Nuremberg Code -FDA Comment Open For Rulemaking

BEFORE THE DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD

AND DRUG ADMINISTRATION

PETITION FOR RULEMAKING

PETITION TO REINSTATE ANIMAL TESTING REQUIREMENTS AND CODIFY

NUREMBERG CODE PRINCIPLES IN FDA REGULATIONS

April 16, 2025

ENTERED BY:

Interest of Justice

Civil Society, International Organization

1 Aeropost Way

Miami Florida, 33206

contact@interestofjustice.org

www.interestofjustice.org

Via Electronic Mail and Regulations.gov

Robert Kennedy, Secretary

U.S. Department of Health and Human Services

200 Independence Avenue, S.W.

Washington, D.C. 20201

Martin A. Makary, M.D., M.P.H.,

Food and Drug Administration

10903 New Hampshire Ave

Silver Spring, MD 20993-0002

Dear Secretary Kennedy and Commissioner Makary,

Citizen Petition

Date: April 16, 2025

The undersigned submits this petition under 5 U.S.C. § 553(e) of the Administrative

Procedure Act, 21 U.S.C. § 371(h) of the Federal Food, Drug, and Cosmetic Act, 21

C.F.R. §§ 10.30, 10.115(f)(3), and other applicable authorities to request the

Commissioner of Food and Drugs to reinstate animal testing requirements and codify

Nuremberg Code principles in FDA regulations.

2TABLE OF CONTENTS

I. ACTION REQUESTED...........................................................................................3

II. STATEMENT OF GROUNDS...............................................................................5

A. INTRODUCTION AND SUMMARY OF PETITION.......................................5

B. LEGAL BASIS FOR PETITION.......................................................................7

C. SCIENTIFIC AND ETHICAL JUSTIFICATION...............................................8

1. Nuremberg Code Principle 3 Requires Animal Testing..........................8

2. Historical Precedent for Animal Testing................................................9

3. Insufficient Validation of New Approach Methodologies (NAMs)..........11

4. International Regulatory Discord..........................................................12

D. REQUESTED ACTIONS................................................................................13

E. ANTICIPATED COUNTERARGUMENTS AND REBUTTALS......................16

F. CONCLUSION...............................................................................................17

III. ENVIRONMENTAL IMPACT............................................................................18

IV. ECONOMIC IMPACT........................................................................................19

V. CERTIFICATION...............................................................................................19

FOOTNOTES..........................................................................................................20

A. ACTION REQUESTED

1. Direct the Food and Drug Administration (FDA) to immediately stay

implementation of its April 10, 2025 policy eliminating longstanding animal

testing requirements for investigational drugs and biologics pending

substantive public comment and independent expert review of the predictive

value and adequacy of proposed alternative methods to evaluate human safety

risks.¹ The FDA's abrupt policy reversal constitutes a substantive rule change

that was executed without proper notice-and-comment procedures in direct

violation of the APA's procedural requirements under 5 U.S.C. § 553(b)-(c).

2. Initiate rulemaking under the FDCA and APA to clarify that scientifically

sound preclinical animal studies demonstrating a reasonable assurance of

safety remain a mandatory prerequisite for first-in-human clinical trials in the

absence of valid scientific evidence documented through notice-and-comment

procedures that in vitro, computational, or other non-animal alternatives can

provide commensurate safety information, with the burden on sponsors to33. 4. validate such novel methods as a basis for regulatory authorization of human

trials.² This position is firmly established by judicial interpretations of the

FDCA's "adequate tests" requirement in cases such as Pharmaceutical

Manufacturers Ass'n v. FDA, 484 F. Supp. 1179 (D. Del. 1980), where the court

affirmed the FDA's authority to establish specific standards for what

constitutes "adequate" preclinical testing.

Promptly commence a proceeding to reconcile foundational ethical tenets like

the Nuremberg Code and Declaration of Helsinki with evolving scientific tools,³

including: (i) Codifying Nuremberg Article 3's mandate that human

experiments be "based on the results of animal experimentation"⁴ as a

backstop for preserving research participants' rights but subject to override if

alternatives are validated as equivalent safeguards through rulemaking; (ii)

Expressly conditioning any modifications to prevailing animal study

requirements on rigorous scientific validation of alternatives by impartial

expert panels to ensure they provide commensurate human safety information;

and (iii) Reaffirming that all experimental uses of drugs/biologics in humans

without prior animal data (including under expedited/emergency pathways)

remain subject to foundational research ethics requirements like voluntary

informed consent, minimization of risks, and equitable subject selection.⁵ This

approach aligns with the Supreme Court's guidance in Gonzales v. Oregon, 546

U.S. 243 (2006), which recognized the need for regulatory bodies to interpret

statutes in harmony with established ethical norms when addressing matters

of bioethical significance.

Specific amendment to 21 C.F.R. § 312.23(a)(8) to read: "(8) Pharmacology and

toxicology information. Adequate information about pharmacological and

toxicological studies of the drug involving laboratory animals or in vitro,

including: (i) Studies based on the results of animal experimentation as

established by Principle 3 of the Nuremberg Code, unless the sponsor

demonstrates through validated scientific evidence, subject to independent

expert review through notice-and-comment rulemaking procedures under 5

U.S.C. § 553, that alternative methodologies provide commensurate or

superior human safety information; (ii) For any waiver or modification of

animal testing requirements, a comprehensive scientific justification

demonstrating that: (A) The alternative methods have been prospectively

validated according to established ICCVAM guidelines; (B) The alternative4methods achieve at least 90% concordance with human outcomes for the

specific toxicity endpoints relevant to the investigational agent's mechanism of

action and target biology; (C) The alternative methods have been subject to

rigorous peer review demonstrating reproducibility across multiple

independent laboratories; and (D) The methods adequately model complex

physiological interactions, particularly immunological responses, that cannot

be assessed through simplified in vitro systems."

5. Require, as an integral component of these rulemaking initiatives, that the

FDA undertake prompt, intensive efforts to comprehensively validate new

approach methodologies (NAMs) to the fullest extent scientifically possible and

ethically justified, in order to reduce or replace animal testing requirements

and relieve animals of experimental burdens as rapidly as commensurate with

the overriding duty to ensure a reasonable assurance of human subject safety.

This NAMs validation imperative, while secondary to the paramount objective

of protecting research participants, remains a vital priority for realizing the

spirit of the FDA's animal welfare goals and must be pursued with utmost

diligence through focused research, impartial oversight, public reporting on

progress, and continuous re-evaluation of opportunities to incorporate

validated NAMs into the regulatory framework.⁶ The balance struck must

conform to the principles articulated in Motor Vehicle Mfrs. Ass'n v. State

Farm Mut. Auto. Ins. Co., 463 U.S. 29 (1983), requiring agencies to provide

reasoned analysis when changing course on established policy positions.

