[Federal Register Volume 86, Number 145 (Monday, August 2, 2021)]
[Rules and Regulations]
[Pages 41383-41402]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-15980]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 801

[Docket No. FDA-2015-N-2002]
RIN 0910-AI47


Regulations Regarding ``Intended Uses''

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule to amend its medical product ``intended use'' 
regulations. This final rule amends FDA's regulations describing the 
types of evidence relevant to determining whether a product is intended 
for use as a drug or device under the Federal Food, Drug, and Cosmetic 
Act (FD&C Act), the Public Health Service Act (PHS Act), and FDA's 
implementing regulations, including whether a medical product that is 
approved, cleared, granted marketing authorization, or exempted from

[[Page 41384]]

premarket notification is intended for a new use. This action also 
withdraws and replaces the portions of a final rule issued on January 
9, 2017, that never became effective.

DATES: This rule is effective September 1, 2021.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule 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.

FOR FURTHER INFORMATION CONTACT: Kelley Nduom, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-5400, 
kelley.nduom@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Meaning of Certain Terms in This Preamble
III. Background
    A. Introduction and History of This Rulemaking
    B. Summary of Comments to the Proposed Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Responses
    A. Introduction
    B. Comments and Responses Regarding Statutory and Regulatory 
Authority
    C. Comments and Responses Regarding the Design or Composition of 
an Article
    D. Comments and Responses Regarding the First Amendment
    E. Comments and Responses Regarding the Fifth Amendment
    F. Comments and Responses Regarding Definitions
    G. Comments and Responses Regarding ``Safe Harbors''
    H. Comments and Responses Regarding Examples
    I. Comments on Codified Text and FDA Responses
    J. Comments Recommending That FDA Expand the Scope of This 
Rulemaking
VI. Effective Date
VII. Economic Analysis of Impacts
    A. Introduction and Summary
    B. Final Economic Analysis of Impacts
    C. Final Small Entity Analysis
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 Final Rule

    FDA is taking this action to amend its existing regulations 
(Sec. Sec.  201.128 and 801.4 (21 CFR 201.128 and 801.4)) describing 
the types of evidence relevant to determining a product's intended uses 
under the FD&C Act, the PHS Act, and FDA's implementing regulations. 
The amended regulations better reflect the Agency's current practices 
in evaluating whether a product is intended for use as a drug or 
device, including whether a medical product that is approved, cleared, 
granted marketing authorization, or exempted from premarket 
notification is intended for a new use. This action withdraws the 
portions of the final rule issued on January 9, 2017 (82 FR 2193), that 
never became effective, and it finalizes amendments to the intended use 
regulations for medical products that provide more clarity and 
direction to regulated industry and other stakeholders regarding the 
types of evidence relevant to determining a product's intended uses.

B. Summary of the Major Provisions of the Final Rule

    FDA is finalizing amendments to its intended use regulations for 
medical products (Sec. Sec.  201.128 and 801.4) to better reflect the 
Agency's current practices in evaluating whether a product is intended 
for use as a drug or device, including whether a medical product that 
is approved, cleared, granted marketing authorization, or exempted from 
premarket notification is intended for a new use.
    Several comments on the proposed rule raised legal concerns. Some 
commenters argued that FDA should construe its statutory and regulatory 
authorities more narrowly, and some asserted that the proposed rule 
violates the First and Fifth Amendments. These and similar arguments 
have been raised in comments received during earlier stages of this 
rulemaking as well as in other rulemaking proceedings, petitions, and 
litigation involving intended use issues. A number of other comments 
raised questions about the rule's applicability to certain medical 
devices, such as devices that are exempt from premarket notification 
(510(k)) requirements. These comments also criticized the inclusion of 
language in the regulation clarifying that the design or composition of 
an article may be relevant to determining its intended use.
    The final rule remains largely unchanged from the proposed rule. In 
response to comments received, we have modified the codified language 
of the intended use regulation for medical devices to clarify its 
applicability to devices that are approved, cleared, granted marketing 
authorization, or exempted from premarket notification. That is the 
only change from the codified language in the proposed rule.

C. Legal Authority

    Among the provisions that provide authority for this final rule are 
sections 201, 403(r), 503(g), and 701(a) of the FD&C Act (21 U.S.C. 
321, 343(r), 353(g), 371(a)); section 5(b)(3) of the Orphan Drug Act 
(21 U.S.C. 360ee(b)(3)); and sections 215, 301, 351(i) and (j), and 361 
of the PHS Act (42 U.S.C. 216, 241, 262(i) and (j), and 264).

D. Costs and Benefits

    The benefit of this final rule is the added clarity and certainty 
for firms and stakeholders regarding the evidence relevant to 
establishing whether a product is intended for use as a drug or device, 
including whether a medical product that is approved, cleared, granted 
marketing authorization, or exempted from premarket notification is 
intended for a new use. We do not have evidence that the final rule 
will impose costs on currently marketed products.

II. Meaning of Certain Terms in This Preamble

    As used in this rulemaking, the following terms have the meanings 
noted below.

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                  Term                               Meaning
------------------------------------------------------------------------
A medical product that is approved,      This term refers to a medical
 cleared, granted marketing               product that may be legally
 authorization, or exempted from          introduced into interstate
 premarket notification.                  commerce for at least one use
                                          under the FD&C Act or the PHS
                                          Act as a result of having
                                          satisfied applicable premarket
                                          statutory and regulatory
                                          requirements.

[[Page 41385]]

 
A medical use that is approved,          This term refers to an intended
 cleared, granted marketing               use included in the required
 authorization, or exempted from          labeling for an FDA-approved
 premarket notification.                  medical product, an intended
                                          use included in the
                                          indications for use statement
                                          for a device cleared or
                                          granted marketing
                                          authorization by FDA, or an
                                          intended use of a device that
                                          falls within an exemption from
                                          premarket notification.
Firms..................................  This term refers to
                                          manufacturers, packers, and
                                          distributors of FDA-regulated
                                          products and all their
                                          representatives, including
                                          both individuals and corporate
                                          entities.
Healthcare providers...................  This term refers to individuals
                                          such as physicians,
                                          veterinarians, dentists,
                                          physician assistants, nurse
                                          practitioners, pharmacists, or
                                          registered nurses who are
                                          licensed or otherwise
                                          authorized by the State to
                                          prescribe, order, administer,
                                          or use medical products in a
                                          professional capacity.
Medical products.......................  This term refers to drugs and
                                          devices, including human
                                          biological products.
Products unapproved for any medical use  This term refers to medical
                                          products that are not
                                          approved, cleared, granted
                                          marketing authorization, or
                                          exempted from premarket
                                          notification (as that phrase
                                          is described above) by FDA for
                                          any medical use, and which
                                          must be approved, cleared,
                                          granted marketing
                                          authorization, or exempted
                                          from premarket notification to
                                          be legally marketed for such
                                          use. This term also includes
                                          products that are marketed for
                                          non-medical uses, such as
                                          dietary supplements,
                                          conventional foods, and
                                          cosmetics.
Unapproved use of a medical product      This term refers to an intended
 that is approved, cleared, granted       use that is not included in
 marketing authorization, or exempted     the required labeling of an
 from premarket notification.             FDA-approved medical product,
                                          an intended use that is not
                                          included in the indications
                                          for use statement for a device
                                          cleared or granted marketing
                                          authorization by FDA, or an
                                          intended use of a device that
                                          does not fall within an
                                          exemption from premarket
                                          notification.
------------------------------------------------------------------------

III. Background

A. Introduction and History of This Rulemaking

    The Agency issued a proposed rule in 2015 and a final rule in 2017 
revising the language of its medical product intended use regulations, 
with the intent to conform them to the Agency's current practice in 
applying the regulations (see final rule, ``Clarification of When 
Products Made or Derived From Tobacco Are Regulated as Drugs, Devices, 
or Combination Products; Amendments to Regulations Regarding `Intended 
Uses''' (82 FR 2193, January 9, 2017)). These amendments did not 
reflect a change in FDA's approach regarding types of evidence of 
intended use for drugs and devices. However, after receiving a petition 
that requested the Agency reconsider these amendments, FDA delayed the 
effective date of the 2017 final rule and reopened the docket to invite 
public comment. A number of comments submitted during the reopening 
raised questions and, on March 16, 2018 (83 FR 11639), FDA delayed the 
effective date of the intended use amendments until further notice to 
allow further consideration of the substantive issues raised in the 
comments received. After considering the issues raised in the petition 
and comments submitted during the reopening, FDA issued a notice of 
proposed rulemaking in September 2020 (85 FR 59718, September 23, 2020, 
the ``NPRM'') to withdraw the portions of the final rule issued on 
January 9, 2017, that never became effective and to propose a new rule 
to provide more clarity regarding the types of evidence that are 
relevant in determining a product's intended uses.

B. Summary of Comments to the Proposed Rule

    Approximately 15 comments on the proposed rule were submitted to 
the docket. These comments were submitted by various industry trade 
organizations, consumer advocacy groups, and individuals. Several 
comments raised legal concerns with the proposed rule, including 
arguments to the effect that the rule violates the First and Fifth 
Amendments. Other comments raised questions and concerns about the 
rule's applicability to certain medical devices, such as devices that 
are 510(k)-exempt. These comments also generally objected to the 
inclusion of language in the regulation clarifying that the design or 
composition of an article may be relevant to determining its intended 
use.

IV. Legal Authority

    Among the statutory provisions that provide authority for this 
final rule are sections 201, 403(r), 503(g), and 701(a) of the FD&C 
Act, section 5(b)(3) of the Orphan Drug Act, and section 351(i) of the 
PHS Act. Section 201 of the FD&C Act defines ``drug'' (subsection 
(g)(1)), ``device'' (subsection (h)), ``food'' (subsection (f)), 
``dietary supplement'' (subsection (ff)), ``cosmetic'' (subsection 
(i)), and ``tobacco product'' (subsection (rr)(1)); section 5(b)(3) of 
the Orphan Drug Act defines ``medical food''; and section 503(g)(1) of 
the FD&C Act provides that combination products are those ``that 
constitute a combination of a drug, device, or biological product.'' 
Section 351(i) of the PHS Act defines ``biological products'', and 
section 351(j) of the PHS Act provides that the requirements of the 
FD&C Act apply to biological products. Section 403(r) of the FD&C Act 
establishes the requirements under which certain labeling claims about 
uses of conventional foods and dietary supplements to reduce the risk 
of a disease or affect the structure or function of the human body are 
not evidence of intended use as a drug. Under section 701(a) of the 
FD&C Act, FDA has authority to issue regulations for the efficient 
enforcement of the FD&C Act. FDA regulates the manufacture, sale, and 
distribution of drugs, devices, combination products, tobacco products, 
foods (including dietary supplements), and cosmetics under the 
authority of the FD&C Act.

[[Page 41386]]

V. Comments on the Proposed Rule and FDA Responses

A. Introduction

    We received approximately 15 comment submissions on the proposed 
rule by the close of the comment period, each containing one or more 
comments on one or more issues. We describe and respond to the comments 
in sections B through J of this section. We have numbered each comment 
to help distinguish between different comments. We have grouped similar 
comments together under the same number, and, in some cases, we have 
separated different issues discussed in the same comment and designated 
them as distinct comments for purposes of our responses. The number 
assigned to each comment or comment topic is purely for organizational 
purposes and does not signify the comment's value or importance or the 
order in which comments were received.
    In addition to the comments specific to this rulemaking that we 
address in the following paragraphs, we received several general 
comments expressing support for or opposition to the rule. These 
comments express broad policy views and do not address specific points 
related to this rulemaking. Therefore, these general comments do not 
require a response. To the extent that comments expressing opposition 
to the rule requested that we refrain from finalizing the rule, we 
decline to do so. In general, comments outside the scope of this 
rulemaking have not been addressed here. Summaries of the remaining 
comments, as well as FDA's responses, are included in this document.

