In its announcement regarding the draft guidance, FDA acknowledged that there has been a growing interest in the use of psychedelic drugs for the potential treatment of conditions including depression, post-traumatic stress disorder, and substance abuse disorders. Dr. Tiffany Farchione, director of FDA’s Division of Psychiatry in the Center for Drug Evaluation and Research (CDER), recognized that psychedelic drugs show initial promise, but that they are still investigational products with unique characteristics that should be considered when designing clinical studies.

Indeed, FDA notes that these while the evidentiary standard to establishing the effectiveness for psychedelic drugs is the same as for other drugs, the unique factors should be considered when designing clinical trials in order for the trials to be considered adequate and controlled. Unique characteristics noted in the guidance include the potential for intense perceptual disturbances and alternations of consciousness that can last for several hours, as well as the potential for rapid-onset and long-term benefits after only one or few doses. In turn, the document provides guidance on conducting adequate and well-controlled studies, how to consider abuse potential evaluations, and nonclinical programs. The document frequently refers readers to existing guidance while noting key considerations that are unique to psychedelic drugs in each section.

The following provides a review of each section of the draft guidance.

Chemistry, Manufacturing, and Controls

This section does not provide any policy that is specific or unique to psychedelic drugs but does reference potentially applicable guidance. Two particular topics are discussed, botanicals and current good manufacturing practice (CGMP) requirements for investigational drug products.

FDA explains that investigational products that use plant material, algae, or macroscopic fungi may be considered a botanical, and are covered by FDA’s December 2016 “Botanical Drug Development” guidance. Psychedelic compounds that are genetically modified; produced by fermentation of yeast, bacteria, or plant cells; or are highly purified substances derived from naturally occurring sources are not considered botanicals, even though they may be derived from plants or fungi.

FDA points out that all investigational drug products are subject to CGMP as required by section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. §351(a)(2)(B)). CGMP recommendations for the manufacture of investigational drug products intended for phase I trials are discussed in the July 2008 guidance “CGMP for Phase 1 Investigational Drugs”. CGMP recommendations for investigational drugs intended for phase II and III trials are discussed in the May 2003 guidance “INDs for Phase 2 and 3 Studies; Chemistry, Manufacturing, and Controls Information”.

Nonclinical

Generally, FDA’s recommendations for nonclinical testing are found in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline “M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals”, which was adopted by FDA in January 2010. FDA, however, adds additional points regarding nonclinical psychedelic drug development in its guidance.

FDA notes that “typical” animal toxicology testing may not be necessary where there is already “extensive human exposure and information are available from previously conducted clinical studies and no serious safety concerns were identified.” Where there is no history of adequate clinical exposure, nonclinical data would be required before clinical studies could begin.

FDA separately identifies the need to conduct “a thorough evaluation of binding to [serotonin (5-HT)] receptor subtypes”, with a particular concern that binding to the 5-HT2B receptor subtype has been linked to heart valvulopathy in humans. Due to this concern, FDA recommends that functional activity at the 5-HT2B receptor subtype should be assessed, and that, if the investigational drug is shown to be an agonist at 5-HT2B receptors, a thorough microscopic evaluation to assess the potential heart valve thickening in both rodent and nonrodent repeat-dose toxicity studies should be conducted. This assessment would include sectioning of all heart valves. What is not clear, and may need to be raised in comments, is whether this assessment is necessary where there is already extensive human exposure.

FDA also raises the issue of long-term exposure to 5-HT2B agonists in its clinical pharmacology section. FDA notes that this exposure may induce cardiac valve stiffening, so FDA recommends that sponsors exclude subjects with preexisting valvulopathy or pulmonary hypertension from multiple-dose studies until the risk can be better characterized. In the clinical section, FDA recommends collecting baseline and follow-up echocardiograms to assess valve structure and function and pulmonary artery pressures.

Regarding the length of nonclinical studies, FDA notes that 21 CFR 312.23(a)(8) specifies that “[t]he kind, duration, and scope of animal and other tests required [to conduct the proposed clinical investigation] varies with the duration and nature of the proposed clinical investigations”. Therefore, FDA recommends that “[n]onclinical studies to support chronic or chronic-intermittent dosing should be provided if the treatment effect is not durable and repeat dosing is expected.”

