Rule2021-15980
Regulations Regarding “Intended Uses”
Primary source
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Published
August 2, 2021
Effective
September 1, 2021
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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 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.
Full Text
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<title>Federal Register, Volume 86 Issue 145 (Monday, August 2, 2021)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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,
<a href="/cdn-cgi/l/email-protection#fa919f96969f83d4949e8f9597ba9c9e9bd4929289d49d958c"><span class="__cf_email__" data-cfemail="7318161f1f160a5d1d17061c1e331517125d1b1b005d141c05">[email protected]</span></a>.
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
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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.
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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:
<bullet> 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)).
<bullet> 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).
<bullet> 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)).
<bullet> 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:
<bullet> 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).
<bullet> 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).
<bullet> 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).
<bullet> [Evidence of intended use to be presented at trial
includes:] (1) Defendant intended the nitrous oxide he was offering for
sale on his website <a href="http://bongmart.com">bongmart.com</a> 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).
<bullet> 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).
<bullet> 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).
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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\
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\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).
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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.
<bullet> Marketing a medical device with a name that implies a use
to affect a particular organ or system of the body. Example:
``CardioCalm.''
<bullet> Designing a non-vascular stent with a coating clinically
known to change calcification of blood vessels.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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
<a href="https://www.justice.gov/usao-ndga/pr/five-defendants-charged-illegally-importing-male-enhancement-products">https://www.justice.gov/usao-ndga/pr/five-defendants-charged-illegally-importing-male-enhancement-products</a>).
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, <a href="https://www.justice.gov/usao-pr/pr/woman-arrested-injecting-adultered-liquid-silicone">https://www.justice.gov/usao-pr/pr/woman-arrested-injecting-adultered-liquid-silicone</a>.
15. U.S. Department of Justice, 2018, ``March 2, 2018: Woman
Sentenced for Injecting Adulterated Liquid Silicone,'' accessed
December 23, 2020, <a href="https://www.justice.gov/usao-pr/pr/woman-sentenced-injecting-adulterated-liquid-silicone">https://www.justice.gov/usao-pr/pr/woman-sentenced-injecting-adulterated-liquid-silicone</a>.
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 <a href="https://www.regulations.gov/document?D=FDA-2016-N-1149-0040">https://www.regulations.gov/document?D=FDA-2016-N-1149-0040</a>).
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
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This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.