For Psychedelics, US FDA Is Open To Creative Thinking But Firm On Approval Standards

Psychedelic drugs present unique challenges to the conventional drug development paradigm, so it is fitting that a more unconventional or creative package of clinical trials could make for a more successful NDA than the traditional ideal of two replicate randomized pivotal trials.

“Our regulations are inherently flexible, and the exact types of studies that are needed to provide this data aren’t specified,” FDA Center for Drug Evaluation and Research Division of Psychiatry director Tiffany Farchione told a recent Reagan-Udall Foundation for the FDA meeting on psychedelic clinical study design.

“The standard for substantial evidence for psychedelics is the same as it is for any other drug,” Farchione emphasized as she described the agency’s June 2023 draft guidance “Psychedelic Drugs: Considerations for Clinical Investigations.” (Also see "US FDA Outlines Psychedelic Drug Trial Principles, But It Won’t Be An Easy Trip" - Pink Sheet, 28 July, 2023.)

However, “substantial evidence doesn’t have to mean two trials designed exactly the same,” she said. “I guess this is the bottom line.”

“We don’t have a specific recommendation for how to do these studies the right way,” Farchione observed. “That’s why we describe trial design elements for sponsors to consider rather than characterizing them as best practices or standards in the guidance.”

“You’re going to have different designs within a given program,” CDER Division of Psychiatry deputy director Bernard Fischer noted.

“Instead of having just two placebo-controlled studies, it may be the case that we would want to see a placebo-controlled study to really characterize the safety of an intervention, but then we might want to see something else for a second kind of study … like a dose response study,” he explained.

Or “we might want to see something with an active control, where we wouldn’t necessarily be looking at safety per se” because the study “would be primarily to look at efficacy.”

“Treatments with novel mechanisms of action and new dosing paradigms will require unique clinical development plans to inform labelling and clinical use,” Johnson & Johnson Innovative Medicine VP neuropsychiatry clinical development Carla Canuso advised.

J&J’s Spravato (esketamine), a single-isomer nasal spray formulation of the dissociative anesthetic ketamine, is usually considered the first – and still the only – psychedelic therapy approved by the FDA, although the FDA is reviewing an NDA for midomafetamine (MDMA) for post-traumatic stress disorder from Lykos Therapeutics (formerly known as MAPS Public Benefit Corporation). (See sidebars for more on the US pipeline of psychedelic drugs.)

Regulators in the European Union are wrestling with the same quandaries facing psychedelic drug development. The European Medicines Agency is updating a 10-year-old guidance on major drug depression to address the repurposing of psychedelics and rapid-acting antidepressants, issuing a draft in September 2023 that advises that different types of products may require separate trial design strategies.

At the October RAPS Convergence meeting, EMA senior scientific specialist in psychiatry, mental health and digital health Florence Butlen-Ducuing sounded similar concerns to the Reagan-Udall panelists about the importance of setting, the role of psychotherapy, and the need for unconventional thinking about trial design. (Also see "Psychedelic Drugs: Regulators Still Unsure On Development Path, But Willing To Listen" - Pink Sheet, 10 October, 2023.)

The EMA is seeking comments on its draft MDD guidance until 31 March 2024. (Also see "EMA Addresses Rapid Acting Therapies, Psychedelics In Updated Guidance On Depression Treatments" - Pink Sheet, 20 September, 2023.)

Thinking About Dose, From Response…

“The dose response relationship for most psychedelics is really poorly understood,” Farchione noted, so “it’s important to characterize this in your clinical studies, both for safety and for efficacy.”

Dose response trials could be “another type of adequate and well controlled study” to support a psychedelic NDA, she said.

A dose response trial design “really offers a potential alternative to some of the traditional models with placebo or with having an active comparator,” Farchione suggested. Even if there is no placebo group, a study with multiple different doses “can serve as one of the adequate and well-controlled trials,” with an application rounded out by studies using “different complementary designs.”

In such a scenario, one placebo-controlled trial could “help us assess safety,” and then a dose response trial could “help with the efficacy assessment,” Farchione said. “That could be one strategy to demonstrating substantial evidence.”

…To Maintenance

Canuso highlighted the importance of maintenance of effect data in psychedelic applications based on J&J’s experience with Spravato, which was first approved in treatment-resistant depression in 2019 and for rapid reduction of depressive symptoms in MDD patients with active suicidal ideation with intent in 2020.

“Oral antidepressants, at least those that were approved to modern times, completed the maintenance of effects study post approval,” the J&J exec noted. “Short-term studies were sufficient for the initial FDA approval.”

With esketamine, however, the FDA told J&J that “due to its uniqueness (e.g. safety concerns, questions of how to maintain response), we view esketamine very differently than the previously approved oral antidepressants. We would therefore need to see maintenance data at the time of filing.”

