The FDA has overlooked the red flags in the test of a new drug against depression


By Emmarie Huetteman, Kaiser Health News

Ketamine is a darling of fighting doctors and club lovers, an anesthetic that can soothe your pain without suppressing your breathing and a hallucinogen that can get you up with a low risk of fatal overdose.

For some patients, he has also lived in the shadow of conventional medicine as a treatment for depression – prescribed by their doctor, but not approved for this purpose by the federal agency responsible for determining which treatments are "Safe and effective".

That actually changed in March, when the Food and Drug Administration approved a cousin of ketamine called esketamine, a nasal spray, for patients with insoluble depression. With this, esketamine nasal spray, under the brand name Spravato, was touted as a miracle drug – announced in press releases, celebrated in the evening news and adopted by major health care providers such as the Department of Elders Affairs.

The problem, say the critics, is that the drug's manufacturer, Janssen, has provided the FDA with the best, modest evidence of its effectiveness, and this only in the context of limited testing. He has not submitted any information on 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 to none in the control group, raising red warning signals that Janssen and the FDA rejected.

The FDA, under political pressure, has quickly approved drugs that treat life-threatening diseases. And although the appearance of Spravato on the market was greeted with public applause, deep concerns were expressed at its one-day review meeting and in the agency's summary documents, according to KHN , according to public recordings, documents and interviews with participants.

Dr. Jess Fiedorowicz, director of the Mood Disorders Center at the University of Iowa and a member of the FDA's drug review advisory committee, described her benefit as "almost certainly exaggerated" after hearing the evidence.

Fiedorowicz said he expected at least one shared decision from the committee. "And then, the results were very favorable, which surprised me," he said in an interview.

Esketamine's approval pathway shows, step by step, how drug manufacturers can take advantage of the shortcuts of the FDA process with the blessing and maneuver of the body, through safety reviews and reviews. efficiency, to market a lucrative drug.

Step 1: In late 2013, Janssen asked the FDA to designate esketamine as a "disruptive therapy" because it showed the potential for rapid reversal of depression – a holy grail for suicidal patients, such as those in an emergency room. This potential was based on a two-day study in which 30 patients were receiving intravenous esketamine.

The status of "innovative therapy" accelerates the approval of drugs with the more frequent participation of the FDA.

2nd step: But discussions between regulators and drug manufacturers can affect the amount and quality of evidence required by the agency. In the case of Spravato, these were questions such as: How many drugs should fail before a patient's depression is considered insoluble or "treatment-resistant"? And how many successful clinical trials are required for FDA approval?

Step 3: Any prior agreement may preclude the FDA's expert advisory committees from making a decision. Fiedorowicz refrained from Spravato because, although he considered Janssen's study plan to be defective, the FDA had approved it.

The group of experts authorized the drug based on the evidence that the agency and Janssen had found sufficient. Dr. Matthew Rudorfer, Associate Director of the National Institute of Mental Health, concluded that "the benefits outweigh the risks". Explaining his "yes", he said: "I think we all agree on the very important, and sometimes, life or death, the risk of insufficiently treated depression that has taken into account in my equation . "

But others who also voted "yes" were more explicit in their hesitations. "I do not think we really understand what happens when you take this week, week after week, for weeks, months and years," said Steven Meisel, Drug Safety System Director for Fairview Health Services. based in Minneapolis.

Nasal spray paves way for patent

Spravato is only available under supervision in a registered establishment, such as a doctor's office, where patients must be monitored for at least two hours after taking the drug, in order to detect side effects such as vertigo, detachment from reality and increase blood pressure, reduce the risk of abuse. Patients should take it with an oral antidepressant.

Despite these requirements, Janssen, a subsidiary of Johnson & Johnson, has defended its new offer. "Until the recent approval of Spravato by the FDA, health care providers had no new treatment options," wrote Kristina Chang, a spokeswoman for Janssen, in a statement.

Esketamine is the first new type of drug approved for the treatment of severe depression for about three decades.

Although ketamine has been used for years for reasons that are not consistent with prescribing drugs to treat depression and post-traumatic stress disorder, drug manufacturers saw little benefit in conducting studies to prove to the FDA that it worked for that purpose. However, a nasal spray of esketamine, derived from ketamine and (according to some studies) more powerful, could be patented as a new drug.

Although Spravato costs more than $ 4,700 for the first month of treatment (not counting the cost of control or the oral antidepressant), insurers are more likely to pay Spravato than ketamine, the latter does not. being not approved for depression.

Shortly before the committee began to vote, a participant in the study declaring itself under the name of "Patient 20015525" said: "I am offering a proof of actual effectiveness, c & # 39; that is to say that I am alive and here today.

The drug did not work "for the majority of people who took it," said Meisel, the expert in drug safety, during an interview. "But for a subset of those for whom it worked, it was dramatic."

Concerns about testing previous ones

These considerations apparently helped to compensate for several scientific alarm signals that committee members called to the hearing.

Although the drug has reached a critical stage because of its potential for results within 24 hours, the trials have not been sufficiently convincing for the FDA to qualify as "fast-acting."

As a general rule, the FDA requires applicants to submit at least two clinical trials demonstrating the effectiveness of the drug, "each one convincing by itself". Janssen has provided only one successful double-blind trial of esketamine. The other two tests conducted to test the effectiveness were insufficient.

To reach the threshold of two trials, the FDA broke its precedent for psychiatric drugs and allowed the company to count a trial conducted to study a different subject: relapse and remission patterns. But, by definition, each patient participating in the trial had already taken and found an improvement in esketamine.

In addition, this positive single-efficacy trial showed only a 4-point improvement in the symptoms of depression compared to placebo treatment on a 60-point scale used by some clinicians to measure the severity of depression. Some committee members noted that the trial was not really blind because participants could recognize that they were taking the drug as a result of side effects, such as a temporary feeling out of the body.

Finally, the FDA has lowered the bar of "treatment-resistant depression". Initially, to be included, the trial participants should have failed two classes of oral antidepressants.

Less than two years later, the FDA relaxed this definition, stating that a patient needed only to have taken two different pills, regardless of class.

Forty-nine of the 227 people who participated in Janssen's only efficacy trial had failed for a class of oral antidepressants. "They eliminated the real treatment-resistant patients," said Dr. Erick Turner, a former FDA examiner who sits on the committee but did not attend the meeting.

Six participants died during the studies, three by suicide. Janssen and the FDA rejected the non-drug deaths, highlighting the low numbers and lack of patterns among hundreds of participants. They also pointed out that suicidal behavior was associated with severe depression – even if those who had suicidal thoughts with an intention of acting during the previous six months or a history of suicidal behavior during the first six months of life. previous year had been excluded from the studies.

In a recent commentary published by the American Journal of Psychiatry, Dr. Alan Schatzberg, a researcher at Stanford University and having studied ketamine, suggested that "there might be a link because of one" prolonged withdrawal reaction, as has been reported with opioids ", since ketamine appears to interact with opioid receptors in the brain.

Kim Witczak, consumer representative of the committee, said that Janssen's conclusion on suicides was unsatisfactory. "I just felt that it was kind of a quick brushstroke," Witczak said in an interview. She voted against the drug.

Kaiser Health News (KHN) is a non-profit news service covering health issues. It is an independent editorial program of the Kaiser Family Foundation which is not affiliated with Kaiser Permanente.


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