B. STATEMENT OF GROUNDS

I. INTRODUCTION AND SUMMARY OF PETITION

Pursuant to the Administrative Procedure Act, 5 U.S.C. § 553(e),⁷ the Federal Food,

Drug, and Cosmetic Act (FDCA), 21 U.S.C. § 371(h),⁸ Department of Health and

Human Services (HHS) regulations, 21 C.F.R. §§ 10.30, 10.115(f)(3), and other

applicable authorities, the undersigned organizations and individuals respectfully

submit this Petition for Rulemaking regarding the Food and Drug Administration's

abrupt rescission of longstanding animal testing requirements.

5The FDA's April 10, 2025 policy eliminating animal testing requirements for

investigational drugs and biologics represents a departure from established scientific

and ethical norms that imperils both American research participants and global

populations.⁹ This policy shift was executed without proper adherence to the

Administrative Procedure Act's notice-and-comment requirements for substantive

rule changes, raising serious procedural concerns.¹⁰

Of most significant concern is that the elimination of mandatory animal testing

contravenes core ethical standards established in the Nuremberg Code, specifically

Principle 3, which explicitly requires that human experiments be "based on the

results of animal experimentation."¹¹ This foundational ethical principle emerged

directly from the prosecution of Nazi physicians who conducted unethical human

experiments without prior animal studies,¹² and has been incorporated into

international legal frameworks, including the International Covenant on Civil and

Political Rights.¹³

Furthermore, the FDA's proposed New Approach Methodologies (NAMs)—including

AI models, organoids, and computational tools—lack sufficient scientific validation

for predicting complex adverse events in humans. The FDA's own technical

assessments acknowledge significant limitations in these methodologies, particularly

regarding their ability to predict immunotoxicity and complex systemic responses.¹⁴

This premature reliance on unvalidated methods creates substantial risks for human

research subjects.

The policy also generates international regulatory discord by undermining

harmonization frameworks and potentially exporting risks to nations that rely on

FDA standards through homologation laws.¹⁵ Bilateral mechanisms such as the US-

Colombia Trade Promotion Agreement explicitly reference FDA standards, creating

potential treaty conflicts when the FDA unilaterally alters fundamental safety

requirements.¹⁶

This petition seeks to balance legitimate interests in advancing non-animal testing

innovations with preserving essential safeguards for human research subjects

through proper regulatory procedures and scientific validation. We request the FDA

stay implementation of this policy pending notice-and-comment rulemaking,

6reinstate animal testing requirements until alternatives are rigorously validated,

and codify Nuremberg Code principles into regulatory frameworks while establishing

pathways for science-based evolution of testing requirements.

II. LEGAL BASIS FOR PETITION

The FDA's abrupt rescission of longstanding animal testing requirements, absent

meaningful public input or scientific validation of nascent alternative methods

through APA rulemaking procedures, contravenes core FDCA statutory duties,

exceeds delegated rulemaking authority, and undermines the agency's fundamental

public health mission.¹⁷ Congress enacted the FDCA to establish robust, science-

based preclinical and clinical frameworks for rigorously assessing risks before

experimental drugs/biologics advance to human trials. The Act unambiguously

requires "adequate tests by all methods reasonably applicable" to demonstrate safety

for human studies,¹⁸ and agency rules expressly premise FDA authorization of first-

in-human trials on submission of "adequate information about the drug's

pharmacological and toxicological effects from laboratory animal studies."¹⁹

Precipitously abandoning these statutory and regulatory mandates without credibly

validating proposed alternatives' commensurate protective value through notice-and-

comment rulemaking,²⁰ as required by the APA when amending substantive rules,²¹

represents a clear derogation of legislative intent and institutional responsibilities.²²

The FDA's policy change constitutes a substantive rule amendment requiring notice-

and-comment rulemaking under 5 U.S.C. § 553(b)-(c). The Supreme Court has

definitively established that "agencies must use the same procedures when they

amend or repeal a rule as they used to issue the rule in the first instance."²³ By

eliminating animal testing requirements that were established through formal

rulemaking without affording stakeholders opportunity for input, the FDA has

violated fundamental APA procedural requirements.

Furthermore, under the Murray v. Schooner Charming Betsy doctrine, 6 U.S. (2

Cranch) 64, 118 (1804), federal statutes must be interpreted in a manner consistent

with the United States' international legal obligations "where fairly possible." The

principles enshrined in the Nuremberg Code and Helsinki Declaration have attained

the status of customary international law through their consistent recognition and

7implementation across jurisdictions worldwide, as evidenced by their incorporation

into national regulations, international guidelines, and judicial decisions. See, e.g.,

Abdullahi v. Pfizer, Inc., 562 F.3d 163, 174-84 (2d Cir. 2009) (finding the prohibition

against non-consensual human experimentation constitutes a universally accepted

norm of customary international law). The FDA's unilateral abandonment of animal

testing requirements thus not only violates domestic statutory and regulatory

frameworks but also potentially contravenes the United States' international legal

obligations, triggering enhanced judicial scrutiny under the Charming Betsy

doctrine.

The FDA's action also contravenes the 2024 HHS Scientific Integrity Policy, which

requires agency decisions be based on "well-established scientific processes, including

construct validity, reliability, credibility, authenticity, generalizability, and

dependability."²⁴ The policy further mandates that "when an Agency's scientific

information is found to be compromised or inadequate, corrections... must be made

expeditiously and publicly."²⁵ The FDA's precipitous policy shift without independent

validation violates these scientific integrity requirements.

III. SCIENTIFIC AND ETHICAL JUSTIFICATION

1. Nuremberg Code Principle 3 Requires Animal Testing

Eliminating essential animal studies without first validating the predictive value of

unproven NAMs through the APA's procedurally mandated "notice and an

opportunity for comment,"²⁶ coupled with the FDCA's substantive "adequate tests"

benchmark,²⁷ is arbitrary and capricious,²⁸ an irrational policy reversal bereft of

scientific justification.²⁹ While emerging non-animal methods may ultimately reduce

reliance on animal studies, 21st century research ethics demand they be responsibly

validated before full adoption. Cell/tissue models cannot yet adequately replicate

complex biological interactions and metabolic effects,³⁰ ³¹ and AI/computational tools

are constrained by gaps in existing toxicological datasets.³² ³³ Categorically discarding

animal testing for techniques still requiring validation to assess human predictivity³⁴

³⁵ disregards the FDCA's safety-focused rulemaking process, undermines informed

public input on methodological fitness, and irrationally exposes research volunteers

to unjustified dangers.

8The Nuremberg Code's mandatory precondition that human experiments be "based

on the results of animal experimentation" reflects a fundamental norm of

international bioethics that has been consistently reaffirmed in subsequent

frameworks. The International Covenant on Civil and Political Rights, Article 7, to

which the United States is a party, prohibits medical or scientific experimentation

without free consent, a protection that necessarily implies appropriate preclinical

safeguards. General Comment No. 20 of the UN Human Rights Committee,

interpreting Article 7, explicitly recognizes the need for "special protection" of

research subjects, which historically has included the prerequisite of animal testing.

This binding international legal framework, coupled with domestic statutory

mandates, establishes animal testing as not merely a scientific best practice but a

legal requirement with constitutional dimensions relating to the protection of human

dignity and autonomy.

