The FDA published a New England Journal of Medicine perspective that sets a single well‑controlled clinical trial as the agency’s new default for approvals, authored by Commissioner Marty Makary and CDER leadership. The article clarifies that sponsors must now supply “confirmative evidence” — mechanistic data, related‑indication results, animal models or real‑world evidence — to buttress one pivotal study. Regulators said discretion remains to require additional trials for unclear mechanisms or surrogate endpoints, and agencies signaled they will still demand robustness via complementary data sources. Analysts and sponsors immediately flagged likely shifts in development strategy, with companies expected to lean more heavily on biomarker packages, bridging evidence, and post‑marketing commitments. The note formalizes a trend toward regulatory flexibility while codifying expectations for integrated evidence packages; biotech R&D teams will need to rebalance late‑stage investments, trial design and evidentiary strategies accordingly.