The FDA is taking a harder stance on clinical trials that don't include enough American patients, potentially delaying or blocking drug approvals even when studies show promise in other populations. In two major decisions in 2025, the FDA's Oncologic Drug Advisory Committee (ODAC) voted against approving cancer treatments largely because the trials enrolled too few U.S. participants, signaling a shift in how regulators evaluate evidence from global studies. What Happened With These Recent Drug Trials? In May 2025, the FDA reviewed STARGLO, a phase 3 clinical trial testing glofitamab plus chemotherapy against a standard treatment for a type of blood cancer called diffuse large B-cell lymphoma. The trial showed an overall survival benefit, but ODAC voted 8 to 1 against the drug's applicability to U.S. patients. The main problem: only 25 North American patients were enrolled in the entire study. The results told a striking story. In Asian regions, patients receiving the new drug had a median progression-free survival of 20.4 months compared to just 2 months for those on standard treatment. But in the rest of the worldâincluding the United States, Europe, and Australiaâthe new drug showed a median progression-free survival of 9.2 months versus 7.8 months for the standard treatment. Even more concerning, when looking at overall survival outside Asia, the new drug actually performed worse: 21.2 months versus 27.8 months for the standard approach. Just two months later, in July 2025, ODAC rejected two more trials for a multiple myeloma drug called belantamab mafodotin. This time, the committee voted 5 to 3 and 7 to 1 against the risk-benefit profiles of the two trials. Again, low U.S. enrollment was a critical issueâless than 5% of patients in both trials were from the United States. Why Does U.S. Representation in Trials Matter So Much? The FDA's concern isn't just about numbers. When trials enroll mostly international patients, the results may not reflect how a drug will work in American patients, who may have different genetics, access to other treatments, lifestyle factors, and healthcare practices. In the STARGLO trial, for example, researchers discovered that Asian patients had much less previous exposure to a cutting-edge cancer therapy called CAR-T cell therapy, which is standard care in the U.S. for certain blood cancers. This difference alone could explain why the drug worked so much better in Asia than elsewhere. For the multiple myeloma trials, ODAC noted another practical concern: the eye-related side effects of belantamab mafodotin could be more impactful on American patients. The United States has the longest distance traveled per capita by car, truck, and motorcycle, meaning vision problems could prevent people from drivingâa major quality-of-life issue that might not affect patients in countries with different transportation patterns. Additionally, the trials lacked diversity. Even though 20% of multiple myeloma patients are Black, fewer Black patients were enrolled in these studies, raising questions about whether the results would apply to all Americans. How Is This Changing the Clinical Trial Landscape? These FDA decisions reflect a troubling trend: the proportion of U.S. patients in oncology clinical trials has been declining. It's increasingly common to see multinational trials where 10% or fewer of participants come from the United States. When drug companies design global trials to accommodate different healthcare systems and treatment availability across countries, they often end up with control armsâthe standard treatments patients are compared againstâthat don't match what American doctors actually use. For instance, second-generation Bruton tyrosine kinase (BTK) inhibitors are the most prescribed BTK inhibitors for chronic lymphocytic leukemia in the U.S., but they aren't reimbursed in many Central and Eastern European countries. Similarly, a breast cancer treatment recommended in the U.S. isn't recommended in the United Kingdom. When U.S. patients see they might be randomized to a treatment that's considered outdated or inferior by American standards, they're less likely to enroll in the trial. Ways to Improve U.S. Clinical Trial Enrollment - Strengthen Control Arms for U.S. Patients: Trials could use country-specific control arms, ensuring that American participants aren't randomized to treatments considered substandard by U.S. medical guidelines. Some trials, like DeLLphi-304, have already adopted this approach by varying the control arm depending on where patients are enrolled. - Implement Crossover Trial Designs: Allow patients randomized to the standard treatment to switch to the experimental drug after their disease progresses. This maintains fairness and gives patients confidence they won't be permanently denied access to a potentially beneficial new therapy, which is especially important when drugs receive accelerated approval before full trial results are available. - Increase Diversity and Representation: Actively recruit patients from underrepresented groups, including Black patients and other minorities, to ensure trial results reflect the full range of American patients who will eventually use the drug. The FDA's recent decisions send a clear message: clinical trials submitted for drug approval must do more to recruit American patients so regulators and clinicians can properly assess whether experimental treatments will work and be safe for U.S. populations. Without these changes, promising therapies could face delayed or denied approvals, even if they show benefits elsewhere in the world.
