June 3, 2024
Psychopharmacologic Drugs Advisory Committee
U.S. Food and Drug Administration
5630 Fishers Lane, Rm 1061
Rockville, MD 20852
RE: [Docket No. FDA-2024-N-1938] Psychopharmacologic Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments--Midomafetamine Capsules
Dear Members of the Psychopharmacologic Drugs Advisory Committee,
On behalf of Reason for Hope and the Veteran Mental Health Leadership Coalition, thank you for the opportunity to provide public comments related to new drug application 215455, for midomafetamine (MDMA) capsules, submitted by Lykos Therapeutics, for the proposed indication of treatment of post-traumatic stress disorder. The Committee has specifically been asked to vote on:
Do the available data show that the drug is effective in patients with posttraumatic stress disorder?; and
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.
We strongly encourage the committee to vote “yes” on both questions, and hope our input below helps further inform the committee’s consideration on the overall benefit-risk profile of the treatment, along with the potential public health impact.
Reason for Hope is a non-profit policy and advocacy organization working to advance safe and equitable access to psychedelic therapies to improve mental health and prevent deaths of despair. This mission is extremely personal for Reason for Hope, as our co-founders are connected by the loss of loved ones to suicide. Over the last couple years, we have advocated for the rescheduling of psychedelics that received FDA Breakthrough Therapy designations to reduce barriers to research and compassionate use; and for the Department of Health and Human Services to establish a federal interagency work group; which together could help better inform real-world care delivery models and the integration of psychedelic therapies into the healthcare system. We have also advocated for urgently needed government funding for psychedelic research to help shape policy and practice (e.g., studies including more diverse and complex patient populations, inclusion of patients with suicidal ideation, and use of group therapy models to reduce costs).
The Veteran Mental Health Leadership Coalition (“Coalition”) is a national membership-based Veteran organization focused on education and advocacy to increase safe and affordable access to psychedelic therapies for Veterans and their families. Members of our Coalition have been on the frontlines of this work for several years, including researchers and mental health providers within the VA healthcare system, as well as leaders from various Veteran Service Organizations that have either funded or supported Veterans seeking psychedelic therapies in other countries. Additionally, many of our Coalition members are the Veterans who, after exhausting legally available treatments, either left the country or accessed psychedelic therapy from underground providers in the United States, risking criminal prosecution to heal from psychological wounds incurred in service to our country. Although their stories of healing are inspiring, neither Veterans nor anybody else should be forced to take such measures, with many incurring significant travel costs, risking unknown safety conditions including lack of properly trained staff or oversight, and primarily accessing psychedelic therapies with far less well-controlled clinical trial data than MDMA.
This is a tragic indictment on the current state of mental healthcare in the United States. Indeed, rates of PTSD and suicide have increased for several decades, with Veterans, as well as women and under-served communities, disproportionately impacted. In 2023, we lost over 50,000 lives to suicide, with approximately 17-44 Veterans lost to suicide or overdose per day. Yet, despite the increasing burden, we have seen little progress with new treatment modalities, including no new FDA approved drugs for PTSD in over 20 years (over this approximate timeframe, suicide deaths rose from 81.0 per day in 2001 to 121.0 in 2020).
Currently, there are only two FDA approved medications specifically indicated for PTSD, both of which are SSRIs (sertraline and paroxetine) requiring daily use, often for a lifetime. Many patients experience no response and most patients either modest or limited response from these treatments, and even for responders, there are high rates of negative side effects including weight gain, sexual difficulty, and emotional numbing (60%+ for each). Unsurprisingly, these side effects lead to medication non-adherence, and can also exacerbate PTSD symptoms such as avoidant behavior, resulting in a decreased willingness to participate in psychotherapy.
Further, SSRIs have a delayed onset of action (often requiring weeks to months for any therapeutic benefit), and risk of suicide increases during this latency period (particularly within the first week). For many patients, if they do ever find therapeutic response in an SSRI, this is after multiple attempts with different medications and sometimes combined pharmacotherapies. Adequate trials of these medications mean months to years of struggle to find something that might work and offer healing. Evidence has shown us that with each trial, there are diminishing returns, meaning that the chances of finding a medication or combination of medications that truly ‘works,’ actually flat lines. These circumstances are entirely unacceptable given the resulting day-to-day life lost and in all too many cases, lives lost to suicide, overdose, and other means, and the tragic impact this also has on family and loved ones.
