[Federal Register Volume 87, Number 236 (Friday, December 9, 2022)]
[Proposed Rules]
[Pages 75536-75551]
[FR Doc No: 2022-26728]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 312

[Docket No. FDA-2019-N-2650]
RIN 0910-AH07

Investigational New Drug Applications; Exemptions for Clinical
Investigations To Evaluate a Drug Use of a Product Lawfully Marketed as
a Conventional Food, Dietary Supplement, or Cosmetic

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

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
proposing to amend its regulations on investigational new drug
applications (INDs) to exempt from the IND requirements certain
clinical investigations of lawfully marketed foods for human
consumption (including both conventional foods and dietary supplements)
and cosmetics when the product is to be studied to evaluate its use as
a drug. Under the proposal, clinical studies to evaluate a drug use of
such products would not have to be conducted under an IND when, among
other things, the study is not intended to support a drug development
plan or a labeling change that would cause the lawfully marketed
product to become an unlawfully marketed drug, and the study does not
present a potential for significant risk to the health, safety, or
welfare of subjects. Though exempt from the IND requirements, such
investigations would still be subject to other regulations designed to
protect the rights and safety of subjects, including requirements for
informed consent and review by institutional review boards (IRBs). By
exempting from the IND requirements certain clinical investigations of
products lawfully marketed as a food or cosmetic, the proposed
provisions are intended to reduce the regulatory burden of conducting
such studies while retaining protections for human subjects.

DATES: Submit either electronic or written comments on the proposed
rule by March 9, 2023. Submit comments on the collection of information
under the Paperwork Reduction Act of 1995 by January 9, 2023.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept electronic
comments until 11:59 p.m. Eastern Time at the end of March 9, 2023.
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-2019-N-2650 for ``Investigational New Drug Applications; Exemptions
for Clinical Investigations to Evaluate a Drug Use of a Product
Lawfully Marketed as a Conventional Food, Dietary Supplement, or
Cosmetic.'' 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,<PHONE_NUMBER>.
     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,<PHONE_NUMBER>.
    Submit comments on the information collection under the Paperwork
Reduction Act of 1995 to the Office of Management and Budget (OMB) at
https://www.reginfo.gov/public/do/PRAMain. Find this particular
information collection by selecting ``Currently under Review--Open for
Public Comments'' or by using the search function. The title of this
proposed collection is ``Investigational New Drug Applications;
Exemptions for Clinical Investigations to Evaluate a Drug Use of a
Product Lawfully Marketed as a Conventional Food, Dietary Supplement,
or Cosmetic.''

FOR FURTHER INFORMATION CONTACT:
    Regarding the proposed rule: Brian Pendleton, Office of Policy,
Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring,
MD 20993-0002,<PHONE_NUMBER>, [email protected].
    Regarding the information collection: Domini Bean, Office of
Operations, Food and Drug Administration, Three White Flint North 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852,<PHONE_NUMBER>,
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations and Commonly Used Acronyms in This
Document
III. Background
    A. Definitions
    B. Applicability of the IND Regulations
    C. Guidance on Whether Clinical Investigations Can Be Conducted
Without an IND
    D. Need for the Regulation
IV. Legal Authority
V. Description of the Proposed Rule
    A. Self-Determined Exemption (Proposed Sec.  312.2(b)(4))
    B. FDA-Determined Exemption (Proposed Sec.  312.2(b)(5))
    C. Proposed Technical and Conforming Amendments
VI. Proposed Effective Date
VII. Preliminary Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to amend its IND regulations to exempt from the
scope of the requirements certain clinical investigations studying drug
uses of products that are lawfully marketed as foods for human
consumption (including dietary supplements) or as cosmetics. The
proposed rule would make it easier for sponsors and sponsor-
investigators to conduct certain clinical investigations evaluating
drug uses of foods or cosmetics while maintaining adequate safeguards
for human subjects.
    Currently, FDA regulations provide an exemption from the IND
requirements for studies of lawfully marketed drug products that meet
certain criteria, including that the study does not involve a route of
administration, dosage level, use in a patient population, or other
factor that significantly increases the risks (or decreases the
acceptability of these risks) associated with the use of the drug
product. However, this exemption applies only to clinical
investigations of drug products lawfully marketed in the United States,
and therefore generally does not apply to clinical investigations of
products marketed as foods for human consumption or as cosmetics.
    FDA has exercised its enforcement discretion on a case-by-case
basis and has not objected to certain clinical studies evaluating a
drug use of a product lawfully marketed as a food or cosmetic being
conducted without an IND, based on consideration of factors such as the
purpose of the investigation and whether the study raises any concerns
about the health, safety, and welfare of the subjects. This proposed
rule would now establish exemptions from the IND requirements for drug
studies of products lawfully marketed in the United States as a food or
cosmetic when the studies meet criteria similar to those in the IND
exemption for certain investigations of lawfully marketed drug
products.

B. Summary of the Major Provisions of the Proposed Rule

    The proposed rule would create two types of IND exemptions for drug
studies of products lawfully marketed in the United States as foods or
cosmetics. One exemption, the proposed ``self-determined exemption,''
would specify that a clinical investigation to evaluate a drug use of a
product lawfully marketed in the United States as a conventional food
for human consumption, a dietary supplement, or a cosmetic is exempt
from the IND requirements if certain conditions are met:
     The investigation is not intended to support a drug
development plan for the product (including a future IND or application
for marketing approval) or a labeling change that would cause the
lawfully marketed product to become an unlawfully marketed drug;
     The investigation is conducted in compliance with the
requirements for IRB review and informed consent;
     The investigation is conducted in compliance with the
regulations governing promotion and commercial distribution of
investigational drugs;
     The route of administration of the product in the
investigation is the same as that of the lawfully marketed product; and
     The investigation meets certain criteria designed to
protect the health, safety, and welfare of subjects.
    Under this self-determined exemption, if a clinical investigation
to evaluate a drug use of a product lawfully marketed in the United
States as a food or cosmetic meets these criteria, the study would be
exempt from the IND regulations. Provided the criteria are met, the
study's sponsor (who may also be an investigator conducting the study,
i.e., a sponsor-investigator) would not be required to submit an IND
for the study or request that FDA exempt the study from the IND
requirements (and we would not accept an IND for a study that we had
determined was exempt).
    Under the second IND exemption we propose to establish, the ``FDA-
determined exemption,'' the sponsor of a clinical investigation to
evaluate a drug use of a product lawfully marketed in the United States
as a food or cosmetic could ask the Agency to exempt the investigation
from the IND requirements when the investigation meets the self-
determined exemption criteria except for one or more of the subject
health, safety, and welfare criteria, but the sponsor has concluded
that the investigation nevertheless does not present a potential for
significant risk to subjects. To obtain such an exemption, the sponsor
would submit a written request that includes information on the
sponsor, the proposed investigation, and the product to be studied, as
well as a description of why the investigation does not present a
potential for significant risk to the health, safety, or welfare of
subjects.
    Upon receiving such a request for exemption from the IND
requirements, FDA would evaluate any risks to subjects and would grant
an exemption if we found that the investigation did not present a
potential for significant risk (or decrease the acceptability of the
risks) to the health, safety, or welfare of subjects. The proposal also
would authorize FDA to exempt a study from the IND requirements on our
own initiative if we determined, upon review of an IND for the study,
that the study met the decision criteria for an FDA-determined
exemption. The FDA-determined exemption proposal also states that we
may revoke an exemption if we become aware of information suggesting
that the investigation: (1) could present a potential for significant
risk to the health, safety, or welfare of subjects or (2) does not meet
any other eligibility requirement for the exemption.
    Adopting these proposed IND exemptions would reduce the burden of

conducting certain clinical investigations evaluating drug uses of
products lawfully marketed as foods or cosmetics, as well as the
Agency's burden of reviewing such studies, without eliminating
requirements that help ensure the safety of subjects and the quality of
data submitted in support of drug product approval.

C. Legal Authority

    We are issuing this proposed rule under FDA's authority to regulate
drug products under the Federal Food, Drug, and Cosmetic Act (FD&C Act)
and the Public Health Service Act (PHS Act).

D. Costs and Benefits

    Quantifiable benefits of this proposed rule are cost savings that
come from reducing the burden of submitting INDs to FDA for clinical
investigations to evaluate a drug use of a food or cosmetic. The
proposed rule would have a one-time, upfront cost for current and
future sponsors and sponsor-investigators who would have to read the
rule, if it is finalized. In addition, there would be costs to FDA
associated with a new type of IND-related submission, a request for an
FDA-determined exemption. The impact of reviewing this new submission
is analyzed in section II.E of the Preliminary Economic Analysis of
Impacts for this proposed rule, as a partial offset to the cost savings
of the rule. Discounted over 10 years, the total net benefit of the
rule is estimated to be $33 million at a 3 percent discount rate and
$27 million at a 7 percent discount rate.

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

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       Abbreviation  or acronym                  What it means
------------------------------------------------------------------------
ANDA.................................  Abbreviated New Drug Application.
BLA..................................  Biologics License Application.
CBER.................................  Center for Biologics Evaluation
                                        and Research.
CDER.................................  Center for Drug Evaluation and
                                        Research.
FD&C Act.............................  Federal Food, Drug, and Cosmetic
                                        Act.
FDA..................................  Food and Drug Administration.
IND..................................  Investigational New Drug
                                        Application.
IRB..................................  Institutional Review Board.
NDA..................................  New Drug Application.
OMB..................................  Office of Management and Budget.
PHS Act..............................  Public Health Service Act.
------------------------------------------------------------------------

III. Background

    This proposed rule concerns the establishment of exemptions from
the requirement to submit an IND before initiating certain clinical
investigations evaluating drug uses of lawfully marketed food for human
consumption (including both conventional foods and dietary supplements)
and cosmetics. (We refer to these product categories collectively as
``foods and cosmetics'' in this document.) Following is a brief
discussion of important terms used in this proposed rule, the
applicability of the IND regulations in part 312 (21 CFR part 312) to
clinical investigations of foods and cosmetics for use as drugs, and
why the proposed exemptions are needed.

