After a remarkably sensational regulatory drug review, advisers for the Food and Drug Administration on Tuesday voted overwhelmingly against approving midomafetamine (MDMA, aka ecstasy or molly) as part of therapy for post-traumatic stress disorder.
In a response to the question, “Do the available data show that the drug is effective in patients with posttraumatic stress disorder?” advisers voted 9 “no” to 2 “yes” against MDMA.
In response to the second question, “Do the benefits of midomafetamine with FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD?” the advisers voted 10 “no” to 1 “yes” against MDMA. The one expert who voted “yes” said afterward that his confidence in that vote was low.
The votes come after a full-day meeting in which the independent expert advisers heard detailed reviews of clinical trial data from the company that proposed the therapy—Lykos, formerly MAPS—as well as internal FDA reviews.
The top-line results from two clinical trials had impressively positive results, with MDMA therapy in combination with psychotherapy showing statistically significant, clinically meaningful improvements for PTSD symptoms. But, as the discussion dove deeper into the data, the experts identified a damningly large number of trial flaws, including missing data and bias, that threw the validity of those positive results into serious question.
For one thing, the experts, along with the FDA, found that the double-blind trials were essentially unblinded—both therapists and participants knew whether participants received MDMA, given the potent effects of the drug. This introduces significant bias. Therapists may expect to see bigger effects if they know MDMA was given or lesser effects if they know a participant received a placebo. Further, about 40 percent of trial participants had prior MDMA exposure, making them more likely to be able to identify and anticipate the effects of the treatment. Experts also worried that it would likely have introduced significant selection bias. That is, those who had used MDMA in the past and had negative or neutral experiences with it would be less likely to enroll in such a trial.
The FDA and the experts also called out a plethora of missing data. Lykos did not collect laboratory data on the biological effects of MDMA in the participants. In response to this point, the FDA stunningly admitted in the meeting that it had overlooked the fact that the company didn’t plan on collecting that data while it was designing the trial. Lykos also did not collect enough data on the known cardiovascular effects of MDMA, which could pose significant risks to patients with high blood pressure and heart arrhythmias. Last, the trial did not collect data on the positive effects of MDMA, such as the feeling of “euphoria,” which could indicate abuse potential. This was something the FDA had specifically advised Lykos to collect prior to conducting the trials.
In a nearly two-hour public comment hearing in the afternoon, the experts heard from various participants, experts, and advocates. Some people who said they participated in the trials relayed their positive experiences, while others said the trial was devastating for them. A few researchers who offered public comment noted that the psychotherapy technique used along with MDMA is not evidence-based. They also claimed that the touch-based psychotherapy technique that Lykos used for the trial ties to dubious cult-like new-age psychospiritual therapy, which, among other things, intends to bring about a “global spiritualized society” and suggests suicidal ideation stems from suffering that occurred in the birth canal. This therapy has the potential to allow for abuse and exploitation, the researchers claimed in their public comment. At least one participant in the trial has accused a therapist involved with the trial of sexual assault during the trial’s therapy sessions.
“Unfortunately, there potentially has been some misconduct … that has really polluted or corrupted our ability to interpret the data,” adviser and psychiatry expert Walter Dunn, of the University of California Los Angeles, said at the end of the meeting.
The FDA does not regulate psychotherapy, and the advisory committee members had several questions about how to standardize a therapy technique that is not yet based on evidence. One adviser called that aspect of the trial a “black box.”
Adviser and psychologist Melissa Decker Barone, of the VA Maryland Health Care System, summarized the general feeling of the committee in the discussion period. “I think that there are a number of things that make me question how robust the results are,” she said. “It sounds like MDMA and this treatment have really impacted a number of people in positive ways, but it seems like there are so many problems with the data. Each one alone might be kind of OK, but when you pile them up on top of each other… there’s just a lot of questions still.”
The FDA will now make its own decision on whether to approve MDMA for PTSD therapy. Although it often follows the advice of its advisory committees, it is not obligated to do so. The FDA said it was also still conducting its own investigation into some of the accusations of possible data manipulation during the trials. There have been claims that some trial participants were discouraged from reporting negative responses to the therapy and encouraged to report positive responses. A representative for the FDA said the agency would not make a determination on MDMA until that investigation is complete.
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