Complement-ARIE: Catalyzing the Development and Adoption of New Approach Methodologies.

New approach methodologies (NAMs) are proving to be invaluable tools in basic and clinical research to better understand human health and disease, elucidate mechanisms, and study the efficacy and toxicity of novel therapeutics that can improve upon and complement animal-based methodologies. Over the last 15 years, the National Institutes of Health (NIH) has increased investment in NAMs, including in chemico, in silico, and in vitro approaches, such as cell-free assay systems, digital twins, and microphysiological systems (MPS). To further catalyze and innovate the use of NAMs, the NIH Common Fund has initiated a new program, Complement Animal Research In Experimentation (Complement-ARIE), which aims to pioneer the development, standardization, validation, and regulatory use of combinatorial NAMs that will more accurately model human biology and disease states. This program specifically aims to 1) better model human health and disease differences in outcomes across populations, 2) develop NAMs that can provide insights into specific biological processes or disease states, 3) validate mature NAMs to support regulatory use and standardization, and 4) complement traditional animal models to make research more efficient and effective. To inform the implementation of Complement-ARIE, the NIH organized strategic planning activities including an inter-agency retreat, public listening sessions, scientific literature landscape analysis, and a challenge prize. Here we discuss the goals and findings of these activities, and how these results helped identify and address scientific and operational opportunities and roadblocks for implementation of the program towards broader acceptance and impact of NAMs. We anticipate these new methods and approaches could transform the way we do basic, translational, and clinical sciences.