A. Definitions

    Before explaining the need for the proposed IND exemptions, we
believe it is helpful to discuss several terms used in the proposed
rule. Under Sec.  312.3(a), the definitions and interpretations of
terms contained in section 201 of the FD&C Act (21 U.S.C. 321) apply to
those terms when used in the IND regulations. Therefore, the terms
``food,'' ``dietary supplement,'' ``cosmetic,'' and ``drug'' in the
proposed exemptions are defined as they are in the FD&C Act.
    ``Food'' is defined as articles used for food or drink for man or
other animals, chewing gum, and articles used for components of any
such article (section 201(f) of the FD&C Act). For purposes of the
proposed exemptions, ``food'' does not include animal feed, pet food,
or other food intended for consumption by animals other than humans.
Examples of food include, but are not limited to, fruits, vegetables,
fish, dairy products, eggs, raw agricultural commodities for use as
food or as components of food, food ingredients, food additives
(including substances that migrate into food from packaging and other
articles that contact food), dietary supplements, dietary ingredients,
infant formula, medical foods, beverages (including alcoholic beverages
and bottled water), bakery goods, snack foods, candy, and canned foods.
    ``Dietary supplement'' is defined, in part, as a product that is
intended for ingestion to supplement the diet and that contains one or
more dietary ingredients (section 201(ff) of the FD&C Act). Dietary
ingredients include vitamins, minerals, herbs and other botanicals,
amino acids, other dietary substances intended to supplement the diet
by increasing the total dietary intake, and concentrates, metabolites,
constituents, extracts, and combinations of the preceding types of
ingredients (section 201(ff)(1) of the FD&C Act). Because dietary
supplements are deemed to be food for most purposes, the term ``food''
includes dietary supplements (see section 201(ff) of the FD&C Act).
Notably, however, dietary supplements are not deemed to be food for
purposes of section 201(g) of the FD&C Act, which, as discussed below,
defines ``drug'' for purposes of the FD&C Act (section 201(ff) of the
FD&C Act).
    The term ``conventional food'' is not defined in the FD&C Act or in
FDA's regulations. In this proposed rule, we use it to mean any food
that is not a dietary supplement.
    A ``cosmetic'' is an article (other than soap) intended to be
rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise
applied to the human body or any part thereof for cleansing,
beautifying, promoting attractiveness, or altering the appearance, or
an article intended for use as a component of any such article (section
201(i) of the FD&C Act).
    The definition of ``drug'' includes, among other things, ``articles
intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease in man or other animals'' and ``articles (other
than food) intended to affect the structure or any function of the body
of man or other animals'' (section 201(g)(1)(B) and (C) of the FD&C
Act). This proposed rule applies only to products that are intended for
investigational use as drugs in humans. A biological product subject to
licensure under section 351 of the PHS Act (42 U.S.C. 262) fits within
the drug definition under the FD&C Act. A ``biological product'' is a
virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, protein, or analogous
product, or arsphenamine or derivative of arsphenamine (or any other
trivalent organic arsenic compound), applicable to the prevention,
treatment, or cure of a disease or condition of human beings (section
351(i) of the PHS Act).
    ``Clinical investigation'' is defined in the IND regulations as any
experiment in which a drug is administered or dispensed to, or used
involving, one or more human subjects (excluding use of a marketed drug
in medical practice) (Sec.  312.3(b)). A ``subject'' is defined in the
IND regulations as a human who participates in an investigation, either
as a recipient of an investigational new drug or as a control; subjects
may be healthy or have a disease (Sec.  312.3(b)).
    A ``sponsor'' of a clinical investigation is an individual or
entity (e.g., pharmaceutical or other company, governmental agency,
academic

institution, private organization, or other organization) who takes
responsibility for and initiates the investigation (Sec.  312.3(b)). An
``investigator'' is an individual who actually conducts a clinical
investigation (i.e., the investigational drug is administered or
dispensed to subjects under his or her immediate direction) (Sec.
312.3(b)). A person may be a ``sponsor-investigator,'' who is an
individual who initiates and conducts an investigation, and under whose
immediate direction the investigational drug is administered or
dispensed (Sec.  312.3(b)). For simplicity, we refer to sponsors and
sponsor-investigators collectively as ``sponsors'' in this document
except in the proposed regulatory text.

B. Applicability of the IND Regulations

    The new drug provisions of the FD&C Act require that a person
obtain approval of a new drug application (NDA) or abbreviated new drug
application (ANDA) before introducing or delivering for introduction
into interstate commerce a new drug (section 505(a) of the FD&C Act (21
U.S.C. 355(a))). Similarly, the PHS Act requires that a person obtain
approval of a biologics license application (BLA) before introducing or
delivering for introduction into interstate commerce a biological
product (section 351(a) of the PHS Act). However, these approval
requirements do not apply to a drug or biological product intended
solely for investigational use by experts qualified by scientific
training and experience to investigate the safety and effectiveness of
drugs, provided the sponsor of the study complies with the regulations
in part 312 governing the use of investigational new drugs (section
505(i) of the FD&C Act). These regulations include provisions for the
submission and FDA review of INDs (see, e.g., Sec. Sec.  312.20,
312.40).
    There are two primary objectives of IND review. First, IND review
is designed to help ensure that the safety and rights of subjects of
clinical investigations are protected. Second, as applied to Phase 2
and Phase 3 studies, IND review is intended to help ensure that the
quality of data obtained from a clinical study is adequate to permit
evaluation of the safety and effectiveness of a drug for which
marketing approval is sought (Sec.  312.22(a)). Phase 2 studies are
controlled clinical studies conducted to evaluate the effectiveness of
a drug for a particular indication in patients with the disease or
condition under study or to determine the short-term side effects and
risks associated with the drug (Sec.  312.21(b)). Phase 3 studies are
expanded controlled and uncontrolled trials performed after preliminary
evidence suggesting a drug's effectiveness has been obtained; they are
intended to gather additional information about effectiveness and
safety needed to evaluate the overall benefit-risk relationship of the
drug and to provide an adequate basis for physician labeling (Sec.
312.21(c)). Sponsor compliance with IND requirements (such as for the
content and format of INDs (Sec.  312.23), safety reports (Sec.
312.32), annual progress reports (Sec.  312.33), and monitoring of
investigations (e.g., Sec. Sec.  312.50, 312.53, and 312.56)) and FDA
review of the content of INDs, protocol amendments (Sec.  312.30),
safety reports, annual progress reports, and other IND-related
information help ensure that subjects are adequately protected and that
sponsors may rely on data from investigations to support applications
for approval.
    Section 312.2(a) states that the IND requirements apply to all
clinical investigations of products that are subject to section 505 of
the FD&C Act (which includes the new drug approval requirement) or the
biological product licensing provisions of the PHS Act. However, there
are a few exemptions from the IND requirements set forth in Sec.
312.2(b). For the purposes of the proposed rule, the most significant
of these exemptions concerns certain investigations of drug products
lawfully marketed in the United States. Under Sec.  312.2(b)(1), a
clinical investigation of a drug product that is lawfully marketed in
the United States is exempt from the IND regulations if all the
following apply:
     The investigation is not intended to be reported to FDA as
a well-controlled study in support of a new indication for use nor to
support any other significant change in the labeling for the drug;
     If the drug that is undergoing investigation is lawfully
marketed as a prescription drug product, the investigation is not
intended to support a significant change in the advertising for the
product;
     The investigation does not involve a route of
administration, dosage level, use in a patient population, or other
factor that significantly increases the risks (or decreases the
acceptability of the risks) associated with use of the drug;
     The investigation is conducted in compliance with the
requirements for review by an IRB in part 56 (21 CFR part 56) and the
requirements for informed consent in part 50 (21 CFR part 50); and
     The investigation is conducted in compliance with the
requirements in Sec.  312.7, which govern promotion and commercial
distribution of investigational new drugs, among other things.
    Section 312.2(b)(1) was created during the revision of the IND
regulations in the 1980s (``IND Rewrite'') because it became clear that
physicians, especially those affiliated with academic institutions,
sought to conduct clinical investigations using marketed drugs, either
to investigate new uses or to use the drug as a research tool to
explore biological phenomena or disease processes (48 FR 26720, June 9,
1983). Although such clinical investigations are subject to section
505(i) of the FD&C Act, FDA reevaluated the utility of reviewing these
INDs and concluded that our review of certain categories of INDs was
not necessary to ensure the protection of study subjects. Accordingly,
in the final rule adopting the IND Rewrite, we exempted from the IND
requirements clinical investigations of lawfully marketed drugs that
meet specific criteria designed to help ensure that exempted
investigations do not expose subjects to new risks (52 FR 8798 at 8832,
March 19, 1987) (codified in Sec.  312.2(b)(1)). Under Sec.
312.2(b)(1)(iv), investigators conducting exempt studies are still
required to conform to all ethical principles applicable to the conduct
of clinical investigations, including the statutory requirement for
informed consent (section 505(i)(4) of the FD&C Act). Thus, a study's
exemption is conditioned on a sponsor complying with the requirements
for informed consent set forth in part 50 as well as the requirements
for review and approval by an IRB set forth in part 56. Finally, the
sponsor is prohibited from test marketing or commercially distributing
the product and from promoting the product for its investigational use
(see Sec. Sec.  312.2(b)(1)(v) and 312.7).