B. Comments and Responses Regarding Statutory and Regulatory Authority

    (Comment 1) One comment asserted that under the relevant statutes, 
legislative history, and case law, evidence of intended use is limited 
to promotional claims that have been made in the marketplace. The 
comment argued that the NPRM was wrong in stating that evidence of 
intended use can be derived from ``any relevant source,'' including 
``circumstances surrounding distribution.'' Other comments also 
encouraged the Agency to focus primarily or only on promotional claims.
    (Response) We disagree. Nothing in the statute requires the narrow 
scope that the comment suggested. Although the first comment mentioned 
above loosely refers to the statutory and regulatory regime as support 
for its preferred interpretation, it does not cite any statutory 
language that dictates an exclusively claims-based approach to intended 
use. As four justices of the Supreme Court recognized in rejecting the 
argument that the statute limits evidence of intended use to 
promotional claims: ``The [FD&C Act] . . . does not use the word 
`claimed'; it uses the word `intended' '' (FDA v. Brown & Williamson 
Tobacco Corp., 529 U.S. 120, 170 (2000) (dissenting opinion) (the 
majority declined to resolve the issue, id. at 131-32)). The fact that 
intended use can be established through promotional claims does not 
preclude the possibility that other evidence may be relevant as well.
    Nor does the comment cite any legislative history that supports an 
exclusively claims-based approach to intended use. Indeed, the 
legislative history supports reliance on evidence of use by healthcare 
practitioners and consumers as relevant to intended use. The House 
Report on the Medical Device Amendments of 1976 states that ``[t]he 
Secretary may consider . . . use of a product in determining whether or 
not it is a device'' (see H.R. Rep. 853, 94th Cong., 2d Sess. 14 
(1976), reprinted in An Analytical Legislative History of the Medical 
Device Amendments of 1976, Appendix III (Daniel F. O'Keefe, Jr. and 
Robert A. Spiegel, eds. 1976)). Similarly, the legislative history of 
the 1938 Act states expressly that ``the use to which the product is to 
be put will determine the category into which it will fall'' (see S. 
Rep. No. 361, 74th Cong., 1st Sess. 4 (1935), reprinted in 3 
Legislative History 660, 663).
    Nor does the language of the existing regulation support the 
commenter's position. ``[N]owhere does the regulation state that'' 
evidence of intended use is limited to statements or claims ``published 
to the marketplace'' (see United States v. Vascular Solutions, Inc., 
181 F. Supp. 3d 342, 347 (W.D. Tex. 2016)). Indeed, the existing 
regulations specifically state that evidence of intended use includes 
``circumstances surrounding the distribution of the article'' and 
``circumstances that the article . . . is offered or used for a purpose 
for which it is neither labeled or advertised.'' This language was 
included when the regulation was first codified in 1952 (see 17 FR 
6818, 6820 (1952) (Ref. 1)).
    Furthermore, the case law does not resolve the matter in favor of 
the position advanced by the commenter. Courts have repeatedly held 
that intended use is determined by looking to any relevant evidence, 
including statements and circumstances surrounding the manufacture and 
distribution of a medical product (see, e.g., United States v. Article 
of 216 Cartoned Bottles, ``Sudden Change,'' 409 F.2d 734, 739 (2d Cir. 
1969) (``It is well settled that the intended use of a product may be 
determined from its label, accompanying labeling, promotional material, 
advertising and any other relevant source.'') (citations omitted); V.E. 
Irons, Inc. v. United States, 244 F.2d 34, 44 (1st Cir. 1957) 
(observing that a court is ``free to look to all relevant sources in 
order to ascertain what is the `intended use' of a drug'')). As 
explained by one court: ``Whether a product's intended use makes it a 
device depends, in part, on the manufacturer's objective intent in 
promoting and selling the product. All of the circumstances surrounding 
the promotion and sale of the product constitute the `intent'. It is 
not enough for the manufacturer to merely say that he or she did not 
`intend' to sell a particular product as a device. Rather, the actual 
circumstances surrounding the product's sale, such as the identi[t]y of 
actual customers and their use of the product and labeling claims, 
determine the 'intended' use of the product as a device under the Act'' 
(United States v. 789 Cases, More or Less, of Latex Surgeons' Gloves, 
799 F. Supp. 1275, 1285 (D. Puerto Rico 1992) (internal citations 
omitted)).
    Courts have rejected the commenter's proposition that evidence of 
intended use is limited to a manufacturer's public claims concerning a 
device or drug (see Nat'l Nutritional Foods Ass'n v. Matthews, 557 F.2d 
325, 334 (2d Cir. 1977) (``In determining whether an article is a 
`drug' because of an intended therapeutic use, the FDA is not bound by 
the manufacturer's subjective claims of intent but can find actual 
therapeutic intent on the basis of objective evidence. Such intent also 
may be derived or inferred from labeling, promotional material, 
advertising, and any other relevant source.'') (internal citation and 
quotations omitted); United States v. Travia, 180 F. Supp. 2d 115, 119 
(D.D.C. 2001) (``Labeling is not exclusive evidence of the sellers' 
intent. Rather, . . . `it is well established that the intended use of 
a product, within the meaning of the [FD&C Act], is determined from its 
label, accompanying labeling, promotional claims, advertising, and any 
other relevant source' . . . even consumer intent could be relevant, so 
long as it was pertinent to demonstrating the seller's intent . . . 
[I]f the government's allegations are true, the sellers did not need to 
label or advertise their product, as the environment provided the 
necessary information between buyer and seller. In this context, 
therefore, the

[[Page 41387]]

fact that there was no labeling may actually bolster the evidence of an 
intent to sell a mind-altering article without a prescription-that is, 
a misbranded drug.'') (citations omitted); United States v. Vascular 
Solutions, Inc., 181 F. Supp. 3d at 347 (the position that evidence of 
objective intent is limited to statements ``published to the 
marketplace'' is ``absurd[]'')); see also United States v. Storage 
Spaces Designated Nos. 8 and 49, 777 F.2d 1363, 1366 n.5 (9th Cir. 
1985) (concluding that products innocuously labeled as ``incense'' and 
``not for drug use'' were in fact drugs where the ``overall 
circumstances'' demonstrated vendor's intent that products be used as 
cocaine substitutes); United States v. An Article of Device Toftness 
Radiation Detector, 731 F.2d 1253, 1257 (7th Cir. 1984) (intended use 
established in part by witness testimony that device had been used to 
treat patients, together with other evidence regarding a training 
program and financial arrangements offered by the defendant); United 
States v. Undetermined Quantities of an Article of Drug Labeled as 
``Exachol'', 716 F. Supp. 787, 791 (S.D.N.Y. 1989) (explaining that 
``FDA is not bound by the vendor's subjective claims of intent'' and 
that ``[a]n article intended to be used as a drug will be regulated as 
a drug . . . even if the product[']s labelling states that it is not a 
drug''); United States v. 22 Rectangular or Cylindrical Finished 
Devices, 714 F. Supp. 1159, 1165 (D. Utah 1989) (``The objective intent 
referred to in the regulation may be shown not only by a product's 
labeling claims, advertising or written statements relating to the 
circumstances of a product's distribution, . . . but also by a 
product's actual use. See H.R. Rep. No. 853, 94th Cong., 14 (1976). . . 
. There also can be no dispute that the sterilizer, in its actual use, 
plays an integral role in the surgical treatment of patients.''); 
Hanson v. United States, 417 F. Supp. 30, 35 (D. Minn. 1976) (finding 
plaintiffs' beliefs that many people will die if they are deprived of 
the tablets and vials at issue relevant to establishing intended use), 
aff'd, 540 F.2d 947 (8th Cir. 1976); United States v. Device Labeled 
``Cameron Spitler Amblyo-Syntonizer'', 261 F. Supp. 243, 245 (D. Neb. 
1966) (``While claimant contends that the machines have not been 
represented as a cure for any particular eye malfunction, he admits the 
use of them in the treatment of certain eye maladies. Clearly, the 
seized machines are each a device within the meaning of Sec.  
321(h).'')).
    Although one comment cited to several cases that relied only on 
promotional claims as evidence of intended use, only a very few, if 
any, cases have actually excluded non-claims evidence from 
consideration as evidence of intended use on the ground that the 
evidence was not promotional. The presence of claims may be 
particularly significant in determining intended use where a product, 
such as honey, does not have a therapeutic benefit or physiological 
effect (see, e.g., United States v. An Article . . . ``U.S. Fancy Pure 
Honey'', 218 F. Supp. 208, 211 (E.D. Mich. 1963) (claim that honey is a 
panacea for various diseases and ailments established the intended use 
as a drug), aff'd, 344 F.2d 288 (6th Cir. 1965). But the converse is 
not true--the absence of claims on a product that does have a 
physiological effect will not automatically render the product immune 
from FDA jurisdiction (see, e.g., United States v. Carlson, 810 F.3d 
544 (8th Cir. 2016) (synthetic drugs, such as synthetic marijuana, 
labeled as incense, herbal incense, herbal potpourri, bath salts, etc., 
and that also bore the statement ``not for human consumption,'' found 
to be subject to FDA's jurisdiction as drugs)).
    As FDA has explained, limiting evidence of intended use to only 
promotional claims would allow manufacturers to circumvent FDA 
regulation by masking their true intent, either by simply omitting 
explicit promotional claims or by making claims that are not true (for 
example, ``not for human use''). See 82 FR 14319 at 14321 through 14322 
(March 20, 2017); 82 FR 2193 at 2196 (January 9, 2017); 80 FR 57756 at 
57757 (September 25, 2015). As courts have recognized, ``[s]elf-serving 
labels cannot be allowed to mask the vendor's true intent as indicated 
by the overall circumstances.'' United States v. Storage Spaces 
Designated Nos. 8 and 49, 777 F.2d 1363, 1366 n.5 (9th Cir. 1985)). 
This is an issue that comes up frequently with respect to products in 
domestic commerce as well as imported goods and has resulted in FDA-
issued warning letters, import refusals, civil injunction actions, and 
criminal prosecutions. FDA believes it is worth repeating the following 
previously cited examples, see 82 FR 14319 at 14321 through 14322 
(March 20, 2017), of the types of situations in which evidence of 
intended use has been derived from sources other than explicit 
promotional claims:
     Persons distributing substances that are known to be used 
recreationally to achieve a mind-altering effect, such as 
dextromethorphan (the active ingredient in some cough suppressants) and 
nitrous oxide (which is a prescription drug) (see, e.g., United States 
v. Johnson, 471 F.3d 764, 765 (7th Cir. 2006); United States v. 
Schraud, 2007 U.S. Dist. LEXIS 89231, 3-6 (E.D. Mo. December 4, 2007); 
United States v. Travia, 180 F. Supp. 2d 115, 119 (D.D.C. 2001); United 
States v. LA Rush, 2:13-cr-00249, First Superseding Information (C.D. 
Cal. April 3, 2014)).
     Persons distributing synthetic drugs, such as synthetic 
marijuana, labeled as incense, potpourri, bath salts, and/or bearing 
the statement ``not for human consumption'' (see, e.g., United States 
v. Carlson, 810 F.3d 544 (8th Cir. 2016); United States v. Carlson, 12-
cr-00305-DSD-LIB, Amended Superseding Indictment (D. Minn. Sept. 11, 
2013) and Court's Instructions to the Jury, (D. Minn. October 8, 2013); 
United States v. Bowen, 14-cr00169-PAB, Indictment (D. Colo. May 5, 
2014) and Rule 11(c)(1)(A) and (B) Plea Agreement and Statement of 
Facts Relevant to Sentencing (D. Colo. January 29, 2015).
     Persons distributing imitation drugs claimed to be incense 
or dietary supplements, such as imitation cocaine or imitation Ecstasy 
(see, e.g., United States v. Storage Spaces Designated Nos. ``8'' & 
``49'', 777 F.2d 1363, 1366 (9th Cir. 1985); United States v. 
Undetermined Quantities of . . . Street Drug Alternatives, 145 F. Supp. 
2d 692 (D. Md. 2001)).
     Persons distributing products containing the active 
ingredients in prescription drugs, such as VIAGRA, CIALIS, LEVITRA, or 
BOTOX, as less expensive alternatives to the approved products, with 
labeling that states that they are ``all natural'' or ``herbal'' 
supplements or ``for research only'' (see, e.g., United States v. 
Dessart, 823 F.3d 395 (7th Cir. 2016); United States v. Zeyid, 1:14-cr-
0197, First Superseding Indictment (N.D. Ga. June 24, 2014) (see also 
Ref. 2); United States v. Livdahl, 459 F. Supp. 2d 1255, 1260 (S.D. 
Fla. 2005)).
    Other instances where a person's claims about the intended use of a 
product are belied by the person's activities or non-promotional 
statements or by circumstantial evidence (see, e.g., United States v. 
An Article of Device Toftness Radiation Detector, 731 F.2d 1253, 1257 
(7th Cir. 1984); United States v. 789 Cases of Latex Surgeons' Gloves, 
799 F. Supp. 1275, 1294-1295 (D.P.R. 1992)).
    In these situations, the evidence relied on to establish intended 
use has included general knowledge of actual use by customers to 
achieve a mind-altering effect; the known effects of a product or 
substance; implied claims

[[Page 41388]]

from using names that sound similar to the names of controlled 
substances; the circumstances surrounding the sale (e.g., a rock 
concert venue; receiving the product in bulk and repackaging into 
smaller plastic bags; the use of private email addresses; the absence 
of labeling); shipping orders, other correspondence, and memoranda 
relating to marketing and distribution; statements made in training 
sessions; and admissions.
    Evidence other than promotional claims has also been used to 
establish that products offered for import into the United States 
without labeling or other claims that identify them as a drug or device 
are in fact intended for use as a drug or device and are therefore 
subject to refusal if it appears that they fail to meet certain 
requirements for importing medical products (see 21 U.S.C. 381(a)(3)). 
For example, the defendants in United States v. Zeyid, 1:14-cr-0197, 
First Superseding Indictment (N.D. Ga. June 24, 2014) (see Ref. 2), 
imported products containing active ingredients that were the same as 
those used in prescription drugs but that were labeled as ``tea,'' 
``coffee,'' and ``beauty products.''
    (Comment 2) One comment asserted that the position on intended use 
described by FDA in the NPRM was an ``alternative, novel interpretation 
[] with which FDA has flirted from time to time in the past.''
    (Response) We disagree. This is not the first time FDA has 
responded to arguments that its interpretation of the scope of evidence 
relevant to ``intended use'' is too broad--those arguments have been 
raised in comments in earlier stages of this and other rulemaking 
proceedings, petitions, and litigation involving intended use issues. 
Contrary to the comment's assertion that the NPRM presented a novel 
interpretation of intended use, FDA has steadfastly maintained for 
decades that, in determining a product's intended use, the Agency may 
look to any relevant source of evidence, including a variety of direct 
and circumstantial evidence. FDA's position is reflected in the notices 
issued in this rulemaking over the past 5 years (see, e.g., 85 FR 59718 
at 59721 (September 23, 2020); 82 FR 14319 at 14320 (March 20, 2017); 
82 FR 2193 at 2206 (January 9, 2017); 80 FR 57756 at 57757 (September 
25, 2015)), and has been noted in court decisions (see, e.g., Spectrum 
Pharma. v. Burwell, 824 F.3d 1062, 1069 (D.C. Cir. 2016) (``To be sure, 
FDA recognizes that there may be situations in which it will look 
beyond just the manufacturer's statements [to determine intended 
use].''); United States v. Travia, 180 F. Supp. 2d 115, 119 (D.D.C. 
2001) (``The government argues that the Court should look to the 
objective intent of the sellers in this case, which would permit the 
Court to view the totality of the circumstances--namely, the selling of 
balloons of laughing gas in the parking lot at a rock concert--
surrounding the sale of the nitrous oxide here. See, e.g., 21 CFR 
201.128.'')). This position has also been explained in numerous 
litigation briefs and other FDA pronouncements, such as in the 
following excerpts from examples of such documents issued from 2000 to 
2017:
     In determining a product's intended uses, ``[l]abeling is 
not [the] exclusive evidence.'' See United States v. Travia, 180 F. 
Supp. 2d 115, 119 (D.D.C. 2001). Instead, ``it is well established that 
the `intended use' of a product, within the meaning of the Act, is 
determined from its label, accompanying labeling, promotional claims, 
advertising, and any other relevant source.'' Action on Smoking and 
Health v. Harris, 655 F.2d 236, 239 (D.C. Cir. 1980) (quotation marks 
omitted); see also V.E. Irons, Inc. v. United States, 244 F.2d 34, 44 
(1st Cir. 1957) (``[W]e are free to look to all relevant sources in 
order [to] ascertain what is the `intended use' of a drug.''). Courts 
have considered ``relevant sources'' to include, for example, product 
formulation and method of intake, actual use of the product by 
consumers and medical practitioners, and circumstances of sale in 
determining intended use. See, e.g., United States v. Ten Cartons, More 
or Less, of an Article . . . Ener-B Vitamin B-12, 72 F.3d 285, 287 (2d 
Cir. 1995); United States v. Storage Spaces, 777 F.2d 1363, 1367 (9th 
Cir. 1985); United States v. An Article of Device . . . Toftness 
Radiation Detector, 731 F.2d 1253, 1257-58 (7th Cir. 1984) (Litigation 
brief (2011), Ref. 3).
     Courts have recognized that intended use may be shown by 
non-speech evidence that has included, for example, product formulation 
and method of intake, actual use of the product by consumers and 
medical practitioners, and circumstances of sale (Litigation brief 
(2010), Ref. 4 at 8-9 n.5).
     Courts have repeatedly held that, although promotional 
claims are one source of evidence of intended use, FDA is authorized to 
rely on any other relevant source of evidence [including] . . . [the 
product's] method of intake, . . . [how any claims are] understood by a 
consumer. . ., [suggestive] product names, . . . [and] meta-tags 
(Litigation brief (2001), Ref. 5 at 20-26).
     [Evidence of intended use to be presented at trial 
includes:] (1) Defendant intended the nitrous oxide he was offering for 
sale on his website bongmart.com to be used as a drug, despite his 
marking the nitrous oxide `For Food Use Only;' (2) Defendant knew that 
the nitrous oxide cartridges were commonly used as a drug for getting 
high; and (3) Defendant's customers actually used the nitrous oxide 
sold by Defendant as a drug (Litigation brief (2000), Ref. 6 at 6).
     It has been the Agency's longstanding position that in 
determining a product's intended use, the Agency may look to any 
relevant source of evidence. . . . To hold accountable firms that 
attempt to evade FDA drug jurisdiction by avoiding making express 
claims about their products or disclaiming a particular intended use, 
courts have relied on a variety of evidence to establish intended use, 
including general knowledge of actual use by customers to get high or 
have some other mind-altering effect; the known effects of a product or 
substance; implied claims from using names that sound similar to 
controlled substances; the circumstances surrounding the sale (e.g., a 
rock concert venue; receiving the product in bulk and repackaging into 
smaller plastic bags; the use of private email addresses; the absence 
of labeling); shipping orders, other correspondence, and memoranda 
relating to marketing and distribution; statements made in training 
sessions; and admissions (Regulatory letter (2017), Ref. 7 at 9-10).
     The manufacturer's intent will necessarily be determined 
on a case-by-case basis, looking at the totality of the facts and 
circumstances. . . . The trier of fact will take into account the full 
body of evidence. If evidence of distribution or sponsorship activity 
forms part of the basis of FDA's claim, the trier of fact will consider 
the context of that activity . . . in assessing the manufacturer's 
objective intent (Regulatory letter (2002), Ref. 8 at 6).\1\
---------------------------------------------------------------------------

