Boston : About 10% of drugs approved by the US Food and Drug Administration (FDA) between 2018 and 2021 had pivotal trials with null findings, according to a research letter published in JAMA Internal Medicine.
“Our findings underscore the complexity of regulatory decision-making, as exemplified by evidence of effectiveness despite a null primary end point finding,” James L. Johnston, MD, of the department of medicine at Brigham and Women’s Hospital in Boston, and colleagues wrote in their research letter. “For other drugs, the evidence of efficacy was less clear.”
Johnston and colleagues analyzed 210 drugs in the Drugs@FDA database approved by the FDA through the new drug applications (NDA) vehicle between 2018 and 2021, as well as the drugs’ pivotal trials, trial primary endpoints and prespecified criteria. When a drug did not meet one or more prespecified primary endpoints, the researchers dug in further, examining the characteristics of the drug, the study and the study endpoint. They also evaluated the FDA’s reasoning for the drug’s approval, any additional requested/required postmarketing studies and if the postmarketing study was designed to address the primary endpoint not met in the pivotal trial.
Of the 210 drugs, 21 drugs (10.%) with 21 unique indications had null findings for one or more primary efficacy endpoints in pivotal studies. Overall, 14 of 21 drugs (66.7%) were small-molecule drugs, 11 of 21 drugs (52.4%) were deemed first-in-class, 10 of 21 drugs (47.6%) were designed as orphan drugs and 13 of 21 drugs (61.9%) were granted expedited review. The most common therapeutic areas for approved drugs with null findings were oncology (19.0%), infectious disease (14.3%) and psychiatry (14.3%). FDA convened an advisory committee for 3 of 21 drugs (14.3%) prior to approval.
There were 56 pivotal trials for the 21 drugs with null findings and 74 primary efficacy endpoints in the 56 trials, with 27 endpoints (36.5%) being null findings. Of these, 13 endpoints (48.1%) consisted of clinical outcomes, 7 endpoints (25.9%) were surrogate markers, 4 endpoints (14.8%) were clinical scales and 3 endpoints (11.1%) were composite.
The researchers also found 5 of 21 drug approvals (23.8%) were based on 1 trial. Four drugs that received FDA approval but had null findings in primary endpoints and were based on a single pivotal study, which included asparaginase erwinia chrysanthemi (recombinant) for acute lymphoblastic leukemia and lymphoblastic lymphoma, migalastat hydrochloride for Fabry disease, naxitamab-gqgk for high-risk refractory or relapsed neuroblastoma and tazemetostat hydrobromide for epithelioid sarcoma.
FDA cited success in one or more other pivotal studies in 13 approvals (61.9%), secondary or exploratory endpoint positive outcomes in 10 approvals (47.6%) and “favorable post hoc analysis” in 7 approvals (33.3%) as the most common reasons for approval among drugs that had null findings. In 7 drug approvals, the agency “required or requested postmarketing studies” that met a null endpoint or related clinical endpoint.
“Greater transparency regarding FDA decision-making could increase clinician, patient, and payer confidence in novel drugs and improve clinical use,” Johnston and colleagues said. “Timely completion of postapproval studies addressing areas of clinical uncertainty is also necessary.”
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