[Federal Register Volume 85, Number 185 (Wednesday, September 23, 2020)]
[Proposed Rules]
[Pages 59718-59729]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-20437]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
proposing to amend its medical product ``intended use'' regulations. 
This action, if finalized, will amend 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 an approved or cleared 
medical product is intended for a new use. This action will also repeal 
and replace the portions of a final rule issued on January 9, 2017, 
that never became effective. This action is intended to provide 
direction and

[[Page 59719]]

clarity to regulated industry and other stakeholders.

DATES: Submit either electronic or written comments on the proposed 
rule by October 23, 2020.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before October 23, 2020. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of October 23, 2020. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before that date.

Electronic Submissions

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2015-N-2002 for ``Amendments to Regulations Regarding `Intended 
Uses'.'' Received comments, those filed in a timely manner (see 
ADDRESSES), will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

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, 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Meaning of Certain Terms in This Preamble
III. Background
    A. Introduction and History of the Rulemaking
    B. How Intended Use Is Evaluated
IV. Legal Authority
V. Description of the Proposed Rule
    A. Introduction
    B. Types of Evidence Relevant to Establishing Intended Use
    C. Examples of Evidence That, Standing Alone, Are Not 
Determinative of Intended Use
VI. Proposed Effective Dates
VII. Preliminary Economic Analysis of Impacts
    A. Introduction and Summary
    B. Preliminary Economic Analysis of Impacts
    C. Initial 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 Proposed Rule

    FDA is proposing 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, including 
whether a product meets the definition of a drug or device and whether 
an approved or cleared medical product is intended for a new use. The 
Agency issued a proposed rule in 2015 and a final rule in 2017 revising 
the language of these 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 final rule and reopened the docket to invite public comment. A 
number of comments submitted during the reopening raised questions and

[[Page 59720]]

concerns about the amendments. On March 18, 2018, 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 is proposing to repeal the portions 
of the final rule issued on January 9, 2017, that never became 
effective and to issue a new rule to provide more clarity regarding the 
types of evidence that are relevant in determining a product's intended 
uses. This action is intended to provide direction and clarity to 
regulated industry and other stakeholders.

B. Summary of the Major Provisions of the Proposed Rule

    FDA proposes to amend 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 an approved or cleared medical 
product is intended for a new use. Some firms have expressed concern 
that the last sentence of Sec.  201.128 could be read to mean that a 
firm's mere knowledge of an unapproved use of its approved drug product 
automatically triggers requirements for new labeling that in turn 
renders distribution of that approved product unlawful without approval 
of a supplemental application. Section 801.4 contains comparable 
language regarding medical devices. The Agency is proposing to delete 
the last sentence of Sec. Sec.  201.128 and 801.4 and to insert a new 
clause in the body of the regulations (``provided, however, that a firm 
would not be regarded as intending an unapproved new use for an 
[approved or cleared medical product] based solely on that firm's 
knowledge that such [product] was being prescribed or used by health 
care providers for such use'') to clarify that a firm's knowledge that 
health care providers are prescribing or using its approved or cleared 
medical product for an unapproved use would not, by itself, 
automatically trigger obligations for the firm to provide labeling for 
that unapproved use. In addition, FDA proposes amending the text of 
Sec. Sec.  201.128 and 801.4 to provide additional clarification 
regarding the types of evidence that are relevant to determining a 
product's intended uses. Additional clarification is provided in the 
preamble.
    FDA is also proposing to insert in Sec. Sec.  201.128 and 801.4 a 
reference to Sec.  1100.5 (21 CFR 1100.5), which describes when a 
product made or derived from tobacco that is intended for human 
consumption will be subject to regulation as a drug, device, or 
combination product. This change is being proposed to clarify the 
interplay between the drug and device intended use regulations and 
FDA's regulations governing products that are made or derived from 
tobacco and intended for human consumption.

C. Legal Authority

    Among the provisions that provide authority for this proposed 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 proposed 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 an approved or cleared medical product is intended 
for a new use. We do not have evidence that the proposed rule would 
impose costs on currently marketed products.

II. Meaning of Certain Terms in This Preamble

    As used in this preamble, the following terms have the meanings 
noted below.\1\
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    \1\ Nothing in this table is intended to construe terms in the 
FD&C Act, the PHS Act, or FDA's implementing regulations, nor does 
the information in the table otherwise affect discussions outside 
the context of this preamble.

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             Term                               Meaning
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Approved or cleared medical    This term refers to a medical product
 product.                       that may be legally introduced into
                                interstate 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 (including devices that are
                                granted marketing authorization or are
                                exempt from premarket notification).
Approved or cleared medical    This term refers to an intended use
 use.                           included in the required labeling for an
                                FDA-approved 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.
Health care 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.
Medical products.............  This term refers to drugs and devices,
                                including human biological products.
Products unapproved for any    This term refers to medical products that
 medical use.                   are not approved or cleared (as that
                                term is described above) by FDA for any
                                medical use, and which must be approved
                                or cleared 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 an approved  This term refers to an intended use that
 product.                       is not included in the required labeling
                                of an 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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[[Page 59721]]

