FDA Officially Shifts to One-Trial Standard for New Drug Approvals

The FDA has announced a major change to its regulatory framework, formally establishing that a single well-designed pivotal clinical trial will be the new default basis for most drug and therapeutic approvals—replacing the long-standing expectation that two independent trials are required. The shift, detailed in a New England Journal of Medicine article by FDA leaders, is poised to reshape drug development in the United States.

For more than half a century, the FDA’s standard for demonstrating “substantial evidence” of safety and efficacy has typically meant two adequate and well-controlled clinical trials showing positive results. That requirement, established in the 1960s, was designed to protect against false positives—the idea that a single trial could succeed merely by chance.

But in a policy article published this week, FDA Commissioner Dr. Marty Makary and Deputy Dr. Vinay Prasad argued that the two-trial benchmark has become outdated in an era of more sophisticated scientific methods and broader sources of data. Under the new default policy, sponsors of new drugs, biologics, and certain medical products will generally only need one high-quality pivotal study, bolstered by confirmatory evidence, to support an application.

Drs. Makary and Prasad argue that advances in trial design, biomarkers, statistical methods, and real-world evidence have increased confidence in single-trial results when they are well executed. These developments, they say, make two trials less essential to establishing whether a product truly benefits patients.

“Default options anchor individuals and institutions psychologically,” the authors wrote, noting that formalizing the one-trial approach could stimulate biomedical innovation, reduce development costs, and accelerate patient access to new therapies.

In practice, many recent drug approvals have already relied on a single pivotal trial—especially in oncology and rare diseases, where clinical conditions or small patient populations make multiple large trials difficult or infeasible. A recent analysis found that approximately two-thirds of novel drugs approved in 2024 were based on just one pivotal study.

The FDA emphasized that a one-trial default does not eliminate robust scientific scrutiny. Sponsors will be expected to provide supplementary confirmatory evidence alongside the pivotal trial. This could include mechanistic data, results from related indications, animal studies, or real-world evidence that supports the biological rationale behind the product.

The agency also retains the discretion to require multiple trials in cases where a single study does not provide sufficient clarity.

Supporters of the policy say it could dramatically lower clinical development costs, shorten timelines, and encourage investment in innovative therapies. By reducing the need for redundant trials, drug developers may be able to bring products to market more quickly and at lower cost. 

However, the shift is also drawing criticism from some scientists, clinicians, and regulatory experts who worry that loosening the evidentiary bar could weaken safety and efficacy standards and erode public confidence in FDA decisions. In particular, some have raised concerns that a one-trial default might lead to approvals based on borderline results that have not been sufficiently replicated.

The FDA’s new default policy is expected to be codified through updated guidance and internal procedures over the coming months. Implementation could occur within 3 to 6 months, as the agency aligns its review processes with the revised standard.

Originally published online on Eyewire+.