Researchers stress need for clear, consistent standards in FDA review of psychiatric drugs

Key takeaways:

• 16 novel psychiatric drugs received FDA approval in the past decade.
• Many had the same mechanisms of action as drugs developed decades ago.
• Three approved drugs had more negative trials than positive ones.

The FDA approved 16 psychiatric drugs over the last decade, most of which shared similar mechanisms of action with previously developed drugs, according to data in a research latter published in JAMA Network Open.

There also appeared to be substantial variation in the quality of evidence supporting approval, underscoring the need for clearer, consistent approval standards, the researchers wrote.

“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 Y. Ahn-Horst, MD, MPH, resident physician at Massachusetts General Hospital/McLean Hospital, and colleagues wrote.

This inspired Ahn-Horst and colleagues to perform a cross-sectional retrospective study of psychiatric drugs approved by the FDA over the past 10 years to gain an understanding of the evidence required for approval and the regulatory background of new psychiatric medications.

The researchers identified 16 novel drugs approved to treat psychiatric diseases — specifically targeting mood, behavioral, attention and psychotic disorders — between 2013 and October 2024 using the publicly accessible Drugs@FDA website. They considered the agent novel if it was reformulated or used new molecular entities or active ingredients.

Of the total drugs, most (n = 11) use a mechanism of action that involved a combination of serotonin, dopamine or norepinephrine.

The approvals were linked to 73 clinical trials, of which the researchers judged 62% (n = 45) to be positive based on the assessment of the FDA.

Further, they found that the FDA classified 46 of the trials as pivotal trials, with a median of three pivotal trials per drug. Among the pivotal trials, the researchers observed a fairly equal representation of men and women (48.9% women), and most patients were white (61.2%) or Black (30%). All the pivotal trials were randomized and double-masked and most (83%) were placebo-controlled with clinical scales used to define the primary endpoint (97.8%).

Notably, the researchers found that there were three medications submitted for approval that had more negative efficacy trials than positive ones: brexpiprazole (57%); pimavanserin (75%; Nuplazid, Acadia Pharmaceuticals), which the researchers noted was originally rejected by the FDA, although that decision was overturned following a favorable advisory committee vote; and gepirone (83%; Exxua, Fabre-Kramer Pharmaceuticals), which the FDA rejected three times before approving.

The researchers noted some limitations to this study, including that these results may not be generalizable to other types of drugs, such as those targeting substance-use related disorders.

“The quality of evidence supporting psychiatric drug approvals varied substantially, underscoring the need for increased clarity and consistent application of FDA approval standards among drugs treating mental illnesses,” Ahn-Horst and colleagues wrote.