III. Background

A. Introduction and History of the Rulemaking

    In the Federal Register of September 25, 2015 (80 FR 57756), FDA 
issued a proposed rule entitled ``Clarification of When Products Made 
or Derived From Tobacco Are Regulated as Drugs, Devices, or Combination 
Products; Amendments to Regulations Regarding `Intended Uses.''' Among 
other proposals, that 2015 notice of proposed rulemaking proposed 
certain changes to FDA's existing regulations describing the types of 
evidence relevant to determining a product's intended uses (see 
Sec. Sec.  201.128 (drugs) and 801.4 (devices)). These amendments were 
intended to clarify FDA's existing interpretation and application of 
these regulations (see 80 FR 57756 at 57761). Specifically, the 
amendments were intended to clarify that a firm would not be regarded 
as intending an unapproved new use for an approved product based solely 
on that firm's knowledge that its product was being prescribed or used 
by health care providers for such use (see 80 FR 57756 at 57761). FDA 
proposed to delete the last sentence of the intended use regulations 
(Sec. Sec.  201.128 and 801.4) to provide this clarification, in 
addition to some other changes.
    Before FDA's issuance of the proposed rule in 2015, some firms had 
expressed concern with the last sentence of Sec.  201.128. (Refs. 1 to 
3). That sentence states that if a manufacturer knows, or has knowledge 
of facts that would give him notice, that a drug introduced into 
interstate commerce by him is to be used for conditions, purposes, or 
uses other than the ones for which he offers it, he is required to 
provide adequate labeling for such a drug that accords with such other 
uses. (Sec.  801.4 contains comparable language.) These firms asserted 
(with some variations in the argument) that this sentence could be read 
to mean that whenever a manufacturer knew that its approved drug was 
being prescribed or used by a health care provider for an unapproved 
use, the manufacturer would be required to alter the labeling of a drug 
to provide adequate directions for such unapproved use. Firms further 
asserted that this addition to FDA-approved labeling would transform 
the drug into a new drug that cannot be sold without first obtaining 
approval of a supplemental new drug application pursuant to sections 
201(p) and 505(a) (21 U.S.C. 355(a)) of the FD&C Act.\2\ Firms asserted 
that, based on this, under the last sentence of Sec.  201.128, a 
manufacturer's mere knowledge of an unapproved use of its approved drug 
automatically triggers requirements for new labeling that in turn 
renders distribution of that approved product unlawful without approval 
of a supplemental application.
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    \2\ The same argument could apply with respect to new animal 
drugs (see sections 201(v) and 512(a) (21 U.S.C. 360b(a) of the FD&C 
Act).
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    In the 2015 proposed rule, the proposed deletion of the last 
sentence of Sec. Sec.  201.128 and 801.4 was intended to clarify the 
following: When a firm is distributing an approved or cleared medical 
product, evidence that the firm knows that health care providers are 
prescribing or using that approved or cleared medical product for an 
unapproved use would not, by itself, automatically trigger obligations 
for the firm to provide labeling for the uses for which the health care 
providers are prescribing or using the product. FDA's clarification of 
its position and proposed deletion of the last sentence of these 
regulations in the proposed rule was not intended to suggest that FDA 
sought to otherwise change the scope of evidence relevant to intended 
use.
    At the time the final rule issued in January 2017, FDA believed 
that the goals described in the preceding paragraph would be better 
achieved by amending the last sentence of each intended use regulation, 
rather than by deleting the sentences (see 82 FR 2193 at 2206). In the 
preamble to that final rule, FDA explained that the revised language 
was intended to achieve the goal described in the proposed rule by 
amending the last sentence so that it no longer suggested that a firm's 
mere knowledge that its approved or cleared product is being prescribed 
or used for an unapproved use would, on its own, trigger the 
requirement to provide adequate labeling (see 82 FR 2193 at 2206). The 
revised sentence was also intended to reflect FDA's longstanding 
position, discussed in both the preambles to the 2015 proposed rule and 
the 2017 final rule, that the intended use of a product can be 
evaluated based on ``any relevant source of evidence,'' including a 
variety of direct and circumstantial evidence (see 82 FR 2193 at 2206). 
The text of the final rule used the phrase ``the totality of the 
evidence'' to accomplish these goals (see 82 FR 2193 at 2206).
    The final rule was published with an initial effective date of 
February 8, 2017, which was delayed until March 21, 2017, in accordance 
with the memorandum of January 20, 2017, from the Assistant to the 
President and Chief of Staff, entitled ``Regulatory Freeze Pending 
Review'' (Ref. 4). On February 8, 2017, various industry organizations 
filed a petition (Docket No. FDA-2015-N-2002-1977) raising concerns 
with the January 2017 final rule. In March 2017, we further delayed the 
effective date of the final rule and reopened the docket to invite 
additional public comment. In March 2018, we delayed the effective date 
of the intended use amendments until further notice to allow for 
further consideration of the substantive issues raised in the comments 
received. Having considered these issues, FDA is proposing to repeal 
the intended use amendments contained in the final rule issued on 
January 9, 2017, that never took effect, and to issue a new rule that 
would replace the January 2017 rule in amending the intended use 
regulations to further clarify the types of evidence relevant to 
determining a product's intended uses. The January 2017 final rule also 
added a new regulation (Sec.  1100.5) to title 21 of the CFR (see 82 FR 
2193 at 2217). That regulation became effective on March 19, 2018. Its 
status is unaffected by this proposed rule.

