FDA Open to Alternative Approaches For Psychedelic Drug Trials
FDA says it welcomes novel approaches for evaluating psychedelic drugs for mental health conditions, including changes to how the products are studied, administered and monitored over the long term, agency officials said in a New England Journal of Medicine article. The agency's willingness to consider alternative approaches reflects the unusual challenges posed by psychedelic drugs, especially the difficulty of maintaining blinding in conventional placebo-controlled trials because patients can easily recognize the drugs' effects.
CDER director Michael Davis and other agency officials wrote that the need for new treatments for patients who do not respond to existing therapies warrants greater flexibility in psychedelic-drug development. Among the approaches FDA is willing to consider are active comparators instead of placebo controls and different dosing strategies. Such approaches could help address the functional-unblinding problem that can undermine conventional psychedelic trials.
“Sponsors can propose active comparators, such as psychoactive agents with subjective effects, to preserve blinding and to enhance the validity of outcome measures,” the officials wrote. “Another option is comparison to lower doses of the investigational psychedelic.”
The authors note that while placebo-controlled studies raise the issue of functional unblinding and may complicate determinations of efficacy, the agency may still recommend such a study. “Comparison with inactive placebo in at least one trial can help determine whether adverse events stem from the investigational drug or from other causes (such as underlying psychiatric or medical conditions),” they said, adding that “close discussion with FDA staff is advisable.”
In July, FDA issued a guidance detailing its current recommendations for developing psychedelic drug products, providing sponsors with the agency's most comprehensive roadmap to date for addressing manufacturing, nonclinical testing, clinical trial design, abuse potential, and long-term safety considerations. The guidance acknowledges the growing interest in psychedelic therapies for psychiatric and neurological disorders while emphasizing that these products will be held to the same statutory standards for safety and effectiveness as other prescription drugs.
Although many psychedelic therapies are intended to produce durable benefits after only one or a few doses, FDA says sponsors should demonstrate the durability of treatment effects and evaluate the safety and efficacy of repeat dosing. For chronic conditions such as major depressive disorder or post-traumatic stress disorder, the agency recommends evaluating treatment effects through at least 12 weeks using double-blind study designs, followed by longer-term follow-up — typically up to 12 months — to assess symptom recurrence and the potential need for retreatment. If repeat dosing appears necessary, sponsors should study appropriate maintenance dosing intervals, potentially through postmarketing studies.