While trauma-focused psychotherapy can be highly effective for some in reducing PTSD symptoms, it is difficult for many individuals to commit to and stick with a process that involves repeatedly engaging with traumatic events and upsetting memories in a highly structured fashion. The impact of this form of treatment is often hampered by low patient engagement, and high rates of clinical non-response and dropout.
Considering the above, MDMA-assisted therapy (MDMA-AT) offers a seemingly obvious and logical approach to PTSD treatment, as the drug’s ability to rapidly establish therapeutic rapport and reduce fear response makes it easier to commit to and engage in a psychotherapeutic process that involves confronting often highly traumatic memories. It is notable that symptoms of PTSD decline precipitously after treatment initiation and continue to improve for the duration of treatment and follow-up. A truly novel treatment option of this sort is desperately needed for many long-struggling individuals who have not benefited, and in many cases experienced brutal side effects, from existing treatments; and there are ample patients who will be eager to move away from the need for chronic daily medication, toward a more holistic, robust, and seemingly durable approach to healing.
Despite noting certain challenges in data interpretability, FDA directly worked with the study sponsor and agreed to the protocols that generated the data under review. And FDA acknowledges in its briefing document that both MDMA-AT Phase III trials were statistically positive for efficacy on the FDA-agreed upon primary endpoint as well as a prespecified secondary endpoint. The effect sizes were large, and long-term follow-up data also shows likely durability of effect at least 6 months after completion of treatment, which FDA’s briefing document acknowledged “may signify a greater possibility that there is a drug treatment effect that is longer-lasting and larger than would be seen with expectation bias alone.”
However, we also encourage the Committee to look beyond the data captured by CAPS-5 (amongst other measures) and to consider the stories submitted by patients and providers of profound healing that is quite rarely achievable in clinical practice with our existing treatments. These stories cannot be overstated as we often miss critical aspects of change and healing with the ‘gold standard’ assessment measures.
While we believe MDMA-assisted therapy is clearly efficacious, any treatment that can produce such benefits can also cause harm. We know there are some patients who will have a very difficult time and potentially feel worse before improving, who may not improve at all, or who experience concerning psychological side effects ranging from suicidal ideation to rare extended difficulties such as dissociation or derealization. Moreover, patients are in a vulnerable state that may leave them at greater risk of exploitation by abusive providers. Nonetheless, MDMA’s safety profile when taken in medically supervised contexts is comparable, if not better, to that of SSRIs.
To minimize risks, FDA has proposed a REMS comprised of the following elements to assure safe use:
the drug can only be dispensed in certain healthcare settings,
the drug be dispensed to patients with evidence or other documentation of safe-use conditions,
each patient using the drug be subject to monitoring, and
each patient using the drug be enrolled in a registry.
Notably, to be certified in the REMS, a healthcare setting would require (amongst other measures) that a prescriber be available during MDMA administration and monitoring, and at least two healthcare providers are onsite (but not necessarily in the treatment room), one of which must be a licensed healthcare provider. We believe this is reasonable to allow flexibility with roving and/or remote monitoring support staff, and preferable to FDA requiring two providers in the room.
In our response to FDA’s clinical trial guidance, we suggested safety could be increased through remote live video monitoring and a default requirement that all psychedelic administration sessions (in research and clinical practice) be video-recorded, unless explicitly objected to by a patient in writing. Recordings would help protect patients by discouraging and providing accountability against abuse from providers, while protecting providers against false or mistaken accusations from patients (e.g., false memories induced by a psychedelic experience).
Nonetheless, given FDA’s already very stringent proposed REMS (including enrolling each patient in a registry), we believe the benefits of MDMA-AT clearly outweigh the risks. The unfortunate reality is that even with potentially imminent FDA approval, we are many years away from this resource-intensive treatment ever reaching a significant number of people, so there is ample time for additional real-world safety data collection before any notable public health impact.
Thus, we urge FDA to approve this application without delay. While it is unfortunately too late for those we have lost, it is not too late for so many others who have been suffering for so long, particularly within the Veteran community, who have tried everything at their disposal over the course of many years, and who deserve the opportunity to legally access this powerful novel treatment. There are many lives that will be not only saved, but greatly improved, which will have a major ripple effect for caregivers, family, friends, and communities at-large. It is truly a reason for hope.
Brett M. Waters, Esq.
Co-Founder and Executive Director
Reason for Hope
Martin R. Steele
Lieutenant General, US Marine Corps (Retired)
Founder and President
Veteran Mental Health Leadership Coalition
Lynnette A. Averill, PhD,
Associate Professor of Psychiatry and Behavioral Sciences,
Baylor College of Medicine
Chief Science Officer,
Reason for Hope
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