Top FDA officials authored a New England Journal of Medicine perspective establishing a single well‑controlled clinical trial as the agency’s new default for approvals, while urging sponsors to provide “confirmative evidence” (mechanistic data, related‑indication findings, animal models or real‑world evidence) when appropriate. Commissioner Marty Makary and CBER Director Vinay Prasad argued the two‑trial dogma is outdated and that integrated evidence can substitute for a second trial. The move formalizes a major regulatory shift that could lower late‑stage costs and speed product approvals, but the change has stirred debate inside and outside the agency about statistical robustness and exceptions for unclear mechanisms or surrogate endpoints. Analysts flagged that the policy retains FDA discretion to require additional studies when warranted. Stakeholders are assessing potential impacts on development timelines, statistical planning, and investment in confirmatory mechanistic work.