For mental health professionals and patients suffering from serious depression, the recent recommendation from FDA expert panels to approve esketamine is an exciting development. The drug, manufactured by Johnson & Johnson, is a single-use nasal spray of ketamine to be used for treatment-resistant depression. One panelist called the drug a “gamechanger” and some patients reported feeling hopeful that this treatment would prove more effective for them than existing antidepressants.
However, other researchers are concerned that this panel recommendation represents a further lowering of the bar for clinical evidence, and that the drug is not as safe and effective as the company claims.
Lower standard of evidence
FDA experts gave an overall strong recommendation for approving esketamine, with 14 voting yes, two voting no, and one abstaining. However, a few reviewers, as well as some other researchers, questioned the low standard of evidence provided by Johnson & Johnson on the drug’s effectiveness and safety.
The agency’s “gold standard” for formal approval is two positive, well-controlled studies. However, J&J presented just one positive short-term trial and a positive randomized withdrawal trial. What’s the difference? As Dr. Erick Turner, researcher at Oregon Health & Science University and former FDA reviewer pointed out on Twitter, withdrawal trials are more likely to be positive because the patients being tested have already reacted well to the drug in an earlier trial. The other two studies presented were negative, although again Turner points out that J&J tried to spin the studies as positive during the panel review.
“What precedent is set when 2 of 3 shorter efficacy studies didn’t meet the primary endpoint?” asked panel member Dr. Steven Meisel, system director of medication safety at Fairview Health Services, Endpoints News reports. “That’s something the agency has to wrestle with. Do we set a precedent that may be hard to step back from?”
Safety issues
As for safety, some panelists were concerned about potential side effects, such as disassociation (feeling “spacey” or confused), sedation, and increased blood pressure. Ultimately, 15 panelists voted that the outline of the drug’s safety profile was sufficient for initial review, despite the fact that J&J only presented information from dog and rat studies showing that esketamine did not cause neurotoxicity (see the last page of J&J’s presentation).
Another safety issue is the potential for abuse of esketamine, which is why the FDA panel recommended that the drug only be given in the health care setting under supervision. However, it is unclear how this process would work in practice, and there is a chance that people could obtain and use ketamine illegally as has happened with opioids and benzodiazepines.
“The thing I’m most concerned about really is diversion and misuse and things like that,” said one panelist, but she believed that “ultimately, the benefits outweigh the risks.”
Marketing before approval
A few doctors on social media noted that J&J has not waited for FDA approval before marketing esketamine. Though drug marketing before FDA approval is illegal, many companies get around this regulation through a loophole — by doing presentations or educational sessions about a condition without mentioning the drug.
One doctor wrote on Twitter about attending a talk about “the future of antidepressant treatment” that turned out to be “all about glutamate and ketamine.” They also showed attendees a cartoon music video about how ketamine works to reduce depression.
Another doctor mentioned that J&J has already been offering lunch presentations on treatment-resistant depression and “the role of glutamate in depression” but did not mention esketamine specifically.
These pre-approval marketing tactics are worrisome. Hiding drug marketing behind informational lectures means that doctors are primed to think of this treatment as positive. Despite the best of intentions from the FDA panel to restrict esketamine use to the indication it is meant for, in the settings it is meant for, we’ve seen time and time again that marketing can lead to non-indicated and harmful uses of powerful drugs.