New approach methodologies for drug discovery

Traditional animal-based drug discovery has high failure rates, prompting the search for and adoption of human-centered new approach methodologies (NAMs).Rapid advances in stem cell-, organoid-, and in silicobased NAMs, supported by evolving frameworks from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), now span the entire drug-discovery continuum, from disease modeling and drug design to efficacy testing.Our review highlights recent progress across these domains, including the identification of therapeutic candidates, the development of cutting-edge models and technologies, and the potential of NAMs themselves as treatments in preclinical and clinical contexts, while examining the key biological, technical, and regulatory bottlenecks that need to be addressed to enable robust translational adoption.We conclude by discussing the translational and societal considerations essential to the responsible adoption of NAMs and outlining future human-centric pipelines poised to redefine the landscape of drug discovery.Figure 1.Timeline of transformative shifts in drug discovery Key milestones highlight the transition from animal-based testing to human-relevant NAMs.(A) Policy and guidance: FDA Modernization Acts 1.0 to 2.0 to 3.0, and NIH initiatives, including stem cell guidelines, the Tissue Chip program, investment in NAMs, and, together with enabling legislation, the first Organoid Development Center, mark the shift from mandatory animal use.(B) Technology: stem cells, iPSCs, organoids, organ-on-chips, and AI platforms establish human-centric models.(C) Clinical: NAMs now inform disease modeling, drug screening, and therapy development, underscoring a paradigm shift in discovery pipelines.