[Federal Register Volume 87, Number 123 (Tuesday, June 28, 2022)]
[Proposed Rules]
[Pages 38313-38331]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-13309]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 314

[Docket No. FDA-2021-N-0862]
RIN 0910-AH62


Nonprescription Drug Product With an Additional Condition for 
Nonprescription Use

AGENCY: Food and Drug Administration, Department of Health and Human 
Services (HHS).

ACTION: Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA, the Agency, or we) is 
proposing to establish requirements for a nonprescription drug product 
with an additional condition for nonprescription use (ACNU). The 
proposed rule, if finalized, would establish requirements for a 
nonprescription drug product that has an ACNU that an applicant must 
implement to ensure appropriate self-selection or appropriate actual 
use, or both, by consumers without the supervision of a healthcare 
practitioner. The proposed rule is intended to increase options for 
applicants to develop and market safe and effective nonprescription 
drug products, which could improve public health by broadening the 
types of nonprescription drug products available to consumers.

DATES: Either electronic or written comments on the proposed rule must 
be submitted by October 26, 2022. Submit comments (including 
recommendations) on information collection issues under the Paperwork 
Reduction Act of 1995 by July 28, 2022.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of October 26, 2022. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

[[Page 38314]]

     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2021-N-0862 for ``Nonprescription Drug Product with an Additional 
Condition for Nonprescription Use.'' Received comments, those filed in 
a timely manner (see ADDRESSES), will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    Submit comments on information collection issues under the 
Paperwork Reduction Act of 1995 to the Office of Management and Budget 
(OMB) at https://www.reginfo.gov/public/do/PRAMain. Find this 
particular information collection by selecting ``Currently Under 
Review--Open for Public Comments'' or by using the search function. The 
title of this proposed collection is ``Premarket applications, 
postmarketing reports and recordkeeping, and labeling for 
Nonprescription Drug Products With an Additional Condition for 
Nonprescription Use.''

FOR FURTHER INFORMATION CONTACT: 
    With regard to the proposed rule: Chris Wheeler, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 3330, Silver Spring, MD 20993-0002, 301-
796-0151, [email protected].
    With regard to the information collection: Domini Bean, Office of 
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Need for the Regulation
    B. FDA's Current Regulatory Framework
    C. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
    A. Applicability
    B. Definitions (Proposed Sec. Sec.  314.56(a) and 201.67(b))
    C. Separate Application Required for a Nonprescription Drug 
Product With an ACNU (Proposed Sec.  314.56(b))
    D. Specific Requirements for an Application for a 
Nonprescription Drug Product With an ACNU (Proposed Sec.  314.56(c))
    E. Nonprescription and Prescription Approval and Simultaneous 
Marketing (Proposed Sec.  314.56(d))
    F. Refusal To Approve an Application With an ACNU (Proposed 
Sec. Sec.  314.125(b)(20) and 314.127(a)(15))
    G. Other Postmarketing Reports (Proposed Sec.  314.81(b)(3)(v))
    H. General Labeling Requirements (Proposed Sec.  201.67(c))
    I. Format Requirements for Required ACNU Statement (Proposed 
Sec.  201.67(d))
    J. Exemption From Adequate Directions for Use (Proposed Sec.  
201.130)
    K. Misbranding (Proposed Sec.  201.67(e))
VI. Proposed Effective Date
VII. Preliminary Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to establish requirements for a nonprescription 
drug product with an additional condition for nonprescription use 
(ACNU), which is a drug product that could be marketed without a 
prescription if an applicant implements an additional condition to 
ensure appropriate self-selection or appropriate actual use, or both, 
by consumers without the supervision of a healthcare practitioner. 
Currently, nonprescription drug products are limited to drugs that can 
be labeled with sufficient information for consumers to appropriately 
self-select and use the drug product. For certain drug products, 
limitations of labeling present challenges for adequate communication 
of information needed for consumers to appropriately self-select or use 
the drug product without the supervision of a healthcare practitioner. 
The proposed rule is intended to increase options for applicants to 
develop and market safe and effective nonprescription drug products, 
which could improve public health by broadening the types of 
nonprescription drug products available to consumers.

B. Summary of the Major Provisions of the Proposed Rule

    The proposed rule, if finalized, would establish requirements for a 
nonprescription drug product with an ACNU. The evidentiary standards 
that an application must meet under the Federal Food, Drug, and 
Cosmetic Act (FD&C Act) and current FDA regulations for demonstrating 
safety and effectiveness would continue to apply to nonprescription 
drug products approved with an ACNU. This proposed rule would establish 
additional application requirements, labeling requirements, and 
postmarketing reporting requirements for a nonprescription drug product 
with an ACNU.
    The proposed rule would establish the requirements for a new drug 
application (NDA) or abbreviated new drug application (ANDA) for a 
nonprescription drug product with an ACNU. An applicant would be 
required

[[Page 38315]]

to submit a separate application for the approval of a nonprescription 
drug product with an ACNU, rather than a supplement to an application 
approved as a prescription drug product. In addition to applicable 
existing application requirements, NDA applicants would also be 
required to describe the ACNU and submit information to support the 
ACNU.
    The proposed rule would clarify that an ACNU would constitute a 
meaningful difference between a prescription drug product and a 
nonprescription drug product that makes the nonprescription drug 
product safe and effective for use without the supervision of a 
healthcare practitioner licensed by law to administer the drug. For 
instance, two drug products could have the same active ingredient, 
dosage form, strength, route of administration, and indication, with 
one made available as a nonprescription drug product with an ACNU and 
the other product made available only by prescription.
    The proposed rule would specify that FDA would refuse to approve an 
NDA or ANDA for a nonprescription drug product with an ACNU if the 
application fails to meet the applicable requirements of proposed Sec.  
314.56 (21 CFR 314.56).
    The proposed rule would establish postmarketing reporting 
requirements for a nonprescription drug product with an ACNU. NDA and 
ANDA applicants would be required to submit a report with information 
concerning any incident of failure in the implementation of an ACNU, 
such as a consumer gaining access to the drug product without 
fulfilling the ACNU.

C. Legal Authority

    FDA's proposal to establish requirements for a nonprescription drug 
product with an ACNU is authorized by sections 201(n), 502, 503(b), 
505, and 701(a) of the FD&C Act (21 U.S.C. 321(n), 352, 353(b), 355, 
and 371(a)).

D. Costs and Benefits

    The proposed rule, if finalized, would establish, for any 
applicant, the requirements for a nonprescription drug product with an 
ACNU. Compared to the traditional labeling paradigm of nonprescription 
drug products, this approved ACNU in addition to the labeling would 
ensure the appropriate self-selection, appropriate use, or both, of a 
drug product. We expect that this proposed rule, if finalized, would 
expand consumer access to certain drug products in a nonprescription 
setting.
    Greater access to drug products would allow consumers to treat 
certain medical conditions using nonprescription drug products with an 
ACNU without the supervision of a healthcare practitioner. We estimate 
a reduction in access costs to consumers who could transfer from a 
prescription to a nonprescription drug product with an ACNU. Our 
primary estimate for this item is $26.70 with a range of $0 to $53.40 
per consumer per purchase. There may also be cost savings associated 
with a potential reduction in the number of repetitive meetings between 
FDA and industry. Our primary estimate is $55,469 per applicant with a 
range of $45,260 to $66,174. Government and private insurance payers 
may also experience cost savings because the availability of 
nonprescription drug products with an ACNU may decrease future medical 
costs and the number of submitted insurance claims. In addition, we 
assume that applicants would submit applications when they believe that 
the profits from a potential approval would exceed the costs of the 
application. We lack information to monetize these potential profits 
and costs. We do not monetize our estimates of benefits over a 10-year 
horizon because of the high uncertainty about the number of applicants, 
applications, potential approvals, the number of purchases that might 
occur, and consumer preferences to switch products. For details, see 
the Preliminary Regulatory Impact Analysis (PRIA), the Uncertainty and 
Sensitivity section, as well as the Appendix of the same document.
    Monetized costs include a one-time cost of reading and 
understanding the rule for those applicants potentially interested in 
submitting applications for their nonprescription drug products with an 
ACNU. Our primary estimate of these costs equals $821 with a range of 
$379 and $1,264 using a 7-percent discount rate annualized over a ten-
year horizon.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

------------------------------------------------------------------------
             Abbreviation/acronym                    What it means
------------------------------------------------------------------------
ACNU.........................................  Additional Condition for
                                                Nonprescription Use.
ANDA.........................................  Abbreviated New Drug
                                                Application.
DFL..........................................  Drug Facts Labeling.
FAERS........................................  FDA Adverse Event
                                                Reporting System.
FD&C Act.....................................  Federal Food, Drug, and
                                                Cosmetic Act.
FDA..........................................  Food and Drug
                                                Administration.
ICSR.........................................  Individual Case Safety
                                                Report.
NDA..........................................  New Drug Application.
NDC..........................................  National Drug Code.
OMB..........................................  Office of Management and
                                                Budget.
OTC..........................................  Over-the-Counter.
PDP..........................................  Principal Display Panel.
RLD..........................................  Reference Listed Drug.
------------------------------------------------------------------------

III. Background

A. Need for the Regulation

    Nonprescription drug products are important for the treatment of 
many conditions and diseases, although at present most nonprescription 
drug products are intended to provide temporary relief of minor 
symptoms or self-diagnosable, self-limited conditions and diseases, 
rather than chronic diseases. Unlike prescription drug products, 
nonprescription drug products may be accessed and used safely and 
effectively by consumers without the supervision of a healthcare 
practitioner when certain conditions are met. Currently, 
nonprescription drug products are limited to drugs that can be labeled 
with sufficient information to enable consumers to appropriately self-
select and use the drug product without the supervision of a healthcare 
practitioner. Self-selection is the decision consumers make to use or 
not to use a drug product based on reading the information on the drug 
product labeling and applying knowledge of their personal medical 
history (Ref. 1). Nonprescription drug products are usually available 
for consumers to purchase at pharmacies, supermarkets,

[[Page 38316]]

or other retail locations, and from online retailers.
    FDA recognizes the potential benefit of providing consumers with 
access to additional types of nonprescription drug products, such as 
some drug products that are currently available only by prescription 
and that treat chronic diseases or conditions. However, there are 
certain drug products that an applicant may seek to market on a 
nonprescription basis where labeling alone cannot adequately 
communicate the information needed for consumers to appropriately self-
select, use, or both self-select and use the drug product safely and 
effectively without the supervision of a healthcare practitioner.
    The proposed rule has the potential to broaden the types of drug 
products that FDA could approve as nonprescription. Under the proposed 
rule, when labeling alone is not sufficient to ensure that the consumer 
can appropriately self-select or appropriately actually use, or both, a 
drug product correctly in a nonprescription setting, an applicant may 
submit an application proposing an ACNU that a consumer must 
successfully fulfill to obtain the nonprescription drug product with an 
ACNU. For example, an applicant may submit an application for a 
nonprescription drug product with an ACNU that enables a consumer to 
treat a chronic condition that currently does not have a 
nonprescription treatment. The availability of nonprescription drug 
products with an ACNU may provide public health benefits by 
facilitating consumers' self-care and autonomy over their medical 
treatment (Ref. 2).

