Rule2026-19350
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
Effective
February 4, 2027
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, Agency, or we) is issuing a direct final rule that substitutes references to "animal" tests or studies with "nonclinical" tests or studies, adds a definition of the terms "nonclinical test" and "nonclinical study," and makes other comparable or conforming amendments in certain safety and reporting sections of its regulations. The direct final rule also substitutes "nonclinical" for "preclinical" and "in vitro" for consistency in terminology. The Agency is issuing these amendments directly as a final rule because we believe they are noncontroversial changes in terminology that are not expected to affect industry practice and FDA anticipates no significant adverse comments. These 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 rule adds no new requirements.
Full Text
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<title>Federal Register, Volume 91 Issue 182 (Tuesday, September 22, 2026)</title>
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[Federal Register Volume 91, Number 182 (Tuesday, September 22, 2026)]
[Rules and Regulations]
[Pages 59988-60004]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-19350]
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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: Direct final rule.
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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
issuing a direct final rule that substitutes references to ``animal''
tests or studies with ``nonclinical'' tests or studies, adds a
definition of the terms ``nonclinical test'' and ``nonclinical study,''
and makes other comparable or conforming amendments in certain safety
and reporting sections of its regulations. The direct final rule also
substitutes ``nonclinical'' for ``preclinical'' and ``in vitro'' for
consistency in terminology. The Agency is issuing these amendments
directly as a final rule because we believe they are noncontroversial
changes in terminology that are not expected to affect industry
practice and FDA anticipates no significant adverse comments. These
amendments align with recent amendments to the Federal
[[Page 59989]]
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 rule adds no new requirements.
DATES: This rule is effective February 4, 2027. Either electronic or
written comments on the direct final rule or its companion proposed
rule must be submitted by December 7, 2026. If FDA receives no
significant adverse comments within the specified comment period, the
Agency intends to publish a document confirming the effective date of
the direct final rule in the Federal Register within 30 days after the
comment period on this direct final rule ends. If timely significant
adverse comments are received, the Agency will publish a document in
the Federal Register withdrawing this direct final rule within 30 days
after the comment period on this direct final rule ends.
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 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 Direct Final Rule
B. Summary of the Major Provisions of the Direct Final Rule
C. Legal Authority
D. Costs and Benefits
II. Direct Final Rulemaking Procedures
III. Table of Abbreviations/Commonly Used Acronyms in This Document
IV. Background
A. Need for the Regulation
B. FDA's Current Regulatory and Policy Framework
V. Description of the Direct Final 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
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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 Direct Final 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.
Because we believe the rule contains noncontroversial changes and
we do not expect significant adverse comment on the rulemaking, we are
using direct final rulemaking procedures, as described in this
document. We are also publishing elsewhere in this issue of the Federal
Register a companion proposed rule proposing to take the actions
described in this direct final rule. The companion proposed rule
provides a procedural framework within which the rule may be finalized
if the direct final rule is withdrawn because of any significant
adverse comments. The comment period for the direct final rule runs
concurrently with the comment period for the companion proposed rule.
Any comments received in response to the companion proposed rule will
be considered as comments regarding the direct final rule.
B. Summary of the Major Provisions of the Direct Final Rule
This direct final rule substitutes the terms ``nonclinical test''
or ``nonclinical study'' for the terms ``animal test, '' ``animal
study,'' ``preclinical test,'' and ``in vitro test,'' and makes 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
also adds 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 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\
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\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).
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C. Legal Authority
FDA is issuing this rule under the authority granted to it by 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 direct final 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 direct final rule substitutes ``nonclinical'' for ``animal''
in phrases like ``animal test'' and ``animal study;'' substitutes
``nonclinical'' for ``preclinical'' and ``in vitro'' for consistency in
terminology; and adds a definition of ``nonclinical test'' and
``nonclinical study'' to the definitions section of several of FDA's
drug and biological product regulations. This rule imposes no new
requirements on industry and so is expected to generate no costs. The
rule 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 final 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, we conclude this direct
final rule is classifiable as an Executive Order 14192 deregulatory
action.
