The U.S. Food and Drug Administration announced major shifts in evidentiary expectations: endorsing reliance on one well‑controlled pivotal trial in appropriate circumstances and publishing draft guidance for individualized therapies under a 'plausible mechanism' framework. Agency leaders argued modern analytic methods and biologic readouts can provide confirmatory evidence alongside a single trial. The changes target rare and ultra‑rare development programs, gene‑editing and individualized cell or gene therapies where randomized controls are infeasible. The guidance outlines evidentiary routes, manufacturing considerations and post‑approval confirmatory commitments, signalling a regulatory pathway that could accelerate approvals for bespoke medicines while emphasizing post‑market evidence collection.