Proposed Rule2026-19349
Nonclinical Testing Terminology
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
September 22, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, Agency, or we) is proposing to substitute references to "animal" tests or studies with "nonclinical" tests or studies, add a definition of the terms "nonclinical test" and "nonclinical study," and make other comparable or conforming amendments in certain safety and reporting sections of its regulations. The proposed rule would also substitute "nonclinical" for "preclinical" and "in vitro" for consistency in terminology. These proposed amendments align with recent amendments to the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act) and are intended to remove an emphasis, in certain places, on the use of animal testing as the only scientific methodology to assess the safety of a drug in the nonclinical setting. These changes may also foster the development and use of scientifically valid new testing methodologies, potentially improving predictive accuracy of product safety testing while replacing, reducing, or refining animal use. The proposed rule would add no new requirements.
Full Text
<html>
<head>
<title>Federal Register, Volume 91 Issue 182 (Tuesday, September 22, 2026)</title>
</head>
<body><pre>
[Federal Register Volume 91, Number 182 (Tuesday, September 22, 2026)]
[Proposed Rules]
[Pages 60036-60051]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-19349]
[[Page 60036]]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 312, 314, 315, 361, and 601
[Docket No. FDA-2026-N-5347]
RIN 0910-AJ27
Nonclinical Testing Terminology
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
proposing to substitute references to ``animal'' tests or studies with
``nonclinical'' tests or studies, add a definition of the terms
``nonclinical test'' and ``nonclinical study,'' and make other
comparable or conforming amendments in certain safety and reporting
sections of its regulations. The proposed rule would also substitute
``nonclinical'' for ``preclinical'' and ``in vitro'' for consistency in
terminology. These proposed amendments align with recent amendments to
the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public
Health Service Act (PHS Act) and are intended to remove an emphasis, in
certain places, on the use of animal testing as the only scientific
methodology to assess the safety of a drug in the nonclinical setting.
These changes may also foster the development and use of scientifically
valid new testing methodologies, potentially improving predictive
accuracy of product safety testing while replacing, reducing, or
refining animal use. The proposed rule would add no new requirements.
DATES: Either electronic or written comments on the proposed rule or
its companion direct final rule must be submitted by December 7, 2026.
If FDA receives any timely significant adverse comments on this
proposed rule or the direct final rule with which this proposed rule is
associated, we will publish a document in the Federal Register
withdrawing the direct final rule within 30 days after the comment
period ends, and we will then proceed to respond to comments under this
proposed rule using the usual notice and comment procedures.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of December 7, 2026. 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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-2026-N-5347 for ``Nonclinical Testing Terminology.'' 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> 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.'' We will review
this copy, including the claimed confidential information, in our
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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:
<a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents, the
plain language summary of the proposed rule of not more than 100 words
as required by the ``Providing Accountability Through Transparency
Act,'' or the electronic and written/paper comments received, go to
<a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in
brackets in the heading of this document, into the ``Search'' box and
follow the prompts and/or go to the Dockets Management Staff, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Shena Arellano, Office of Policy,
Office of Policy, Legislation, and International Affairs, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, 301-
796-8353.
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. Companion Document To Direct Final Rulemaking
III. Table of Abbreviations/Commonly Used Acronyms in This Document
IV. Background
A. Need for the Regulation
[[Page 60037]]
B. FDA's Current Regulatory and Policy Framework
V. Description of the Proposed Rule
A. Amendment of Part 312--Investigational New Drug Application
1. Section 312.3(b)
2. Section 312.22
3. Section 312.23(a)(3)
4. Section 312.23(a)(5)(ii)
5. Section 312.23(a)(5)(iii)
6. Section 312.23(a)(8)
7. Section 312.23(a)(8)(i)
8. Section 312.23(a)(8)(ii)(a)
9. Section 312.23(a)(10)(i)
10. Section 312.23(a)(10)(ii)
11. Section 312.32(b)
12. Section 312.32(c)(1)(iii)
13. Section 312.32(c)(1)(v)
14. Section 312.33(b)(6)
15. Section 312.82
16. Section 312.82(a)
17. Section 312.86
18. Section 312.88
B. Amendment of Part 314--Applications for FDA Approval To
Market a New Drug
1. Section 314.3(b)
2. Section 314.50(d)(2)
3. Section 314.50(d)(2)(iv)
4. Section 314.50(d)(4)(ii)
5. Section 314.50(d)(5)(i)
6. Section 314.50(d)(5)(vi)(a)
7. Section 314.50(d)(5)(vi)(b)
8. Section 314.81(b)(2)(v)
9. Section 314.81(b)(2)(vii)(a)(7)
10. Section 314.93
11. Section 314.200(d)(3)
12. Section 314.430(a)
C. Amendment of Part 315--Diagnostic Radiopharmaceuticals
1. Section 315.2
2. Section 315.6(c)(2)
3. Section 315.6(d)
D. Amendment of Part 361--Prescription Drugs for Human Use
Generally Recognized as Safe and Effective and Not Misbranded: Drugs
Used in Research
1. Section CFR 361.1(d)(7)
E. Amendment of Part 601--Licensing
1. Section 601.31
2. Section 601.35(c)(2)
3. Section 601.35(d)
4. Section 601.70(b)(7)
VI. Economic Analysis of Impacts
A. Introduction
B. Overview of Benefits, Costs, and Transfers
VII. Analysis of Environmental Impact
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. Consultation and Coordination With Indian Tribal Governments
XI. References
I. Executive Summary
A. Purpose of the Proposed Rule
FDA recognizes that some provisions of its human drug and
biological product safety testing and reporting regulations refer only
to the use of animal tests where alternatives may be available. FDA is
updating these regulations by replacing the terms ``animal test'' and
``animal study'' with ``nonclinical test'' or ``nonclinical study,''
terms which are defined to encompass a broad variety of tests or
studies in addition to animal testing, including scientifically valid
new approach methodologies (NAMs) that do not use animals. NAMs have
the potential to improve predictivity while replacing, reducing, or
refining the use of animal testing for evaluating medical product
safety. For consistency in terminology, we are also substituting the
term ``nonclinical'' for the terms ``preclinical'' and ``in vitro.'' We
also replace ``animal'' with ``nonclinical'' in regulations that use
the terms ``animal testing,'' ``animal data,'' ``animal findings'' and
``animal models'' to refer to testing, data, findings and models that
are performed with, derived from, or made using nonclinical tests or
studies.
This proposed rule is a companion to the direct final rule
published elsewhere in this issue of the Federal Register. This
proposed rule provides the procedural framework to finalize the rule in
the event the direct final rule receives any significant adverse
comment and is withdrawn. The comment period for this companion
proposed rule runs concurrently with the comment period for the direct
final rule. Any comments received in response to this companion
proposed rule will also be considered as comments regarding the direct
final rule.
B. Summary of the Major Provisions of the Proposed Rule
This proposed rule would substitute the terms ``nonclinical test''
or ``nonclinical study'' for the terms ``animal test,'' ``animal
study,'' ``preclinical test,'' and ``in vitro test,'' and make other
comparable or conforming changes in sections addressing human drug and
biological product safety and reporting within parts 312, 314, 315, 361
and 601 of Title 21 of the Code of Federal Regulations (21 CFR). It
would also add a definition for ``nonclinical test'' and ``nonclinical
study'' to part 312 and a definition for ``nonclinical study'' to parts
314, 315, 361, and 601. The proposed definitions are adapted from the
definition of ``nonclinical test'' in section 505(z) of the FD&C Act
(21 U.S.C. 355(z)).\1\
---------------------------------------------------------------------------
\1\ Section 505(z) of the FD&C Act was added by section 3209 of
the Food and Drug Omnibus Reform Act of 2022 (FDORA), which was
enacted as part of the Consolidated Appropriations Act, 2023. Public
Law 117-328, Div. FF, Title III, Sec. Sec. 3001-3631 (2022).
---------------------------------------------------------------------------
C. Legal Authority
This rulemaking is based on FDA's authority under the FD&C Act (21
U.S.C. 301 et seq.) and the PHS Act (42 U.S.C. 201 et seq.). By
delegation from the Secretary of the Department of Health and Human
Services, FDA is authorized to issue regulations for the efficient
enforcement of the FD&C Act (section 701; 21 U.S.C. 371), including
provisions addressing the regulation of drug products to ensure their
safety and effectiveness, and to regulate biological products to ensure
that they are safe, effective, pure, and potent (PHS Act section 351;
42 U.S.C. 262). This proposed rule will help with the efficient
enforcement of provisions relating to the following: (1)
investigational use of human drugs and biological products and (2)
safety of human drugs and biological products.
D. Costs and Benefits
This proposed rule would substitute ``nonclinical'' for ``animal''
in phrases like ``animal test'' and ``animal study;'' substitutes
``nonclinical'' for ``preclinical'' and ``in vitro'' for consistency in
terminology; and add a definition of ``nonclinical test'' and
``nonclinical study'' to the definitions section of several of FDA's
drug and biological product regulations. If finalized as proposed, this
rule would impose no new requirements on industry and so is expected to
generate no costs. The proposed amendments may foster the development
and use of scientifically valid new testing methodologies and so may
yield benefits, but we do not anticipate being able to quantify these
benefits. Since this proposed rule would update terminology to
unambiguously allow for a broader range of nonclinical studies to meet
current requirements without limiting existing options or imposing new
requirements, we conclude this proposed rule is classifiable as an
Executive Order 14192 deregulatory action.
II. Companion Document To Direct Final Rulemaking
This proposed rule is a companion to the direct final rule
published elsewhere in this issue of the Federal Register. This
companion proposed rule provides the procedural framework to finalize
the rule in the event the direct final rule receives any significant
adverse comment and is withdrawn. The comment period for this companion
proposed rule runs concurrently with the comment period for the direct
final rule. Any comments received in response to this companion
proposed rule will also be considered as comments regarding the direct
final rule. FDA is publishing the direct final rule because we believe
the rule
[[Page 60038]]
contains noncontroversial changes and there is little likelihood that
there will be significant adverse comments on the rule.
A significant adverse comment is defined as a comment that explains
why the rule would be inappropriate, including challenges to the rule's
underlying premise or approach, or would be ineffective or unacceptable
without a change. In determining whether an adverse comment is
significant and warrants terminating a direct final rulemaking, we will
consider whether the comment raises an issue serious enough to warrant
a substantive response in a notice-and-comment process. Comments that
are frivolous, insubstantial, or outside the scope of the rule will not
be considered significant or adverse under this procedure. A comment
recommending a regulation change in addition to those in the direct
final rule and proposed in this rule would not be considered a
significant adverse comment unless the comment states why the
regulatory change would be ineffective without the additional change.
In addition, if a significant adverse comment applies to a part of the
direct final rule and that part can be severed from the remainder of
the rule, we may adopt as final those provisions of the rule that are
not the subject of the significant adverse comment.
If any significant adverse comments to the direct final rule or
this proposed rule are received during the comment period, FDA will
publish in the Federal Register, within 30 days after the comment
period ends, a notice of significant adverse comment and withdraw the
direct final rule. If we withdraw the direct final rule, any comments
received will be considered comments on the proposed rule and will be
considered in developing a final rule using the usual notice-and-
comment procedure.