B. How Intended Use Is Evaluated

    FDA's longstanding position is that, in evaluating a product's 
intended use, any relevant source of evidence may be considered. This 
position is unchanged and has solid support in the case law (see, e.g., 
United States v. Storage Spaces Designated Nos. 8 and 49, 777 F.2d 
1363, 1366 (9th Cir. 1985); Action on Smoking and Health v. Harris, 655 
F.2d 236, 239 (D.C. Cir. 1980); Nat'l Nutritional Foods Ass'n v. 
Mathews, 557 F.2d 325, 334 (2d Cir. 1977); United States v. Article of 
216 Cartoned Bottles, ``Sudden Change,'' 409 F.2d 734, 739 (2d Cir. 
1969); V.E. Irons, Inc. v. United States, 244 F.2d 34, 44 (1st Cir. 
1957); United States v. LeBeau, 2016 U.S. Dist. LEXIS 13612, *27, 2016 
WL 447612 (E.D. Wis. Feb. 3, 2016), aff'd, 654 Fed. App'x 826, 831 (7th 
Cir. 2016); United States v. Schraud, 2007 U.S. Dist. LEXIS 89231, *5 
(E.D. Mo. Dec. 4, 2007); Hanson v. United States, 417 F. Supp. 30, 35 
(D. Minn.), aff'd, 540 F.2d 947 (8th Cir. 1976)). Evidence of intended 
use may include, but is not limited to, the product's labeling, 
promotional claims, and advertising. For example, any claim or 
statement made by or on behalf of a firm that explicitly or implicitly 
promotes a product for a particular use may be taken into account.
    A firm's subjective claims of intent, however, are not necessarily 
determinative of a product's intended use. Objective evidence of the 
firm's intent, which can include a variety of direct and circumstantial 
evidence, is also relevant, particularly when it

[[Page 59722]]

contradicts the firm's claims. Indeed, courts have rejected the 
proposition that evidence of intended use is limited to labeling or 
other claims by a manufacturer concerning a device or drug (see Nat'l 
Nutritional Foods Ass'n v. Mathews, 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, as the very language 
quoted by the defendants themselves states, `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 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 342, 347 (W.D. Tex. 2016) (``[T]hough 
[21 CFR] 801.4 indeed says that `objective intent may, for example, be 
shown by labeling claims, advertising matter, or oral or written 
statements by such persons or their representatives,' nowhere does the 
regulation state that such statements or claims cannot be used to show 
objective intent unless they were published to the marketplace.''); 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 when 
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 products [sic] labelling 
states that it is not a drug'')).
    Courts have repeatedly held that intended use is determined by 
looking to all relevant evidence, including statements and 
circumstances surrounding the manufacture and distribution of a 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 . . . 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.P.R.1992) (emphasis 
in original) (internal citations omitted)).
    As FDA has previously stated, however, the Agency would not regard 
a firm as intending an unapproved use for its approved medical product 
based solely on the firm's knowledge that such product was being 
prescribed or used by health care providers for such use (80 FR 57756 
at 57757; 82 FR 2193 at 2206-2207). Health care providers sometimes 
prescribe or use approved or cleared medical products for unapproved 
uses when they judge that the unapproved use is medically appropriate 
for their individual patients.\3\ In such circumstances, FDA does not 
consider a firm's knowledge that a health care provider has prescribed 
or used its approved or cleared medical product for an unapproved use 
to be sufficient by itself to establish the intended use element of a 
prohibited act related to the lack of premarket approval or clearance 
of that use or the lack of adequate directions for use.\4\ Instead, FDA 
examines all relevant evidence, which could include, in combination 
with other facts, a firm's knowledge that health care providers are 
prescribing or using its approved or cleared medical product for an 
unapproved use, to determine whether there is sufficient evidence to 
establish a new intended use.
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    \3\ FDA generally does not seek to interfere with the exercise 
of the professional judgment of health care 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 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).
    \4\ See 21 U.S.C. 331(a), 331(d), 351(f), 352(f)(1), 355(a), 
360b. That position 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 
interfere with 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 a disease or other 
recognized medical condition, where such use has been authorized by 
the Secretary of Health and Human Services under section 505 [of the 
FD&C Act] and pursuant to the order of a physician.'' Furthermore, 
Congress or the Agency could issue other product-specific or product 
class-specific provisions that recognize knowledge as sufficient 
evidence of a particular element of a prohibited act.
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    Some comments submitted in the earlier rulemaking presented views 
regarding First Amendment considerations relating to how a product's 
intended use is established. However, treating knowledge as a category 
of evidence that may be considered as evidence of intended use does 
not, in itself, implicate the First Amendment. Knowledge and speech are 
not coextensive. A variety of direct and circumstantial evidence can 
establish a person's knowledge; a person's speech can be one source--
but is not the only source--of evidence of that person's knowledge. The 
proposed amendments are not intended to address specific concerns 
arising under the First Amendment, but instead seek to address an 
ambiguity in the language of the regulations and to conform that 
language to FDA's existing policy. Accordingly, and consistent with the 
statutory framework and purposes, FDA

[[Page 59723]]

