It’s Official: FDA Will Now Default to One Clinical Trial for Drug Applications

The FDA, by default, will now only look for one well-controlled and adequately-run clinical trial as the basis of its drug approvals, making official a controversial policy change that has pushed out at least one high-ranking agency official.

“We believe that this could have meaningful readthroughs to the broader space and individual companies . . . improving likelihoods of drugs ultimately getting over the line and/or reducing late-stage development costs,” RBC Capital Markets wrote in a Feb. 18 note.

In an article published Wednesday in The New England Journal of Medicine, FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research Director Vinay Prasad called the regulator’s long-running use of two studies for approval a “dogma.” This standard, they suggested, “has a powerful theoretical basis to reduce false-positive conclusions.”

In practice, however, it “no longer makes sense,” Makary and Prasad continued, especially as drug development “becomes increasingly precise and scientific.” Specifically, they noted that the FDA not only looks at survival outcomes, but also a drug candidate’s effects on biomarkers and other secondary outcomes, in order to “tell a complete biologic story.”

“Two trials should be seen as just one of many interlocking facets of clinical credibility,” according to the FDA leaders. “In 2026, there are powerful alternative ways to feel assured that our products help people live longer or better.”

Along with the single-trial requirement, the FDA will also require drug sponsors to provide certain “confirmative evidence” to bolster their cases. Applicants could file data showing that their products work on a mechanistic, biological level. Data from related indications, animal models or other drugs that belong to the same class could also qualify as supportive, confirmatory evidence, according to the article. The FDA will also consider real-world evidence.

“The FDA will still retain discretion to require additional studies when warranted,” RBC wrote on Wednesday. These exceptions to what is now the new default will likely apply to drugs that have unclear mechanisms of actions or trials that use short-term surrogate endpoints. “Where FDA’s discretion will be applied remains a key unknown,” the analysts noted.

“Overall, positive vibes, but likely more evolution than revolution,” RBC said.

Not everyone was impressed, however.

“The agency’s new ‘one pivotal trial policy’ appears to undermine its commitment to patients,” Steven Grossman, president of policy and regulatory consulting firm HPS Group, said in a statement emailed to BioSpace, adding that the FDA has supported this option since the late ‘90s and has issued guidance on the topic to sponsors as recently as 2023. “What is the problem with existing policy that requires change?”

The new policy also sends the wrong message, Grossman added. “Second studies can be important. I know because I have worked on drugs and biologics that had a great first study and didn’t fare as well on the second. Shifting to one-trial is also inconsistent with recent FDA rejections citing a need for additional evidence and Dr. Prasad’s ongoing rhetoric about how many unsafe drugs are on the market.”

At least one former high-ranking official at the FDA has made it clear that he also has concerns with lowering the trial requirements: Richard Pazdur, who had been with the agency for more than two decades and became the inaugural head of the Oncology Center of Excellence when it was established in 2017.

In November 2025, Pazdur was named director of the Center for Drug Evaluation and Research, with Makary expressly promising that he would be able to operate independently in his new role. But shortly after his appointment, Pazdur was made to sign off on a “press release with a quotation by myself written in it,” regarding the single-trial policy, he told The Wall Street Journal in an interview last week—a policy on which he was undecided.

He was “asked to just agree to it,” Pazdur added. He ultimately retired in December last year.

Editor’s note: This story has been updated to include comments from Steven Grossman, president of policy and regulatory consulting firm HPS Group.