02175nas a2200253   4500000000100000008004100001260001400042100001900056700001800075700002000093700001700113700002500130700002000155700002300175700001600198700001900214700001700233245009100250856005500341300001400396490000800410520148900418022001401907       2026                            d  c2026-9-031 aKsenia Blinova1 aKimberly Chiu1 aAnik Chaturbedi1 aJahan Cooper1 aTromondae K. Feaster1 aPaula L. Hyland1 aLidiya Stavitskaya1 aWendy W. Wu1 aJeffry Florian1 aRodney Rouse00aAdvances in New Approach Methodologies at FDA's Division of Applied Regulatory Science  uhttps://pmc.ncbi.nlm.nih.gov/articles/PMC13539334/  a1250-12540 v1203 aNew Approach Methodologies (NAMs) represent a paradigm shift in drug development and regulatory science, offering human‐relevant alternatives to traditional preclinical models. This mini‐review highlights recent advances in NAM development, validation, and regulatory application from FDA's Division of Applied Regulatory Science (DARS). We describe in silico NAMs including quantitative systems pharmacology (QSP) modeling for opioid overdose scenarios, (quantitative) structure–activity relationship ((Q)SAR) modeling for toxicity prediction and drug–drug interaction assessment, and multi‐omics approaches for pharmacodynamic biomarker discovery. Additionally, we present in vitro NAMs including human‐induced pluripotent stem cell (hiPSC)‐derived neural networks for opioid pharmacology assessment, microphysiological systems (MPS) for pulmonary drug permeability, gastrointestinal models for intestinal transport, and standardized cardiac ion channel and hiPSC‐CM MEA assays for proarrhythmia risk prediction. These case studies demonstrate how NAMs can reduce reliance on animal studies while improving translation to clinical outcomes. The NAMs described here range from exploratory research tools to approaches actively informing regulatory submissions review. The integration of in silico and in vitro NAMs into regulatory decision‐making frameworks represents a critical step toward more efficient, human‐relevant drug development and safety assessments.  a0009-9236