is clarifying in this rulemaking that while knowledge can be within the 
types of evidence that are relevant to establishing intended use, a 
firm's knowledge that its approved or cleared medical product is being 
prescribed or used by health care providers for an unapproved use would 
not be relied upon as the sole evidence of a new intended use.
    Some comments submitted in the earlier rulemaking suggested that 
FDA should rely exclusively on firms' claims to establish intended use. 
This narrow view of intended use would not only create a loophole for 
firms that would enable them to evade FDA oversight of the marketing of 
approved or cleared medical products for unapproved uses, but would 
also open the door to the marketing of products that are unapproved for 
any medical use--all to the detriment of the public health. 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)). As one court explained, ``[a] disease 
claim made with a wink and a nudge is still a disease claim. To hold 
otherwise would create an `obviously wide loophole' that would defeat 
the `high purpose of the Act to protect consumers' '' (United States v. 
Cole, 84 F. Supp. 3d 1159, 1166 (D. Or. 2015) (citation omitted)). 
Examples where the government has relied on evidence other than express 
claims to establish intended use include situations where products 
contained a pharmacological ingredient such as the active ingredient 
from approved erectile dysfunction and hair-loss products, albuterol, 
or steroids, but were labeled as herbal supplements, leather cleaner, 
incense, potpourri, bath salts, or ``for research purposes only.'' 
Similar examples for devices include: (1) Products that are labeled as 
laser pointers or hyperbaric chambers but, based on other objective 
evidence, are actually intended by the manufacturer or the distributor 
to treat serious conditions such as cancer, diabetes, multiple 
sclerosis, human immunodeficiency virus (HIV), and autism; and (2) a 
product with a reservoir that is cleared for use with a saline solution 
to moisten tissue but, based on other objective evidence, is actually 
intended to deliver a drug (e.g., steroids) to the tissue. The 
government has also considered firms' directions to their sales forces 
in determining intended use. Thus, in addition to claims, FDA may also 
take into account any circumstances surrounding the distribution of the 
product or the context in which it is sold (see An Article of Device 
Toftness Radiation Detector, 731 F.2d at 1257; see also United States 
v. Travia, 180 F. Supp. 2d 115, 119 (D.D.C. 2001)). Considering 
evidence other than express claims often ensures that FDA is able to 
pursue firms that attempt to evade FDA medical product regulation by 
avoiding making express claims about their products.
    This rule, if finalized, would be consistent with the First 
Amendment. First, the rule is limited in scope. It describes evidence 
that may be relevant to establishing intended use, but it does not 
dictate that certain evidence will be determinative of intended use in 
an individual case.\5\ Second, nothing in this proposed rule, if 
finalized, would affect any exclusion explicitly provided by statute or 
regulation from the definitions of drug or device.\6\ Third, the 
proposed revisions to the intended use regulations do not reflect 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 an 
approved or cleared medical product be used for an unapproved use.\7\ 
If a firm's communication is consistent with the recommended practices 
described in FDA guidance, such a communication, on its own, would not 
be evidence of a new intended use.\8\
---------------------------------------------------------------------------

    \5\ Because ``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.
    \6\ For example, section 201(g)(1) of the FD&C Act contains 
exclusions from the drug definition for two types of labeling claims 
that would otherwise subject a product to regulation as a drug: (1) 
Structure/function claims and certain related claims in the labeling 
of dietary supplements, when made in accordance with section 
403(r)(6) of the FD&C Act; (2) health claims in the labeling of a 
conventional food or dietary supplement, when made in accordance 
with section 403(r)(3) or (r)(5)(D) of the FD&C Act, as applicable.
    \7\ The Agency has issued several final 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 (sometimes referred to as ``safe 
harbors'') (Refs. 5 to 7). The Agency has also recognized ``safe 
harbors'' in draft guidance documents (Refs. 8 and 9). When final, 
these documents will represent FDA's current thinking on these 
topics. The Agency invites comment on whether any elements of these 
guidances warrant codification in the regulations.
    \8\ As noted elsewhere in this preamble, this is not to suggest 
that these communications must be excluded from consideration 
altogether. For example, if there is other evidence of a new 
intended use for a product, such communications may be evaluated in 
assessing the classification and regulatory status of the product.
---------------------------------------------------------------------------

    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,\9\ as necessary to promote and protect the public health and 
as fully consistent with the First Amendment. Courts have held that 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 based on Supreme Court precedent establishing that ``[t]he 
First Amendment . . . does not prohibit the evidentiary use of speech 
to establish the elements of a crime or to prove motive or intent'' 
(Wisconsin v. Mitchell, 508 U.S. 476, 489 (1993)). The D.C. Circuit 
applied that precedent in the context of the FD&C Act and held that 
``th[e] use of speech to infer intent, which in turn renders an 
otherwise permissible act unlawful, is constitutionally valid'' and 
hence ``it is constitutionally permissible for the FDA to use speech 
[by the manufacturer] . . . to infer intent for purposes of determining 
that [the manufacturer's] proposed sale . . . would constitute the 
forbidden sale of an unapproved drug'' (Whitaker v. Thompson, 353 F.3d 
947, 953 (D.C. Cir. 2004); see also Nicopure Labs, LLC v. FDA, 944 F.3d 
267, 283 (D.C. Cir. 2019) (``Just as the government may consider speech 
that markets a copper bracelet as an arthritis cure . . . in order to 
subject the item to appropriate regulation, so, too, the FDA may rely 
on e-cigarette labeling and other marketing claims in order to subject 
e-cigarettes to appropriate regulation''); Flytenow, Inc. v. FAA, 808 
F.3d 882, 894 (D.C. Cir. 2015) (upholding ``us[e of] speech (postings 
on Flytenow.com) as evidence that pilots are offering service that 
exceeds the limits of their certifications''). Likewise, although the 
Second Circuit's decision in United States v. Caronia, 703 F.3d 149 (2d 
Cir. 2012), ``construe[d] the misbranding provisions of the FDCA as not 
prohibiting and criminalizing the truthful off-label promotion of FDA-
approved prescription drugs'' and concluded that ``the government 
cannot prosecute pharmaceutical manufacturers and their representatives 
under the FDCA for speech promoting the lawful, off-label use of an 
FDA-

[[Page 59724]]

approved drug,'' id. at 168-169,\10\ the decision ``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).
---------------------------------------------------------------------------

    \9\ It should be noted that intended use is relevant in contexts 
other than premarket approval and clearance. For example, FDA 
evaluates intended use in determining whether research studies 
involving human subjects involve the administration of a drug and 
must be conducted under an investigational new drug application (see 
21 CFR part 312).
    \10\ This holding was ``limited to FDA-approved drugs for which 
off-label use is not prohibited.'' 709 F.3d at 168-69. Any 
constitutional interest in such speech does not extend to speech 
promoting the introduction of a whoolly unapproved medical product 
into interstate commerce, which is an illegal activity. See United 
States v. Caputo, 517 F.3d 935, 939-40 (7th Cir. 2008); United 
States v. Cole, 84F. Supp. 3d 1159, 1166-67 (D.Or. 2015).
---------------------------------------------------------------------------