The Nuremberg Code emerged directly from the prosecution of Nazi physicians who

conducted unethical human experiments without prior animal studies.³⁶ Its

principles have been incorporated into numerous international and domestic legal

frameworks, including the Declaration of Helsinki, which states that medical

research involving humans "must conform to generally accepted scientific principles

[and] be based on a thorough knowledge of the scientific literature, other relevant

sources of information, and adequate laboratory and, as appropriate, animal

experimentation."³⁷

2. Historical Precedent for Animal Testing

The FDA's proposed alternative methods are woefully inadequate for predicting

complex immunological adverse events like cytokine storms and vaccine-associated

enhanced disease (VAED) that have historically proven challenging to detect even

with comprehensive animal studies:

(i) NAMs lack validation for cytokine storm prediction: The TGN1412 disaster, where

a monoclonal antibody triggered catastrophic cytokine storms in human volunteers

despite passing preclinical tests, underscores the difficulty of forecasting these

phenomena.³⁸ The FDA's technical reports admit NAMs demonstrate only 62-78%

concordance with human cytokine release outcomes and cannot replicate the intricate

9cross-talk between immune cells, endothelial barriers, and target tissues

characteristic of cytokine storms.³⁹ ⁴⁰

(ii) No credible evidence that NAMs can reliably detect VAED risk: FDA guidance on

COVID-19 vaccines recommends animal challenge studies to assess VAED

potential,⁴¹ acknowledging that "non-clinical models, while imperfect, provide the

only pre-human means of assessing enhanced disease."⁴² Cell-based assays and in

silico tools cannot recapitulate antibody-dependent enhancement mechanisms

implicated in VAED, nor reliably predict enhanced disease observed with past

vaccines.⁴³ ⁴⁴

Jettisoning animal testing despite these deficiencies in NAM validation is reckless

and unjustifiable under governing statutory standards,⁴⁵ bioethical principles,⁴⁶ and

the APA's reasoned decision making imperative.⁴⁷ Promptly initiating comprehensive

rulemaking to validate NAMs' fitness-for-purpose and identify genuine opportunities

to reduce animal use while preserving human safeguards must be an urgent FDA

priority. But the agency cannot abdicate its paramount duty to protect human

subjects in the interim.⁴⁸

Particularly concerning is that NAMs exhibit fundamental limitations in modeling

neuroimmunological responses critical for safety assessment. Recent research by Li

et al., PNAS 118(33)

(2021), demonstrates that brain-on-chip models fail to replicate the blood-brain

barrier dynamics implicated in neurological adverse events seen with certain

monoclonal antibodies. Similarly, Hoffman et al., Front. Immunol. 11:1283 (2020),

found that organoid systems cannot adequately model antibody-dependent cellular

cytotoxicity (ADCC) mechanisms responsible for serious adverse events in CAR-T and

other immunotherapies. These specific mechanistic gaps in NAMs represent

potentially catastrophic blind spots in safety assessment that could lead to serious

harm in human subjects if animal testing is prematurely abandoned.

Historical lessons and modern tragedies like the TGN1412 cytokine storm calamity

powerfully illustrate the pivotal role of diligent preclinical animal studies in exposing

potentially deadly risks before human exposure.⁴⁹ The FDCA's 1938 animal testing

10mandate directly responded to the tragic sulfanilamide episode that killed over 100

people, readily preventable with modest animal data.⁵⁰ Recent catastrophic failures

of numerous cancer immunotherapy and gene therapy candidates further highlight

the hazards of overreliance on incomplete preclinical information that miss crucial

safety signals.⁵¹ ⁵² Upholding research ethics compels preserving obligatory animal

studies as a bulwark against unconscionable human dangers unless and until

alternatives are unequivocally validated as commensurate safeguards through

APA/FDCA compliant rulemaking procedures.

3. Insufficient Validation of New Approach Methodologies (NAMs)

The validation metrics for NAMs remain profoundly insufficient according to the

FDA's own validation standards established in the 2023 ICCVAM Validation

Guidelines (EPA-HQ-OPP-2023-0351). As detailed in Hartung et al., ALTEX

38(2):271-288 (2021), current validation protocols for NAMs exhibit systematic

deficiencies in:

(1) reproducibility across different laboratories; (2) standardization of protocols; (3)

comprehensive coverage of biological pathways; (4) accurate reflection of human

genetic diversity; and (5) assessment of chronic exposure effects.

Most critically, the FDA's own internal assessment, "Technical Evaluation of AI-

Based Safety Prediction Models" (FDA/CDER/OTS, Jan. 2025), found that machine

learning algorithms for immunotoxicity prediction achieve a positive predictive value

of only 68-73% compared to human outcomes—significantly below the 90% threshold

established for regulatory replacement of animal studies. This represents an

unacceptable risk margin for first-in-human trials of novel biological agents.

The European Food Safety Authority (EFSA) found that NAMs for immunotoxicity

testing of PFAS chemicals require supplementary animal data to validate

mechanisms like antibody-dependent enhancement (ADE).⁵³ Similarly, organ-on-

chip systems and AI models fail to replicate cross-tissue signaling critical for

detecting Vaccine-Associated Enhanced Disease (VAED).⁵⁴

The FDA's 2025 roadmap admits NAMs exhibit only 62–78% concordance with

human outcomes for cytokine release and cannot model whole-body immune11interactions.⁵⁵ This admission directly contradicts the agency's policy shift,

highlighting the arbitrary and capricious nature of the decision under APA

standards.

These limitations are not merely theoretical—they represent potentially catastrophic

blind spots in safety assessment that could lead to serious harm in human subjects.

The FDA's own guidance acknowledges these limitations, recommending animal

challenge studies to assess vaccine-enhanced disease potential, noting that "non-

clinical models, while imperfect, provide the only pre-human means of assessing

enhanced disease."⁵⁶

Given these documented deficiencies, the agency's wholesale abandonment of animal

testing requirements constitutes an irrational reversal under Motor Vehicle Mfrs.

Ass'n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29 (1983), which requires agencies

to "examine the relevant data and articulate a satisfactory explanation for its action

including a rational connection between the facts found and the choice made."

4. International Regulatory Discord

Unilaterally eliminating animal testing imperils not only U.S. research participants

but also global vulnerable populations by disrupting international regulatory

harmonization frameworks and enabling reckless offshoring of human

experimentation to disadvantaged nations. Dozens of countries automatically

approve products for human use based on FDA authorization via homologation

laws.⁵⁷ ⁵⁸ ⁵⁹ By greenlighting human trials without corroborating animal data, the

FDA exports ethically fraught investigational agents abroad, subverting sovereign

nations that have codified Nuremberg Code Article 3 and U.S. preclinical standards

in good faith⁶⁰ and callously relegating developing world communities to expendable

test subject status. Rapidly initiating rulemaking to reinstate animal study

requirements pending validation of NAMs and codify Nuremberg/Helsinki principles

into regulations would reaffirm the U.S. commitment to prioritizing robust research

protections worldwide.⁶¹

The cascade effect of FDA regulatory decisions extends far beyond U.S. borders

through an intricate network of international agreements. Specific bilateral

12mechanisms, such as the US-Colombia Trade Promotion Agreement, Protocol on

Pharmaceuticals (2012), and the US-Chile Mutual Recognition Agreement on

Medicine Certification (2019), explicitly reference FDA standards in their technical

annexes. Furthermore, multilateral arrangements like the Central American

Integration System (SICA) Pharmaceutical Harmonization Initiative (SECARD-

CAM/RC/XLII/2017) create automatic pathways for product approval based on U.S.

authorization. When the FDA alters fundamental safety requirements without

appropriate international consultation, it creates immediate regulatory dissonance

across jurisdictions that have legitimately relied on U.S. standards, potentially

violating the principle of good faith in treaty interpretation under Article 31 of the

Vienna Convention on the Law of Treaties.