If no significant adverse comment is received in response to the
direct final rule of this proposed rule during the comment period, no
further action will be taken related to this proposed rule. Instead, we
will publish a document confirming the effective date of the final rule
within 30 days after the comment period ends. Additional information
about direct final rulemaking procedures is set forth in the document
entitled ``Guidance for FDA and Industry: Direct Final Rule
Procedures,'' announced and provided in the Federal Register of
November 21, 1997 (62 FR 62466). The guidance may be accessed at
<a href="https://www.fda.gov/RegulatoryInformation/Guidances/ucm125166.htm">https://www.fda.gov/RegulatoryInformation/Guidances/ucm125166.htm</a>.
If FDA receives no significant adverse comments during the
specified comment period, FDA intends to publish a document confirming
the effective date within 30 days after the comment period ends.
III. Table of Abbreviations/Commonly Used Acronyms in This Document
------------------------------------------------------------------------
Abbreviation/acronym What it means
------------------------------------------------------------------------
BLA............................... Biologics License Application.
CFR............................... Code of Federal Regulations.
DDT............................... Drug Development Tools.
FD&C Act.......................... Federal Food, Drug, and Cosmetic
Act.
FDA or Agency..................... Food and Drug Administration.
FDORA............................. Food Drug Omnibus Reform Act.
GST............................... General Safety Test.
ICCVAM............................ Interagency Coordinating Committee
on the Validation of Alternative
Methods.
ICH............................... International Council for
Harmonisation of Technical
Requirements for Pharmaceuticals
for Human Use.
IND............................... Investigational New Drug
Application.
ISTAND............................ Innovative Science and Technology
Approaches for New Drugs.
MDDT.............................. Medical Device Development Tools.
NAMs.............................. New Approach Methodologies.
NDA............................... New Drug Application.
OECD.............................. Organisation for Economic Co-
operation and Development.
OIRA.............................. Office of Information and Regulatory
Affairs.
PDUFA............................. Prescription Drug User Fee Act.
PHS Act........................... Public Health Service Act.
U.S.C............................. United States Code.
------------------------------------------------------------------------
IV. Background
A. Need for the Regulation
Currently, some human drug and biological product regulations refer
to animal studies or tests. For example, section 312.88 states that
safeguards for patient safety ``include the review of animal studies
prior to initial human testing.'' However, the Food and Drug Omnibus
Reform Act (FDORA) amended Section 505(i) of the FD&C Act by replacing
the term ``preclinical tests (including tests on animals)'' in
paragraph (1)(A) and ``animal'' in paragraph (2)(B) with the term,
``nonclinical tests.'' FDORA section 3209(a)(1)-(2). It also added a
definition of ``nonclinical test'' to Section 505(z) of the FD&C Act
\2\ to mean:
---------------------------------------------------------------------------
\2\ Two subsecs. (z) have been enacted in Section 505. Both were
enacted in the Consolidated Appropriations Act, 2023 (Pub. L. 117-
328).
---------------------------------------------------------------------------
[A] test conducted in vitro, in silico, or in chemico, or a
nonhuman in vivo test that occurs before or during the clinical trial
phase of the investigation of the safety and effectiveness of a drug.
Such test may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests.
FDORA section 3209(a)(2). FDORA also amended item (bb) of section
351(k)(2)(A)(i)(I) of the PHS Act (42 U.S.C. 262(k)(2)(A)(i)(I)) to
replace ``animal studies (including assessment of toxicity)'' with ``an
assessment of toxicity (which may rely on, or consist of, a study or
studies described in item (aa) or (cc)).'' The studies described in
items (aa) and (cc) include analytical studies that demonstrate that
the biological product is highly similar to the reference product
notwithstanding minor differences in clinically inactive components,
and clinical studies (including the assessment of immunogenicity and
pharmacokinetics or pharmacodynamics) that are sufficient to
demonstrate safety, purity,
[[Page 60039]]
and potency under certain conditions of use.
This proposed rule would align the terminology used in FDA's drug
and biological product regulations more closely with the FD&C Act
amendments made by FDORA and with the growing prevalence and
capabilities of NAMs.
B. FDA's Current Regulatory and Policy Framework
FDA's current regulatory framework generally allows and encourages
the use of non-animal testing, including NAMs, as communicated through
regulations, guidance, recognition of international standards, and
participation with the International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use (ICH) and the
Interagency Coordinating Committee on the Validation of Alternative
Methods (ICCVAM).
In general, drugs and biological products may only be tested in or
on humans if their use in this context complies with part 312, which
implements section 505(i) of the FD&C Act (21 U.S.C. 355(i)) and
section 351(a)(3) of the PHS Act (42 U.S.C. 262(a)(3)). These
regulations aim to ensure that these products are reasonably safe for
use in or on humans under the conditions described in the proposed
clinical investigations. The clinical investigations may in turn serve
to provide evidence as to whether the medical product is safe and
effective as part of a marketing application to FDA.
Generally, a person seeking to market a new drug must submit to FDA
a new drug application (NDA) with full reports of investigations,
including clinical investigations that show whether the drug is safe
and effective (21 U.S.C. 355(b)). Generally, a person seeking to market
a new biological product must submit to FDA a biologics license
application (BLA), which generally includes data derived from
nonclinical laboratory and clinical studies demonstrating the product
meets prescribed requirements of safety, purity, and potency (Sec.
601.2(a)).
FDA encourages the use of innovative approaches to safety testing
that may provide predictive data for medical products in our review
process, including through guidance documents. The Agency explains in
guidance documents, such as those included as references in this
proposed rule (Refs. 1-16), our support for moving away from animal
testing--and encourages parties to contact us to discuss alternative
testing methods early on in their development plans. FDA guidances may
be accessed at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents#guidancesearch">https://www.fda.gov/regulatory-information/search-fda-guidance-documents#guidancesearch</a>.
In addition to guidance, FDA has signaled its support for
alternatives to animal testing in other contexts. In a 2015 final rule,
FDA removed the codified general safety test (GST) requirements for
biological products, which required rodent testing, because the
regulations were duplicative of safety test requirements set forth in
approved BLAs for products that present specific safety concerns. In
that rule, we noted that the ``elimination of the codified GST
regulations would encourage the implementation of the principles of the
`3Rs,' to reduce, refine, and replace animal use in testing'' while
continuing to ensure the safety of biological products using
appropriate and specific test methods identified in the product's
approved BLA or supplement BLA. (80 FR 37971 at 37972).
In December of 2017, FDA published a roadmap for integrating
emerging predictive toxicology methods and new technologies into
regulatory safety and risk assessments to potentially reduce the use of
animal testing (Ref. 17). This work includes collaborating with ICH,
ICCVAM, and the Organisation for Economic Co-operation and Developments
(OECD) Test Guidelines Programme.
Section 507 of the FD&C Act requires establishment of a process for
the qualification, based on scientific merit, of drug development tools
for a proposed context of use; once qualified, any sponsor can then use
the tool(s) in the development and evaluation of their products within
the qualified context of use. FDA is making use of the Drug Development
Tools (DDT) and Innovative Science and Technology Approaches for New
Drugs (ISTAND) programs to evaluate, validate, and qualify various
tools, including NAMs. DDT and ISTAND submissions include new
biomarkers, clinical assessments, animal models for use with the Animal
Rule, and other novel approaches or methodologies of potential benefit
to drug development and evaluation. These programs support innovation
and regulatory science and foster early communication and collaboration
with FDA and sponsors helping to bridge the gap between the research of
medical products and their delivery to patients.
Sponsors may contact the Center for Drug Evaluation and Research
(CDER) or the Center for Biologics Evaluation and Research (CBER) to
request feedback on their development programs, the use of nonclinical
tests, and feedback on the use of a NAM for a particular development
program, such as through a Type D meeting.\3\ Alternatively, if a
sponsor seeks feedback on the use of a novel manufacturing method that
incorporates use of a NAM to support multiple products, the sponsor
could consider engaging the CBER Advanced Technologies Team.
---------------------------------------------------------------------------
\3\ A Type D meeting is a type of formal meeting described in
the Prescription Drug User Fee Act (PDUFA) Commitment letter (Ref.
18) and the August 2026 guidance on Formal Meetings Between the FDA
and Sponsors or Applicants of PDUFA Products (Ref. 15). A Type D
meeting is focused on a narrow set of issues (e.g., often one, but
typically not more than two issues and associated questions). In
addition, the issue should not require input from more than 3
disciplines or Divisions.
---------------------------------------------------------------------------
A 2024 report to the Science Board to FDA from its New Alternative
Methods Subcommittee, entitled ``Potential Approaches to Drive Future
Integration of New Alternative Methods for Regulatory Decision-Making''
(Ref. 19), noted that FDA has accepted approaches that reduce the
number of animals used in test protocols, including by adopting and
issuing ICH guidances that recommend testing of relevant species (ICH
S6), that reduce or eliminate animal testing recommendations for
reproductive toxicology (ICH S5(R3)) and carcinogenicity testing (ICH
S1B(R1)), and that reduce the duration of recommended chronic
toxicology studies for oncology indications (ICH S9). The report also
noted that FDA has explored options like the use of virtual control
groups to support a reduction of animals in studies, and that newer
methods are largely already available at FDA to produce scientifically
valid data to meet FDA's regulatory needs, including those using
systems biology, engineered biologically active tissues, in silico
methods, alternative organisms such as Zebrafish and C. elegans, and
microphysiological systems, including organs-on-chips.
FDA, along with a number of other federal regulatory agencies and
research laboratories, participated in the development of the 2024
ICCVAM report entitled ``Validation, Qualification, and Regulatory
Acceptance of New Approach Methodologies'' (Ref 20). ICCVAM developed
the report to help developers and end users build confidence in NAMs.
It recommends the implementation of flexible, fit-for-purpose
validation strategies that consider the intended application of the
NAM, and describes concepts such as context of use, biological
relevance, and technical characterization of NAMs.
In April 2025, FDA announced a roadmap to reduce animal testing in
safety studies by replacing them in a stepwise approach with
scientifically
[[Page 60040]]
valid NAMs (Ref. 21). The approach outlined in the roadmap is designed
to improve drug safety and identify more efficient methods to inform
the evaluation process while reducing animal experimentation. The
roadmap provided an overview of key NAM categories and their
applicability to drug development and laid out a stepwise list of
specific actions FDA is considering for validation and integration of
NAMs into its regulatory process, initially focusing on safety testing
of monoclonal antibodies.
