Study finds variation in evidence for FDA approval of novel psychiatric drugs
There is substantial variation in the supporting evidence for US Food and Drug Administration (FDA) approvals of novel psychiatric drugs, according to a recent research letter published in JAMA Network Open.“Mental illnesses are among the most common and disabling diseases with substantial unmet need. Unlike many other fields of medicine, psychiatric diagnoses lack validated biomarkers, and relatively little is known about the pathophysiology of psychiatric disorders, posing major challenges in drug development,” Rosa Ahn-Horst, of the Program on Regulation, Therapeutics, and Law (PORTAL) group in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston, and colleagues wrote in their paper.
Ahn-Horst and colleagues performed a cross-sectional study of new molecular entities (NME), new active ingredients, and reformulated drugs approved by FDA for psychiatric indications between January 2013 and October 2024. The researchers analyzed regulatory characteristics of each drug, pivotal trial features associated with the drug, and demographic information of the patients in the trials. They also assessed whether a pivotal trial was positive or negative, and evaluated supportive efficacy trials included with FDA drug submissions.
They identified 16 drugs approved for psychiatric conditions such as schizophrenia (brexpiprazole, aripiprazole lauroxil, lumateperone, olanzapine/samidorphan, combination xanomeline tartrate and trospium chloride, cariprazine), major depressive disorder (levomilnacipran, vortioxetine, gepirone), attention-deficit/hyperactivity disorder (serdexmethylphenidate/dexmethylphenidate, viloxazine), postpartum depression (brexanolone, zuranolone), treatment-resistant depression (esketamine), bipolar disorder (cariprazine), adjunctive therapy for major depressive disorder (brexpiprazole), Parkinson’s disease psychosis (pimavanserin), and acute agitation associated with schizophrenia or bipolar disorder (dexmedetomidine). Overall, one drug had a mechanism of action that was associated with muscarinic acetylcholine receptors, while one drug involving alpha-2 adrenergic, one drug involving N-methyl-D-aspartate, two drugs involving gamma-aminobutyric acid, and 11 drugs involving a combination serotonin, norepinephrine, and/or dopamine system mechanism of action.
Of 73 clinical trials associated with the 16 approved drugs, 45 trials (62%) were judged by FDA to be positive. Ahn-Horst and colleagues found 3 of 16 drugs had fewer than half of their associated clinical trials have positive outcomes as identified by FDA, which included 3 of 7 trials for brexipiprazole (43%), 1 of 4 trials for pimavanserin (25%), and 2 of 12 trials for gepirone (17%).
The researchers also identified 46 of 73 clinical trials as pivotal trials, with three drugs (19%) approved based on one pivotal trial. These trials recruited a similar rate of male (51.1%) and female (48.9%) participants, with a majority of participants being white (61.2%), Black (30.0%), or Asian (5.3%). Pivotal trials were randomized and double-masked, while a majority were placebo-controlled (83.0%) and had clinical scales as a primary endpoint (97.8%) such as the Positive and Negative Syndrome Scale, Montgomery-Asberg Depression Rating Scale, or Hamilton Depression Scale.
Ahn-Horst and colleagues said most drugs were supported by phase 3 trials with a positive outcome as judged by FDA but called attention to the three drugs with more negative than positive failed trials. In particular, they noted that gepirone had two positive trials and ten negative trials, and the drug was rejected three times before gaining approval.
Because the quality of supporting evidence for drugs approved for psychiatric indications “varied substantially,” there is a need for “increased clarity and consistent application of FDA approval standards among drugs treating mental illnesses,” they concluded.
JAMA Netw Open Ahn-Horst et al.
