foil width (mm)
 rectangular shape foil).                    (for square or rectangular
                                             shape foil).
 Diameter (mm) (for circular shape   Diameter (mm) (for
 foil).                                      circular shape foil).
 Foil thickness (mm).                Foil thickness
                                             (mm).
 Number of holes.                    Diameter of the
                                             holes (mm).
 Diameter of the holes (mm).        ............................
------------------------------------------------------------------------


 Table 18 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                           for Waterpipe Head
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Head height (mm),                   Head height (mm).
 Head top diameter (mm),             Head top diameter
                                             (mm).
 Head bottom diameter (mm),          Head bottom
                                             diameter (mm).
 Number of holes,                    Head volume
                                             (mm\3\).
 Head volume (mm\3\),               ............................
 Head materials,                    ............................
------------------------------------------------------------------------


 Table 19 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                                for Pipes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Bowl chamber cover outer diameter   Bowl chamber volume
 (mm).                                       (cm\3\).
 Bowl chamber cover inner diameter   Pipe pressure drop
 (mm).                                       (mm H2O).
 Draught hole diameter (mm).         Air flow through
                                             air valve (cc/min).
 Screen (if applicable).             Airway volume
                                             (cm\3\).
 Draught hole shape.                 Filter pressure
                                             drop (mm H2O).
 Draught hole location.              Filter efficiency
                                             (%) {If no filter
                                             efficiency data is
                                             available for the products,
                                             include information
                                             sufficient to show that the
                                             cigar filter is unchanged
                                             [e.g., denier per filament
                                             (DPF), total denier (g/
                                             9000m), and filter
                                             density(g/cm\3\)]{time} .
 Bowl chamber hole shape.           ............................
 Bowl chamber volume (cm\3\)        ............................
 Airway volume (cm\3\)              ............................
 Stem length (mm).                  ............................

[[Page 55427]]

 
 Stem diameter (mm).                ............................
 Shank length (mm).                 ............................
 Shank diameter (mm).               ............................
 Draught hole dimension.            ............................
 Pressure drop through air valve    ............................
 (mm H2O).
 Air flow through air valve (cc/    ............................
 min).
 Filter efficiency (%) {If no       ............................
 filter efficiency data is available for
 the products, include information
 sufficient to show that the cigar filter
 is unchanged [e.g., denier per filament
 (DPF), total denier (g/9000m), and filter
 density(g/cm\3\)]{time} .
 Filter pressure drop (mm H2O).     ............................
 Filter length (mm).                ............................
------------------------------------------------------------------------


 Table 20 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                            for Pipe Tobacco
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Tobacco cut size (CPI or mm).       Tobacco cut size
                                             (CPI or mm).
 Tobacco moisture or oven            Tobacco moisture or
 volatiles (%).                              oven volatiles (%).
------------------------------------------------------------------------


 Table 21 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                                for ENDS
------------------------------------------------------------------------
                                             Provide test data (include
                                                   test protocols,
  Provide target specification with upper      quantitative acceptance
        and lower range limits for:          criteria, data sets, and a
                                            summary of the results) for:
------------------------------------------------------------------------
 Draw resistance (mm H2O).          ............................
 Puff count (for full tank/          Draw resistance (mm
 cartridge).                                 H2O).
 Atomizer tank/cartridge volume      Puff count (for
 (mL).                                       full tank/cartridge).
 Number of heating elements (e.g.,   Atomizer tank/
 coil).                                      cartridge volume (mL).
 Heating Element diameter (gauge).   Heating Element
                                             diameter (gauge).
 Heating Element length (mm).        Heating Element
                                             resistance (Ohms).
 Heating Element resistance          Heating Element
 (Ohms).                                     temperature range ([deg]C).
 Heating Element temperature range   Battery voltage
 ([deg]C).                                   operating range (V).
 Heating Element configuration       Battery current
 (target only).                              operating range (mA).
 Battery voltage operating range     PDU voltage
 (V).                                        operating range (V).
 Battery current operating range     PDU current
 (mA).                                       operating range (mA).
 Battery Capacity (mAh).             PDU wattage
                                             operating range (watts).
 Battery Nominal Voltage (V).        PDU Current cut-off
                                             (mA) (if applicable).
 Battery Current rating (mA).        PDU temperature cut-
                                             off ([deg]C) (if
                                             applicable).
 Battery charging temperature        Battery Capacity
 limits ([deg]C).                            (mAh).
 Battery discharge temperature       Battery Nominal
 limits ([deg]C).                            Voltage (V).
 Battery end of discharge voltage    Battery Current
 (V).                                        rating (mA).
 Battery maximum charging current    Battery charging
 (mA).                                       temperature limits
                                             ([deg]C).
 Battery maximum discharging         Battery discharge
 current (mA).                               temperature limits
                                             ([deg]C).
 Battery upper limits charging       Battery maximum
 voltage (V).                                charging current (mA).
 Power Delivery Unit (PDU) voltage   Battery maximum
 operating range (V).                        discharging current (mA).
 PDU current operating range (mA).   Battery upper
                                             limits charging voltage
                                             (V).
 PDU wattage operating range         Inhaled aerosol
 (watts).                                    temperature ([deg]C).
 PDU temperature cut-off ([deg]C)    Airflow rate (L/
 (if applicable).                            min) (if applicable).
 Airflow rate (L/min) (if            Ventilation (%).
 applicable).
 PDU Current cut-off (mA) (if       ............................
 applicable).
 PDU Temperature cut-off ([deg]C)   ............................
 (if applicable).
 Inhaled aerosol temperature        ............................
 ([deg]C).
 Ventilation (%).                   ............................
------------------------------------------------------------------------


 Table 22 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                              for E-liquids
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 E-liquid viscosity (at 20[deg]C).   E-liquid viscosity
                                             (at 20[deg]C).
 E-liquid volume (ml).               E-liquid volume
                                             (ml).
 Particle number concentration (#/   Particle number
 cm\3\).                                     concentration (#/cm\3\).
 Count median diameter (nm).         Count median
                                             diameter (nm).
 PM2.5 ([micro]g/m\3\).              PM2.5 ([micro]g/
                                             m\3\).
------------------------------------------------------------------------


[[Page 55428]]