Although the Agency is optimistic that fostering the use of
scientifically valid NAMs will lead to a reduced need for animal
testing and to the use of fewer animals and of animals lower on the
phylogenetic scale, it is also important to recognize that there remain
areas where animal testing is important and necessary. For example, for
a product inhibiting a novel molecular target, animal studies may
enable the evaluation of toxicities that occur through complex
physiologic interactions such as the release of hormones,
neurotransmitters, cytokines, and other internally secreted chemicals
that maintain homeostasis within an organism and communication between
organ systems. However, we also recognize that NAMs using human-derived
cells may be able to assess additional or more relevant endpoints for
clinical drug development. Thus, it is important that developers
consult with FDA about their use of NAMs, including providing
information about the technical characterization of the NAM and its
biological relevance for particular contexts of use. As is its general
practice, FDA also will develop guidance to support specific
recommendations to sponsors about study design, conduct, and
interpretation of NAMs as it gains experience with their use and as
data and information become available.
In sum, we believe the changes to the terminology used in FDA
regulations described in this proposed rule should foster the
development and use of new alternative research methods where feasible
while ensuring that nonclinical test methods used in drug and
biological product development generate data appropriate for
demonstrating the safety of the drug product.
V. Description of the Proposed Rule
The rule proposes to amend certain provisions of FDA's drug and
biological product regulations addressing the collection, analysis,
submission, reporting, and surveillance of safety and toxicological
data.\4\ Specifically, this rule proposes to:
---------------------------------------------------------------------------
\4\ We determined that certain regulations fall outside the
scope of this rule. For example, FDA has regulations under which
efficacy data may be provided from studies conducted in carefully
vetted animal models because it would not be ethical or feasible to
conduct definitive efficacy studies in humans for human drugs and
biological products intended to ameliorate or prevent serious or
life-threatening conditions caused by exposure to lethal or
permanently disabling toxic chemical, biological, radiological or
nuclear substances. (These regulations, 21 CFR 314 subpart I for
drugs and 21 CFR 601 subpart H for biological products, are commonly
known as the Animal Rule.) These regulations are specific to the use
of animals to provide efficacy data under very limited conditions
and are not within the scope of this rule. Similarly, part 316 on
orphan drugs is outside the scope of this rule. Any studies in
animals to support an orphan-drug designation are generally limited
to ``preclinical efficacy studies conducted in an animal model for
the human disease or condition.'' 21 CFR 316.20(b)(4). Section
316.20(b)(4) also states that ``[a]nimal toxicology studies are
generally not relevant to a request for orphan-drug designation.''
---------------------------------------------------------------------------
<bullet> Amend Sec. 312.3(b) by adding a definition of the terms
``nonclinical test'' and ``nonclinical study'' and Sec. Sec. 314.3,
315.2 and 601.31 by adding a definition of the term ``nonclinical
study.'' The definitions are adapted from the definition of
``nonclinical test'' in section 3209(a) of FDORA. This proposed change
aligns the regulations that use the terms ``nonclinical test'' and
``nonclinical study'' \5\ with the amendments made to the FD&C Act and
the PHS Act by FDORA. Like the statutory definition, the regulatory
definitions we are proposing to add include an illustrative, non-
exhaustive list of examples of nonclinical tests and studies. The
proposed definition is broader than the statutory definition to include
``study'' because part 312 refers to both tests and studies and parts
314, 315, and 601 generally refer to studies instead of tests. Further,
FDA considers nonclinical tests and nonclinical studies to be
equivalent for purposes of these requirements and does not believe that
these changes result in any substantive differences compared to the
definition in section 505(z) of the FD&C Act because both definitions
describe the same types of nonclinical data that can be used to satisfy
the underlying requirement. The definitions we are proposing in this
rule also omit reference to when the nonclinical test or study occurs
because the regulations being revised focus on the type of data needed
to address the requirement, not on when the nonclinical test or study
to generate the data occurs. To include the temporal part of the
statutory definition (``a test . . . that occurs before or during the
clinical trial phase'') would change the meaning of some of the
regulatory provisions being revised under this proposal to use
``nonclinical study'' or ``nonclinical test''.
---------------------------------------------------------------------------
\5\ The term ``nonclinical study'' is not a ``nonclinical
laboratory study'' which is regulated under 21 CFR part 58 and is
outside the scope of this rule.
---------------------------------------------------------------------------
<bullet> Amend the other regulations specified below by
substituting the term ``nonclinical test'' or ``nonclinical study'' for
the terms ``animal test,'' ``animal study,'' ``preclinical test,'' and
``in vitro test,'' and making other comparable or conforming changes.
These proposed changes result in more consistent and updated
terminology that is not unduly focused on animal testing and that
encompasses the use of scientifically valid NAMs.
<bullet> Where FDA's existing regulations that are being revised
under this rule use ``animal'' and ``in vitro'' together to describe
the scope of nonclinical testing (such as ``animal or in vitro
studies''), FDA has historically treated these paired terms here to
encompass all nonclinical testing conducted outside of humans. When
these regulations were originally developed, in chemico and in silico
methodologies were not widely used and the pairing of ``animal'' and
``in vitro'' reflected the available testing methods that were in
common use at the time. As in chemico and in silico methods evolved and
became scientifically established, they became more widely used in drug
development, results from these nonclinical tests were submitted to the
Agency under these same provisions, and FDA accepted such data under
these provisions when appropriate. Substituting ``nonclinical'' in
instances where ``animal'' and ``in vitro'' are used in conjunction as
proposed in this rule does not in practice expand the scope of data
that must be reviewed, submitted, or reported under the affected
provisions because the existing regulatory requirements, in these
specific instances, generally focus on the significance or relevance of
the information to human safety (e.g., ``all information relevant to
the safety of the drug,'' ``findings that suggest a significant risk in
humans''), not on the specific methodology used to generate that
information. Sponsors have submitted data from in silico, in chemico,
and other nonclinical methodologies conducted outside a living organism
under the current regulations, consistent with this position.
A. Amendment of Part 312--Investigational New Drug Application
Part 312 lists requirements for an investigational new drug
application (IND).
[[Page 60041]]
1. Section 312.3(b)
Section 312.3(b) lists definitions in alphabetical order that apply
to part 312. We are proposing to amend Sec. 312.3(b) by adding, after
the definition of ``Marketing application,'' the following definition
\6\ of the terms ``nonclinical test'' and ``nonclinical study'':
---------------------------------------------------------------------------
\6\ This definition is adapted from the definition of
nonclinical test added to section 505(z) of the FD&C Act (21 U.S.C.
355(z)) by section 3209(a) of FDORA.
---------------------------------------------------------------------------
Nonclinical test and nonclinical study mean a test or study
conducted in vitro, in silico, or in chemico, or a nonhuman in vivo
test or study. Such test or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
2. Section 312.22
Section 312.22 provides general principles of the IND submission.
Paragraph 312.22(c) notes that amendments to INDs ``should build
logically on previous submissions and should be supported by additional
information, including the results of animal toxicology studies or
other human studies as appropriate.'' We are proposing to amend the
paragraph by replacing ``animal'' with ``nonclinical.'' This proposed
change clarifies that the types of supportive toxicology studies that
may be appropriate can include nonanimal studies, highlighting the
flexibility inherent in this provision. As with toxicology data from
animal studies or other human studies, FDA will examine any
toxicological data from nonanimal nonclinical studies to determine
whether they adequately support the clinical studies identified in the
IND if the proposed changes are finalized.
3. Section 312.23(a)(3)
Section 312.23 lists requirements for IND content and format, and
paragraph (a) lists the elements that the IND must contain and in what
order. Paragraph (a)(3) describes what is included in the IND's
introductory statement and general investigational plan. Paragraph
(a)(3)(iv)(f) provides that the plan should include ``any risks of
particular severity or seriousness anticipated on the basis of the
toxicological data in animals or prior studies in humans with the drug
or related drugs.'' We are proposing to amend the paragraph by
replacing the word ``animals'' with the phrase ``nonclinical studies.''
While this change would expand the types of studies or tests that may
be used to provide the basis for a sponsor to identify ``any risks of
particular severity or seriousness'' that a sponsor should anticipate,
and thus should be included in the investigational plan, this proposed
change does not increase the amount of information needed to meet
current requirements because the regulatory change does not impose any
requirement to conduct additional tests or studies to identify such
risks. This proposed change reflects how there is flexibility in the
types of toxicological data that can be used to identify risks to be
addressed in the general investigational plan. As with toxicological
data from animal studies or prior human studies, FDA will examine any
toxicological data from nonanimal nonclinical studies to determine
whether they adequately support the clinical studies identified in the
IND if the proposed changes are finalized.
4. Section 312.23(a)(5)(ii)
Section 312.23(a)(5) describes what must be included in the IND's
investigator's brochure, when such brochure is required by Sec.
312.55. Section 312.23(a)(5)(ii) requires that there be a ``summary of
the pharmacological and toxicological effects of the drug in animals
and, to the extent known, in humans.'' We are proposing to amend the
regulation by replacing the word ``animals'' with the phrase
``nonclinical studies.'' This change would add flexibility and clarify
that the pharmacological and toxicological effects of the drug that
must be included in the IND submission may be derived from a broader
range of studies than animal studies. This change would not expand the
scope of the submission requirement. The investigator's brochure is
intended to inform investigators of information relevant to the safe
conduct of the clinical investigation, and the obligation to summarize
pharmacological and toxicological effects is grounded in that goal
rather than in the methodology used to generate the data. Consistent
with this, data from nonclinical studies other than animal studies
would be included in the brochure to the extent they are relevant to
the safe conduct of the proposed investigation. This change would not
impose any new testing requirements. As with pharmacological and
toxicological effects derived from animal studies or prior human
studies, FDA will examine any pharmacological and toxicological data
from nonanimal nonclinical studies to determine whether they adequately
support the clinical studies identified in the IND if the proposed
changes are finalized.
5. Section 312.23(a)(5)(iii)
Section 312.23(a)(5) describes what must be included in the IND's
investigator's brochure, when such brochure is required by Sec.
312.55. Section 312.23(a)(5)(iii) requires that there be a ``summary of
the pharmacokinetics and biological disposition of the drug in animals
and, if known, in humans.'' As above, we are proposing to amend the
regulation by replacing the word ``animals'' with the phrase
``nonclinical studies.'' This proposed change would provide flexibility
and clarify that the pharmacokinetics and biological disposition of the
drug may be derived from a broader range of studies than animal
studies. This change would not expand the scope of the submission
requirement. The investigator's brochure is intended to inform
investigators of information relevant to the safe conduct of the
clinical investigation, and the obligation to summarize pharmacological
and toxicological effects is grounded in that goal rather than in the
methodology used to generate the data. Consistent with this, data from
nonclinical studies other than animal studies would be included in the
brochure to the extent they are relevant to the safe conduct of the
proposed investigation. This change would not impose any new testing
requirements. As with pharmacokinetics and biological disposition of
the drug derived from animal studies or prior human studies, FDA will
examine data from nonanimal nonclinical studies to determine whether
they adequately support the clinical studies identified in the IND if
the proposed changes are finalized.
6. Section 312.23(a)(8)
Section 312.23(a)(8) describes what pharmacology and toxicology
information must be provided in an IND and the first two sentences of
the paragraph state that ``[a]dequate information about pharmacological
and toxicological studies of the drug involving laboratory animals or
in vitro, on the basis of which the sponsor has concluded that it is
reasonably safe to conduct the proposed clinical investigations. The
kind, duration, and scope of animal and other tests required varies
with the duration and nature of the proposed clinical investigations.''