C. Guidance on Whether Clinical Investigations Can Be Conducted Without
an IND

    To address questions about the applicability of the IND regulations
to certain types of clinical investigations, in the Federal Register of
October 14, 2010, we issued a notice of availability (75 FR 63189) of a
draft guidance entitled ``Guidance for Industry: Investigational New
Drug Applications (INDs)--Determining Whether Human Research Studies
Can Be Conducted Without an IND'' (``2010 Draft IND Guidance''). In
addition to explaining when the FD&C Act and FDA regulations require an
IND to be

submitted, the draft guidance described the types of clinical
investigations that are exempt by regulation from the IND requirements
and addressed a range of issues that commonly arise in inquiries to FDA
about the application of those requirements.
    On September 10, 2013, we issued a notice of availability (78 FR
55262) of the final version of that draft guidance, entitled ``Guidance
for Clinical Investigators, Sponsors, and Institutional Review Boards
(IRBs) on Investigational New Drug Applications--Determining Whether
Human Research Studies Can Be Conducted Without an IND'' (``2013 IND
Guidance'' (Ref. 1)). Like the draft guidance (2010 Draft IND
Guidance), the final guidance notes that a ``drug'' is not limited to
articles intended to have a therapeutic purpose (i.e., to diagnose,
cure, mitigate, treat, or prevent a disease), but also includes
articles (other than food) intended to affect the structure or function
of the body. For example, an article administered to healthy
individuals to prevent pregnancy or treat male pattern baldness is a
drug. The 2013 IND Guidance further explained that the drug definition
also includes articles used for research purposes in healthy subjects
to blunt or provoke a physiologic response or study the mechanism of
action or metabolism of a drug (Ref. 1 at 3).
    The final guidance also explains the application of the IND
regulations to studies of ingredients or products marketed as foods or
cosmetics. The guidance explains that a clinical investigation
assessing the use of a conventional food for a therapeutic purpose
(e.g., to relieve symptoms of Crohn's disease) would be a study to
evaluate a drug use of the food and would therefore require an IND
(Ref. 1 at 12-13; see also section 201(g)(1)(B) of the FD&C Act).
However, a clinical study designed to evaluate the safety or
tolerability of a food ingredient when ingested as food (i.e.,
primarily for its taste, aroma, or nutritive value) would not be a
study to evaluate a drug use, so an IND would not be required (Ref. 1
at 13-14; see also section 201(g)(1)(C) of the FD&C Act and Nutrilab v.
Schweiker, 713 F.2d 335 (7th Cir. 1983)).
    Regarding dietary supplements, the final guidance explains that a
dietary supplement intended only to affect the structure or function of
the body and not intended for a therapeutic purpose is not a drug (Ref.
1 at 12; see also sections 201(g)(1) and 403(r)(6) of the FD&C Act (21
U.S.C. 321(g)(1) and 343(r)(6)). Therefore, an IND is not required for
a clinical investigation intended only to evaluate a dietary
supplement's effect on the structure or function of the body. However,
if a clinical investigation is intended to evaluate a dietary
supplement's ability to diagnose, cure, mitigate, treat, or prevent a
disease, an IND is required.
    The final guidance explains that clinical investigations of
ingredients or products marketed as cosmetics require an IND if the
ingredient is being studied for use to affect the structure or function
of the body or for a therapeutic purpose (Ref. 1 at 11). This is
because section 201(g)(1)(B) and (C) of the FD&C Act defines as drugs
both articles (other than food) intended to affect the structure or
function of the body and articles intended to diagnose, cure, mitigate,
treat, or prevent a disease.
    Because FDA received multiple comments asking for further
opportunity to comment on portions of the final guidance (sections VI.C
and VI.D) addressing the applicability of the IND regulations to
clinical investigations evaluating drug uses of foods (including
dietary supplements) or cosmetics, on February 6, 2014, we reopened the
comment period on those sections of the guidance (79 FR 7204). These
comments raised questions about application of the IND requirements to
certain clinical studies of conventional foods, dietary supplements,
and cosmetics being investigated for uses covered by the drug
definition in section 201(g)(1)(B) or (C) of the FD&C Act.
    On October 30, 2015, we issued a notice of administrative stay of
action staying parts of the final guidance to allow for further
consideration of issues raised by comments received following the
reopening of the comment period (80 FR 66907). Specifically, we stayed
portions of section VI.D.2, ``Conventional Food'' (concerning clinical
studies to evaluate non-nutritional effects on the structure or
function of the body), and all of section VI.D.3, ``Studies Intended to
Support a Health Claim'' (except as to studies intended to evaluate
whether a food substance reduces the risk of a disease in individuals
less than 12 months old, those with altered immune systems, and those
with serious or life-threatening medical conditions). The stayed
portion of section VI.D.2 states that under the applicable regulations,
a clinical investigation intended only to evaluate the nutritional
effects of a food (including medical foods) would not require an IND,
but an investigation intended to evaluate other effects of a food on
the structure or function of the body would require an IND. Section
VI.D.3 (stayed except as to studies that include subjects in the three
medically vulnerable categories previously described) states that under
the applicable regulations, a clinical study designed to evaluate the
relationship between a food substance and a disease, and intended to
provide support for a health claim about reducing the risk of the
disease, must be conducted under an IND, unless the substance-disease
relationship being studied is already the subject of an authorized
health claim under section 403(r)(1)(B) and (r)(3) of the FD&C Act (for
a conventional food) or section 403(r)(1)(B) and (r)(5)(D) (for a
dietary supplement). The notice announcing the administrative stay of
portions of the final guidance states that we do not intend to enforce
the IND requirement for studies in the stayed categories while the stay
is in effect (80 FR 66907 at 66908 to 66909).
    As previously stated, some clinical investigations of products
marketed as foods and cosmetics are included among the types of studies
that are required by the FD&C Act and FDA regulations to be conducted
under an IND. Under the proposed rule, some of these clinical
investigations would be exempt from the IND requirements if they meet
the proposed exemption criteria discussed in section V of this
document. At the completion of this rulemaking, we anticipate taking
action to resolve related issues in the final guidance, including the
stayed portions of the guidance.

D. Need for the Regulation

    In recent years, FDA has received inquiries about many clinical
investigations evaluating a drug use of an article marketed as a food
or cosmetic. Examples of such articles include conventional foods such
as potatoes and dried fruit; dietary supplements such as soy
isoflavones, vitamins, and green tea extract; and cosmetics such as
lavender oil and hydroquinone (which is a cosmetic when used as a
fragrance ingredient or hair colorant, but a drug when used to bleach
the skin by decreasing the formation of melanin). Products in these
categories have been studied to evaluate their use in treating,
mitigating, curing, or preventing diseases such as asthma, diabetes,
arthritis, gastrointestinal disorders, depression, cardiovascular
disease, and cancer.
    In some cases, the sponsor of a clinical investigation of a food or
cosmetic--often, the manufacturer of the product--seeks to study the
product for use in treating, mitigating, curing, or preventing a
disease because the sponsor hopes to develop and obtain marketing
approval of the product as a

drug, has a financial relationship with an entity that hopes to obtain
such marketing approval, or wishes to market the product for disease
treatment or prevention without seeking approval for it as a new drug.
For example, the manufacturer of a dietary supplement marketed with a
claim that the product ``supports digestive health'' might wish to
sponsor a clinical investigation designed to evaluate the product's
ability to treat a digestive disorder. However, in other cases, a
person or institution may have a purely scientific or medical interest
in studying a conventional food, dietary supplement, or cosmetic for a
drug use. For example, physicians and other researchers in hospitals
and universities often explore potentially novel mechanisms of action
of a food or cosmetic to understand whether such a product could have
an effect on an aspect of a disease or medical condition. In many
cases, such researchers have no intent to seek approval of the product
as a drug or market it unlawfully for disease treatment or prevention
without such approval, no financial interest in the product, and no
research funding or other financial support from the product's
manufacturer or other potential sponsors of an application for drug
marketing approval.
    Review divisions in the Center for Biologics Evaluation and
Research (CBER) and the Center for Drug Evaluation and Research (CDER)
frequently receive inquiries from study sponsors and investigators
about whether the IND requirements apply to a planned study to evaluate
a drug use of a food or cosmetic. In some cases, the sponsor asserts
that the study is exempt from the IND requirements under Sec.
312.2(b)(1). However, most of these studies are not eligible for the
exemption in Sec.  312.2(b)(1) because the study is not a clinical
investigation of a drug product that is lawfully marketed in the United
States. Nevertheless, in some cases, the Agency has concluded that it
is not necessary or desirable to apply the IND requirements to a
proposed drug study of a food or cosmetic because the study poses
minimal risks to subjects and is not intended to be used in support of
a drug marketing application, drug development plan, or labeling change
that would cause the lawfully marketed food or cosmetic to become an
unlawfully marketed drug. In such cases, we have exercised enforcement
discretion regarding the submission of an IND for the study and the IND
reporting requirements (e.g., study progress and safety reports).
Sponsors of such studies must still comply with FDA regulations on the
protection of human subjects and IRB review (parts 50 and 56,
respectively), along with the IND regulation regarding promotion and
commercial distribution of investigational drugs (Sec.  312.7), and
they are expected to notify us of any changes to the study protocol
that could affect subjects' safety.
    We believe that establishing IND exemptions for certain clinical
investigations of drug uses of foods and cosmetics based on the
principles behind the adoption of Sec.  312.2(b)(1) would reduce
regulatory and resource burdens on sponsors, investigators, and the
Agency in circumstances when application of the IND requirements is not
needed to ensure adequate protection of human subjects. Many of the
proposed clinical investigations of foods and cosmetics that we have
considered in recent years would have been eligible for either the
proposed self-determined exemption or FDA-determined exemption.
Codifying IND exemptions for investigations of drug uses of foods and
cosmetics that meet certain criteria similar to the eligibility
criteria for exempting studies of lawfully marketed drug products under
Sec.  312.2(b)(1) could result in reduced research costs for sponsors,
fewer inquiries submitted to CBER and CDER review divisions, and
greater numbers of clinical trials (because FDA consultation would not
be needed for the self-determined exemption), without compromising the
health, safety, or welfare of subjects or undermining the quality of
data needed to support drug marketing approval.