    In addition, FDA's consideration of speech as one type of evidence 
of intended use under its statutory and regulatory framework directly 
advances, and is appropriately tailored to achieve, substantial public 
health interests relevant to analyses under Central Hudson Gas & 
Electric Corp. v. Public Service Comm'n, 447 U.S. 557, 563-64 
(1980).\11\ 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.\12\ 
Accordingly, these premarket review provisions ``do[] not ban 
manufacturers from making accurate claims'' but instead ``require[] 
them to substantiate such claims.'' Nicopure Labs, LLC, 944 F.3d at 
285.
---------------------------------------------------------------------------

    \11\ In Sorrell v. IMS Health Inc., 564 U.S. 552, 565 (2011), 
the Supreme Court explained that content-based commercial speech 
restrictions may be subject to ``heightened judicial scrutiny.'' 
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, 2020 U.S. LEXIS 
2437 (Apr. 27, 2020).
    \12\ See Eguale, T., D.L. Buckeridge, A. Verma, et al., 
``Association of Off-Label Drug Use and Adverse Drug Events in an 
Adult Population,'' Journal of American Medical Association Internal 
Medicine, 176(1):55-63, 2016 (summarizing study across cohort of 
46,000 patients, and concluding that unapproved use of prescription 
drugs is associated with adverse drug events, particularly where 
those uses lack strong scientific evidence in the form of at least 
one randomized controlled trial) (Ref. 10).
---------------------------------------------------------------------------

IV. Legal Authority

    Among the statutory provisions that provide authority for this 
proposed 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 (21 U.S.C. 262). 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) 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'' (21 U.S.C. 262), 
and section 351(j) of the PHS Act provides that the requirements of the 
FD&C Act apply to biological products (21 U.S.C. 262). 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.

V. Description of the Proposed Rule

A. Introduction

    FDA is issuing this proposed rule to clarify the types of evidence 
relevant to determining a product's intended uses, including 
determining whether a product meets the definitions of drug or device 
and whether an approved or cleared medical product is intended for a 
new use. The proposed rule would insert in Sec. Sec.  201.128 and 801.4 
a reference to Sec.  1100.5, to clarify the interplay between the 
medical product intended use regulations and the regulation that 
describes when a product made or derived from tobacco that is intended 
for human consumption will be subject to regulation as a drug, device, 
or combination product. The Agency also proposes to delete the final 
sentence of Sec. Sec.  201.128 and 801.4 and to insert a new clause in 
the body of the regulations (``provided, however, that a firm would not 
be regarded as intending an unapproved new use for an [approved or 
cleared medical product] based solely on that firm's knowledge that 
such [product] was being prescribed or used by health care providers 
for such use'') to clarify that a firm would not be regarded as 
intending an unapproved use for its approved product based solely on 
that firm's knowledge that its product was being prescribed or used by 
health care providers for such use. FDA is also proposing additional 
changes to the codified text to clarify and reinforce that intended use 
can be based on any relevant source of evidence, including a variety of 
direct and circumstantial evidence.
    In the following sections, FDA provides several examples of types 
of evidence relevant to establishing intended use. These examples are 
provided for illustrative purposes only and are not intended to be 
comprehensive or restrictive. 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.

B. Types of Evidence Relevant to Establishing Intended Use

1. Express Claims and Representations
    In determining a product's intended use, any claim or statement 
made by or on behalf of a firm that explicitly represents a product for 
a particular use is relevant. This can include, but is not limited to, 
labeling claims and representations (whether made in required labeling 
or labeling that is optional or promotional), advertising matter, and 
oral or written statements by persons responsible for the labeling, or 
their representatives.
2. Implied Claims
    Any claim or statement made by or on behalf of a firm that 
implicitly represents a product for a particular use is also relevant 
to intended use. Examples of such implicit claims may include the 
following:
     Suggestive product names such as Chronix, Shroomz, or e-
Cialis;

[[Page 59725]]

     Statements that imply an intended use, such as ``For best 
results use approximately 30-45 minutes prior to engaging in sexual 
intercourse''; or
     Representations that the product contains a particular 
ingredient to imply a physiological effect, such as the inclusion of 
``aspirin'' or ``sildenafil'' in the ingredient list.
3. Product Characteristics and Design
    The characteristics of the product and its design are relevant to 
establishing intended use. Examples of such evidence include the 
following:
     The known physiological effects (medical or recreational) 
of a product that is unapproved for any medical use (for example, 
products containing an active pharmaceutical ingredient (API) \13\ or 
an analogue of an API or controlled substance).
---------------------------------------------------------------------------

    \13\ The acronym ``API'' in this category includes active drug 
ingredients, whether or not they are in an approved drug. As used 
here, ``API'' does not include a biologically active dietary 
ingredient in a dietary supplement.
---------------------------------------------------------------------------