II. Direct Final Rulemaking Procedures
In the document titled ``Guidance for FDA and Industry: Direct
Final Rule Procedures,'' announced and provided in the Federal Register
of November 21, 1997 (62 FR 62466), FDA described its procedures on
when and how we will employ direct final rulemaking. 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>. We have determined that this rule is appropriate for
direct final rulemaking because we believe that it includes only
noncontroversial amendments and we anticipate no significant adverse
comments. Consistent with our procedures on direct final rulemaking,
FDA is also publishing elsewhere in this issue of the Federal Register
a companion proposed rule with the regulatory amendments described in
this direct final rule. The companion proposed rule provides a
procedural framework within which the rule may be finalized in the
event that the direct final rule is withdrawn because of any
significant adverse comments. The comment period for the direct final
rule runs concurrently with the comment period for the companion
proposed rule. Any comments received in response to the companion
proposed rule will be considered as comments regarding the direct final
rule.
We are providing a comment period on the direct final rule of 75
days after the date of publication in the Federal Register. If we
receive any significant adverse comments, we intend to withdraw this
direct final rule before its effective date by publication of a notice
in the Federal Register. A significant adverse comment is defined as a
comment that explains why the rule would be inappropriate, including
challenges to the rule's underlying
[[Page 59991]]
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 this direct
final rule would not be considered a significant adverse comment unless
the comment states why the rule would be ineffective without the
additional change. In addition, if a significant adverse comment
applies to part of this 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 subject to the significant adverse comment.
If any significant adverse comments are received during the comment
period, FDA will publish in the Federal Register, before the effective
date of this direct final rule, a notice of significant adverse comment
and withdraw the direct final rule. If we withdraw the direct final
rule, any comments received will be applied to the proposed rule and
will be considered in developing a final rule using the usual notice-
and-comment procedures.
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
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Abbreviation/acronym What it means
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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.
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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:
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\2\ Two subsecs. (z) have been enacted in Section 505. Both were
enacted in the Consolidated Appropriations Act, 2023 (Pub. L. 117-
328).
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[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, and potency under certain conditions of
use.
This direct final rule aligns 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
[[Page 59992]]
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 direct
final 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.
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\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.
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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 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
[[Page 59993]]
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 direct final 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 Direct Final Rule
The rule amends 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:
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\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.''
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<bullet> Amends 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 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 adding include an illustrative, non-exhaustive list
of examples of nonclinical tests and studies. We broadened the
definition compared to 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 adopting 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 to use ``nonclinical study'' or
``nonclinical test''.
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\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.
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<bullet> Amends 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 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
does not in practice expand the scope of data that must be reviewed,
submitted, or reported under the affected provisions because the
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).
1. Section 312.3(b)
Section 312.3(b) lists definitions in alphabetical order that apply
to part 312. We are amending Sec. 312.3(b) by adding, after the
definition of ``Marketing application,'' the following definition \6\
of the terms ``nonclinical test'' and ``nonclinical study'':
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\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.
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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
[[Page 59994]]
animal toxicology studies or other human studies as appropriate.'' We
are amending the paragraph by replacing ``animal'' with
``nonclinical.'' This 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.
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 amending the paragraph by replacing the word
``animals'' with the phrase ``nonclinical studies.'' While this change
expands 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 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 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.
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 amending the regulation
by replacing the word ``animals'' with the phrase ``nonclinical
studies.'' This change adds flexibility and clarifies 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 does 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 does 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.
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 amending the regulation by
replacing the word ``animals'' with the phrase ``nonclinical studies.''
This change provides flexibility and clarifies that the
pharmacokinetics and biological disposition of the drug may be derived
from a broader range of studies than animal studies. This change does
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
does 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.