B. FDA's Current Regulatory Framework

    There are two regulatory pathways to bring a nonprescription drug 
product to market in the United States: (1) the over-the-counter (OTC) 
drug review process under section 505G of the FD&C Act (21 U.S.C. 
355h); and (2) the new drug application process under section 505 of 
the FD&C Act. Under the OTC drug review process, a nonprescription drug 
product may be marketed without an approved NDA or ANDA under section 
505 of the FD&C Act if the nonprescription drug product meets the 
requirements of section 505G of the FD&C Act, and other applicable 
requirements.
    FDA approves drugs as either prescription or nonprescription drug 
products under section 505 of the FD&C Act. A drug must be dispensed by 
prescription when it is not safe for use except under the supervision 
of a healthcare practitioner licensed by law to administer such drug 
product because of its toxicity or other potentiality for harmful 
effect, or the method of its use, or the collateral measures necessary 
to its use (see section 503(b)(1) of the FD&C Act). If the approved 
drug does not meet the criteria for prescription-only dispensing, it 
may be marketed as nonprescription.
    Section 503(b)(4)(B) of the FD&C Act provides that a drug product 
to which the prescription provisions of the FD&C Act do not apply 
(i.e., a nonprescription drug product) will be deemed to be misbranded 
if at any time before dispensing, the label of the drug bears the ``Rx 
only'' symbol. Read together with section 503(b)(4)(A) of the FD&C Act, 
which requires prescription drug products to bear the ``Rx only'' 
symbol, this effectively means that absent a meaningful difference 
between the products, simultaneous marketing of two drug products with 
the same active ingredient as both a prescription and a nonprescription 
drug would result in one of the two products being misbranded. Examples 
of meaningful differences that can make a prescription drug product 
safe and effective only under the supervision of a healthcare 
practitioner licensed by law to administer such drug include the 
indication, strength, route of administration, dosage form, or patient 
population (see 83 FR 13994 at 13995, April 2, 2018; see also 70 FR 
52050, September 1, 2005).
    An applicant may submit an NDA for a nonprescription drug product 
using the pathways described in section 505(b)(1) or (2) of the FD&C 
Act to market a new drug product. A 505(b)(1) NDA includes full reports 
of investigations to demonstrate that the proposed drug product is safe 
and effective under the conditions prescribed, recommended, or 
suggested in its proposed labeling (see sections 505(d) and (b)(1) of 
the FD&C Act). Thus, an NDA for a nonprescription drug product must 
include, among other things, information to demonstrate that consumers 
can appropriately self-select and use the proposed drug product safely 
and effectively without the supervision of a healthcare practitioner. 
An NDA submitted under section 505(b)(2) of the FD&C Act also includes 
information to demonstrate that the proposed drug product is safe and 
effective under the conditions prescribed, recommended, or suggested in 
its proposed labeling, but at least some of the information required 
for approval comes from studies not conducted by or for the applicant 
and for which the applicant has not obtained a right of reference or 
use (21 U.S.C. 355(b)(2)).
    Applicants may submit an ANDA using the pathway described in 
section 505(j) of the FD&C Act for a drug product that is a generic 
version of a previously approved drug product. An ANDA for a 
nonprescription drug product generally references a nonprescription 
drug product previously approved under section 505(c) of the FD&C Act 
(known as the RLD) and relies on the Agency's finding that the RLD is 
safe and effective. An ANDA generally must contain information to show 
that the proposed generic product (1) is the same as the RLD with 
respect to the active ingredient(s), conditions of use, route of 
administration, dosage form, strength, labeling (with certain 
permissible differences) and (2) is bioequivalent to the RLD. The 
procedures and requirements for the submission and approval of NDAs, 
ANDAs, and supplements to those applications are provided in part 314 
(21 CFR part 314).
    Generally, nonprescription drug products must be labeled with 
adequate directions for use so the consumer: (1) can use the drug 
product safely and for the purposes for which it is intended and (2) 
make an appropriate self-selection decision and appropriately use the 
nonprescription drug product (see section 502(f)(1) of the FD&C Act and 
Sec.  201.5 (21 CFR 201.5)). Consumer studies can help demonstrate that 
the requirement for adequate directions for use is met. These studies 
may include label comprehension studies (Ref. 3), self-selection 
studies (Ref. 1), actual-use studies, and other human factors studies.
    Nonprescription drug products must also comply with applicable 
labeling requirements under part 201 (21 CFR part 201), including the 
format and content requirements for OTC drug product labeling under 
Sec.  201.66. Labeling created to satisfy the requirements in Sec.  
201.66 is commonly referred to as the Drug Facts labeling (DFL). The 
DFL is intended to enable consumers to appropriately self-select and 
use the nonprescription drug product safely and effectively. In 
addition to the DFL, FDA may approve additional labeling for 
nonprescription drug products.

C. History of the Rulemaking

    FDA has received a number of inquiries from stakeholders about 
whether applications may be submitted for nonprescription drug products 
with one or more additional conditions that consumers must fulfill to 
ensure that the drug product is safe and effective for nonprescription 
use. As explained in detail below, FDA held a public hearing

[[Page 38317]]

and participated in a series of workshops convened by the Engelberg 
Center for Health Care Reform at the Brookings Institution (Brookings 
Institution) to solicit public input on expanding the approval of 
nonprescription drug products. FDA used stakeholder input from the 
public hearing and the workshops to develop the proposed rule.
1. FDA 2012 Public Hearing
    In the Federal Register of February 28, 2012 (77 FR 12059), FDA 
announced a public hearing under part 15 (21 CFR part 15) entitled 
``Using Innovative Technologies and Other Conditions of Safe Use to 
Expand Which Drug Products Can Be Considered Nonprescription'' (2012 
public hearing). FDA held this public hearing on March 22 and 23, 2012, 
to: (1) seek input from interested stakeholders on a potential new 
paradigm where FDA would approve certain drug products for 
nonprescription use with certain conditions specific to a drug product 
that would otherwise require a prescription and (2) obtain information 
and comments on the feasibility of this paradigm and its potential 
benefits and costs. As part of the public hearing, FDA requested 
information and public comment on the types of technology that could be 
used; the types of conditions of safe use; and the potential impacts on 
pharmacies, consumers, and healthcare practitioners, as well as other 
issues that might arise under the paradigm. FDA received comments from 
various stakeholders, including consumers, private industry, healthcare 
professional associations, academic institutions, and patient advocacy 
organizations, on a broad range of topics such as: (1) access to care, 
(2) medication nonadherence, (3) practitioner oversight, (4) potential 
effect on healthcare and healthcare costs, (5) potential impact on 
medical conditions or diseases, (6) use of diagnostic aids and 
technologies as possible conditions of safe use, and (7) potential 
barriers to successful implementation and adoption (see Docket No. FDA-
2012-N-0171).
2. Brookings Institution Workshops
    The Brookings Institution convened a series of three expert 
workshops, based on a cooperative agreement with FDA, to seek 
stakeholder feedback on practical considerations for the development of 
a new paradigm focused on developing innovative approaches for 
consumers to self-select nonprescription drug products appropriately 
and maintain their safe and effective use and to explore potential 
practical strategies. Participants included a diverse set of 
stakeholders from both public and private sectors, including FDA and 
other Government agencies, healthcare professional associations, trade 
associations, technology developers, pharmaceutical manufacturers, 
healthcare professionals, academic institutions, retail pharmacy 
representatives, and patient advocacy organizations.
    On November 8, 2012, the Brookings Institution convened the first 
expert workshop, ``Nonprescription Medications With Conditions of Safe 
Use as a Novel Solution for Undertreated Diseases or Conditions.'' This 
workshop explored issues and practical considerations for the 
development of this new paradigm (Ref. 4).
    On May 9, 2013, the Brookings Institution held the second expert 
workshop, ``Innovative Technologies and Nonprescription Medications: 
Addressing Undertreated Diseases and Conditions Through Technology 
Enabled Self-Care.'' This workshop explored the potential for 
innovative technologies to facilitate safe and effective use of 
nonprescription drug products (Ref. 5).
    On November 4, 2013, the Brookings Institution held the final 
expert workshop, ``Exploring Implications of the Nonprescription Drug 
Safe Use Regulatory Expansion Initiative on Reimbursement and Access.'' 
This workshop focused on assessing this paradigm's potential impact on 
consumer access and reimbursement (Ref. 6).
3. Innovative Approaches for Nonprescription Drug Products; Draft 
Guidance for Industry
    In the Federal Register of July 18, 2018 (83 FR 33938), FDA 
published a notice of availability of a draft guidance entitled 
``Innovative Approaches for Nonprescription Drug Products'' and 
established Docket No. FDA-2018-D-2281. This draft guidance describes 
two innovative approaches that may be useful for applicants to consider 
in cases where the DFL alone is not sufficient to ensure that a drug 
product can be used safely and effectively in a nonprescription 
setting. These approaches include the development of labeling in 
addition to the DFL and the implementation of additional conditions so 
that consumers can appropriately self-select and use the product.

IV. Legal Authority

    FDA's proposal to establish requirements for a nonprescription drug 
product with an ACNU is authorized by sections 201(n), 502, 503(b), 
505, and 701(a) of the FD&C Act (21 U.S.C. 321(n), 352, 353(b), 355, 
and 371(a)). Section 502(f) of the FD&C Act deems a drug to be 
misbranded unless its labeling bears adequate directions for use and 
adequate warnings against use in those conditions where its use may be 
dangerous to health, as well as adequate warnings against unsafe dosage 
or methods or duration of administration or application, in such manner 
and form, as are necessary for the protection of users. Section 502(f) 
also authorizes the promulgation of regulations exempting a drug or 
device from the requirement to bear adequate directions for use upon a 
determination that such directions are not necessary for the protection 
of public health.
    We are proposing to add an exemption for human nonprescription drug 
products approved with an ACNU from the requirement in section 
502(f)(1) of the FD&C Act for drug products to have labeling that 
provides adequate directions for use (see proposed Sec.  201.130). When 
labeling alone cannot provide adequate directions for use for a human 
nonprescription drug product, FDA may approve the nonprescription drug 
product with an ACNU under proposed Sec.  314.56.
    In addition, section 502(a) of the FD&C Act deems a drug to be 
misbranded if its labeling is false or misleading in any particular. 
Under section 201(n) of the FD&C Act, in determining whether labeling 
is misleading, there shall be taken into account (among other things), 
not only representations made or suggested but also the extent to which 
the labeling fails to reveal facts material in the light of such 
representations or material with respect to consequences that may 
result from the use of the drug under the conditions of use prescribed 
in the labeling or under usual or customary conditions of use.
    In addition, under section 505 of the FD&C Act, FDA will approve an 
NDA only if the drug is shown to be both safe and effective for use 
under the conditions prescribed, recommended, or suggested in the 
proposed labeling for the product. See section 505(c)(1) and (d) of the 
FD&C Act. If, for example, on the basis of information submitted as 
part of the application or on the basis of any other information before 
the Agency with respect to such drug, there is insufficient information 
to determine whether such drug is safe for use under such conditions, 
the Agency will not approve the drug. Section 505(j) of the FD&C Act 
describes the requirements

[[Page 38318]]

for ANDAs. In particular, section 505(j)(2)(A) specifies the 
information that must be included in an ANDA, and section 505(j)(4) 
describes the approval standard for an ANDA.
    In addition, section 503(b) of the FD&C Act contains provisions 
regarding the marketing of a drug as either a prescription drug product 
or a nonprescription drug product.
    Finally, section 701(a) of the FD&C Act authorizes FDA to issue 
regulations for the efficient enforcement of the FD&C Act.

V. Description of the Proposed Rule

    We are proposing to add Sec.  314.56 to part 314, subpart B, to 
establish additional application requirements for a nonprescription 
drug product with an ACNU under an NDA or an ANDA. The evidentiary 
standards that an NDA for a nonprescription drug product must meet 
under the FD&C Act and current FDA regulations to demonstrate the 
safety and effectiveness of the drug product would apply to a 
nonprescription drug product approved with an ACNU. An ANDA referencing 
a nonprescription drug product with an ACNU previously approved under 
an NDA may rely on FDA's finding that the listed drug product is safe 
and effective for use under the conditions described in the labeling. 
We are proposing to add Sec.  314.125(b)(20) to part 314, subpart D, to 
specify that FDA would refuse to approve an NDA for a nonprescription 
drug product with an ACNU that does not meet the applicable 
requirements established in Sec.  314.56. We are also proposing to add 
Sec.  314.127(a)(15) to part 314, subpart D, to specify that FDA would 
refuse to approve an ANDA for a nonprescription drug product with an 
ACNU that does not meet the applicable requirements established in 
Sec.  314.56. We are proposing to add Sec.  314.81(b)(3)(v) to part 
314, subpart B, to establish postmarketing reporting requirements for a 
nonprescription drug product with an ACNU. We are also proposing to add 
Sec.  201.67 to part 201, subpart C, to establish labeling requirements 
for a nonprescription drug product with an ACNU. We are proposing to 
add Sec.  201.130 to part 201, subpart D, to establish an exemption 
from the statutory requirement for adequate directions for use for a 
nonprescription drug product with an ACNU. The proposed rule is 
intended to increase options for applicants to develop and market safe 
and effective nonprescription drug products, which could improve public 
health by broadening the types of nonprescription drug products 
available to consumers. For example, FDA may approve a nonprescription 
drug product with an ACNU to treat a chronic condition that currently 
does not have nonprescription treatments.
    A detailed description of each proposed section is provided in 
sections V.A through V.K of this document.