    \1\ The comment erroneously asserts that FDA's reliance on 
evidence other than promotional claims to assert jurisdiction over 
cigarettes in a 1996 final rule was ``roundly rejected by the 
courts.'' In fact, the Supreme Court's majority opinion declined to 
address the issue, and the dissent endorsed FDA's analysis (see FDA 
v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 131-32 (2000); 
id. at 170 (dissenting opinion).
---------------------------------------------------------------------------

    In addition, issues involving the scope of evidence relevant to 
establishing intended use frequently arise in FDA's day-to-day 
operations in protecting the public health, including Warning Letters 
and import determinations (see, e.g., FDA Warning

[[Page 41389]]

Letter to HelloCig Electronic Technology Co., Ltd (Ref. 9) (relying in 
part on undeclared active pharmaceutical ingredient as well as implied 
claims from imagery to determine product's intended use); FDA Warning 
Letter to Duy Drugs, Inc. (Ref. 10) (relying in part on undeclared 
sildenafil to establish intended use); Letter from Steven B. Barber, 
District Director, Cincinnati District, FDA to Marc C. Sanchez, Esq., 
Mood and Mind, LLC, (Ref. 7 at 9-10) (relying in part on known 
attributes and common uses of product to establish use; Letter from 
Daniel Solis, Director, Import Operations Branch, Los Angeles District 
to Carol A. Pratt, K&L Gates LLP (Ref. 11) (relying in part on 
information available on the internet reflecting general understanding 
by consumers of mind-altering properties and purported medical uses of 
product, as well as pattern of changes to the importer's website and 
blog to conceal the true intended use of the product by deleting 
references to the amount of a psychoactive component in the product); 
FDA Warning Letter to Lifetech Resources Labs Inc. (Ref. 12) (relying 
in part on ``presence of the prostaglandin analog, isopropyl 
cloprostenate, along with appearance claims'' to establish intended 
use); FDA Warning Letter to INZ Distributors (Ref. 13) (relying in part 
on presence of analogue of an erectile dysfunction drug to determine 
product's intended use)). One of the purposes of this rulemaking is to 
put to rest any dispute about FDA's interpretation of its statute and 
regulations, and its policy--as embodied in this rule as well as in the 
precedent cited above--regarding evidence that may be relevant to 
establishing intended use.
    (Comment 3) With respect to the many situations where manufacturers 
and distributors attempt to evade FDA regulatory oversight by omitting 
promotional medical product claims, examples of which are provided 
above, one comment suggested that the Government could use other 
regulatory tools rather than apply FDA's authorities for premarket 
review of medical products. Specifically, the comment suggested that 
FDA employ ``a combination of post-market risk mitigation techniques'' 
which would require FDA to engage in the ``collection, review, and 
potential description in labeling'' of the risks associated with the 
``unlabeled use'' before taking enforcement action against the product 
to protect the public health. The same comment suggested that, 
alternatively, FDA could consider evidence other than promotional 
claims, but only to establish that in fact a promotional claim had been 
made.
    (Response) FDA declines this suggestion. The fundamental purpose of 
the FD&C Act is to help protect ``the lives and health of people which, 
in the circumstances of modern industrialism, are largely beyond self-
protection'' (United States v. Dotterweich, 320 U.S. 277, 280 (1943)). 
``[R]emedial legislation such as the Food, Drug, and Cosmetic Act is to 
be given a liberal construction consistent with the Act's overriding 
purpose to protect the public health'' (United States v. An Article of 
Drug . . . Bacto Unidisk, 394 U.S. 784, 798 (1969)). Although FDA 
generally considers risk as part of its determination whether to take 
enforcement action, part of the impetus for Congress' development of 
the premarket review requirements was the determination that exclusive 
reliance on postmarket remedies, such as enforcement actions for false 
or misleading labeling, is inadequate because it does not prevent 
consumers from experiencing harm from unsafe and/or ineffective 
treatments.
    FDA's position regarding evidence relevant to establishing intended 
use helps protect the public health. To describe more fully one of the 
examples cited above: In United States v. Johnson, 471 F.3d 764 (7th 
Cir. 2006), the defendant imported dextromethorphan hydrobromide (DXM), 
the active ingredient in some cough suppressants, and distributed it 
for recreational use. During the 4 months his company was in operation, 
five customers died. Because DXM is not a controlled substance, no 
charges were brought under the Controlled Substances Act, but the court 
found that FDA had jurisdiction under the FD&C Act (id. at 765). 
Defendant pleaded guilty to three counts of introducing a misbranded 
drug into interstate commerce and received a 77-month sentence (id.). 
In upholding that sentence, the Seventh Circuit noted that the 
defendant ``knew--not merely should have known--that there was a 
substantial risk that more of his customers would die, and yet he 
continued to sell DXM for recreational use and failed to warn existing 
customers, including the two teenagers who died after he learned of the 
first two deaths'' (id.).
    Because FDA's position on intended use helps ensure that it can 
help curb the distribution of dangerous and fraudulent products, FDA 
declines to construe intended use more narrowly than the statute 
provides.
    (Comment 4) One comment objected to FDA's statement in the proposed 
rule that relying exclusively on firms' claims to determine intended 
use would adversely affect public health by opening the door to the 
marketing of products that are unapproved for any medical use. The 
comment argued that there is no public health need for FDA to rely on 
evidence other than express claims to determine intended use because 
the FD&C Act and other statutes provide other authorities that allow 
FDA to take action against products that contain an active ingredient 
from an FDA-approved drug, controlled substance, or other 
pharmacological ingredient. Specifically, the comment recommended that 
FDA use its dietary supplement and food additive authorities to keep 
products containing pharmacological ingredients out of dietary 
supplements and conventional foods, rather than using an intended use 
analysis to classify and regulate the products as drugs. The specific 
authorities mentioned in the comment were the definitions of ``food'' 
and ``dietary supplement'' and the corresponding adulteration 
provisions of the FD&C Act; the premarket notification requirement for 
certain dietary ingredients not marketed in the United States before 
October 15, 1994; and the premarket approval requirement for food 
additives. Similarly, another comment argued that rather than 
continuing to take the approach to intended use outlined in the NPRM, 
the Government could apply other provisions of Federal law; and that 
where there are gaps in existing legal provisions, FDA could seek 
specific product-based legislative changes.
    (Response) We decline the comments' suggestions. Although it is 
true that the authorities mentioned in the comment enable FDA to keep 
some products containing pharmacological ingredients out of the food 
supply and dietary supplement marketplace, the comment overstates the 
reach of FDA's other authorities and overlooks the fact that simply 
being outside the dietary supplement or food definition does not make a 
product unlawful and subject to enforcement action. To establish 
jurisdiction over a product as a drug and remove it from the 
marketplace, or require the manufacturer to obtain FDA approval for the 
product before marketing it, FDA must be able to establish that the 
product is a drug based on evidence of its intended use Thus, the 
regulatory tools the comment recommends are not a substitute for FDA's 
medical product authorities that include an intended use determination.
    As the previous comment response explained, suggestions that FDA 
use other regulatory tools in place of

[[Page 41390]]

intended use would have a significant negative impact on public health. 
To protect consumers from dangerous products containing pharmacological 
ingredients like the cough suppressant in United States v. Johnson that 
caused several deaths, FDA intends to continue considering the full 
range of evidence relevant to determining intended use.
    (Comment 5) One comment agreed with the NPRM that evidence of 
intended use could include conduct other than claims, but suggested 
that the rule clarify that the conduct must be promotional.
    (Response) FDA declines this suggestion. FDA believes that the key 
issue in the intended use analysis is whether the evidence is 
``relevant,'' which does not necessarily depend on whether there is 
evidence of ``promotional'' activity. The NPRM provided several 
examples to help inform the assessment of relevance. As the preamble 
explained, where a firm disseminates additional specific safety and 
warning information to healthcare providers to minimize the risk to 
patients receiving the drug for the unapproved use--an example of non-
promotional speech--FDA would not consider such evidence to be relevant 
to intended use (see 85 FR 59718 at 59726). But the preamble provided 
other examples of evidence that would not necessarily be considered 
promotional that would still be relevant to intended use--such as 
designing a stent to be specifically sized for a use that is different 
from the purported use (see 85 FR 59718 at 59725). As another example, 
a factfinder might consider, as evidence of a new intended use, a 
spacer that the manufacturer claims can be used to elute one liquid, 
but is in fact designed with holes that are sized to elute a more 
viscous substance that contains a different active ingredient. 
Accordingly, FDA declines the suggestion to include ``promotional'' as 
a limiting principle for non-claims-based evidence that may be relevant 
to intended use.
    This conclusion is consistent with recent case law. The case law 
describes the standard for determining intended use as ``all relevant 
evidence.'' This allows the fact finder to evaluate the facts of the 
specific case, which may involve a variety of situations and 
circumstances. For example, in United States v. Carlson, 810 F.3d 544 
(8th Cir. 2016), defendants owned and/or worked at the Last Place on 
Earth, a head shop in Duluth, Minnesota, which sold synthetic drugs, 
such as synthetic marijuana. The products were labeled as incense, 
herbal incense, herbal potpourri, bath salts, etc., and also bore the 
label statement ``not for human consumption,'' but defendants knew that 
customers purchased them to consume as drugs (see id. at 549; see also 
Amended Superseding Indictment, 12-cr-00305-DSD-LIB ] 9 (D. Minn. 
September 11, 2013)). The trial court instructed the jury that the 
product's intended use ``is what a reasonable person would conclude the 
manufacturer, seller or dispenser of the product intended the product 
to be used for, based on all of the relevant information'' (see The 
Court's Instructions to the Jury, 12-cr-00305-DSD-LIB at 58 (D. Minn. 
October 8, 2013)). The court explained that the jury could consider 
``any and all testimony and evidence,'' whether or not the 
manufacturer, seller, or dispenser made contrary claims or no claims 
(see id. at 58-59). All of the defendants were convicted of 
distributing misbranded drugs in violation of the FD&C Act (see 
Carlson, 810 F.3d at 550).
    In United States v. Dessart, 823 F.3d 395 (7th Cir. 2016), the 
defendant used a website to sell products containing human growth 
hormone (``HGH''), steroids, and the active ingredients in the 
prescription drugs VIAGRA (sildenafil), CIALIS (tadalafil), and LEVITRA 
(vardenafil). Id. at 398. The website said that the products were ``for 
research only.'' Id. The defendant was indicted on 23 counts of 
violating the FD&C Act. Id. at 399. The court instructed the jury: 
``[Y]ou should consider what a reasonable person would conclude the 
manufacturer or seller of the product intended the product to be used 
for, based on all of the relevant information. . . . You are not bound 
by any claims or statements made by the manufacturer or seller if there 
is other evidence concerning the use intended by the manufacturer or 
seller that conflicts with those claims or statements.'' Jury 
Instructions, Case No. 12-CR-85 at 4-5 (E.D. Wis. June 19, 2014). The 
jury convicted on all counts. Dessart, 823 F.3d at 400.
    In United States v. 789 Cases of Latex Surgeons' Gloves, 799 F. 
Supp. 1275, 1294-1295 (D.P.R. 1992), the Government sought condemnation 
of surgeon's gloves and their components, including cornstarch, stored 
in a rodent-infested facility. Although the product manufacturer argued 
that it did not intend for the gloves to be used in medical procedures, 
the court found that ``[t]he circumstances surrounding the manufacture, 
distribution, and actual use of Plastic Material's gloves present 
overwhelming evidence that claimant's gloves are intended for use as--
and therefore are--devices within the meaning of the Act'': e.g., the 
sole customer, the United States, purchased gloves only for medical 
use; and the cornstarch used to store the gloves was of a type used 
only with gloves intended for medical procedures.
    In each of these cases, restricting relevant evidence to 
promotional claims and conduct could have led the factfinder to 
conclude that the products were outside of FDA's jurisdiction.
    (Comment 6) One comment asserted that the phrase ``any relevant 
evidence'' as used in the case law should be understood, under the 
statutory interpretation principle ejusdem generis, to refer only to 
evidence of promotional claims.
    (Response) FDA disagrees. First, most obviously, principles of 
statutory construction are not typically applied to language in court 
decisions. Second, throughout this preamble, we have cited numerous 
examples where courts and FDA have considered evidence other than 
promotional claims to be relevant to establishing intended use.