IV. Legal Authority

    This proposed rule would exempt from the IND regulations in part
312 certain clinical investigations evaluating drug uses of products
lawfully marketed in the United States as foods (including dietary
supplements) or cosmetics. These exemptions would track the exemption
already provided in Sec.  312.2(b)(1) for certain clinical
investigations of lawfully marketed drugs.
    Under section 701(a) of the FD&C Act (21 U.S.C. 371(a)), the Agency
is empowered to issue regulations for the efficient enforcement of that
statute. FDA's primary objective in reviewing an IND is to assure the
rights, safety, and welfare of subjects (see 48 FR 26720 at 26725 and
Sec.  312.60), with a secondary objective of helping to ensure that the
quality of data obtained from a Phase 2 or Phase 3 clinical study is
adequate to permit evaluation of the drug's safety and effectiveness
(Sec.  312.22(a)). Like any other clinical investigation where the
intended use to be studied brings the investigational product within
the drug definition, clinical investigations evaluating drug uses of
foods and cosmetics are subject to section 505(i) of the FD&C Act.
However, after reevaluating the utility of requiring such clinical
investigations to be conducted under an IND, FDA finds that these
investigations are remarkably diverse with respect to the composition
and risk profile of the products studied, the health of the study
subjects, and the nature of the study procedures (e.g., invasive vs.
non-invasive testing). Accordingly, we have drafted subject protection
and study purpose criteria in an attempt to define categories of low-
risk clinical investigations that can be exempted from the IND
requirements without compromising human subject protection or the
quality of data used to support drug marketing applications. FDA
tentatively concludes that, for clinical investigations that meet the
proposed criteria, review of an IND is not necessary for subject
protection and would be an inefficient use of sponsor and Agency
resources. Therefore, under our authority to issue regulations for the
efficient enforcement of the FD&C Act, we are proposing to exempt
clinical investigations that meet the proposed criteria from the IND
requirements.
    We are also issuing this proposed rule under FDA's authority to
regulate unapproved new drug products under the FD&C Act (see sections
201, 301, 501, 502, 503, 505, 561, and 701) (21 U.S.C. 321, 331, 351,
352, 353, 355, 360bb, and 371) and section 351 of the PHS Act.

V. Description of the Proposed Rule

    We are proposing to amend the IND regulations to establish two
exemptions for clinical investigations evaluating a drug use of a food
or cosmetic. Under the first exemption provision, a clinical
investigation to evaluate a drug use of a food or cosmetic would be
exempt from the IND requirements if certain criteria were met
regarding: (1) the intent of the investigation; (2) compliance with
requirements and restrictions regarding institutional review, informed
consent, and promotion and commercial distribution of investigational
drugs; (3) the route of administration of the product as used in the
investigation; and (4) protection of subjects' health, safety, and
welfare. Because a sponsor would self-determine whether the
investigation met the criteria to be conducted without an IND, we refer
to this exemption as the ``self-determined exemption.''

    Under the second proposed exemption, a sponsor of an investigation
that did not meet one or more of the self-determined exemption's
health, safety, and welfare criteria, but did meet all the other
criteria for the self-determined exemption, could submit to us a
written request for exemption if the sponsor concluded that the study
nevertheless did not present a potential for significant risk to the
health, safety, or welfare of subjects. Under this ``FDA-determined
exemption,'' we would grant an exemption if we found that the
investigation did not present a potential for significant risk. In
addition to authorizing the Agency to grant an FDA-determined exemption
upon the request of a sponsor, the proposed rule would allow FDA to
exempt a study on our own initiative if we determined, upon review of
an IND that had been submitted for the study, that the study met the
decision criteria for an FDA-determined exemption. The proposed rule
would also permit us to revoke an exemption we had granted if we
subsequently became aware of information suggesting that the study
presented a potential for significant risk to the health, safety, or
welfare of subjects, or that the study did not meet any of the other
requirements for the exemption.
    The proposed self-determined and FDA-determined exemptions
(including the FDA-initiated exemption) would be set forth in proposed
Sec.  312.2(b)(4) and (5), respectively, with existing exemptions and
related provisions in current Sec.  312.2(b)(4) through (6) to be
renumbered accordingly. In addition, we propose to amend current Sec.
312.2(b)(4), which states that we will not accept an IND for
investigations exempt under Sec.  312.2(b)(1), to specify that we also
would not accept an IND for investigations exempt under proposed Sec.
312.2(b)(4) and (5).
    The following paragraphs describe the proposed self-determined and
FDA-determined exemption provisions and other proposed changes to Sec.
312.2(b).

A. Self-Determined Exemption (Proposed Sec.  312.2(b)(4))

    Under proposed Sec.  312.2(b)(4), a clinical investigation to
evaluate a drug use of a product lawfully marketed in the United States
as a food intended for human consumption (including as a conventional
food or dietary supplement) or as a cosmetic would be exempt from the
IND requirements if the following criteria are met:
     The investigation is not intended to support a drug
development plan for the product, including a future IND or application
for marketing approval (an application under section 505 of the FD&C
Act or section 351 of the PHS Act), or to support a change in the
labeling of the lawfully marketed product that would cause it to become
an unlawfully marketed drug;
     The investigation is conducted in compliance with the
requirements for institutional review in part 56 and the requirements
for informed consent in part 50;
     The investigation is conducted in compliance with the
requirements of Sec.  312.7;
     The route of administration of the product in the
investigation is the same as that of the lawfully marketed product; and
     The investigation meets the following criteria relating to
the health, safety, and welfare of study subjects:
    [cir] The investigation does not include subjects who are less than
12 months of age or subjects who are pregnant or lactating;
    [cir] The investigation does not include subjects with a
compromised immune system or a serious or life-threatening disease or
condition;
    [cir] The investigation does not restrict subjects from continuing
with treatments or therapies prescribed or recommended by a healthcare
provider;
    [cir] The investigation does not involve any procedures that would
increase the risks (or decrease the acceptability of the risks) to
subjects beyond what they would ordinarily encounter during routine
physical or psychological examinations or standard of care procedures
to treat their medical condition;
    [cir] The product is being used in the investigation consistent
with its labeled conditions of use or, in the absence of labeled
conditions of use, consistent with its ordinary conditions of use
(e.g., same dose range and total daily intake, same formulation, same
duration of use); and
    [cir] During the investigation, subjects are not taking and will
not be treated with any other product(s) that would significantly
increase the risks (or decrease the acceptability of the risks) they
will encounter in the investigation (e.g., because of drug
interactions).
    The following paragraphs discuss the scope and criteria of the
proposed self-determined exemption in more detail.
1. Products Lawfully Marketed in the United States as Foods or
Cosmetics
    The self-determined exemption would apply to studies of products
that are lawfully marketed in the United States as foods intended for
human consumption (including as a dietary supplement) or as cosmetics
(proposed Sec.  312.2(b)(4)). For purposes of the proposed self-
determined exemption, ``lawfully marketed'' means the product is
marketed in the United States as a food or cosmetic consistent with the
FD&C Act and any applicable FDA regulations.
2. Clinical Investigation To Evaluate a Drug Use
    The proposed self-determined exemption would apply to clinical
investigations evaluating a food or cosmetic for use as a drug
(proposed Sec.  312.2(b)(4)). The intended use of a product determines
whether the product fits within the definition of a ``drug'' under the
FD&C Act (see section III.C of this document).
3. Not Intended To Support a Drug Development Plan or Marketing for Use
as a Drug
    The proposed self-determined exemption would not apply to a
clinical investigation intended to support a drug development plan for
a food or cosmetic, including a future IND or marketing approval
application, or to support a change in the labeling of the food or
cosmetic that would cause the product to become an unlawfully marketed
drug (proposed Sec.  312.2(b)(4)(i)). For example, this means that if
the investigation were intended to support a future IND for a clinical
trial investigating a drug use of the product, or a future NDA or BLA
for the product, the investigation would not be eligible for the
exemption.
    As previously noted, the IND exemption for clinical investigations
of lawfully marketed drug products in existing Sec.  312.2(b)(1) does
not apply to a study intended to be reported to FDA as a well-
controlled study in support of a new indication for use or intended to
be used to support any other significant change in a drug's labeling.
In proposing this criterion in the 1983 IND Rewrite, FDA stated that
the criterion was ``aimed at helping ensure that investigations
intended to be submitted to FDA for labeling or advertising changes are
adequate in design to serve that purpose'' (48 FR 26720 at 26733). We
further stated that this is the ``same reason the agency evaluates the
design of Phase 2 and Phase 3 studies,'' noting that this review ``adds
considerable efficacy to the drug development process'' (48 FR 26720 at
26733). Similarly, if a clinical investigation of a food or cosmetic is
intended to support a drug development plan for that product, the
investigation must be conducted under an IND to help ensure that the
quality of the scientific evaluation of the product is adequate to