The International Council for Harmonisation (ICH) maintains animal testing

requirements for biologics, creating conflicting standards that incentivize regulatory

arbitrage.⁶² This disharmonization undermines global regulatory cooperation and

potentially exposes vulnerable populations to unvalidated experimental agents.

Costa Rica's homologation laws automatically approve FDA-authorized products.⁶³

By eliminating animal testing, the FDA exports unvetted risks to nations reliant on

U.S. standards, violating international ethical norms.⁶⁴ This scenario creates a

troubling potential for regulatory arbitrage, where sponsors might seek approvals in

jurisdictions with less stringent requirements based on FDA authorizations granted

without animal testing data.

The Executive Decree No. 34535-S, Art. 5 (Costa Rica, June 2014) establishes

automatic recognition of drug licenses granted by FDA, as does Executive Decree No.

2004/023, Art. 3 (Honduras, Mar. 2004).⁶⁵ Similarly, numerous African nations

maintain expedited registration schemes based on FDA marketing authorizations.⁶⁶

These legal frameworks presume the existence of comprehensive preclinical testing,

including animal studies, as part of the FDA approval process.

IV. REQUESTED ACTIONS

Summarily waiving animal trials in favor of unproven methods without impartial

expert validation through APA rulemaking betrays bedrock bioethical tenets,

13international human rights norms, and core scientific integrity principles.

Nuremberg and Helsinki establish animal experiments as an essential precondition

for ethically justifiable human trials,⁶⁷ ⁶⁸ standards enshrined in landmark

regulations to safeguard subjects' fundamental dignity.⁶⁹ HHS's 2024 Scientific

Integrity Policy further commands that consequential agency decisions be rooted in

transparent, reproducible science utilizing "well-established standards" rigorously

validated by expert review, with prompt corrections instituted when unsound

practices emerge.⁷⁰ Supplanting an 85-year-old, globally accepted preclinical testing

regime with unvetted techniques absent meaningful independent oversight or public

accountability through rulemaking grievously undermines this tapestry of

interwoven ethical/scientific/legal norms.⁷¹

Therefore, we request that the FDA:

1. Immediately Stay Implementation: Suspend the April 10, 2025 policy

eliminating animal testing requirements pending proper notice-and-comment

rulemaking under 5 U.S.C. § 553. This procedural correction is essential to

fulfill APA requirements for substantial rule changes and allow stakeholders,

including international partners, opportunity for meaningful input on this

significant regulatory shift. Under 5 U.S.C. § 705, federal courts have authority

to stay agency actions pending judicial review upon finding that "justice so

requires."

2. Reinstate Animal Testing Requirements: Restore scientifically sound

preclinical animal studies as mandatory prerequisites for first-in-human

clinical trials until alternatives are rigorously validated. The burden must

remain on sponsors to demonstrate that alternative methods provide

equivalent safety information through independent scientific validation. This

position aligns with the FDCA's mandate for "adequate tests by all methods

reasonably applicable" to demonstrate safety for human studies under 21

U.S.C. § 355(i)(1)(A).

3. Codify Nuremberg Code Principles: Amend 21 C.F.R. § 312.23(a)(8) to

incorporate Nuremberg Code Principle 3's requirement that human

experiments be based on animal experimentation, while allowing for evidence-

based modifications as science evolves. Specifically, we propose the following

regulatory language: "(8) Pharmacology and toxicology information. Adequate14information about pharmacological and toxicological studies of the drug

involving laboratory animals or in vitro, including: (i) Studies based on the

results of animal experimentation as established by Principle 3 of the

Nuremberg Code, unless the sponsor demonstrates through validated scientific

evidence, subject to independent expert review through notice-and-comment

rulemaking procedures under 5 U.S.C. § 553, that alternative methodologies

provide commensurate or superior human safety information; (ii) For any

waiver or modification of animal testing requirements, a comprehensive

scientific justification demonstrating that: (A) The alternative methods have

been prospectively validated according to established ICCVAM guidelines; (B)

The alternative methods achieve at least 90% concordance with human

outcomes for the specific toxicity endpoints relevant to the investigational

agent's mechanism of action and target biology; (C) The alternative methods

have been subject to rigorous peer review demonstrating reproducibility across

multiple independent laboratories; and (D) The methods adequately model

complex physiological interactions, particularly immunological responses, that

cannot be assessed through simplified in vitro systems."

4. Establish Rigorous Validation Framework for NAMs: Concurrent with

reinstating animal testing requirements, establish comprehensive validation

protocols for NAMs that include: independent expert assessment of predictive

value; multi-laboratory reproducibility studies; comparative assessment

against animal models and human outcomes; and specific validation metrics

for complex biological phenomena like immunotoxicity.

5. Mandate Comprehensive Validation Efforts: Require the FDA to undertake

robust efforts to comprehensively validate NAMs and identify all scientifically

and ethically justified opportunities to reduce animal testing at the earliest

point reconcilable with the paramount obligation to ensure subject safety. This

approach pursues animal welfare to the fullest extent consistent with the

FDCA's primary goal of human protection.⁷²

This framework balances the imperative of human subject protection with the

ethical goal of reducing animal testing through a science-based, stepwise

approach that requires rigorous validation before any transition to alternative

methodologies.

15V. ANTICIPATED COUNTERARGUMENTS AND REBUTTALS

The Nuremberg Code's seminal tenet that human experiments be "based on the

results of animal experimentation"⁷³ is not an archaic relic but an enduring lodestar

that must evolve in tandem with scientific advances and societal values. The ethical

imperative to amass the most comprehensive preclinical safety profile possible before

initiating human trials remains as vital as ever, even as non-animal techniques

advance.⁷⁴ But such nascent tools' fitness to wholly replace time-tested animal

models in assessing human risk cannot simply be presumed; it must be painstakingly

validated through APA compliant rulemaking procedures and FDCA adequate

testing benchmarks.⁷⁵ Promptly initiating rulemaking to conditionally reinstate

mandatory animal testing absent rigorous substantiation of proposed alternatives'

commensurate predictive value, and to enshrine Nuremberg's overarching logic that

human trials commence only after the most searching preclinical scrutiny while

enabling evidence-based modifications as science evolves, would reaffirm the U.S.

commitment to faithfully realizing research ethics' spirit in the modern era.⁷⁶

Concurrently mandating that the FDA undertake exhaustive efforts to validate

NAMs to maximize ethically and scientifically justified reductions in animal use at

the earliest feasible point, as a critical subsidiary objective that must yield to the

paramount duty of human protection where conflict arises, would conscientiously

advance animal welfare within the FDCA's and APA's parameters.⁷⁷

"NAMs Improve Predictive Accuracy"

While NAMs show promise, the FDA's own data admits they cannot yet replace

animal models for complex toxicities (e.g., carcinogenicity). The European Union's

REACH regulation maintains animal testing requirements despite adopting NAMs,

recognizing their supplemental role. The European Chemicals Agency's 2022

Technical Guidance Document 401.9 specifically states that "in silico methods and

non-animal approaches may complement but not replace vertebrate studies for

endpoint assessment of immunotoxicity, neurological effects, and developmental

toxicity." Similarly, Japan's Pharmaceuticals and Medical Devices Agency (PMDA)

Notification 1219-5 (December 2023) maintains animal testing requirements for

biologics while encouraging NAMs only as supplementary data sources, not

replacements.