C. Comments and Responses Regarding the Design or Composition of an 
Article

    (Comment 7) Several comments stated that FDA should reconsider the 
proposed regulatory text identifying evidence about the ``design or 
composition'' of an article as a type of evidence relevant to 
establishing intended use. Some comments also asserted that the 
characteristics and design of a medical product that is approved, 
cleared, granted marketing authorization, or exempted from premarket 
notification do not determine intended use and that intended use does 
not depend on the design of the product. Some comments requested that 
FDA remove this phrase from the codified language describing the types 
of evidence relevant to determining a product's intended uses.
    (Response) We disagree with the comments and decline to remove 
``design or composition'' from the codified language. As explained in 
the preamble, the revisions to the intended use regulations do not 
reflect a change in FDA's policies and practices. Rather, the 
amendments to the intended use regulations are intended to describe the 
types of evidence relevant to determining a product's intended use 
based on FDA's current practices. The design and composition of an 
article are examples of the types of evidence that may be relevant when 
determining the article's intended use. For example, FDA may consider 
the design or composition of a product, which includes product 
characteristics, when determining whether the product is ``intended to 
affect the structure or any

[[Page 41391]]

function of the body'' and therefore meets the device definition in 
section 201(h) of the FD&C Act (21 U.S.C. 321(h)). The addition of the 
phrase ``design or composition'' to the codified reflects FDA's 
longstanding and current policy that these are relevant to intended 
use.
    As discussed in the preamble to the NPRM, an example of a situation 
where design features have been found relevant to intended use include 
the design of a stent to be specifically sized for a use that is 
different from the purported use (see 85 FR 59718 at 59725). Another 
example can be found in United States v. Caputo, 517 F.3d 935 (7th Cir. 
2008), where the Seventh Circuit upheld a conviction for misbranding 
under the FD&C Act where design features were part of the evidence of 
intended use. There, the district court recited evidence of the 
differences in design between two versions of the device that 
necessitated separate premarket review applications: ``The larger 
sterilizer had different design and engineering characteristics: a six 
cubic foot chamber; a 5% peracetic acid mixture; different temperature, 
pressure, and gas flow rate; and a single, as opposed to multiple, use 
of the sterilant'' (United States v. Caputo, 456 F. Supp. 2d 970, 973 
(N.D. Ill. 2006), aff'd in relevant part, 517 F.3d 935 (7th Cir. 
2008)). As another example, a factfinder might consider, as evidence of 
a new intended use, a spacer that the manufacturer claims can be used 
to elute one liquid, but is in fact designed with holes that are sized 
to elute a more viscous substance that contains a different active 
ingredient.
    Another example where composition has been found relevant to 
intended use is United States v. Undetermined Quantities . . .``Pets 
Smellfree,'' 22 F.3d 235 (10th Cir. 1994). In that case, the Government 
had seized and sought to condemn ``Pets Smellfree'' as an adulterated 
and misbranded drug. The product was promoted as an animal food 
additive to reduce pet odor when ingested. In determining that the 
product was a drug, the Tenth Circuit relied heavily on expert 
testimony about the physiological effects of a pharmacologically active 
ingredient, chlortetracycline, in reducing the level of bacteria in the 
animals' digestive systems and oral cavities (see id. at 240). Other 
examples include United States v. Zeyid, 1:14-cr-0197, First 
Superseding Indictment (N.D. Ga. June 24, 2014) (see Ref. 2), where 
imported products labeled as ``tea,'' ``coffee,'' and ``beauty 
products'' contained active ingredients that were the same as those 
used in prescription drugs; FDA Warning Letter to HelloCig Electronic 
Technology Co., Ltd. (Ref. 9), where undeclared active pharmaceutical 
ingredient was considered relevant to intended use; and FDA Warning 
Letter to INZ Distributors (Ref. 13), where presence of analogue of an 
erectile dysfunction drug was considered relevant to intended use.
    (Comment 8) Some comments suggested that consideration of ``design 
or composition of the article'' as a type of evidence of intended use 
may inhibit technological advancements and discourage manufacturers 
from developing products that, based on their design, may be used for 
multiple uses.
    (Response) FDA disagrees with these comments. We do not believe 
that considering a product's design or composition to be relevant to 
the intended use of a product impedes technological advancements or 
discourages product development. As stated above, the relevance of a 
product's design and composition to intended use is a part of FDA's 
longstanding policy and has not hindered such improvements. For 
example, during premarket review of software, FDA may not always review 
a software device function that is included in the design but has been 
locked out, because it is not part of that specific premarket 
submission by the firm. If, however, the firm wants to unlock the 
software device function in the future, it must first obtain any 
necessary premarket clearance, marketing authorization or approval for 
the product with that function.
    (Comment 9) One comment suggested that FDA should not seek 
enforcement after a product is approved, cleared, or granted marketing 
authorization solely based on that product's design or characteristics, 
and another comment suggested that FDA should not assert a new intended 
use based solely on such features.
    (Response) FDA applies applicable premarket and postmarket 
statutory and regulatory requirements to determine whether a product is 
legally marketed. FDA examines all relevant evidence in assessing 
compliance with such requirements. As previously noted, FDA may 
consider a product's design or composition as one type of evidence 
relevant to the product's intended use.

D. Comments and Responses Regarding the First Amendment

    (Comment 10) One comment stated that because the rule identifies 
speech as potentially relevant to establishing intended use, and such 
speech may be truthful, the rule is ``suspect'' under the First 
Amendment. The comment requested that FDA add specific statements to 
the codified language to address these concerns. Other comments 
similarly stated that the proposal does not adequately take into 
account the limitations on FDA's authority to regulate truthful and 
non-misleading speech.
    (Response) We disagree that the rule is vulnerable under the First 
Amendment. First, as noted in the preamble to the NPRM, we do not 
believe this rulemaking implicates the First Amendment. The intended 
use regulations describe evidence that may be relevant to establishing 
intended use; they do not in themselves directly regulate speech (85 FR 
59718 at 59723). Indeed, the changes to the codified language proposed 
and finalized in this rulemaking do not directly involve speech: 
Whether, and to what extent, a factfinder may rely on product design, 
product composition, and knowledge as evidence of intended use, is not 
itself a First Amendment question, because speech will not typically be 
involved in such evidence. See 82 FR 2193 at 2207.
    Second, in the regulatory regime under the FD&C Act and the PHS 
Act, intended use helps determine the marketing status for products 
that are potentially subject to those Acts, which products Congress has 
directed FDA to regulate in the interest of the public health. Part of 
the regulatory regime for medical products involves, for example, the 
review of appropriate labeling in the context of premarket review and 
postmarket regulatory surveillance. The categorical exclusion of all 
truthful speech from regulatory review would undermine FDA's ability to 
promote and protect the public health through premarket review of 
medical products, including review of proposed labeling, and postmarket 
regulatory surveillance and actions.
    For example, the Government prosecuted a clinic operator under the 
FD&C Act for injecting liquid silicone into the body to augment tissues 
such as the buttocks or breasts (Refs. 14 and 15). Silicone when used 
for industrial purposes would not fall within FDA's jurisdiction. 
However, in this case, evidence that helped establish the intended use 
of the products included testimony of victims about the claims made to 
them by the defendant that the product would enhance the size of their 
buttocks. Those claims may have been truthful in the sense that they 
revealed one effect of the product. However, the injection of liquid 
silicone into the body for tissue augmentation can result in serious 
adverse health consequences, including hardening of tissue at the 
injection site, embolization, and even

[[Page 41392]]

death. FDA has not approved any liquid silicone products for injection 
to augment tissues anywhere in the body. Therefore, it was in the 
interest of public health for FDA to take action against the person 
responsible for the administration of these products, and such action 
was well within FDA's jurisdiction and permissible under the First 
Amendment.
    There are many industries whose operations involve some amount of 
communication with the public. The fact that those communications may 
be truthful does not shield those industries' operations from 
Government regulation. ``[I]t has never been deemed an abridgment of 
freedom of speech . . . to make a course of conduct illegal merely 
because the conduct was in part initiated, evidenced, or carried out by 
means of language, either spoken, written, or printed'' (Rumsfeld v. 
Forum for Academic and Institutional Rights, Inc., 547 U.S. 47, 62 
(2006) (citation omitted)). And, as the Court recently confirmed, `` 
`the First Amendment does not prevent restrictions directed at commerce 
or conduct from imposing incidental burdens on speech' '' (Barr v. Am. 
Ass'n of Political Consultants, 140 S. Ct. 2335, 2347 (2020) (quoting 
Sorrell v. IMS Health Inc., 564 U.S. 552, 567 (2011))).
    Thus, as we explained in the NPRM, courts have long upheld the 
premarket review requirements of the FD&C Act and the PHS Act, and the 
role of intended use within that framework, as necessary to promote and 
protect the public health and as fully consistent with the First 
Amendment (see 85 FR 59718 at 59723). More specifically, courts have 
held that, under the holding of Wisconsin v. Mitchell, 508 U.S. 476, 
489 (1993), the Government's reliance on speech as evidence of intended 
use under the FD&C Act does not infringe the right of free speech under 
the First Amendment (see, e.g., Whitaker v. Thompson, 353 F.3d 947, 953 
(D.C. Cir. 2004); Nicopure Labs, LLC v. FDA, 944 F.3d 267, 283 (D.C. 
Cir. 2019); United States v. Cole, 84 F. Supp. 3d 1159, 1166 (D. Or. 
2015); United States v. Regenerative Sciences, LLC, 878 F. Supp. 2d 
248, 255-56 (D.D.C. 2012), aff'd, 741 F.3d 1314 (D.C. Cir. 2014); 
United States v. Livdahl, 459 F. Supp. 2d 1255, 1268 (S.D. Fla. 2005); 
United States v. Lane Labs-USA, Inc., 324 F. Supp. 2d 547, 579-80 
(D.N.J. 2004); see also United States v. Article of Drug Designated B-
Complex Cholinos Capsules, 362 F.2d 923, 927 (3d Cir. 1966); United 
States v. General Nutrition, Inc., 638 F. Supp. 556, 562 (W.D.N.Y. 
1986)). Indeed, reliance on speech as evidence of intent is common in 
the law.\2\
---------------------------------------------------------------------------

    \2\ See Reference 16 (``This pattern in the law--using intent as 
the predicate for regulation and then using speech as evidence of 
intent--is quite common, and not peculiar to pharmaceutical 
regulation. As early as 1888, the Supreme Court affirmed a state 
court criminal conviction for someone who manufactured an 
`oleaginous substance' otherwise perfectly legal, except that he 
intended for it to be used as food, and thereby his manufacture of 
it fell under the purview of a state regulator. Similarly, a hollow 
piece of glass with a bowl on the end is illegal drug paraphernalia 
only if intended for such illicit uses. An automobile is not subject 
to regulation by the Federal Aviation Administration, unless it is 
`intended to be used for flight in the air.' '') (citations 
omitted).
---------------------------------------------------------------------------

    Third, as also explained in the NPRM, even if this rulemaking or 
regulatory regime were appropriately subject to First Amendment review, 
FDA's consideration of speech as one type of evidence of intended use 
under its statutory and regulatory framework easily satisfies any 
applicable test. Under the Central Hudson framework, the threshold 
question is whether the speech is false or inherently or actually 
misleading or concerns unlawful activity--such speech may be prohibited 
(see Central Hudson Gas & Elec. Corp. v. Pub. Serv. Comm'n, 447 U.S. 
557 (1980); In re R.M.J., 455 U.S. 191, 203 (1982); 44 Liquormart, Inc. 
v. Rhode Island, 517 U.S. 484, 497 n.7 (1996); 1-800-411-Pain Referral 
Serv., LLC v. Otto, 744 F.3d 1045, 1056 (8th Cir. 2014)). When 
commercial speech relates to an illegal activity, there is no First 
Amendment interest to weigh against the governmental interest 
supporting the regulation of commercial activity (Pittsburgh Press Co. 
v. Human Relations Comm'n, 413 U.S. 376, 389 (1973)). Regulated parties 
cannot be allowed to escape reasonable Government regulations by 
``bootstrap[ping] themselves into the heightened scrutiny of the First 
Amendment simply by infusing the prohibited conduct with some element 
of speech'' (Ford Motor Co. v. Tex. DOT, 264 F.3d 493, 506-507 (5th 
Cir. Tex. 2001)).
    For example, in United States v. Caputo, 517 F.3d 935 (7th Cir. 
2008), the court found that it did not need to resolve the question of 
whether promotional claims for an approved medical device were 
protected by the First Amendment because defendants' product was not 
approved: ``[t]here was no lawful activity for speech to promote'' (id. 
at 941). In United States v. Cole, 84 F. Supp. 3d 1159 (D. Or. 2015), 
defendants distributed unapproved products with claims that they 
treated diseases, including Alzheimer's and HIV infection. The court 
rejected defendants' First Amendment defense, explaining that, because 
``[d]efendants' speech concerns an illegal activity--the introduction 
into interstate commerce of unapproved new drugs[,] . . . the First 
Amendment is not violated'' (id. at 1166-67). In United States v. 
LeBeau, 2016 U.S. Dist. LEXIS 13612 (E.D. Wisc. February 3, 2016), the 
court similarly rejected defendant's First Amendment defense to a 
charge of distributing an unapproved new drug and explained that, 
because defendant's speech occurred while promoting and distributing a 
product that was intended for treatment of diseases and had not been 
approved by the FDA, his commercial speech did not concern lawful 
activity and did not pass step (1) of Central Hudson (see id. at 29). 
The Seventh Circuit affirmed, explaining that ``[b]ecause LeBeau's 
statements promoted the unlawful sale of an unapproved drug, they were 
not entitled to protection'' (United States v. LeBeau, 654 Fed. App'x 
826, 831 (7th Cir. 2016)).
    Even where the threshold step of Central Hudson does not apply, 
FDA's reliance on speech as evidence of intended use in the context of 
premarket review directly advances, and is appropriately tailored to 
achieve, substantial public health interests and therefore satisfies 
the remaining steps of the Central Hudson analysis. The medical 
products FDA regulates have the potential to adversely impact public 
health and safety. The premarket review requirements of the FD&C Act 
and the PHS Act require companies to conduct scientific research to 
determine the safety and effectiveness of medical products before they 
are marketed and provide mechanisms to help ensure that protections are 
in place that will allow the public to obtain the benefits of these 
products while mitigating the risks. Accordingly, these premarket 
review provisions ``do not ban manufacturers from making accurate 
claims'' but instead ``require them to substantiate such claims.'' 
Nicopure Labs, LLC v. FDA, 944 F.3d 267, 285 (D.C. Cir. 2019).
    (Comment 11) One comment asserted that the NPRM failed to provide a 
meaningful explanation of how its consideration of speech as evidence 
of intended use comports with the Central Hudson test, particularly 
whether there are any less speech-restrictive alternatives with respect 
to speech regarding unapproved uses of approved products. The comment 
cites United States v. Caronia, 703 F.3d 149 (2d Cir. 2012) and 
criticizes the Government for not providing a sufficient explanation of 
its consideration of less-restrictive alternatives in the context of 
that lawsuit. Another commenter similarly