 Table 23 to Paragraph (i)(2)(ii)--Required Design Parameter Information
                    for Heated Tobacco Products (HTP)
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Overall Product.                    Overall Product.
    [cir] Mass (mg).                         [cir] Draw resistance (mm
                                             H2O).
    [cir] Length (mm).                       [cir] Puff count (for full
                                             tank/cartridge).
    [cir] Width (mm).                        [cir] Product volume (mL).
    [cir] Height (mm).                       [cir] Airflow rate (L/min)
                                             (if applicable).
    [cir] Diameter (mm).                     [cir] Ventilation (%).
    [cir] Draw resistance (mm H20).          [cir] Operational
                                             Temperature ([deg]C).
    [cir] Puff Count (for full tank/         [cir] Temperature sensor
     cartridge).                             (if applicable).
    [cir] Puff volume (mL).                  [cir] Material wrapper
                                             length (mm) (if
                                             applicable).
    [cir] Product volume (mL).               [cir] Material wrapper
                                             width (mm) (if applicable).
    [cir] Airflow rate (L/min) (if           [cir] Material wrapper
     applicable).                            basis weight (g/m\2\) (if
                                             applicable).
    [cir] Ventilation (%).                   [cir] Material porosity
                                             (permeability) (CU) (if
                                             applicable).
    [cir] Operational Temperature            Heating element.
     ([deg]C).
    [cir] Temperature sensor (if             [cir] Heating Element
     applicable).                            diameter (gauge).
    [cir] Material wrapper length (mm) (if   [cir] Heating Element
     applicable).                            resistance (Ohms).
    [cir] Material wrapper width (mm) (if    [cir] Heating Element
     applicable).                            temperature range ([deg]C).
    [cir] Material wrapper basis weight (g/  E-liquid.
     m\2\) (if applicable).
    [cir] Material porosity (permeability)   [cir] E-liquid viscosity
     (CU) (if applicable).                   (at 20[deg]C).
 Heating element.                    [cir] E-liquid volume (ml).
    [cir] Heating element source/type/       Tobacco (if
     approach (electrical, carbon,           applicable).
     aerosol, etc.).
    [cir] Heating element temperature        [cir] Tobacco moisture (%).
     range ([deg]C).
    [cir] Heating element operational        [cir] Tobacco cut size (CPI
     temperature ([deg]C).                   or mm).
    [cir] Heating element maximum            [cir] Tobacco density (g/
     temperature (boost temperature)         cm\3\)
     ([deg]C).
    [cir] Heating element material.          Battery.
    [cir] Heating element Configuration     ............................
     (i.e., the shape and design of the
     heating element. If the heating
     element is a coil, it is the shape
     and arrangement of the coil. If the
     heating element is a novel design,
     provide the configuration and its
     design targets.).
    [cir] Heating element length (mm).
    [cir] Heating element mass (mg).
    [cir] Heating element location.         ............................
    [cir] Number of heating elements         [cir] Battery voltage
     (e.g., coil) (dimensionless).           operating range (V).
    [cir] Heating Element diameter (gauge)   [cir] Battery current
     (if applicable).                        operating range (mA).
    [cir] Heating Element resistance         [cir] PDU voltage operating
     (Ohms) (if applicable).                 range (V).
 Tobacco/E-liquid.                   [cir] PDU current operating
                                             range (mA) PCO wattage
                                             operating range (W).
    [cir] Tobacco mass (mg) (if             ............................
     applicable).
    [cir] Tobacco density (g/cm\3\) (if      [cir] PDU Current cut-off
     applicable).                            (mA) (if applicable).
    [cir] Tobacco moisture or oven           [cir] PDU temperature cut-
     volatiles (%) (if applicable).          off ([deg]C).
    [cir] Tobacco cut size (CPI or mm) (if   [cir] Battery Capacity
     applicable).                            (mAh).
    [cir] E-liquid volume (mL) (if           [cir] Battery Nominal
     applicable).                            Voltage (V).
    [cir] E-liquid viscosity (at 20[deg]C)   [cir] Battery Current
     (if applicable).                        rating (mA).
 Battery (if applicable).            [cir] Battery charging
                                             temperature limits
                                             ([deg]C).
    [cir] Battery capacity (mA).             [cir] Battery discharge
                                             temperature limits
                                             ([deg]C).
    [cir] Battery Voltage Operating Range    [cir] Battery maximum
     (V) or Wattage (W).                     charging current (mA).
    [cir] Battery Current Charging range     [cir] Battery maximum
     (amps).                                 discharging current (mA).
    [cir] Battery Nominal Voltage (V).       [cir] Battery upper limits
                                             charging voltage (V).
    [cir] Battery Current rating (mA).       Aerosol.
    [cir] Battery charging temperature
     limits ([deg]C).
    [cir] Battery discharge temperature
     limits ([deg]C).
    [cir] Battery end of discharge voltage   [cir] Inhaled aerosol
     (V).                                    temperature ([deg]C).
    [cir] Battery maximum charging current   [cir] Aerosol Particle
     (mA).                                   number concentration (#/
                                             cm\3\).
    [cir] Battery maximum discharging        [cir] Count median diameter
     current (mA).                           (nm).
    [cir] Battery upper limits charging      [cir] PM2.5 ([micro]g/
     voltage (V).                            m\3\).
    [cir] Power Delivery Unit (PDU)          Filter (if
     voltage operating range (V).            applicable).
    [cir] PDU current operating range        [cir] Filter efficiency (%)
     (mA).                                   {If no filter efficiency
                                             data is available for the
                                             products, include
                                             information sufficient to
                                             show that the cigar filter
                                             is unchanged [e.g., denier
                                             per filament (DPF), total
                                             denier (g/9000m), and
                                             filter density(g/
                                             cm\3\)]{time} .
    [cir] PDU wattage operating range        [cir] Filter ventilation
     (watts).                                (%).
    [cir] PDU temperature cut-off ([deg]C)   [cir] Filter pressure drop
     (if applicable)                         (mm H2O).
    [cir] PDU Current cut-off (mA) (if      ............................
     applicable).
 Aerosol.                           ............................
    [cir] Inhaled aerosol temperature       ............................
     ([deg]C).
    [cir] Aerosol Particle number           ............................
     concentration (#/cm\3\).
    [cir] Count median diameter (nm).       ............................
    [cir] PM2.5 ([micro]g/m\3\).            ............................
 Filter (if applicable).            ............................

[[Page 55429]]

 
    [cir] Filter efficiency (%) {If no      ............................
     filter efficiency data is available
     for the products, include information
     sufficient to show that the cigar
     filter is unchanged [e.g., denier per
     filament (DPF), total denier (g/
     9000m), and filter density(g/
     cm\3\)]{time} .
    [cir] Filter pressure drop (mm H2O).    ............................
    [cir] Filter length (mm).               ............................
    [cir] Filter diameter (mm).             ............................
    [cir] Filter ventilation (%).           ............................
------------------------------------------------------------------------

    (iii) Function. How the product is intended to function.
    (iv) Product pH and nicotine formulation. The pH of the product and 
the formulation of nicotine in the product, if applicable, including 
the form (e.g., unprotonated nicotine, nicotine salts) and quantity.
    (v) Fermentation process. For smokeless tobacco products and 
tobacco products that contain fermented tobacco (including naturally 
fermented tobacco), information on the fermentation process, including 
the following:
    (A) Description of the fermentation process;
    (B) Composition of the inoculum (starter culture) with genus and 
species name(s) and concentration(s) (if applicable);
    (C) Any step(s) taken to reduce endogenous microbes (e.g., cleaning 
of product contact surfaces);
    (D) Specifications and test data for pH, temperature, moisture 
content, and water activity;
    (E) Frequency of aeration or turning (if applicable);
    (F) Duration of fermentation;
    (G) Added ingredients;
    (H) Method used to stabilize or stop fermentation (e.g., heat 
treatment) (if applicable), including parameters of the method (e.g., 
length of treatment, temperature) and method validation data; and
    (I) Storage conditions of the fermented tobacco prior to further 
processing or packaging and duration of storage (if applicable).
    (vi) Heat treatment process. For tobacco products that are heat 
treated, the application must contain the following information 
regarding the heat treatment process:
    (A) Description of the heat treatment process;
    (B) Type of heat treatment;
    (C) Conditions of heat treatment, including time, temperature, and 
moisture; and
    (D) Method validation data, including microbial loads (including 
bacteria, spores, yeast, and fungi) and TSNAs before and after heat 
treatment.
    (vii) Shelf life and stability information. With the exception of 
applications for roll-your-own tobacco products and cigarettes that are 
not HTPs, the application must contain information on the stability of 
the tobacco product over the shelf life and including the following:
    (A) The length of the shelf life, a description of how the shelf 
life is determined, and a description of how shelf life is indicated on 
the tobacco product, if applicable;
    (B) Stability data assessed at the beginning (zero time), middle, 
and end of the expected shelf life. If a tobacco product does not have 
a defined shelf life, provide stability data over a specified amount of 
time and a justification for why that time period is appropriate. 
Stability testing must be performed for the microbial and chemical 
endpoints as follows: Microbial content data, including total aerobic 
microbial count and total yeast and mold count; water activity; 
tobacco-specific nitrosamines (TSNAs) yields (total TSNAs, N'-
nitrosonor-nicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone) (NNK)); and preservatives content.
    (C) Stability testing details for each microbial and chemical 
endpoint, including: The mean quantity and variance with unit of 
measures; the number of samples and measurement replicates for each 
sample; the methods used, including any deviation(s) from the methods, 
associated reference(s), and full validations reports for each method; 
the testing laboratory or laboratories and documentation showing that 
the laboratory or laboratories is (or are) accredited by a nationally 
or internationally recognized external accreditation organization; 
length of time between date of tobacco product manufacture and date(s) 
of testing; storage conditions of the tobacco product before it was 
tested; a statement that the testing was performed on a tobacco product 
in the same container closure system in which the tobacco product is 
intended to be marketed; and full test data (including quantitative 
acceptance (pass/fail) criteria, complete data sets, and a summary for 
the results) for all stability testing performed.
    (viii) Product and packaging design risks and misuse hazards. A 
review and assessment of reasonably foreseeable risks associated with 
the design of the tobacco product and its package that may occur during 
normal use of the tobacco product or during any foreseeable misuse of 
the product, including user error, which may cause illness, injury, or 
death not normally associated with the use of the tobacco product. The 
review and assessment must identify the measures taken to reduce or 
eliminate each risk associated with the design of the tobacco product 
and package.
    (3) Principles of operation. The applicant must provide a full 
statement of the principle or principles of operation of the tobacco 
product, including full narrative descriptions of:
    (i) The way in which a typical consumer will use the new tobacco 
product, including a description of how a consumer operates the 
product, how long a single unit of product is expected to last (e.g., 
total length of time of use to consume a unit, number of use sessions 
expected per unit), and, where applicable, how a consumer can change 
the product design and add or subtract ingredients;
    (ii) A justification for an applicant's determination of what 
constitutes a single unit of product as described in the PMTA; and
    (iii) Whether the product incorporates a heating source, and if so, 
a description of the heating source.
    (4) Product testing and analysis information. Each analysis 
required in this paragraph must be performed on test samples that 
reflect the finished tobacco product composition and design, and must 
be conducted using a sufficient sample size and number of