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 amending these two sentences in the regulation by replacing the
phrase ``pharmacological and toxicological studies of the drug
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 change provides flexibility and clarifies 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 does not mandate what types of studies are performed to
generate this information; rather, it requires 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 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 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. The remainder of
this paragraph, describing FDA guidance
[[Page 59995]]
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 amending the
regulation by replacing the word ``animals'' with the phrase
``nonclinical tests.'' This change provides flexibility and clarifies
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. It does 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 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 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.
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 amending 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
change provides flexibility and clarifies 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 direct final rule to encompass
all nonclinical testing conducted outside of humans and this change is
consistent with that position. It does not mandate what types of
studies are performed to generate this information but continues to
require submission in the IND of this information regardless of the
type of nonclinical study generating the data. 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
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.
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 amending 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 provides flexibility
and clarifies 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. It does not
mandate what types of studies are performed to generate this
information but continues to require submission in the IND of this
information regardless of the type of nonclinical study generating the
data. 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 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.
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 amending the regulation by replacing the
word ``animal'' with the word ``nonclinical.'' This change adds
flexibility and clarifies 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. It does 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. 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.
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 amending the regulation by replacing
[[Page 59996]]
the phrase ``animal or in vitro studies'' with the phrase ``nonclinical
studies.'' This 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 change does 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 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 change does 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 amending the
regulation by replacing the phrase ``animal or in vitro'' with the word
``nonclinical'' in both the heading and first sentence. This change
clarifies 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 change brings the
language up-to-date, consistent with scientific progress and the
modernization of testing methods; it does 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 amending the regulation by replacing
the phrase ``in vitro, animal'' with ``nonclinical'' in this sentence.
This 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 conforms 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 does 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
amending the regulation by replacing the phrase ``preclinical studies
(including animal studies)'' with ``nonclinical studies'' and replacing
``preclinical findings'' with ``nonclinical findings.'' This change
conforms 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 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 change does 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 humans), the 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 does 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 amending the regulation by replacing
``preclinical'' with ``nonclinical.'' This change conforms 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 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 amending the
regulation by replacing ``animal'' with ``nonclinical.'' This change
provides flexibility and clarifies 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
[[Page 59997]]
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 amending this paragraph by replacing
``preclinical'' with ``nonclinical.'' This change conforms this
regulation with the changes we are making in the rest of part 312 and
will 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 amending the regulation by replacing ``animal'' with
``nonclinical'' to conform to the changes we are making 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 amending 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 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 direct final
rule, all 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 amending 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 provides flexibility and clarifies 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,
it 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.
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 amending this sentence to read: ``Any nonclinical
studies of the absorption, distribution, metabolism, and excretion of
the drug.'' This change provides flexibility and clarifies 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. It does 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.
4. Section 314.50(d)(4)(ii)
Section 314.50(d)(4)(ii) requires that the microbiology section of
an NDA for 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 amending the regulation by replacing the
phrase ``in vitro preclinical'' with ``nonclinical.'' This change
provides flexibility and clarifies that we will accept additional types
of nonclinical studies to support the microbiology section of an NDA
for an anti-infective drug. It 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. We also are correcting 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 amending the regulation by replacing the word
``animal'' with ``nonclinical''. This change provides flexibility and
clarifies 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. It
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.
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
[[Page 59998]]
from epidemiological studies of related drugs.'' We are amending the
regulation by replacing the word ``animal'' with ``nonclinical.'' This
change clarifies that ``all available information about the safety of
the drug product'' includes pertinent nonclinical data not obtained
from animals. It does not require that applicants conduct additional
studies. It 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 amending 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 does 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.'' It 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 amending 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 change does not require NDA holders
to conduct new or additional studies. It 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 amending the regulation by replacing the phrase
``an animal'' with ``a nonclinical.'' This change provides 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 314.81(b)(2)(vii)(a) is limited to postmarketing study
commitments and this 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 amending Sec. 314.93(e)(2) by replacing
``animal'' with ``nonclinical.'' This change in terminology does 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. It brings 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 provides flexibility and clarifies 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, 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 amending 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 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
[[Page 59999]]
diagnostic radiopharmaceuticals. We are amending 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
adding, 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 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 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 amending the regulation by
replacing ``preclinical'' with ``nonclinical.'' This 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 revision does 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 amending the regulation by replacing the phrase
``animal'' with ``nonclinical.'' This change provides flexibility and
clarifies 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.
