When two positive trials outweigh a dozen negatives

Clinical Takeaway: FDA approval may rest on as few as 2 positive trials—even when most studies are negative—underscoring the need to critically appraise the full evidence base, not just approval status.

Clinicians may assume FDA approval reflects a consistently positive evidence base, but gepirone ER’s approval for major depressive disorder shows why prescribing decisions should consider the full trial record—not just the pivotal studies in labeling.

A JAMA Psychiatry special communication examines the long and controversial FDA review of gepirone ER, offering a rare window into how drugs with conflicting trial results can still reach the market.

Across 13 preapproval studies (12 acute trials plus 1 maintenance trial), only 2 acute trials were deemed “positive.” The remaining studies largely failed to show benefit over placebo, and 3 even suggested statistical inferiority to an active comparator.

Despite this imbalance, the FDA ultimately determined that the 2 positive trials met the statutory requirement for “substantial evidence” of efficacy. This decision came after multiple rejections—four complete response letters issued between 1999 and 2007—and a 2015 advisory committee vote concluding efficacy had not been established.

The turning point followed a sponsor-led dispute resolution request in 2014, prompting senior FDA leadership to re-evaluate whether the positive findings could reasonably be attributed to chance. Regulators ultimately sided with the sponsor, concluding they were unlikely to be spurious and approving the drug.

As the authors note, the case “illustrates how the FDA evaluates an investigational drug with conflicting evidence,” emphasizing regulatory flexibility when interpreting mixed results.

The broader implication is clear: while about half of recent FDA approvals are supported by at least two positive trials, regulations do not explicitly address how to weigh numerous negative studies against a few positive ones.

For clinicians, gepirone’s path underscores the importance of looking beyond approval status—carefully reviewing the magnitude, consistency, and clinical relevance of trial outcomes before prescribing.

Source: Turner EH, et al. 2026 June 24. JAMA Psychiatry. Assessing Drug Efficacy After Multiple Negative Trials—Gepirone’s Journey Through the FDA