Concerns about data on MDMA use in PTSD trial threaten bid for first U.S. approval of psychedelic drug
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An independent expert panel has poured cold water on hopes that MDMA, better known as the party drug ecstasy, could soon be part of a new treatment for post-traumatic stress disorder—and the first psychedelic drug with regulatory approval in the United States. The advisory committee, convened by the U.S. Food and Drug Administration (FDA), concluded yesterday that clinical trial data provided by Lykos Therapeutics were not enough to show that MDMA-assisted psychotherapy was effective and safe. The 11 members voted 9-2 that the available data do not show the drug’s effectiveness, and 10-1 that its benefits do not outweigh the risks. A final decision by FDA is expected by 11 August.
The decisions mark a reversal of fortune for MDMA. FDA granted the drug an expedited review process in 2017 based on encouraging early reports about its ability, in combination with talk therapy, to alleviate the PTSD that afflicts millions, including some military veterans. That possibility has been a centerpiece of the recent renaissance of medical research on psychedelic drugs. (MDMA is often termed a psychedelic, though it is less likely to produce some effects, such as visual hallucinations, that are typical for classic psychedelics such as LSD or psilocybin.) Ongoing clinical trials are testing several psychedelic compounds to treat other conditions, including depression and addiction.
In a press release issued after the meeting, Lykos Therapeutics emphasized that FDA is not bound by the committee’s decision. “While we are disappointed in the vote, we are committed to continuing to collaborate with the FDA with their ongoing review of our NDA [new drug application] over the coming weeks,” the release said.
In the all-day meeting, committee members had to grapple not just with the data from two phase 3 clinical trials, but also with allegations that participants were pressured to not report negative outcomes—and with a case of sexual misconduct by a therapist in an earlier stage MDMA trial. At the same time, FDA faces intense public pressure to approve the compound; at the meeting yesterday veterans pleaded for wider access to the promising therapy. “Today you will vote on whether my friends live or die,” Jonathan Lubecky told the committee. “I pray you vote to save them.”
The committee’s decision is “truly bizarre,” says David Nutt, a pharmacologist at Imperial College London and longtime psychedelics researcher. “It calls into question a regulatory system that allows new versions of potentially lethal opioids for pain yet denies the most novel and safe intervention for treatment-resistant PTSD ever seen.” If FDA follows the panel, “it will be very deleterious for the field,” he says.
But Neşe Devenot, a lecturer in the writing program at Johns Hopkins University who is involved in psychedelic research, said the problems were no one’s fault but Lykos’s.
(Devenot was one of the authors of a citizen petition that raised concerns about the research and led FDA to include a longer than normal public comment session in the meeting.)
“People were cutting all kinds of corners,” she says. “Today was a huge victory and validation for those of us in the field who have been trying to raise the alarm about this.”
According to the Department of Veterans Affairs, about 13 million adults in the U.S. suffer from PTSD in any given year. Haunted by the memory of a traumatic event, “their bodies are responding as if there’s the same level of threat as when the event was actually occurring,”
says Barbara Rothbaum, a clinical psychologist at Emory University who is currently conducting a separate trial of MDMA-assisted psychotherapy. The antidepressants sertraline and paroxetine, both greenlit by FDA in 2000, generally have a small effect and work in less than two-thirds of patients, Rothbaum notes. Some forms of psychotherapy have also been shown to work, but only for some patients.
The two Lykos trials, conducted in the U.S., Israel, and Canada, included close to 200 people with PTSD who received a course of psychotherapy that included three 8-hour sessions with either MDMA or a placebo. The combination of the drug and the talk therapy is meant to help patients to relive and process their traumatic memory. In both trials, participants who received MDMA saw a significantly greater reduction in symptoms than those receiving placebo.
But member after member of the advisory committee raised concerns about how to interpret those data. One challenge that has long plagued psychedelics research is how to keep study participants blinded—unaware of which study arm they are in—given that the experimental drug dramatically alters their mental state. Data from the second trial revealed more than 90% of those in the MDMA arm and 75% of those in the placebo arm correctly guessed their group. In a briefing document released before the meeting, FDA warned that this “functional unblinding” could allow patients’ and therapists’ expectations to bias the results.
Nutt counters that concerns about unblinding are overblown and would apply equally to other drugs such as antipsychotics. “So why focus on it here?” he asks. Detractors of psychedelics “are hiding their prejudice, moral objections, dislike of illegal drugs, behind a sort of pseudoscientific smokescreen,” he argues. Lykos also tried to allay those concerns by having independent raters evaluate participants’ PTSD symptoms in video meetings without knowing which study arm they were in.
A follow-up study that included 137 of the patients from the phase 3 trials showed a durable effect of MDMA from 6 months to more than 2 years later. But that finding, too, is difficult to interpret because those with more positive experiences might have been more likely to take part in the follow-up study.
Expectations may also have skewed recruitment into the phase 3 trials, said Elizabeth Joniak-Grant, a sociologist at the University of North Carolina’s Injury Prevention Research Center and a patient representative on the advisory panel, who noted that 40% of participants who got MDMA in the trials reported having taken it before. “If you had a terrible experience, or it didn’t do anything worthwhile for you, are you going to go through the effort of being in a clinical trial?” Adverse events may be less likely to show up in these participants than in the general population, Joniak-Grant added. Although the company reported its data on adverse events revealed MDMA-assisted therapy to be “generally safe and well-tolerated,” committee members noted that data to assess the drug’s liver toxicity and abuse potential were missing.
Further complicating the debate was the fact that members were asked to decide on the efficacy not of MDMA alone, but in combination with the psychotherapy offered by Lykos.
(The trials compared psychotherapy plus MDMA with psychotherapy plus placebo.)
Committee members at times seemed confused about whether and how to evaluate the talk therapy element of the treatment. “The challenge here is that the FDA doesn’t regulate the practice of psychotherapy,” says Andrew Penn, a psychiatric nurse practitioner at the University of California San Francisco who was involved as a therapist in one of the two phase 3 trials. The therapeutic method used in the trials left a lot of room for individual therapists to proceed in different ways, Penn notes. “Probably one lesson from this is to not allow for such a broad definition of therapy.”
Looming over the meeting was a report by the Institute for Clinical and Economic Review, an independent nonprofit that analyzes the evidence for clinical and cost effectiveness of treatments, which alleged, based on “interviews with those with firsthand or secondhand knowledge of the trials and related events” that “therapists encouraged favorable reports by patients and discouraged negative reports … [including] reports of substantial harms.” Risks to PTSD patients in drug trials include self-harm and thoughts of suicide. FDA psychiatry Director Tiffany Farchione said the agency is “quite concerned by” the allegations and is conducting an investigation that will conclude before an approval decision on MDMA.
At the meeting, Lykos’s Senior Medical Director Alia Lilienstein denied specific allegations that some participants were discouraged from participating in the long-term follow-up study but didn’t respond to the suggestion that therapists discouraged patients’ negative reports.
Lykos did acknowledge that one participant in a phase 2 trial was sexually abused by her therapist. Mandating specific training and qualifications for therapists might help protect vulnerable patients from harm during the ecstasy sessions. But for most members of the panel, the combination of misconduct allegations and the uncertainties about how to interpret the data seemed to create an unsurmountable hurdle. “It’s actually strange to vote no,” when trial data suggested such a clear effect from the drug, one of the committee members, Satish Iyengar, a statistician at the University of Pittsburgh, said while explaining his vote. “But there were just too many problems.”
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