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 amending the regulation by replacing ``animal
studies'' with ``nonclinical studies, as defined in Sec. 312.3(b) of
this chapter.'' This change adds flexibility and clarifies 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.
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 amending the section by first
redesignating the introductory text as paragraph (a) and redesignating
current 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
adding, 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 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 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 amending the regulation by
replacing ``preclinical'' with ``nonclinical.'' This change conforms
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 amending the regulation by replacing ``animal'' with
``nonclinical.'' This change conforms the terminology in this
regulation with that used in its counterpart regulation section
315.6(d) and is being made for the same reasons; as noted earlier, part
of the intent of this rule is to bring more
[[Page 60000]]
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 amending the regulation by replacing
the phrase ``an animal'' with ``a nonclinical'' in this provision. This
change provides 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. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the direct final rule under
Executive Order 12866, Executive Order 13563, Executive Order 14192,
the Regulatory Flexibility Act (5 U.S.C. 601-612), the Congressional
Review Act/Small Business Regulatory Enforcement Fairness Act (5 U.S.C.
801, Pub. L. 104-121), 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 direct final 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 direct final rule
is classifiable as an Executive Order 14192 deregulatory action.
Because this rule is not likely to result in an annual effect on
the economy of $100 million or more or to meet other criteria specified
in the Congressional Review Act/Small Business Regulatory Enforcement
Fairness Act, OIRA has determined that this rule does not fall within
the scope of 5 U.S.C. 804(2).
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 direct final rule will produce
no quantifiable costs, we certify that this direct final rule will not
have a significant economic impact on a substantial number of small
entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes 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. This direct final rule will not result in an
expenditure in any year that meets or exceeds this amount.
B. Overview of Benefits, Costs, and Transfers
This direct final rule substitutes ``nonclinical'' for ``animal''
in phrases like ``animal test,'' substitutes ``nonclinical'' for
``preclinical'' and ``in vitro'' for consistency in terminology, and
adds 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 rule substitutes the term
``nonclinical'' for the paired terms ``animal'' and ``in vitro,'' this
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
direct final 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, this rule imposes no new
requirements on industry and so is expected to generate no costs.
Hence, we estimate that this direct final 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, this direct
final 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 direct
final 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.
[[Page 60001]]
Table 1--Summary of Benefits, Costs, and Distributional Effects of the Direct Final Rule
[Millions of 2025 dollars]
----------------------------------------------------------------------------------------------------------------
Units
Primary Low High ----------------------------------
Category estimate estimate estimate Year Discount Period Notes
dollars rate (%) covered
----------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $0 $0 $0 2025 7 2025-2034
($millions/year).............
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 0 0 0 2025 7 2025-2034
($millions/year).............
0 0 0 2025 3 2025-2034
Annualized Quantified......... ......... ......... ......... ......... 7 ..........
......... ......... ......... ......... 3 ..........
-----------------------------------------------------------------------------
Qualitative.
----------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized ......... ......... ......... ......... 7 ..........
($millions/year).............
......... ......... ......... ......... 3 ..........
-----------------------------------------------------------------------------
From:
To:
-----------------------------------------------------------------------------
Other Annualized Monetized ......... ......... ......... ......... 7 ..........
($millions/year).............
......... ......... ......... ......... 3 ..........
-----------------------------------------------------------------------------
From:
To:
----------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government: None.....................................................................
Small Business: None........................................................................................
Wages: None.................................................................................................
Growth: None................................................................................................
----------------------------------------------------------------------------------------------------------------
This direct final rule addresses provisions in human drug and
biological product regulations that refer to animal studies or tests.
