What's in a NAM?

The transition away from animal experimentation is gaining momentum across scientific disciplines, driven by technological advancements, ethical imperatives and policy support. At the forefront of this movement is the development of New Approach Methodologies (NAMs). Rather than serving as mere substitutes for animal testing, NAMs represent a paradigm shift. Their growing acceptance has been reinforced by recent policy advancements, such as the US Food and Drug Administration Modernization Act 2.0 and the European Chemicals Agency's commitment to transitioning toward an animal-free regulatory system, both of which promote the adoption of NAMs. However, the term NAMs has become increasingly ambiguous, leading to confusion and potential misuse. To address this, we propose a unified definition: NAMs are species-specific methodologies, not including the use of living animals. NAMs prioritize the use of the target species in some form or another, eliminating the need for interspecies extrapolation. If the target species is human, this simple definition implies that working with experimental animals as a model never qualifies as a NAM. This distinction positions NAMs as a fundamentally different approach to the 3Rs framework of Replacement, Reduction and Refinement, and practical examples are discussed. Critically, this definition extends beyond toxicology and regulatory science, encompassing basic, applied and translational research. By leveraging cutting-edge technologies, including organoids, organ-on-chip, microfluidics, 3D bioprinting, bioinformatics, artificial intelligence and machine learning, NAMs provide novel biological insights that differ from those obtained through animal models while enhancing species-relevant data accuracy. Although challenges remain, particularly in their validation and widespread adoption, continued innovation, policy support and interdisciplinary collaboration will be key to unlocking their full potential, fostering more sustainable, humane and human-relevant approaches in biomedical research.