[[Page 55430]]

replicates to substantiate the results of the type of testing 
conducted. Additionally, the applicant must provide the following 
information:
    (i) The name and location of the testing laboratory or laboratories 
and documentation showing that the laboratory or laboratories is (or 
are) accredited by a nationally or internationally recognized external 
accreditation organization;
    (ii) The length of time between dates of manufacture and date(s) of 
testing;
    (iii) The storage conditions of the tobacco product before it was 
tested;
    (iv) The number of samples and measurement replicates for each 
sample;
    (v) A description of method procedure, method validation 
information and rationale for selecting each test method, including 
relevant voluntary testing standards, test protocols, quantitative 
acceptance criteria, line data, and a summary of the results;
    (vi) Reports of product formulation testing that include test 
protocols, quantitative acceptance criteria, line data, and a summary 
of the results, for each applicable design parameter; and
    (vii) Complete descriptions of any smoking or aerosol-generating 
regimens used for analytical testing that are not standardized or 
widely accepted by the scientific community, if applicable.
    (j) Manufacturing. The application must contain a full description 
of the methods used in, and the facilities and controls used for, the 
design (including design validation and design verification, to assess 
whether the tobacco product, as manufactured, performs in accordance 
with design specifications), manufacture, packing, and storage of the 
tobacco product in sufficient detail to demonstrate whether the product 
meets manufacturing specifications, can be manufactured in a manner 
consistent with the information submitted in the application, and 
conforms to the requirements of any regulations issued under section 
906(e) of the Federal Food, Drug, and Cosmetic Act, including:
    (1) A list of all manufacturing, packaging, storage, and control 
facilities for the product, including the facility name, address, and 
FEI number, if applicable, and a contact name and telephone number for 
a representative from each facility;
    (2) A narrative description, accompanied by a list and summary, of 
all standard operating procedures (SOPs) and examples of relevant forms 
and records for the following categories of information for all 
manufacturing, design controls, packing, and storage for the tobacco 
product:
    (i) Manufacturing and production process activities at each 
establishment, including a description of each establishment, all 
production steps, and process controls, process specifications with 
relevant acceptance criteria, and monitoring and acceptance activities;
    (ii) Managerial oversight and employee training related to the 
manufacture, processing, packing, and installation of the tobacco 
product, as applicable;
    (iii) Monitoring procedures and manufacturing controls for product 
design, product characteristics, and changes in products, 
specifications, methods, processes, or procedures, including a hazard 
analysis that details the correlation of the product design attributes 
with public health risk, as well as any mitigation strategies 
implemented;
    (iv) Activities related to identifying and monitoring suppliers and 
the products supplied (including, for example, purchase controls and 
product acceptance activities);
    (v) Handling of complaints, nonconforming products and processes, 
and corrective and preventative actions;
    (vi) Testing procedures carried out before the product is released 
to market, including:
    (A) A list and summary of any standards used for all testing 
methods;
    (B) Validation and verification activities for all test methods 
used to ensure that the tobacco product meets specifications;
    (C) Documentation of accreditation information for all testing 
laboratories;
    (D) Complete description of smoking or aerosol-generating regimes 
used for analytical testing, if any; and
    (E) Tobacco product specifications (including any physical, 
chemical, and biological specifications) and acceptance criteria for 
those specifications;
    (F) Reports of release testing performed on finished products to 
demonstrate conformity with established specifications, including test 
protocols, line data, and a summary of the results for each applicable 
testing.
    (k) Health risk investigations--(1) Study types. The application 
must contain full reports of all information, both favorable and 
unfavorable, published or known to, or which should reasonably be known 
to, the applicant concerning investigations, including nonclinical and 
human subject studies regarding the following topics. If no substantive 
information exists regarding the topics specified in Sec.  
1114.27(b)(1)(ii), including information from published literature or 
that may be bridged from an investigation of another tobacco product, 
an applicant may need to conduct its own investigation(s) to ensure 
substantive information is included in the PMTA to meet the application 
filing requirements.
    (i) Health risks of the product. The potential health risks of the 
tobacco product to users and nonusers, including potential exposures 
and information regarding risks to youth, young adults, and other 
relevant vulnerable populations, and whether the product may present 
different risks than other tobacco products, including:
    (A) The health effects of the constituents, including HPHCs, at the 
quantitative levels delivered to both users and nonusers under the 
range of conditions under which the product might be used;
    (B) The toxicological profile of the new tobacco product related to 
the route of administration, including the genotoxicity, 
carcinogenicity, reproductive toxicity, immunotoxicity, acute toxicity, 
and repeat dose (chronic) toxicity of the new tobacco product relative 
to other tobacco products. The toxicological profile also includes 
information on the toxicity of the ingredients, additives, and HPHCs, 
relative to the route of administration and the range of potential 
levels of exposure resulting from the use of, or exposure to, the new 
tobacco product, including studies which discuss the toxicological 
effects of any leachables and extractables that can appear from the 
container closure system and the ingredient mixture, such as additive 
or synergistic effects;
    (C) The pharmacological profile of the new tobacco product, 
including the pharmacokinetics, pharamacodynamics, metabolism, and 
elimination profile, of any of the ingredients, additives, and HPHCs 
for the range of potential levels of exposure resulting from the use 
of, or exposure to, the new tobacco product relative to other tobacco 
products. The applicant must specify whether the studies were conducted 
in vitro, in vivo, ex vivo, or in silico; and
    (D) The health risks of the tobacco product compared to other 
tobacco products on the market, never using tobacco products, quitting 
tobacco product use, and using the tobacco product in conjunction with 
other tobacco products.
    (ii) Impacts on tobacco use behavior of tobacco product users. How 
the product and its label, labeling, and advertising, to the extent 
that advertising has been studied, will affect the tobacco use behavior 
of tobacco product users, specifically considering

[[Page 55431]]

youth, young adults, and other relevant vulnerable populations, 
including:
    (A) The abuse liability of the tobacco product;
    (B) How users actually use the product, including use topography, 
product use frequency, use trends over time, and how such use affects 
the health risks of the product to individual users;
    (C) The likelihood that users will use the product in conjunction 
with other tobacco products;
    (D) The likelihood that current tobacco product users will start 
using the product;
    (E) The likelihood that current tobacco users who adopt the product 
will switch to or switch back to other tobacco products that may 
present increased risks to individual health; and
    (F) The likelihood that current tobacco users who may have 
otherwise quit using tobacco products will instead start or continue to 
use the product.
    (iii) Impacts on tobacco use initiation by nonusers, including 
youth, young adults, and other relevant vulnerable populations. The 
impact of the tobacco product and its label, labeling, or advertising, 
to the extent that advertising has been studied, on tobacco use 
initiation by nonusers, including:
    (A) The likelihood that consumers who have never used tobacco 
products, particularly youth, young adults, and other relevant 
vulnerable populations, will initiate use of the tobacco product;
    (B) The likelihood that nonusers of tobacco products who adopt the 
tobacco product will switch to other tobacco products that may present 
higher levels of individual health risk; and
    (C) The likelihood that former users of tobacco products will re-
initiate use with the tobacco product.
    (iv) Perceptions and use intentions. The impact of the product and 
its label, labeling, and advertising, to the extent that advertising 
has been studied, on individuals:
    (A) Perception of the product;
    (B) Use intentions; and
    (C) Ability to understand the labeling and instructions for use and 
use the product in accordance with those instructions.
    (v) Human factors. The impact of human factors on product risk, 
including discussion of use conditions, use environments, use related 
hazards, estimated use error risk, potential unintended uses, risk 
controls to ensure that harms and unintended consequences are 
minimized, and adverse experiences related to such uses.
    (2) Literature search. The applicant must conduct a literature 
search for each type of information described in paragraph (k)(1) of 
this section, and the application must contain a description of the 
literature search performed, including the databases searched and the 
date searched, search terms, reasons for inclusion or exclusion of 
documents, and the strategy for study quality assessment. The 
application must also contain a bibliography of all published studies 
and articles referenced in the application. If a literature search was 
performed and resulted in no information found, the application must 
contain a statement to that effect.
    (3) Study reports. The full report of each study included in the 
application must describe the specific product studied and include the 
following items, where applicable and to the extent reasonably 
available. For applicable items not contained in the full report of an 
investigation, the applicant must contain a description of the actions 
taken to obtain the information and why the document is not reasonably 
available.
    (i) Full copies of any published articles and other reference 
materials;
    (ii) Documentation of all actions taken to ensure the reliability 
of the study. For all studies, to the extent reasonably available or 
obtainable, the application must contain a certification that 
investigators do not have, or documentation fully disclosing, any 
financial conflicts of interest, such as the financial arrangements 
specified in the Financial Disclosure by Clinical Investigators 
regulation in part 54 of this chapter. Additionally, for nonclinical 
laboratory studies, the application must contain, for each study, 
documentation of all actions taken to ensure the reliability of the 
study, e.g., documentation of whether the study was conducted in 
accordance with good laboratory practices, such as those specified in 
part 58 of this chapter;
    (iii) Copies of all versions of protocols and amendments that were 
used in the study;
    (iv) Copies of all versions of investigator instructions, if any 
were produced in addition to the protocol;
    (v) The statistical analysis plan, including a detailed description 
of the statistical analyses used (including all variables, confounders, 
and subgroup analyses), the scientific rationale for the choice of 
sample sizes, and any amendments to the plan;
    (vi) Line data, including data definition files that include the 
names of the variables, codes, and formats in each dataset, and copies 
of programs and any necessary macro-programs used to create derived 
datasets, and the results included in the study reports;
    (vii) A list of sites and clinical investigators that conducted the 
study, including contact information and physical address(es);
    (viii) The location of all source data. If the site where the study 
was conducted has not maintained all of the source data, indicate where 
the data are located;
    (ix) The format of the records and data (e.g., electronic or hard 
copy);
    (x) A list of all sites that had early termination and the reason 
for early termination, if applicable;
    (xi) A list of contractors who participated in the study, the role 
of each contractor, and the initiation and termination dates of the 
participation of each contractor;
    (xii) A signed full report of all findings;
    (xiii) For human subject studies:
    (A) All versions of study materials (e.g., consent forms, 
questionnaires, stimuli) used;
    (B) All versions of case report forms used; and
    (C) Individual case report forms related to participant deaths, 
other serious and unexpected adverse experiences, withdrawals, and 
participant discontinuation where the study participant was exposed to 
the tobacco product that is the subject of the PMTA or similar 
products; and
    (xiv) For tobacco product perception and use intention studies that 
use advertising as stimuli, a statement describing whether the 
advertising used is representative of advertising that the applicant 
intends to use in marketing the product. If the advertising is not 
representative of the advertising an applicant intends to use in 
marketing the product, the applicant must describe whether the study 
results are still relevant to the likely impact of the advertising on 
tobacco product perceptions and use intentions.
    (l) The effect on the population as a whole. The application must 
contain an analysis and discussion of how the data and information 
contained in the application establish that permitting the tobacco 
product to be marketed would be appropriate for the protection of 
public health determined with respect to the population as a whole, 
including users and nonusers of the tobacco product. The analysis and 
discussion must integrate all of the information in the application 
regarding the product and its likely effects on health, and tobacco use 
behavior, including tobacco use cessation and initiation, to provide an 
overall assessment of the likely effect that the marketing of the 
tobacco product may have on overall tobacco-related morbidity and 
mortality.

