Assessing Drug Efficacy After Multiple Negative Trials—Gepirone’s Journey Through the FDA

Importance: Surveys have indicated that patients and clinicians can overestimate the efficacy and safety of drugs approved by the US Food and Drug Administration (FDA). In recent years, only approximately half of new drug approvals have been based on 2 or more adequate and well-controlled trials; furthermore, regulations do not limit how many trials can be conducted or provide clear guidance on how the FDA should consider a drug with conflicting evidence of benefit from multiple trials. Objective: To understand how the FDA evaluated a single investigational drug with positive and negative preapproval trials. Findings: The case of gepirone extended release (ER), approved for major depressive disorder, was reviewed. The FDA based its efficacy evaluation of gepirone ER on 13 trials: 12 acute treatment trials and 1 maintenance or relapse prevention trial. The FDA judged 2 acute treatment trials as positive. In the others, gepirone ER did not demonstrate superiority to placebo; and for 3, the FDA found evidence of statistical inferiority to an active comparator. Concerned that the positive trials might have occurred by chance and the amount of countervailing evidence, the FDA rejected the New Drug Application from the sponsor 4 times (Organon in 1999, 2002, and 2004, and Fabre-Kramer Pharmaceuticals, Inc in 2007). In 2014, the sponsor filed a dispute resolution request, leading to intervention by senior FDA leaders. In 2015, an FDA Advisory Committee voted that drug efficacy had not been demonstrated. Nevertheless, FDA leaders came to agree with the sponsor's arguments that the 2 positive trials had not occurred by chance and that the drug satisfied the FDA statutory standard for efficacy, and the drug was approved. Conclusions and Relevance: The case of gepirone shows how the FDA evaluated an investigational drug with conflicting evidence. The FDA sometimes exercises "regulatory flexibility" and focuses on statistical (as opposed to clinical) significance in a few trials, allowing the approval of drugs with scant benefits. Product labeling should transparently report on all adequate and well-controlled trials relating to an FDA-approved indication, not just those with positive outcomes, so that clinicians can make better-informed prescribing decisions.