Psychedelics: FDA offers clarifications, compromises in final clinical trial guidance
The US Food and Drug Administration (FDA) has finalized its guidance on clinical trial requirements for developing psychedelic therapies. The final version clarifies the agency's thinking, based on industry feedback, especially regarding clinical and safety considerations in the design of clinical trials.
The guidance was released in draft form in June 2023 and details the nonclinical, clinical, and safety considerations for running trials for classic psychedelics. The category of drugs includes 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD), as well as methylenedioxymethamphetamine (MDMA). (RELATED: FDA issues first psychedelic drug trial guidance, Regulatory Focus 28 June 2023)
FDA received over 200 comments on the draft guidance; stakeholders raised concerns about decoupling administering the investigational drug from psychotherapy support, the proposed credentials for lead safety monitors, and the agency’s characterization of the abuse potential of psychedelic drugs. (RELATED: Psychedelic drug trial guidance: Commenters see vital role for psychotherapy, Regulatory Focus 29 August 2023)
FDA said it made a few clarifications to the guidance in response to stakeholder feedback, but otherwise, the guidance has not changed substantially. Most notably, the agency has updated the clinical considerations section of the guidance to emphasize that it is essential for sponsors to distinguish the effect of the investigational drug from other potential influences, such as spontaneous changes in the course of the disease, placebo effect, or biased observation, when establishing the drug's effectiveness.
"This is the basis for the statutory requirement that a new drug approval be based on adequate and well-controlled investigation(s), as well as the basis for FDA’s regulations describing the characteristics of an adequate and well-controlled investigation," said FDA. "Designing an adequate and well-controlled clinical investigation of psychedelic drugs can be challenging for sponsors given the often intense perceptual changes induced by the drugs.
"This increases the potential for bias due to functional unblinding of patients, therapists, monitors, or raters," the agency added. "Functional unblinding can lead to expectation bias in the patients who experience perceptual disturbances, or in those who observe them, which may lead to an expectation that the participant will experience clinical benefit; alternatively, those who receive a placebo and do not experience or observe a perceptual change may expect that the participant will not benefit."
FDA also added considerations for trial design and safety when designing clinical trials. While both the draft and final versions raise concerns that the use of traditional placebos may be problematic because they may lead to unblinding in the trial, the agency said sponsors may consider alternatives to an inert placebo, such as lower doses of a psychedelic drug, and other psychoactive drugs that mimic some aspects of the investigational psychedelic drug.
The final guidance notes that while some of the drugs may be expected to produce long-lasting benefits from just a dose or a few doses, many of the conditions they are intended to treat may last for months or years, and sponsors should evaluate the durability of the responses as well as their safety and efficacy after repeat dosing. As examples, the agency said that before sponsors begin a trial to treat chronic illnesses such as post-traumatic stress disorder or major depressive disorder, they should evaluate their drug with a double-blind design at 12 weeks. Regulators said sponsors should then follow the subjects beyond 12 weeks to assess symptom recurrence and determine whether repeat dosing is needed.
Additionally, FDA emphasized in the final guidance that sponsors should plan to characterize the dose-response relationship for both safety and efficacy of the drug early in the development program and should ensure that subjects are reasonably representative of the intended treatment population. The agency also noted that including subjects who have had psychedelic drugs before may lead to expectation bias because they are more likely to recognize the drug effects and anticipate a treatment benefit and said such patients should not be overrepresented in the trial, and they should be properly randomized.
"Although the FDA does not address inclusion and exclusion criteria in this guidance, we advise that the included population be representative of the population intended to receive the treatment," said FDA. "Trials should not unnecessarily exclude subjects who have certain health characteristics (e.g., age, treatment history, concurrent treatments, pregnancy) if these groups are intended to receive the treatment post-approval, but they should be appropriately stratified.
"Excluded populations may not be described in the approved indication in prescribing information," the agency added.
Both the draft and final versions of the guidance note that an independently licensed healthcare provider with graduate-level professional training and clinical experience in psychotherapy should serve as the lead clinical trial monitor. However, in response to stakeholder feedback that the agency should broaden who can serve as a monitor, the final version does not include a list of examples of such professionals.
In terms of safety considerations, FDA said sponsors should identify the incidence, duration, and severity of all central nervous system effects, including expected psychedelic effects, in the trials. The agency also said they should conduct a literature review for adverse events if their drug has a history of human use to identify potential safety issues.
In the draft version, FDA said sponsors should plan to characterize the durability of response for their drug product, the recommended inter-dose interval for maintenance of effect, and the safety and efficacy of repeat dosing. However, in the final guidance, the agency has significantly changed that requirement, instead focusing on assessing the drug's effects, especially as they relate to everyday activities.
"Sponsors should plan to provide a quantitative and qualitative assessment of the drug effects, including effects on orientation to time and place, thought and perception, and subjective effects across time that could inform recommendations for monitoring, safety of discharge, and impact on driving," said the agency in the final guidance. "Sponsors should consider including a formal driving study in their drug development plan."