[[Page 55432]]

    (m) Certification statement. The application must contain the 
following certification, with the appropriate information inserted (as 
indicated by parenthetical italicized text), signed by an authorized 
representative of the applicant:

    ``I (name of responsible official) on behalf of the applicant, 
(applicant name), hereby certify that the applicant will maintain 
all records to substantiate the accuracy of this application for the 
period of time required in 21 CFR 1114.45 and ensure that such 
records remain readily available to FDA upon request. I certify that 
this information and the accompanying submission are true and 
correct, that no material fact has been omitted, and that I am 
authorized to submit this on the applicant's behalf. I understand 
that under section 1001 of title 18 of the United States Code anyone 
who knowingly and willfully makes a materially false, fictitious, or 
fraudulent statement or representation in any matter within the 
jurisdiction of the executive, legislative, or judicial branch of 
the Government of the United States is subject to criminal 
penalties.''


Sec.  1114.9   Amendments.

    (a) General. FDA may request, or an applicant may submit on its own 
initiative, an amendment to a PMTA containing information that is 
necessary for FDA complete the review of a pending PMTA. An amendment 
must include the appropriate form and specify the STN assigned to the 
original submission and, if submitted other than at FDA's request, the 
reason for submitting the amendment. An amendment must also include the 
certification statement set forth in Sec.  1114.7(m), with the 
appropriate information inserted, and signed by an authorized 
representative of the applicant.
    (b) Review of an amendment. Submission of an amendment may affect 
the timing of review of an amended submission as follows:
    (1) If the amendment is a major amendment (e.g., an amendment that 
contains significant new data from a previously unreported study, 
detailed new analyses of previously submitted data, or substantial new 
manufacturing information), FDA will restart the 180-day review period 
after receipt of the amendment.
    (2) If FDA requests a minor amendment (i.e., an amendment that is 
not a major amendment) and receives a written response submitting the 
requested amendment, FDA may pause the review period for the number of 
days elapsed between the date of the request and the date that FDA 
receives the written response.
    (c) Failure to respond to amendment request. If FDA requests an 
amendment and the applicant does not respond within the time period 
specified in FDA's request, FDA may consider the applicant to have 
submitted a request to voluntarily withdraw the pending PMTA under 
Sec.  1114.11 and issue an acknowledgment letter notifying the 
applicant of the withdrawal.
    (d) No amendment to closed or withdrawn application. An applicant 
may not amend an application after FDA has closed the application 
through an action under Sec.  1114.29 or it has been withdrawn under 
Sec.  1114.11.


Sec.  1114.11  Withdrawal by applicant.

    (a) An applicant may at any time make a written request using the 
appropriate form to withdraw a PMTA that FDA has not acted on as 
described in Sec.  1114.29. The withdrawal request must state:
    (1) Whether the withdrawal is due to a health concern related to 
the tobacco product and, if so, a description of those concerns, 
including the extent, duration, and frequency of the health effects, 
and what gave rise to the concerns, such as reports of adverse 
experiences;
    (2) The application STN; and
    (3) The name(s) of the new tobacco product that is the subject of 
the application.
    (b) An application will be considered withdrawn when FDA issues an 
acknowledgement letter stating that the application has been withdrawn.
    (c) The application is an Agency record, even if withdrawn. FDA 
will retain the withdrawn application under Federal Agency records 
schedules. The availability of the withdrawn application will be 
subject to FDA's public information regulation in Part 20 of this 
chapter.


Sec.  1114.13  Change in ownership of an application.

    An applicant may transfer ownership of a PMTA. At or before the 
time of transfer, the new owner and the former owner must submit 
information to FDA using the appropriate form as follows:
    (a) The new and former owner must sign and submit a notice to FDA 
stating that all of the former applicant's rights and responsibilities 
relating to the PMTA have been transferred to the new owner. This 
notice must identify the name and address of the new owner and the PMTA 
transferred by tobacco product name(s) and STN.
    (b) The new owner must sign and submit a notice to FDA containing 
the following:
    (1) The new owner's commitment to agreements, promises, and 
conditions made by the former owner and contained in the application 
and marketing granted order, if applicable;
    (2) The date that the change in ownership is effective;
    (3) Either a statement that the new owner has a complete copy of 
the application, including all amendments, the marketing granted order 
(if applicable), and any records that are required to be kept under 
Sec.  1114.45, or a request for a copy of the application, including 
all amendments, and the modified risk order (if applicable) from FDA's 
files in accordance with part 20 of this chapter. In accordance with 
the Freedom of Information Act, FDA will provide a copy of the 
application to the new owner under the fee schedule in FDA's public 
information regulations in Sec.  20.45 of this chapter; and
    (4) A certification that no modifications have been made to the 
tobacco product since the application, including amendments (if any), 
was submitted to FDA.


Sec.  1114.15   Supplemental applications.

    (a) Supplemental PMTA submission. Applicants that have received a 
marketing granted order for a tobacco product may, as an alternative 
format of submitting an application that meets the content requirements 
of Sec.  1114.7, submit a supplemental PMTA to seek marketing 
authorization for modifications to such product, which result in a new 
tobacco product under section 910(a)(1) of the Federal Food, Drug, and 
Cosmetic Act. Supplemental PMTAs must include new information 
concerning modifications that create the new tobacco product but allow 
the applicant to satisfy the remaining application requirements by 
cross-referencing applicable content from the previously submitted PMTA 
for the original tobacco product. Applicants may submit supplemental 
PMTAs only for modifications that require the submission of limited new 
information or where specified in a rule under section 907 of the FD&C 
Act. Except as permitted in a rule under section 907 of the Federal 
Food, Drug, and Cosmetic Act, an applicant may not submit a 
supplemental PMTA where:
    (1) Modifications to the product that result in the new tobacco 
product require the submission of new information or revisions to the 
PMTA for the original product to the extent that reviewing a 
supplemental application for the new tobacco product would be 
confusing, cumbersome, or otherwise inefficient and submitting a 
standard PMTA under Sec.  1114.7 would better facilitate review.

[[Page 55433]]

