A US Food and Drug Administration (FDA) expert panel will meet Tuesday to consider whether to recommend approval of an investigational midomafetamine (MDMA) capsule in combination with psychological intervention for the treatment of posttraumatic stress disorder (PTSD).
But as the drug manufacturer, Lykos Therapeutics, inches closer to a final decision on its new drug application for MDMA-assisted therapy (MDMA-AT), a hail of questions has rained down on the company and its founder about the ethics — and validity — of the two pivotal clinical trials Lykos officials will use to make their case to the FDA’s Psychopharmacologic Drugs Advisory Committee.
An independent medical effectiveness review organization, a “citizen’s petition” to the FDA, and a number of media reports have alleged problems with study design, ethical lapses, a failure to report adverse events, and a raft of concerns from former employees about Rick Doblin, PhD, founder and president Multidisciplinary Association for Psychedelic Studies (MAPS), the nonprofit that launched Lykos.
An FDA review released Friday raises a number of issues as well, specifically citing functional unblinding in a study that was designed to be a double-blind trial.
The FDA panel will probably hear about these potential problems, but they will also receive testimony from those who champion MDMA as a therapy for PTSD. Several veterans groups have already submitted public comments urging the FDA to approve MDMA-AT. About 7% of veterans will experience PTSD during their lifetime (compared with 6% of the general population), but for some service members this proportion is reportedly as high as 29%. Indeed, the US Department of Veterans Affairs has thrown its weight behind the promise of psychedelics with a request for proposals to study the compounds — including MDMA — in treating PTSD.
Critics and supporters will converge on the FDA expert panel, which will evaluate the scientific evidence. If approved, MDMA-AT would be the first psychedelic-based therapeutic cleared by the FDA for any condition in the US and the first PTSD medication to receive approval in 24 years.
Investigator Bias at Play?
Patented by Merck in 1914, MDMA was never formally studied but was used by psychiatrists and therapists over the years. It became a popular street drug in the 1980s, known as “ecstasy” or “molly.”
Doblin formed the nonprofit MAPS in 1986 in the wake of a failed legal challenge to stop the Drug Enforcement Administration (DEA) from criminalizing MDMA, which the agency did in 1985 by regulating it as a schedule 1 controlled substance with no accepted medical use. Multiple attempts during the late 1980s to get the FDA to approve formal clinical studies were rejected, but the logjam at the agency began to break in the early 1990s.
MAPS embarked on its clinical studies and became a public benefit company in 2014. In 2017, the FDA designated MDMA-AT as a breakthrough therapy, putting it on a fast track for approval.
In 2021, investigators presented data from the company’s first clinical trial of MDMA-AT, MAPP1, at the European Psychiatric Association congress and published the research in Nature Medicine. The study evaluated 90 patients with PTSD randomly assigned to receive MDMA 80 mg or 120 mg or placebo, followed by three integrative psychotherapy sessions lasting a total of 8 hours.
Patients could receive a supplemental dose of MDMA after the first dose. The company reported that 82% of patients reported a significant improvement, with more than half saying they no longer had PTSD. Eleven patients (12%) experienced relapse within 12 months.
A few years later, findings from the second trial, MAPP2, were published in Nature Medicine, with similar results in 104 patients.
Lack of Blinding, Unreported Side Effects
Despite widespread and mostly positive media coverage, the research has had its critics. Chief among them has been the Boston-based independent nonprofit Institute for Clinical and Economic Review (ICER).
ICER first delved into the trials last fall, David Rind, MD, chief medical officer, told Medscape Medical News. Several experts reported concerns about safety to the organization and claimed that some abuse had occurred during the trials.
When ICER published its initial report in March, a lack of blinding in the studies was cited as a main issue. MAPP2 researchers reported that 49 of 52 (94%) of people in the MDMA treatment arm “were certain or thought that they received MDMA.”
“Lots of people, including clinical experts, separate from any of the concerned citizens who might have talked to us on this report, raised concerns about bias,” Rind said. And 40% of the trial participants had prior exposure to MDMA, he added.
ICER investigators “heard from multiple experts about the very strong prior beliefs of those involved in the trials (as investigators, therapists and patients) about the benefits of MDMA-AT,” the report claimed.
Lykos waved away bias charges, noting in its response to ICER that it “has consistently sought and received feedback from the FDA throughout the development program.”
But others also took issue.
“If you wanted to design the worst possible study in the world, you couldn’t do better,” Allen Frances, MD, professor emeritus of psychiatry and behavioral sciences at Duke University, Durham, North Carolina, told Medscape Medical News. “This is something that should never be considered for FDA approval on the basis of the very limited data available.”
The lack of blinding and “a hot-house therapy environment” are two critical issues, Frances noted.
“There’s no research environment more exotic than this study with two therapists spending 8 hours with a single patient,” he said. Even though no serious adverse events were reported in the studies, “that doesn’t mean that there won’t be problems in the real world,” said Frances.
‘A Therapy Cult’
Neşe Devenot, a senior lecturer at Johns Hopkins University’s writing program who had been affiliated with MAPS in the mid-2000s, has been vocal about her concerns.