    [cir] Example scenarios might include dried herbs treated with 
synthetic tetrahydrocannabinol (THC), or coffee containing sildenafil.
     The known use (recreational or medical) of a product that 
is unapproved for any medical use.
    [cir] Example scenarios might include 2,4-Dinitrophenol (DNP) being 
used for weight loss, herbal products being used for pain management, 
or a product being used for a medical purpose for which it provides no 
known benefit (e.g., Laetrile (amygdalin) for cancer).
     The product's design or technical features.
    [cir] Example scenarios might include a stent that is specifically 
sized for a use that is different from the purported use; a suture 
delivery device with a snare loop sized for a specific procedure that 
is different from the purported use; a device that includes software 
with a diagnostic function when the purported use does not include 
diagnosis; or products that purport to remove only the stratum corneum 
(outer layer of the skin) but that are actually designed to penetrate 
below the stratum corneum into the living layers of the skin.
4. Circumstances of the Sale or Distribution
    The types of evidence relevant to establishing intended use also 
include circumstances surrounding the distribution of the product and 
the context in which it is sold, including the following:
     To whom and for whom the products are offered, such as a 
firm's repeated proactive detailing and delivery of large amounts of 
complimentary product samples to a health care provider whose patient 
population does not fall within the product's approved population.
     Circumstances and context surrounding the sale, such as 
balloons containing laughing gas (nitrous oxide) being sold outside a 
rock concert, or the repackaging of bulk product into smaller plastic 
bags and using personal, not business, emails and addresses for 
communications and deliveries.

C. Examples of Evidence That, Standing Alone, Are Not Determinative of 
Intended Use

1. Knowledge, Alone or in the Context of ``Safe Harbors,'' of Health 
Care Providers Prescribing or Using an Approved Product for an 
Unapproved Use
    As discussed previously, a firm will not be regarded as intending 
an unapproved use of an approved product based solely on that firm's 
knowledge that the product is being prescribed or used by health care 
providers for such use.\14\ One example that would not, standing alone, 
be considered evidence of a new intended use might include the 
following scenario:
---------------------------------------------------------------------------

    \14\ Nothing in this rulemaking is intended to change a firm's 
existing obligations and responsibilities under the FD&C Act, the 
PHS Act, or FDA's implementing regulations to take action with 
respect to safety information including: (1) Updating its labeling 
to ensure that the labeling is not false or misleading or for other 
reasons; (2) reporting serious adverse events or other postmarketing 
safety reports to the Agency; or (3) issuing recalls, corrections, 
and removals. See, for example, 21 CFR 201.56(a)(2) (``[approved 
human prescription drug and biological product] labeling must be 
updated when new information becomes available that causes the 
labeling to become inaccurate, false, or misleading''); 21 CFR 
314.70, 514.8(c), 601.12, 814.39, and 814.108 (concerning 
supplements and other changes to approved medical product 
applications, including labeling); 21 U.S.C. 321(n) and 21 CFR 
1.21(a) (providing that material omissions can be misleading); 21 
CFR 314.80 (postmarketing reporting of adverse drug experiences); 21 
CFR 514.80 (records and reports concerning experience with approved 
new animal drugs); 21 CFR part 803 (obligations under medical device 
reporting); 21 CFR part 806 (medical device reports of corrections 
and removals); 21 CFR part 810 (medical device recalls); 21 CFR part 
7, subpart B (recalls).
---------------------------------------------------------------------------

     A pharmaceutical firm tracks sales and distribution 
metrics. The firm notes that one of its products, approved for use only 
in adults, is being ordered by and distributed to many medical 
practices that treat exclusively pediatric populations. The firm does 
not give any direction to its sales or marketing staff to disseminate 
samples or information about this product to these pediatric practices.
    Similarly, knowledge in combination with conduct that falls within 
an acknowledged FDA ``safe harbor'' would not be determinative of 
intended use. For example:
     A pharmaceutical firm tracks sales and distribution 
metrics. The firm notes that one of its products, approved for the 
treatment of adult patients with acute lymphoblastic leukemia (ALL), is 
being ordered by and distributed to many medical practices that treat 
exclusively pediatric oncology populations. The firm also notes that 
the National Comprehensive Cancer Network clinical practice guidelines 
(CPG) for the treatment of ALL in pediatric patients recommends the 
firm's drug product as a treatment option. The pharmaceutical firm 
distributes copies of the CPG at medical conferences, following all 
recommendations made in the revised draft guidance, ``Distributing 
Scientific and Medical Publications on Unapproved New Uses--Recommended 
Practices'' (Ref. 8). The firm does not give any direction to its sales 
or marketing staff to disseminate samples or information about this 
product to practices that treat pediatric cancer patients exclusively.
    We note that in some cases, knowledge that a product was being 
prescribed or used by health care providers for an unapproved use could 
be considered relevant to establishing a new intended use where there 
is additional evidence of intended use (but excluding, as discussed 
above, evidence that falls within FDA's acknowledged ``safe harbors'' 
for dissemination of information about an unapproved use of an approved 
product).
2. Additional Examples That, Standing Alone, Are Not Determinative of 
Intended Use
    There are examples of other circumstances that, standing alone, 
would not be determinative of intended use. For example, there may be 
limited instances where a firm disseminates safety information about an 
unapproved use to health care providers to minimize risk to patients. 
Such dissemination, on its own, would not ordinarily be dispositive 
evidence of a new intended use. The scenario below provides one example 
of a situation in which a firm could disseminate safety and warning 
information without triggering the prohibitions on distributing a 
product for an unapproved use and misbranding a product by failing to 
provide adequate directions for use. The following example is fact-
specific and is provided for illustrative purposes only.
     The unapproved use of a firm's approved drug is broadly 
accepted by the medical community and the firm

