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, 75536-75551 [2022-26728]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 87, Number 236 (Friday, December 9, 2022)]
[Proposed Rules]
[Pages 75536-75551]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-26728]



[[Page 75536]]

=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    Submit comments on 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.''

[[Page 75537]]


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, 301-796-4614, [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, 301-796-5733, 
[email protected].

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations 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

[[Page 75538]]

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

------------------------------------------------------------------------
       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

[[Page 75539]]

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

[[Page 75540]]

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

[[Page 75541]]

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.''

[[Page 75542]]

    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

[[Page 75543]]

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

[[Page 75544]]

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

[[Page 75545]]

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

[[Page 75546]]

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

[[Page 75547]]

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:.............................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------


[[Page 75548]]

    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

[[Page 75549]]

(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

[[Page 75550]]

    (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

[[Page 75551]]

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