[[Page 41393]]

asserted that the NPRM did not adequately justify under Central Hudson 
the Government's policy regarding off-label use/promotion.
    (Response) Again, as noted above and in the NPRM, we do not believe 
this rulemaking implicates the First Amendment, particularly given that 
the changes to the codified language proposed and finalized in this 
rulemaking do not directly involve speech. As further explained in the 
NPRM, ``[b]ecause `intended use' is only one element of an alleged 
violation of the FD&C Act, this rule does not itself implicate the 
First Amendment and does not attempt to resolve all First Amendment 
arguments that might be made by a firm in defending against an 
enforcement action under the FD&C Act.'' 85 FR 59798 at 59723 n.5. 
Nevertheless, in another proceeding, FDA has addressed in detail the 
issues raised by these comments (see Memorandum: Public Health 
Interests and First Amendment Considerations Related to Manufacturer 
Communications Regarding Unapproved Uses of Approved or Cleared Medical 
Products (January 2017) (Ref. 17)). Rather than repeat that analysis 
here, we summarize it briefly and incorporate the relevant portions of 
the document. The memorandum describes in detail the public health 
interests underlying and advanced by FDA's consideration of 
communications regarding unapproved uses of medical products that are 
approved, cleared, granted marketing authorization, or exempted from 
premarket notification as relevant to the premarket review requirements 
of the FD&C Act and PHS Act (see Ref. 17 at 3-16). As the memorandum 
explains, those requirements, among other things, motivate the 
development of scientific evidence that enables the reliable, 
population-level determination of the safety and efficacy of medical 
products for each intended use; require that the evidence be developed 
and independently reviewed before the products are marketed to the 
general public for each intended use; and require that the product bear 
labeling that identifies each medical use of the product that is 
approved, cleared, granted marketing authorization, or exempted from 
premarket notification and provides information for healthcare 
providers and patients on using the product safely and effectively for 
those uses that are approved, cleared, granted marketing authorization, 
or exempted from premarket notification. In the memorandum, FDA also 
examined alternative approaches suggested by the court in United States 
v. Caronia, as well as by commentators (see id. at 26-34). FDA 
explained that, although many of these proposed approaches addressed 
one or more of the interests served by the premarket review 
requirements, FDA found that none of them integrated the complex mix of 
numerous interests at play and thus none of the proposed approaches 
best advanced those multiple interests (see id.).
    (Comment 12) One comment asserted that the right of a manufacturer 
to convey truthful and non-misleading information is protected under 
Thompson v. Western States Medical Center, 535 U.S. 357 (2002).
    (Response) We disagree with the suggestion that Western States 
shields truthful and non-misleading speech from Government regulation. 
In that case, the Court applied the Central Hudson test to evaluate the 
regulation of the speech at issue, 535 U.S. at 368-77. In an analysis 
that broke no ``new ground'' (id. at 368), the Court explained that, in 
general, the Government should not restrict the communication of 
truthful and non-misleading information for the sole purpose of 
preventing members of the public from making bad decisions with the 
information (see id. at 374). However, that rationale is not applicable 
to this rulemaking because the premarket review requirements of the 
FD&C Act and PHS Act advance several different Government interests in 
protecting public health, as discussed above (see also Ref. 17).
    (Comment 13) One comment asserted that the First Amendment protects 
not only the right to speak freely but also the right to hear and 
receive valuable information, and that this interest is particularly 
acute for the audience of physicians.
    (Response) FDA has recognized that, under certain circumstances, 
both healthcare providers and patients may be interested in information 
about unapproved uses of products (see Ref. 17 at 17). In part because 
of this consideration, FDA has issued guidance documents describing 
circumstances in which the Agency does not intend to object to a firm's 
product communications or to view such communications as evidence of a 
new intended use (see 85 FR 59718 at 59723 & n.7). Nothing in this 
final rule reflects a change in FDA's policies and practices, as 
articulated in various guidance documents, regarding the types of firm 
communications that ordinarily would not, on their own, establish the 
firm's intent that a medical product that is approved, cleared, granted 
marketing authorization, or exempted from premarket notification be 
used for an unapproved use. As discussed elsewhere in this preamble, 
FDA declines the suggestion to expand the scope of this rulemaking to 
additional subjects.
    (Comment 14) One comment referenced for support a 1999 district 
court decision in a case brought by Washington Legal Foundation. 
Another comment referenced the same litigation and asserted that FDA is 
subject to a permanent injunction curtailing the Agency's authority to 
bar manufacturers from sharing peer-reviewed medical texts and journal 
articles about off-label uses of their FDA-approved products.
    (Response) We believe these comments have little bearing on the 
current rulemaking. First, as explained in the NPRM, the proposed 
revisions to the intended use regulations do not reflect any change in 
FDA's policies and practices, as articulated in various guidance 
documents, regarding the types of firm communications to which the 
Agency does not intend to object or to view as evidence of a new 
intended use. Among the guidance documents describing these existing 
policies are several that relate to the distribution of peer-reviewed 
medical texts and journal articles (see 85 FR 59718 at 59723 & n.7). 
Second, with respect to the district court decision referenced in the 
comments, the D.C. Circuit ``vacate[d] the district court's decisions 
and injunctions insofar as they declare the FDAMA and the CME Guidance 
unconstitutional'' (see Washington Legal Found. v. Henney, 202 F.3d 
331, 337 (D.C. Cir. 2000); see also Washington Legal Found. v. Henney, 
128 F. Supp. 2d 11, 15 (D.D.C. 2000) (holding that ``injunction has 
been wholly vacated by the Court of Appeals''); id. (holding that Court 
of Appeals ``vacated all of this Court's previous constitutional 
rulings on the matter''); 65 FR 14286 (2000) (describing FDA's 
understanding of the outcome of the Washington Legal Found. 
litigation); Letter from Margaret M. Dotzel, Assoc. Commissioner for 
Policy, FDA to Daniel J. Popeo & Richard A. Samp, Wash. Legal Found., 
Docket No. 01P-0250 (January 28, 2002) (same)).
    (Comment 15) Some comments asserted that content-based restrictions 
on commercial speech are subject to strict scrutiny or heightened 
scrutiny. One comment argued that Sorrell v. IMS Health Inc., 564 U.S. 
552 (2011), Reed v. Town of Gilbert, 135 S. Ct. 2218 (2015), Matal v. 
Tam, 137 S. Ct. 1744 (2017), and Barr v. Am. Ass'n of Political 
Consultants, 140 S. Ct. 2335 (2020) support the proposition that all 
content-based speech restrictions, even

[[Page 41394]]

those involving commercial speech, are subject to strict scrutiny, 
effectively overruling the Central Hudson and Wisconsin v. Mitchell 
lines of cases. Relying primarily on Sorrell and mentioning Barr, 
another comment asserted that FDA understated the constitutional limits 
on its authority in the NPRM. Another comment suggested that heightened 
scrutiny is warranted under Sorrell in the fields of medicine and 
public health.
    (Response) We disagree. As we discussed in the NPRM, the Supreme 
Court in Sorrell suggested that content- and speaker-based restrictions 
would be subject to ``heightened scrutiny,'' but nevertheless continued 
to apply the ``commercial speech inquiry'' as outlined in Central 
Hudson (85 FR 59718 at 59724 n.11). Several courts of appeals have 
subsequently concluded that Sorrell did not overrule or fundamentally 
alter the Central Hudson analysis (see Retail Digital Network, LLC v. 
Prieto, 861 F.3d 839, 846 (9th Cir. 2017) (en banc) (Sorrell ``did not 
mark a fundamental departure from Central Hudson's four factor test, 
and Central Hudson continues to apply'' to regulations of commercial 
speech, regardless of whether they are content based); Missouri Broad. 
Ass'n v. Lacy, 846 F.3d 295, 300 n.5 (8th Cir. 2017) (``The upshot [of 
Sorrell] is that when a court determines commercial speech restrictions 
are content- or speaker-based, it should then assess their 
constitutionality under Central Hudson.'') (quotation marks omitted; 
alteration in original); see also Vugo, Inc. v. City of New York, 931 
F.3d 42, 50 (2d Cir. 2019) (``No Court of Appeals has concluded that 
Sorrell overturned Central Hudson. We agree with our sister circuits 
that have held that Sorrell leaves the Central Hudson regime in place, 
and accordingly we assess the constitutionality of the City's ban under 
the Central Hudson standard.''), cert. denied, 140 S. Ct. 2717 (2020)).
    In Reed v. Town of Gilbert, the Court applied strict scrutiny to 
content-based restrictions on non-commercial speech in sign ordinances. 
Although some of the language in the majority opinion in that case is 
broad, most lower courts have subsequently rejected arguments that Reed 
applies to the regulation of commercial speech (see, e.g., Vugo, Inc. 
v. City of New York, 931 F.3d 42, 49-50 & n.6 (2d Cir. 2019) (holding 
that Central Hudson still applies to commercial speech after Reed and 
Sorrell), cert. denied, 140 S. Ct. 2717 (2020); Nationwide Biweekly 
Admin., Inc. v. Owen, 873 F.3d 716, 732 (9th Cir. 2017) (``Reed did not 
relate to commercial speech . . . and therefore did not have occasion 
to consider th[at] doctrine[.]'')). Indeed, as one comment noted, in 
Matal v. Tam, a decision regarding content-based commercial speech 
issued after Reed, only one Justice advocated overruling Central Hudson 
in favor of strict scrutiny (137 S. Ct. 1744, 1769 (2017) (Thomas, J., 
concurring in part and concurring in the judgment)). No other Justice 
joined that opinion. While no First Amendment analysis garnered five 
votes in Matal, one four-Justice opinion applied Central Hudson (id. at 
1764); the other four-Justice opinion stated that heightened scrutiny 
should be applied to viewpoint discrimination, but explained that 
viewpoint discrimination is an ``egregious'' subcategory of content-
based regulation, and further noted that regulations regarding product 
labeling or consumer protection may be evaluated differently from the 
trademark matter at issue in that case (id. at 1766, 1768).
    There was similarly no majority First Amendment analysis in Barr v. 
Am. Ass'n of Political Consultants, 140 S. Ct. 2335 (2020). There, the 
plurality opinion explained that strict scrutiny should be applied to a 
law that singled out a specific subject matter for differential 
treatment--permitting robocalls for collecting money owed to the 
Government while prohibiting robocalls for all other purposes (see id. 
at 2346). Similarly, Justice Gorsuch's opinion emphasized that the 
statute under review favored certain voices while punishing others (see 
id. at 2364) (Gorsuch, concurring in the judgment in part and 
dissenting in part). In addition, the plurality opinion further 
circumscribed the scope of its holding: ``The issue before us concerns 
only robocalls to cell phones. . . . Our decision is not intended to 
expand existing First Amendment doctrine or to otherwise affect 
traditional or ordinary economic regulation of commercial activity'' 
(see id. at 2347; see also Am. Hosp. Ass'n v. Azar, 983 F.3d 528, 542 
(D.C. Cir. 2020) (in upholding an HHS rule challenged in part on First 
Amendment grounds, the court distinguished Barr on the grounds that the 
restrictions in Barr involved political speech and the regulation at 
issue in Am. Hosp. Ass'n involved ordinary regulation of commercial 
activity)).
    Accordingly, given that the Supreme Court has not overruled Central 
Hudson or Wisconsin v. Mitchell and given that the laws being reviewed 
in the cited cases were quite different from the premarket review 
provisions of the FD&C Act, we believe it would be wrong to conclude 
that the Supreme Court has implicitly but sweepingly reversed these 
long-standing precedents to invalidate the regulatory regime under the 
FD&C Act. And even if some form of heightened scrutiny were applicable 
to reliance on speech as evidence of intended use, FDA believes that 
the public health necessity of the premarket review provisions 
discussed in this preamble, including its references, justifies and 
necessitates this regime under any standard.
    (Comment 16) One comment asserted that scientific speech has been 
recognized as core speech that merits the highest degree of 
constitutional protection, citing Washington Legal Foundation v. 
Friedman, 13 F. Supp. 2d 51, 62 (D.D.C. 1998).
    (Response) FDA agrees that, in certain contexts, scientific speech 
merits the highest degree of constitutional protection. However, the 
comment failed to note that the cited opinion determined that 
scientific speech will be evaluated under the First Amendment as 
commercial speech when a commercial entity seeks to distribute it in 
order to increase its sales of the product (see id. at 64-65).
    (Comment 17) One comment urged FDA to follow the Sixth Circuit's 
decision in Int'l Outdoor, Inc. v. City of Troy, 974 F.3d 690 (6th Cir. 
2020), which the comment claimed held that all content-based speech 
restrictions are subject to strict scrutiny, even when the restrictions 
concern commercial speech.
    (Response) FDA declines that suggestion for several reasons. First, 
Int'l Outdoor--like Reed--involved review of a sign ordinance, which 
does not raise the same complex regulatory and public health issues as 
premarket review under the FD&C Act and PHS Act. Second, a holding that 
strict scrutiny applies to all content-based commercial speech would 
run contrary to the weight of circuit court authority discussed above, 
including the Second Circuit's recent decision in Vugo, Inc. confirming 
that Central Hudson continues to govern review of commercial speech 
(see 931 F.3d at 50). Third, the Sixth Circuit in Int'l Outdoor did not 
actually hold that strict scrutiny applies to all content-based 
commercial speech; the Sixth Circuit distinguished Vugo on the ground 
that the Second Circuit case involved only commercial speech, where 
Int'l Outdoor involved both core and commercial speech (see 974 F.3d at 
705).
    (Comment 18) One comment asserted that FDA should not continue to 
rely on Wisconsin v. Mitchell and its progeny because the district 
court in Amarin Pharma, Inc. v. FDA, 119 F. Supp. 3d 196 (S.D.N.Y. 
2015) construed United