We are proposing to amend these two sentences in the regulation by
replacing the phrase ``pharmacological and toxicological studies of the
drug
[[Page 60042]]
involving laboratory animals or in vitro'' with the phrase
``nonclinical pharmacological and toxicological studies of the drug''
and replacing ``animal and other tests'' with ``nonclinical tests.''
This proposed change would provide flexibility and clarify that the
pharmacological and toxicological studies of the drug may be derived
from a broader range of studies than laboratory animal and in vitro
studies. As discussed above, FDA has treated the paired terms
``animal'' and ``in vitro'' to encompass all nonclinical testing
conducted outside of humans and this change is consistent with that
position. Additionally, this change would not mandate what types of
studies are performed to generate this information; rather, it would
require disclosure in the IND of information about the pharmacological
and toxicological studies, regardless of the type of non-clinical study
that has generated the information. This is not an increase in burden
because FDA already permits the use of non-animal studies to satisfy
these requirements where appropriate, this proposed change would not
preclude sponsors from using any types of studies that are currently
permitted to meet these requirements, and this change would not
increase the amount of information required to meet these existing
requirements. As with pharmacological and toxicological studies of the
drug derived from laboratory animal or in vitro studies, FDA will
examine data from other types of nonclinical studies to determine
whether they adequately support the clinical studies identified in the
IND if the proposed changes are finalized. The remainder of this
paragraph, describing FDA guidance documents and more detail about the
required information to be submitted, is not being amended.
7. Section 312.23(a)(8)(i)
Section 312.23(a)(8)(i) requires that each IND contain a ``section
describing the pharmacological effects and mechanism(s) of action of
the drug in animals, and information on the absorption, distribution,
metabolism, and excretion of the drug, if known.'' We are proposing to
amend the regulation by replacing the word ``animals'' with the phrase
``nonclinical tests.'' This proposed change would provide flexibility
and clarify that the pharmacological effects and mechanism(s) of action
of the drug, and information on the absorption, distribution,
metabolism, and excretion of the drug, if known, may be derived from a
broader range of studies than animal studies. The change would not
mandate what types of studies are performed to generate this
information but will require submission in the IND of this information
regardless of the type of nonclinical study generating the data. This
would not increase burden on regulated entities because FDA already
permits the use of non-animal studies to satisfy these requirements
where appropriate, this change will not preclude sponsors from using
any types of studies that are currently permitted to meet these
requirements, and this change would not increase the amount of
information required to meet these requirements. As with such
information derived from animal studies, FDA will examine information
from nonanimal nonclinical studies to determine whether they adequately
support the clinical studies identified in the IND if the proposed
changes are finalized.
8. Section 312.23(a)(8)(ii)(a)
Section 312.23(a)(8)(ii)(a) requires that the toxicology
information in the IND contain an ``integrated summary of the
toxicological effects of the drug in animals and in vitro. Depending on
the nature of the drug and the phase of the investigation, the
description is to include the results of acute, subacute, and chronic
toxicity tests; tests of the drug's effects on reproduction and the
developing fetus; any special toxicity test related to the drug's
particular mode of administration or conditions of use (e.g.,
inhalation, dermal, or ocular toxicology); and any in vitro studies
intended to evaluate drug toxicity.'' We are proposing to amend the
regulation by replacing the phrase ``in animals and in vitro'' with the
phrase ``based on nonclinical studies'' and replacing the phrase ``and
any in vitro studies'' with the phrase ``and any nonclinical studies.''
This proposed change would provide flexibility and clarify that the
``integrated summary of the toxicological effects of the drug'' may be
derived from a broader range of studies than animal and in vitro
studies. As discussed above, FDA has treated the paired terms
``animal'' and ``in vitro'' in the regulations being amended in this
proposed rule to encompass all nonclinical testing conducted outside of
humans and this change is consistent with that position. The proposed
change does not mandate what types of studies are performed to generate
this information but would continue to require submission in the IND of
this information regardless of the type of nonclinical study generating
the data. This would not be an increase in burden because FDA already
permits the use of non-animal studies to satisfy these requirements
where appropriate, this change would not preclude sponsors from using
any types of studies that are currently permitted to meet these
requirements, and this change does not increase the amount of
information required to meet these requirements. As with such
information derived from animal and in vitro studies, FDA will examine
information from other types of nonclinical studies to determine
whether they adequately support the clinical studies identified in the
IND if the proposed changes are finalized.
9. Section 312.23(a)(10)(i)
Section 312.23(a)(10)(i) provides that ``[i]f the drug is a
psychotropic substance or otherwise has abuse potential,'' then the IND
must include ``a section describing relevant clinical studies and
experience and studies in test animals.'' We are proposing to amend the
regulation by replacing the phrase ``clinical studies and experience
and studies in test animals'' with the phrase ``clinical and
nonclinical studies and experience.'' This change would provide
flexibility and clarify that the relevant experience and studies do not
have to be limited to that which occurred in humans and test animals,
but may include studies and experience using nonclinical tests. The
proposed change does not mandate what types of studies are performed to
generate this information but would continue to require submission in
the IND of this information regardless of the type of nonclinical study
generating the data. This would not be an increase in burden because
FDA already permits the use of non-animal studies to satisfy these
requirements where appropriate, this change would not preclude sponsors
from using any types of studies that are currently permitted to meet
these requirements, and this change would not increase the amount of
information required to meet these requirements. As with clinical
studies and experience and studies in test animals, FDA will examine
studies and experience from nonanimal nonclinical studies to determine
their relevance to support an IND for a drug that is a psychotropic
substance or otherwise has abuse potential if the proposed changes are
finalized.
10. Section 312.23(a)(10)(ii)
Section 312.23(a)(10)(ii) provides that if the drug is a
radioactive drug, then the IND must include ``sufficient data from
animal or human studies to allow a reasonable calculation of radiation-
absorbed dose to the whole body and critical organs upon administration
to a human subject.'' We are proposing to amend the regulation by
replacing the
[[Page 60043]]
word ``animal'' with the word ``nonclinical.'' This proposed change
would add flexibility and clarify that the data sufficient to allow a
reasonable calculation of radiation-absorbed dose to the whole body and
critical organs upon administration to a human subject may be obtained
from a broader range of studies than animal studies. The change would
not mandate what types of studies are performed to generate this
information but would continue to require submission in the IND of this
information regardless of the type of nonclinical study generating the
data. We believe that this is not an increase in burden because FDA
already permits the use of non-animal studies to satisfy these
requirements where appropriate, this change will not preclude sponsors
from using any types of studies that are currently permitted to meet
these requirements, and this change does not increase the amount of
information required to meet these requirements. As with data obtained
from animal studies or human studies, FDA will examine any data from
nonanimal nonclinical studies to determine whether they allow a
reasonable calculation of radiation-absorbed dose to the whole body and
critical organs of a human subject if the proposed changes are
finalized.
11. Section 312.32(b)
Section 312.32 describes what must be contained in IND safety
reporting. Paragraph 312.32(b) requires the sponsor to ``promptly
review all information relevant to the safety of the drug obtained or
otherwise received by the sponsor from foreign or domestic sources,
including information derived from any clinical or epidemiological
investigations, animal or in vitro studies, reports in the scientific
literature, and unpublished scientific papers, as well as reports from
foreign regulatory authorities and reports of foreign commercial
marketing experience for drugs that are not marketed in the United
States.'' We are proposing to amend the regulation by replacing the
phrase ``animal or in vitro studies'' with the phrase ``nonclinical
studies.'' This proposed change clarifies that ``all information
relevant to the safety of the drug obtained or otherwise received by
the sponsor from foreign or domestic sources'' includes information
from nonclinical studies. This proposed change would not expand the
scope of information sponsors must review under this provision; rather,
it clarifies FDA's longstanding position that sponsors are required to
review all information relevant to the safety of the drug that the
sponsor received or obtained from foreign or domestic sources. The list
of specific sources of information to be reviewed is a list of examples
and has never been intended to be an exhaustive list of potentially
relevant sources of information that should be reviewed by a sponsor.
The proposed change from ``animal or in vitro studies'' to the broader
term ``nonclinical studies'' better captures that intent by explicitly
including modern technologies such as computer modeling and organ
chips. This proposed change would not impose any new testing
requirements.
12. Section 312.32(c)(1)(iii)
Section 312.32(c) requires a sponsor to notify FDA and all
participating investigators ``of potential serious risks, from clinical
trials or any other source'' in a safety report provided as soon as
possible (but not later than 15 calendar days after the sponsor
determines that the information qualifies for reporting under the
regulation). Section 312.32(c)(1)(iii) is headed ``Findings from animal
or in vitro testing.'' The first sentence of the paragraph states:
``The sponsor must report any findings from animal or in vitro testing,
whether or not conducted by the sponsor, that suggest a significant
risk in humans exposed to the drug, such as reports of mutagenicity,
teratogenicity, or carcinogenicity, or reports of significant organ
toxicity at or near the expected human exposure.'' We are proposing to
amend the regulation by replacing the phrase ``animal or in vitro''
with the word ``nonclinical'' in both the heading and first sentence.
This change would clarify FDA's longstanding position that any findings
``from clinical trials or any other source'' (21 CFR 312.32(c)(1)),
including non-clinical studies, that suggest a significant risk to
humans from exposure to the drug must be reported to FDA, including
from modern technologies like computer modeling and organ chips that
were not commonly used when the regulation was originally written. The
information covered by this provision is critical to FDA's ability to
protect human subjects in clinical investigations, as it encompasses
data that would ``[o]rdinarily . . . result in a safety-related change
in the protocol, informed consent, investigator brochure (excluding
routine updates of these documents), or other aspects of the overall
conduct of the clinical investigation.'' This proposed change brings
the language up-to-date, consistent with scientific progress and the
modernization of testing methods; it would not impose any additional
testing requirements.
13. Section 312.32(c)(1)(v)
Section 312.32(c)(1)(v) describes the format in which sponsors must
submit IND safety reports and contains the statement ``Reports of
overall findings or pooled analyses from published and unpublished in
vitro, animal, epidemiological, or clinical studies must be submitted
in a narrative format.'' We are proposing to amend the regulation by
replacing the phrase ``in vitro, animal'' with ``nonclinical'' in this
sentence. This proposed change clarifies FDA's longstanding position
that any findings ``from clinical trials or any other source,''
including non-clinical studies, that suggest a significant risk to
humans from exposure to the drug must be reported to FDA (and
participating investigators) (21 CFR 312.32(c)(1)). Further, this
revision would conform section 312.32(c)(1)(v) with the changes made to
sections 312.32(b) and 312.32(c)(1)(iii) in describing the format for
the IND safety reports required by the remainder of section
312.32(c)(1). It would not impose any additional testing requirements.
