Three psychiatric drugs approved by the US Food and Drug Administration between 2013 and 2024 had more negative or failed efficacy trials than positive ones, according to a recent letter.

Researchers evaluated the characteristics of clinical trials supporting US Food and Drug Administration (FDA) approvals for novel psychiatric drugs between 2013 and 2024. The study examined 16 drugs approved for psychiatric conditions, including mood, psychotic, attention-deficit/hyperactivity, and behavioral disorders. Using the publicly available Drugs@FDA database, the researchers analyzed trial design features, demographic characteristics, and regulatory outcomes for pivotal and supportive efficacy trials.

Published in JAMA Network Open, the study identified 73 clinical trials submitted for FDA review, of which 45 (62%) were deemed positive by FDA reviewers. Among the drugs reviewed, 11 targeted serotonin, norepinephrine, and/or dopamine systems, while others acted on γ-aminobutyric acid (2 drugs), N-methyl-D-aspartate (1 drug), α-2 adrenergic receptors (1 drug), and muscarinic acetylcholine receptors (1 drug). Notably, 3 drugs were associated with more negative or failed efficacy trials than positive ones: brexipiprazole (3 of 7 positive trials, 43%), pimavanserin (1 of 4 positive trials, 25%), and gepirone (2 of 12 positive trials, 17%).

The researchers led by Rosa Y. Ahn-Horst. MD, MPH, of the Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, reported a total of 46 pivotal trials (median, 3 trials per drug; range, 1-6). Three drugs (19%) were approved based on a single pivotal trial. All pivotal trials were randomized and double-masked, with 83% (38 of 46) using placebo-only comparators and 15.2% (7 of 46) employing both placebo and active controls. The primary endpoints were clinical scales in 45 trials (97.8%), including the Positive and Negative Syndrome Scale (26%) and the Montgomery-Åsberg Depression Rating Scale (26%). Trial participants included 10,884 White patients (61.2%), 5328 Black patients (30.0%), and 946 Asian patients (5.3%), with near-equal representation of male (51.1%) and female patients (48.9%).

This study identified variability in the evidence supporting psychiatric drug approvals, with some drugs approved despite significant negative trial outcomes alongside positive phase 3 trials.

Full disclosures can be found in the published letter.