From animal testing to model-informed drug development: building on ICH M15 and EMA initiatives to make new approach...

The transition from animal-based experimentation toward New Approach Methodologies (NAMs) requires not only technological innovation but also regulatory frameworks that enable evidence-based decision-making. We discuss how the European Medicines Agency's evolving strategy for regulatory acceptance of NAMs, combined with the ICH M15 guideline on Model-Informed Drug Development (MIDD), can support the integration of mechanistic pharmacokinetic/pharmacodynamic modeling, physiologically based pharmacokinetic models, quantitative systems pharmacology, and artificial intelligence-driven approaches into medicines development. We argue that NAMs and MIDD are complementary: NAMs generate human-relevant experimental and computational evidence, whereas MIDD provides a quantitative framework to integrate and evaluate this evidence for defined regulatory questions and contexts of use. We further propose that routine MIDD planning, context-of-use-based case studies, regulatory-grade models and data infrastructures, and shared regulatory expertise are needed to move NAMs toward more central regulatory evidence. Rather than implying an immediate replacement of animal studies, this approach could progressively support a more simulation-informed, human-relevant, and risk-based drug development paradigm.