The drug’s labeling will include a warning that patients who take esketamine are at risk for sedation and issues with attention, judgement, and thinking. It will also warn that there is a risk of misuse, abuse, and suicidal thoughts after taking esketamine. Patients who receive the drug will have to be monitored for at least two hours every time they get esketamine.
Johnson & Johnson submitted five Phase 3 studies on the drug: three-short term studies, one maintenance study, and a long-term safety study. Aside from the safety study, two of those turned up positive, clinically significant results. One was a randomized trial in adults under age 65 with treatment-resistant depression who were started on an oral antidepressant and esketamine. After a month, roughly 70 percent of patients who received the treatment responded, compared to just over half in a placebo group. An improvement of 50 percent or more on a common depression rating scale was seen as a successful response.
The other positive study was a maintenance-of-effect study, in which participants who responded to esketamine in one of the short-term studies were randomly assigned to either keep taking it or be switched to a placebo. The FDA generally wants to see two successful studies for approval — but historically, withdrawal studies haven’t counted toward that total.
But the FDA said the evidence — and input from external advisers — played a role in the decision to approve the drug.
“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment,” Dr. Tiffany Farchione, acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.
Not all experts are convinced there was enough data to approve esketamine yet.
“The threshold has been two adequate and well-controlled trials. In this case, they only got one,” Dr. Erick Turner, a psychiatrist at Oregon Health and Science University, told STAT in an interview last month. Turner serves on the FDA advisory committee that recommended last month that the FDA approve esketamine, but didn’t take part in that meeting.
The committee emphasized the need for a robust strategy to prevent diversion and misuse, given that ketamine is commonly abused. Ketamine is a combination of two enantiomers, or mirror image molecules. Esketamine is what’s known as the s-enantiomer. But the experts generally agreed that the risk of abuse with esketamine seems to be low.
“There will be all kinds of monitoring to make sure the drug doesn’t get diverted,” Manji said. That includes strict distribution requirements and a suspicious order monitoring program.
The FDA has also expressed concern that patients could be harmed if they experience dissociation, or an out-of-body experience that can leave people less aware of their surroundings. In briefing documents submitted before the advisory committee meeting, the agency also noted six deaths — including three suicides — among patients who were taking the drug. But FDA reviewers said that given that the patients had severe illnesses and there wasn’t a pattern seen in the deaths, it’s “difficult to consider these deaths as drug related.”