Deramiocel

iStock, bpawesome Last week, the FDA made its one pivotal trial policy official, sparking myriad questions from industry leaders, including around specific evidence required for the single study and why it hasn’t been implemented across all therapeutic areas before now. Last week, the FDA officially moved from a requirement of two pivotal trials to one for new drug applications. Reaction to the move has been tempered, with one regulatory expert referring to the new policy as being not necessarily a revolution but more an evolution. “This is not a new paradigm, particularly for oncology and rare [disease],” Harpreet Singh, chief medical officer at global clinical research organization Precision for Medicine, said in an interview. In 2024, 66% of all new molecular entities approved by the Center for Drug Evaluation and Research relied on evidence from just one clinical trial, according to AgencyIQ . Kristen Hege, former senior vice president of Early Clinical Development, Hematology/Oncology & Cell Therapy at Bristol Myers Squibb, agreed with Singh’s assessment. “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 recalled a debate with a regulatory affairs colleague in the 1990s over whether one or two well-controlled trials were required to get a product across the finish line. “Since then, I have never run two trials for approval,” she said. This is in the oncology space, of course, which has long been a trailblazer in leveraging the FDA’s accelerated approval pathway . Implemented in 1992, the accelerated approval pathway allows for the use of surrogate endpoints to predict clinical benefit as opposed to directly measuring it, followed by a confirmatory trial. This can allow for earlier market entry, often after only a single pivotal trial. The new policy, laid out last week in a The New England Journal of Medicine article published by FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research Director Vinay Prasad, theoretically expands the one-trial allowance to therapeutic areas that haven’t typically gotten away with one trial, such as neuropsychiatry, metabolic and immunology and inflammation. Indeed, a Department of Health and Human Services spokesperson told BioSpace via email that the new policy could apply to either the accelerated or traditional pathway, “depending on whether the sponsor seeks approval based on a surrogate endpoint or on a demonstrated clinical benefit.” But some experts doubt that the new policy represents a substantive change in practice, even on a broader scale. “FDA is likely to still want two trials for approval of treatments for more common diseases,” Steven Grossman, president of policy and regulatory consulting firm HPS Group, told BioSpace in an email, “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.” Rather, Grossman believes the new policy changes the balance of power between FDA and industry. “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,” he said. Lack of Clarity: A Continuing Trend For Singh, who previously served as a division director of oncology at the FDA, the key issue is regulatory clarity In the NEJM article, Makary and Prasad acknowledged that the new policy isn’t novel but said its intent is to bolster innovation. Singh, however, said this is “somewhat misguided. “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, the FDA has been repeatedly accused of issuing vague guidance. In September 2025, the agency unveiled a new framework , the Rare Disease Evidence Principles (RDEP), meant to streamline the approval of therapies for ultra-rare diseases. But some analysts and rare disease advocates were unimpressed. The RDEP “is all wrapper and no gift,” Paul Kim, advisor at the National Organization for Rare Disorders, wrote in a LinkedIn post at the time. “At its core, it is merely a restatement of current agency practice.” The FDA’s Plausible Mechanism Pathway, introduced in November 2025 in an article also published by Makary and Prasad in the NEJM , drew criticism for lack of clarity. On Monday, the regulator released draft guidance further elucidating the program but many questions remain. Rare disease FDA’s Bespoke Pathway To Focus on Gene Editing and RNA-Based Treatments for Rare Diseases The framework, first introduced by FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research head Vinay Prasad in November, was criticized for lacking detailed guidance. Agency leaders elucidated on the pathway for personalized medicines on Monday. February 23, 2026 · 3 min read · Nick Paul Taylor As for the new one-trial policy, Grossman noted that, unknown details notwithstanding, it appears to be at odds with the agency’s overall push toward a higher standard for drug approvals. “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.” Points of Clarification The fact that the policy was announced via a medical journal itself raises questions, according to Kinnari Patel, CEO of think tank RTW Institute. “What I would like to see is all of these criteria to become a statutory requirement and/or draft guidance documents,” Patel, who previously served as head of R&D and chief operating officer at Rocket Pharmaceuticals, told BioSpace . “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 a manuscript or from a press release.” Should the single-trial policy turn into formal guidance in the coming months, there are several points of clarification that industry is seeking. “It needs to be explained why in therapeutic areas [besides cancer], this traditionally has not been the case,” Singh said. “Generally that’s because the populations are much larger.” In hypercholesterolemia or diabetes, for example, even one large, well-controlled trial may not adequately depict all the benefits and risks, she added. Another point of concern is Makary and Prasad’s contention that the FDA will exercise discretion as to when two trials will still be required. This could apply if a candidate “has a nebulous, pluripotent, or nonspecific mechanism of action; if it affects a labile, short-term, or surrogate outcome; or if a trial has some underlying limitation or deficiency,” according to the NEJM article. “Where [that] discretion will be applied remains a key unknown, and the agency’s recent mixed messaging to several companies has continued to highlight regulatory unpredictability,” RBC Capital Markets said in a Feb. 18 note. Indeed, over the past year, Capricor Therapeutics, Replimune , Saol Therapeutics and others have been sent into a regulatory tailspin after the FDA reversed course on previous guidance. FDA FDA Reversals Send UniQure, Biohaven, Capricor, More Into a ‘Tailspin’ Since July, several biotechs have been forced to pivot as previous agreements with the FDA around evidence required for approval were reversed, a phenomenon that, according to experts, could portend a more restrictive regulator. November 24, 2025 · 7 min read · Heather McKenzie RBC added that the broader application of these requirements could “[improve] likelihoods of drugs ultimately getting over the line and/or reducing late-stage development costs.” But Singh questioned this sentiment, pointing out that companies that conduct only one trial could actually be assuming additional risk. Currently, “We are being hit with regulatory reversals on previously agreed upon programs and endpoints, and so therefore a company could be incurring a much greater fiduciary risk to embark on only one study,” she said. For Hege, whether it’s one trial or two, it all comes down to endpoints. “It’s what endpoints can you use for that initial trial, that initial approval, whether it’s accelerated or full, is the key.” Endpoints were the primary sticking point for Capricor in the July 2025 rejection of its deramiocel, in development for Duchenne muscular dystrophy cardiomyopathy. Given all the uncertainty that still surrounds the regulatory shift to one trial, Singh and Faltum offered differing advice to companies. The overarching theme in the NEJM article, Faltum said, is to let the data speak. “If you have a second trial running, I would take a step back, and I would take a careful look at how strong and how robust was my first trial, and how strong is my package,” he said. “And if you feel that you have something that, well, this might fly . . . I would probably request a Type C meeting with the FDA” to discuss options. Singh, however, recommended a wait-and-watch approach. “If I were the CEO of a biotech and I had alignment to run two trials and I had the funding by which to do so, I would continue,” she said, citing inconsistencies in approach as FDA leadership has evolved. “While this [one-trial approach] may be a valid effort to bolster biomedical innovation,” she said, “I don’t think companies will move in this direction until they get, in other parts of the agency, more certainty around regulatory pathways.” .responsive-container { display: flex; flex-wrap: wrap; border: 1px solid #ededed; font-family: Helvetica, Arial, Sans-Serif; padding: 20px 20px 10px 20px; } .column-left { flex: 1; max-width: 45%; padding: 20px 20px 10px 20px; } .column-right { flex: 2; padding: 20px 20px 10px 20px; } @media (max-width: 768px) { .column-left, .column-right { max-width: 100%; flex: 100%; padding: 10px 0; } } Subscribe to ClinicaSpace! 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