14. Section 312.33(b)(6)
Section 312.33(b)(6) requires, as part of annual reports, a summary
of information ``obtained during the previous year's clinical and
nonclinical investigations,'' including ``[a] list of the preclinical
studies (including animal studies) completed or in progress during the
past year and a summary of the major preclinical findings.'' We are
proposing to amend the regulation by replacing the phrase ``preclinical
studies (including animal studies)'' with ``nonclinical studies'' and
replacing ``preclinical findings'' with ``nonclinical findings.'' This
proposed change would conform the terminology in this regulation with
that used in the rest of part 312, as amended in this rule. Paragraphs
(b)(1) through (b)(6) of section 312.33 identify the type and scope of
information to be included but the proposed change to paragraph (b)(6)
does not change the purpose of the summary section of the annual report
to ``bring together data from individual studies and briefly
communicate what was learned during the past year about the
investigational drug's safety and effectiveness'' (75 FR 8819 [emphasis
added]). The proposed change would not expand the requirements, because
section 312.33(b) already specifies that the summary of information
covers both clinical and non-clinical information. Although paragraph
(b)(6) specifies ``preclinical'' studies and findings (meaning studies
and tests before clinical, that is testing or use in
[[Page 60044]]
humans), the proposed revision to refer to nonclinical studies and
findings leaves out that temporal component because some nonclinical
studies may take place after the start of clinical studies.
Nonetheless, this section of the annual report is intended to be brief
and does not require extensive discussion of all activities during the
year. Otherwise, the scope of tests and studies described in this
provision is the same. Based on these points, we believe that the
change to section 312.33(b) and the scope of the required summary of
information in the annual report would not increase burden.
15. Section 312.82
Section 312.82 provides that for ``products intended to treat life-
threatening or severely-debilitating illnesses, sponsors may request to
meet with FDA-reviewing officials early in the drug development process
to review and reach agreement on the design of necessary preclinical
and clinical studies.'' We are proposing to amend the regulation by
replacing ``preclinical'' with ``nonclinical.'' This proposed change
would conform the terminology in this regulation with that used in the
rest of part 312, as amended in this rule, and reflects the fact that
some nonclinical studies may take place after the start of clinical
studies. This proposed change also reflects that scientific and
regulatory recommendations provided during drug development meetings
with sponsors may result in more efficient and robust development
programs and that engagement with FDA may occur and be fruitful at
multiple stages in drug development.
16. Section 312.82(a)
Section 312.82(a) provides that the ``primary purpose of this
meeting is to review and reach agreement on the design of animal
studies needed to initiate human testing.'' We are proposing to amend
the regulation by replacing ``animal'' with ``nonclinical.'' This
change would provide flexibility and clarify that the meeting may also
be used to review and reach agreement on the design of any nonclinical
studies needed to initiate human testing, which is consistent with
FDA's support for moving away from animal testing.
17. Section 312.86
Section 312.86 states that ``FDA may undertake focused regulatory
research on critical rate-limiting aspects of the preclinical,
chemical/manufacturing, and clinical phases of drug development and
evaluation.'' We are proposing to amend this paragraph by replacing
``preclinical'' with ``nonclinical.'' This proposed change would
conform this regulation with the changes we are making in the rest of
part 312 and better reflect the potential scope of FDA regulatory
research.
18. Section 312.88
Section 312.88 states that the safeguards for patient safety
incorporated within parts 50, 56, 312, 314 and 600 ``include the review
of animal studies prior to initial human testing (Sec. 312.23).'' We
are proposing to amend the regulation by replacing ``animal'' with
``nonclinical'' to conform to the changes we are proposing in section
312.23 and to be more consistent with FDA's support for moving away
from animal testing.
B. Amendment of Part 314--Applications for FDA Approval To Market a New
Drug
1. Section 314.3(b)
Section 314.3(b) lists definitions of terms in alphabetical order
that apply to parts 314 and 320. We are proposing to amend the section
by adding, after the definition of ``Newly acquired information,'' the
following definition of ``nonclinical study'' adapted from the
definition of ``nonclinical test'' added to section 505 of the FD&C Act
by section 3209(a) of FDORA:
Nonclinical study means a test or study conducted in vitro, in
silico, or in chemico, or a nonhuman in vivo test or study. Such a test
or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
This proposed definition varies from the definition added to Sec.
312.3(b) in that it only defines ``nonclinical study'' rather than both
``nonclinical test'' and ``nonclinical study.'' This is because part
314 generally uses the term ``study'' rather than ``test.'' To be
consistent in terminology across the provisions in this proposed rule,
all proposed definitions list ``animal tests and studies'' as an
example of non-clinical studies whether the definition is for
``nonclinical studies'' or ``nonclinical test'' and ``nonclinical
study.''
2. Section 314.50(d)(2)
Section 314.50 establishes the content and format of an
application, new drug application or NDA. It provides that the NDA is
required to contain reports of all investigations of the drug product
sponsored by the applicant, and ``all other information about the drug
pertinent to an evaluation of the NDA that is received or otherwise
obtained by the applicant from any source.'' Section 314.50(d)(2)
requires that an NDA contain a ``section describing, with the aid of
graphs and tables, animal and in vitro studies with drug, . . .'' We
are proposing to amend the regulation by replacing ``animal and in
vitro'' with ``nonclinical'' and correcting the typographical error
``with drug'' so that the relevant part of the sentence will read
``nonclinical studies with the drug.'' This change would provide
flexibility and clarify that nonclinical studies other than animal or
in vitro studies may be used to support the pharmacology and toxicology
section of an NDA. As discussed above, FDA has treated the paired terms
``animal'' and ``in vitro'' to encompass all nonclinical testing
conducted outside of humans and this change is consistent with that
position. Furthermore, the proposed changes does not specify which
types of nonclinical studies must be used and thus does not broaden the
testing requirement or impose any additional testing requirements. As
with such data and information derived from animal studies, if FDA
receives data and information from other types of nonclinical studies,
FDA will examine it to determine whether it adequately supports the NDA
if the proposed changes are finalized.
3. Section 314.50(d)(2)(iv)
Section 314.50(d)(2)(iv) requires that the NDA's nonclinical
pharmacology and toxicology section include ``Any studies of the
absorption, distribution, metabolism, and excretion of the drug in
animals.'' We are proposing to amend this sentence to read: ``Any
nonclinical studies of the absorption, distribution, metabolism, and
excretion of the drug.'' This change would provide flexibility and
clarify that nonclinical studies other than animal studies may be used
to provide data and information on the absorption, distribution,
metabolism, and excretion of the drug. The proposed change would not
impose any additional testing requirements. As with such data and
information derived from animal studies, if FDA receives data and
information from other types of nonclinical studies, FDA will examine
it to determine whether it adequately supports the NDA if the proposed
changes are finalized.
4. Section 314.50(d)(4)(ii)
Section 314.50(d)(4)(ii) requires that the microbiology section of
an NDA for
[[Page 60045]]
an anti-infective drug include a ``description of the antimicrobial
spectra of the drug, including results of in vitro preclinical studies
to demonstrate concentrations of the drug required for effective use.''
We are proposing to amend the regulation by replacing the phrase ``in
vitro preclinical'' with ``nonclinical.'' This change would provide
flexibility and clarify that we will accept additional types of
nonclinical studies to support the microbiology section of an NDA for
an anti-infective drug. The proposal does not add any testing
requirements. As with such information derived from in vitro
preclinical studies, if FDA receives data and information from other
types of nonclinical studies, FDA will examine it to determine whether
it adequately supports the microbiology section of the NDA if the
proposed changes are finalized. We also are proposing to correct a
typographical error by replacing ``antimicrobial spectra'' with
``antimicrobial spectrum.''
5. Section 314.50(d)(5)(i)
Section 314.50(d)(5)(i) requires that the clinical data section of
the NDA include ``[a] description and analysis of each clinical
pharmacology study of the drug, including a brief comparison of the
results of the human studies with the animal pharmacology and
toxicology data.'' We are proposing to amend the regulation by
replacing the word ``animal'' with ``nonclinical''. This change would
provide flexibility and clarify that we will accept comparison of the
results of the human studies with pharmacology and toxicology data from
nonanimal nonclinical studies to support the clinical data section of
an NDA. The proposed change does not add any testing requirements. As
with animal pharmacology and toxicology data, if FDA receives
pharmacology and toxicology data from nonanimal nonclinical studies,
FDA will examine it to determine whether it adequately supports the NDA
if the proposed changes are finalized.
6. Section 314.50(d)(5)(vi)(a)
The first sentence of section 314.50(d)(5)(vi)(a) requires the
applicant to ``submit an integrated summary of all available
information about the safety of the drug product, including pertinent
animal data, demonstrated or potential adverse effects of the drug,
clinically significant drug/drug interactions, and other safety
considerations, such as data from epidemiological studies of related
drugs.'' We are proposing to amend the regulation by replacing the word
``animal'' with ``nonclinical.'' This proposed change clarifies that
``all available information about the safety of the drug product''
includes pertinent nonclinical data not obtained from animals. The
proposal does not require that applicants conduct additional studies.
The proposal recognizes that there are newer methods of assessing
safety and brings the requirements up-to-date, consistent with
scientific progress and the modernization of testing methods.
7. Section 314.50(d)(5)(vi)(b)
The second sentence of section 314.50(d)(5)(vi)(b) requires that an
applicant's safety update reports ``include the same kinds of
information (from clinical studies, animal studies, and other sources)
. . .'' We are proposing to amend the regulation by replacing the word
``animal'' with ``nonclinical'' to conform to the amendment we are
making to section 314.50(d)(5)(vi)(a). This proposed change would not
expand the requirements because this provision already contemplates
including information from sources outside of animal studies through
the use of the phrase ``and other sources.'' The proposal recognizes
that there are newer methods of assessing safety and brings the
requirements up-to-date, consistent with scientific progress and the
modernization of testing methods.
8. Section 314.81(b)(2)(v)
Section 314.81(b)(2)(v) requires that the postmarketing annual
report of an NDA holder include ``[c]opies of unpublished reports and
summaries of published reports of new toxicological findings in animal
studies and in vitro studies (e.g., mutagenicity) conducted by, or
otherwise obtained by, the applicant concerning the ingredients in the
drug product.'' The paragraph heading reads, ``Nonclinical laboratory
studies.'' We are proposing to amend the regulation by replacing the
phrase ``toxicological findings in animal studies and in vitro studies
(e.g., mutagenicity)'' with ``nonclinical toxicological findings,
including, for example, from mutagenicity studies.'' As discussed
above, FDA has treated the paired terms ``animal'' and ``in vitro'' to
encompass all nonclinical testing conducted outside of humans and this
change is consistent with that position. This proposed change does not
require NDA holders to conduct new or additional studies. The proposal
simply brings the reporting requirements up to date, to capture newer
methods of generating toxicological findings, consistent with
scientific progress and the modernization of testing methods.