permit an evaluation of the product's effectiveness and safety when
used as a drug, including whether data from the investigation can be
used to support approval of the product as a drug (see Sec.
312.22(a)).
    The self-determined exemption also would not apply if the sponsor
of the clinical investigation intended to use the study to support
marketing of the food or cosmetic for a use that caused the product to
be an unlawfully marketed drug. For example, if a sponsor sought to
study a dietary supplement to support marketing it for a disease
treatment use (rather than for a structure or function use), the study
would not be eligible for the self-determined exemption. Similarly, the
exemption would not apply to a study intended to support the addition
of a drug claim to the label of a conventional food or a cosmetic.
4. Conducted in Compliance With Part 56 and Informed Consent
Requirements of Part 50
    To be eligible for the proposed self-determined exemption, the
study must also be conducted in compliance with the IRB requirements in
part 56 and the informed consent requirements in part 50 (proposed
Sec.  312.2(b)(4)(ii)). This criterion would mirror the provision in
Sec.  312.2(b)(1)(iv) that requires compliance with the IRB and
informed consent requirements as a condition of eligibility for the IND
exemption for certain studies of drug products lawfully marketed in the
United States.
5. Conducted in Compliance With Sec.  312.7
    Another eligibility criterion for the proposed self-determined
exemption matching a criterion for the exemption for lawfully marketed
drugs is the proposed requirement that the investigation be conducted
in compliance with Sec.  312.7 (proposed Sec.  312.2(b)(4)(iii)). Among
other things, Sec.  312.7 prohibits commercially distributing or test
marketing an investigational new drug, as well as representing in a
promotional context that an investigational new drug is safe or
effective for the purposes for which it is under investigation.
6. Same Route of Administration as Lawfully Marketed Food or Cosmetic
    Another eligibility criterion for the proposed self-determined
exemption that is based on a criterion for the exemption for lawfully
marketed drugs is the requirement that the route of administration of
the product in the investigation be the same as that of the lawfully
marketed product (proposed Sec.  312.2(b)(4)(iv)). For example, a
clinical investigation of a product lawfully marketed as a dietary
supplement for oral ingestion would not qualify for the exemption if
the product would be administered topically or transmucosally (i.e.,
sublingually, buccally, or intranasally) when used as a drug in the
investigation. Similarly, a clinical investigation of a product
lawfully marketed as a cosmetic applied to the skin would not qualify
for the exemption if the product would be administered subcutaneously,
intravenously, or intramuscularly when used as a drug in the
investigation. This requirement would ensure that the self-determined
and FDA-determined exemptions are limited to investigations evaluating
drug uses of foods and cosmetics when the investigational products are
administered in the same way as the marketed products, thereby avoiding
potential safety risks posed by atypical routes of administration
(e.g., products marketed as dietary supplements being studied as
injectable drugs).
7. Criteria To Help Ensure Health, Safety, and Welfare of Subjects
    The proposed self-determined exemption includes several eligibility
criteria designed to protect the health, safety, and welfare of study
subjects (proposed Sec.  312.2(b)(4)(v)). These criteria, discussed in
the following paragraphs, are intended to serve the same purpose as the
requirement under the lawfully marketed drug exemption that the
investigation not involve a dosage level, use in a patient population,
or other factor that significantly increases the risks (or decreases
the acceptability of the risks) associated with use of the drug product
(Sec.  312.2(b)(1)(iii)). Because of age-dependent development, immune
system impairment, or other physiological differences, certain
populations (described in the following paragraphs) may have the
potential for a higher degree of risk or different risks compared to
the general population. The proposed health, safety, and welfare
criteria are especially important because, under the self-determined
exemption, FDA would not have an opportunity to evaluate potential
safety concerns before a proposed study begins.
    a. No subjects less than 12 months of age or who are pregnant or
lactating.
    To be eligible for the self-determined exemption, a proposed study
could not involve subjects less than 12 months of age or subjects who
are pregnant or lactating (proposed Sec.  312.2(b)(4)(v)(A)). We are
proposing this criterion because foods and cosmetics that would not
pose a safety concern in the general population may not be safe for
study in these vulnerable populations. For example, a study to evaluate
use of honey or a honey-containing product to prevent diarrhea in
subjects less than 12 months of age would pose a risk of botulism if
Clostridium botulinum spores were present in the honey. These medically
vulnerable populations pose special safety concerns typically requiring
that an investigation be conducted under the protections afforded by an
IND (although it is possible that a sponsor could show, in a request
for an FDA-determined exemption, that a particular investigation
involving such a population does not present a potential for
significant risk to subjects' health, safety, or welfare).
    b. No subjects with a compromised immune system or a serious or
life-threatening disease or condition.
    The self-determined exemption would not apply if a proposed study
included subjects with a compromised immune system or a serious or
life-threatening disease or condition (proposed Sec.
312.2(b)(4)(v)(B)). A person with an immune system impaired or weakened
by disease (e.g., diabetes, cancer), malnutrition, or drugs (e.g.,
chemotherapy) may be unable to fight off an infection. For example, a
study to evaluate use of a probiotic dietary supplement in adult
subjects to prevent nausea associated with chemotherapy might pose a
risk of mucormycosis due to fungal contamination of the probiotic.
    A ``serious'' disease or condition is one that is associated with
persistent or recurrent morbidity (a diseased condition or state) that
has substantial impact on day-to-day functioning; the morbidity need
not be irreversible to be ``serious'' if it is persistent or recurrent
(see Sec.  312.300(b)). FDA considers a disease or condition to be
``life-threatening'' if: (1) the likelihood of death is high unless the
course of the disease is interrupted or (2) the disease or condition
has a potentially fatal outcome (see Sec.  312.81(a)). For example, a
study to evaluate high doses of a vitamin in adults with insulin-
dependent diabetes might pose risks of worsening kidney or heart
function. Similarly, a study of the herbal product valerian, which
potentiates the effects of alcohol, could be dangerous in adults with
alcohol use disorder. Because the potential risks to subjects would
generally warrant that the investigation be conducted under the IND
requirements and their protections for subjects who have a serious or
life-threatening disease, a study of a food or

cosmetic to treat even a non-serious disease would not be eligible for
the self-determined exemption if the study included such subjects.
    c. Continuing treatments or therapies prescribed or recommended by
a healthcare provider.
    To be eligible for the self-determined exemption, the investigation
could not restrict the subjects of the study from continuing with any
treatment or therapy prescribed or recommended for them by a healthcare
provider (proposed Sec.  312.2(b)(4)(v)(C)). Healthcare providers could
include, for example, physicians, physician assistants, dentists,
physical therapists, and nurses. Being unable to continue a course of
treatment or therapy that one's physician, therapist, or other
healthcare provider has prescribed or recommended could significantly
increase risks for a subject; therefore, an investigation in which this
might occur usually warrants the protections of an IND.
    d. No study procedures that would increase the risks to subjects
beyond what are ordinarily encountered.
    Another proposed eligibility criterion for the self-determined
exemption is that the investigation not involve any procedures that
would increase the risks (or decrease the acceptability of the risks)
to subjects beyond what they would ordinarily encounter during a
routine physical or psychological examination or standard of care
procedures to treat their medical condition (proposed Sec.
312.2(b)(4)(v)(D)). For example, using an invasive technique such as a
biopsy to evaluate a study endpoint in subjects who ordinarily would be
monitored with routine blood tests might increase risks to the
subjects. Studies with the potential to expose subjects to greater risk
than they would normally encounter in the course of their clinical care
should not be conducted without an IND unless the sponsor can show (in
a request for an FDA-determined exemption) that no such increase in
risk will occur.
    e. Product used consistent with labeled or ordinary conditions of
use.
    Another proposed criterion for eligibility for the self-determined
exemption is that the product would have to be used in the
investigation consistent with its labeled conditions of use when
lawfully marketed as a food or cosmetic (Sec.  312.2(b)(4)(v)(E)). In
the absence of labeled conditions of use, the product would have to be
used consistent with its ordinary conditions of use as a lawfully
marketed food or cosmetic (e.g., same dose range and total daily
intake, same formulation, same duration of use). This eligibility
criterion would help ensure that a clinical investigation not conducted
under an IND does not pose significant risks to subjects due to
atypical use of the product.
    For a product that does not have labeled conditions of use, the
``ordinary'' conditions of use would be those found in a regulation
prescribing conditions of safe use (e.g., a food additive or color
additive regulation), if such a regulation exists. For products that do
not have a regulation prescribing conditions of safe use (such as
dietary supplements, cosmetics, and most conventional foods), the
``ordinary'' conditions of use could be those recommended in, for
example, the following: guidelines issued by the Department of Health
and Human Services, one of its components (such as the National
Institutes of Health), or another Federal Agency; recommendations from
a division of the National Academy of Sciences or the National Academy
of Medicine; publicly available websites of medical societies and
professional associations; and guidelines recognized by a professional
medical society or nutrition association. For example, although vitamin
D products may lack directions for use in children, the American
Academy of Pediatrics has issued recommendations on vitamin D
supplementation in children.
    f. No other product taken by or used to treat subjects during the
investigation would significantly increase the risks (or decrease
acceptability of the risks) encountered in the investigation.
    The last proposed eligibility criterion for the self-determined
exemption would limit the exemption to clinical investigations in which
the subjects are not taking and will not be treated with any other
product that would significantly increase the risks (or decrease the
acceptability of the risks) they will encounter in the investigation
(proposed Sec.  312.2(b)(4)(v)(F)). For example, drinking grapefruit
juice can increase the bioavailability of blood pressure-lowering drugs
in the body, and taking the herb ginseng can enhance the bleeding
effects of heparin, aspirin, and nonsteroidal anti-inflammatory drugs
such as ibuprofen (Ref. 2). Because administering a food or cosmetic as
an investigational drug to study subjects who are taking or are being
treated with another FDA-regulated product could significantly increase
risks to these subjects, such an investigation should not be conducted
without an IND unless the sponsor can show (in a request for an FDA-
determined exemption) that no such increase in risk will occur.
8. Application of the Self-Determined Exemption
    Under the proposed self-determined exemption, a sponsor would not
be required to submit a request to FDA for exemption from the IND
requirements. (Moreover, as discussed in section V.C of this document,
we would not accept an IND for an investigation that is exempt from the
IND requirements under the self-determined exemption.) If a sponsor
determines that its proposed study meets the eligibility criteria for
the exemption, the sponsor may proceed with the study without having to
submit an IND.
    If the sponsor later revises the protocol or otherwise changes the
study so that it no longer meets the eligibility criteria for the self-
determined exemption, the sponsor would have to submit an IND for the
study or a request for an FDA-determined exemption under proposed Sec.
312.2(b)(5). In addition, if FDA becomes aware (such as during an IRB
inspection or through communications from the sponsor, an investigator,
a subject, or the IRB) that a study conducted without an IND in
reliance on the self-determined exemption is ineligible for the
exemption, we may issue an untitled letter or warning letter to the
study sponsor and, if necessary, take appropriate enforcement action,
such as seeking an injunction.