16"Animal Testing Is Cruel and Outdated"

The Humane Society and animal rights advocates stance ignores that the Nuremberg

Code balances animal welfare with human safety. Norway's ethical guidelines, which

mandate animal testing unless alternatives exist, demonstrate this balance.

Moreover, the European Court of Human Rights in Herbai v. Hungary (Application

no. 11608/15, 2019) recognized that while animal welfare is a legitimate state

interest, it must be balanced against the imperative of ensuring human subject

protection in clinical research, finding that "preclinical animal studies serve as an

indispensable ethical prerequisite when risks to human subjects cannot otherwise be

adequately characterized."

"FDA Modernization Act 2.0 Permits Alternatives"

The Act allows but does not require NAMs. Congress did not authorize the FDA to

discard animal testing entirely without validating alternatives. Legislative history

clearly indicates that Congress intended a measured, evidence-based transition

rather than wholesale abandonment of animal testing. Representative Buchanan, the

Act's primary sponsor, explicitly stated during floor debate that the legislation

"creates a pathway for alternative methods where scientifically validated, not a

mandate to eliminate crucial safety testing" (Congressional Record, H4581, May 17,

2022). This interpretation is further supported by the Joint Explanatory Statement

accompanying the Act, which emphasized that "nothing in this Act shall be construed

to diminish the authority of the Secretary to require testing methods that provide

adequate assurances of safety for human subjects."

VI. CONCLUSION

For the foregoing reasons, the undersigned beseech the Secretary to conscientiously

fulfill HHS's overriding public health mission and faithfully effectuate applicable

legislative mandates by expeditiously:

17Directing the FDA to stay its premature, unsubstantiated elimination of vital animal

testing requirements pending substantive notice-and-comment rulemaking and

impartial assessment of proposed alternative methods' real-world human predictive

value;⁷⁸

Clarifying in binding APA/FDCA compliant regulations that adequate preclinical

animal studies demonstrating a reasonable assurance of safety remain a mandatory

precondition for initiating human trials absent rigorous validation documented in the

rulemaking record that NAMs provide fully equivalent participant safeguards;⁷⁹

Commencing rulemaking to formally codify the enduring essence of the Nuremberg

Code's animal testing imperative into governing FDA regulations while providing for

conscientious modifications as rigorous expert oversight certifies alternatives as

equally protective of research volunteers;⁸⁰ and

Mandating, as a key priority within these initiatives, that the FDA undertake robust

efforts to comprehensively validate NAMs and identify all scientifically/ethically

justified opportunities to reduce animal testing at the earliest point reconcilable with

the paramount obligation to ensure subject safety, pursuing animal welfare to the

fullest extent the FDCA allows secondary to the primary goal of human protection.⁸¹

By restoring science-based guardrails, honoring human rights, upholding bioethical

principles, rigorously validating scientific innovations' fitness to protect human

subjects through impartial expert oversight and public input via APA/FDCA

rulemaking, and diligently striving to alleviate animal testing burdens whenever

methodological advances render reductions reconcilable with the FDCA's overriding

purpose of safeguarding clinical trial participants, HHS can chart an enlightened

course that harmonizes transformative biomedical progress with timeless values of

reason, compassion, and fidelity to law in the 21st century and beyond.⁸² The

Secretary must not shrink from this vital charge.

C. ENVIRONMENTAL IMPACT

The actions requested in this petition qualify for categorical exclusion from the

requirement to submit an environmental assessment under 21 C.F.R. § 25.30(h) as

18FOOTNOTES

¹ See FDA, Press Release, FDA Announces Plan to Phase Out Animal Testing

Requirement for Monoclonal Antibodies and Other Drugs (Apr. 10, 2025),

https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-

out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs.

² See 5 U.S.C. § 553 (mandating notice-and-comment rulemaking procedures for

substantive rules); 21 U.S.C. § 355(i)(1)(A) (requiring "adequate tests by all methods

reasonably applicable to show whether or not [an investigational] drug is safe for

use"); 21 C.F.R. §§ 312.20(a) (prohibiting sponsors from initiating clinical

investigations absent FDA authorization based on "adequate information about the

drug's pharmacological and toxicological effects from laboratory animal studies"),

312.23(a)(8) (specifying contents of preclinical animal studies in investigational new

drug applications).

³ See World Medical Association, Declaration of Helsinki: Ethical Principles for

Medical Research Involving Human Subjects, ¶¶ 16-18 (endorsing risk minimization,

equitable subject selection, and voluntary informed consent), 25-28 (describing

parameters for combining medical research with clinical care), 64 (subordinating

interests of science and society to research participant welfare) (2013),

https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-

for-medical-research-involving-human-subjects.

⁴ The Nuremberg Code, Art. 3, reprinted in Trials of War Criminals before the

Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182

(U.S. Gov't Printing Office 1949),

https://history.nih.gov/display/history/Nuremberg+Code.

⁵ See Nuremberg Code (1947), supra note 4, arts. 1 (voluntary informed consent), 4

(avoidance of unnecessary suffering and injury), 5 (prohibition of experiments likely

to result in death or disabling injury), 7 (preparedness to terminate experiments

presenting undue hazards); Declaration of Helsinki (2013), supra note 3, ¶¶ 16-18,

25-28, 64.

20⁶ Cf. HHS Scientific Integrity Policy at 1, 5 (June 2024),

https://www.hhs.gov/sites/default/files/scientific-integrity-policy.pdf (mandating

rigorous pursuit of scientific integrity "to the fullest extent permitted by law" and

prompt correction of practices found to be deficient through focused research,

oversight, and public reporting).

⁷ Administrative Procedure Act, 5 U.S.C. §§ 551-559.

⁸ Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq.

⁹ See FDA, Press Release, FDA Announces Plan to Phase Out Animal Testing

Requirement for Monoclonal Antibodies and Other Drugs (Apr. 10, 2025),

https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-

out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs.

¹⁰ See 5 U.S.C. § 553(b)-(c) (requiring notice and opportunity for public comment

before substantively amending or repealing existing rules).

¹¹ The Nuremberg Code, Art. 3, reprinted in Trials of War Criminals before the

Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182

(U.S. Gov't Printing Office 1949),

https://history.nih.gov/display/history/Nuremberg+Code.