9. Section 314.81(b)(2)(vii)(a)(7)
Section 314.81(b)(2)(vii)(a)(7) specifies that the status report of
the schedule for completion and reporting of the postmarketing study
commitment ``should include the actual or projected dates for
submission of the study protocol to FDA, completion of patient accrual
or initiation of an animal study, completion of the study, submission
of the final study report to FDA, and any additional milestones or
submissions for which projected dates were specified as part of the
commitment.'' We are proposing to amend the regulation by replacing the
phrase ``an animal'' with ``a nonclinical.'' This proposed change would
provide flexibility by recognizing that a postmarketing study
commitment may include nonanimal nonclinical studies, and therefore,
the status report should include the date for initiation of a nonanimal
nonclinical study that is part of a postmarketing study commitment. We
note that the obligation to include information in the status report
required under section 314.81(b)(2)(vii)(a) is limited to postmarketing
study commitments and this proposed amendment would not require
additional reporting of nonclinical studies that are outside of such
commitments.
10. Section 314.93
Section 314.93 describes conditions under which FDA will or will
not approve a petition to submit an ANDA for a drug product that is not
identical to a listed drug in route of administration, dosage form, and
strength, or in which one active ingredient is substituted for one
active ingredient in a listed combination drug. Paragraph (e)(1) of
section 314.93 lists a series of conditions under which FDA will not
approve such a petition, one of which is if it finds that
``[i]nvestigations must be conducted to show the safety and
effectiveness of the drug product . . .'' The first sentence of
paragraph 314.93(e)(2) states that ``[f]or purposes of this paragraph,
`investigations must be conducted' means that information derived from
animal or clinical studies is necessary to show that the drug product
is safe or effective.'' We are proposing to amend Sec. 314.93(e)(2) by
replacing ``animal'' with ``nonclinical.'' This proposed change in
terminology would not alter FDA's implementation through regulation of
the requirement articulated in section 505(j)(2)(C)(i) that if the
Agency finds investigations must be conducted to show safety and
effectiveness of the petitioned drug product then it will not approve a
petition to submit such an ANDA. The
[[Page 60046]]
proposal would bring the regulation up-to-date, consistent with
scientific progress and the modernization of testing methods, by
recognizing that when studies are necessary to determine that a drug
product is safe or effective, nonclinical methods other than animal
studies might be used to make that determination.
11. Section 314.200(d)(3)
Section 314.200 addresses the procedures for issuing a notice of
opportunity for a hearing on CDER's proposal to refuse to approve an
application or to withdraw the approval of an application or
abbreviated application under section 505(e) of the FD&C Act, filing a
notice of participation and request for a hearing, and submitting
studies and comments. Section 314.200(d) provides that the person
requesting a hearing is required to submit certain information on which
the person relies to justify a hearing with respect to the drug product
and paragraph (d)(3) specifies FDA's preferred format for such
submissions. Roman numeral heading I, letter A of that format
identifies ``Animal safety data'' as a component of such submissions.
FDA is amending the regulation by replacing ``Animal'' with
``Nonclinical.'' This change would provide flexibility and clarify that
the safety data in support of the submission may come from nonclinical
tests other than animal tests. To the extent that such tests have not
been performed or the submitter does not rely on the data to justify a
hearing with respect to the drug product, the regulation, including as
amended under this proposal, does not require such tests to be
performed or data submitted.
12. Section 314.430(a)
Section 314.430(a) specifies that the safety and effectiveness data
for which FDA will determine public availability include ``all studies
and tests of a drug on animals and humans'' as well as studies and
tests to establish identity, stability, purity, potency, and
bioavailability. FDA is proposing to amend the regulation by replacing
the phrase ``all studies and tests of a drug on animals and humans''
with ``all nonclinical and clinical studies and tests of a drug.'' This
proposed change conforms the regulation to the scope of data that may
be submitted to support the safety and effectiveness of a drug.
C. Amendment of Part 315--Diagnostic Radiopharmaceuticals
1. Section 315.2
Section 315.2 is the definition section of part 315, with
paragraphs (a) and (b) currently defining two types of diagnostic
radiopharmaceuticals. We are proposing to amend the section by first
redesignating the introductory text as paragraph (a) and redesignating
current paragraphs (a) and (b) as paragraphs (a)(1) and (a)(2) such
that the two types of diagnostic radiopharmaceuticals are defined in
paragraph (a); our amendments include minor revisions to refer to
``paragraph (a)(1)'' rather than ``paragraph (a)'' in the cross-
reference in the definition of nonradioactive reagent kit. We are also
proposing to add, as a new paragraph (b), the definition of
``nonclinical study'' adapted from the definition of ``nonclinical
test'' added to section 505 of the FD&C Act by section 3209(a) of FDORA
as follows: (b) For purposes of this part, nonclinical study means a
test or study conducted in vitro, in silico, or in chemico, or a
nonhuman in vivo test or study. Such test or study may include the
following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
This proposed definition varies from the definition added to Sec.
312.3(b) in that it only defines ``nonclinical study'' rather than both
``nonclinical test'' and ``nonclinical study''. This is because part
315 generally uses the term ``study'' rather than ``test.'' To be
consistent in terminology, all proposed definitions list ``animal tests
or studies'' as an example of non-clinical studies, whether the
definition is for ``nonclinical studies'' or ``nonclinical test'' and
``nonclinical study''.
2. Section 315.6(c)(2)
Section 315.6(c)(2) states that safety data required by FDA for
diagnostic radiopharmaceuticals ``may include, but is not limited to,
the dose, route of administration, frequency of use, half-life of the
ligand or carrier, half-life of the radionuclide, and results of
clinical and preclinical studies.'' We are proposing to amend the
regulation by replacing ``preclinical'' with ``nonclinical.'' This
proposed change conforms the terminology in this regulation with the
other regulations in this rule; as noted earlier, part of the intent of
this rule is to bring more consistency to these regulations in
referring to non-clinical tests. This proposed revision would not
expand the requirements because the revision is to an example of the
type of information that the regulation requires.
3. Section 315.6(d)
Section 315.6(d) states that ``[t]he radiation safety assessment
must establish the radiation dose of a diagnostic radiopharmaceutical
by radiation dosimetry evaluations in humans and appropriate animal
models.'' We are proposing to amend the regulation by replacing the
phrase ``animal'' with ``nonclinical.'' This change would provide
flexibility and clarify that radiation dosimetry evaluations may be
conducted in appropriate nonclinical models other than animal models.
As with data obtained from animal models and human studies, FDA will
examine data from nonanimal nonclinical models to determine whether
they support the establishment of a safe radiation dose if the proposed
changes are finalized.
D. Amendment of Part 361--Prescription Drugs for Human Use Generally
Recognized as Safe and Effective and Not Misbranded: Drugs Used in
Research
1. Section CFR 361.1(d)(7)
Section CFR 361.1(d)(7) states in the second sentence after the
heading that a protocol for determining the safety of radioactive drugs
to be used for human research ``shall be based upon a sound rationale
derived from appropriate animal studies or published literature and
shall be of sound design such that information of scientific value may
result.'' We are proposing to amend the regulation by replacing
``animal studies'' with ``nonclinical studies, as defined in Sec.
312.3(b) of this chapter.'' This change would add flexibility and
clarify that the sound rationale may be derived from appropriate
nonclinical studies other than animal studies. As with animal studies,
FDA will examine information from nonanimal nonclinical studies to
determine if it supports a sound rationale for the use of the
radioactive drugs in human research if the proposed changes are
finalized.
E. Amendment of Part 601--Licensing
1. Section 601.31
Section 601.31 establishes definitions for certain terms used in
part 601, with paragraphs (a) and (b) currently defining two types of
diagnostic radiopharmaceuticals. We are proposing to amend the section
by first redesignating the introductory text as paragraph (a) and
redesignating current
[[Page 60047]]
paragraphs (a) and (b) as paragraph (a)(1) and (a)(2) such that the two
types of diagnostic radiopharmaceuticals are defined in paragraph (a);
our amendments include minor revisions to refer to ``paragraph (a)(1)''
rather than ``paragraph (a)'' in the cross-reference in the definition
of nonradioactive reagent kit. We are proposing to add, as a new
paragraph (b), the proposed definition of ``nonclinical study'' adapted
from the definition of ``nonclinical test'' added to section 505 of the
FD&C Act by section 3209(a) of FDORA as follows:
(b) For purposes of this part, nonclinical study means a test or
study conducted in vitro, in silico, or in chemico, or a nonhuman in
vivo test or study. Such test or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
This proposed definition varies from the definition added to Sec.
312.3(b) in that it only defines ``nonclinical study'' rather than both
``nonclinical test'' and ``nonclinical study.'' This is because part
601 generally uses the term ``study'' rather than ``test.'' To be
consistent in terminology, all proposed definitions list ``animal tests
or studies'' as an example of non-clinical studies, whether the
definition is for ``nonclinical studies'' or ``nonclinical test'' and
``nonclinical study.''
2. Section 601.35(c)(2)
Section 601.35(c)(2) states that safety data required by FDA for
diagnostic radiopharmaceuticals ``may include, but is not limited to,
the dose, route of administration, frequency of use, half-life of the
ligand or carrier, half-life of the radionuclide, and results of
clinical and preclinical studies.'' We are proposing to amend the
regulation by replacing ``preclinical'' with ``nonclinical.'' This
change would conform the terminology in this regulation with that used
in its counterpart regulation section 315.6(c)(2); as noted earlier,
part of the intent of this rule is to bring more consistency to these
regulations in referring to non-clinical tests.
3. Section 601.35(d)
Section 601.35(d) states that ``[t]he radiation safety assessment
must establish the radiation dose of a diagnostic radiopharmaceutical
by radiation dosimetry evaluations in humans and appropriate animal
models.'' We are proposing to amend the regulation by replacing
``animal'' with ``nonclinical.'' This change would conform the
terminology in this regulation with that used in its counterpart
regulation section 315.6(d) and is being proposed for the same reasons;
as noted earlier, part of the intent of this rule is to bring more
consistency to these regulations in referring to non-clinical tests.
4. Section 601.70(b)(7)
Section 601.70(b)(7) states that the schedule of a BLA holder's
completion and reporting of a postmarketing study commitment in the
holder's annual progress report ``should include the actual or
projected dates for submission of the study protocol to FDA, completion
of patient accrual or initiation of an animal study, completion of the
study, submission of the final study report to FDA, and any additional
milestones or submissions for which projected dates were specified as
part of the commitment.'' We are proposing to amend the regulation by
replacing the phrase ``an animal'' with ``a nonclinical'' in this
provision. This change would provide flexibility by recognizing that a
postmarketing study commitment may include nonanimal nonclinical
studies, and therefore, the status report should include the date for
initiation of a nonanimal nonclinical study that is part of a
postmarketing study commitment. We note that this obligation to include
information in the status report required under section 601.70(b)(8) is
limited to postmarketing studies described in 21 CFR 601.70(a) and this
amendment would not require additional reporting of nonclinical studies
that are outside of such commitments.
VI. Preliminary Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 14192, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4).
Executive Orders 12866 and 13563 direct us to assess all benefits
and costs of available regulatory alternatives and, when regulation is
necessary, to select regulatory approaches that maximize net benefits.
The Office of Information and Regulatory Affairs (OIRA) has determined
that this proposed rule is a significant regulatory action under
section 3(f) of Executive Order 12866.