[[Page 41395]]

States v. Caronia, 703 F.3d 149 (2d Cir. 2012) to foreclose that 
position. Another comment similarly argued that the NPRM understated 
the meaning and impact of Caronia.
    (Response) We disagree. As we explained in the NPRM, the Second 
Circuit has explicitly confirmed--contrary to the cited conclusion in 
Amarin--that Caronia ``left open the government's ability to prove 
misbranding on a theory that promotional speech provides evidence that 
a drug is intended for a use that is not included on the drug's FDA-
approved label.'' United States ex rel. Polansky v. Pfizer, Inc., 822 
F.3d 613 n.2 (2d Cir. 2016). And the Second Circuit has more generally 
confirmed the continued viability of the Wisconsin v. Mitchell theory 
after Caronia, finding a First Amendment challenge to reliance on 
speech to show an element of violation ``meritless'' because ``the 
speech is not `itself the proscribed conduct.' '' United States v. 
Pierce, 785 F.3d 832, 841 (2d Cir. 2015) (quoting Caronia, 703 F.3d at 
161). It is also noteworthy that the first comment did not cite any 
case other than Amarin, a district court decision on a motion for a 
preliminary injunction, in support of its position limiting the 
application of Wisconsin v. Mitchell. Indeed, decisions from other 
circuits issued after Caronia have upheld the application of Wisconsin 
v. Mitchell in the context of the premarket review requirements of the 
FD&C Act (see Nicopure Labs, LLC v. FDA, 944 F.3d 267, 283 (D.C. Cir. 
2019); United States v. Lebeau, 654 Fed. App'x 826, 830-31 (7th Cir. 
2016); United States v. Facteau, 2020 U.S. Dist. LEXIS 167169 (D. Mass. 
September 14, 2020); United States v. Cole, 84 F. Supp. 3d 1159, 1166 
(D. Or. 2015)).

E. Comments and Responses Regarding the Fifth Amendment

    (Comment 19) Some comments questioned the constitutionality of the 
intended use regulations and asserted that the Fifth Amendment requires 
that the boundaries between permissible and impermissible 
communications be clearly drawn, particularly with respect to matters 
involving speech. One comment criticized FDA's reliance on guidance 
documents to describe its enforcement policies in this regard.
    (Response) While FDA agrees that laws must give a ``person of 
ordinary intelligence a reasonable opportunity to know what is 
prohibited,'' ``meticulous specificity'' is not required (see Grayned 
v. City of Rockford, 408 U.S. 104, 110 (1972)). The Supreme Court has 
recognized that laws may embody ``flexibility and reasonable breadth'' 
(see id.) and officials implementing them may ``exercise considerable 
discretion'' (see Ward v. Rock Against Racism, 491 U.S. 781, 794 
(1989)), without the laws being declared unconstitutionally vague.
    More specifically, the Supreme Court has held that ``perfect 
clarity and precise guidance have never been required even of 
regulations that restrict expressive activity'' (see Ward, 491 U.S. at 
794 (citations omitted)). It is also well established that the use of 
an intent standard does not render a statute unconstitutionally vague 
(see United States v. Williams, 553 U.S. 285, 306 (2008); Nat'l Ass'n 
of Manufacturers v. Taylor, 582 F.3d 1, 26 (D.C. Cir. 2009) (``an 
intent standard is not per se vague, even in a statute regulating 
speech'')). Indeed, ``absent special circumstances not present here, 
there is no reason to conclude that the `every day' task of assessing 
intent is inherently vague [even] when protected speech is involved'' 
(see Taylor, 582 F.3d at 27).
    Moreover, courts have repeatedly rejected due process challenges to 
the FD&C Act as unconstitutionally vague or ambiguous. In United States 
v. Hohensee, 243 F.2d 367 (3d Cir. 1957), the Third Circuit rejected an 
unconstitutional vagueness challenge to provisions of the FD&C Act, 
which included the determination of intended use. In upholding the 
provisions, the court relied in part on the Supreme Court determination 
that the FD&C Act should ``be given a liberal interpretation to 
effectuate its high purpose of protecting unwary consumers in vital 
matters of health'' (see id. at 370; see also United States v. 
Sullivan, 332 U.S. 689, 695 (1948) (rejecting due process challenge to 
FD&C Act and finding no ambiguity in the misbranding language); United 
States v. Caputo, 517 F.3d 935, 941 (7th Cir, 2008) (rejecting argument 
that line between new and modified devices is too vague to be 
enforceable); V.E. Irons v. United States, 244 F.2d 34, 45 (First Cir. 
1957) (rejecting as ``untenable'' the claim that the FD&C Act's 
misdemeanor misbranding provisions are unconstitutionally vague and 
upholding misbranding conviction for distribution of vitamin and 
mineral products shown to be intended for use as drugs.); United States 
v. General Nutrition, Inc., 638 F. Supp. 556, 564 (W.D.N.Y. 1986) 
(``The Act on numerous occasions has been upheld against vagueness 
challenges . . . and this Court is unaware of any case holding any 
provision of the Act void for vagueness in any circumstance.'') 
(citations omitted)).
    The first FDA regulation describing how ``intended use'' is 
determined was issued in 1952 (see 17 FR 6818, 6820 (1952) (Ref. 1)), 
and there have been only minor amendments since that time, including 
those being made through this rulemaking. Over nearly seven decades, 
medical product manufacturers have shown little difficulty in 
understanding how the regulations are applied. And, as noted in the 
NPRM, FDA has issued several guidance documents that describe 
circumstances in which the Agency does not intend to object to a firm's 
product communications or to view such communications as evidence of a 
new intended use (85 FR 59718 at 59723). FDA issues these guidance 
documents to better inform stakeholders regarding its policies, and 
feedback from stakeholders has generally been positive. The NPRM also 
goes further than previous rulemakings related to these regulations in 
providing illustrative examples of types of evidence that would and 
would not be relevant to establishing intended use. Accordingly, we do 
not believe that the intended use regulations are unconstitutionally 
vague.

F. Comments and Responses Regarding Definitions

    (Comment 20) Some comments suggested clarifying and defining the 
terms ``intended use'' and ``indications for use'' as these terms are 
used for devices in Sec.  801.4. One comment suggested defining these 
terms by adopting definitions used in other FDA regulations and 
guidance documents. The comment also suggested clarifying the 
definitions of ``intended use'' and ``indications for use'' as part of 
a substantial equivalence determination for a device and distinguishing 
these terms from the intended use regulations for drugs.
    (Response) FDA disagrees with these comments. The intended use 
regulations, including Sec.  801.4, describe the types of evidence 
relevant to determining a product's intended uses under the FD&C Act, 
the PHS Act, and FDA's implementing regulations. The term ``indications 
for use'' is not used in this rulemaking and as such, FDA does not 
believe there is a need to define the term here. Further, FDA's 
substantial equivalence determination during its review of a premarket 
notification is beyond the scope of this rulemaking.
    (Comment 21) Several comments suggested revising Sec.  801.4 to 
expressly include devices that are legally marketed without approval or 
clearance, such as devices exempt from premarket notification and 
granted marketing authorization. Some comments asserted that the terms 
``approved or cleared medical products'' and ``approved or

[[Page 41396]]

cleared medical uses'' do not include such legally marketed devices and 
asked FDA to modify these terms to include 510(k)-exempt devices. One 
comment also suggested that FDA recognize how its review of drug and 
device labeling differ.
    (Response) FDA agrees with adding language to Sec.  801.4 to 
clarify that the regulation applies to devices that are exempt from 
premarket notification and devices that are granted marketing 
authorization through De Novo classification. We are adding the phrase 
``granted marketing authorization, or exempt from premarket 
notification'' to the fourth sentence of Sec.  801.4 to make this 
clarification.
    FDA declines to compare FDA's review of drug and device labeling 
because such comparison is beyond the scope of this rulemaking.
    (Comment 22) Some comments suggested defining the terms 
``unapproved new use for an approved or cleared'' and ``unapproved use 
of an approved product'' in the codified. Another comment asserted that 
these terms were not consistently used throughout the preamble.
    (Response) We have included related terms and phrases in the 
definitions section of the preamble above to help clarify our use of 
these and similar phrases. We do not believe that it is necessary to 
include these definitions in the codified language.
    (Comment 23) Some comments requested FDA expressly include 
laboratorians in the definition of ``healthcare providers.''
    (Response) The term ``healthcare provider'' includes a non-
exhaustive list of individuals who are licensed or otherwise authorized 
by the State to prescribe, order, administer, or use medical products 
in a professional capacity. In some cases, this may include such 
licensed or otherwise State-authorized individuals with certain roles 
in a laboratory.

G. Comments and Responses Regarding ``Safe Harbors''

    (Comment 24) A number of comments suggested modifications to FDA 
policies that the comments sometimes refer to as ``safe harbors'' for 
certain kinds of medical product communications. Some comments 
suggested the establishment of a ``safe harbor'' for scientific 
exchange, whereby scientific exchange would be excluded from 
determinations of intended use. Other comments suggested the creation 
of ``safe harbors'' for other types of communications, including 
discussions with healthcare providers about investigational uses, 
discussions held in the course of providing training or demonstrations 
to healthcare providers, market research about unapproved uses, and 
communications related to the collection of postmarket data. Another 
comment urged that FDA ``codify in binding regulations its policies 
regarding manufacturer communication of scientific and medical 
information,'' noting that guidance documents are not binding on 
enforcement authorities including the Department of Justice.
    (Response) FDA welcomes and will continue to consider these 
comments related to ``safe harbors.'' However, the recommendations made 
in these comments go beyond the scope of this rulemaking, which is ``to 
conform Sec. Sec.  201.128 and 801.4 to reflect how the Agency 
currently applies them to drugs and devices,'' 80 FR 57756 (2015). This 
rule, as proposed and as finalized, does not reflect a change in FDA's 
policies and practices regarding the types of firm communications that 
ordinarily would not, on their own, establish a new intended use. 
Expanding the scope of this rule to codify FDA's acknowledged ``safe 
harbors'' or to acknowledge additional ``safe harbors,'' as suggested 
in these comments, might warrant reproposing the rule to solicit 
additional input, unduly delaying the Agency's clarification of its 
regulations on intended use. Therefore, while FDA will continue to 
consider the issues raised by these comments, the Agency declines the 
present suggestions to modify its acknowledged ``safe harbors'' or 
codify them in the intended use regulation.
    With regard to the suggestion that the Agency establish a ``safe 
harbor'' for scientific exchange, whereby scientific exchange would be 
excluded from determinations of intended use: the Agency notes that if 
all scientific exchange were excluded from determinations of intended 
use, companies might have an incentive to create and promote new 
intended uses for marketed products based on incomplete or otherwise 
flawed data. That outcome would not serve the public health. At the 
same time, FDA recognizes the importance of scientific exchange, 
including information regarding unapproved uses of products that 
healthcare providers may choose to take into account when making 
professional judgments regarding the use of medical products that are 
approved, cleared, granted marketing authorization, or exempted from 
premarket notification. Balancing these public health considerations, 
some of which are in tension with each other, is a complex and 
important task. FDA believes this rulemaking, the purpose of which is 
to finalize amendments to the intended use regulations, is not the 
appropriate forum to resolve separate questions relating to scientific 
exchange. As noted in the NPRM, FDA has issued several guidance 
documents that describe circumstances in which the Agency does not 
intend to object to a firm's medical product communications or to view 
such communications as evidence of a new intended use. See 85 FR 59718 
at 59723 n.7. This final rule does not disturb any of FDA's 
acknowledged ``safe harbors,'' including those that encompass various 
types of scientific exchange. In addition, as discussed in the preamble 
to the proposed rule, a firm's knowledge of off-label use plus safe-
harbored communication would not, without more, be determinative of a 
new intended use. See 85 FR 59718 at 59725.