Clinical Pharmacology

FDA highlights several areas where sponsors may need to study the clinical pharmacology of their investigational psychedelic drug. For example, FDA recommends evaluating the effect of a high-fat meal on the pharmacokinetics of oral psychedelic drugs “early in development”. Results of this testing may require changing clinical study design.

There are a number of drug-drug and drug-disease interactions that FDA flags in the guidance. These include:

• cytochrome P450 enzyme- and transporter-mediated drug interactions that may affect the metabolism of LSD or other psychedelics,
• gastric pH-dependent drug interactions with acid-reducing agents that may affect the metabolism of psilocybin or other psychedelics,
• chronic use of selective serotonin reuptake or monoamine oxidase inhibitors that may reduce the effect of psychedelic drugs, and
• chronic use of tricyclic antidepressants or lithium and acute use of selective serotonin reuptake or monoamine oxidase inhibitors that may potentiate psychedelic effects.

FDA also recommends characterizing the dose-response relationship, as this is poorly understood for most psychedelic drugs.

Abuse Potential Assessment

FDA notes that psychedelic drugs need to be evaluated for abuse potential during drug development. FDA recommends referring to its 2017 guidance “Assessment of Abuse Potential of Drugs” for details. FDA recommends using scientifically valid published investigations to support the abuse potential assessment unless the investigational drug has not been well-characterized in previous preclinical and clinical studies. Clinical safety reporting should track all abuse-related adverse events (AEs), such as euphoria, hallucinations, stimulation, and emotional lability. Animal and human abuse potential and dependence-related studies should only be conducted after the therapeutic dose range is determined (typically once phase 2 clinical studies are completed).

Clinical

FDA believes that the characteristics of psychedelic drugs present challenges in designing adequate and well-controlled (AWC) clinical studies. For one, the use of an inert placebo may present a challenge. FDA recommends an inactive control (which allows for better contextualization of any safety findings) or an alternative to an inert placebo (such as subperceptual doses of a psychedelic drug, or other psychoactive drugs that mimic some aspects of the psychedelic experience). FDA also expresses concern that the incorporation of psychological support or psychotherapy either while the subject is experiencing the effects of the drug or in a subsequent session both complicates the assessment of effectiveness and presents a challenge for product labeling.

FDA suggests that clinical trials may be subject to a clinical hold if they don’t include safety-monitoring according to FDA’s recommendations. FDA indicates that subjects receiving active treatment with psychedelic drugs remain in a vulnerable state for as long as 12 hours. Safety-monitoring should involve two monitors, including a healthcare provider with graduate-level professional training and clinical experience in psychotherapy, licensed to practice independently, and an assistant monitor with a bachelor’s degree and at least 1 year of clinical experience in a licensed mental healthcare setting. This draft guidance also prefers that the person monitoring the subject during the active treatment of the study, not be involved in the post-treatment psychotherapy session to potentially control for bias. This recommendation may need to be addressed in comments as the cost of having multiple monitors dedicated to only specific parts of the study, could raise costs or could be prohibitive to running the study if there are not enough trained personnel available, in light of the shortage of mental health care providers.

FDA has also suggested a factorial study design in an effort to tease apart the psychedelic’s efficacy from the psychotherapy component. In the case of psychedelic-assisted psychotherapy, the investigator would need to run: 1) psychedelic+psychotherapy, 2) psychedelic alone, 3) placebo+psychotherapy and 4) placebo alone. A factorial design would likely increase the cost of running psychedelic clinical trials as more subjects will need to be recruited to satisfy multiple interventions.

Informed consent is recommended to include notice that subjects may experience changes in perception, cognition, and judgment that persist for many hours, as well as increased vulnerability and suggestibility during the treatment session.

Treatment of chronic illnesses are recommended to evaluate the effect of treatment at 12 weeks, with subjects followed in an open-label extension period for a year beyond the Week 12 endpoint to monitor for symptom recurrence or the need for repeat dosing.

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FDA is accepting comments on the draft guidance document until August 23, 2023. Comments can be submitted to Regulations.gov. All comments should be identified with the docket number FDA-2023-D-1987.

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