One and Done: FDA Rips Up the Two-Trial Playbook

The FDA now accepts a single pivotal trial as its default for drug approval, a shift that could transform rare disease development

7 May 2026

America's Food and Drug Administration has made a significant change to how it evaluates new drugs, establishing a single well-designed clinical trial as its standard for approval, replacing the long-standing expectation of two. Announced in February 2026 and detailed in the New England Journal of Medicine, the shift carries particular weight for developers of treatments targeting rare diseases.

Patient enrolment has long been the central constraint in rare disease research. With eligible populations often numbering in the hundreds or low thousands globally, running two parallel pivotal studies has rendered many ultra-rare programmes commercially unviable. FDA Commissioner Martin Makary described the two-trial standard as a "psychological anchor" that had stifled development without delivering a proportionate benefit to safety.

What has changed is not the approval threshold, but the starting assumption. By 2024, 66 per cent of new molecular entity approvals were already supported by a single trial, a fact that made the two-trial expectation increasingly difficult to defend. Sponsors must still provide substantial evidence of efficacy, and the agency retains authority to require additional studies where trial design or a drug's mechanism is insufficiently understood.

A companion framework released alongside the announcement extends the shift further. Gene-editing and RNA-based treatments for ultra-rare genetic conditions, including those where conventional trials are not feasible, may now qualify for approval, provided developers can demonstrate biological plausibility and evidence of target engagement.

Structural barriers to rare disease investment have eased measurably. Lower development costs and compressed timelines could make niche conditions more commercially attractive, expanding a pipeline that has historically struggled to move from laboratory to clinic. Whether the change meaningfully increases the number of approved treatments will depend on how the agency applies its remaining oversight powers, and on how sponsors respond to the implicit demand for stronger single-study evidence.