H. Comments and Responses Regarding Examples

    (Comment 25) One comment requests that FDA clarify, consistent with 
the Government's brief filed in Par Pharmaceutical Inc. v. United 
States, 1:11-cv-01820 (D.D.C.), that the example of ``repeated 
proactive detailing'' in the preamble to the proposed rule would not 
create a new intended use if the firm's communications with the 
healthcare professionals are consistent with the approved labeling.
    (Response) FDA declines the suggestion because FDA does not believe 
the proposed clarification is warranted. As explained in the preamble, 
the revisions to the intended use regulations do not reflect a change 
in FDA's policies and practices, including as articulated in various 
guidance documents, regarding the types of firm communications that 
ordinarily would not, on their own, establish the firm's intent that a 
medical product that is approved, cleared, granted marketing 
authorization, or exempted from premarket notification be used for an 
unapproved use (see 85 FR 59718 at 59723). The NPRM references guidance 
documents including FDA Guidance for Industry, ``Medical Product 
Communications That Are Consistent With the FDA-Required Labeling--
Questions and Answers,'' June 2018 (see id. Ref. 5). As explained in 
that guidance, FDA does not intend to rely exclusively on a firm's 
communication of information that is consistent with a medical 
product's FDA-required labeling to establish a new intended use. The 
example in the NPRM, however, describes a circumstance involving a 
patient population that does not fall within the product's approved 
population (see 85 FR 59718 at 59725) and, to the extent

[[Page 41397]]

the communication relates to a patient population outside the approved 
patient population reflected in the FDA-required labeling, the 
communication may not be considered consistent with the approved 
labeling. The Par brief cited in the comment confirms that a 
manufacturer's communication of information regarding an approved use 
to a physician whose patients do not fall within the product's approved 
population would not by itself establish a new intended use, but may be 
relevant together with other evidence in establishing the 
manufacturer's intent to distribute the product for an unapproved use 
(Ref. 3 at 17-18).
    (Comment 26) Several comments requested modification to or 
clarification of the examples provided in section V.C. of the preamble 
to the proposed rule.
    (Response) We decline to make the requested modifications to the 
examples. These examples were provided to illustrate evidence that, 
standing alone, would not be determinative of intended use, and they 
remain illustrative of that point. Although one comment suggested that 
the examples caused further confusion, most commenters indicated that 
the examples were helpful and encouraged FDA to offer additional 
examples. We continue to believe the examples provided in the preamble 
to the NPRM are helpful, and we are providing additional examples 
below. The list of examples in the proposed rule is not intended to be 
comprehensive or restrictive. Each scenario described in the preamble 
is fact-specific, and, under other circumstances or in other contexts, 
similar material may be evaluated differently.
    (Comment 27) Several comments requested that FDA describe the 
intended use framework from the device industry perspective and provide 
additional device-specific examples.
    (Response) The examples FDA provided in the preamble to the 
proposed rule were provided for illustrative purposes only and were not 
intended to be comprehensive or restrictive. In our responses to 
comments 7, 8, and 9 in this final rule preamble, we have provided 
additional examples of types of evidence \3\ related to product design 
and composition that may be relevant when determining a medical 
device's intended use. Those examples describe evidence that may be 
relevant, but is not necessarily determinative, to establishing 
intended use.
---------------------------------------------------------------------------

    \3\ As described in the preamble to the proposed rule, these 
types of evidence include express claims and representations; 
implied claims; product characteristics and design; and the 
circumstances of the product's sale or distribution (see 85 FR 59718 
at 59725). In fulfilling its mission to protect the public health, 
FDA will evaluate the individual and unique circumstances of each 
case in determining a product's intended use. In some cases, a 
single piece of evidence may be dispositive of a product's intended 
use. In others, several elements combined may establish a product's 
intended use.
---------------------------------------------------------------------------

    To further clarify this regulation as it applies to devices, we are 
providing here additional device-specific examples of types of evidence 
that may be relevant, but are not necessarily determinative, in 
establishing intended use. As with the examples in the preamble to the 
proposed rule, the following examples are fact-specific and are 
provided for illustrative purposes only.
     Marketing a medical device with a name that implies a use 
to affect a particular organ or system of the body. Example: 
``CardioCalm.''
     Designing a non-vascular stent with a coating clinically 
known to change calcification of blood vessels.
     Marketing a device that uses ultrasonic waves as a 
therapeutic massager, despite the fact that ultrasonic waves do not 
physically massage tissue but rather affect the underlying tissue 
through a sonic mechanism.

I. Comments on Codified Text and FDA Responses

    (Comment 28) In the NPRM, FDA proposed to amend Sec. Sec.  201.128 
and 801.4 to provide that a firm would not be regarded as intending an 
unapproved new use for an approved drug or for a device approved, 
cleared, granted marketing authorization, or exempted from premarket 
notification based solely on that firm's knowledge that such drug or 
device was being prescribed or used by healthcare providers for such 
use. One commenter argued that FDA should delete ``solely'' from the 
regulations on intended use because this phrasing suggests that a 
firm's knowledge of unapproved use could be used in combination with 
other factors to determine the intended use of a product. Another 
commenter suggested that FDA should replace ``solely'' with a term that 
would clarify that such knowledge would be relevant only if such use is 
widespread and if a company's promotional activities are a primary 
reason for this widespread off-label use. This commenter also 
maintained that the final rule should be clear that only activities 
that are, at their core, promotional should be relevant for determining 
intended use.
    (Response) FDA disagrees with these comments. The use of the word 
``solely'' in Sec. Sec.  201.128 and 801.4 is intended to convey that 
FDA does not intend to consider a firm's knowledge that a healthcare 
provider has used or prescribed the firm's medical product that has 
been approved, cleared, granted marketing authorization, or is exempt 
from 510(k) for an unapproved use, by itself, as sufficient to 
establish intended use. The removal of the word ``solely'' from the 
regulation and the suggestion that FDA consider only activities that 
are fundamentally promotional in determining intended use would be 
inconsistent with the Agency's longstanding position that determining a 
product's intended use is a fact-specific inquiry and that FDA may 
consider all relevant sources of evidence. These sources of evidence 
may include a firm's knowledge that a healthcare provider has used or 
prescribed the firm's medical product that is approved, cleared, 
granted marketing authorization, or exempted from premarket 
notification for an unapproved use, and may include activities that are 
not strictly promotional in nature. In short, direct promotion of the 
use is not necessary to establish intended use.
    (Comment 29) One comment asked FDA to change ``article'' to 
``device'' throughout Sec.  801.4.
    (Response) FDA disagrees with this suggestion. The use of the term 
``article'' in Sec. Sec.  201.128 and 801.4 is consistent with the use 
of that term in section 201 of the FD&C Act.
    (Comment 30) A comment suggested deleting the phrase ``or used'' 
from the fourth sentence of Sec.  801.4, asserting that a healthcare 
provider's use is not ``under the control of the firm.''
    (Response) FDA disagrees with the comment's suggestion because, 
although the healthcare provider's use is not under the firm's control, 
what may be relevant to intended use is the firm's knowledge that the 
article is being used by the healthcare provider. As discussed above, 
both legislative history and the case law support reliance on actual 
use by healthcare providers as relevant to intended use. See, e.g., 
United States v. An Article of Device Toftness Radiation Detector, 731 
F.2d 1253, 1257 (7th Cir. 1984); United States v. 22 Rectangular or 
Cylindrical Finished Devices, 714 F. Supp. 1159, 1165 (D. Utah 1989); 
United States v. Device Labeled ``Cameron Spitler Amblyo-Syntonizer,'' 
261 F. Supp. 243, 245 (D. Neb. 1966); H.R. Rep. No. 853, 94th Cong., 2d 
Sess. 14 (1976). However, a firm's knowledge that healthcare providers 
are prescribing or using its product that has been approved, cleared, 
granted marketing authorization, or is 510(k)-exempt for an

[[Page 41398]]

unapproved use would not, by itself, automatically trigger an 
obligation to provide labeling for that unapproved use.
    (Comment 31) One comment suggested that FDA explain how Sec.  801.4 
applies to modifications of 510(k)-cleared devices.
    (Response) FDA declines to adopt this suggestion because it is 
beyond the scope of this rulemaking.
    (Comment 32) One comment stated that section 513(i)(1)(E) of the 
FD&C Act (21 U.S.C. 360c(i)(1)(E)) constrains how FDA ``responds to an 
intended use not reflected in device labeling when reviewing a 510(k)'' 
and that FDA ``cannot require that the company obtain clearance or 
approval of another potential unapproved use.'' The comment also 
suggested FDA disassociate intended use regulations for devices from 
drugs and add a reference to section 513(i)(1)(E) of the FD&C Act in 
the codified text of Sec.  801.4.
    (Response) FDA's application of section 513(i)(1)(E) of the FD&C 
Act is beyond the scope of this rulemaking.

J. Comments Recommending That FDA Expand the Scope of This Rulemaking

    (Comment 33) A number of comments urged FDA to expand this 
rulemaking beyond the scope of the proposed rule. For example, one 
comment urged FDA to ``complete its long-promised `comprehensive 
review' of regulations to assess alignment with constitutional and 
statutory requirements.'' Another comment proposed that FDA adopt a 
regulatory approach to manufacturer speech consistent with the 
``Principles on Responsible Sharing of Truthful and NonMisleading 
Information About Medicines with Health Care Professionals and Payers'' 
developed by Pharmaceutical Research and Manufacturers of America and 
the Biotechnology Innovation Organization.
    (Response) Although FDA welcomes the submission of ideas regarding 
a broader list of suggested policy changes, we decline to adopt the 
suggestions in these comments because they are beyond the scope of this 
rulemaking. Expanding the scope of this rule as suggested in these 
comments would potentially delay FDA's clarification of its regulations 
on intended use. FDA has been engaged in a continuing review of 
regulations and policies regarding communications with healthcare 
providers and payors (and other similar entities with knowledge and 
expertise in healthcare economic analysis) regarding medical products, 
and has taken other initiatives as part of that effort.
    (Comment 34) One comment contended that the regulatory requirements 
for premarket approval and authorization are too burdensome so that it 
is unreasonable to require that manufacturers conduct studies and 
submit applications for every intended use.
    (Response) This comment also raises issues that are different from 
and beyond the scope of this rulemaking. To the extent this comment is 
suggesting that the best way to address complex questions concerning 
premarket authorization is through limiting the scope of intended use, 
we disagree that this is an appropriate tool.
    (Comment 35) One comment requested that FDA acknowledge that 
healthcare providers may prescribe and use approved/cleared medical 
products for unapproved uses when they judge that the unapproved use is 
medically appropriate for their patients and that manufacturers are not 
required to confirm the nature of a healthcare provider's planned use 
for an approved medical product before distributing such product to the 
healthcare provider.
    (Response) Healthcare providers prescribe or use medical products 
that are approved, cleared, granted marketing authorization, or 
exempted from premarket notification for unapproved uses based on their 
medical judgment regarding any potential benefits and risks of the 
unapproved use for their individual patients.\4\ In these limited 
circumstances, FDA's longstanding position is that the Agency does not 
consider a firm's knowledge that a healthcare provider has used or 
prescribed its medical product that is approved, cleared, granted 
marketing authorization, or exempted from premarket notification for an 
unapproved use, by itself, as sufficient to establish the intended use 
element of a prohibited act based on failing to meet applicable 
premarket requirements for that use or failing to provide adequate 
directions for use.\5\
---------------------------------------------------------------------------

    \4\ FDA generally does not seek to interfere with the exercise 
of the professional judgment of healthcare providers in prescribing 
or using, for unapproved uses for individual patients, most legally 
marketed medical products. This longstanding position has been 
codified with respect to devices (see 21 U.S.C. 396). Although FDA 
generally does not seek to interfere with the exercise of the 
professional judgment of veterinarians, certain unapproved uses of 
drugs in animals are not permitted (see section 512(a)(4) and (5)) 
of the FD&C Act (21 U.S.C. 360b(a)(4) and (5) and 21 CFR part 530) 
and result in the drug being deemed ``unsafe'' and therefore 
adulterated under sections 512 and 501(a)(5) (21 U.S.C. 351(a)(5)) 
of the FD&C Act.
    \5\ See 21 U.S.C. 331(d), 351(f), 352(f)(1), 355(a). The 
position described in the text does not apply to products that are 
not already legally marketed as medical products for at least one 
use. Similarly, nothing in this regulation or preamble is intended 
to impact the application of 21 U.S.C. 333(e), which, subject to 
limited exceptions, penalizes anyone who ``knowingly distributes, or 
possesses with intent to distribute, human growth hormone for any 
use in humans other than the treatment of disease or other 
recognized medical conditions, where such use has been authorized by 
the Secretary of Health and Human Services under section 505 and 
pursuant to the order of a physician.'' Further, Congress or the 
Agency could promulgate other provisions regarding specific products 
or classes of medical products that recognize knowledge as 
sufficient evidence of a particular element of a prohibited act.
---------------------------------------------------------------------------

VI. Effective Date

    This final rule will become effective 30 days after the date of its 
publication in the Federal Register.

VII. Economic Analysis of Impacts

A. Introduction and Summary

1. Introduction
    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). 
This final rule is not a significant regulatory action as defined by 
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. We cannot predict how many companies may revise labeling, 
advertising, or other materials, or otherwise modify their behavior, 
following issuance of this rule. However, this rule would merely 
clarify, but not change, the types of evidence relevant to determining 
manufacturers' intended use of products. Because the rule would not 
extend FDA's authority to additional products or impose any additional 
requirements on currently regulated products, we expect the rule will 
impose negligible costs, if any. As a result, we certify that the final 
rule will not have a significant economic impact on a substantial 
number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal

[[Page 41399]]

mandate that may result in the expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.'' The current threshold after adjustment for inflation is $158 
million, using the most current (2020) Implicit Price Deflator for the 
Gross Domestic Product. This final rule would not result in an 
expenditure in any year that meets or exceeds this amount.
2. Summary of Costs and Benefits
    The final rule clarifies but does not change FDA's interpretation 
and application of existing intended use regulations for medical 
products.
    The benefits of this rule are additional clarity and certainty for 
manufacturers and stakeholders regarding evidence that is relevant in 
evaluating whether an article is intended for use as a drug or device.
    This final rule is not expected to impose any significant 
additional costs on firms. Although this rule may impact firms' future 
marketing, product development, and communication strategies, firms are 
not required to make any changes to labeling, marketing materials, or 
operating procedures. Additionally, this rule does not extend FDA's 
jurisdiction to any new products.

                  Table 1--Summary of Benefits, Costs, and Distributional Effects of Final Rule
----------------------------------------------------------------------------------------------------------------
                                                                                 Units
                                Primary       Low        High    ------------------------------------
          Category             estimate    estimate    estimate      Year      Discount     Period       Notes
                                                                    dollars    rate  (%)    covered
----------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized      ..........  ..........  ..........  ..........           7  ..........
     $millions/year.........
                              ..........  ..........  ..........  ..........           3  ..........
    Annualized Quantified...  ..........  ..........  ..........  ..........           7  ..........
                              ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    Qualitative.............     Clarification of intended use
                                interpretation and application
 
----------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized      ..........  ..........  ..........  ..........           7  ..........
     $millions/year.........
                              ..........  ..........  ..........  ..........           3  ..........
    Annualized Quantified...  ..........  ..........  ..........  ..........           7  ..........
                              ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    Qualitative.............       Negligible costs, if any
 
----------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized        ..........  ..........  ..........  ..........           7  ..........
     Monetized $millions/
     year...................
                              ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    From/To.................  From:
                              To:
                             -----------------------------------------------------------------------------------
    Other Annualized          ..........  ..........  ..........  ..........           7  ..........
     Monetized $millions/
     year...................
                              ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    From/To.................  From:
                              To:
----------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.....................................................................
    Small Business: None........................................................................................
    Wages: None.................................................................................................
    Growth: None................................................................................................
----------------------------------------------------------------------------------------------------------------

3. Comments on the Preliminary Economic Analysis of Impacts and Our 
Response
    We did not receive any comments on the Preliminary Economic 
Analysis of Impacts.
4. Summary of Changes
    We have made no significant changes from the Preliminary Economic 
Analysis of Impacts.

