A CDER perspective: Landscape of New Approach Methodologies (NAMs) submitted in drug development programs

Abstract

This study analyzes the landscape of studies using New Approach Methodologies (NAMs) and submitted to the FDA over the past 15 years. The study utilized a custom-developed Center for Drug Evaluation and Research (CDER) search tool to examine keywords in Module 4 of the Electronic Common Technical Document (eCTD) across various drug applications. The investigation focused on five NAM categories, including some of those identified in the 2022 Food and Drug Omnibus Reform Act (FDORA): in vitro, in silico, in chemico, nonhuman in vivo, and other NAMs. Results indicated that 93 % of NAM submissions were concentrated in two categories: in silico (49 %) and in vitro (44 %), with other categories (including in chemico, nonhuman in vivo from phylogenetically lower species and other combined methods) demonstrating significantly lower representation. In vitro NAMs, including stem cell-derived and sandwich culture models, showed higher prevalence compared to 3D models and organ chip or MPS models. The relatively high prevalence of in silico NAMs, was due to the submission of multiple study reports per application, attributed to various metabolites and the use of different in silico platforms. In chemico and nonhuman in vivo NAMs demonstrated limited submissions, with zebrafish studies predominating in the latter category. This study highlights one of CDER's activities aimed at better understanding the current usage of NAMs in drug development, while providing evidence to support areas of focus and prioritization of resources towards the validation of NAMs with significant regulatory impact potential. Despite technical limitations in the datamining work presented here, the findings confirm that CDER has been receiving NAMs data in drug applications for a long time. Nevertheless, we acknowledge that industry submits only a fraction of their NAM data to FDA, therefore we encourage increased NAM submissions which would contribute to building scientific confidence in these methods. It is only through the availability of sufficient case studies, that CDER can move towards reaching the goals of NAMs Roadmap issued in April 2025, and ultimately phasing out animal studies when possible and feasible.