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Study Explores FDA Approvals for Drugs With Uncertain Pivotal Trial Results

For a research letter appearing in JAMA Internal Medicine, a team at Brigham and Women's Hospital, the Yale School of Medicine, and Yale School of Public Health presents findings from an analysis of drugs that were given accelerated approval by the US Food and Drug Administration, despite falling short of primary end points in corresponding pivotal trials. Building from the example of aducanumab — an Alzheimer's disease drug that received accelerated approval in 2021 based on an exploratory, surrogate marker rather than the initial primary trial end point — the researchers considered 210 such drug approvals made by the FDA between 2018 and 2021. Among other results, they found that 10 percent of those approvals involved drugs will null findings on at least one primary end point in an associated pivotal study. Of those, 11 of 21 drugs were first-in-class drugs, they note, while 10 were considered orphan drugs. Across 56 pivotal trials associated with the drugs, 27 of 74 primary efficacy end points were null, including more than a dozen clinical outcomes. "Our findings underscore the complexity of regulatory decision-making, as exemplified by evidence of effectiveness despite null primary end point findings," the authors explain, noting that "evidence of efficacy was less clear" for other drugs in this category. They suggest "[g]reater transparency regarding FDA decision-making could increase clinician, patient, and payer confidence in novel drugs and improve clinical use."