“Given the great importance of the maintenance-of-effect data with this drug,” the FDA said it “would consider one positive short-term study along with a positive maintenance-of effect-study to be sufficient for NDA submission,” Canuso reported.

Ultimately the FDA approval of Spravato for treatment-resistant depression in 2019 rested on five completed Phase III trials that addressed different concerns, Canuso summarized, including three short-term acute induction studies (TRANSFORM-1, -2 and -3); SUSTAIN-1, an integrated acute/maintenance trial using a randomized withdrawal design; and the SUSTAIN-2 open-label safety study.

Ongoing trials included a US-only short-term Phase III and SUSTAIN-3, which provided patients from prior studies access to esketamine nasal spray while assessing long-term individualized dosing.

The FDA approval carried an enhanced Risk Evaluation and Mitigation Strategy and long-term postmarketing safety study.

The decision also marked the first time the Division of Psychiatry had considered a randomized withdrawal trial as one of two adequate and well-controlled trials to demonstrate substantial evidence of effectiveness. (Also see "Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy Trial" - Pink Sheet, 7 March, 2019.)

Single-Dose Therapy But Chronic Disorders

“Even though current psychedelic drug development programs are exploring mostly single dose or intermittent dose treatment paradigms, most of the conditions that are being studied, at least in psychiatry, are for chronic disorders like major depressive disorder and PTSD,” Farchione stated. “Bear this in mind when we talk about durability of treatment response.”

“Until we know how long a treatment effect lasts … we don’t know yet whether chronic quality studies are going to be required for these programs,” she noted. “This is a major unanswered question.”

“Our a priori assumption is that … the symptoms will come back when you don’t continue to treat,” she said. “We need to be able to write a label information about more than just the first dose or two.”

“Durability of effect becomes an even greater factor in the overall benefit-risk assessment of novel therapeutics with safety and abuse liabilities,” J&J’s Canuso stated.

During Spravato’s development, the FDA advised that “in order to approve such a product, we would need to be able to advise clinicians on how best to use the product after an initial response,” she reported.

“We are interested in understanding the dose response with regards to the efficacy and how that might or might not affect the psychedelic effects,” FDA psychiatry division clinical team lead Martine Solages told the Reagan-Udall meeting.

“We’re still in the phase of gathering data, but if any of these products were ever to get to the point where we’re talking about labeling” the agency will want to describe for practitioners what doses might be useful and what the associated safety concerns might be.

Currently, “we don’t have information to guide whether a lower dose would still be effective, or potentially mitigate risk,” Solages said. “We don’t have information to understand whether a higher dose could be used, including in different populations that might have differential responses.”

“It’s a very heavy regulatory challenge for us,” she stated. “We certainly want as much information as we can to help us with those decisions.”

Lykos Therapeutics chief scientific officer Berra Yazar-Klosinski emphasized the work the company put into designing and justifying an empirical dosing regimen for midomafetamine (MDMA) for PTSD. “We need to understand what’s the relationship between drug dose and various intrinsic factors such as weight when determining what dose to study for MDMA.”

“We really had to learn from empiric recommendations from clinicians in order to design this development program,” she said. MDMA does not have a linear dose response curve, but it did show a threshold effect – and it does have extensive use outside of conventional medicine.

“Essentially, we reverse engineered what the clinicians were telling us was most beneficial, utilizing PK studies,” Yazar-Klosinksi said. The company used a fixed-dose paradigm in Phase II/III, not based on weight, in a split dose approach with dose escalation.

Standardizing Set And Setting

Under Lykos’ pending NDA, midomafetamine is given at three medication sessions, at least 21 days part, administered in combination with psychological intervention provided a qualified healthcare provider.

“We’ve described the therapy component of these sessions as a psychological intervention to reflect the intensive nature of these sessions, which go beyond a standard talk therapy session,” Yazar-Klosinski emphasized. “They involve the intentional use of the effects of the medication.”

“We’ve intentionally not characterized the risk of use of MDMA without adequate psychological support due to the seriousness of the underlying disease,” PTSD, she explained.

Lykos’ perspective on the importance of set and setting to the success of midomafetamine treatment is a majority position.

COMPASS Pathways’ psilocybin therapy COMP360 includes “psychological support,” chief medical officer Guy Goodwin noted. “And the reason we provide psychological support is essentially for the reasons of safety.”

“We need to further standardize psychological support,” Goodwin continued, to “ensure we’re clearly measuring the drug effects and not … differential behavior by therapists.”

“The issue at stake here is whether preparation and integration should be best considered psychological support, or supportive psychotherapy,” David Yaden, Johns Hopkins University, said.