Lykos has “essentially misrepresented what they’re doing to the FDA,” Devenot told Medscape Medical News.
In comments that will be submitted to the FDA expert panel on June 4 that Devenot shared with Medscape Medical News, she wrote that MAPS is “a therapy cult” that indoctrinates therapists and participants into “an ideological system of ‘true beliefs.'”
In this model, therapists and clients form unusually close relationships, wrote Devenot, also a research affiliate with the Petrie-Flom Center’s Project on Psychedelics Law and Regulation (POPLAR) at Harvard Law School. She said several episodes of alleged abuse that occurred during trials reflect this therapy model.
“There are several well-documented cases of high-profile therapists who have exploited the increased vulnerability of patients in MDMA therapy, including incidents of entrapment, sexual abuse, and coercive control,” wrote Devenot and more than 70 researchers, clinicians, and others in a citizen’s petition filed with the FDA in late April, calling on the agency to convene an advisory panel to look at the Lykos trials and to have an extended open public hearing. The petition alleged the company committed data fraud and withheld information about adverse events.
Unethical conduct was also cited by the ICER report authors who noted that “sexual boundaries were severely crossed with at least one patient in a phase 2 trial.”
A 2023 paper in the Canadian Journal of Bioethics described that case, which involved Meaghan Buisson and has since been widely covered in the media. Buisson co-authored a JAMA Psychiatry viewpoint with Devenot that highlighted some other alleged lapses in the MAPS/Lykos trials, and she also signed the citizen’s petition.
Devenot alleges other ethical violations in her comments to the FDA, including that MAPS board chair Vicky Dulai “was part of a community of MAPS associates” that exploited “psychedelics’ known ability to increase vulnerability to ‘love bombing’ and other forms of psychological manipulation” to swindle money from wealthy patients.
The citizen’s petition and ICER investigators also cited a number of reports of severe harms that were not disclosed in the published studies.
Lykos Responds
In a statement to Medscape Medical News, Lykos denied that anything had gone unreported. “All adverse events and serious adverse events were reported to the FDA,” officials wrote in the statement.
In addition, in public comments on the ICER report, about 70 of the 109 clinical investigators, clinicians, supervisors, trainers and medical monitors who worked on the MAPS/Lykos studies defended their work.
“One hundred and nine therapists and principal/co-investigators contributed to the Phase 3 trials of MDMA-AP [MDMA-assisted psychotherapy] for PTSD. To our knowledge, none of them were consulted before the preliminary report was issued,” the investigators wrote in their response. “However, this group is in the strongest position to describe the studies and address accusations related to inappropriate study design and conduct. In the absence of such input, a number of assertions in the ICER report represent hearsay and should be weighted accordingly.”
Participants were “invited to access and process traumatic memories,” which meant that “short-term destabilization” could be expected, they added. They also noted that therapists were guided by the “MAPS Code of Ethics,” which prescribes that practitioners should “respect the inner healing intelligence of participants to guide their experience.”
ICER said that Lykos never offered direct access to its researchers and that there were reports that patients feared being shunned or denied MDMA in the future if they reported bad outcomes. “This is a particular problem in people receiving MDMA as it makes them particularly suggestible and susceptible to context,” authors of the ICER report wrote.
Opening the Door to Wider Illicit Use?
Frances and Devenot said that FDA approval could open the door to more unprescribed and unsupervised use of MDMA.
Devenot believes that MDMA has potential but said that given that Doblin has been touting MDMA for years, “a lot of people have really taken him at his word and are doing this outside of a formal medical context.” FDA approval would lead people to “think that it’s useful and safe” and would probably increase illegitimate use, she said.
Even if the FDA restricts use of the Lykos therapy to the trial conditions — as the American Psychiatric Association has urged the agency to do — the risk for misuse remains, said Frances.
If you’re someone who does not meet eligibility requirements or can’t afford the drug, “you’re likely to buy the drug on the street and take it yourself,” said Frances.
The company has not yet determined a price for the treatment, a Lykos spokesperson told Medscape Medical News, but has worked with the American Medical Association to establish a code for the combination therapy, in part to lay the groundwork for insurance coverage.
Rind wants MDMA-AT to get a thorough vetting by the FDA and its advisers. “I’m hoping that the FDA looks carefully at the evidence in ways that we certainly were unable to do,” he said.
The FDA is due to make a decision on the MDMA-AT’s fate by August 11. If the drug is approved, the DEA would still have to reschedule the drug so that physicians can prescribe it.
The agency is under no legal obligation to change MDMA’s status unless it is directed to do so by the US Department of Health and Human Services. The DEA would have 90 days to act on the request, according to an analysis from the Harvard Law School’s Petrie-Flom Center. A similar path was followed for the cannabis-based pharmaceutical Epidiolex.
Lykos said it would make its therapy available in 2025 if it is approved and the DEA reschedules MDMA.
Alicia Ault is a Saint Petersburg, Florida–based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault.
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