[[Page 59726]]

has submitted an efficacy supplement to add the unapproved use to the 
labeling of the drug. The boxed warning and risk evaluation and 
mitigation strategy (REMS) materials for the drug warn of potential 
risks related to the unapproved use in general terms, but the firm 
disseminates additional specific safety and warning information to 
health care providers to minimize the risk to patients receiving the 
drug for the unapproved use. The safety and warning information does 
not expressly or implicitly promote the efficacy of the unapproved use.
    Below are some additional examples that, without other evidence, 
would not establish a new intended use. This list is not intended to be 
comprehensive or restrictive. Each scenario is fact-specific, and, 
under other circumstances or in other contexts, similar material may be 
evaluated differently.
     A firm's official social media account ``follows'' the 
social media account for a 501(c)(3) non-profit that supports patients 
with a rare disease for which there is no FDA-approved treatment. The 
firm is in the process of investigating one of its FDA-approved 
products for use in the rare disease that the non-profit account 
supports. The non-profit account disseminates messages about charity 
events, scientific conferences, support groups, and rare disease 
research and drug development. The firm account does not make any 
comments or otherwise endorse any specific posts on the non-profit 
account.
     During an internal meeting, a firm's CEO displays a slide 
of internal sales projections for its approved product. The slide 
reflects potential sales for an unapproved use that is widely 
recognized as the standard of care.
     A firm makes corporate filings or submissions to the U.S. 
Securities and Exchange Commission that include required disclosures of 
development activities or potential or actual sales for an unapproved 
use.
     Following a clinical trial, the sponsoring firm prepares a 
plain-language summary of the aggregated clinical trial results and 
provides the summary solely to clinical trial participants to 
acknowledge their contributions to scientific and medical advancement 
(not to inform prescribing and use decisions). The summary provides a 
factual, balanced, and complete presentation of the trial results, 
including relevant safety information and any limitations of the study. 
The summary does not make any conclusions about the safety or 
effectiveness of the unapproved product or the unapproved use, and it 
includes a conspicuous and prominent statement that the product or use 
has not been approved, cleared, or licensed by FDA.

VI. Proposed Effective Dates

    The Agency proposes that any final rule based on this proposed rule 
will become effective 30 days after the date of publication of the 
final rule in the Federal Register.

VII. Preliminary Economic Analysis of Impacts

A. Introduction and Summary

1. Introduction
    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, Executive Order 13771, 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). Executive Order 13771 
requires that the costs associated with significant new regulations 
``shall, to the extent permitted by law, be offset by the elimination 
of existing costs associated with at least two prior regulations.'' 
This proposed rule is not expected to be subject to the requirements of 
Executive Order 13771 because this proposed rule is expected to result 
in no more than de minimis costs. This proposed rule is a significant 
regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. We cannot predict how many companies may revise labeling, 
advertising, or other materials, or otherwise modify their behavior, 
following issuance of this rule. However, because this rule would 
merely clarify, but not change, the types of evidence relevant to 
determining manufacturers' intended use of products, any such changes 
would be voluntarily undertaken by firms. Because the proposed rule 
would not extend FDA's authority to additional products or impose any 
additional requirements on currently regulated products, we expect the 
proposed rule will impose negligible costs, if any. As a result, we 
propose to certify that the proposed rule will not have a significant 
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $154 million, using the most current (2018) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.
2. Summary of Costs and Benefits
    The proposed 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 proposed 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 Proposed Rule
----------------------------------------------------------------------------------------------------------------
                                                                                 Units
                                                                 ------------------------------------
          Category              Primary       Low        High                  Discount                  Notes
                               estimate    estimate    estimate      Year        rate       Period
                                                                    dollars    (percent)    covered
----------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized..............  ..........  ..........  ..........  ..........           7  ..........  ..........

[[Page 59727]]

 
    Monetized $millions/year  ..........  ..........  ..........  ..........           3  ..........  ..........
    Annualized..............  ..........  ..........  ..........  ..........           7  ..........  ..........
    Quantified..............  ..........  ..........  ..........  ..........           3  ..........  ..........
----------------------------------------------------------------------------------------------------------------
    Qualitative.............     Clarification of intended use    ..........  ..........  ..........  ..........
                                interpretation and application
----------------------------------------------------------------------------------------------------------------
Costs:
    Annualized..............  ..........  ..........  ..........  ..........           7  ..........  ..........
    Monetized $millions/year  ..........  ..........  ..........  ..........           3  ..........  ..........
    Annualized..............  ..........  ..........  ..........  ..........           7  ..........  ..........
    Quantified..............  ..........  ..........  ..........  ..........           3  ..........  ..........
----------------------------------------------------------------------------------------------------------------
    Qualitative.............       Negligible costs, if any       ..........  ..........  ..........  ..........
----------------------------------------------------------------------------------------------------------------
Transfers:
    Federal.................  ..........  ..........  ..........  ..........           7  ..........  ..........
    Annualized Monetized      ..........  ..........  ..........  ..........           3  ..........  ..........
     $millions/year.........
----------------------------------------------------------------------------------------------------------------
    From/To.................  From:
                              To:                                 ..........
----------------------------------------------------------------------------------------------------------------
    Other...................  ..........  ..........  ..........  ..........           7  ..........  ..........
    Annualized Monetized      ..........  ..........  ..........  ..........           3  ..........  ..........
     $millions/year.........
----------------------------------------------------------------------------------------------------------------
    From/To.................  From:
                              To:                                 ..........
----------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.....................................................................
    Small Business: None........................................................................................
    Wages: None.................................................................................................
    Growth: None................................................................................................
----------------------------------------------------------------------------------------------------------------

B. Preliminary 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 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 proposed rule adopts the general approach 
set forth in the September 2015 proposed rule by deleting the final 
sentence; the proposed rule also clarifies FDA's interpretation and 
application of evidence relevant to determining intended use.
2. Benefits of the Proposed Rule
    The proposed 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. Removal of the 
final sentence in Sec. Sec.  201.128 and 801.4 and the inclusion of a 
new clarifying clause (``provided, however, that a firm would not be 
regarded as intending an unapproved new use for an [approved or cleared 
medical product] based solely on that firm's knowledge that such 
[product] was being prescribed or used by health care providers for 
such use'') eliminate any question about whether manufacturers need to 
think about developing an action plan or strategy related to a 
potential new intended use of their approved or cleared medical

[[Page 59728]]

products due merely to knowledge of unapproved uses of these products 
by third parties. We believe this clarification is the benefit of the 
proposed rule; we request comment on this assumption.
3. Costs of the Proposed Rule
    The proposed rule is not expected to impose significant additional 
costs on manufacturers and distributors of FDA-regulated products. The 
proposed 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 request comment on this assumption. We do not have 
evidence that this proposed rule would impose costs on currently 
marketed products. We request comment on this assumption.

