Industry says FDA’s guidance on animal testing alternatives needs work
Pharmaceutical industry groups say they support the US Food and Drug Administration's (FDA) draft guidance on new approach methodologies (NAM), which aims to replace animal testing with innovative models, such as in silico modeling, to assess drug safety.
However, in public comments submitted to the agency, they said that the guidance needs to be refined. Specifically, they are calling for more details to make the adoption of these methodologies feasible, including clearer guidelines on how to validate these new approaches.
Respondents also expressed the need for FDA to provide additional information on how biologics makers can utilize NAMs.
In March 2026, FDA released draft guidance to assist pharmaceutical manufacturers in transitioning from animal studies to non-animal alternatives for drug development through a new approach methodologies (NAM) framework, incorporating in vitro human-based systems, such as organs-on-chips and in silico modeling, to assess drug safety. (RELATED: FDA drafts guidance on animal testing alternatives, Regulatory Focus 8 March 2026)
FDA received 118 comments on the guidance prior to the 19 May deadline.
Industry seeks clarity
Multiple groups that provided feedback on the guidance generally supported it; however, they noted that greater clarity is needed in certain areas.
The Biotechnology Innovation Organization (BIO) wrote that it “supports FDA’s flexible and science-driven approach to NAM integration and appreciates the Agency’s commitment to advancing alternative methods in drug development. Maintaining this flexibility will be important as the field continues to evolve. At the same time, additional clarity and illustrative examples would provide sponsors with greater confidence in how NAMs will be evaluated and applied in regulatory decision-making.” Similar sentiments were echoed by several other commenters.
Amgen wrote that “the Draft Guidance would benefit from a clearer framework describing when and how NAMs may be used across different regulatory contexts, including exploratory, supportive, partial replacement, and stand-alone uses. Greater clarity regarding validation, qualification, technical characterization, biological relevance, fit-for-purpose, and the role of NAMs within a weight-of-evidence framework versus as stand-alone evidence would strengthen the guidance.”
Amgen also recommended that the guidance provide more “concrete” context-of-use examples, decision matrices, benchmarking principles, and illustrative submission packages.
Validation approaches
Many respondents requested that FDA shed more light on its expectations for manufacturers to conduct validation studies.
BIO wrote that “the guidance is framed as a ‘validation framework,’ yet also acknowledges that NAMs do not necessarily require formal validation for regulatory consideration. This contradiction creates confusion regarding the intent of the document and may unintentionally discourage the use of NAMs, particularly given the limited number of fully validated NAMs.”
Genentech wrote that “the guidance provides a framework to develop NAMs and notes the need for ‘validation’ to employ them in regulatory decision-making. To delineate and avoid confusion about FDA’s expectations, we suggest the Agency adopt an alternative term for the ‘validation’ sufficient for regulatory decision-making.”
The company further observed that the current draft guidance sows confusion by stating that a test "does not necessarily need to be validated" but later asserts that "validation is critical to establishing the reliability of NAM data for specific situations."
Amgen said that “we recommend more specificity about validation expectations.”
Otsuka also concurred. The company “suggests clarifying the methods that do not need to be validated throughout the document, unless the NAM will replace a required in-vivo study.”
Remove references to validation in the title
BIO and Pharmaceutical Research and Manufacturers of America (PhRMA) also suggested removing the reference to validation in the title, saying that the guidance is more focused on general considerations for using NAM methodologies than it is on validation.
PhRMA wrote that “the guidance title reflects general considerations. The purpose in the introduction can be better aligned with the title and content of the guidance by expanding the verbiage from just the validation framework to general considerations that fit where scientific advancements currently are.”
More clarity on early interactions
Amgen and BIO requested that the FDA clarify its expectations for early interactions with the agency regarding sponsors interested in utilizing the NAM approaches.
Amgen wrote that “while we support the Draft Guidance’s encouragement of early engagement with review divisions, the guidance does not explain how to seek advice generally on NAMs for platform approaches across multiple review divisions, how to discuss prior knowledge on one application for another, or when sponsors should use existing Drug Development Tools (DDT)/ Innovative Science and Technology Approaches for New Drugs (ISTAND)-type communication pathways versus standard review interactions.”
BIO stated that “the guidance appropriately encourages early engagement with FDA review divisions; however, sponsors would benefit from additional clarity regarding when such interactions may be most helpful within the development lifecycle and which meeting pathways may be most appropriate (e.g., Type B, Type C, or INTERACT).”
Greater clarity needed for biologics developers
A significant number of respondents indicated that the guidance was insufficient in detailing how developers of biologics could utilize these NAM models for safety testing.
BIO wrote that “although the guidance originates from CDER-regulated human drugs and biologics, it does not discuss how expectations may differ for monoclonal antibodies, antibody drug conjugates, oligonucleotides, cell-penetrating constructs, etc. This matters because modality-specific pharmacokinetics, target biology, and off-target liabilities strongly affect NAM utility.”
“Greater alignment across FDA centers would also be beneficial as NAM development increasingly spans products regulated by both CDER and CBER. While this draft guidance was issued by CDER, the absence of CBER participation or signatory alignment may create uncertainty for sponsors developing biologics and other CBER-regulated products that may also benefit from NAM-based approaches. Greater clarity on whether similar principles will apply across centers would help reduce uncertainty and support more consistent implementation across product types,” BIO stated.
Amgen said that “although the guidance originates from CDER-regulated human drugs and biologics, it does not discuss how expectations may differ for monoclonal antibodies, antibody drug conjugates, oligonucleotides, cell-penetrating constructs, etc. This matters because modality-specific pharmacokinetics, target biology, and off-target liabilities strongly affect NAM utility.”
Genentech also called for FDA to “ensure the final guidance aligns CDER and CBER on this topic. Given the significant potential for NAMs in Cell and Gene Therapy development, we question why the CBER did not co-sign this guidance, which currently applies only to CDER.”
