Finding a place for new approach methodologies (NAMs) in biomedical research.

New approach methodologies (NAMs) can greatly contribute to the replacement and reduction of animal experiments in biomedical science. However, while NAMs have seen considerable investment and adoption in toxicology, this growth has not found a parallel in basic and translational biomedical research. Here we examine the opportunities and the challenges of systematic implementation of NAMs in biomedical research. We demonstrate that NAMs offer considerable scientific value by enabling tailored investigations into biological mechanisms and disease processes, addressing aspects of human biology that may be difficult to capture or extrapolate from animal models, and harnessing cutting-edge technological innovations. We highlight key areas, such as neuroscience, cardiovascular research and oncology, where NAMs have a distinct advantage and the potential to drive major advancements. However, realizing their full potential requires overcoming critical barriers, including technological limitations, gaps in education and training and insufficient funding. To facilitate broader adoption of NAMs, we propose adapting clinical outcome pathways, originally developed to link mechanistic biology to clinical outcomes, as a framework to guide the selection, combination and interpretation of NAMs in biomedical research. This approach could help to address a central limitation of individual NAMs, namely their restricted ability to capture whole-organism complexity, by enabling the meaningful combination of complementary models. Finally, we outline a stepwise strategy to accelerate the adoption of NAMs, emphasizing interdisciplinary collaboration, parallel studies alongside existing animal models and sustained investment in infrastructure and education.