The U.S. Food and Drug Administration (FDA) has shifted its policy, now allowing new drug applications to rely on a single pivotal clinical trial instead of the previous standard of two. This change, announced last week, has drawn mixed reactions from experts in the pharmaceutical industry.
Harpreet Singh, chief medical officer at Precision for Medicine and former FDA division director of oncology, described the move as an evolution rather than a revolution. “This is not a new paradigm, particularly for oncology and rare [disease],” Singh said in an interview.
Recent data indicates that this practice is already common. In 2024, 66% of all new molecular entities approved by the Center for Drug Evaluation and Research were based on evidence from just one clinical trial, according to AgencyIQ.
Kristen Hege, former senior vice president at Bristol Myers Squibb, echoed Singh’s view. “I think it’s more of a talking point,” she told BioSpace. “The reality is the FDA has been applying that rule for almost as long as I’ve been in the industry.” Hege noted that since a debate with a regulatory colleague in the 1990s over trial requirements, she has not run two trials for approval—at least within oncology.
Oncology has long used the FDA’s accelerated approval pathway established in 1992. This allows surrogate endpoints to predict clinical benefit and can lead to earlier market entry after only one pivotal trial.
The updated policy was detailed by FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research Director Vinay Prasad in The New England Journal of Medicine (NEJM). It could extend single-trial approvals into areas like neuropsychiatry or metabolic diseases—fields that have typically required more evidence. A Department of Health and Human Services spokesperson told BioSpace via email that this policy could apply to either accelerated or traditional pathways “depending on whether the sponsor seeks approval based on a surrogate endpoint or on a demonstrated clinical benefit.”
However, some experts question how much will actually change under this new guidance. Steven Grossman, president of HPS Group, said: “FDA is likely to still want two trials for approval of treatments for more common diseases but it has always been true that a company could build a clinical development plan around one trial and submit it to FDA for feedback and approval. It might be granted. As a practical matter, the number of one-study approvals may not increase by much.” Grossman added: “The FDA is proposing a massive precedent shift: from, essentially, two studies but we will listen to any reasonable argument that one is sufficient to only one study is required unless we tell you a second is needed.”
Singh highlighted concerns about regulatory clarity following recent trends at the agency. In their NEJM article announcing the policy shift, Makary and Prasad stated its intent was to bolster innovation; Singh disagreed: “I feel that in the macro picture of things, what bolsters innovation is regulatory certainty,” she said. “And we very much are lacking that right now.”
Over the past year there have been complaints about vague guidance from regulators. For example, when introducing frameworks such as Rare Disease Evidence Principles (RDEP), some analysts felt these were simply reiterations of existing practices rather than substantive changes.
Paul Kim from National Organization for Rare Disorders commented on RDEP: “At its core, it is merely a restatement of current agency practice.”
Another program—the Plausible Mechanism Pathway—also faced criticism over lack of clarity when introduced by Makary and Prasad last November.
Grossman pointed out apparent inconsistencies between this single-trial policy and recent FDA actions requiring additional evidence before approving certain drugs: “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.”
Some stakeholders questioned why such significant policies are announced through journal articles rather than formal guidance documents or statutory requirements—a concern raised by Kinnari Patel, CEO at RTW Institute: “What I would like to see is all of these criteria become statutory requirement and/or draft guidance documents… Because I think only when that happens every single reviewer at the FDA is trained on it and can consistently apply it.” Singh agreed: “I think it’s important that we don’t make policy from a podium or from manuscript or press release.”
Industry leaders are seeking clarification regarding application across therapeutic areas beyond cancer where patient populations tend to be larger; here even large trials may not capture all benefits or risks adequately.
Makary and Prasad wrote in NEJM that discretion would remain with regulators—for example if mechanisms are unclear or outcomes uncertain—but where this discretion applies remains uncertain according to RBC Capital Markets analysts who noted ongoing unpredictability after several companies experienced reversals in previously agreed-upon regulatory paths.
Several biotechs including Capricor Therapeutics have recently had agreements reversed mid-development after initial feedback suggested their plans were sufficient—a trend seen as potentially increasing risk if relying solely on single studies.
RBC analysts suggested broader application might improve chances for approval while reducing late-stage costs but Singh cautioned against assuming less risk with fewer trials due to ongoing regulatory unpredictability: "We are being hit with regulatory reversals... so therefore company could be incurring much greater fiduciary risk..."
Hege emphasized endpoints remain central regardless whether using one or two trials—a key issue during Capricor's rejection last July concerning Duchenne muscular dystrophy therapy deramiocel.
Advice differs among experts regarding next steps; Celex Oncology CEO Carsten Faltum recommended reviewing data strength before proceeding while Singh advised maintaining dual-trial strategies until clearer direction emerges:
“If I were CEO...and had alignment...to run two trials...I would continue,” she said citing inconsistencies as leadership changes occur within FDA leadership circles.“While this [one-trial approach] may be valid effort...I don’t think companies will move in this direction until they get...more certainty around regulatory pathways.”