A. Applicability

    The proposed rule would apply to NDAs and ANDAs for nonprescription 
drug products with an ACNU (see proposed Sec. Sec.  314.56, 314.81, 
314.125, 314.127, 201.67, and 201.130). Nonprescription drug products 
currently marketed under an approved application do not need an ACNU to 
ensure appropriate self-selection and appropriate actual use because 
FDA previously determined that labeling alone is sufficient for these 
drugs to be used safely and effectively without a prescription. The 
proposed rule would not apply to nonprescription drugs marketed under 
section 505G of the FD&C Act. Therefore, a requestor (as defined in 
section 505G(q)(3) of the FD&C Act) cannot submit a request under 
section 505G(b) of the FD&C Act for a nonprescription drug product with 
an ACNU.

B. Definitions (Proposed Sec. Sec.  314.56(a) and 201.67(b))

    We are proposing to define the term ``additional condition for 
nonprescription use'' (ACNU) as one or more FDA-approved conditions 
that an applicant of a nonprescription drug product must implement to 
ensure consumers' appropriate self-selection or appropriate actual use, 
or both, of the nonprescription drug product without the supervision of 
a healthcare practitioner if the applicant demonstrates and FDA 
determines that labeling alone is insufficient to ensure appropriate 
self-selection or appropriate actual use, or both (see proposed 
Sec. Sec.  314.56(a) and 201.67(b)). If the ACNU is intended to address 
appropriate self-selection only, the labeling must enable appropriate 
actual use of the nonprescription drug product by consumers. 
Alternatively, if the ACNU is intended to address appropriate actual 
use only, the labeling must enable consumers to appropriately self-
select the nonprescription drug product.
    The proposed definition for an ACNU is intentionally broad to give 
applicants flexibility regarding the types of additional conditions 
applicants may propose and how those additional conditions can be 
implemented. For example, an applicant could propose an ACNU that 
requires a consumer, in order to purchase the nonprescription drug 
product, to respond with specific answers to a set of questions on a 
self-selection test available by either a mobile application or an 
automated telephone response system. An applicant may also propose that 
before purchasing the nonprescription drug product with an ACNU, a 
consumer be required to view labeling (for example, text or images in a 
video), that describes how to appropriately use the nonprescription 
drug product and to respond to questions to confirm understanding.

C. Separate Application Required for a Nonprescription Drug Product 
With an ACNU (Proposed Sec.  314.56(b))

    The proposed rule would not require a nonprescription drug product 
with an ACNU to be first marketed as a prescription drug product. 
However, in cases where there is an approved prescription drug product, 
the proposed rule would establish the requirement that a 
nonprescription drug product with an ACNU cannot be approved through a 
supplement to the approved prescription application. Rather, an 
applicant must submit a separate application for a nonprescription drug 
product with an ACNU. Although a separate application would be 
required, an applicant may cross reference information in its approved 
NDA for the prescription product and would not need to duplicate 
studies already conducted for and submitted in its NDA for the 
prescription product. As explained in Section III.B., a different 
applicant may submit an NDA under section 505(b)(2) of the FD&C Act, 
where at least some of the information required for approval comes from 
studies not conducted by or for the applicant and for which the 
applicant has not obtained a right of reference or use. This is 
provided the 505(b)(2) applicant establishes that the relied upon NDA 
or literature is relevant to its nonprescription drug product with an 
ACNU and its application includes support for any differences between 
the applicant's proposed drug product and the listed drug on which the 
applicant is relying to demonstrate the safety and effectiveness of the 
proposed nonprescription drug product with an ACNU.
    As explained in section V.E of this document, the approved 
prescription drug product and the approved nonprescription drug product 
with an ACNU are two different products and could be simultaneously 
marketed.
    Requiring a separate application for the nonprescription drug 
product with an ACNU would enable continued marketing of the 
prescription product under the original NDA and would

[[Page 38319]]

allow it to serve as an RLD for ANDAs for the prescription product. 
Continued access to the prescription drug product, along with 
availability of the nonprescription drug product approved with an ACNU, 
would ensure greater access to needed drugs by providing flexibility in 
how to obtain them. For example, if a nonprescription drug product 
approved with an ACNU is available through a kiosk in a pharmacy, 
patients who do not live near a pharmacy with such a kiosk may find it 
easier to obtain the drug through a prescription.
    Additionally, patients who prefer to continue interacting with 
their healthcare providers and obtain the drug by prescription would 
have that option. Patients who had not previously used the drug may 
also feel more comfortable initiating treatment and obtaining the drug 
with the involvement of their healthcare providers. While FDA would 
generally expect any technology that is used to operationalize an ACNU 
to be easily usable to the majority of consumers, there may be some 
consumers who may not be comfortable using such technology. Continued 
availability of the prescription drug product would provide greater 
flexibility in obtaining the drug and enable these patients to continue 
their care without potential interruption.
    An applicant seeking an initial approval of an ANDA to market a 
nonprescription drug product with an ACNU may submit an ANDA 
referencing a nonprescription drug product with an ACNU previously 
approved under an NDA and may rely on FDA's finding that the RLD is 
safe and effective. This ANDA would also be required to have a separate 
application from an existing ANDA approved as a prescription drug 
product. Because the RLD nonprescription drug product with an ACNU 
would have a separate NDA from the NDA approved as a prescription drug 
product, the ANDA would be using a different NDA as its RLD from the 
RLD for the ANDA for the prescription product. Section 505(j)(2)(D) of 
the FD&C Act prohibits an applicant from amending or supplementing its 
ANDA to rely on a different listed drug from the listed drug identified 
in the ANDA submitted to FDA.
    An applicant may submit an amendment, supplement, or annual report 
to an application for a nonprescription drug product with an ACNU, 
consistent with FDA regulations (Sec. Sec.  314.60, 314.96, 314.70, and 
314.97). An applicant seeking to make changes to an NDA or ANDA 
submitted for a nonprescription drug product with an ACNU that is under 
review by FDA would submit an amendment to the application to request a 
change (Sec. Sec.  314.60 and 314.96). An applicant seeking to make 
changes to an FDA-approved NDA or ANDA for a nonprescription drug 
product with an ACNU would submit a supplement to the approved NDA or 
ANDA (Sec. Sec.  314.70 and 314.97).

D. Specific Requirements for an Application for a Nonprescription Drug 
Product With an ACNU (Proposed Sec.  314.56(c))

    The proposed rule would establish the specific NDA and ANDA 
requirements for a nonprescription drug product with an ACNU (see 
proposed Sec.  314.56(c)).
1. New Drug Application
    In addition to applicable existing application requirements, NDA 
applicants would also be required to describe the ACNU and submit 
information to support the ACNU. Specifically, the proposed rule would 
require that an NDA for a nonprescription drug product with an ACNU 
must, when fulfilling the content and format requirements under Sec.  
314.50, include the following information about the ACNU in the 
application: (1) a statement regarding the purpose of the ACNU (i.e., 
appropriate self-selection or appropriate actual use, or both, by 
consumers of the nonprescription drug product without the supervision 
of a healthcare practitioner) (see proposed Sec.  314.56(c)(1)(i)); (2) 
a statement of the necessity of the ACNU (see proposed Sec.  
314.56(c)(1)(ii)); (3) a description of how the ACNU ensures 
appropriate self-selection or appropriate actual use, or both (see 
proposed Sec.  314.56(c)(1)(iii)); (4) a description of the key 
elements of the ACNU (see proposed Sec.  314.56(c)(1)(iv)); (5) 
adequate data or other information that demonstrate the necessity of 
the ACNU to ensure appropriate self-selection or appropriate actual 
use, or both (see proposed Sec.  314.56(c)(1)(v)); (6) adequate data or 
other information that demonstrate the effect of the ACNU on the 
appropriate self-selection or appropriate actual use, or both (see 
proposed Sec.  314.56(c)(1)(vi)); and (7) a description of the specific 
way the ACNU is operationalized (see proposed Sec.  314.56(c)(1)(vii)). 
The first four requirements for the ACNU in the application (see 
proposed Sec.  314.56(c)(1)(i) through (iv)) and the last requirement 
for the ACNU in the application (see proposed Sec.  314.56(c)(1)(vii) 
provide statements, including explanations, descriptions, and 
justifications, about the ACNU; the remaining requirements for the ACNU 
in the application (see proposed Sec.  314.56(c)(1)(v) through (vi)) 
provide data or other information to support these statements. Each of 
these seven requirements for the ACNU to be included in the application 
are further described in this section.
    We are providing an example of one fictitious nonprescription drug 
product with an ACNU, Drug X, to provide a simplified illustration of a 
product that may potentially be considered under this proposed 
regulatory framework. We will use Drug X to explain examples of 
information that the applicant would submit in the NDA for a 
nonprescription drug product with an ACNU. This is only one type of 
example; many other types of ACNUs for nonprescription drug products 
could be possible.
    Drug X is proposed as a nonprescription drug product indicated for 
the treatment of symptom Y in adults who have a disease-specific risk 
score below the threshold for developing serious side effect E when 
taking Drug X. As part of the nonprescription development program, the 
applicant conducted robust self-selection and label comprehension 
studies. The results of the self-selection and label comprehension 
studies demonstrated that consumers cannot appropriately self-select 
Drug X with labeling alone. FDA acknowledges these self-selection and 
label comprehension studies were well designed and conducted and 
concurs that consumers cannot self-select Drug X with labeling alone. 
Results of the self-selection and label comprehension studies show 
that, although consumers recognize that they have symptom Y, they 
cannot appropriately calculate their disease-specific risk score for 
side effect E. Therefore, the applicant proposes an ACNU for Drug X to 
ensure consumers' appropriate self-selection and now seeks approval of 
Drug X as a nonprescription drug product with an ACNU. The ACNU 
requires all consumers to complete a questionnaire located on a secure 
website created by the applicant to determine whether Drug X is 
appropriate for the consumer. The questionnaire has a series of 
questions that the consumer answers. The underlying program or other 
operating information used by the secure website calculates the risk 
score for serious side effect E using the consumer's answers and 
determines if the consumer has an acceptable disease-specific risk 
score to use Drug X. A consumer with an acceptable risk score can then 
either: (1) purchase Drug X on the applicant's secure website or (2) 
purchase Drug X

