Feature

FDA overlooked red flags in esketamine testing


 

Ketamine is a darling of combat medics and clubgoers, an anesthetic that can quiet your pain without suppressing breathing and a hallucinogenic that can get you high with little risk of a fatal overdose.

For some patients, it also has dwelled in the shadows of conventional medicine as a depression treatment – prescribed by their doctors, but not approved for that purpose by the federal agency responsible for determining which treatments are “safe and effective.”

That effectively changed in March, when the Food and Drug Administration approved a ketamine cousin called esketamine, taken as a nasal spray, for patients with intractable depression. With that, the esketamine nasal spray, under the brand name Spravato, was introduced as a miracle drug – announced in press releases, celebrated on the evening news, and embraced by major health care providers like the Department of Veterans Affairs.

The problem, critics say, is that the drug’s manufacturer, Janssen, provided the FDA with at best modest evidence it worked and then only in limited trials. It presented no information about the safety of Spravato for long-term use beyond 60 weeks. And three patients who received the drug died by suicide during clinical trials, compared with none in the control group, which raised red flags Janssen and the FDA dismissed.

The FDA, under political pressure to rapidly green-light drugs that treat life-threatening conditions, approved it anyway. And, though Spravato’s appearance on the market was greeted with public applause, some deep misgivings were expressed at its day-long review meeting and in the agency’s own briefing materials, according to public recordings, documents, and interviews with participants, KHN found.

Jess Fiedorowicz, MD, director of the Mood Disorders Center at the University of Iowa, Iowa City, and a member of the FDA advisory committee that reviewed the drug, described its benefit as “almost certainly exaggerated” after hearing the evidence.

Dr. Fiedorowicz said he expected at least a split decision by the committee. “And then it went strongly in favor, which surprised me,” he said in an interview.

Esketamine’s trajectory to approval shows – step by step – how drugmakers can take advantage of shortcuts in the FDA process with the agency’s blessing and maneuver through safety and efficacy reviews to bring a lucrative drug to market.

Step 1: In late 2013, Janssen got the FDA to designate esketamine a “breakthrough therapy” because it showed the potential to reverse depression rapidly — a holy grail for suicidal patients, such as those in an emergency room. That potential was based on a 2-day study during which 30 patients were given esketamine intravenously.

“Breakthrough therapy” status puts drugs on a fast track to approval, with more frequent input from the FDA.

Step 2: But discussions between regulators and drug manufacturers can affect the amount and quality of evidence required by the agency. In the case of Spravato, they involved questions like “How many drugs must fail before a patient’s depression is considered intractable or ‘treatment resistant’?” and “How many successful clinical trials are necessary for FDA approval?”

Step 3: Any prior agreements can leave the FDA’s expert advisory committees hamstrung in reaching a verdict. Dr. Fiedorowicz abstained on Spravato because, though he considered Janssen’s study design flawed, the FDA had approved it.

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