It implements 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 direct final rule will 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 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 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, 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 direct final 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 time horizon. Since this final 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, we conclude this direct final 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
----------------------------------------------------------------------------------------------------------------
[[Page 60002]]
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 concludes that this direct final 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 direct final rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this direct final 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 direct final rule in accordance with the
principles set forth in Executive Order 13175. We have determined that
the rule does not contain policies that would have a substantial direct
effect on one or more Indian Tribes, on the relationship between the
Federal Government and Indian Tribes, or on the distribution of power
and responsibilities between the Federal Government and Indian Tribes.
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), 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, 21 CFR parts
312, 314, 315, 361, and 601 are 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.
[[Page 60003]]
0
2. In Sec. 312.3, amend paragraph (b), by adding in alphabetical order
the definition for ``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.
* * * * *
Sec. 312.22 [Amended]
0
3. In Sec. 312.22, amend paragraph (c) in the second sentence by
removing the word ``animal'' and adding in its place the word
``nonclinical''.
0
4. Amend Sec. 312.23 by:
0
a. In paragraph (a)(3)(iv)(f), removing the word ``animals'' and adding
in its place the phrase ``nonclinical studies'';
0
b. In paragraphs (a)(5)(ii) and (iii), removing the word ``animals'',
wherever it appears, and adding in its place the phrase ``nonclinical
studies'';
0
c. Revising paragraph (a)(8);
0
d. In paragraph (a)(10)(i), removing the phrase ``clinical studies and
experience and studies in test animals'' and adding in its place the
phrase ``clinical and nonclinical studies and experience''; and
0
e. In paragraph (a)(10)(ii), removing the word ``animal'' and adding in
its place the word ``nonclinical''.
The revisions 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. Guidance
documents are available from FDA that describe ways in which these
requirements may be met. Such information is required to include the
identification and qualifications of the individuals who evaluated the
results of such studies and concluded that it is reasonably safe to
begin the proposed investigations and a statement of where the
investigations were conducted and where the records are available for
inspection. As drug development proceeds, the sponsor is required to
submit informational amendments, as appropriate, with additional
information pertinent to safety.
(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.
(B) For each toxicology study that is intended primarily to support
the safety of the proposed clinical investigation, a full tabulation of
data suitable for detailed review.
* * * * *
Sec. 312.32 [Amended]
0
5. Amend Sec. 312.32 by:
0
a. In paragraph (b), removing the phrase ``animal or in vitro studies''
and adding in its place the phrase ``nonclinical studies'';
0
b. In paragraph (c)(1)(iii), removing the phrase ``animal or in
vitro'', wherever it appears, and adding in its place the word
``nonclinical''; and
0
c. In paragraph (c)(1)(v), removing the phrase ``in vitro, animal'',
wherever it appears, and adding in its place the word ``nonclinical''.
Sec. 312.33 [Amended]
0
6. In Sec. 312.33, amend paragraph (b)(6) by:
0
a. Removing the phrase ``preclinical studies (including animal
studies)'' and adding in its place the phrase ``nonclinical studies'';
and
0
b. Removing the phrase ``preclinical findings'' at the end of the
sentence and adding in its place the phrase ``nonclinical findings''.
Sec. 312.82 [Amended]
0
7. Amend Sec. 312.82 by:
0
a. Removing the word ``preclinical'' and adding in its place the word
``nonclinical''; and
0
b. Removing the word ``animal'' and adding in its place the word
``nonclinical''.
Sec. 312.86 [Amended]
0
8. Amend Sec. 312.86 by removing the word ``preclinical'' and adding
in its place the word ``nonclinical''.
Sec. 312.88 [Amended]
0
9. Amend Sec. 312.88 by removing the word ``animal'' and adding in its
place the word ``nonclinical''.
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
0
10. 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
11. In Sec. 314.3, amend paragraph (b), by adding in alphabetical
order the definition for ``nonclinical study'' to read as follows:
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 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.