B. FDA-Determined Exemption (Proposed Sec.  312.2(b)(5))

    Some proposed investigations to evaluate a drug use of a food or
cosmetic may not meet all the safety-related eligibility criteria for
the self-determined exemption, but FDA still might conclude, under
appropriate circumstances, that the study does not pose a significant
risk to the health, safety, or welfare of subjects. For example, even
in an investigation that included subjects with a serious disease, if
the product to be studied and the study procedures were low risk, we
might conclude, depending on other subject characteristics and the
intended use of the investigational product, that the study did not
present a potential for significant risk that would necessitate
conducting the study under an IND. For example, we might conclude that
an investigation evaluating the use of beetroot juice to mitigate,
treat, or prevent signs and symptoms of chronic kidney disease did not
present a potential for significant risk to subjects because, among
other factors, subjects would continue to receive standard of

care treatment for their disease. Therefore, we propose to establish an
``FDA-determined exemption'' under which a sponsor of a study that does
not meet one or more of the subject health, safety, and welfare
criteria for the self-determined exemption could request an IND
exemption from FDA.
1. Request for an Exemption
    Under the FDA-determined exemption, a sponsor could request that we
exempt from the IND requirements a clinical investigation to evaluate a
drug use of a product lawfully marketed in the United States as a food
or cosmetic when the investigation satisfies the requirements of the
self-determined exemption except for one or more of the criteria
related to the health, safety, or welfare of subjects (in proposed
Sec.  312.2(b)(4)(v)), but the sponsor has concluded that the study
nevertheless does not present a potential for significant risk to
subjects' health, safety, or welfare (proposed Sec.  312.2(b)(5)(i)).
The request would have to be in writing and would be required to
contain the following information.
    a. Study protocol or protocol summary.
    A request for an FDA-determined IND exemption for a drug study of a
food or cosmetic would be required to include a copy of the study
protocol or a detailed protocol summary that includes, at a minimum,
the following: the study design and duration; proposed endpoints; the
study population, including inclusion and exclusion criteria for
subjects; a description of the specific product to be studied as an
investigational drug, including ingredients, composition, and any
labeling; the dosage form, dosing regimen, and route of administration
of the investigational drug; the study procedures (including safety
monitoring procedures); and planned modifications to the protocol in
the event of adverse events (proposed Sec.  312.2(b)(5)(i)(A)). This
information about the proposed study is necessary to give FDA an
adequate context in which to assess the potential risks to subjects and
decide whether to exempt the study from the IND requirements.
    b. Names of manufacturer and source of product to be studied.
    A request for exemption would have to include the names of the
manufacturer and the entity that is the source of the specific product
to be studied in the investigation (proposed Sec.  312.2(b)(5)(i)(B)).
In cases where the product to be studied will be provided directly by
the manufacturer, the manufacturer and source of the investigational
product will be the same. However, in some cases, the investigational
product might be obtained from someone other than the manufacturer,
such as a distributor.
    For foods not in package form and not labeled with the name of the
manufacturer, the exemption request would only have to provide the
source of the product.
    c. Name and form of lawfully marketed food or cosmetic product;
labeling.
    A request for exemption would have to include the name (if
different from the name of the product to be studied in the
investigation) and form (e.g., conventional food, liquid, tablet,
lotion) of the lawfully marketed food or cosmetic product, and a copy
of the product labeling (proposed Sec.  312.2(b)(5)(i)(C)). If the
product's labeling does not identify its ingredients, the sponsor would
also be required to provide a description of the composition of the
product.
    d. Source(s) of funding for the investigation.
    A request for exemption would have to include the source(s) of
funding for the investigation (proposed Sec.  312.2(b)(5)(i)(D)). This
information is needed to help ensure that an investigation is not
intended to support a drug development plan for the product being
studied, which is a requirement for eligibility for the FDA-determined
exemption. For example, if an investigation is funded by the
manufacturer of the investigational product or by a trade association
representing the interests of firms that manufacture that type of
product, we would consider the funding source as a factor in
determining whether an investigation is intended to support a drug
development plan for the product.
    e. Information about the sponsor.
    A request for exemption would have to include the name, address,
telephone number, email address, and contact name for the sponsor
(proposed Sec.  312.2(b)(5)(i)(E)). This information will, among other
things, enable us to contact the sponsor if we have any questions and
to provide our response to the request.
    f. Description of why the investigation does not present a
potential for significant risk to the health, safety, or welfare of
subjects.
    A request for exemption would have to include a brief description
of why the investigation does not present a potential for significant
risk to the health, safety, or welfare of subjects, including, where
relevant, the following information regarding the subject health,
safety, and welfare eligibility criteria set out in the self-determined
exemption (proposed Sec.  312.2(b)(5)(i)(F)):
     If the proposed investigation includes subjects who are
less than 12 months of age or subjects who are pregnant or lactating,
the exemption request would have to include information to demonstrate
that the use of the investigational product does not present a
potential for significant risk to the health, safety, or welfare of
these subjects (proposed Sec.  312.2(b)(5)(i)(F)(1)).
     If the investigation includes subjects with a compromised
immune system or a serious or life-threatening disease or condition,
the exemption request would have to include information to demonstrate
that the use of the investigational product does not present a
potential for significant risk to the health, safety, or welfare of
these subjects (proposed Sec.  312.2(b)(5)(i)(F)(2));
     If participation in the investigation will preclude
subjects from continuing with a treatment or therapy prescribed or
recommended for them by a healthcare provider (e.g., if some subjects
randomized to the investigational product or placebo will be instructed
to discontinue their current treatment), the exemption request would
have to include an explanation of why this restriction would not
present a potential for significant risk to the health, safety, or
welfare of these subjects (proposed Sec.  312.2(b)(5)(i)(F)(3));
     If the subjects in the investigation will undergo any
procedures during the investigation that would expose them to more risk
than they would ordinarily encounter during routine physical or
psychological examinations or standard of care procedures to treat
their medical condition, the exemption request would have to include
information to demonstrate that the procedures do not present a
potential for significant risk to the health, safety, or welfare of
these subjects (proposed Sec.  312.2(b)(5)(i)(F)(4));
     If the proposed conditions of use of the product in the
investigation differ from the product's labeled or ordinary conditions
of use, the exemption request would have to include an explanation of
why the proposed conditions of use do not present a potential for
significant risk to the health, safety, or welfare of the subjects
(proposed Sec.  312.2(b)(5)(i)(F)(5)); and
     If the investigational product is being used concurrently
with other products that a subject is taking or being treated with,
either as part of the study or as prescribed or recommended by a
healthcare provider outside the study, the exemption request would have
to include information to demonstrate that the investigational product
has a history

of safe use with those products or is otherwise not expected to have
clinically significant interactions with the other products (proposed
Sec.  312.2(b)(5)(i)(F)(6)).
    g. Other information as requested by FDA.
    A request for exemption would have to include any other information
requested by FDA for use in reviewing the exemption request (proposed
Sec.  312.2(b)(5)(i)(G)). This means that the sponsor would have to
provide additional information if, upon reviewing the request, we found
that such information was necessary to determine whether the
investigation met the exemption criteria. For example, if a sponsor
provided insufficient information to explain why use of the
investigational product in a manner that differs from its labeled
conditions of use did not present a potential for significant risk to
subjects, we would ask for additional information to address concerns
about the different conditions of use.
2. Submitting a Request for Exemption
    A sponsor seeking an FDA-determined exemption would have to submit
a written request to CBER or CDER at the appropriate address set forth
in Sec.  312.140(a), which specifies where to send a new IND for a drug
or biological product (proposed Sec.  312.2(b)(5)(ii)). Sponsors should
consult the 2013 IND Guidance (or successor guidance) to find the
appropriate contact for inquiries about when the IND requirements apply
(see Ref. 1). The FDA components listed in the guidance may also be
consulted for help in determining the appropriate Center to which an
exemption request should be submitted.
3. FDA Action on a Request for Exemption
    Upon receiving a complete exemption request, FDA would evaluate any
risks to subjects that may result from participation in the clinical
investigation (proposed Sec.  312.2(b)(5)(iii)). We would grant an
exemption from the IND regulations if we found that the investigation
satisfied the requirements of Sec.  312.2(b)(4)(i) through (iv) and did
not present a potential for significant risk to the health, safety, or
welfare of the subjects. We would notify the sponsor in writing whether
the request for an FDA-determined exemption was granted. An exemption
granted under this provision would not become effective until the
sponsor received written notification that we had granted the
exemption.
4. FDA-Initiated Exemption
    In addition to permitting FDA to grant an exemption following the
request of a sponsor, the proposed rule would allow FDA to exempt a
study from the IND requirements if we determine, after reviewing an IND
for a study, that the study meets the decision criteria for an FDA-
determined exemption (i.e., the study meets the requirements in
proposed Sec.  312.2(b)(4)(i) through (iv) and the study does not
present a potential for significant risk to the health, safety, or
welfare of subjects). We believe there might be instances in which,
although a sponsor had submitted an IND for a study and had not
requested an exemption, we might conclude, upon reviewing the IND, that
the study meets the decision criteria for an FDA-determined exemption.
(We also might conclude that a study for which an IND has been
submitted meets all the criteria for a self-determined exemption. If
so, we would simply refuse to accept the IND under Sec.  312.2(b)(4)
(redesignated in the proposed rule as Sec.  312.2(b)(6)), as we do when
we receive an IND for a study of a lawfully marketed drug product that
meets the exemption criteria in Sec.  312.2(b)(1).) Exempting on our
own initiative a study that meets the criteria for an FDA-determined
exemption would reduce the regulatory burden on both the sponsor and
FDA without causing harm to the health, safety, or welfare of study
subjects. Therefore, proposed Sec.  312.2(b)(5)(iv) provides that FDA
may grant an exemption from the IND requirements on our own initiative
after reviewing an IND and determining that the clinical investigation
for which the IND was submitted satisfies the requirements of Sec.
312.2(b)(4)(i) through (iv) and does not present a potential for
significant risk to the health, safety, or welfare of subjects.
Proposed Sec.  312.2(b)(5)(iv) further states that if FDA decides to
grant an exemption under Sec.  312.2(b)(5)(iv), we will notify the
sponsor or sponsor-investigator of the exemption in writing, and that
the exemption will become effective when the sponsor or sponsor-
investigator receives written notification that we have granted the
exemption.
5. Revocation of an FDA-Determined Exemption
    Under proposed Sec.  312.2(b)(5)(v), we could revoke a previously
granted exemption (whether requested by a sponsor under proposed Sec.
312.2(b)(5)(i) or initiated by FDA under proposed Sec.
312.2(b)(5)(iv)) if we become aware of information suggesting that the
clinical investigation presents a potential for significant risk to the
health, safety, or welfare of study subjects, or that the investigation
does not meet any other requirement for the FDA-determined exemption
(such as the requirement that the route of administration of the
product in the investigation be the same as that of the lawfully
marketed product). For example, we might revoke an exemption if we
learn that subjects are experiencing clinically significant adverse
events associated with the investigational product or if we learn of an
interaction between the investigational product and another product
prescribed for or dispensed to study subjects. If we learn of something
that creates a potential for significant risk to subjects, we may
conclude that the study must be conducted in accordance with the IND
requirements to provide adequate protection to subjects. If we decided
to revoke an exemption, we would notify the sponsor of the reason for
revoking the exemption and, if appropriate, direct the sponsor to
suspend the investigation and/or cease recruiting new subjects to the
investigation.