B. Final Economic Analysis of Impacts

1. Background
    This rule clarifies FDA's longstanding position that the intended 
use of a drug or device product can be based on any relevant source of 
evidence by describing types of evidence relevant to the intended use 
of a product and types of evidence that, standing alone, are not 
determinative of intended use.
    One important clarification involves a manufacturer's knowledge of 
unapproved uses of its approved product. Current versions of Sec. Sec.  
201.128 and 801.4 specify that a manufacturer of a drug (Sec.  201.128) 
or device (Sec.  801.4) must include adequate labeling if it knows its 
product is used for an unapproved purpose. The September 2015 proposed 
rule (80 FR 57756 at 57764) removed the sentence regarding the 
requirement to provide adequate labeling if a firm knows its product is 
being used for an unapproved use. The amended January 2017 final rule 
(82 FR 2193 at 2217) was intended to clarify FDA's position by 
requiring manufacturers to include adequate labeling ``if the totality 
of the evidence establishes that a manufacturer objectively intends 
that a drug introduced into interstate commerce by him is to be used 
for conditions, purposes, or uses other than ones for which it is 
approved (if any).''
    In the Federal Register of February 7, 2017 (82 FR 9501), FDA 
delayed the effective date of the January 2017 final rule until March 
2017. In February 2017, various industry organizations filed a petition 
raising concerns with the January 2017 final rule, requesting 
reconsideration and a stay. The petition requested that FDA reconsider 
the amendments to the ``intended use'' regulations and issue a new 
final rule that, with respect to the intended use regulations at 
Sec. Sec.  201.128 and 801.4, reverted to the language of the September 
2015 proposed rule. The

[[Page 41400]]

petition also requested that FDA indefinitely stay the rule because 
petitioners argued that the final rule was issued in violation of the 
fair notice requirement under the Administrative Procedure Act and that 
the ``totality of the evidence'' language in the 2017 final rule was a 
new and unsupported legal standard.
    In the Federal Register of March 20, 2017 (82 FR 14319), FDA 
further delayed the effective date of the final rule until March 2018 
and opened the docket for additional public comment. Following some 
comments supporting the delay and proposing specific changes to the 
language in Sec. Sec.  201.128 and 801.4, on March 16, 2018 (83 FR 
11639), FDA delayed the amendments to Sec. Sec.  201.128 and 801.4 
until further notice. This final rule adopts the general approach set 
forth in the September 2015 proposed rule by deleting the final 
sentence; the final rule also clarifies FDA's interpretation and 
application of evidence relevant to determining intended use.
2. Benefits of the Final Rule
    The final rule clarifies FDA's existing interpretation of the 
determination of the intended use of drugs and devices. This 
clarification should reduce manufacturer and stakeholder uncertainty 
regarding the scenarios in which specific types of evidence may or may 
not show a product is intended for a drug or device use. The removal of 
the final sentence in Sec. Sec.  201.128 and 801.4 and the inclusion of 
new clarifying clauses (``provided, however, that a firm would not be 
regarded as intending an unapproved new use for [a medical product that 
is approved, cleared, granted marketing authorization, or exempted from 
premarket notification] based solely on that firm's knowledge that such 
[product] was being prescribed or used by health care providers for 
such use'') resolve questions about whether manufacturers need to think 
about developing an action plan or strategy related to a potential new 
intended use of their medical products that are approved, cleared, 
granted marketing authorization, or exempted from premarket 
notification simply because a manufacturer has knowledge of unapproved 
uses of these products by third parties. We believe this clarification 
is the benefit of the final rule.
3. Costs of the Final Rule
    The final rule is not expected to impose significant additional 
costs on manufacturers and distributors of FDA-regulated products. The 
final rule does not extend FDA's regulatory authority to any new or 
additional products, nor does the rule change the current approach to 
evaluating intended use or impose any additional requirements on 
manufacturers or distributors. We do not have any reason to believe 
firms will change their marketing or operating procedures as a result 
of this rule. We do not have evidence that this final rule would impose 
costs on currently marketed products.

C. Final Small Entity Analysis

    In table 2, we describe the Small Business Administration's size 
thresholds for industries affected by the final rule. Based on U.S. 
Census data, at least 22.9 percent of businesses in NAICS code 21323 
(Tobacco Manufacturing) are considered small; at least 17.5 percent of 
businesses in NAICS code 32541 (Pharmaceutical and Medicine 
Manufacturing) are considered small; and at least 32.6 percent of 
businesses in NAICS code 33911 (Medical Equipment and Supplies 
Manufacturing) are considered small. Because the final rule is not 
expected to impose costs on manufacturers or distributors of FDA-
regulated products, the final rule is also not expected to impose costs 
on small entities. Therefore, we certify that the final rule will not 
have a significant economic impact on a substantial number of small 
entities.

                                      Table 2--Small Business Administration Size Standards for Affected Industries
--------------------------------------------------------------------------------------------------------------------------------------------------------
        NAICS code             Industry description                                         Small business threshold
--------------------------------------------------------------------------------------------------------------------------------------------------------
312230....................  Tobacco Manufacturing.....  Fewer than 1,500 Employees.
325411....................  Medicinal and Botanical     Fewer than 1,000 Employees.
                             Manufacturing.
325412....................  Pharmaceutical Preparation  Fewer than 1,250 Employees.
                             Manufacturing.
325413....................  In-vitro Diagnostic         Fewer than 1,250 Employees.
                             Substance Manufacturing.
325414....................  Biological Product (except  Fewer than 1,250 Employees.
                             Diagnostic) Manufacturing.
339112....................  Surgical and Medical        Fewer than 1,000 Employees.
                             Instrument Manufacturing.
339113....................  Surgical Appliance and      Fewer than 750 Employees.
                             Supplies Manufacturing.
339114....................  Dental Equipment and        Fewer than 750 Employees.
                             Supplies Manufacturing.
339115....................  Ophthalmic Goods            Fewer than 1,000 Employees.
                             Manufacturing.
339116....................  Dental Laboratories.......  Fewer than 500 Employees.
--------------------------------------------------------------------------------------------------------------------------------------------------------

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h), (i), 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 final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the 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 rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects on one or 
more Indian Tribes, on the relationship between the Federal Government 
and Indian Tribes, or on the distribution of power and responsibilities 
between the Federal

[[Page 41401]]

Government and Indian Tribes. Accordingly, we conclude that the rule 
does not contain policies that have tribal implications as defined in 
the Executive Order and, consequently, a tribal summary impact 
statement is not required.

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 are also 
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. Regulations for the Enforcement of the Federal Food, Drug, and 
Cosmetic Act, 17 FR 6818, 6820 (1952).
2. U.S. Department of Justice, U.S. Attorney's Office, Northern 
District of Georgia, ``Five Defendants Charged With Illegally 
Importing Male Enhancement Products,'' May 29, 2014 (available at 
https://www.justice.gov/usao-ndga/pr/five-defendants-charged-illegally-importing-male-enhancement-products).
3. Defendants' Memorandum in Support of Motion to Dismiss or for 
Summary Judgment and in Opposition to Motion for Preliminary 
Injunction at 8, Par Pharmaceutical Inc. v. United States, 1:11-cv-
01820 (D.D.C. December 23, 2011).
4. Defendants' Memorandum of Points and Authorities in Support of 
Motion to Dismiss or for Summary Judgment at 8-9 n.5, Allergan Inc. 
v. United States, 1:09-cv-01879-JDB, (D.D.C. January 11, 2010).
5. Plaintiff's Motion for Summary Judgment at 20-26, United States 
v. Undetermined Quantities of Articles of Drug, Street Drug 
Alternatives, Identified in Attachment A, et al., Civil No. AW-00-
1687 (D. Md. January 12, 2001).
6. Government Trial Memorandum at 6, United States v. Teiman, 
Criminal No: 7:00CR00054 (W.D. Va. September 29, 2000).
7. Letter from Steven B. Barber, District Director, Cincinnati 
District, FDA to Marc C. Sanchez, Esq., Mood and Mind, LLC, at 9-10 
(April 6, 2017).
8. Letter from Margaret M. Dotzel, Assoc. Commissioner for Policy, 
FDA to Daniel J. Popeo and Richard A. Samp, Wash. Legal Found., at 
6, Docket No. 01P-0250 (January 28, 2002).
9. Letter from Ann Simoneau, J.D., Director, Office of Compliance 
and Enforcement, Center for Tobacco Products and Donald D. Ashley, 
J.D., Director, Office of Compliance, Center for Drug Evaluation and 
Research, FDA to HelloCig Electronic Technology Co., Ltd (October 
11, 2018).
10. Letter from Ramon A. Hernandez, Director, San Juan District 
Office and Program Division Director, Office of Human and Animal 
Food Operations, Division IV East, FDA, to Ricardo Mayo-Alvarez, Duy 
Drugs, Inc. (August 28, 2018).
11. Letter from Daniel Solis, Director, Import Operations Branch, 
Los Angeles District to Carol A. Pratt, K&L Gates LLP (December 3, 
2012).
12. Letter from Alonza E. Cruse, District Director, Los Angeles 
District, FDA to Richard Carieri, Lifetech Resources Labs Inc. 
(April 18, 2011).
13. Letter from Ronald M. Pace, District Director, New York 
District, FDA to Peter Erlikh, INZ Distributors, Inc. (August 23, 
2010).
14. U.S. Department of Justice, ``December 2, 2016: Woman Arrested 
for Injecting Adulter[at]ed Liquid Silicone,'' accessed December 23, 
2020, https://www.justice.gov/usao-pr/pr/woman-arrested-injecting-adultered-liquid-silicone.
15. U.S. Department of Justice, 2018, ``March 2, 2018: Woman 
Sentenced for Injecting Adulterated Liquid Silicone,'' accessed 
December 23, 2020, https://www.justice.gov/usao-pr/pr/woman-sentenced-injecting-adulterated-liquid-silicone.
16. Robertson, C.T. ``When Truth Cannot be Presumed: The Regulation 
of Drug Promotion Under An Expanding First Amendment,'' 94 B.U.L. 
REV. 545, 549-50 (2014).
17. Memorandum: Public Health Interests and First Amendment 
Considerations Related to Manufacturer Communications Regarding 
Unapproved Uses of Approved or Cleared Medical Products (January 
2017) (available at https://www.regulations.gov/document?D=FDA-2016-N-1149-0040).

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 801

    Labeling, Medical devices, Reporting and recordkeeping 
requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, 21 CFR 
parts 201 and 801 are amended as follows:

PART 201--LABELING

0
1. The authority citation for part 201 is revised 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.

0
2. Revise Sec.  201.128 to read as follows:


Sec.  201.128  Meaning of intended uses.

    The words intended uses or words of similar import in Sec. Sec.  
201.5, 201.115, 201.117, 201.119, 201.120, 201.122, and 1100.5 of this 
chapter refer to the objective intent of the persons legally 
responsible for the labeling of an article (or their representatives). 
The intent may be shown by such persons' expressions, the design or 
composition of the article, or by the circumstances surrounding the 
distribution of the article. This objective intent may, for example, be 
shown by labeling claims, advertising matter, or oral or written 
statements by such persons or their representatives. Objective intent 
may be shown, for example, by circumstances in which the article is, 
with the knowledge of such persons or their representatives, offered or 
used for a purpose for which it is neither labeled nor advertised; 
provided, however, that a firm would not be regarded as intending an 
unapproved new use for an approved drug based solely on that firm's 
knowledge that such drug was being prescribed or used by health care 
providers for such use. The intended uses of an article may change 
after it has been introduced into interstate commerce by its 
manufacturer. If, for example, a packer, distributor, or seller intends 
an article for different uses than those intended by the person from 
whom he or she received the article, such packer, distributor, or 
seller is required to supply adequate labeling in accordance with the 
new intended uses.

PART 801--LABELING

0
3. The authority citation for part 801 continues to read as follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 360d, 360i, 360j, 371, 
374.

0
4. Revise Sec.  801.4 to read as follows:


Sec.  801.4  Meaning of intended uses.

    The words intended uses or words of similar import in Sec. Sec.  
801.5, 801.119, 801.122, and 1100.5 of this chapter refer to the 
objective intent of the persons legally responsible for the labeling of 
an article (or their representatives). The intent may be shown by such 
persons' expressions, the design or composition of the article, or by 
the circumstances surrounding the distribution of the article. This 
objective intent may, for example, be shown by labeling claims, 
advertising matter, or oral or written statements by such persons or 
their representatives. Objective intent may be shown, for example, by 
circumstances in which the article is, with the knowledge of such 
persons or their representatives, offered or used for a purpose for 
which it is neither labeled nor advertised; provided, however, that a 
firm would not be regarded as intending an unapproved new use for a 
device approved, cleared, granted marketing authorization, or exempted 
from premarket notification based solely

[[Page 41402]]

on that firm's knowledge that such device was being prescribed or used 
by health care providers for such use. The intended uses of an article 
may change after it has been introduced into interstate commerce by its 
manufacturer. If, for example, a packer, distributor, or seller intends 
an article for different uses than those intended by the person from 
whom he or she received the article, such packer, distributor, or 
seller is required to supply adequate labeling in accordance with the 
new intended uses.

    Dated: July 14, 2021.
Janet Woodcock,
Acting Commissioner of Food and Drugs.
    Dated: July 22, 2021.
Xavier Becerra,
Secretary, Department of Health and Human Services.
[FR Doc. 2021-15980 Filed 7-30-21; 8:45 am]
BILLING CODE 4164-01-P