    (2) The marketing granted order for the original tobacco product 
has been withdrawn; or
    (3) The marketing granted order for the original tobacco product 
has been temporarily suspended or is subject to temporary suspension or 
withdrawal proceedings by FDA, except where authorized in writing by 
FDA.
    (b) Required format. The supplemental PMTA must comply with format 
requirements of Sec.  1114.7(b), except that an applicant must include 
certain content in a supplemental PMTA by cross-referencing a PMTA, or, 
where applicable, a supplemental PMTA, for an original tobacco product 
that is owned by that applicant, and may include other content by 
cross-referencing a tobacco product master file and postmarket reports 
for the original tobacco product. FDA will not consider content 
included by cross-reference to other sources of information outside of 
the submission.
    (c) Required content. The supplemental PMTA must provide sufficient 
information for FDA to determine whether any of the grounds for denial 
listed in section 910(c)(2) of the Federal Food, Drug, and Cosmetic Act 
apply to the application.
    (1) The application must contain the full text of all the 
information described in the following sections:
    (i) General information that identifies the submission as a 
supplemental PMTA (as described in Sec.  1114.7(c));
    (ii) New product information (as described in paragraph (d) of this 
section);
    (iii) Statement of compliance with 21 CFR part 25 (as described in 
Sec.  1114.7(g));
    (iv) Labeling (as described in Sec.  1114.7(f)) if the labeling is 
not identical to the labeling submitted in the PMTA or postmarket 
reports for the original product;
    (v) Postmarket information (as described in paragraph (e) of this 
section); and
    (vi) Certification statement (as described in paragraph (f) of this 
section);
    (2) The application must include the following sections by cross-
reference to the PMTA for the original tobacco product and contain any 
additional information that is necessary to supplement or update the 
cross-referenced information:
    (i) Descriptive information (as described in Sec.  1114.7(d));
    (ii) Product samples (as described in Sec.  1114.7(e));
    (iii) Labeling (as described in Sec.  1114.7(f)) if the labeling is 
identical to the labeling that was submitted in the PMTA or postmarket 
reports for the original tobacco product;
    (iv) Summary of all research findings (as described in Sec.  
1114.7(h));
    (v) Product formulation (as described in Sec.  1114.7(i));
    (vi) Manufacturing (as described in Sec.  1114.7(j)); and
    (vii) Health risk investigations (as described in Sec.  1114.7(k)).
    (d) New product information. The application must contain a section 
that includes:
    (1) Full descriptions of each modification to the product and 
comparisons to the original product version described in the previously 
authorized PMTA;
    (2) A statement as to whether the new tobacco product, if it 
receives a marketing granted order, will replace the original tobacco 
product, will be a line extension of the original tobacco product, or 
will be introduced as an additional product by the same manufacturer;
    (3) All data and information relating to each modification to the 
product that would be required in an application under Sec.  1114.7; 
and
    (4) A concluding summary of how the new tobacco product meets the 
requirements to receive a marketing granted order, including how the 
data and information contained in both the supplemental PMTA and cross-
referenced from the previously authorized PMTA constitute valid 
scientific evidence and establishes that the PMTA meets the 
requirements of section 910(c) of the Federal Food, Drug, and Cosmetic 
Act to receive a marketing granted order, including that permitting the 
new tobacco product to be marketed would be appropriate for the 
protection of the public health determined with respect to the risks 
and benefits to the population as a whole, including users and nonusers 
of the tobacco product.
    (e) Postmarket reports. (1) If an applicant has submitted 
postmarket reports for the original tobacco product, the applicant must 
include all such reports in the application by cross-reference.
    (2) If an applicant is required to, but has not yet submitted a 
postmarket report, the applicant must submit a report as part of its 
application that contains all of the information for the original 
tobacco product that would otherwise be required in a report under 
Sec.  1114.41 covering the period of time from when it received a 
marketing granted order for the original tobacco product to when it 
submits the supplemental PMTA.
    (f) Certification statement. The application must contain the 
following certification, with the appropriate information inserted as 
indicated by parenthetical italicized text, signed by an authorized 
representative of the applicant:
    ``I, (name of responsible official), on behalf of (name of 
applicant), certify that (new tobacco product name) has a different 
(describe each modification to the product) than (name of original 
tobacco product) described in (STN of the PMTA for the original 
product) but is otherwise identical to (name(s) of original tobacco 
product). I certify that (name of applicant) understands this means 
there is no other modification to the materials, ingredients, 
design, composition, heating source, or any other feature of the 
original tobacco product. I also certify that (name of applicant) 
will maintain all records that substantiate the accuracy of this 
application and ensure that such records remain readily available to 
FDA upon request for the period of time required in 21 CFR 1114.45. 
I certify that this information and the accompanying submission are 
true and correct, and that I am authorized to submit this on the 
applicant's behalf. I understand that under section 1001 of title 18 
of the United States Code, anyone who knowingly and willfully makes 
a materially false, fictitious, or fraudulent statement or 
representation in any matter within the jurisdiction of the 
executive, legislative, or judicial branch of the Government of the 
United States is subject to criminal penalties.''


Sec.  1114.17  Resubmissions.

    (a) General. An applicant may, as an alternative format of 
submitting an application that meets the content requirements of Sec.  
1114.7 or 1114.15 (if applicable), submit a resubmission to address 
deficiencies set forth in a marketing denial order. The resubmission 
must contain new information necessary to address application 
deficiencies and cross-reference applicable content from the PMTA that 
received the marketing denial order. An applicant may utilize the 
resubmission format for the same tobacco product for which FDA issued a 
marketing denial order or a new tobacco product that results from 
modifications to the product necessary to address the deficiencies 
described in a marketing denial order. An applicant may not submit a 
resubmission when:
    (1) It incorporates new information or revisions to the PMTA for 
the original product to the extent that reviewing a resubmission for 
the new tobacco product would be confusing, cumbersome, or otherwise 
inefficient and submitting a standard PMTA under Sec.  1114.7 would 
better facilitate review; or
    (2) The marketing denial order states that the applicant may not 
submit a resubmission.

[[Page 55434]]

    (b) Required format. The resubmission must comply with format 
requirements of Sec.  1114.7(b), except that an applicant must include 
content in the resubmission by cross-referencing the PMTA, or, where 
applicable, supplemental PMTA, that received the marketing denial 
order. An applicant may also include content in a resubmission by 
cross-reference to a TPMF. FDA will not consider content included by 
cross-reference to other sources of information outside of the 
submission.
    (c) Required content. The resubmission must provide sufficient 
information for FDA to determine whether any of the grounds for denial 
listed in section 910(c)(2) of the Federal Food, Drug, and Cosmetic Act 
apply to the application.
    (1) The application must include the full text of the information 
described in the following paragraphs:
    (i) General information that identifies the submission as a 
resubmission (as described in paragraph Sec.  1114.7(c));
    (ii) Response to deficiencies (as described in paragraph (d) of 
this section); and
    (iii) Certification statement (as described in paragraph (e) of 
this section).
    (2) The application must include the following sections from the 
PMTA that received a marketing denial order by cross-reference to the 
PMTA and contain all additional information, in full text or by 
reference to a tobacco product master file, that is necessary to 
supplement or update the cross-referenced information:
    (i) Descriptive information (as described in Sec.  1114.7(d));
    (ii) Product samples (as described in Sec.  1114.7(e));
    (iii) Labeling (as described in Sec.  1114.7(f));
    (iv) Statement of compliance with 21 CFR part 25 (as described in 
Sec.  1114.7(g));
    (v) Summary of all research findings (as described in Sec.  
1114.7(h));
    (vi) Product formulation (as described in Sec.  1114.7(i));
    (vii) Manufacturing (as described in Sec.  1114.7(j)); and
    (viii) Health risk investigations (as described in Sec.  
1114.7(k)).
    (d) Response to deficiencies. (1) The application must include a 
section that lists and provides a separate response to each deficiency 
described by FDA in the original marketing denial order, including all 
data and information necessary to complete each response, and that also 
addresses any applicant-identified deficiencies.
    (2) Where an applicant modifies the product in a way that would 
result in a new tobacco product under section 910(a)(1) of the Federal 
Food, Drug, and Cosmetic Act in order to address the deficiencies, the 
application must also include:
    (i) A full description of each modification to the product and 
comparisons of that change to the original version of the product 
described in the previously submitted PMTA; and
    (ii) All data and information relating to each modification to the 
product that would be required in an application under Sec.  1114.7.
    (e) Certification statement. The application must contain one of 
the two following certifications that corresponds to the application, 
with the appropriate information inserted as indicated by parenthetical 
italicized text, signed by an authorized representative of the 
applicant.
    (1) Same tobacco product certification. An application for the same 
tobacco product must contain the following certification:

    ``I, (name of responsible official), on behalf of (name of 
applicant), certify that this submission for (new tobacco product 
name(s)) responds to all deficiencies outlined in the marketing 
denial order issued in response to (STN of the previously submitted 
PMTA) and the new tobacco product described herein is identical to 
the product described in the previously submitted PMTA. I certify 
that (name of applicant) understands this means there is no 
modification to the materials, ingredients, design, composition, 
heating source, or any other feature. I also certify that (name of 
applicant) will maintain all records that substantiate the accuracy 
of this statement, and ensure that such records remain readily 
available to FDA upon request for the period of time required in 21 
CFR 1114.45. I certify that this information and the accompanying 
submission are true and correct, and that I am authorized to submit 
this on the company's behalf. I understand that under section 1001 
of title 18 of the United States Code, anyone who knowingly and 
willfully makes a materially false, fictitious, or fraudulent 
statement or representation in any matter within the jurisdiction of 
the executive, legislative, or judicial branch of the Government of 
the United States is subject to criminal penalties.''

    (2) Different tobacco product certification. An application for a 
different tobacco product than the original tobacco product that 
results from changes necessary to address the deficiencies must contain 
the following certification:

    ``I, (name of responsible official), on behalf of (name of 
applicant), certify that this submission for (new tobacco product 
name(s)) responds to all deficiencies outlined in the marketing 
denial order issued in response to (STN of the previously submitted 
PMTA) and the new tobacco product described herein has a different 
(describe each modification to the product) than (name(s) of 
original tobacco product) described in (STN of the previously 
submitted PMTA) but is otherwise identical to (name(s) of original 
tobacco product) described in (STN of the previously submitted 
PMTA). I certify that (name of applicant) understands this means 
there is no modification to the materials, ingredients, design 
features, heating source, or any other feature of the original 
tobacco product, except for the (describe each modification to the 
tobacco product). I also certify that (name of applicant) will 
maintain all records that substantiate the accuracy of this 
statement, and ensure that such records remain readily available to 
FDA upon request for the period of time required in 21 CFR 1114.45. 
I certify that this information and the accompanying submission are 
true and correct, and that I am authorized to submit this on the 
company's behalf. I understand that under section 1001 of title 18 
of the United States Code, anyone who knowingly and willfully makes 
a materially false, fictitious, or fraudulent statement or 
representation in any matter within the jurisdiction of the 
executive, legislative, or judicial branch of the Government of the 
United States is subject to criminal penalties.''