Executive Order 14192 requires that any new incremental costs
associated with certain significant regulatory actions ``shall, to the
extent permitted by law, be offset by the elimination of existing costs
associated with at least 10 prior regulations.'' This proposed rule is
classifiable as an Executive Order 14192 deregulatory action.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because we estimate that this proposed rule would produce no
quantifiable costs, 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 estimates of
anticipated impacts, 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 $193
million, using the most current (2025) Implicit Price Deflator for the
Gross Domestic Product. If finalized as proposed, this proposed rule
would not result in an expenditure in any year that meets or exceeds
this amount.
B. Overview of Benefits, Costs, and Transfers
This proposed rule would substitute ``nonclinical'' for ``animal''
in phrases like ``animal test,'' substitutes ``nonclinical'' for
``preclinical'' and ``in vitro'' for consistency in terminology, and
add a definition of ``nonclinical test'' and ``nonclinical study'' to
the definitions section of FDA's drug and biological product
regulations. Nonclinical tests and studies include but are not limited
to the following: cell-based assays, organ chips and microphysiological
systems, computer modeling, other nonhuman or human biology-based test
methods (e.g., bioprinting), and animal tests or studies. FDA already
permits the use of nonanimal studies and this rule will not preclude
sponsors from using any types of studies that are currently permitted;
industry will continue to provide information on the nonanimal studies
that they use and rely on. The terminology changes in this rule also
address existing obligations to submit and report information on
nonclinical testing to FDA. Where the proposed rule would substitute
the term ``nonclinical'' for the paired terms ``animal'' and ``in
[[Page 60048]]
vitro,'' this proposed change does not expand the scope of data that
must be reviewed, submitted, or reported, because FDA has historically
treated those paired terms in the context of the regulations being
amended in this proposed rule to encompass all nonclinical testing
conducted outside of humans. These regulatory requirements generally
focus on the significance or relevance of the information to human
safety rather than on the methodology used to generate it. As described
in section V of this rule, sponsors have submitted data from in silico,
in chemico, and other nonclinical methodologies under the current
regulations consistent with this position and FDA has accepted such
data under these provisions when appropriate. In short, the proposed
regulatory changes in rule would impose no new requirements on industry
and so are expected to generate no costs. Hence, we estimate that this
proposed rule will produce no quantifiable savings, costs, or
transfers. We do not expect any loss of public health benefits as a
result of this rule. In fact, the proposed changes in this rule may
foster the development and use of scientifically valid non-animal
methods and so may yield benefits from this added flexibility.
Table 1 summarizes the estimated benefits and costs of the proposed
rule using a 10-year time horizon. We estimate that annualized benefits
would be $0 million per year using either a 3 or 7 percent discount
rate and that annualized costs would be $0 million per year using
either a 3 or 7 percent discount rate.
Table 1--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
[Millions of 2025 dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
Primary High ------------------------------------
Category estimate Low estimate estimate Year Discount Period Notes
dollars rate (%) covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized ($millions/year).................. $0 $0 $0 2025 7 2025-2034
0 0 0 2025 3 2025-2034
--------------------------------------------------------------------------------------------
Annualized Quantified.................................. ............ ............ ........... .......... 7 ..........
............ ............ ........... .......... 3 ..........
--------------------------------------------------------------------------------------------
Qualitative............................................ The rule may foster the development and use of scientifically valid new testing
methodologies.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized ($millions/year).................. 0 0 0 2025 7 2025-2034
0 0 0 2025 3 2025-2034
Annualized Quantified.................................. ............ ............ ........... .......... 7 ..........
............ ............ ........... .......... 3 ..........
--------------------------------------------------------------------------------------------
Qualitative............................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized ($millions/year).......... ............ ............ ........... .......... 7 ..........
............ ............ ........... .......... 3 ..........
--------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------
Other Annualized Monetized ($millions/year)............ ............ ............ ........... .......... 7 ..........
............ ............ ........... .......... 3 ..........
--------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government: None.............................................................................................................
Small Business: None................................................................................................................................
Wages: None.........................................................................................................................................
Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
This proposed rule addresses provisions in human drug and
biological product regulations that refer to animal studies or tests.
It proposes updates to definitions based on new statutory provisions
enacted in the Consolidated Appropriations Act, 2023 (Pub. L. 117-328)
that unambiguously allow for a broader range of nonclinical studies to
meet current requirements without imposing new requirements. Prior to
legislative action, some sponsors likely relied on existing terminology
in codified regulations that emphasized the use of animal testing as
the only scientific methodology to assess the safety of a drug in the
nonclinical setting. Adopting a pre-statutory baseline for analysis, we
anticipate that this proposed rule would serve as an enabling action
that results in an incremental shift by some sponsors from animal
testing to other types of nonclinical testing, when appropriate. Under
the new proposed definition, some sponsors will shift to other methods,
including those enumerated in a new definition of ``nonclinical test'':
(1) cell-based assays; (2) organ chips and microphysiological systems,
(3) computer modeling, and (4) other nonhuman or human biology-based
test methods, such as bioprinting; or they may continue to pursue the
methods emphasized in the baseline scenario of (5) animal tests or
studies. Because the proposed rule updates terminology to unambiguously
allow for a broader range of nonclinical studies to meet current
requirements without limiting existing options or imposing new
requirements, if finalized as proposed, it is classified as a
deregulatory action under Executive Order 14192.
In line with Executive Order 14192, in Table 2 we estimate present
and annualized values of costs, cost savings, and net costs over a
perpetual time horizon. We estimate that this proposed rule would
generate $0 million per year in annualized net cost savings at a 7
percent discount rate, discounted relative to year 2024 over a
perpetual
[[Page 60049]]
time horizon. Since this proposed rule would update terminology to
unambiguously allow for a broader range of nonclinical studies to meet
current requirements without limiting existing options or imposing new
requirements, we conclude this proposed rule is classifiable as an
Executive Order 14192 deregulatory action.
Table 2--Executive Order 14192 Summary Table
[Millions of 2025 dollars, discounted over a perpetual time horizon relative to year 2024 at a 7 percent
discount rate]
----------------------------------------------------------------------------------------------------------------
Primary
estimate Low estimate High estimate
----------------------------------------------------------------------------------------------------------------
Present Value of Costs.......................................... $0 $0 $0
Present Value of Cost Savings................................... 0 0 0
Present Value of Net Costs...................................... 0 0 0
Annualized Costs................................................ 0 0 0
Annualized Cost Savings......................................... 0 0 0
Annualized Net Costs............................................ 0 0 0
----------------------------------------------------------------------------------------------------------------
VII. Analysis of Environmental Impacts
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.
VIII. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 (44
U.S.C. 3501-3521) is not required.
IX. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We tentatively determine
that this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive Order and,
consequently, a federalism summary impact statement is not required.
X. 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 tentatively determine
that the rule does not contain policies that would have a substantial
direct effect on one or more Indian Tribes, on the relationship between
the Federal Government and Indian Tribes, or on the distribution of
power and responsibilities between the Federal Government and Indian
Tribes.
XI. References
The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. FDA guidance for industry ``S6 Addendum to Preclinical Safety
Evaluation of Biotechnology-Derived Pharmaceuticals,'' May 2012,
available at <a href="https://www.fda.gov/media/78034/download">https://www.fda.gov/media/78034/download</a>.
2. FDA guidance for industry ``S2(R1) Genotoxicity Testing and Data
Interpretation for Pharmaceuticals Intended for Human Use,'' June
2012, available at <a href="https://www.fda.gov/media/71980/download">https://www.fda.gov/media/71980/download</a>.
3. FDA guidance for industry ``S3A Guidance: Note for Guidance on
Toxicokinetics: The Assessment of Systemic Exposure in Toxicity
Studies: Focus on Microsampling, Questions and Answers,'' May 2018,
available at <a href="https://www.fda.gov/media/100027/download">https://www.fda.gov/media/100027/download</a>.
4. FDA guidance for industry ``S9 Nonclinical Evaluation for
Anticancer Pharmaceuticals, Questions and Answers,'' June 2018,
available at <a href="https://www.fda.gov/media/100344/download">https://www.fda.gov/media/100344/download</a>.
5. FDA guidance for industry ``Microdose Radiopharmaceutical
Diagnostic Drugs: Nonclinical Study Recommendations,'' August 2018,
available at <a href="https://www.fda.gov/media/107641/download">https://www.fda.gov/media/107641/download</a>.
6. FDA guidance for industry ``Testicular Toxicity: Evaluation
During Drug Development,'' October 2018, available at <a href="https://www.fda.gov/media/117948/download">https://www.fda.gov/media/117948/download</a>.
7. FDA guidance for industry ``Oncology Pharmaceuticals:
Reproductive Toxicity Testing and Labeling Recommendations,'' May
2019, available at <a href="https://www.fda.gov/media/124829/download">https://www.fda.gov/media/124829/download</a>.
8. FDA guidance for industry ``Oncology Therapeutic
Radiopharmaceuticals: Nonclinical Studies and Labeling
Recommendations,'' August 2019, available at <a href="https://www.fda.gov/media/129547/download">https://www.fda.gov/media/129547/download</a>.
9. FDA guidance for industry ``Long Term Follow-Up After
Administration of Human Gene Therapy Products,'' January 2020,
available at <a href="https://www.fda.gov/media/113768/download">https://www.fda.gov/media/113768/download</a>.
10. FDA guidance for industry ``Human Gene Therapy for Hemophilia,''
January 2020, available at <a href="https://www.fda.gov/media/113799/download">https://www.fda.gov/media/113799/download</a>.
11. FDA guidance for industry ``Human Gene Therapy for Retinal
Disorders,'' January 2020, available at <a href="https://www.fda.gov/media/124641/download">https://www.fda.gov/media/124641/download</a>.
12. FDA guidance for industry ``Human Gene Therapy for Rare
Diseases,'' January 2020, available at <a href="https://www.fda.gov/media/113807/download">https://www.fda.gov/media/113807/download</a>.
13. FDA guidance for industry ``S9 Nonclinical Evaluation for
Anticancer Pharmaceuticals,'' March 2010, available at <a href="https://www.fda.gov/media/73161/download">https://www.fda.gov/media/73161/download</a>.
14. FDA guidance for industry ``S5(R3) Detection of Reproductive and
Developmental Toxicity for Human Pharmaceuticals,'' May 2021,
available at <a href="https://www.fda.gov/media/148475/download">https://www.fda.gov/media/148475/download</a>.
15. FDA guidance for industry ``Formal Meetings Between the FDA and
Sponsors or Applicants of PDUFA Products,'' August 2026, available
at <a href="https://www.fda.gov/media/172311/download">https://www.fda.gov/media/172311/download</a>.
16. FDA draft guidance for industry ``General Considerations for the
Use of New Approach Methodologies in Drug Development,'' March 2026,
available at <a href="https://www.fda.gov/media/191589/download">https://www.fda.gov/media/191589/download</a>.