[[Page 38320]]

at a retail site specified by the applicant after presenting a barcoded 
voucher that can be printed or downloaded onto the consumer's mobile 
device from the applicant's secure website.
    a. Statement regarding the purpose of the ACNU. The proposed rule 
would require the applicant to provide a statement regarding the 
purpose of the ACNU (see proposed Sec.  314.56(c)(1)(i)). This 
statement would indicate whether the ACNU is intended for: (1) 
appropriate self-selection, (2) appropriate actual use, or (3) both. 
For example, the purpose of the ACNU for Drug X is to ensure 
appropriate self-selection by consumers.
    b. Statement of the necessity of the ACNU. The proposed rule would 
require the applicant to explain why the ACNU is necessary to ensure 
appropriate self-selection or appropriate actual use, or both, by 
consumers of the nonprescription drug product (see proposed Sec.  
314.56(c)(1)(ii)). The applicant must explain why labeling alone cannot 
be sufficient for the purposes of meeting the approval requirements for 
a nonprescription drug product. The applicant may include a summary of 
the adequate data or other information that is submitted as part of an 
application for a nonprescription drug product with an ACNU, pursuant 
to proposed Sec.  314.56(c)(1)(v), to explain why labeling alone cannot 
be sufficient.
    c. Description of how the ACNU ensures appropriate self-selection 
or appropriate actual use, or both. The proposed rule would require the 
applicant to describe how the ACNU will ensure appropriate self-
selection or appropriate actual use, or both, by consumers (see 
proposed Sec.  314.56(c)(1)(iii)). For example, with Drug X, the 
applicant would describe that the ACNU requires a consumer to complete 
a questionnaire, located on a website, created by the applicant, that 
would assist in calculating a consumer's risk score for developing 
serious side effect E. This questionnaire would determine whether Drug 
X is appropriate for the consumer. The applicant may be expected, among 
other things, to justify the appropriateness of the self-selection 
questions, including the criteria and/or considerations used in 
calculating the risk score for a particular consumer. This may include 
a description of the algorithm in the underlying program or other 
operating information used by the website that calculates the risk 
score for serious side effect E to determine if the consumer has an 
acceptable risk score to use Drug X. The applicant would also describe 
how a consumer with an acceptable risk score can then purchase Drug X.
    d. Description of key elements of the ACNU. The proposed rule would 
require the applicant to describe the key elements of the ACNU (see 
proposed Sec.  314.56(c)(1)(iv)). The description of the key elements 
must include: (1) the additional condition(s) implemented by the 
applicant to be fulfilled by the consumer to be able to obtain or use 
the nonprescription drug product with an ACNU, (2) the labeling 
specifically associated with the ACNU, and (3) the criteria by which 
the consumer would successfully fulfill the ACNU, including a 
description of the specific actions to be taken by a consumer or 
required responses to be provided by a consumer. Labeling specifically 
associated with the ACNU should be annotated with each specific element 
of the ACNU. All labeling, including labeling specifically associated 
with the ACNU, should be provided in editable documents whenever 
possible. For example, labeling specifically associated with Drug X 
would include the carton and container annotated with the elements 
specific to the ACNU. All questions in the questionnaire would be 
submitted as labeling. The applicant for Drug X would describe the 
criteria by which the consumer would fulfill the ACNU including the 
questions and all potential consumer responses that would determine 
that Drug X was appropriate or not appropriate for the consumer.
    e. Adequate data or other information that demonstrates the 
necessity of the ACNU to ensure appropriate self-selection or 
appropriate actual use, or both. The proposed rule would require an 
applicant to include data or other information that demonstrates the 
necessity of the ACNU to ensure appropriate self-selection or 
appropriate actual use, or both (see proposed Sec.  314.56(c)(1)(v)). 
To do so, the applicant must conduct or reference adequate testing to 
show that labeling alone would not support the safe and effective use 
of the nonprescription drug product. For example, the applicant of Drug 
X would submit adequate data from robust self-selection studies and 
label comprehension studies that demonstrate that consumers could not 
appropriately self-select Drug X with labeling alone.
    Alternatively, the applicant can submit information explaining the 
necessity of the ACNU for appropriate self-selection or appropriate 
actual use, or both, when FDA has previously signaled that labeling 
alone is not sufficient to ensure appropriate self-selection or 
appropriate actual use, or both. For example, this might apply if FDA 
has previously approved multiple nonprescription drug products for the 
same indication with a similar ACNU. The applicant is encouraged to 
discuss its drug development plans with FDA if the applicant has 
questions about whether an ACNU would be appropriate.
    f. Adequate data or other information that demonstrates the effect 
of the ACNU on the appropriate self-selection or appropriate actual 
use, or both. The applicant must also submit adequate data or 
information that demonstrates the effect of the ACNU on the appropriate 
self-selection or appropriate actual use, or both, by the consumer of 
the nonprescription drug product (see proposed Sec.  314.56(c)(1)(vi)). 
The data must show that consumers can appropriately self-select or use 
the drug product safely and effectively, or both, with the ACNU. For 
example, the applicant of Drug X would submit adequate data from robust 
self-selection studies that demonstrate that consumers could 
appropriately self-select Drug X with the ACNU.
    g. Description of how the applicant will operationalize the ACNU. 
The proposed rule would require that the applicant describe the 
specific way the ACNU is operationalized (see proposed Sec.  
314.56(c)(1)(vii)). While it is important for FDA to understand how the 
ACNU is operationalized because this is part of achieving appropriate 
self-selection or use, the specific way an ACNU is operationalized is 
not a key element of the ACNU. The purpose of the ACNU is to enable 
self-selection and appropriate use without the oversight of a 
healthcare practitioner. The ACNU can be operationalized in different 
ways provided it reliably meets the objective. Alternatives to the way 
the ACNU is operationalized in the previous example, which involves 
administration of a questionnaire using a website, might include: (1) 
administering the questionnaire using a display screen at a pharmacy 
kiosk, (2) administering the questionnaire using a mobile application, 
and (3) administering the questionnaire using an automated telephone 
response system. These examples differ in the way the ACNU is 
operationalized (i.e., how the questionnaire is being administered), 
but the key elements (including the questions in the questionnaire and 
responses that ensure appropriate self-selection) remain the same. FDA 
seeks comment on any unique issues that might arise for retailers or 
consumers based on the way the applicant operationalizes the ACNU in 
the previous examples, e.g., in a store kiosk, online, or otherwise.
    h. Additional considerations. If an NDA applicant submits an 
application

[[Page 38321]]

for a nonprescription drug product with an ACNU that proposes to use 
certain technologies, but FDA determines that labeling alone is 
sufficient to enable appropriate self-selection and appropriate actual 
use, FDA would refuse to approve the application for the 
nonprescription drug product with the ACNU (see proposed Sec. Sec.  
314.125(b)(20) and 314.127(a)(15)). However, FDA may approve an 
application for a nonprescription drug product with technologies that 
do not meet the definition of an ACNU. In cases where FDA determines 
that labeling alone is sufficient to enable appropriate self-selection 
and appropriate actual use, the labeling statements specifically 
required for a nonprescription drug product with an ACNU under this 
proposed rule (see proposed Sec.  201.130) must not appear on the drug 
product labeling.
2. Abbreviated New Drug Application
    Applicants may submit an ANDA referencing a listed drug that has 
been approved with an ACNU under section 505(c) of the FD&C Act and 
rely on FDA's previous finding that the RLD is safe and effective. The 
proposed rule would require that an ANDA for a nonprescription drug 
product with an ACNU must, when fulfilling the content and format 
requirements under Sec.  314.94: (1) state the purpose of the ACNU (the 
same purpose as the ACNU for the RLD), (2) include information 
demonstrating that the key elements of the proposed ACNU are the same 
as the key elements of the ACNU for its RLD, and (3) include 
information on the way the ANDA applicant intends to operationalize the 
proposed ACNU. If an applicant believes the ACNU is operationalized in 
the same way as the RLD (e.g., both use a mobile application), the ANDA 
must include information demonstrating the operationalization of the 
ACNU is the same as the RLD. If the ANDA proposes a different way to 
operationalize the proposed ACNU, the ANDA must include information to 
show that this different operationalization of the proposed ACNU 
achieves the same purpose as the ACNU for its RLD and the differences 
from the RLD are otherwise acceptable in an ANDA (see proposed Sec.  
314.56(c)(2)). As with all ANDAs, an ANDA for a nonprescription drug 
product with an ACNU also would be expected to be pharmaceutically 
equivalent and bioequivalent to its RLD and to have the same clinical 
effect and safety profile as its RLD when administered to patients 
under the conditions specified in the labeling. Information concerning 
the purpose of the reference product's ACNU and the description of the 
key elements should be available in the approval letter for the 
reference product or in the publicly available approval package.
    The labeling for the ANDA drug product must be the same as the 
labeling for its RLD at the time of the ANDA's approval, except for 
changes required because of differences approved under a petition filed 
under Sec.  314.93 or because the drug product for which an ANDA is 
submitted and the RLD are produced or distributed by different 
manufacturers (see sections 505(j)(2)(A) and (j)(4) of the FD&C Act) 
and Sec. Sec.  314.94(a)(8) and 314.127(a)(7)).
    a. Statement regarding the purpose of the ACNU. As part of the 
submission, an ANDA applicant would state the purpose of the ACNU (the 
same purpose as the ACNU for the RLD) (see proposed Sec.  
314.56(c)(2)(i)). Although an ANDA must state the purpose of the ACNU, 
an ANDA would not be required to include the explanation of the 
necessity for the ACNU or how the ACNU would ensure appropriate self-
selection, appropriate actual use, or both. As a general matter, the 
ANDA would rely on FDA's findings of safety and effectiveness for an 
RLD with an ACNU.
    b. Description of key elements of the ACNU. An ANDA applicant would 
also provide information to show that the key elements of the proposed 
ACNU are the same as the key elements of the ACNU approved for its RLD 
(see proposed Sec.  314.56(c)(2)(ii)).
    c. Description of how the applicant will operationalize the ACNU. 
An ANDA applicant would include information on how the ACNU would be 
operationalized. The proposed rule would allow ANDA applicants to 
operationalize its ACNU in a different way from its RLD. For instance, 
an ANDA applicant may consider proposing to make available on the 
internet a self-selection aid for its nonprescription drug product with 
an ACNU, whereas the self-selection aid for its RLD is made available 
at a physical retail store via an electronic display. Consistent with 
section 505(j) of the FD&C Act and our general approach to ANDAs, an 
ANDA would have a variety of ways to achieve the same purpose as the 
ACNU for its RLD. The ANDA would contain information to support that 
the way in which it is operationalized, as proposed, achieves the same 
purpose as the ACNU for its RLD and the differences from the RLD are 
otherwise acceptable in an ANDA (see proposed Sec.  314.56(c)(2)(iii)). 
As with all ANDAs, an ANDA for a nonprescription drug product with an 
ACNU also would be expected to be pharmaceutically equivalent and 
bioequivalent to its RLD and have the same clinical effect and safety 
profile as its RLD when administered to patients under the conditions 
specified in the labeling.
    FDA requests comment on the proposal to allow potential permissible 
differences between the NDA and the ANDA in the ways to operationalize 
the ACNU and how an applicant would demonstrate that the ACNU for the 
ANDA achieves the same purpose as the ACNU for its RLD.
    As stated earlier in this proposed rule, the specific ways to 
operationalize the ACNU are not considered key elements of the ACNU and 
otherwise are not considered a condition of use of the drug product. 
For example, to the extent NDA applicants operationalize their ACNUs 
using proprietary means, ANDA applicants can use different ways than 
their RLD for operationalizing the ACNU (provided that the purpose of 
the ACNU is achieved through the same key elements).
    Although FDA plays a ministerial role in listing patents in the 
publication ``Approved Drug Products with Therapeutic Equivalence 
Evaluations'' (commonly known as the Orange Book), FDA seeks comment on 
whether patents claiming aspects of the ACNU for the nonprescription 
drug product may be submitted for listing consistent with Sec.  314.53 
and section 505(b)(1)(A)(viii) and (c)(2) of the FD&C Act. FDA seeks 
comments on this topic and other issues FDA should consider in 
implementing this proposal that will help avoid unnecessarily delaying 
the entry of ANDA nonprescription drug products with an ACNU to the 
drug market.