Subpart C--FDA Review


Sec.  1114.25   Communication between FDA and applicants.

    During the course of reviewing an application, FDA may communicate 
with an applicant about relevant matters, including scientific, 
medical, and procedural issues that arise during the review process and 
inspections. These communications may take the form of telephone 
conversations, letters, electronic communications, or meetings, and 
will be documented in the administrative file in accordance with Sec.  
10.65 of this chapter.


Sec.  1114.27  Review procedure.

    (a) Acceptance review. (1) After an applicant submits a PMTA, FDA 
will perform an initial review of the PMTA to determine whether it may 
be accepted for further review. FDA may refuse to accept an application 
that:
    (i) Does not comply with the applicable format requirements in 
Sec.  1114.7(b), Sec.  1114.15, or Sec.  1114.17 (as applicable);
    (ii) Is not administratively complete because it does not appear to 
contain the information required by Sec.  1114.7 (excluding product 
samples), Sec.  1114.15 or Sec.  1114.17, as applicable;
    (iii) Does not pertain to a tobacco product subject to chapter IX 
of the Federal Food, Drug, and Cosmetic Act (as required by Sec.  
1105.10 of this chapter); or
    (iv) FDA can otherwise refuse to accept under Sec.  1105.10.

[[Page 55435]]

    (2) If FDA accepts an application for further review, FDA will 
issue an acknowledgement letter to the applicant that specifies the 
PMTA STN. If FDA determines that it will require product samples as 
part of the PMTA, it will send instructions on how and where to submit 
product samples, as described in Sec.  1114.7(e) of this chapter.
    (3) If FDA refuses to accept an application, FDA will issue a 
letter to the applicant identifying the deficiencies, where 
practicable, that prevented FDA from accepting the application.
    (b) Filing review. (1) After accepting a PMTA, FDA will make a 
threshold determination of whether the application contains sufficient 
information to permit a substantive review. FDA may refuse to file a 
PMTA if any of the following applies:
    (i) The PMTA does not contain sufficient information required by 
section 910(b)(1) of the Federal Food, Drug, and Cosmetic Act and by 
Sec.  1114.7, Sec.  1114.15, or Sec.  1114.17, as applicable, to permit 
a substantive review of the application;
    (ii) The application does not contain any substantive information, 
including information from published literature or bridged from an 
investigation of another tobacco product, regarding each of the 
following topics.
    (A) The health risks of the new tobacco product as described in 
either Sec.  1114.7(k)(1)(i)(A), (B), or (C));
    (B) The health risks of the new tobacco product compared to the 
health risks generally presented by products in the same product 
category as well as products in at least one different category that 
are used by the consumers an applicant expects will use its new tobacco 
product (as described in a portion of Sec.  1114.7(k)(1)(i)(D)).
    (C) The abuse liability of the new tobacco product (as set forth in 
Sec.  1114.7(k)(1)(ii)(A));
    (D) How consumers would be expected to actually use the product, 
such as use frequency, use trends over time, and how such use affects 
the health risks of the product to individual users (as described in 
Sec.  1114.7(k)(1)(ii)(B));
    (E) The potential impact that the marketing of the new tobacco 
product would have on the likelihood that current tobacco product users 
would change their tobacco product use behavior, such as starting to 
using the new tobacco product, using the product in conjunction with 
other tobacco products, or, after using the product, switching to or 
switch back to other tobacco products that may present increased risks 
to individual health (i.e., any of the information set forth in either 
Sec.  1114.7(k)(1)(ii)(C), (D), (E), or (F));
    (F) The impact of the tobacco product and its label, labeling, or 
advertising, to the extent that advertising has been studied, on 
tobacco product use behavior of current nonusers of tobacco products 
(i.e., any of the information described in Sec.  1114.7(k)(1)(iii));
    (G) The impact of the product and its label, labeling, or 
advertising, to the extent that advertising has been studied, on 
individuals' perception of the product and their use intentions (i.e., 
any of the information described in Sec.  1114.7(k)(1)(iv)); and
    (H) The ways in which human factors can affect the health risks of 
the new tobacco product (i.e., any of the information described in 
Sec.  1114.7(k)(1)(v));
    (iii) The PMTA contains a false statement of material fact;
    (iv) The PMTA is a supplemental PMTA that does not comply with 
Sec.  1114.15; or
    (v) The PMTA is a resubmission that does not comply with Sec.  
1114.17.
    (2) If FDA refuses to file an application, FDA will issue a letter 
to the applicant identifying the deficiencies, where practicable, that 
prevented FDA from filing the application.
    (3) If FDA files an application, FDA will issue a filing letter to 
the applicant.
    (c) Application review. (1) Except as described in this paragraph 
and Sec.  1114.9(b), within 180 days of receipt of an application 
described in section 910(b)(1) of the Federal Food, Drug, and Cosmetic 
Act meeting the filing requirements set out in 1114.27(b), FDA will 
complete its review of the PMTA and act on the application.
    (2) FDA will begin substantive review of the application after it 
is filed under paragraph (b) of this section. FDA may communicate with 
the applicant as set forth under Sec.  1114.25 to seek additional or 
clarifying information.
    (3) FDA may refer the PMTA or portions of the PMTA, upon its own 
initiative or applicant request, to TPSAC for reference and for the 
submission of a report and recommendation respecting the application, 
together with all underlying data and the reasons or basis for the 
recommendation.
    (4) FDA may conduct inspections of the applicant's manufacturing 
sites, and sites and entities involved with clinical and nonclinical 
research (including third parties and contract research organizations) 
to support FDA's review of the PMTA. Where an applicant prevents FDA 
from scheduling and conducting inspections that are necessary for FDA 
to complete its review of the PMTA in a timely manner, FDA may pause 
the 180-day review period for the number of days necessary to complete 
the inspection.
    (5) FDA may defer review of a PMTA for a new product that, if 
introduced or delivered for introduction into interstate commerce, 
would be adulterated or misbranded due to the manufacturer or 
importer's failure to comply with user fee payment and reporting 
requirements under part 1150.


Sec.  1114.29  FDA action on an application.

    After receipt of an application, FDA will:
    (a) Refuse to accept the application as described in Sec.  
1114.27(a);
    (b) Issue a letter administratively closing the application;
    (c) Issue a letter canceling the application if FDA finds that it 
mistakenly accepted the application or that the application was 
submitted in error;
    (d) Refuse to file the application as described in Sec.  
1114.27(b);
    (e) Issue a marketing granted order as described in Sec.  1114.31; 
or
    (f) Issue a marketing denial order as described in Sec.  1114.33.


Sec.  1114.31  Issuance of a marketing granted order.

    (a) FDA will issue a marketing granted order if it finds that none 
of the grounds for denial listed in section 910(c)(2) of the Federal 
Food, Drug, and Cosmetic Act apply. A marketing granted order becomes 
effective on the date it is issued.
    (b) FDA may include, as part of the marketing granted order:
    (1) Restrictions on the sale and distribution of the product, 
including restrictions on the access to, and the advertising and 
promotion of, the tobacco product, to the extent that it would be 
authorized to impose such restrictions under a regulation issued under 
section 906(d) of the Federal Food, Drug, and Cosmetic Act;
    (2) Any restrictions on the sales, distribution, advertising, and 
promotion of the new tobacco product that the applicant proposed to be 
included as part of a marketing granted order under section 
910(c)(1)(B) of the Federal Food, Drug, and Cosmetic Act to support a 
finding by FDA that permitting the product to be marketed would be 
appropriate for the protection of the public health; and
    (3) Requirements to establish and maintain records, and submit 
postmarket reports under section 910(f) of the Federal Food, Drug and 
Cosmetic Act in addition to those described in Sec.  1114.41, including 
but not limited to

[[Page 55436]]

information such as labeling, advertising, marketing, promotional 
materials, or marketing plans not previously submitted to FDA.


Sec.  1114.33  Issuance of a marketing denial order.

    (a) Issuance. FDA will issue a marketing denial order if:
    (1) Upon the basis of the information submitted as part of the 
application and any other information before FDA with respect to the 
new tobacco product, FDA finds that any of the grounds for denial 
listed in section 910(c)(2) of the Federal Food, Drug, and Cosmetic Act 
apply;
    (2) The applicant does not permit an authorized FDA employee, at a 
reasonable time and in a reasonable manner, an opportunity to:
    (i) Inspect the facilities and controls described in the 
application; or
    (ii) Have access to, copy, and verify all records pertinent to the 
application, which results in FDA finding that one or more of the 
grounds for denial specified in section 910(c)(2) of the Federal Food, 
Drug and Cosmetic Act apply.
    (b) Description of deficiencies. The marketing denial order will, 
where practicable, identify measures to remove the application from 
deniable form.


Sec.  1114.35  Withdrawal of a marketing granted order.

