Beyond NAMs versus animal models: Context of use as the governing framework for integrated nonclinical strategies in drug development

New approach methodologies (NAMs) grew out of chemical hazard assessment, a field shaped by two pressures: the sheer number of substances requiring characterization, and a long-standing ethical and legal push to replace animal testing. Drug development, this paper argues, is a different problem — a translational and decision-making challenge applied to a small number of compounds at pharmacologically active exposures. As NAM capabilities have expanded, the two domains have been conflated, and framing NAMs against animal studies as a binary choice risks undermining both.

The authors also reframe the “translatability crisis” as several distinct problems rather than one. Clinical attrition reflects gaps in mechanistic understanding, exposure-irrelevant study designs, underpowered analyses, and survivorship bias that hides the screening value nonclinical studies already deliver. Their proposed answer is an integrated strategy in which platform choice, endpoint design, and validation rigor are all governed by a clearly defined context of use — a biologically relevant model being defined not by its type but by its fitness for the purpose it serves. The paper makes the case for a patient-centered nonclinical paradigm combining animal and non-animal approaches, aligned with recent FDA, NIH, and EMA direction.