E. Nonprescription and Prescription Approval and Simultaneous Marketing 
(Proposed Sec.  314.56(d))

    FDA has interpreted the language in section 503(b)(4) of the FD&C 
Act to allow simultaneous marketing of drug products with the same 
active ingredient as prescription and nonprescription if some 
meaningful difference, such as indication, strength, route of 
administration, dosage form, or patient population, exists between the 
drug products that makes the prescription product safe and effective 
only under the supervision of a healthcare practitioner licensed by law 
to administer the drug (see 83 FR 13994, April 2, 2018; see also 70 FR 
52050, September 1, 2005). Section 503(b)(1) of the FD&C Act requires a 
drug which: (1) because of its toxicity or other potentiality for 
harmful effect, or the method of its use, or the collateral measures 
necessary to its use, is not safe for use except under the supervision 
of

[[Page 38322]]

a practitioner licensed by law to dispense such drug or (2) is limited 
by an approved application under section 505 of the FD&C Act to use 
under the professional supervision of a practitioner licensed by law to 
administer such drug, to be dispensed only upon prescription of a 
practitioner licensed to administer such drug. Under section 
503(b)(4)(B) of the FD&C Act, a drug, for which the prescription 
dispensing provisions of section 503(b)(1) of the FD&C Act do not 
apply, shall be deemed to be misbranded if at any time before 
dispensing, the label of the drug bears the ``Rx only'' symbol. 
Likewise, under section 503(b)(4)(A), drugs that are subject to the 
prescription dispensing provisions of section 503(b)(1) must bear the 
``Rx only'' symbol, or else they are misbranded. This effectively means 
that, absent a meaningful difference between the products, simultaneous 
marketing of two drug products with the same active ingredient as both 
a prescription and a nonprescription drug product would result in one 
of the two products being misbranded.
    Under this proposed rule, the additional condition(s) that allow a 
nonprescription drug product to be safely used without the supervision 
of a healthcare practitioner would be a meaningful difference between 
the prescription drug product and the nonprescription drug product with 
an ACNU. Therefore, under the proposed rule, a prescription drug 
product and a nonprescription drug product with an ACNU that contain 
the same active ingredient can be simultaneously marketed even if they 
do not have other meaningful differences, such as different indications 
or strengths (see proposed Sec.  314.56(d)).
    The proposed rule would require applicants seeking approval for the 
first time of an NDA for a nonprescription drug product with an ACNU to 
submit a separate NDA, rather than a supplement to an approved NDA (see 
proposed Sec.  314.56(b)). The approval of a separate NDA would permit 
simultaneous marketing and access to the drug as both a prescription 
drug product and a nonprescription drug product with an ACNU. 
Consistent with FDA's goal of increasing options for applicants to 
develop and market safe and effective drugs for consumers, this 
proposed rule would enable continued access to the drug product as a 
prescription drug product, while also extending access to the drug 
product in the nonprescription setting with the ACNU. Even if the 
application holder of the NDA for the prescription drug product decides 
to discontinue marketing of the NDA for the prescription drug product, 
generic versions of the prescription drug product would be eligible for 
approval relying on the discontinued NDA for the prescription product 
as an RLD, so long as FDA determines that the NDA for the prescription 
product was not discontinued for reasons of safety or effectiveness 
(see Sec.  314.161).

F. Refusal To Approve an Application With an ACNU (Proposed Sec. Sec.  
314.125(b)(20) and 314.127(a)(15))

    The proposed rule would specify that FDA would refuse to approve an 
NDA for a nonprescription drug product with an ACNU if FDA has 
determined the NDA failed to meet the requirements in Sec.  314.56 
applicable to NDAs (see proposed Sec.  314.125(b)(20)). Similarly, the 
proposed rule would specify that FDA would refuse to approve an ANDA 
for a nonprescription drug product with an ACNU that fails to meet the 
requirements in Sec.  314.56 applicable to ANDAs (see proposed Sec.  
314.127(a)(15)). In addition to other reasons cited in Sec.  314.125 or 
Sec.  314.127, FDA would refuse to approve an application for a 
nonprescription drug product with an ACNU if FDA has determined that 
the applicant failed to demonstrate that labeling is insufficient to 
ensure consumers' appropriate self-selection or appropriate actual use, 
or both, of the nonprescription drug product without the supervision of 
a healthcare practitioner or if the applicant failed to demonstrate 
that its proposed ACNU is adequate to ensure appropriate self-selection 
or appropriate actual use, or both, by consumers without the 
supervision of a healthcare practitioner. We also note that under 
current Sec.  314.125(b)(8), FDA may refuse to approve an NDA if the 
drug product's proposed labeling does not comply with the requirements 
for labels and labeling in part 201. This authority would permit FDA to 
refuse to approve an NDA with an ACNU if the labeling does not comply 
with labeling requirements specific to such NDAs, such as proposed 
Sec. Sec.  201.67 and 201.130. Similarly, under current Sec.  
314.127(a)(7), FDA will refuse to approve an ANDA if its labeling is 
not the same as the labeling of its RLD, with certain permitted 
exceptions. Thus, FDA may refuse to approve an ANDA with an ACNU if its 
proposed labeling does not comply with labeling requirements specific 
to nonprescription products with an ACNU, such as proposed Sec. Sec.  
201.67 and 201.130.

G. Other Postmarketing Reports (Proposed Sec.  314.81(b)(3)(v))

    The proposed rule would require NDA and ANDA applicants to report 
to FDA information concerning any incident of failure in the 
implementation of an ACNU using the FDA Adverse Event Reporting System 
(FAERS) (see proposed Sec.  314.81(b)(3)(v)). A failure in 
implementation of an ACNU would include any event that results from a 
deviation in an applicant's implementation of the ACNU that may cause 
or lead to inappropriate medication use or consumer harm, such as a 
consumer gaining access to the drug product without fulfilling all 
necessary conditions for the nonprescription drug product with an ACNU. 
A failure in implementation of an ACNU must be reported by the 
applicant whether or not the failure is associated with an adverse 
event. To meet these reporting requirements, applicants will likely 
need quality assurance systems in place to capture instances where 
failures in implementation of an ACNU occur. A failure in 
implementation of an ACNU includes the following circumstances: (1) the 
consumer accessed or used the drug product without successfully 
fulfilling the ACNU, (2) the consumer successfully fulfilled the ACNU 
but could not access or appropriately use the drug product in the 
nonprescription setting, or (3) the consumer was unable to make an 
attempt to fulfill the ACNU due to systematic, technological, or 
mechanical errors in the implementation of the ACNU. For example, for 
the fictitious nonprescription drug product with an ACNU Drug X (as 
discussed in section V.D of this document), a report would be required 
to be submitted to FDA if the consumer with an acceptable risk score, 
was unable to purchase Drug X on the applicant's website or receive a 
voucher from the applicant's website in order to purchase Drug X at a 
retail site specified by the applicant. Failure to access the drug 
product could result in the consumer missing doses of the drug product.
    The applicant must submit a single report (an individual case 
safety report (ICSR) of an adverse event) describing both the failure 
in implementation of an ACNU and an associated adverse event when both 
occur and the applicant is aware of both before submitting a report. If 
the applicant determines that a failure of implementation of an ACNU 
occurred that is associated with a previously submitted ICSR of an 
adverse event, a followup report must be submitted to FAERS using the 
same unique

[[Page 38323]]

identification number as the original ICSR of an adverse event and must 
include the information concerning the failure in implementation of an 
ACNU as required by proposed Sec.  314.81(b)(3)(v)(A). If the applicant 
receives information of an adverse event associated with a previously 
submitted report in FAERS of a failure in implementation of an ACNU, a 
followup report must be submitted to FAERS as an ICSR of an adverse 
event. Such followup report must use the same unique identification 
number as the original report in FAERS of a failure in implementation 
of an ACNU and must include the information concerning the adverse 
event as required in Sec.  314.80(f).
    A report to FAERS for a failure in implementation of an ACNU would 
be submitted when the applicant has at least the minimum dataset for a 
failure in implementation, which includes the following three elements: 
(1) an identifiable reporter, (2) the drug product name, and (3) a 
description of the failure in implementation of the ACNU. The proposed 
rule would require the report to include certain information that the 
applicant is aware of about the drug product and the initial reporter, 
as well as a narrative summary of the failure in implementation of an 
ACNU and a description of the action initiated or completed to address 
the failure in implementation of an ACNU. The applicant would be 
required to submit a report for each failure in implementation of an 
ACNU as soon as possible but no later than 15 calendar days from the 
date when the applicant has acquired the minimum dataset for a report 
of a failure in implementation of an ACNU. Additionally, if an 
applicant obtains or otherwise receives any new information about 
previously submitted reports about the failure in implementation of an 
ACNU, the applicant would be required to investigate the new 
information, assess the relationship or impact of the new information 
on the initial report, and submit followup reports as soon as possible 
but no later than 15 calendar days after obtaining the new information. 
Proposed Sec.  314.81(b)(3)(v)(C) would require the report to be 
submitted to FDA in an electronic format that FDA can process, review, 
and archive unless a waiver has been requested and granted. To better 
enable FDA to assess compliance with reporting requirements and to 
facilitate FDA's inspection of related records, we are proposing to 
require an applicant to maintain for a period of 10 years the records 
of all reports of failures in implementations of an ACNU and associated 
adverse events known to the applicant (proposed Sec.  
314.81(b)(3)(v)(D)).
    FDA seeks specific comment on the burden and benefits of submitting 
an individual report to FDA for each individual failure in 
implementation of an ACNU encountered by a consumer resulting from the 
same cause of failure, as opposed to a single, consolidated report for 
all such failures. For example, there could be a situation where an 
ACNU involves administration of a questionnaire using a pharmacy kiosk, 
and the kiosk screen malfunctions, preventing multiple consumers from 
fulfilling the ACNU because they cannot complete the questionnaire on 
the kiosk screen. We are seeking comment on the benefits and burdens in 
this type of situation of submitting individual reports for each 
consumer affected by the malfunction versus one single, consolidated 
report for all consumers affected.

H. General Labeling Requirements (Proposed Sec.  201.67(c))

    The proposed rule would clarify that a nonprescription drug product 
with an ACNU must comply with all applicable regulatory requirements 
for nonprescription drug products, including those under part 201. 
Specifically, the applicant must comply with the existing content and 
format requirements for nonprescription drug products in Sec.  201.66, 
known as the DFL (see proposed Sec.  201.67(c)(1)). As required in 
Sec.  201.66(c)(6), the labeling for all nonprescription drug products 
must contain directions for use under the heading ``Directions.'' The 
proposed rule would require the labeling for all nonprescription drug 
products approved with an ACNU to include the following statement, as 
specified in proposed Sec.  201.130(a)(1), as the first statement under 
the heading ``Directions'': ``To check if this drug is safe for you, go 
to [insert where or how consumers can find information about the ACNU; 
for example, applicant's website, applicant's phone number, or specific 
retail location] and [insert action to be taken by consumer]. Do not 
take this drug without completing this step.'' This initial statement 
would be followed by the other required information in Sec.  
201.66(c)(6). This proposed statement would alert consumers that the 
nonprescription drug product with an ACNU has a requirement that must 
be fulfilled to ensure safe and effective use. The proposed statement 
would further remind the original purchaser and alert persons other 
than the original purchaser that the product is not suitable for all 
individuals and that consumers should carefully examine any labeling 
accompanying the nonprescription product with an ACNU before using the 
product.
    As stated previously, FDA may currently approve labeling for 
nonprescription drug products in addition to the DFL, and this would 
continue if the proposed rule is finalized (see proposed Sec.  
201.67(c)(2)). For example, FDA could approve information leaflets or 
other documents contained inside the carton or container for a 
nonprescription drug product, including for a nonprescription drug 
product with an ACNU.
    A list of questions to be answered by the consumer in a self-
selection aid could be labeling necessary to effectively implement the 
ACNU. All labels and other written, printed, or graphic matter that are 
necessary to effectively implement the ACNU (e.g., questions associated 
with a self-selection aid) would be considered to accompany the 
nonprescription drug product and, therefore, would meet the definition 
of labeling under the FD&C Act.
    Approved labeling for a nonprescription drug product with an ACNU 
must be available to consumers at the time of purchase and use as 
required in section 502(c) of the FD&C Act. In general, we believe that 
the applicant should describe in their application the process for 
ensuring consumers have access to the approved labeling prior to 
fulfilling the ACNU.