* * * * *
Sec. 314.50 [Amended]
0
12. Amend Sec. 314.50 by:
0
a. In paragraph (d)(2) introductory text, removing the phrase ``animal
and in vitro studies with drug'' and adding in its place the phrase
``nonclinical studies with the drug'';
0
b. In paragraph (d)(2)(iv), adding the word ``nonclinical'' before the
word ``studies'', and removing the phrase ``in animals'' at the end of
the sentence;
0
c. In paragraph (d)(4)(ii), removing the word ``spectra'' and adding in
its place the word ``spectrum'', and removing the phrase ``in vitro
preclinical'' and adding in its place the word ``nonclinical'';
0
d. In paragraph (d)(5)(i), removing the word ``animal'' and adding in
its place the word ``nonclinical'';
0
e. Redesignating paragraphs (d)(5)(vi)(a) and (d)(5)(vi)(b) as
[[Page 60004]]
paragraphs (d)(5)(vi)(A) and (d)(5)(vi)(B);
0
f. In newly redesignated paragraph (d)(5)(vi)(A), removing the word
``animal'' in paragraph (a) and adding in its place the word
``nonclinical''; and
0
g. In newly redesignated paragraph (d)(5)(vi)(B), removing the word
``animal'' in paragraph (b) and adding in its place the word
``nonclinical''.
Sec. 314.81 [Amended]
0
13. Amend Sec. 314.81 by:
0
a. In paragraph (b)(2)(v), removing the phrase ``toxicological findings
in animal studies and in vitro studies (e.g., mutagenicity)'' and
adding in its place the phrase ``nonclinical toxicological findings,
including, for example, from mutagenicity studies''; and
0
b. In paragraph (b)(2)(vii)(a)(7), removing the phrase ``an animal''
and adding in its place the phrase ``a nonclinical''.
Sec. 314.93 [Amended]
0
14. In Sec. 314.93, amend paragraph (e)(2) by removing the word
``animal'' and adding in its place the word ``nonclinical''.
Sec. 314.200 [Amended]
0
15. In Sec. 314.200, in the analysis format in paragraph (d)(3), amend
the heading for item I.A. by removing the word ``Animal'' and adding in
its place the word ``Nonclinical.''
Sec. 314.430 [Amended]
0
16. In Sec. 314.430, amend paragraph (a) by removing the phrase ``all
studies and tests of a drug on animals and humans'' and adding in its
place the phrase ``all nonclinical and clinical studies and tests of a
drug''.
PART 315--DIAGNOSTIC RADIOPHARMACEUTICALS
0
17. 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
18. Revise Sec. 315.2 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.
Sec. 315.6 [Amended]
0
19. Amend Sec. 315.6 by:
0
a. In paragraph (c)(2), removing the word ``preclinical'' and adding in
its place the word ``nonclinical''; and
0
b. In paragraph (d), removing the word ``animal'' and adding in its
place the word ``nonclinical''.
PART 361--PRESCRIPTION DRUGS FOR HUMAN USE GENERALLY RECOGNIZED AS
SAFE AND EFFECTIVE AND NOT MISBRANDED: DRUGS USED IN RESEARCH
0
20. 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.
Sec. 361.1 [Amended]
0
21. In Sec. 361.1, amend paragraph (d)(7) by removing the phrase
``animal studies'' and adding in its place the phrase ``nonclinical
studies, as defined in Sec. 312.3(b) of this chapter''.
PART 601--LICENSING
0
22. 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
23. Revise Sec. 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.
Sec. 601.35 [Amended]
0
24. Amend Sec. 601.35 by:
0
a. In paragraph (c)(2), removing the word ``preclinical'' and adding in
its place the word ``nonclinical''; and
0
b. In paragraph (d), removing the word ``animal'' and adding in its
place the word ``nonclinical''.
Sec. 601.70 [Amended]
0
25. In Sec. 601.70, amend paragraph (b)(7) by removing the phrase ``an
animal'' and adding in its place the phrase ``a nonclinical''.
Robert F. Kennedy, Jr.,
Secretary, Department of Health and Human Services.
[FR Doc. 2026-19350 Filed 9-21-26; 8:45 am]
BILLING CODE 4164-01-P
</pre></body>
</html>Indexed from Federal Register on September 22, 2026.
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