“I think going forward more and more standardization is ideal, mostly for scientific reasons,” Yaden suggested. A set of concepts could be provided in the psychological support model “to cut down on the variability of what facilitators are drawing on.”

Many non-mainstream therapies are used in the psychedelic community, he pointed out, but “the main issue is the lack of safety testing related to concepts. There’s minimal careful research done on these concepts.”

Cognitive behavioral approaches are a more realistic source of therapeutic concepts suitable for supportive psychotherapy, Yaden said. CBT and its ideas about cognitive beliefs, mindfulness and emotional regulation are “relevant and resonant with the psychedelic experience” while giving facilitators “a common constellation of concepts to draw from.”

“We’re seeing a lot of psychedelic scientific and ethical exceptionalism,” Yarden observed, “and they do have distinct qualities.” However, “rather than treating psychedelics as something new under the sun, I think we can apply existing concepts, guidelines and standards in psychedelic research and perhaps in clinical applications,” he concluded.

MindMed Aims For Standard Endpoints

MindMed is taking a stand against psychedelic exceptionalism in its development of MM-120 (lysergide D-tartrate), an LSD therapy in Phase IIb for generalized anxiety disorders. “We decided that really what needs to be done here is a standard drug development, standard clinical trials and standard endpoints and to the greatest extent possible, to treat patients and our protocol the exact same way that we would treat any other CNS drug,” CEO Robert Barrow said.

In contrast to the other late-stage psychedelic sponsors, “we were not going to do any sort of therapeutic intervention other than administration of the drug,” he said. “We’re not going to do any assisted therapy or therapeutic intervention prior to treatment.”

Patients in MindMed’s trials are under observation by staff who are qualified under FDA’s draft guidance on psychedelic development, Barrow emphasized, and have follow up visits and comprehensive informed consent.

When MindMed read out four-week primary Phase II results in December 2023, “we were very happy to have seen that even when we remove any of those other [therapy] elements that have been used historically, we saw a drastic reduction in anxiety symptoms,” Barrow said.

A Placebo Wrapped In A Complex Therapeutic Milieu?

“The combined use of drug and therapy in an intervention ultimately complicates our assessment of the drug’s effectiveness, and presents a challenge for future labeling,” Farchione observed.

Even if the value of psychological support can be measured, an integral role as part of drug treatment regimen poses stark challenges to the FDA’s regulatory authority. “We don’t regulate psychotherapy,” Farchione reminded the Reagan-Udall meeting. “And we don’t regulate the practice of medicine.”

The FDA’s ability to regulate the circumstances around drug administration is pegged to safety. Farchione noted a few examples of psychological support in labeling, emphasizing that “the descriptions of the therapy type intervention that are in labeling are very abbreviated and very general”:

• Naltrexone extended-release injectable suspension for alcohol and opioid dependence, where the Indications and Usage section of labeling states that “treatment … should be part of a comprehensive management program that includes psychosocial support.”
• Bupropion extended-release tablets for smoking cessation, where the Dosage and Administration section that that “it is important that patients continue to receive counseling and support throughout treatment … and for a period of time thereafter.”
• Buprenorphine sublingual tablets for opioid dependence, where the Clinical Studies section of labeling reports that “all trials used buprenorphine in conjunction with psychosocial counseling as part of a comprehensive addiction treatment program. There were no clinical studies conducted to assess the efficacy of buprenorphine as the only component of treatment.”

“We can mandate certain credentials for clinical studies,” Farchione noted, but “we do not have the authority to say that similar credentials will be needed for similar roles in the post-market setting.”

From a regulatory and labeling perspective, another major problem with psychotherapy-assisted psychedelic therapy “is the lack of a rigorous definition of what the psychotherapeutic interventions are,” she said.

“Overall, the therapy is not just a confounding factor in the overall treatment model” for psychedelics, Farchione noted. “It appears to be integral to the treatment as a as a safety feature, and in order to maximize the treatment effect. But we don’t know what major components of this psychotherapeutic intervention are necessary to ensure safety.”

“Identifying what is really the active component in this paradigm will help us come up with better designs and better controls,” Fischer commented.

The FDA will want to know “which features are critical for efficacy and what are the minimum components necessary to control safety,” Division of Psychiatry associate director Javier Muniz added. “This is ultimately extremely important to write a label.”

“A factorial study would be highly informative, and allow us to write a better label, but we just haven’t seen that,” Farchione said. “These are big and expensive.”

“But each of these elements can impact the therapeutic response, so it’s important to tease out the contribution from these various issues in order to avoid ultimately approving a placebo that’s just wrapped in a complex therapeutic milieu,” Farchione stated.