C. Initial Small Entity Analysis

    In table 2, we describe the Small Business Administration's size 
thresholds for industries affected by the proposed rule. Based on U.S. 
Census data, at least 22.9% of businesses in NAICS code 21323 (Tobacco 
Manufacturing) are considered small; at least 17.5% of businesses in 
NAICS code 32541 (Pharmaceutical and Medicine Manufacturing) are 
considered small; and at least 32.6% of businesses in NAICS code 33911 
(Medical Equipment and Supplies Manufacturing) are considered small. 
Because the proposed rule is not expected to impose costs on 
manufacturers or distributors of FDA-regulated products, the proposed 
rule is also not expected to impose costs on small entities. Therefore, 
we propose to certify that the proposed 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
------------------------------------------------------------------------
                                                       Small business
       NAICS code           Industry description          threshold
------------------------------------------------------------------------
312230.................  Tobacco Manufacturing....  Fewer than 1,500
                                                     Employees.
325411.................  Medicinal and Botanical    Fewer than 1,000
                          Manufacturing.             Employees.
325412.................  Pharmaceutical             Fewer than 1,250
                          Preparation                Employees.
                          Manufacturing.
325413.................  In-vitro Diagnostic        Fewer than 1,250
                          Substance Manufacturing.   Employees.
325414.................  Biological Product         Fewer than 1,250
                          (except Diagnostic)        Employees.
                          Manufacturing.
339112.................  Surgical and Medical       Fewer than 1,000
                          Instrument Manufacturing.  Employees.
339113.................  Surgical Appliance and     Fewer than 750
                          Supplies Manufacturing.    Employees.
339114.................  Dental Equipment and       Fewer than 750
                          Supplies Manufacturing.    Employees.
339115.................  Ophthalmic Goods           Fewer than 1,000
                          Manufacturing.             Employees.
339116.................  Dental Laboratories......  Fewer than 500
                                                     Employees.
------------------------------------------------------------------------

VIII. Analysis of Environmental Impact

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

IX. Paperwork Reduction Act of 1995

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

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the rule does not contain policies that would have a 
substantial direct effect on one or more Indian Tribes, on the 
relationship between the Federal Government and Indian Tribes, or on 
the distribution of power and responsibilities between the Federal 
Government and Indian Tribes. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XII. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

1. Plaintiff's Memorandum of Law at 38-40, Allergan Inc. v. United 
States, 1:09-cv-01879-JDB (D.D.C. January 15, 2010).
2. Complaint at ]] 35-37, Par Pharmaceutical Inc. v. United States, 
1:11-cv-01820 (D.D.C. October 10, 2011).
3. Citizen Petition from the Medical Information Working Group at 
18, FDA-2013-P-1079 (Sept. 3, 2013).
4. Memorandum for the Heads of Executive Departments and Agencies, 
from Reince Priebus, Assistant to the President and Chief of Staff, 
``Regulatory Freeze Pending Review,'' January 20, 2017 (available at 
https://www.whitehouse.gov/presidential-actions/memorandum-heads-executive-departments-agencies/), accessed February 5, 2020.
5. FDA, Guidance for Industry, ``Medical Product Communications That 
Are Consistent With the FDA-Required Labeling--Questions and 
Answers,'' June 2018 (available at https://www.fda.gov/media/102575/download), accessed February 5, 2020.
6. FDA, Guidance for Industry and Review Staff, ``Drug and Device 
Manufacturer Communications With Payors, Formulary Committees, and 
Similar Entities--Questions and Answers,'' June 2018 (available at 
https://www.fda.gov/media/102683/download), accessed February 5, 
2020.
7. FDA, Guidance for Industry, ``Industry-Supported Scientific and 
Educational Activities,'' December 1997 (available at

[[Page 59729]]

https://www.fda.gov/media/70844/download), accessed February 5, 
2020.
8. FDA, Draft Guidance for Industry, ``Distributing Scientific and 
Medical Publications on Unapproved New Uses--Recommended 
Practices,'' February 2014 (available at https://www.fda.gov/media/88031/download), accessed February 5, 2020.
9. FDA, Draft Guidance for Industry, ``Responding to Unsolicited 
Requests for Off-Label Information About Prescription Drugs and 
Medical Devices,'' December 2011 (available at https://www.fda.gov/media/82660/download), accessed February 5, 2020.
10. Eguale, T., D.L. Buckeridge, A. Verma, et al., ``Association of 
Off-Label Drug Use and Adverse Drug Events in an Adult Population,'' 
Journal of American Medical Association Internal Medicine, 
176(1):55-63, 2016.

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 and under 
authority delegated to the Commissioner of Food and Drugs, we propose 
that 21 CFR parts 201 and 801 be 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 an 
approved or cleared device based solely 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: September 8, 2020.
Stephen M. Hahn,
Commissioner of Food and Drugs.
[FR Doc. 2020-20437 Filed 9-22-20; 8:45 am]
BILLING CODE 4164-01-P