    (a) Grounds for withdrawal. FDA will withdraw a marketing granted 
order for a new tobacco product issued under this part if FDA 
determines that:
    (1) Any of the grounds for withdrawal under section 910(d)(1) of 
the Federal Food, Drug, and Cosmetic Act apply; or
    (2) Any postmarket requirement imposed by the marketing granted 
order or by this part has not been met, which results in FDA finding 
that one or more of the grounds for withdrawal specified in section 
910(d)(1) of the Federal Food, Drug and Cosmetic Act apply.
    (b) Advice and other information. (1) FDA may seek advice on 
scientific matters from any appropriate FDA advisory committee in 
deciding whether to withdraw a marketing granted order.
    (2) FDA may use information other than that submitted by the 
applicant in deciding whether to withdraw a marketing granted order.
    (c) Informal hearing. Prior to withdrawing a marketing granted 
order, FDA will offer the holder of the marketing granted order an 
opportunity for an informal hearing under part 16 of this chapter.
    (d) Order issuance. If the applicant does not request a hearing or, 
if after the part 16 hearing is held, the Agency decides to proceed 
with the withdrawal, FDA will issue to the holder of the marketing 
granted order an order withdrawing the marketing granted order for the 
new tobacco product.
    (e) Public notice. FDA will give the public notice of an order 
withdrawing a marketing granted order for a tobacco product and will 
announce the basis of the withdrawal.


Sec.  1114.37  Temporary suspension of a marketing granted order.

    (a) FDA will temporarily suspend a marketing granted order if FDA 
determines that there is a reasonable probability that the continued 
distribution of such tobacco product would cause serious, adverse 
health consequences or death, that is greater than ordinarily caused by 
tobacco products on the market.
    (b) Before temporarily suspending a marketing granted order of a 
tobacco product, FDA will offer the holder of the marketing granted 
order an opportunity for an informal hearing under part 16 of this 
chapter.
    (c) If, after offering the holder of the marketing granted order an 
opportunity for a part 16 hearing, the Agency decides to proceed with 
the temporary suspension, FDA will issue an order temporarily 
suspending the marketing granted order for a tobacco product.
    (d) After issuing an order temporarily suspending the marketing 
granted order, FDA will proceed expeditiously to withdraw the marketing 
granted order for the tobacco product.

Subpart D--Postmarket Requirements


Sec.  1114.39  Postmarket changes.

    A marketing granted order authorizes the marketing of a new tobacco 
product in accordance with the terms of the order. Prior to the 
introduction or delivery for introduction into interstate commerce of a 
new tobacco product that results from modification(s) to the product, 
an applicant must submit a new PMTA under Sec.  1114.7 or a 
supplemental PMTA under Sec.  1114.15 and obtain a marketing granted 
order for the new tobacco product, unless the new tobacco product can 
be legally marketed through another premarket pathway.


Sec.  1114.41   Reporting requirements.

    (a) Required reports. Each applicant that receives a marketing 
granted order must submit to FDA all information required by the terms 
of the marketing granted order and by this section as described below. 
Each postmarket report must be well-organized, legible, and written in 
English. Documents that have been translated from another language into 
English (e.g., original study documents written in a language other 
than English) must be accompanied by the original language version of 
the document, a signed statement by an authorized representative of the 
manufacturer certifying that the English language translation is 
complete and accurate, and a brief statement of the qualifications of 
the person that made the translation.
    (1) Periodic reports. Each applicant must submit a periodic report 
to the Center for Tobacco Products (CTP) within 60 calendar days of the 
reporting dates specified in the applicant's marketing granted order 
for the life of the order and as may be required for the submission of 
a supplemental PMTA under Sec.  1114.15. The report must include the 
following:
    (i) A cover letter that contains the PMTA STN, tobacco product 
name(s) (including the original name described in the PMTA if 
different), company name, date of report, and reporting period;
    (ii) A description of all changes made to the manufacturing, 
facilities, or controls during the reporting period, including:
    (A) A comparison of each change to what was described in the PMTA;
    (B) The rationale for making each change and, if any, a listing of 
any associated changes; and
    (C) The basis for concluding that each change does not result in a 
new tobacco product that is outside the scope of the marketing granted 
order and will not result in a finding that the marketing granted order 
must be withdrawn or temporarily suspended under section 910(d) of the 
Federal Food, Drug, and Cosmetic Act;
    (iii) An inventory of ongoing and completed studies about the 
tobacco product conducted by, or on behalf of, the applicant that are 
within the scope of Sec.  1114.7(k) and that have not been previously 
reported;
    (iv) Full reports of information published or known to, or which 
should be reasonably known to, the applicant concerning scientific 
investigations and literature about the tobacco product that have not 
been previously reported, including significant findings from 
publications not previously reported;
    (v) A summary and analysis of all serious and unexpected adverse 
experiences associated with the tobacco product that have been reported 
to the applicant or that the applicant is aware of, accompanied by a 
statement of any changes to the overall risk associated with the 
tobacco product, and a summary of any changes in the health

[[Page 55437]]

risks, including the nature and frequency of the adverse experience, 
and potential risk factors;
    (vi) A summary of sales and distribution of the tobacco product for 
the reporting period, to the extent that the applicant collects or 
receives such data, including:
    (A) Total U.S. sales reported in dollars, units, and volume with 
breakdowns by U.S. census region, major retail markets, and channels in 
which the product is sold;
    (B) The Universal Product Code that corresponds to the product(s) 
identified in the PMTA; and
    (C) Demographic characteristics of product(s) purchasers, such as 
age, gender, race or ethnicity, geographic region, and tobacco use 
status;
    (vii) A summary of the implementation and effectiveness of policies 
and procedures regarding verification of the age and identity of 
purchasers of the product; and
    (viii) A summary of all formative consumer research studies 
conducted (if any), among any audiences, in the formation of new 
labeling, advertising, marketing, or promotional materials, not 
previously submitted, including qualitative and quantitative research 
studies used to determine message effectiveness, consumer knowledge, 
attitudes, beliefs, intentions and behaviors toward using the products, 
and including the findings or these studies and copies of the stimuli 
used in testing;
    (xi) A summary of all consumer evaluation research studies 
conducted (if any), among any audiences, not previously submitted, to 
determine the effectiveness of labeling, advertising, marketing, or 
promotional materials and shifts in consumer knowledge, attitudes, 
beliefs, intentions, and behaviors toward using the products, and 
including the findings of these studies and copies of the stimuli used 
in testing;
    (xii) A summary of the creation and dissemination of the products' 
labeling, advertising, marketing, and promotional materials (if any), 
including a list of all entities involved and a description of their 
involvement, including a description of contractual agreements with 
such entities;
    (xiii) Specimens of all labeling and descriptions of all labeling 
changes that have not been previously submitted under section 905(i) of 
the Federal Food, Drug, and Cosmetic Act, including the date the 
labeling was first disseminated and the date when dissemination was 
completely terminated;
    (xiv) Full color copies of all advertising for the tobacco product 
that has not been previously submitted, and the original date the 
materials were first disseminated and the date when their dissemination 
was completely terminated;
    (xv) A description of the implementation of all advertising and 
marketing plans, not previously submitted to FDA, by channel and by 
product, including strategic creative briefs and paid media plans, and 
the dollar amount(s) and flighting of such plans, by channel and by 
product, including a description of any of the following activities 
that an applicant may have engaged in:
    (A) Use of competent and reliable data sources, methodologies, and 
technologies to establish, maintain, and monitor highly targeted 
advertising and marketing plans and media buys, including a list of all 
data sources used to target advertising and marketing plans and media 
buys;
    (B) Targeting of specific group(s) by age-range(s), including young 
adults, ages 21 to 24, and other demographic or psychographic 
characteristics that reflect the intended target audience, including 
the source of such data;
    (C) With respect to individuals below the minimum age of sale, 
actions taken to restrict access to the products and exposure to the 
products' labeling, advertising, marketing, or promotion, or other 
consumer-directed activities;
    (D) Use of owned, earned, shared, or paid media to create labeling 
for, advertise, market, or promote the product;
    (E) Use of partners, influencers, bloggers, or brand ambassadors to 
create labeling for, advertise, market, or promote the product;
    (F) Consumer engagements conducted by the applicant, on its behalf, 
or at its direction, including events at which the products were 
demonstrated and how access was restricted to individuals at or above 
the minimum age of sale;
    (G) Use of public-relations or other communications outreach to 
create labeling for, advertise, market, or promote the products;
    (xvi) A summary of media tracking and optimization, by channel, by 
product, and by audience demographics (e.g., age, gender, race/
ethnicity, geographic region), including a summary of any real-time 
digital media monitoring and including a summary of implementation of 
any corrective and preventive measures to identify, correct, and 
prevent delivery of advertising to individuals below the minimum age of 
sale, not previously submitted;
    (xvii) An analysis of the actual delivery of advertising 
impressions, by channel, by product, and by audience demographics, that 
have not been previously submitted, and verified against post-launch 
delivery-verification reports submitted to the applicant from an 
accredited source, where applicable;
    (xviii) Additional information required to be reported under the 
terms of a marketing granted order (if applicable); and
    (xix) An overall assessment of how the tobacco product continues to 
be appropriate for the protection of the public health.
    (2) Serious and unexpected adverse experience reporting. The 
applicant must report all serious and unexpected adverse experiences 
associated with the tobacco product that have been reported to the 
applicant or of which the applicant is aware to CTP's Office of Science 
through the Health and Human Services' Safety Reporting Portal or in 
another manner designated by FDA (if applicable) within 15 calendar 
days after the report is received by the applicant.
    (b) FDA review of postmarket reports. (1) As part of its review of 
a postmarket report, FDA may require the applicant to submit additional 
information to enable it to determine whether a change results in a new 
tobacco product, or to facilitate a determination of whether there are 
or may be grounds to withdraw or temporarily suspend the marketing 
granted order.
    (2) FDA may notify an applicant that FDA has determined that a 
change described in a periodic report made under this section results 
in a new tobacco product outside the scope of the marketing granted 
order, requiring the submission of a new PMTA under Sec.  1114.7 or a 
supplemental PMTA under Sec.  1114.15 and issuance of a marketing 
granted order if the applicant seeks to market the new tobacco product, 
unless the new tobacco product can be legally marketed through a 
different premarket pathway.

