Live Coverage: FDA Advisory Committee Reviews MDMA-Assisted Therapy for PTSD

Walter Dunn begins by asking two questions of the agency. The first draws on the ICER review to ask about claims that investigators discouraged people from encouraging in MPLONG, that therapists discouraged reports of adverse events, and so on. “Is the agency investigating this?”, he asked.Farchione said that “there isn’t a lot I can say with regard specific details” in terms of what she is looking into. “We certainly take those allegations very seriously and are quite concerned”, she said, adding that “we do have inspections ongoing at this point, but can’t really speak to the details as those are ongoing.”Satish Iyengar, Professor of Statistics at the University of Pittsburgh, asked whether an analysis is possible that accounts for inter-therapist (dyad) variability in outcomes. Inter-site variability had been reviewed, the agency said, but not inter-therapist.Holtzheimer asked how therapist unblinding might lead to differences in how the psychotherapy is delivered between the two arms. Lykos told him that there was assessment of fidelity to the protocol in both arms, but Holtzheimer asked FDA if it had reviewed such data.“I would just say that based on the description of the therapy in the manual, and the sort of flexibility inherent in the manualised psychotherapy, we assumed that there would be variability among the different therapeutic approaches,” Farchione said. Whether that differed based on therapists’ guesses of treatment assignment, ‘we don’t have any insight into that’.Joniak-Grant said that, as a patient, the flexibility in Lykos’ therapy manual makes her uneasy. She asked how the FDA might manage this.“The difficult thing…is that we don’t regulate psychotherapy, and also we don’t really have any say in the design or the implementation of the particular therapy that is going to be used”, Farchione said.“Even when it comes to the parameters of the REMS”, she said, it comes down to safety and monitoring, not the psychotherapy component.She also asked that, if inspections into allegations of misconduct are ongoing, could the product come to market before those are completed?Farchione said that the agency “would complete the inspections before taking action.”Hertig asked the agency to comment on accessibility: “I’m trying to get a sense for, after we do all of these things, how many patients are gonna get access?”“We don’t have an answer to that”, Farchione said. “In terms of trying to design a REMS that can appropriately mitigate the risks we have identified,” the agency had tried to consider accessibility, too.“But at the same time, we do have a lot of unknowns, and we do have some clear risks with this product”, she added.“We do periodic REMS assessments as well”, she added, suggesting that new information could justify modifying a REMS.Witczak, the consumer representative, asked if there would be a way (in the postmarketing world) to separate out drug-related vs. psychotherapy-related incidents or adverse events.Farchione suggested that state medical boards and other licensing bodies, as well as the potential for criminal charges, would need to play a role in regulating the delivery of MDMA-assisted therapy, if approved. ‘The FDA can’t regulate everything’, she implied.Amirshahi brought up hyponatremia, noting that it hadn’t been discussed in great detail thus far. “Do we have a plan for that?”, she asked.Farchione said that “we are considering what kind of postmarketing requirements” the agency might mandate, both for clinical laboratory assessments and additional data from cardiovascular studies.Barone said that the fact that the therapy guide had such flexibility is inconsistent with clinical practice guidelines for PTSD, and asked how the FDA views it.Farchione said that “there is not a great answer to that question”, reiterating that the psychotherapy does not fall within its remit.Dunn asked another question, asking how the agency views the incident in a Phase 2 study that “happened long after the last dose was administered”. Given the drug’s pro-social effects, would the agency be monitoring for these types of longer-term events?Farchione said that this is an area in which it would be useful to hear from the committee, such as how to incorporate this type of monitoring into its REMS structure. She noted that ‘the further out you get from the administration session, the harder it is to attribute that to the drug’, though.Dunn also wondered whether, if Lykos’ model of psychological intervention was demonstrated as essential to the safety of the drug product, FDA could mandate it.FDA’s Cynthia LaCivita said that would be something the agency would have to look into, as this is something novel for them.Dunn then asked what the rationale was with regard to only requiring one licensed therapist in the room. “Why not have both be licensed?”, he asked.Farchione explained that this mirrored the trials, adding that it “primarily has to do with the concerns of balancing access, as well”.Dunn reminded the audience that the transgression in the Phase 2 study happened with an unlicensed therapist. Dunn also said he was “thinking about for-profit operations which may misrepresent the training status of people who are unlicensed, claiming they are in training when they’re not”, adding that his personal feeling is that both therapists should hold licenses.Joniak-Grant also commented on the licensure element, reminding the agency that power imbalances in the relationship between therapists might reduce the likelihood of the lesser-credentialed therapist reporting the other in the case of misconduct.She also sought clarification for what ‘on-site’ means, saying that the “idea that someone is just going to be ‘around’” might not be enough for patients.Canuso asked how there was no requirement for laboratory assessment at the time of submission.“It was missed”, Farchione admitted. “Every program we have ever reviewed has labs…perhaps the primary reviewer, because it’s always there, just didn’t notice it wasn’t”, she continued, adding that “both the applicant and we have to take responsibility for [that].” “It is a hole in the program”, she acknowledged.Dunn asked whether the agency has data regarding how many additional hours of therapy those in the MDMA arm might have received versus those in the placebo arm, as some had additional integration sessions. ‘That’s probably a question for the sponsor’, Farchione said.Dunn then asked whether the agency would consider a warning label for the therapist, pointing to things like transference, and citing a Stanford animal study where mice ‘acted differently’ when in the presence of mice that had ingested MDMA.Even though the prescribing information is generally directed toward the prescriber, an FDA staffer said, one might expect the therapists to be familiar.Witczak asked if the total number of study participants is adequate, in the FDA’s mind.Farchione said that if this were something that needed to be dosed more frequently, the agency would expect more data, “primarily to have more safety data”. But, given the proposed protocol, it’s a different matter.Narendran said he was “struggling with” a lot of missing data, and asked FDA whether the agency could restrict patient populations to maintain safety, such as for cardiovascular risk.“It’s certainly something that we could consider”, Farchione said, which was echoed by Director of the Division of Risk Management, LaCivita. They both encouraged the committee to make suggestions to the agency after lunch.



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