FDA sets one pivotal trial as new default standard for regulatory approvals

The US Food and Drug Administration (FDA) has announced that one adequate and well-controlled clinical trial, supported by confirmatory evidence, will generally be sufficient for marketing authorization, formally moving away from the long-standing expectation of two pivotal studies. 

The policy shift is outlined in the New England Journal of Medicine article, “One Pivotal Trial, the New Default Option for FDA Approval — Ending the Two-Trial Dogma,” authored by Vinay Prasad, Director of the agency's Center for Biologics Evaluation and Research (CBER) and FDA Commissioner Marty Makary. In the paper, the authors set out the scientific and regulatory rationale for redefining the agency’s default evidentiary standard. 

The change formalizes statutory flexibility that has existed since 1997, when Congress authorized the US FDA to approve drugs on the basis of a single adequate and well-controlled study combined with confirmatory evidence. This evidence may include mechanistic science, data from related indications, animal models, class effects, real-world evidence (RWE), or a second adequate and well-controlled trial. 

Although the FDA has applied disease specific flexibility in recent decades, particularly in oncology where single trials have supported many approvals, agency leaders state that uncertainty has remained about when one trial is sufficient.  

“Moving forward, we are announcing that a one-trial requirement will be the FDA’s new default standard,”  

write Prasad and Makary. The change is being implemented alongside a broader postmarket initiative to collect robust data on all drugs and devices. 

The expectation of two trials originated in the 1960s as a safeguard against false-positive findings. Statistically, requiring two successful studies lowers the probability of a type I error because “one must be lucky twice.” In an era of more limited biological understanding, duplicate trials provided additional assurance when mechanistic plausibility was less clear. 

However, the authors argue that advances in biology, trial methodology, and statistical science have altered that landscape, noting that: 

“Modern drug development establishes credibility in multiple ways, relying on both statistical and biologic inferences.” 

Regulators now consider not only clinical outcomes such as survival, but also biomarker changes and intermediate endpoints that “tell a complete biologic story: does this drug actually work?” In this context, they contend, “overreliance on two trials no longer makes sense,” and two trials should instead be viewed as “just one of many interlocking facets of clinical credibility.” 

Under the revised default, greater emphasis will be placed on the quality of a single pivotal study. Key considerations include the magnitude of treatment effect, the use of a contemporary and appropriate control group, prespecification of hypotheses and primary endpoints, statistical power, blinding, and the handling of missing data. Reviewers will also assess whether findings are consistent with biological evidence and aligned with current US standards of care. 

The authors also cite cost and timing implications. A single pivotal study may cost between $30 million and $150 million and can take years to complete, contributing to average development timelines exceeding seven years.  

“Lowering capital costs for drug developers may remove a persistent argument in justification of lofty and rising drug prices for everyday Americans — the onerous cost of research and development,” they write. 

At the same time, Prasad and Makary emphasize that the revised default does not reduce evidentiary standards. They note that even under a two-trial framework, some approved products later demonstrated safety or efficacy concerns.  

“Without examination of the quality of a study, two trials may even provide a false assurance,”  

they state, arguing that concentrating review resources on one rigorous study may strengthen oversight.  

The FDA will retain discretion to require more than one study where appropriate, such as when a therapy has a “nebulous, pluripotent, or nonspecific mechanism of action,” relies on surrogate or short-term outcomes, or presents other limitations. Within the bounds of US law, the agency will continue to determine the appropriate evidentiary threshold on a case-by-case basis.