Subpart E--Miscellaneous


Sec.  1114.45   Record retention.

    (a) Record retention by the applicant. (1) Each applicant that 
receives a marketing granted order must maintain all records necessary 
to facilitate a determination of whether there are or may be grounds to 
withdraw or temporarily suspend the marketing granted order, including 
records related to both the application and postmarket reports, and 
ensure that such records remain readily available to the Agency upon 
request (including where records are maintained by a third party on an 
applicant's behalf). These records include, but are not limited to:

[[Page 55438]]

    (i) All documents submitted to FDA as part of an application, 
periodic postmarket reports, and adverse experience reports;
    (ii) All documentation demonstrating whether each:
    (A) Nonclinical laboratory study was conducted in accordance with 
good laboratory practices that support the reliability of the results, 
such as the records described in part 58 of this chapter; and
    (B) Clinical investigator has any financial conflicts of interest 
that may be a source of bias, such as the documentation described in 
part 54 of this chapter;
    (iii) All other documents generated during the course of a study 
necessary to substantiate the study results, including:
    (A) Communications related to the investigation between the 
investigator and the sponsor, the monitor, or FDA; and
    (B) All source data for human subject and nonclinical 
investigations included in the application and postmarket reports, 
including records of each study subject's case history and exposure to 
tobacco products used in the investigation, including case report 
forms, progress notes, hospital records, clinical charts, X-rays, lab 
reports, and subject diaries; and
    (iv) A list of each complaint, and a summary and analysis of all 
complaints, associated with the tobacco product reported to the 
applicant;
    (2) These records must be legible, in the English language, and 
available for inspection and copying by officers or employees duly 
designated by the Secretary. Documents that have been translated from 
another language into English (e.g., original study documents written 
in a language other than English) must be accompanied by the original 
language version of the document, a signed statement by an authorized 
representative of the manufacturer certifying that the English language 
translation is complete and accurate, and a brief statement of the 
qualifications of the person that made the translation.
    (3) All records must be retained as follows:
    (i) Records related to and including the PMTA must be retained for 
a period of at least 4 years from the date that the marketing granted 
order is issued.
    (ii) Records related to postmarket reports, including both periodic 
and adverse experience reports, must be retained for a period of at 
least 4 years from the date the report was submitted to FDA or until 
FDA inspects the records, whichever occurs sooner.
    (b) Record retention by FDA. FDA will retain information submitted 
to it in accordance with Federal Agency Records schedules and will 
provide a copy to persons to whom such information may legally be 
disclosed on request under the fee schedule in FDA's public information 
regulations in Sec.  20.45 of this chapter.


Sec.  1114.47  Confidentiality.

    (a) General. FDA will determine the public availability of any part 
of an application and other content related to such an application, 
including all data and information submitted with or incorporated by 
reference in the application, under this section and part 20 of this 
chapter.
    (b) Confidentiality of data and information prior to an order. 
Prior to issuing an order under this part:
    (1) FDA will not publicly disclose the existence of an application 
unless:
    (i) The applicant has publicly disclosed or acknowledged (as such 
disclosure is defined in Sec.  20.81 of this chapter), or has 
authorized FDA in writing to publicly disclose or acknowledge, that the 
applicant has submitted an application to FDA; or
    (ii) FDA refers the application to TPSAC.
    (2) Except as described in paragraph (b)(4) of this section, FDA 
will not disclose the existence or contents of an FDA communication 
with an applicant regarding its application except to the extent that 
the applicant has publicly disclosed or acknowledged, or authorized FDA 
in writing to publicly disclose or acknowledge, the existence or 
contents of that particular FDA communication.
    (3) Except as described in paragraph (b)(4) of this section, FDA 
will not disclose the existence or contents of information contained in 
an application unless the applicant has publicly disclosed or 
acknowledged, or authorized FDA in writing to publicly disclose or 
acknowledge, the existence or contents of that particular information. 
If the applicant has publicly disclosed or acknowledged, or authorized 
FDA in writing to publicly disclose or acknowledge, the existence or 
contents of that particular information contained in an application, 
FDA may disclose the existence or contents of that particular 
information.
    (4) If FDA refers an application to TPSAC, the contents of the 
application will be available for public disclosure, except information 
that is exempt from disclosure under part 20 of this chapter.
    (c) Disclosure of data and information after issuance of a 
marketing granted order. After FDA issues a marketing granted order, it 
may make the following information related to the application and order 
available for public disclosure upon request or at FDA's own 
initiative, including information from amendments to the application 
and FDA's reviews of the application:
    (1) All data previously disclosed to the public, as such disclosure 
is defined in Sec.  20.81 of this chapter;
    (2) Any protocol for a test or study, unless it is shown to fall 
within the exemption established for trade secrets and confidential 
commercial information in Sec.  20.61 of this chapter;
    (3) Information and data submitted to demonstrate that the new 
tobacco product is appropriate for the protection of public health, 
unless the information is shown to fall within the exemptions 
established in Sec.  20.61 of this chapter for trade secrets and 
confidential commercial information, or in Sec.  20.63 of this chapter 
for personal privacy;
    (4) Correspondence between FDA and the applicant, including any 
requests FDA made for additional information and responses to such 
requests, and all written summaries of oral discussions between FDA and 
the applicant, unless it is shown to fall within the exemptions in 
Sec.  20.61 of this chapter for trade secrets and confidential 
commercial information, or in Sec.  20.63 of this chapter for personal 
privacy;
    (5) In accordance with Sec.  25.51(b) of this chapter, the 
environmental assessment or, if applicable, the claim for categorical 
exclusion from the requirement to submit an environmental assessment 
under part 25 of this chapter; and
    (6) Information and data contained in postmarket reports submitted 
to FDA, unless the information is shown to fall within the exemptions 
established in Sec.  20.61 of this chapter for trade secrets and 
confidential commercial information, or in Sec.  20.63 of this chapter 
for personal privacy
    (d) Disclosure of data and information after the issuance of a 
marketing denial order. After FDA issues a marketing denial order, FDA 
may make certain information related to the application and the order 
available for public disclosure upon request or at FDA's own initiative 
unless the information is otherwise exempt from disclosure under part 
20 of this chapter. Information FDA may disclose includes, but is not 
limited to the tobacco product category (e.g., cigarette), tobacco 
product subcategory (e.g., filtered, combusted cigarette), package 
size, product quantity, characterizing flavor, and the basis for the 
marketing denial order.

[[Page 55439]]

Sec.  1114.49  Electronic submission.

    (a) Electronic format requirement. Applicants submitting any 
documents to the Agency under this part must provide all required 
information to FDA using the Agency's electronic system, except as 
provided in paragraph (b) of this section. The application and all 
supporting information must be submitted in an electronic format that 
FDA can process, review, and archive.
    (b) Waivers from electronic format requirement. An applicant may 
submit a written request, that is legible and in English, to the Center 
for Tobacco Products asking that FDA waive the requirement for 
electronic format and content. Waivers will be granted if use of 
electronic means is not reasonable for the applicant. To request a 
waiver, applicants can send the written request to the address included 
on our website (www.fda.gov/tobacco-products). The request must include 
the following information:
    (1) The name and address of the applicant, a list of individuals 
authorized by the applicant to serve as the contact person and contact 
information. If the applicant has submitted a PMTA previously, the 
regulatory correspondence should also include any identifying 
information about the previous submission.
    (2) A statement that creation and/or submission of information in 
electronic format is not reasonable for the applicant, and an 
explanation of why creation and/or submission in electronic format is 
not reasonable. This statement must be signed by the applicant or by a 
representative who is authorized to make the declaration on behalf of 
the applicant.
    (c) Paper submission. An applicant who has obtained a waiver from 
filing electronically must send a written application through the 
Document Control Center to the address provided in the FDA 
documentation granting the waiver.

    Dated: September 21, 2021.
Janet Woodcock,
Acting Commissioner of Food and Drugs.
[FR Doc. 2021-21011 Filed 10-4-21; 8:45 am]
BILLING CODE 4164-01-P


