Comment from ESQlabs

ESQlabs welcomes the FDA's draft guidance on New Approach Methodologies as a timely and constructive step toward broader integration of NAMs in drug development, and we strongly endorse the decision-driven, fit-for-purpose framing built around Context of Use. Our full comments, submitted as an attachment, offer 16 specific recommendations to make the guidance more operational. Our highest-priority points concern areas where additional specificity would substantially improve regulatory clarity. The guidance would benefit from explicit treatment of in vitro to in vivo extrapolation, including which methods (PBPK, QSP, QST) are appropriate for which contexts and how the extrapolation itself should be qualified. It also does not currently address how sponsors should handle conflicting results between NAM and in vivo data, a situation that is among the most consequential sponsors will encounter. We recommend the Agency consider indicative, non-binding quantitative performance thresholds and a tiered validation approach in which evidentiary stringency scales with the regulatory reliance placed on the NAM. We further recommend that sponsors be asked to define the applicability domain of any NAM across compound space, biological space, endpoint scope, and extrapolation boundaries. Several additional points warrant attention. The term "NAMs" groups methodologically distinct approaches (in vitro, ex vivo, organoid, in silico) under a single umbrella, and a more granular taxonomy would support more consistent expectations. Exposure characterization in complex NAMs such as microphysiological systems frequently diverges from nominal concentration and merits explicit guidance. The framework should also reference Good Laboratory Practices (21 CFR Part 58), the required standard for nonclinical studies supporting IND and NDA submissions, alongside GIVIMP as its in vitro analogue. Finally, the inclusion of anonymized case studies of accepted and rejected NAM submissions would meaningfully reduce sponsor uncertainty and accelerate adoption. ESQlabs supports the FDA's commitment to advancing human-relevant, mechanistic approaches to predictive toxicology and would welcome the opportunity to discuss any of these points further. Cleo Demeester and Marco Siccardi on behalf of ESQlabs