The U.S. Food and Drug Administration (FDA) has formalized a transformative shift in nonclinical safety assessments as part of the drug development process, emphasizing human relevance and mechanistic insight through the expanded adoption of New Approach Methodologies (NAMs). Codified under the Food and Drug Omnibus Reform Act of 2022 (FDORA), this performance-based framework moves beyond conventional animal testing and aligns with the ethical principles of the 3Rs (Replace, Reduce, Refine).
This white paper reflects the FDA's emerging expectations – particularly as articulated by Center for Drug Evaluation and Research/ Office of New Drugs (CDER/OND) reviewers in the recently published paper by Yao et al. (2025)[1] – and outlines what this paradigm means for Sponsors of drug candidates. We highlight how early, strategic planning reduces uncertainty, enhances regulatory confidence, and accelerates translational success.
The FDA’s message is clear: NAMs gain regulatory traction only when supported by strong biological and technical rigor and anchored by a reviewer-ready Context of Use (COU). For Sponsors, mastering these elements is essential to strengthen early decision-making, reduce unnecessary nonclinical studies, and future-proof their drug development programs.
In 2022, FDORA (FDA Modernization Act 2.0) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to remove the statutory requirement for animal testing and formally authorize scientifically valid nonclinical alternatives, including NAMs. In April 2025, FDA published a roadmap that outlines a phased approach to reduce reliance on animal studies and encourages drug candidate Sponsors to incorporate human-relevant methods where appropriate, provided they meet regulatory standards and do not compromise public health.[1]
NAMs include in vitro, ex vivo, in silico (computational), and in chemico methods designed to improve the prediction of human safety. Among these, Complex In Vitro Models (CIVM) and Microphysiological Systems (MPS), including organ-on-chip technologies represent increasingly sophisticated tools that aim to recapitulate organ-level human biology. Although some NAMs are well established, the critical challenge lies in identifying the most effective points of integration within the nonclinical drug development pathway and demonstrating their validity and correlation with established in vivo endpoints.
NAMs can be incorporated across the entire nonclinical drug development continuum. When applied thoughtfully, NAMs complement traditional approaches, reduce animal use, and improve development efficiency.
Strategic applications include:
FDA reviewers consistently identify COU clarity as the strongest predictor of NAM success. Submissions fail when COUs are vague (e.g., “screening cytotoxicity”) rather than tied to a specific regulatory decision (e.g., “assessing relative Drug-Induced Liver Injury (DILI) risk vs comparator”). The case studies discussed in the Yao et al. (2025) manuscript affirm that the FDA evaluates NAM data not as preliminary screens, but as targeted, mechanistic evidence designed to support specific regulatory decisions.
A successful COU requires:
FDA recognizes NAMs across various categories, as outlined in the table below.
|
Acceptance Category |
Regulatory Purpose |
Examples (per FDA Review) |
|
Validated Replacements |
Full substitution of an animal test following international validation (e.g., OECD/ICCVAM) |
In vitro assays for ocular irritation (e.g., BCOP, RhCE); tiered photosafety testing |
|
Weight of Evidence (WoE) |
Integration of multiple data streams to refine, reduce, or replace animal studies |
ICH S1B(R1) WoE approach to determine if a 2-year rat carcinogenicity study is warranted; using alternative assays for MEFL assessment (ICH S5(R3)) |
|
Supportive & Mechanistic Use |
Mechanistic insight or pharmacodynamic data, particularly when no pharmacologically relevant animal model exists |
A WoE approach, using high-affinity human cell-based assays (as used for Kimmtrak, an oncology biologic); mechanistic DILI models noting current limitations in technical validation |
OECD=Organization for Economic Co-operation and Development; ICCVAM=Interagency Coordinating Committee on the Validation of Alternative Methods; Bovine Corneal Opacity and Permeability; RhCE = Reconstructed Human Cornea-Like Epithelium; MEFL= Malformation and Embryo-Fetal Lethality; DILI= Drug-Induced Liver Injury.
FDA reviewers repeatedly highlight technical and strategic deficiencies that undermine otherwise promising NAM data, as summarized below.
Across FDA case reviews, one unifying theme is clear: robust experimental design remains essential, and studies must be transparently reported, regardless of whether studies are performed in accordance with Good Laboratory Practice (GLP) (USFDA 21 CFR58) or non-GLP.
Sponsors should ensure:
In several cases, reviewers accepted non-GLP NAMs where reports were thorough, transparent, and well-justified - highlighting that scientific rigor can outweigh GLP status for NAMs inclusion.
FDA’s acceptance of the first human Liver-Chip MPS Letter of Intent into Innovative Science and Technology Approaches for New Drugs (ISTAND, 2024) is a pivotal milestone. The qualified tool aims to assess relative DILI risk, addressing species discordance before Investigational New Drug (IND) submission. As more tools achieve qualification, MPS platforms will increasingly inform IND-enabling dose selection and mechanistic safety predictions.
Regulatory reliance on computational tools already exists (e.g., ICH M7(R2) for genotoxicity). The next phase will integrate AI/ML, multi-omics, and population variability to strengthen predictive modeling for endpoints such as DILI. While standalone predictive use of these models remains aspirational currently, these computational tools can significantly strengthen WoE arguments and inform clinical risk management.
Innovative therapeutics like gene therapies often present toxicity profiles poorly captured in animals. For example, the risk of sensory neuropathies, often subtle or unmonitored in animal toxicology, drives the need for human-relevant cellular models. Advances in iPSC-derived sensory neuron models (Dorsal Root Ganglia) are demonstrating utility in anticipating human-specific risks such as Chemotherapy-Induced Peripheral Neuropathy before clinical exposure.
The FDA's NAMs paradigm offers tremendous opportunity, along with significant complexity. Biologics Consulting can help Sponsors by:
FDA reviewers acknowledge that while NAMs have the potential to offer improved human relevance for investigating drug candidate safety and efficacy, in vivo systems remain complex, and no single NAM can currently replace all aspects of animal testing across all key in vivo endpoints. However, their value as complementary translational tools is undeniable. NAMs can provide mechanistic insights, support clinical biomarker selection, refine risk assessments, and contextualize unexpected findings. As technology advances and methods become more widely used and validated, the integration of NAMs with traditional toxicology testing and assessments will increasingly shape more predictive, human-aligned safety strategies.
The FDA’s embrace of NAMs under FDORA marks a definitive shift toward human-relevant nonclinical science in the drug development space. With the right strategy, Sponsors can leverage NAMs to strengthen regulatory confidence, streamline development, and reduce overall program risk.
Biologics Consulting empowers innovation through nonclinical and regulatory strategies aligned with FDA’s evolving paradigm. Contact us to discuss your drug development program and explore how our experts can support your nonclinical testing strategy.
[1] Yao J, Peretz J, Bebenek I, et al. FDA/CDER/OND Experience With New Approach Methodologies (NAMs). Int J Toxicol. Published online November 13, 2025. doi:10.1177/10915818251384270
[2] U.S. Food and Drug Administration. Roadmap to reducing animal testing in preclinical safety studies. April 10, 2025.