I. Format Requirements for Required ACNU Statement (Proposed Sec.  
201.67(d))

    The proposed rule would require that the statement specified in 
Sec.  201.130(a)(2) meet specific format requirements (see proposed 
Sec.  201.67(d)). This statement must be visible to consumers at the 
time of purchase and use. Additionally, the statement would alert 
persons that may have access to the drug product (e.g., family members 
in the purchaser's home), including the individual who originally 
purchased the product, that these nonprescription drug products are not 
suitable for all individuals and should only be used after fulfilling 
the ACNU. The proposed rule would require that the statement appear on 
the principal display panel (see Sec.  201.60) and the immediate 
container surface that the consumer is most likely to view when seeking 
information about the drug product (see proposed Sec.  201.67(d)(1)). 
If the immediate container is a bottle, the statement must appear on 
the surface that the consumer would most likely consider to be the 
front of the bottle. If

[[Page 38324]]

the immediate container is a blister card, the statement must appear on 
the blister card surface that the consumer would most likely view when 
removing the drug product from the blister card. If the blister card 
contains more than one blister unit, the statement would not need to be 
included on each blister unit of a blister card. However, the statement 
must remain intact and be readable on the blister card when the drug 
product is removed from each blister unit.
    The proposed rule would require that the statement be prominently 
presented in boldface and black type in a yellow background banner (see 
proposed Sec.  201.67(d)(2) and (3)). No other information or statement 
may be included in the yellow background banner. The hue of the yellow 
color in the background banner must be a shade that provides a high 
contrast with the black type of the statement. The font size of the 
statement would be at least 25 percent as large as the font size of the 
largest printed words on the container surface that the consumer would 
most likely view when seeking information about the drug product; in no 
case could the font size be smaller than 12 point type (1 point = 
0.0138 inches) (see proposed Sec.  201.67(d)(4)). For containers where 
the size would render compliance with this requirement impractical, the 
applicant would be able to request an exception to the minimum font 
size requirement (see proposed Sec.  201.67(d)(5)). However, FDA would 
not determine an exception is warranted if the statement is not 
prominent in relation to other elements on the container surface 
containing the statement.

J. Exemption From Adequate Directions for Use (Proposed Sec.  201.130)

    Consistent with the proposed definition of ACNU, a drug product can 
only be approved with an ACNU if the applicant demonstrates and FDA 
determines that labeling alone is insufficient to ensure appropriate 
self-selection or appropriate actual use, or both. Therefore, it is not 
possible for these products to be labeled with adequate directions for 
use under section 502(f)(1) of the FD&C Act, as defined in Sec.  201.5. 
The proposed rule would exempt a nonprescription drug product with an 
ACNU from the statutory requirement to be labeled with adequate 
directions for use, provided that certain conditions are met. 
Specifically, a nonprescription drug product approved with an ACNU 
under section 505(c) or (j) of the FD&C Act would be exempt from 
section 502(f)(1) if the product contains the labeling required under 
proposed Sec.  201.130(a) and the ACNU is implemented by the applicant 
as approved by FDA in the application (see proposed Sec.  201.130). FDA 
is proposing this exemption to the requirement for adequate directions 
for use for a nonprescription drug product with an ACNU because we have 
determined that the labeling and the ACNU are sufficient to ensure 
consumers' appropriate self-selection and actual use of the 
nonprescription product without the supervision of a healthcare 
practitioner. Therefore, adequate directions for use, as required by 
section 502(f)(1) of the FD&C Act and Sec.  201.5, would not be 
necessary for the protection of the public health.
    The proposed rule would require that the following statement appear 
as the first direction under the heading ``Directions'' in the 
labeling, as required in Sec.  201.66(c)(6): ``To check if this drug is 
safe for you, go to [insert where or how consumers can find information 
about the ACNU; for example, applicant's website, phone number, or 
specific retail location] and [insert action to be taken by consumer]. 
Do not take this drug without completing this step.'' (See proposed 
Sec.  201.130(a)(1).) The applicant would include information to inform 
consumers where the additional condition would be found and explain the 
additional condition that the consumer must fulfill. For example, ``To 
check if this drug is safe for you, go to www.XYZCompany.com and take 
the self-selection questionnaire. Do not take this drug without 
completing this step.'' The statement would be followed by the other 
information required in Sec.  201.66(c)(6). FDA is specifically seeking 
comment on the content of the statements and the ability of these 
statements to sufficiently inform consumers that the product is a 
nonprescription drug product with an ACNU and how consumers would 
fulfill the ACNU.
    The proposed rule would also require that the following statement 
appear on the immediate container label and, if one exists, the outside 
container or wrapper of the retail package: ``You must complete an 
extra step to see if this drug is safe for you before you use it. Do 
not take this drug without completing this step. See the Drug Facts 
labeling for more information.'' (See proposed Sec.  201.130(a)(2).) 
This statement must meet the specific format requirements as specified 
in proposed Sec.  201.67(d). The statement would remind the original 
purchaser and alert persons other than the original purchaser that 
these nonprescription drug products are not suitable for all 
individuals and should only be used after fulfilling the ACNU. FDA is 
specifically seeking comment on whether this statement would 
sufficiently alert consumers that this product is a nonprescription 
drug product with an ACNU.
    The proposed rule would require the ACNU to be implemented by the 
applicant under the conditions set forth in the approved application 
for the nonprescription drug product with an ACNU to be exempt from the 
requirement to be labeled with adequate directions for use (see 
proposed Sec.  201.130(b)).

K. Misbranding (Proposed Sec.  201.67(e))

    As noted immediately above, the proposed rule would exempt a 
nonprescription drug product with an ACNU from the requirement to be 
labeled with adequate directions for use under section 502(f)(1) of the 
FD&C Act, provided that certain conditions are met (see proposed Sec.  
201.130). If a nonprescription drug product with an ACNU is made 
available to consumers without the labeling specified in proposed Sec.  
201.130(a) or the ACNU is not implemented by the applicant as approved 
by FDA in the application, the drug product would be misbranded under 
section 502(f)(1) of the FD&C Act (see proposed Sec.  201.67(e)).
    As discussed in sections V.H and V.I of this document, the proposed 
rule would include specific labeling requirements for a nonprescription 
drug product with an ACNU. If the nonprescription drug product with an 
ACNU is made available to consumers without the specific required 
labeling, the product would also be misbranded under section 502(a) of 
the FD&C Act, which provides that a drug's labeling must not be false 
or misleading in any particular (see proposed Sec.  201.67(e)). Under 
section 201(n) of the FD&C Act, in determining whether labeling is 
misleading, there shall be taken into account (among other things), not 
only representations made or suggested but also the extent to which the 
labeling fails to reveal facts material in the light of such 
representations or material with respect to consequences that may 
result from the use of the drug under the conditions of use prescribed 
in the labeling or under usual or customary conditions of use. The 
required labeling statements described in proposed Sec.  201.130(a) are 
intended to inform consumers that the product is a nonprescription drug 
product with an ACNU; to instruct consumers on how to fulfill the ACNU; 
and to remind the original purchaser (and alert persons other than the 
original purchaser) that

[[Page 38325]]

the nonprescription drug product is not suitable for all individuals 
and should only be used after fulfilling the ACNU. Thus, failure of a 
nonprescription drug product approved with an ACNU to bear the required 
labeling statements described in proposed Sec.  201.130(a) would 
constitute a failure to reveal material facts about the product or with 
respect to consequences that might result from its use and would 
misbrand the product.
    In addition, a nonprescription drug product with an ACNU could be 
misbranded under other provisions of section 502 of the FD&C Act. For 
example, in certain circumstances, such a drug may be misbranded under 
section 502(j) if the product does not meet the requirements of this 
proposed rule.
    Under the proposed rule, a nonprescription drug product with an 
ACNU must only be made available to the consumer after the ACNU has 
been fulfilled by the consumer. It is a prohibited act under section 
301(a) of the FD&C Act to introduce or deliver for introduction into 
interstate commerce any drug that is misbranded (21 U.S.C. 331(a)). It 
is also a prohibited act under section 301(k) of the FD&C Act to do any 
act with respect to a drug if such act is done while such drug is held 
for sale after shipment in interstate commerce and results in the drug 
being misbranded.
    Additionally, a nonprescription drug product approved with an ACNU 
would be an unapproved new drug if it is made available to consumers 
without the ACNU. With certain limited exceptions not relevant here, it 
is a violation of sections 301(d) and 505(a) of the FD&C Act to 
introduce or deliver for introduction into interstate commerce an 
unapproved new drug.

VI. Proposed Effective Date

    We propose that a final rule based on this proposed rule become 
effective 60 days after the date the final rule publishes in the 
Federal Register.

VII. Preliminary Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed 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 proposed rule has been designated by the Office of Information and 
Regulatory Affairs as 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. This rule would establish the requirements for a 
nonprescription drug product with an ACNU. We cannot anticipate the 
number of applicants that would submit applications or the types of 
drug products that would be covered under such applications. However, 
we estimate the costs for any applicant to read and understand the rule 
would likely range between 0.04 percent and 0.14 percent of the gross 
receipts of very small applicants. Therefore, we propose to certify 
that the proposed rule, if finalized, would 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 $165 million, using the most current (2021) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

B. Summary of Costs and Benefits

    The proposed rule, if finalized, would establish the requirements 
for a nonprescription drug product with an ACNU. Compared to the 
traditional labeling paradigm of nonprescription drug products, this 
approved ACNU in addition to the labeling would ensure the appropriate 
self-selection, appropriate use, or both, of a drug product. We expect 
this rule could expand consumer access to certain drug products in a 
nonprescription setting.
    Table 1 shows our quantified benefits. We estimate a reduction in 
access costs to consumers who could transfer from a prescription to a 
nonprescription drug product with an ACNU. Our primary estimate for 
this item is $26.70 with a range of $0 to $53.40 per consumer per 
purchase. We also quantify the value of the potential reduction in the 
number of repetitive meetings with sponsors that the rule could 
eliminate, which occur during the approval process. This estimate 
includes benefits to FDA and industry. Our primary estimate is $55,469 
per applicant with a range of $45,260 to $66,174. We do not monetize 
our estimates of benefits over a 10-year horizon because of the high 
uncertainty about number of applicants, applications, potential 
approvals, the number of purchases that might occur, and consumer 
preferences to switch products but present estimates in the uncertainty 
section of the full preliminary analysis of economic impacts.
    Although an applicant would incur the development and 
postmarketing, including reporting of failure in the implementation of 
the ACNU and recordkeeping costs, we assume that applicants submit 
applications when they believe that their expected profits from the 
approval will exceed the costs of the application. We present a range 
of these potential development and postmarketing costs in the appendix 
of the complete economic analysis. However, we lack information to 
monetize these costs over a 10-year horizon and request comment or data 
on these potential costs.
    Monetized costs include a one-time cost of reading and 
understanding the rule. Using a 7-percent discount rate, the primary 
estimate, annualized over a 10-year horizon, equals $821 with a range 
of $379 to $1,264. These annualized costs are the same using a 3-
percent discount rate.
    Government and private insurance payers may experience positive 
transfers because consumers may decrease future medical costs and the 
number of submitted insurance claims. Earlier access to drug products 
would allow consumers to treat medical conditions using nonprescription 
drug products with an ACNU without the supervision of a healthcare 
practitioner.