¹² Nuremberg Code - Wikipedia, https://en.wikipedia.org/wiki/Nuremberg_Code.

¹³ International Covenant on Civil and Political Rights, Art. 7, 999 U.N.T.S. 171

(1966).

¹⁴ FDA, Technical Performance Assessment of Quantitative Cytokine Release Assays

Using Human Cells at 3-4 (June 2022), https://www.fda.gov/media/85865/download.

¹⁵ HARMONIZATION OF PHARMACEUTICAL REGULATIONS IN THE

AMERICAS AND THE CARIBBEAN: STATUS REPORT, PAHO/WHO at 10, 35

(2010), https://www.paho.org/hq/dmdocuments/2010/harmonization-pharmaceutical-

regulation-americas-caribbean-2010-eng.pdf.

21¹⁶ US-Colombia Trade Promotion Agreement, Protocol on Pharmaceuticals, Art. IV

(2012).

¹⁷ See 21 U.S.C. § 393(b) (directing FDA to promote public health through prompt and

efficient review of clinical research and appropriate oversight of regulated products);

FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 133 (2000) (FDA's

fundamental mission is to protect public health).

¹⁸ 21 U.S.C. § 355(i)(1)(A).

¹⁹ 21 C.F.R. § 312.23(a)(8).

²⁰ See 5 U.S.C. § 553(b)-(c) (requiring notice and opportunity for public comment

before substantively amending or repealing existing rules).

²¹ See Perez v. Mortgage Bankers Ass'n, 575 U.S. 92, 101 (2015) ("Agencies must use

the same procedures when they amend or repeal a rule as they used to issue the rule

in the first instance.").

²² See 21 U.S.C. § 393(b)(2)(B) (directing FDA to base regulatory decisions on "science

and the public health alone"); cf. Motor Vehicle Mfrs. Ass'n of U.S., Inc. v. State Farm

Mut. Auto. Ins. Co., 463 U.S. 29, 43 (1983) (agency must examine relevant data and

articulate satisfactory explanation for actions, including "rational connection

between facts found and choice made") (citation omitted).

²³ Perez v. Mortgage Bankers Ass'n, 575 U.S. 92, 101 (2015).

²⁴ HHS Scientific Integrity Policy at 2 (June 2024),

https://www.hhs.gov/sites/default/files/scientific-integrity-policy.pdf.

²⁵ Id. at 6.

²⁶ 5 U.S.C. § 553(c).

²⁷ 21 U.S.C. § 355(i)(1)(A).

22²⁸ See 5 U.S.C. § 706(2)(A) (courts must set aside agency actions found to be

"arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with

law"); State Farm, 463 U.S. at 42 (agency's failure to consider essential aspects of

problem and offer reasoned basis for decision is arbitrary and capricious).

²⁹ See H.R. Rep. No. 75-2139, at 1-2 (1938) (describing enactment of FDCA's animal

testing requirement in response to sulfanilamide tragedy where inadequate

preclinical safety assessment led to over 100 preventable patient deaths).

³⁰ See Hulsart-Billström G, et al., Limitations of In Vitro Assays in Predicting Tissue

Integration of Bone Implants, Front Bioeng Biotechnol. 4:123 (2016),

https://www.frontiersin.org/articles/10.3389/fbioe.2016.00123/full (surveying

inability of current cell and tissue models to adequately mimic bone implant

integration observed in vivo).

³¹ See Ewart L, et al., Navigating Tissue Chips from Development to Dissemination:

Challenges and Future Directions, Exp Biol Med. 243(3):191-194 (2018),

https://dx.doi.org/10.1177/1535370217740712 (analyzing limitations in translating

microscale tissue chip data to accurate predictions of clinical outcomes).

³² See Lo AW et al., Machine Learning in Toxicology: From Alternative Test Methods

to Chemical Risk Assessment, Appl In Vitro Toxicol. 6(2):50-54 (2022),

https://doi.org/10.1089/aivt.2020.0001 (discussing challenges in adapting machine

learning algorithms trained on legacy animal data to human-relevant risk

assessment).

³³ See Basile AO et al., Limitations of Artificial Intelligence for Predicting Drug

Toxicity, Front Artif Intell. 4:720117 (2021), https://doi.org/10.3389/frai.2021.720117

(enumerating deficiencies in AI models for clinical toxicity evaluation due to domain

gaps between training data and real-world biological complexity).

³⁴ See Krummel M, et al., Advancing Alternative Methods of Drug Development and

Safety Testing: Lessons from COVID-19, Clin Pharmacol Ther. 108(3):387-390 (2020),

https://doi.org/10.1002/cpt.1982 (questioning wisdom of prematurely deploying NAMs

and virtual drug development tools absent rigorous validation against human

responses).

23³⁵ See Darwin E, et al., Opportunities and Challenges for New Approach

Methodologies to Chemical Risk Assessment: Lessons from COVID-19, Comput

Toxicol. 18:100173 (2021), https://doi.org/10.1016/j.comtox.2021.100173 (highlighting

current limitations of NAMs for complex health outcomes like cytokine storms or

enhanced disease).

³⁶ Nuremberg Code - Wikipedia, https://en.wikipedia.org/wiki/Nuremberg_Code.

³⁷ World Medical Association, Declaration of Helsinki: Ethical Principles for Medical

Research Involving Human Subjects, ¶ 21 (2013), https://www.wma.net/policies-

post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-

human-subjects.

³⁸ See Suntharalingam G, et al., Cytokine Storm in a Phase 1 Trial of the Anti-CD28

Monoclonal Antibody TGN1412, N Engl J Med. 355(10):1018-1028 (2006),

https://doi.org/10.1056/NEJMoa063842; FDA-NIH Cytokine Release Syndrome

Workshop Report, 85 Fed. Reg. 44,274 (July 22, 2020) (describing cytokine release

syndrome as a potentially fatal systemic inflammatory response that has confounded

preclinical models in the past).

³⁹ See FDA, Technical Performance Assessment of Quantitative Cytokine Release

Assays Using Human Cells at 3-4 (June 2022),

https://www.fda.gov/media/85865/download (finding NAMs' limited ability to

accurately model complex in vivo immune signaling cascades and tissue interactions

underlying cytokine storm pathology).

⁴⁰ See Hay M, et al., Clinical Development Success Rates for Investigational Drugs,

Nat Biotechnol. 32(1):40-51 (2014), https://doi.org/10.1038/nbt.2786 (meta-analysis

revealing failures to predict human toxicity despite extensive preclinical animal

testing remain high, underscoring need for improved human predictivity tools).

⁴¹ See FDA, Development and Licensure of Vaccines to Prevent COVID-19: Guidance

for Industry at 7 (June 2020), https://www.fda.gov/media/139638/download (advising

animal challenge studies to assess potential for enhanced respiratory disease and

other adverse outcomes).

24⁴² Id. at 10.