17. FDA ``Predictive Toxicology Roadmap,'' December 2017, available
at <a href="https://www.fda.gov/files/science%20&%20research/published/FDA">https://www.fda.gov/files/science%20&%20research/published/FDA</a>'s-
Predictive-Toxicology-Roadmap.pdf.
18. PDUFA Reauthorization Performance Goals and Procedures Fiscal
Years 2023 through 2027 (Commitment Letter),
[[Page 60050]]
available at <a href="https://www.fda.gov/media/151712/download">https://www.fda.gov/media/151712/download</a>.
19. Report to the Science Board to FDA ``Potential Approaches to
Drive Future Integration of New Alternative Methods for Regulatory
Decision-Making,'' October 2024, available at <a href="https://www.fda.gov/media/182478/download">https://www.fda.gov/media/182478/download</a>.
20. ICCVAM ``Validation, Qualification, and Regulatory Acceptance of
New Approach Methodologies,'' March 2024, available at <a href="https://ntp.niehs.nih.gov/sites/default/files/2024-03/VWG_Report_27Feb2024_FD_508.pdf">https://ntp.niehs.nih.gov/sites/default/files/2024-03/VWG_Report_27Feb2024_FD_508.pdf</a>.
21. FDA ``Roadmap to Reducing Animal Testing in Preclinical Safety
Studies,'' April 2025, available at <a href="https://www.fda.gov/media/186092/download?attachment">https://www.fda.gov/media/186092/download?attachment</a>.
List of Subjects
21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 315
Biologics, Drugs.
21 CFR Part 361
Medical research, Prescription drugs, Radiation protection.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, we propose
that 21 CFR parts 312, 314, 315, 361, and 601 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. Section 312.3(b) is amended by adding, after the definition of
``Marketing application,'' a definition of the ``nonclinical test'' and
``nonclinical study'' to read as follows:
Sec. 312.3 Definitions and interpretations.
* * * * *
(b) * * *
Nonclinical test and nonclinical study mean a test or study
conducted in vitro, in silico, or in chemico, or a nonhuman in vivo
test or study. Such test or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
* * * * *
0
3. Section 312.22(c) is amended in the second sentence by removing the
word ``animal'' and replacing it with the word ``nonclinical''.
0
4. Section 312.23(a)(3)(iv)(f) is amended by removing the word
``animals'' and replacing it with the phrase ``nonclinical studies''.
0
5. Section 312.23(a)(5) is amended in paragraphs (ii) and (iii) by
removing the word ``animals'' and replacing it in both locations with
the phrase ``nonclinical studies''.
0
6. Section 312.23(a)(8) is amended to read as follows:
Sec. 312.23 IND content and format.
(a) * * *
(8) Pharmacology and toxicology information. Adequate information
about nonclinical pharmacological and toxicological studies of the
drug, on the basis of which the sponsor has concluded that it is
reasonably safe to conduct the proposed clinical investigations. The
kind, duration, and scope of nonclinical tests required varies with the
duration and nature of the proposed clinical investigations. * * *
(i) Pharmacology and drug disposition. A section describing the
pharmacological effects and mechanism(s) of action of the drug in
nonclinical tests, and information on the absorption, distribution,
metabolism, and excretion of the drug, if known.
(ii) Toxicology. (a) An integrated summary of the toxicological
effects of the drug based on nonclinical studies. Depending on the
nature of the drug and the phase of the investigation, the description
is to include the results of acute, subacute, and chronic toxicity
tests; tests of the drug's effects on reproduction and the developing
fetus; any special toxicity test related to the drug's particular mode
of administration or conditions of use (e.g., inhalation, dermal, or
ocular toxicology); and any nonclinical studies intended to evaluate
drug toxicity.
* * * * *
0
7. Section 312.23(a)(10) is amended by:
0
a. Removing the phrase ``clinical studies and experience and studies in
test animals'' in paragraph (i) and replacing it with the phrase
``clinical and nonclinical studies and experience''; and
0
b. Removing the word ``animal'' paragraph (ii) and replacing it with
the word ``nonclinical''.
0
8. Section 312.32(b) is amended by removing the phrase ``animal or in
vitro studies'' and replacing it with the phrase ``nonclinical
studies''.
0
9. Section 312.32(c)(1)(iii) is amended by removing the phrase ``animal
or in vitro'' in both the heading and first sentence and replacing it
in both places with the word ``nonclinical''.
0
10. Section 312.32(c)(1)(v) is amended by removing the phrase ``in
vitro, animal'' in the fourth sentence after the heading and replacing
it with the word ``nonclinical''.
0
11. Section 312.33(b)(6) is amended by:
0
a. Removing the phrase ``preclinical studies (including animal
studies)'' and replacing it with the phrase ``nonclinical studies'';
and
0
b. Removing the phrase ``preclinical findings'' at the end of the
sentence and replacing it with the phrase ``nonclinical findings''.
0
12. Section 312.82 is amended by:
0
a. Removing the word ``preclinical'' in the first sentence of the
section and replacing it with the word ``nonclinical''; and
0
b. Amending paragraph (a) by removing the word ``animal'' and replacing
it with the word ``nonclinical''.
0
13. Section 312.86 is amended by removing the word ``preclinical'' and
replacing it with the word ``nonclinical''.
0
14. Section 312.88 is amended by removing the word ``animal'' and
replacing it with the word ``nonclinical''.
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
0
15. The authority citation for part 314 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f,
356, 356a, 356b, 356c, 356e, 360cc, 360ddd, 360ddd-1, 371, 374,
379e, 379k-1.
0
16. Section 314.3(b) is amended by adding, after the definition of
``Newly acquired information,'' the following definition of
``nonclinical study'':
Sec. 314.3 Definitions.
* * * * *
(b) * * *
Nonclinical study means a test or study conducted in vitro, in
silico, or in chemico, or a nonhuman in vivo test or
[[Page 60051]]
study. Such test or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
* * * * *
0
17. Section 314.50(d)(2) is amended by:
0
a. Removing the phrase ``animal and in vitro studies with drug'' in the
sentence after the heading and replacing it with the phrase
``nonclinical studies with the drug'';
0
b. Amending paragraph (iv) by inserting the word ``nonclinical'' before
the word ``studies''; and
0
c. Amending paragraph (iv) by removing the phrase ``in animals'' at the
end of the sentence.
0
18. Section 314.50(d)(4)(ii) is amended by
0
a. Removing the word ``spectra'' and replacing it with the word
``spectrum''; and
0
b. Removing the phrase ``in vitro preclinical'' and replacing it with
the word ``nonclinical''.
0
19. Section 314.50(d)(5)(i) is amended by removing the word ``animal''
and replacing it with the word ``nonclinical''.
0
20. Section 314.50(d)(5)(vi) is amended by:
0
a. Removing the word ``animal'' in paragraph (a) and replacing it with
the word ``nonclinical''; and
0
b. Removing the word ``animal'' in paragraph (b) and replacing it with
the word ``nonclinical''.
0
21. Section 314.81(b)(2)(v) is amended by removing the phrase
``toxicological findings in animal studies and in vitro studies (e.g.,
mutagenicity)'' and replacing it with the phrase ``nonclinical
toxicological findings, including, for example, from mutagenicity
studies''.
0
22. Section 314.81(b)(2)(vii)(a)(7) is amended by removing the phrase
``an animal'' and replacing it with the phrase ``a nonclinical'' in the
first sentence after the header.
0
23. Section 314.93(e)(2) is amended by removing the word ``animal'' and
replacing it with the word ``nonclinical''.
0
24. Section 314.200(d)(3) is amended by removing the word ``Animal''
and replacing it with the word ``Nonclinical.''
0
25. Section 314.430(a) is amended by removing the phrase ``all studies
and tests of a drug on animals and humans'' and replacing it with the
phrase ``all nonclinical and clinical studies and tests of a drug.''
PART 315--DIAGNOSTIC RADIOPHARMACEUTICALS
0
26. The authority citation for part 315 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374,
379e; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355
note).
0
27. Section 315.2 is amended to read as follows:
Sec. 315.2 Definitions.
(a) For purposes of this part, diagnostic radiopharmaceutical
means:
(1) An article that is intended for use in the diagnosis or
monitoring of a disease or a manifestation of a disease in humans and
that exhibits spontaneous disintegration of unstable nuclei with the
emission of nuclear particles or photons; or
(2) Any nonradioactive reagent kit or nuclide generator that is
intended to be used in the preparation of such article as defined in
paragraph (a)(1) of this section.
(b) For purposes of this part, nonclinical study means a test or
study conducted in vitro, in silico, or in chemico, or a nonhuman in
vivo test or study. Such test or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
0
28. Section 315.6(c)(2) is amended by removing the word ``preclinical''
and replacing it with ``nonclinical''.
0
29. Section 315.6(d) is amended by removing the word ``animal'' and
replacing it with ``nonclinical''.
PART 361--PRESCRIPTION DRUGS FOR HUMAN USE GENERALLY RECOGNIZED AS
SAFE AND EFFECTIVE AND NOT MISBRANDED: DRUGS USED IN RESEARCH
0
30. The authority citation for part 361 continues to read as follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 371; 42 U.S.C.
262.
0
31. Section 361.1(d)(7) is amended in the second sentence after the
heading by removing the phrase ``animal studies'' and replacing it with
the phrase ``nonclinical studies, as defined in Sec. 312.3(b) of this
chapter''.
PART 601--LICENSING
0
32. The authority citation for part 601 continues to read as follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322
(21 U.S.C. 355 note), sec 7002(e), Pub. L. 111-148, 124 Stat. 817,
as amended by sec. 607, Division N, Pub. L. 116-94, 133 Stat. 3127.
0
33. Section 601.31 is amended to read as follows:
Sec. 601.31 Definitions.
(a) For purposes of this part, diagnostic radiopharmaceutical
means:
(1) An article that is intended for use in the diagnosis or
monitoring of a disease or a manifestation of a disease in humans and
that exhibits spontaneous disintegration of unstable nuclei with the
emission of nuclear particles or photons; or
(2) Any nonradioactive reagent kit or nuclide generator that is
intended to be used in the preparation of such article as defined in
paragraph (a)(1) of this section.
(b) For purposes of this part, nonclinical study means a test or
study conducted in vitro, in silico, or in chemico, or a nonhuman in
vivo test or study. Such test or study may include the following:
(1) Cell-based assays.
(2) Organ chips and microphysiological systems.
(3) Computer modeling.
(4) Other nonhuman or human biology-based test methods, such as
bioprinting.
(5) Animal tests or studies.
0
34. Section 601.35(c)(2) is amended by removing the word
``preclinical'' and replacing it with the word ``nonclinical''.
0
35. Section 601.35(d) is amended by removing the word ``animal'' and
replacing it with the word ``nonclinical''.
0
36. Section 601.70(b)(7) is amended by removing the phrase ``an
animal'' and replacing it with the phrase ``a nonclinical''.
Robert F. Kennedy, Jr.,
Secretary, Department of Health and Human Services.
[FR Doc. 2026-19349 Filed 9-21-26; 8:45 am]
BILLING CODE 4164-01-P
</pre></body>
</html>Indexed from Federal Register on September 22, 2026.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.