[[Page 38326]]



                                     Table 1--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                           Units
                                      Primary       Low        High    --------------------------------------------
             Category                estimate    estimate    estimate      Year      Discount                                       Notes
                                                                          dollars    rate  (%)    Period  covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/
     year.
    Annualized Quantified.........  ..........  ..........  ..........        2018  ..........  ..................  Quantified reduction in access costs
                                                                                                                     per consumer purchase range from
                                                                                                                     $0.0 to $53.40, and a primary
                                                                                                                     estimate of $26.70.
                                                                              2018  ..........  ..................  Quantified reduction in meetings
                                                                                                                     between FDA and applicants range
                                                                                                                     from $45,260 to $66,174 per
                                                                                                                     applicant, and a primary estimate
                                                                                                                     of $55,469.
    Qualitative.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized....................        $0.0        $0.0        $0.0        2018           7  10 years..........  Reading and understanding one-time
                                                                                                                     costs.
    Monetized $millions/year......        $0.0        $0.0        $0.0        2018           3  10 years..........
    Annualized.
    Quantified.
    Qualitative...................  ..........  ..........  ..........  ..........  ..........  ..................  Affected firms would incur costs to
                                                                                                                     develop and submit applications.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal.......................  ..........  ..........  ..........  ..........           7
    Annualized Monetized $millions/                                                          3
     year.
--------------------------------------------------------------------------------------------------------------------------------------------------------
    From/To.......................  From:
                                    To:                                 ..........
                                   ---------------------------------------------------------------------------------------------------------------------
    Other.........................  ..........  ..........  ..........  ..........           7
    Annualized Monetized $millions/                                                          3
     year.
                                   ---------------------------------------------------------------------------------------------------------------------
    From/To.......................  From:
                                    To:                                  Potential
                                                                          benefits
                                                                                to
                                                                        government
                                                                               and
                                                                           private
                                                                         payors if
                                                                            access
                                                                           cost of
                                                                        medication
                                                                        s decline.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: No estimated effect..............................................................................................
    Small Business: The estimated costs to very small potential applicants in this industry would range from 0.04 percent to 0.14 percent of gross
     receipts..
    Wages: No estimated effect..........................................................................................................................
    Growth: No estimated effect.........................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Preliminary Economic Analysis of 
Impacts that assesses the impacts of the proposed rule. The full 
preliminary analysis of economic impacts is available in the docket for 
this proposed rule (Ref. 7) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) and (k) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3521). A description of these provisions is given in 
the Description section below, with an estimate of the annual 
reporting, recordkeeping, and third-party disclosure 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.
    FDA invites comments on these topics: (1) whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Premarket applications, postmarketing reports and 
recordkeeping, and labeling for Nonprescription Drug Products With an 
Additional Condition for Nonprescription Use.
    Description: We are revising requirements applicable to NDA and 
ANDA applicants of nonprescription drug products with an ACNU 
(collectively, respondents). If finalized, the proposed rule will 
modify information collections applicable to regulations in part 314 
governing new and abbreviated new drug application submissions and drug 
labeling provisions in part 201 pertaining to nonprescription drug 
products.
    Description of Respondents: The respondents are: (1) for NDA and 
ANDA

[[Page 38327]]

submissions, an applicant who submits an NDA (including a 505(b)(2) 
application) or an ANDA under part 314 to obtain FDA approval of a 
nonprescription drug with an ACNU; (2) for failure of implementation of 
an ACNU reporting and recordkeeping, any person who holds an approved 
NDA (including a 505(b)(2) application) or an approved ANDA that 
includes an ACNU; and (3) for labeling, any person who holds an 
approved NDA (including a 505(b)(2) application) or an approved ANDA 
that includes an ACNU.
    We estimate the burden of the information collection as follows:

                    Table 2--Estimated Annual Reporting Burden; OMB Control No. 0910-0001\1\
----------------------------------------------------------------------------------------------------------------
Information collection activity;                                                      Average
  21 CFR part 314  (application      Number of       Number of     Total annual     burden per
for FDA approval to market a new    respondents    responses per     responses       response       Total hours
              drug)                                 respondent                        (hours)
----------------------------------------------------------------------------------------------------------------
Submission of separate                         6               1               6             320           1,920
 application for nonprescription
 drug product with an ACNU; Sec.
   314.56(b) and (c)............
Other postmarketing reports;                   6              25             150              40           6,000
 submission of each individual
 consumer affected by a failure
 in implementation of an ACNU;
 Sec.   314.81..................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............             156  ..............           7,920
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital, or operating or maintenance costs associated with the information collection.

NDA and ANDA Submissions

    Based on our experience with information collection associated with 
current NDA and ANDA submissions, we estimate six applications for a 
nonprescription drug product with an ACNU will be submitted annually by 
six respondents. Based on Broad Agency Announcement proposals that set 
forth the number of hours anticipated to produce study reports for 
submission to us, we assume it will take an average of 320 hours per 
application for both NDA and ANDA applicants to prepare and submit the 
information required for applications for nonprescription drugs with an 
ACNU (in addition to meeting the general NDA or ANDA requirements under 
Sec. Sec.  314.50 and 314.94, already approved in OMB control number 
0910-0001).

Reports of a Failure in Implementation of an ACNU

    We estimate six respondents will each submit 25 reports to FDA for 
an individual failure in implementation of an ACNU under Sec.  
314.81(b)(3)(v). We assume an average of 40 hours per response for each 
applicant, for a total of 6,000 hours annually. As noted in the 
preamble of the proposed rule, we are also soliciting comments on the 
alternative reporting mechanism requiring the applicant to submit a 
single, consolidated report for all consumers affected by the same 
failure in implementation of an ACNU rather than a report for each 
individual impacted by the same failure in implementation of an ACNU. 
If that alternative is implemented in the final rule, we estimate that 
the number of reports per respondent would be reduced from 25 annual 
responses per respondent to 1 per year per respondent.

                                      Table 3--Estimated Annual Recordkeeping Burden; OMB Control No. 0910-0001 \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of                      Average  burden
   Information collection; 21 CFR part 314 (applications for FDA        Number of      responses per     Total annual    per  response     Total hours
                   approval to market a new drug)                      respondents       respondent       responses         (hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Requirements for failures in implementation of an ACNU; Sec.                      6               25              150                8            1,200
 314.81............................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital, or operating or maintenance costs associated with the information collection.

    Based on our experience with postmarket recordkeeping requirements, 
we assume an average burden of 8 hours of recordkeeping for each report 
and therefore have calculated 1,200 hours annually.

             Table 4--Estimated Annual Third-Party Disclosure Burden; OMB Control No. 0910-0340 \1\
----------------------------------------------------------------------------------------------------------------
Information collection activity;
   21 CFR part 201, subpart C                        Number of                        Average
(format and content requirements     Number of     responses per   Total annual     burden per      Total hours
    for over-the-counter drug       respondents     respondent       responses       response
        product labeling)
----------------------------------------------------------------------------------------------------------------
Disclosure of information on the               6               1               6              15              90
 principal display panel or
 within Drug Facts Labeling;
 Sec.   201.66 (including
 statements specified in Sec.
 201.130(a)(1)).................
Additional ACNU labeling--Sec.                 6               1               6               9              54
 201.67.........................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............              12  ..............             144
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 38328]]

Labeling for Nonprescription Drugs With an ACNU

    Based on our experience with NDA and ANDA submissions, we estimate 
six respondents will each submit an application for a nonprescription 
drug product with an ACNU, each becoming subject to all nonprescription 
labeling regulations in (21 CFR part 201, subpart C). This includes the 
requirements for statements of identity and net contents (Sec. Sec.  
201.61 and 201.62) which appear on the principal display panel (PDP) 
(defined by Sec.  201.60); the Drug Facts labeling (DFL) requirements 
of Sec.  201.66, as part of which the respondents must also include 
(where applicable) labeling to satisfy sodium, calcium, magnesium, and 
potassium labeling requirements (Sec. Sec.  201.64, 201.70, 201.71, and 
201.72); and the statements proposed to be required by Sec.  
201.130(a)(1). (The proposed requirement in Sec.  201.130(a)(2) to 
place a specified ACNU statement on the product PDP is not included in 
the definition of collection of information under the PRA and is 
therefore not subject to review and approval by OMB. See 5 CFR 
1320.3(c)(2). These products may also have additional labeling beyond 
the DFL requirements (Sec.  201.67(c)(2)).
    Estimating six respondents will each have one new, approved drug 
that must comply with PDP and DFL labeling requirements, including 
statements specified in Sec.  201.130(a)(1), and assuming compliance 
with these disclosures will require 15 hours per drug, we calculate a 
total of 90 hours annually. Additionally, we estimate six respondents 
will each have one new nonprescription drug product approved with an 
ACNU that contains additional labeling requirements, for a total of six 
annual responses. Based on our experience with nonprescription labeling 
requirements, we assume an average burden per response of 9 hours, for 
a total of 54 hours annually.
    To ensure that comments on this information collection are 
received, OMB recommends that written comments be submitted through 
reginfo.gov (see ADDRESSES). All comments should be identified with the 
title of the information collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3407(d)), we have submitted the information collection provisions of 
this proposed rule to OMB for review. These information collection 
requirements will not be effective until FDA publishes a final rule, 
OMB approves the information collection requirements, and the rule goes 
into effect. FDA will announce OMB approval of these requirements in 
the Federal Register.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
this proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
we conclude that the rule does not contain policies that have 
federalism implications as defined in the Executive order and, 
consequently, a federalism summary impact statement is not required.

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the rule does not contain policies that would have a 
substantial direct effect 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. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XII. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) 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. 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.

1. FDA, Guidance for Industry, ``Self-Selection Studies for 
Nonprescription Drug Products,'' April 2013 (available at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs).
2. Chang J., A. Lizer, I. Patel, et al., ``Prescription to Over-the-
Counter Switches in the United States,'' Journal of Research in 
Pharmacy Practice, vol. 5(3), pp. 149-154, doi:10.4103/2279-
042X.185706. Available at: https://www.jrpp.net/text.asp?2016/5/3/149/185706.
3. FDA, Guidance for Industry, ``Label Comprehension Studies for 
Nonprescription Drug Products,'' August 2010 (available at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs).
4. Engelberg Center for Health Care Reform at the Brookings 
Institution, ``Expert Workshop: Nonprescription Medications With 
Conditions of Safe Use as a Novel Solution for Undertreated Diseases 
or Conditions,'' November 8, 2012 (available at https://www.brookings.edu/events/nonprescription-medications-with-conditions-of-safe-use-as-a-novel-solution-for-undertreated-diseases-or-conditions), accessed July 30, 2021.
5. Engelberg Center for Health Care Reform at the Brookings 
Institution, ``Expert Workshop: Innovative Technologies and 
Nonprescription Medications: Addressing Undertreated Diseases and 
Conditions through Technology Enabled Self-Care,'' May 9, 2013 
(available at https://www.brookings.edu/events/innovative-technologies-and-nonprescription-medications-addressing-undertreated-diseases-and-conditions-through-technology-enabled-self-care), accessed July 30, 2021.
6. Engelberg Center for Health Care Reform at the Brookings 
Institution, ``Expert Workshop: Exploring Implications of the 
Nonprescription Drug Safe Use Regulatory Expansion (NSURE) 
Initiative on Reimbursement and Access,'' November 4, 2013 
(available at https://www.brookings.edu/events/exploring-implications-of-the-nonprescription-drug-safe-use-regulatory-expansion-nsure-initiative-on-reimbursement-and-access), accessed 
July 30, 2021.
7. FDA, Preliminary Regulatory Impact Analysis; Initial Regulatory 
Flexibility Analysis; Unfunded Mandates Reform Act Analysis, 
Nonprescription Drug Product With an Additional Condition for 
Nonprescription Use; Proposed Rule (available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm).

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, we 
propose that 21 CFR parts 201 and 314 be amended as follows:

PART 201--LABELING

0
1. The authority citation for part 201 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 343, 351, 352, 353, 355, 358, 
360, 360b, 360ccc, 360ccc-1, 360ee, 360gg-360ss, 371, 374, 379e; 42 
U.S.C. 216, 241, 262, 264.


[[Page 38329]]


0
2. Add Sec.  201.67 to subpart C to read as follows:


Sec.  201.67   Labeling requirements for a nonprescription drug product 
with an additional condition for nonprescription use (ACNU).