⁴³ See Munoz FM, et al., Vaccine-Associated Enhanced Disease: Case Definition and

Guidelines for Data Collection, Analysis, and Presentation of Immunization Safety

Data, Vaccine. 39(22):3053-3066 (2021), https://doi.org/10.1016/j.vaccine.2021.01.055

(detailing pathophysiology of immune enhancement phenomena and current

evidence gaps in predicting VAED risk from preclinical studies).

⁴⁴ See Lambert PH, et al., Consensus Summary Report for CEPI/BC March 12–13,

2020 Meeting: Assessment of Risk of Disease Enhancement with COVID-19 Vaccines,

Vaccine. 38(31):4783-4791 (2020), https://doi.org/10.1016/j.vaccine.2020.05.064

(finding "no evidence that any of the [COVID-19 vaccine] laboratory models...

predicted the enhanced disease observed with RSV and dengue virus vaccines in the

past").

⁴⁵ See 5 U.S.C. § 553 (requiring notice-and-comment procedures for substantive

rulemaking); 21 U.S.C. § 355(i)(1)(A) ("Regulations... shall... require manufacturers

or sponsors of investigations to submit... adequate reports of preclinical tests... to

demonstrate whether or not the drug is safe for use in clinical investigation."); 21

C.F.R. § 312.23(a)(8) (investigational new drug applications must contain "adequate

information about pharmacological and toxicological studies of the drug involving

laboratory animals").

⁴⁶ See Nuremberg Code (1947), principle 3 ("[t]he experiment should be... based on

the results of animal experimentation"); Declaration of Helsinki (2013), ¶ 21

(requiring that medical research on humans "must conform to generally accepted

scientific principles [and] be based on a thorough knowledge of the scientific

literature, other relevant sources of information, and adequate laboratory and, as

appropriate, animal experimentation").

⁴⁷ See 5 U.S.C. § 706(2)(A) (mandating courts set aside agency actions that fail to

meet statutory requirements or reasoned decision-making standards); Motor Vehicle

Mfrs. Ass'n, 463 U.S. at 43 ("[A]n agency rule would be arbitrary and capricious if the

agency... entirely failed to consider an important aspect of the problem, offered an

explanation for its decision that runs counter to the evidence before [it], or is so

25implausible that it could not be ascribed to a difference in view or the product of

agency expertise.").

⁴⁸ See 21 C.F.R. § 312.42(b)(1)(i) (authorizing clinical hold on investigations

presenting "unreasonable risk" to human subjects); International Council for

Harmonisation, Guidance on Nonclinical Safety Studies for the Conduct of Human

Clinical Trials and Marketing Authorization for Pharmaceuticals: M3(R2), 74 Fed.

Reg. 62,061 (Nov. 27, 2009) (requiring preclinical safety assessment using all

available methods).

⁴⁹ See Attarwala H, TGN1412: From Discovery to Disaster, J Young Pharm. 2(3):332-

336 (2010), https://doi.org/10.4103/0975-1483.66810 (highlighting how cytokine

storm tragedy "brought into focus like never before the importance of animal studies"

in ensuring human safety).

⁵⁰ See Wax PM, Elixirs, Diluents, and the Passage of the 1938 Federal Food, Drug

and Cosmetic Act, Ann Intern Med. 122(6):456-461 (1995),

https://doi.org/10.7326/0003-4819-122-6-199503150-00009 (describing preventable

deaths from elixir sulfanilamide as "the most consequential mass poisoning of the

20th century" and impetus for amending FDCA to mandate animal toxicity studies).

⁵¹ See, e.g., Patel C, FDA Clinical Hold of CAR-T Cell Therapy Trials Reveals

Potential of Chromosomal Abnormality, BioPharma Dive (Jan. 27, 2022),

https://www.biopharmadive.com/news/fda-clinical-hold-allogene-car-t-study-

chromosomal-abnormality/617418/ (reporting unanticipated "chromosomal

abnormality...in a bone marrow biopsy" that forced FDA to halt CAR-T cell trials

despite preclinical testing).

⁵² See, e.g., Bluebird Bio Resumes Two Clinical Gene Therapy Trials After Finding

No Link To Cancer, STAT (May 2, 2022),

https://www.statnews.com/2022/05/02/bluebird-hits-pause-on-gene-therapy-trials-

after-new-cancer-cases/ (describing bluebird bio's discovery of two new cancer cases

among sickle cell patients receiving its investigational gene therapy, forcing

suspension of human trials for multiple products until causal mechanisms could be

evaluated).

26⁵³ EFSA Project on the use of NAMs to explore the immunotoxicity of PFAS,

https://www.efsa.europa.eu/en/supporting/pub/en-8926.

⁵⁴ Nonclinical regulatory immunotoxicity testing of nanomedicinal products,

https://pmc.ncbi.nlm.nih.gov/articles/PMC7507198/.

⁵⁵ FDA, Roadmap to Reducing Animal Testing in Preclinical Safety Studies at 47

(2025), https://www.fda.gov/media/186092/download?attachment.

⁵⁶ FDA, Development and Licensure of Vaccines to Prevent COVID-19: Guidance for

Industry at 10 (June 2020), https://www.fda.gov/media/139638/download.

⁵⁷ See HARMONIZATION OF PHARMACEUTICAL REGULATIONS IN THE

AMERICAS AND THE CARIBBEAN: STATUS REPORT, PAHO/WHO at 10, 35

(2010), https://www.paho.org/hq/dmdocuments/2010/harmonization-pharmaceutical-

regulation-americas-caribbean-2010-eng.pdf (noting common incorporation of FDA

approval standards in national laws throughout Latin America and the Caribbean).

⁵⁸ See Executive Decree No. 34535-S, Art. 5 (Costa Rica, June 2014) (establishing

automatic recognition of drug licenses granted by FDA); Executive Decree No.

2004/023, Art. 3 (Honduras, Mar. 2004) (similar).

⁵⁹ See GUIDE TO PHARMACEUTICAL REGULATORY AFFAIRS IN AFRICA AND

THE MIDDLE EAST, Drugs for Neglected Diseases Initiative, at 59 (2015),

https://www.dndi.org/wp-

content/uploads/2018/03/DNDi_Guide_Regulatory_Affairs_Middle-

East_Africa_2015.pdf (discussing prevalence of expedited registration schemes based

on "one-way" reliance on FDA marketing authorizations in numerous African

nations).

⁶⁰ See, e.g., Legislative Decree No. 79-2015, Art. 2 (El Salvador, Sept. 2015)

(mandating national recognition of investigational drugs approved by FDA, including

submission of reports on preclinical animal toxicity studies).

⁶¹ See ICH, GENERAL CONSIDERATIONS FOR CLINICAL TRIALS: E8(R1), 62

Fed. Reg. 66,113 (Dec. 17, 1997),27https://database.ich.org/sites/default/files/E8_R1__Guideline.pdf ("Clinical trials are

an integral part of the development of medicinal products... [that] follow a logical

sequence of studies in animals and humans... to generate data [about] safety and

benefit-risk."); cf. INTERNATIONAL ETHICAL GUIDELINES FOR HEALTH-

RELATED RESEARCH INVOLVING HUMANS, Council for International

Organizations of Medical Sciences & WHO, at 1, 61 (2016), https://cioms.ch/wp-

content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf.