C. Proposed Technical and Conforming Amendments

    In accordance with the proposed addition of the self-determined
exemption in Sec.  312.2(b)(4) and the FDA-determined exemptions in
Sec.  312.2(b)(5), we propose to renumber the existing provisions in
Sec.  312.2(b)(4) through (b)(6) as Sec.  312.2(b)(6) through (b)(8).
    We also propose to make a conforming amendment to existing Sec.
312.2(b)(4) (to be renumbered as Sec.  312.2(b)(6)), which states that
FDA will not accept an application (IND) for an investigation that is
exempt from the IND requirements under Sec.  312.2(b)(1). We propose to
include investigations exempted under the self-determined and FDA-
determined exemption provisions among those for which we will not
accept an IND.

VI. Proposed Effective Date

    We propose that any final rule resulting from this rulemaking
become effective 30 days after the date of its publication in the
Federal Register.

VII. Preliminary Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563

direct us to assess all costs and benefits of available regulatory
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety, and other advantages;
distributive impacts; and equity). We believe that this proposed 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. Because this proposed rule would create net cost savings for
the affected industry by reducing the number of INDs that must be
submitted to FDA, 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 $165 million, using the most current (2021) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.

B. Summary of Costs and Benefits

    Quantifiable benefits of this proposed rule are cost savings that
come from reducing the burden of submitting INDs to FDA for clinical
investigations evaluating drug uses of foods for human consumption
(including dietary supplements) and cosmetics. The cost savings go to
sponsors and sponsor-investigators (collectively, ``sponsors''),
typically physicians and other researchers at hospitals and academic
institutions, who would no longer need to submit as many INDs because
the proposed rule provides exemptions for qualifying drug studies of
products lawfully marketed as a food or cosmetic. The proposed rule
would also provide cost savings to FDA, which would not need to
evaluate and monitor as many INDs. We expect the average present value
of the benefits to be $28 million at a 7 percent discount rate and $34
million at a 3 percent discount rate over a 10-year time horizon.
    If this proposed rule is finalized, sponsors would incur a one-time
cost because they, or lawyers or consultants acting on their behalf,
would have to spend time reading the rule to understand what studies
are eligible for exemption and how to request an FDA-determined
exemption. We estimate that 557 sponsors would read the rule the first
year and 279 additional sponsors would read the rule in subsequent
years. We estimate the cost of reading the rule to be $153 per sponsor.
We expect the average present value of the reading cost to be $418,000
at a 3 percent discount rate and $364,000 at a 7 percent discount rate
over a 10-year time horizon. In addition, there would be costs to FDA
associated with a new type of IND-related submission, a request for an
FDA-determined exemption. We have analyzed this cost as a partial
offset to the cost savings of the rule. The total net benefit of the
rule is estimated to be $33 million at a 3 percent discount rate and
$27 million at a 7 percent discount rate.
    Table 1 provides annualized values for the estimated benefits and
costs of the proposed rule:

                                     Table 1--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                         Primary        Low         High    ------------------------------------
               Category                  estimate     estimate    estimate      Year      Discount     Period                     Notes
                                                                               dollars    rate  (%)    covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized/year........   $3,450,000   ($850,000)  $7,730,000        2021           7          10  Cost savings to FDA and industry.
                                         3,530,000    (780,000)  $7,840,000        2021           3          10
                                      ------------------------------------------------------------------------------------------------------------------
    Annualized Quantified............  ...........  ...........  ..........  ..........  ..........           7  .......................................
                                       ...........  ...........  ..........  ..........  ..........           3  .......................................
                                      ------------------------------------------------------------------------------------------------------------------
    Qualitative......................

--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized/year........       45,300       15,700      77,800        2021           7          10  .......................................
                                            43,800       15,100      75,700        2021           3          10  .......................................
    Annualized Quantified............  ...........  ...........  ..........  ..........           7  ..........  .......................................
                                       ...........  ...........  ..........  ..........           3  ..........  .......................................
                                      ------------------------------------------------------------------------------------------------------------------
    Qualitative......................

--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized Monetized/year  ...........  ...........  ..........  ..........           7  ..........  .......................................
                                       ...........  ...........  ..........  ..........           3              .......................................
                                      ------------------------------------------------------------------------------------------------------------------
    From/To..........................   From:
                                        To:                                           3
                                      ------------------------------------------------------------------------------------------------------------------
    Other Annualized Monetized/year..  ...........  ...........  ..........  ..........           7  ..........  .......................................
                                       ...........  ...........  ..........  ..........           3  ..........  .......................................
                                      ------------------------------------------------------------------------------------------------------------------
    From/To..........................  From:
                                       To:                                            3
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government:..................................................................................................................
    Small Business:.....................................................................................................................................
    Wages:..............................................................................................................................................
    Growth:.............................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. This full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 3) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. Analysis of Environmental Impact

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

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). This
analysis provides a description of these provisions and an estimate of
the annual reporting burden associated with the proposed rule. Included
in the estimate is the time for reviewing instructions, searching
existing data sources, gathering and maintaining the data needed, and
completing and reviewing each collection of information.
    FDA invites comments on these topics: (1) whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Exemptions from IND Requirements for Certain Clinical
Investigations to Evaluate a Drug Use of a Product Lawfully Marketed as
a Food (Including a Dietary Supplement) or Cosmetic (Revision to
Investigational New Drug (IND) Regulations--OMB Control Number 0910-
0014).
    Description: The proposed rule would revise FDA's IND regulations
to exempt from the IND requirements certain clinical investigations of
foods for human consumption (including dietary supplements) or
cosmetics. For one type of proposed exemption, respondents must submit
a written request to FDA electronically or in paper form.
    Description of Respondents: Respondents to the information
collection are individuals and organizations who plan to conduct or
sponsor a clinical investigation evaluating a drug use of a product
lawfully marketed in the United States as a conventional food, dietary
supplement, or cosmetic for human use.
    The reporting and recordkeeping requirements in part 312 provide
the means by which FDA can monitor clinical investigations of the
safety and effectiveness of unapproved new drugs and biological
products. Information provided by applicants (sponsors and sponsor-
investigators) allows us to monitor the safety of ongoing clinical
investigations as well as help ensure the reliability and quality of
data submitted in support of drug marketing applications. While the
regulations provide an exemption from most IND requirements for studies
of lawfully marketed drug products that meet certain criteria,
including that the study does not involve a route of administration,
dosage level, use in a patient population, or other factor that
significantly increases the risks associated with the use of the drug
product (see Sec.  312.2(b)(1)), the proposed rule would codify IND
exemptions for clinical studies investigating drug uses of lawfully
marketed foods for human consumption or cosmetics.
    We estimate the burden of the information collection for the
proposed rule as follows:

                                                     Table 2--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
                            21 CFR part                                 Number of      responses per    Total  annual   Average  burden    Total  hours
                                                                       respondents       respondent       responses      per  response
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.2(b)(5); Written request for exemption.........................              28                1               28               24              672
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    The proposed rule would create two types of IND exemptions for
clinical investigations to evaluate drug uses of products lawfully
marketed for human use in the United States as conventional foods,
dietary supplements, or cosmetics. Under proposed Sec.  312.2(b)(4) and
(5), respondents could qualify for, respectively, either a ``self-
determined exemption'' or an ``FDA-determined exemption'' from the IND
requirements, provided certain criteria were met. Under the self-
determined exemption, if an investigation met the requirements for the
exemption, the sponsor or sponsor-investigator would not have to submit
an IND for the study or request that FDA exempt the study from the IND
requirements. To obtain an FDA-determined exemption, a sponsor or
sponsor-investigator would submit a written request for exemption that
includes a copy of the study protocol or a detailed protocol summary
with information about the study design, investigational product, and
procedures; the names of the manufacturer and source of the product to
be studied; the name (if different from the name of the product to be
studied in the investigation) and form of the lawfully marketed food or
cosmetic product, accompanied by a copy of the product's labeling and,
if the labeling does not list the product's ingredients, a description
of the product's composition; the source(s) of funding for the
investigation; the name, address, telephone number, email address, and
contact name for the sponsor or sponsor-investigator; a brief
description of why the investigation does not present a potential for
significant risk to the health, safety, or welfare of subjects; and any
other information requested by FDA.\1\
---------------------------------------------------------------------------

    \1\ The proposed rule also would authorize FDA to grant an
exemption from the IND requirements on our own initiative when we
determined, upon review of an IND for a study, that the study met
the decision criteria for an FDA-determined exemption. However, as
with the self-determined exemption, this FDA-initiated exemption
would not impose any burden on sponsors or sponsor-investigators.
---------------------------------------------------------------------------

    As shown in table 2, we estimate that 28 total sponsors and
sponsor-investigators will submit requests for exemption annually and
that preparing a request will take approximately 24 hours. The
Preliminary Economic Analysis of Impacts for the proposed rule (Ref. 3)
estimates that, of the 322 clinical investigations of foods

(including dietary supplements) or cosmetics that were the subject of
INDs or IND-related inquiries received between 2016 and 2020, we likely
would have granted an FDA-determined exemption for 68 studies
(approximately 14 each year) had the proposed rule been in effect and
the exemption requests been submitted. Because we believe that
codifying the FDA-determined exemption in the regulations would make
sponsors and sponsor-investigators more likely to seek an exemption, we
have doubled the figure of 14 investigations, resulting in an estimated
28 requests for an FDA-determined exemption each year. The estimated
time for preparation of a request, 24 hours, is based on the time
needed to assemble the information required to be included in the
request and describe why the investigation does not present a potential
for significant risk to the health, safety, and welfare of subjects. We
believe this burden is comparable to the burden associated with
preparing a request for advice on whether the IND requirements apply to
a planned clinical investigation under Sec.  312.2(e), which we have
estimated to be 24 hours (84 FR 3462 at 3463, February 12, 2019).
However, we invite comment on the accuracy of this estimate.
    Although the proposed procedure for requesting an FDA-determined
exemption would create a new reporting element for exemption requests,
the proposed rule would likely also reduce burden associated with
requesting FDA advice on the applicability of the IND regulations to
particular clinical investigations under Sec.  312.2(e). Amending the
IND regulations to exempt certain clinical investigations of foods and
cosmetics would reduce the need for consulting FDA in this regard
because sponsors and sponsor-investigators who use one of the new
exemption pathways would not need to use the Sec.  312.2(e) mechanism
to ask FDA's advice on whether an IND is required for their clinical
investigations to evaluate a drug use of such products.
    To ensure that comments on this information collection are
received, OMB recommends that written comments be through reginfo.gov
(see ADDRESSES). All comments should be identified with the title of
the information collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), we have submitted the information collection provisions of
this proposed rule to OMB for review. These information collection
requirements will not be effective until FDA publishes a final rule,
OMB approves the information collection requirements, and the rule goes
into effect. FDA will announce OMB approval of these requirements in
the Federal Register.

