Beyond NAMs Versus Animal Models: Context of Use As the Governing Framework for Integrated Nonclinical Strategies in Drug Development

New approach methodologies (NAMs) originated in chemical hazard assessment, where two forces operate together: the scale of characterizing many substances, and a long-standing ethical and legal commitment to replacing animal testing. Drug development is weighted differently. It is a translational and decision problem applied to small sets of compounds at pharmacologically active exposures. As NAMs capabilities have expanded, the two domains have been conflated, and framing NAMs against animal studies as a binary choice risks undermining both. The so-called translatability crisis is not a single problem with a single solution. Clinical attrition reflects gaps in mechanistic understanding, exposure-irrelevant study designs, underpowered analyses, and survivorship bias that obscures the screening value of nonclinical studies. Addressing these challenges requires an integrated strategy in which the choice of platform, the design of endpoints, and the rigor of validation are governed by a clearly defined context of use. A biologically relevant model is defined not by its type but by its fitness for the purpose it serves. We argue for a patient-centered nonclinical paradigm that combines animal and non-animal approaches, aligned with recent FDA, NIH, and EMA direction, and note that both domains converge on the same non-dogmatic conclusion.