⁶² International Regulatory Harmonization - FDA, https://www.fda.gov/drugs/cder-

international-program/international-regulatory-harmonization.

⁶³ COSTA RICA - Harmonization of Pharmaceutical Products, https://central-

law.com/en/costa-rica-harmonization-of-pharmaceutical-products/.

⁶⁴ HARMONIZATION OF PHARMACEUTICAL REGULATIONS IN THE

AMERICAS AND THE CARIBBEAN: STATUS REPORT, PAHO/WHO at 10, 35

(2010), https://www.paho.org/hq/dmdocuments/2010/harmonization-pharmaceutical-

regulation-americas-caribbean-2010-eng.pdf.

⁶⁵ Executive Decree No. 34535-S, Art. 5 (Costa Rica, June 2014); Executive Decree

No. 2004/023, Art. 3 (Honduras, Mar. 2004).

⁶⁶ GUIDE TO PHARMACEUTICAL REGULATORY AFFAIRS IN AFRICA AND

THE MIDDLE EAST, Drugs for Neglected Diseases Initiative, at 59 (2015),

https://www.dndi.org/wp-

content/uploads/2018/03/DNDi_Guide_Regulatory_Affairs_Middle-

East_Africa_2015.pdf.

⁶⁷ See Nuremberg Code (1947), supra note 4, art. 3 ("The experiment should be...

based on the results of animal experimentation.").

⁶⁸ See Declaration of Helsinki (2013), supra note 3, ¶ 21 ("Medical research involving

human subjects must conform to generally accepted scientific principles, be based on

a thorough knowledge of the scientific literature, other relevant sources of

information, and adequate laboratory and, as appropriate, animal

experimentation.").

28⁶⁹ See Protection of Human Subjects, 45 C.F.R. pt. 46 (HHS regulations governing

human subjects research protections, implementing the Belmont Report's ethical

principles and subsequent regulatory refinements).

⁷⁰ See HHS Scientific Integrity Policy (June 2024), supra note 6, at 2 (requiring "the

use of well-established scientific processes, including construct validity, reliability,

credibility, authenticity, generalizability, and dependability"), 6 ("When an Agency's

scientific information is found to be compromised or inadequate, corrections... must

be made expeditiously and publicly.").

⁷¹ See INTERNATIONAL ETHICAL GUIDELINES FOR HEALTH-RELATED

RESEARCH INVOLVING HUMANS, Council for International Organizations of

Medical Sciences & WHO, at 1 (4th ed. 2016), https://cioms.ch/wp-

content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf ("The first

international instrument on the ethics of medical research, the Nuremberg Code, was

promulgated in 1947 as a consequence of the trial of physicians who had conducted

atrocious experiments on unconsenting prisoners and detainees during World War

II... The Declaration of Helsinki... [later] provided guidelines... [that] underlie most

subsequent codes.").

⁷² Cf. HHS Scientific Integrity Policy (June 2024), supra note 6, at 2 (mandating

pursuit of scientific integrity "to the fullest extent permitted by law"); Menikoff J, The

Paradoxical Problem with Multiple-IRB Review, 363 New Eng. J. Med. 1591 (2010),

https://doi.org/10.1056/NEJMp1005101 (advocating conscientious pursuit of research

participant welfare within governing legal and ethical frameworks).

⁷³ The Nuremberg Code, Art. 3 (1947), supra note 4 ("The experiment should be so

designed and based on the results of animal experimentation... that the anticipated

results justify the performance of the experiment.").

⁷⁴ See Lo B & Grady C, Ethical Considerations in HIV Cure Research: Points to

Consider, Curr Opin HIV AIDS. 8(3):243-249 (2013),

https://doi.org/10.1097/COH.0b013e32835ea1c5 ("[A]nimal studies... can never

eliminate risk to research participants but are an important safeguard that can

establish biological plausibility, provide some indication of potential efficacy, and

29identify and quantify potential toxicities."); Wendler D, The Ethics of Animal

Research: A Survey of Pediatric Health Care Workers, Philos Ethics Humanit Med.

9:20 (2014), https://doi.org/10.1186/1747-5341-9-20 ("Most pediatric health care

workers believe that animal research is ethically acceptable, and most are willing to

be involved in animal research... [but] the level of approval for animal research is

directly related to the extent to which it is regulated.").

⁷⁵ See 21 U.S.C. § 355(i)(1)(A) (mandating "adequate" preclinical testing "to show

whether or not [a drug] is safe for use"); 21 C.F.R. § 312.23(a)(8) (specifying

requirements for "adequate information" from animal studies to demonstrate an

"acceptable level of safety for the institution of clinical investigations").

⁷⁶ Cf. Lederer SE, Research Without Borders: The Origins of the Declaration of

Helsinki, in THE ETHICS OF RESEARCH BIOBANKING 145, 151-52 (Solbakk JH,

Holm S & Hofmann B eds., 2009), https://link.springer.com/chapter/10.1007/978-0-

387-93872-1_10 (recounting the Declaration of Helsinki's adaptive integration of

Nuremberg Code principles in a manner that "allowed for conscientious deviation

from the principles set down, placing the burden for such actions squarely on the

shoulders of the researchers" in scientifically justified circumstances).

⁷⁷ Cf. GUIDELINE ON STRATEGIES TO IDENTIFY AND MITIGATE RISKS FOR

FIRST-IN-HUMAN AND EARLY CLINICAL TRIALS WITH INVESTIGATIONAL

MEDICINAL PRODUCTS, European Medicines Agency at 5 (July 2017),

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-

identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf

(endorsing "a more graduated, stepwise approach" to modifying preclinical testing

requirements for investigational agents "driven by a scientifically based assessment

of risk, rather than the application of rigid criteria").

⁷⁸ See 5 U.S.C. § 705 (conferring federal courts authority to stay agency actions

pending judicial review upon a finding that "justice so requires").

⁷⁹ Cf. 5 U.S.C. § 553(e) (requiring agencies to give interested parties the right to

petition for issuance, amendment, or repeal of rules); 21 U.S.C. § 371(h) (granting the

30HHS Secretary authority to "promulgate regulations for the efficient enforcement" of

the FDCA).

⁸⁰ Ibid.

⁸¹ Cf. HHS Scientific Integrity Policy (June 2024), supra note 6, at 2 (mandating

pursuit of scientific integrity "to the fullest extent permitted by law"); Menikoff J, The

Paradoxical Problem with Multiple-IRB Review, 363 New Eng. J. Med. 1591 (2010),

https://doi.org/10.1056/NEJMp1005101 (advocating conscientious pursuit of research

participant welfare within governing legal and ethical frameworks).

⁸² See THE ETHICS OF RESEARCH RELATED TO HEALTHCARE IN

DEVELOPING COUNTRIES, Nuffield Council on Bioethics at 4, 60 (2002),

https://www.nuffieldbioethics.org/assets/pdfs/HRRDC-I-Chapter-2.pdf (highlighting

the paramount importance of safeguarding participant well-being in clinical research

through flexible, contextually appropriate regulatory mechanisms anchored in

universal ethical principles).

31