X. Federalism

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
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 proposed 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 proposed 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. We invite comments from tribal officials
on any potential impact on Indian Tribes from this proposed action.

XII. References

    The following references are on display in 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. FDA, ``Guidance for Clinical Investigators, Sponsors, and
Institutional Review Boards (IRBs) on Investigational New Drug
Applications--Determining Whether Human Research Studies Can Be
Conducted Without an IND'', available at https://www.fda.gov/media/79386/download.
2. FDA Consumer Update, ``Avoiding Drug Interactions'', available at
https://www.fda.gov/consumers/consumer-updates/avoiding-drug-interactions.
3. FDA, Preliminary Economic Analysis of Impacts, Docket No. FDA-
2019-N-2650, available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects in 21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.

    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 part 312 be amended as follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
1. The authority citation for part 312 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371;
42 U.S.C. 262.

0
2. Amend Sec.  312.2 by:
0
a. Redesignating paragraphs (b)(4) through (6) as paragraphs (b)(6)
through (8);
0
b. Revising newly redesignated paragraph (b)(6); and
0
c. Adding new paragraphs (b)(4) and (5).
    The revision and additions read as follows:

Sec.  312.2  Applicability.

* * * * *
    (b) * * *
    (4) A clinical investigation to evaluate a drug use of a product
that is lawfully marketed in the United States as a food intended for
human consumption (including as a conventional food or dietary
supplement) or as a cosmetic, is exempt from the requirements of this
part if all of the following apply:
    (i) The investigation is not intended to support:
    (A) A drug development plan for the product, including a future IND
or application for marketing approval (an application under section 505
of the Federal Food, Drug, and Cosmetic Act or section 351 of the
Public Health Service Act); or
    (B) A change in the labeling of the lawfully marketed product that
would cause it to become an unlawfully marketed drug;
    (ii) The investigation is conducted in compliance with the
requirements for institutional review set forth in part 56 of this
title and the requirements for informed consent set forth in part 50 of
this title;
    (iii) The investigation is conducted in compliance with the
requirements of Sec.  312.7;
    (iv) The route of administration of the product in the
investigation is the same as that of the lawfully marketed product; and

    (v) The investigation meets all of the following criteria:
    (A) The investigation does not include subjects who are less than
12 months of age or subjects who are pregnant or lactating;
    (B) The investigation does not include subjects with a compromised
immune system or a serious or life-threatening disease or condition;
    (C) The investigation does not restrict subjects from continuing
with treatments or therapies prescribed or recommended by a healthcare
provider;
    (D) The investigation does not involve any procedures that would
increase the risks (or decrease the acceptability of the risks) to
subjects beyond what they would ordinarily encounter during routine
physical or psychological examinations or standard of care procedures
to treat their medical condition;
    (E) The product is being used in the investigation consistent with
its labeled conditions of use when lawfully marketed as a food or
cosmetic or, in the absence of labeled conditions of use, consistent
with its ordinary conditions of use as a lawfully marketed food or
cosmetic (e.g., same dose range and total daily intake, same
formulation, same duration of use); and
    (F) During the investigation, subjects are not taking and will not
be treated with any other product(s) that would significantly increase
the risks (or decrease the acceptability of the risks) they will
encounter in the investigation (e.g., from drug interactions).
    (5)(i) A sponsor or sponsor-investigator may request that FDA
exempt from the requirements of this part a clinical investigation to
evaluate a drug use of a product that is lawfully marketed in the
United States as a food intended for human consumption (including as a
conventional food or dietary supplement) or as a cosmetic, when the
investigation satisfies the requirements of paragraphs (b)(4)(i)
through (iv) of this section, but not paragraph (b)(4)(v) of this
section, and the sponsor or sponsor-investigator has concluded that the
investigation does not present a potential for significant risk to the
health, safety, or welfare of subjects. Such requests must be made in
writing and must contain the following:
    (A) A copy of the study protocol or protocol summary that includes,
at a minimum, the following:
    (1) Study design;
    (2) Proposed endpoints;
    (3) Study population, including inclusion and exclusion criteria
for subjects;
    (4) Duration of the study;
    (5) Description of the product to be studied as an investigational
drug, including ingredients, composition, and any labeling;
    (6) Dosage form, dosing regimen, and route of administration of the
investigational drug;
    (7) Study procedures (including safety monitoring procedures); and
    (8) Planned modifications to the protocol in the event of adverse
events.
    (B) The names of the manufacturer and of the entity that is the
source of the product to be studied in the investigation. For foods not
in package form and not labeled with the name of the manufacturer, only
the source of the product is required;
    (C) The name (if different from the name of the product to be
studied in the investigation) and form of the lawfully marketed food or
cosmetic product; a copy of the product labeling; and, if the labeling
does not identify the ingredients of the lawfully marketed product, a
description of the product's composition;
    (D) The source(s) of funding for the investigation;
    (E) The name, address, telephone number, email address, and contact
name for the sponsor or sponsor-investigator;
    (F) A brief description of why the investigation does not present a
potential for significant risk to the health, safety, or welfare of
subjects, including, where relevant, the following information to
justify an exemption:
    (1) If the investigation includes subjects who are less than 12
months of age or subjects who are pregnant or lactating, information to
demonstrate that the use of the product in the investigation does not
present a potential for significant risk to the health, safety, or
welfare of these subjects;
    (2) If the investigation includes subjects with a compromised
immune system or a serious or life-threatening disease or condition,
information to demonstrate that the use of the product in the
investigation does not present a potential for significant risk to the
health, safety, or welfare of these subjects;
    (3) If participation in the investigation will preclude subjects
from continuing with a treatment or therapy prescribed or recommended
for them by a healthcare provider (e.g., if some subjects are
randomized to the investigational product or placebo instead of their
current treatment), an explanation of why this restriction does not
present a potential for significant risk to the health, safety, or
welfare of these subjects;
    (4) If the subjects in the investigation will undergo any
procedures during the investigation that would expose them to more risk
than they would ordinarily encounter during routine physical or
psychological examinations or standard of care procedures to treat
their medical condition, information to demonstrate that the procedures
do not present a potential for significant risk to the health, safety,
or welfare of these subjects;
    (5) If the proposed conditions of use of the product in the
investigation differ from the product's labeled or ordinary conditions
of use, an explanation of why the proposed conditions of use do not
present a potential for significant risk to the health, safety, or
welfare of the subjects; and
    (6) If the investigational product is being used concurrently with
other products that the subject is taking or being treated with as part
of the study or for other reasons as prescribed or recommended by a
healthcare provider, information to demonstrate that the
investigational product has a history of safe use with those products
or is otherwise not expected to have clinically significant
interactions with the other products; and
    (G) Any other information requested by FDA for use in reviewing the
exemption request.
    (ii) A sponsor or sponsor-investigator requesting an exemption
under paragraph (b)(5)(i) of this section must submit the request to
the Center for Drug Evaluation and Research or the Center for Biologics
Evaluation and Research at the appropriate address set forth in Sec.
312.140(a).
    (iii) Upon receiving an exemption request under paragraph (b)(5)(i)
of this section, FDA will evaluate any risks to subjects that may
result from participation in the clinical investigation and will grant
an exemption from the requirements of this part if we find that the
investigation satisfies the requirements of paragraphs (b)(4)(i)
through (iv) of this section and does not present a potential for
significant risk to the health, safety, or welfare of the subjects. FDA
will notify the sponsor or sponsor-investigator in writing whether the
request for exemption is granted. An exemption will become effective
when the sponsor or sponsor-investigator receives written notification
that we have granted the exemption.
    (iv) FDA may grant an exemption from the requirements of this part
on our own initiative after reviewing an IND and determining that the
clinical investigation for which the IND was submitted satisfies the
requirements of

paragraphs (b)(4)(i) through (iv) of this section and does not present
a potential for significant risk to the health, safety, or welfare of
the subjects. If FDA grants such an exemption, we will notify the
sponsor or sponsor-investigator of the exemption in writing. The
exemption will become effective when the sponsor or sponsor-
investigator receives written notification that we have granted the
exemption.
    (v) FDA may revoke an exemption granted under paragraph (b)(5)(iii)
or (iv) of this section if we become aware of information suggesting
that the clinical investigation could present a potential for
significant risk to the health, safety, or welfare of subjects, or that
the investigation does not meet any requirement in paragraphs (b)(4)(i)
through (iv) of this section. FDA will notify the sponsor or sponsor-
investigator who received the exemption of the reason for revoking the
exemption and, if appropriate, may direct the sponsor or sponsor-
investigator to suspend the investigation and/or cease recruiting new
subjects to the investigation.
    (6) FDA will not accept an application for an investigation that is
exempt under the provisions of paragraph (b)(1), (b)(4), or (b)(5) of
this section.
* * * * *

    Dated: November 28, 2022.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2022-26728 Filed 12-8-22; 8:45 am]
BILLING CODE 4164-01-P