Comment from International Foundation for Ethical Research (IFER)

The International Foundation for Ethical Research (IFER) appreciates the opportunity to comment on this draft guidance. IFER is a 501(c)(3) nonprofit that funds graduate fellowship research developing and validating human-relevant new approach methodologies (NAMs) across U.S. research universities, with grantees advancing in vitro systems, computational models, microphysiological systems, organoids, and other human biology-based platforms. We offer the following comments from the perspective of researchers actively working to advance the foundational science underlying these methods. A full comment letter with additional recommendations is attached. I. Human Biological Relevance Should Be the Primary Evidentiary Standard Many NAMs under development are designed not to replicate animal findings but to model human-specific biology that animal systems cannot capture. Requiring concordance with animal data as the primary performance criterion can therefore undermine the scientific rationale for NAMs rather than validate it. The guidance should affirm that where mechanistic human data are available, performance against human-relevant reference datasets is the appropriate standard. FDA should clarify that disagreement between NAM-derived results and animal data does not inherently indicate NAM failure and that human clinical, epidemiological, and mechanistic datasets should be incorporated as reference comparators wherever available. The ultimate evidentiary goal is accurate prediction of human outcomes, not replication of legacy testing patterns. Centering human relevance more explicitly would strengthen both the scientific defensibility of the framework and its practical value for researchers designing validation studies. II. Fit-for-Purpose Validation Should Be Tiered by Context of Use Guidance on the three fit-for-purpose objectives (replacement, gap-filling, and confirmation) applies equivalent validation language to all. This conflation creates real and practical problems for the research community. IFER recommends that FDA provide tiered validation guidance corresponding to each fit-for-purpose objective in Section III.D, with proportionate evidentiary expectations for each. The guidance should also clarify that validation evidence is built iteratively, and that NAMs at earlier stages of development may contribute meaningfully within a weight-of-evidence framework. Additional recommendations on integrated multi-platform NAM data packages are included in the attached full comment. III. Early Engagement Should Reach Academic Researchers, Not Only Sponsors The guidance’s encouragement of early engagement with FDA review divisions is directed entirely at drug sponsors. IFER occupies an unusual position in the NAMs ecosystem: as a funder of academic researchers rather than a drug sponsor or industry group, we see directly where the translation pipeline breaks down. Promising validation work stalls not because the science is insufficient, but because researchers lack meaningful signal about whether their methodological choices will be legible to FDA reviewers when the work eventually reaches a regulatory context. This gap is not visible to sponsors, who engage with FDA after a method is already selected, nor to industry, which builds on methods already deemed acceptable. It is most visible to researchers doing upstream work and to the funders supporting them. IFER recommends that FDA expand early engagement opportunities to include academic investigators generating NAM validation data intended for eventual regulatory use, publish appropriately anonymized case studies and NAM acceptance decisions to build a public knowledge base that researchers and sponsors alike can use to calibrate their work, and increase coordination with NIH, NIEHS, and ICCVAM to align academic and governmental validation frameworks with regulatory expectations. Greater transparency about what FDA has accepted and why would meaningfully accelerate field progress. In summary, IFER urges FDA to affirm human biological relevance as the primary evidentiary standard, establish tiered validation expectations by context of use, and expand early engagement pathways to reach the academic research community. The attached full comment includes additional recommendations on integrated NAM approaches and measurable implementation goals. Please see attached word document for the full comment.