Path dependency and the rescuing of the biomedical research enterprise.

In 2025, three U.S. agencies within the Department of Health and Human Services (FDA, NIH, CDC) alongside EPA and the Departments of the Navy and Veterans Affairs, began substituting animal testing applications with reliable, human-relevant methods. The impact of this shift in public policy taking place at agencies historically bullish on animal testing is still reverberating in the United States and around the world. Here, we examine the circumstances that enabled such momentous reforms, including the role of the FDA Modernization Act 2.0 in advancing new alternative methods, collectively referred to as NAMs. We explain how animal testing, despite its poor value in predicting the safety and efficacy of drugs in humans, came to dominate drug discovery, basic sciences, and environmental toxicity assessments since the inception of the Federal Food, Drug, and Cosmetic Act (Federal FD&C Act) in 1938. Specifically, we identify critical junctures, including catastrophic government decisions, that made the overall research enterprise acutely dependent on animals, leading to the existing predicament-an indefensible 92% failure rate in translating drugs from preclinical studies to actual therapies. Notably, our analysis chronicles events through the lens of "path dependency," a social sciences phenomenon that occurs when faulty past decisions lock-in future action. Finally, we recognize that our narrative is a departure from the medical establishment account or the talking points of powerful interest groups, including some in the academic elite who continue to shore up animal-centric paradigms in drug development for reasons we also outline.