    (a) Scope. This section sets forth labeling requirements for a 
nonprescription drug product with an ACNU.
    (b) Definition. The following definition applies to this section:
    (1) Additional condition for nonprescription use (ACNU) means one 
or more FDA-approved conditions that an applicant of a nonprescription 
drug product must implement to ensure consumers' appropriate self-
selection or appropriate actual use, or both, of the nonprescription 
drug product without the supervision of a healthcare practitioner if 
the applicant demonstrates and FDA determines that labeling alone is 
insufficient to ensure appropriate self-selection or appropriate actual 
use, or both.
    (2) [Reserved]
    (c) General labeling requirements. (1) A nonprescription drug 
product with an ACNU must comply with applicable labeling requirements 
for nonprescription drug products under this part, including the format 
and content requirements for nonprescription drug product labeling 
under Sec.  201.66 and the statements specified in Sec.  201.130(a).
    (2) A nonprescription drug product with an ACNU may also be 
approved with additional labeling that supplements the format and 
content requirements for nonprescription drug product labeling under 
Sec.  201.66.
    (d) Format requirements for required ACNU statement. The statement 
specified in Sec.  201.130(a)(2) must meet all format requirements as 
follows:
    (1) The statement must appear on the principal display panel (see 
Sec.  201.60) and the immediate container surface that the consumer is 
most likely to view when seeking information about the drug product. If 
the immediate container is a bottle, the statement must appear on the 
surface that the consumer is most likely to consider the front of the 
bottle. If the immediate container is a blister card (including a card 
that contains more than one blister unit), the statement must appear on 
the blister card surface that the consumer would most likely view when 
removing the drug product from the blister card. If the blister card 
contains more than one blister unit (e.g., perforated blister card 
where individual blister units can be separated from one another), the 
statement does not need to be included on each blister unit of a 
blister card. However, the statement must remain intact and be readable 
on the blister card when the drug product is removed from each blister 
unit.
    (2) The statement must appear in boldface and black type.
    (3) The statement must appear in a yellow background banner. No 
other information or statements may be included within the yellow 
background banner.
    (4) The statement must be in one of the following font sizes, 
whichever is greater:
    (i) At least 25 percent as large as the font size of the largest 
printed words on the principal display panel and immediate container; 
or
    (ii) At least 12 point font (1 point = 0.0138 inches).
    (5) An applicant may request an exception to the minimum font size 
requirement specified in paragraph (d)(4) of this section for 
containers where its size would render compliance with this requirement 
impractical. FDA may allow such an exception upon request by an 
applicant if FDA determines an exception is warranted.
    (e) Misbranding. A nonprescription drug product with an ACNU is 
misbranded under section 502 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 352) if--
    (1) It is made available without the labeling specified in Sec.  
201.130(a); or
    (2) The ACNU is not implemented by the applicant as approved by FDA 
in the application.
0
3. Add Sec.  201.130 to subpart D to read as follows:


Sec.  201.130   Exemption from adequate directions for use for a 
nonprescription drug product with an additional condition for 
nonprescription use.

    A nonprescription drug product approved under section 505(c) or 
505(j) of the Federal Food, Drug, and Cosmetic Act with an ACNU as 
defined in Sec.  201.67(b) is exempt from section 502(f)(1) if all the 
following conditions in paragraphs (a) and (b) of this section are met:
    (a) The label of the drug:
    (1) Bears, as the first direction under the ``Directions'' heading 
required in Sec.  201.66(c)(6), the statement ``To check if this drug 
is safe for you, go to [insert where or how consumers can find 
information about the ACNU; for example, applicant's website, 
applicant's phone number, or specific retail location] and [insert 
action to be taken by consumer]. Do not take this drug without 
completing this step.'' The statement must be followed by the other 
information required in Sec.  201.66(c)(6).
    (2) Bears, in the form and manner required by Sec.  201.67(d), the 
statement ``You must complete an extra step to see if this drug is safe 
for you before you use it. Do not take this drug without completing 
this step. See the Drug Facts labeling for more information.''
    (3) Complies with other applicable labeling requirements for 
nonprescription drug products under this part, including the format and 
content requirements for nonprescription drug product labeling under 
Sec.  201.66.
    (b) The additional condition for nonprescription use is implemented 
by the applicant under the conditions set forth in the approved 
application.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
4. The authority citation for part 314 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 
356, 356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.

0
5. Add Sec.  314.56 to subpart B to read as follows:


Sec.  314.56   Nonprescription drug product with an additional 
condition for nonprescription use (ACNU).

    (a) Definition. The following definition applies to this section:
    (1) Additional condition for nonprescription use (ACNU) means one 
or more FDA-approved conditions that an applicant of a nonprescription 
drug product must implement to ensure consumers' appropriate self-
selection or appropriate actual use, or both, of the nonprescription 
drug product without the supervision of a healthcare practitioner if an 
applicant demonstrates and FDA determines that labeling alone is 
insufficient to ensure appropriate self-selection or appropriate actual 
use, or both.
    (2) [Reserved]
    (b) Separate application required for a nonprescription drug 
product with an ACNU. An applicant must submit a separate application 
for a nonprescription drug product with an ACNU. Initial approval for a 
nonprescription drug product with an ACNU cannot be obtained through a 
supplement to an approved application.
    (c) Specific requirements for an application for a nonprescription 
drug product with an ACNU. The applicant must submit an application 
that complies with the following requirements:
    (1) New drug application (NDA). When fulfilling the content and 
format requirements under Sec.  314.50, an NDA for a nonprescription 
drug product with an ACNU must include--

[[Page 38330]]

    (i) A statement regarding the purpose of the ACNU: ensure 
appropriate self-selection or appropriate actual use, or both, by 
consumers of the nonprescription drug product with an ACNU without the 
supervision of a healthcare practitioner;
    (ii) A statement regarding the necessity of the ACNU;
    (iii) A description of how the ACNU ensures appropriate self-
selection or appropriate actual use, or both;
    (iv) A description of the key elements of the ACNU, including:
    (A) The additional condition implemented by the applicant to be 
fulfilled by the consumer to obtain the nonprescription drug product 
with an ACNU;
    (B) The labeling specifically associated with the ACNU; and
    (C) The criteria by which the consumer would successfully fulfill 
the ACNU, including a description of the specific actions to be taken 
by a consumer or required responses to be provided by a consumer;
    (v) Adequate data or other information that demonstrates the 
necessity of the ACNU to ensure appropriate self-selection or 
appropriate actual use, or both;
    (vi) Adequate data or other information that demonstrates the 
effect of the ACNU on the appropriate self-selection or appropriate 
actual use, or both; and
    (vii) A description of the specific way the ACNU is 
operationalized.
    (2) Abbreviated new drug application (ANDA). When fulfilling the 
content and format requirements under Sec.  314.94, an ANDA for a 
nonprescription drug product with an ACNU must--
    (i) State the purpose of the ACNU;
    (ii) Include information demonstrating that the key elements of the 
proposed ACNU are the same as the key elements of the ACNU for its 
reference listed drug (RLD); and
    (iii) Include information on the way the ACNU would be 
operationalized. If an applicant believes the ACNU is operationalized 
in the same way as the RLD, include information demonstrating that the 
ACNU is operationalized in the same way as the RLD. If a different way 
to operationalize the proposed ACNU is used, include information to 
show that this different way to operationalize the proposed ACNU 
achieves the same purpose as the ACNU for its RLD and that the 
differences from the RLD are otherwise acceptable in an ANDA.
    (d) Simultaneous marketing of nonprescription and prescription 
products. An ACNU constitutes a meaningful difference between a 
nonprescription drug product and a prescription drug product, such that 
a prescription drug product and a nonprescription drug product with an 
ACNU may be simultaneously marketed even if there is not another 
meaningful difference between the two products that makes the 
nonprescription drug product safe and effective for use without the 
supervision of a healthcare practitioner licensed by law to administer 
the drug (e.g., a different active ingredient, indication, strength, 
route of administration, dosage form, or patient population).
0
6. Amend Sec.  314.81 by adding paragraph (b)(3)(v) to read as follows:


Sec.  314.81   Other postmarketing reports.

* * * * *
    (b) * * *
    (3) * * *
    (v) Report of failure in the implementation of an additional 
condition for nonprescription use. The applicant must submit a report 
when a failure in the implementation of an additional condition for 
nonprescription use (ACNU) for a nonprescription drug product occurs. A 
report of a failure in implementation of an ACNU includes any event 
that results from a deviation in an applicant's implementation of the 
ACNU that may cause or lead to inappropriate medication use or consumer 
harm. All failures in implementation of an ACNU must be reported to the 
FDA Adverse Event Reporting System (FAERS), whether or not the failure 
in implementation of an ACNU is associated with an adverse event. If an 
applicant becomes aware of both a failure in implementation of an ACNU 
and an associated adverse event before the submission to FAERS, a 
single individual case safety report (ICSR) that describes both the 
failure in implementation of an ACNU and the associated adverse event 
must be submitted and must contain the information as required in Sec.  
314.80(f) and paragraph (b)(3)(v)(A) of this section. If a previously 
submitted report to FAERS describes only a failure in implementation of 
an ACNU or a previously submitted ICSR reports only an adverse event, 
and the submitter subsequently becomes aware of an associated adverse 
event or associated failure in implementation of an ACNU, the submitter 
must supplement the original report to FAERS with the new information. 
The supplement must include the information required in Sec.  314.80(f) 
or paragraph (b)(3)(v)(A) of this section, as applicable.
    (A) Content. The report must include the following for a failure in 
implementation of an ACNU:
    (1) Required information. The name, address, email, and telephone 
number of the applicant; an identifiable reporter; the drug product 
name; and the description of the failure in implementation of the ACNU.
    (2) Additional information, if known. In addition, the report must 
include the following information, if known:
    (i) Drug product strength; National Drug Code (NDC); lot number; 
and NDA or ANDA number.
    (ii) Initial reporter information including name, address, and 
telephone number of the initial reporter.
    (iii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (iv) Narrative summary of failure in implementation of an ACNU, 
including the date of failure in implementation of an ACNU (or best 
estimate); the date the failure in implementation of an ACNU was 
reported to applicant; the location of failure in implementation of an 
ACNU, including business name and contact information; and whether any 
of the following circumstances occurred: The consumer accessed or used 
the drug product without successfully fulfilling the ACNU; the consumer 
successfully fulfilled the ACNU but could not access or use the drug 
product; or the consumer was unable to make an attempt to fulfill the 
ACNU; and
    (v) The remedial action taken or completed to address the failure 
in implementation of an ACNU, including the type of remedial action 
initiated or completed (for example, repair, replace, recall, 
inspection, modification, or adjustment) and a description of how the 
applicant will prevent failures of the same nature in the future.
    (B) Submission. (1) The applicant must submit the report for each 
failure in implementation of an ACNU as soon as possible but no later 
than 15 calendar days from the date when the applicant has acquired the 
minimum dataset for a failure in implementation of an ACNU.
    (2) The applicant must also investigate any new information it 
obtains or otherwise receives about previously submitted reports and 
assess the relationship or impact of the new information on the initial 
report. The applicant must submit followup reports as soon as possible 
but no later than 15 calendar days after obtaining the new information.
    (C) Electronic format for submissions. (1) The report must be 
submitted to FDA in accordance with Sec.  314.80(g).
    (2) An applicant may request, in writing, a waiver of the 
requirements in paragraph (b)(3)(v)(C)(1) of this section in accordance 
with Sec.  314.90 or Sec.  314.99.

[[Page 38331]]

    (D) Recordkeeping. The applicant must maintain for a period of 10 
years, the records of all reports of failures in implementation of an 
ACNU and associated adverse events known to the applicant, including 
raw data and any correspondence relating to a report of a failure in 
implementation of an ACNU.
* * * * *
0
7. Amend Sec.  314.125 by adding paragraph (b)(20) to read as follows:


Sec.  314.125   Refusal to approve an NDA.

* * * * *
    (b) * * *
    (20) For an NDA for a nonprescription drug product with an 
additional condition for nonprescription use under Sec.  314.56, if FDA 
has determined the application failed to meet the requirements in Sec.  
314.56 applicable to NDAs.
* * * * *
0
8. Amend Sec.  314.127 by adding paragraph (a)(15) to read as follows:


Sec.  314.127   Refusal to approve an ANDA.

    (a) * * *
    (15) For an ANDA for a nonprescription drug product with an 
additional condition for nonprescription use under Sec.  314.56, if FDA 
has determined the application failed to meet the requirements in Sec.  
314.56 applicable to ANDAs.
* * * * *

    Dated: June 15, 2022.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2022-13309 Filed 6-27-22; 8:45 am]
BILLING CODE 4164-01-P


