FDA Issues First Draft Guidance on Clinical Trials for Psychedelic Drug Developers
On June 23, 2023, the U.S. Food and Drug Administration (FDA) issued a draft guidance1 outlining clinical trial considerations for drug sponsors involved in the medicalization of psychedelics.2 This is the FDA’s first guidance focusing on psychedelic drug development.
Although psychedelic drug developers must abide by the same regulatory and evidentiary standards as other drug developers, the FDA’s draft guidance recognizes that psychedelic drug developers face additional unique challenges when designing clinical trials involving psychedelics.
In a press release,3 the director of the Division of Psychiatry in the FDA’s Center for Drug Evaluation and Research, Tiffany Farchione, M.D., noted that psychedelics “show initial promise as potential treatments for mood, anxiety and substance use disorders.” She further stated: “By publishing this draft guidance, the FDA hopes to outline the challenges inherent in designing psychedelic drug development programs and provide information on how to address these challenges. The goal is to help researchers design studies that will yield interpretable results that will be capable of supporting future drug applications.”
The draft guidance offers general considerations as they apply to the psychedelic drug development process, including sections on submission of chemistry data and manufacturing compliance, pharmacokinetic/pharmacodynamic and dose-response characterization, abuse potential determination, and design of adequate and well-controlled clinical studies. Within the various sections, the FDA provides more detailed explanations and solutions to some of the challenges specific to the medicalization of psychedelics, but notes that its goal was not to provide specific recommendations, but rather to “present foundational constructs.”4 Examples of some of the more challenging aspects of psychedelic drug development identified by the draft guidance include:
- Since many psychedelics are still considered Schedule I controlled substances under U.S. federal law, investigators researching the potential clinical uses of such psychedelics must still comply with all Drug Enforcement Agency regulations regarding such substances.5
- Considering that some psychedelic compounds may be derived from plants and fungi, in addition to being chemically synthesized, the draft guidance emphasizes that manufacturers be compliant with current good manufacturing practice (CGMP) requirements and provide sufficient chemistry, manufacturing and controls information (CMC) consistent with guidances for Phase 1-3 clinical studies.6
- For certain psychedelics, drug developers may be able to forego some initial animal toxicology testing “when extensive human exposure and information are available from previously conducted clinical studies and no serious safety concerns were identified.”7
- Traditional placebo-controlled clinical trials present challenges for evaluating the efficacy of psychedelics. The draft guidance provides some suggestions for alternative study designs, which could be paired with placebo-controlled trials, such as using “subperceptual doses of a psychedelic drug” or “other psychoactive drugs that mimic some aspects of the psychedelic experience” as alternatives to using an inactive control.8
- While many current trials involve the use of psychotherapy as an adjunct to the administration of the psychedelic, the draft guidance cautions that the psychotherapy component may create potential difficulties in evaluating the effectiveness of the psychedelic as well as in developing future product labelling.9
- Since “[s]ubjects receiving active treatment with psychedelic drugs remain in a vulnerable state for as long as 12 hours,” clinical trials should include the use of safety monitor personnel for the entire treatment session length during which the patient remains in a vulnerable state.10 The FDA cautions that it would place a study conducted under an investigational new drug (IND) application on clinical hold if it deemed “human subjects are or would be exposed to an unreasonable and significant risk of illness or injury.”11
- Obtaining informed consent presents a number of challenges. Not all are addressed in the draft guidance. Nonetheless, the draft guidance does note that any informed consent “should clearly describe 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.”12 It does not address issues that some investigators have experienced such as how to handle a subject who changes his or her mind about aspects of a previously provided informed consent while under the influence of the investigational psychedelic.
- Some potential interactions that should be considered, according to the draft guidance, include the possibility for decreased psychedelic effect with chronic use of selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs) and the possibility for augmented psychedelic effect with chronic use of tricyclic antidepressants or lithium and acute use of SSRIs and MAOIs.13 The potential for heart valvulopathy with psychedelic drugs that have binding activity at the 5-HT2B receptor subtype is also noted in the draft guidance.14
- The draft guidance advises that drug developers plan for risk mitigation during clinical studies as well as post marketing. “Sponsors should consider where the drug would be dispensed and administered if approved and whether the healthcare system would be able to prevent nonmedical use, accidental exposure, and overdose for both patients and nonpatients. … FDA may consider whether a risk evaluation and mitigation strategy may be necessary to ensure that the benefits of the drug outweigh its risks.”15
- The draft guidance notes that drug developers should plan for characterizing the efficacy and safety dose-response relationships, the durability of response, and the safety and efficacy of repeat dosing.16 “At a minimum, for the treatment of a chronic illness such as post-traumatic stress disorder or major depressive disorder, sponsors should evaluate the effect of treatment at 12 weeks. However, sponsors should continue to follow subjects in an open-label extension period for a year beyond the Week 12 endpoint to monitor for symptom recurrence or, potentially, the need for repeat dosing.”17
The FDA will accept public comment within 60 days of the publication of the draft guidance.
Tiffany Farchione noted: “Sponsors evaluating the therapeutic potential of these drugs should consider their unique characteristics when designing clinical studies.”18
Phillips Lytle’s expertise in pharmaceutical sciences, FDA regulatory compliance, and pharmaceutical product liability litigation and risk management enables it to address complex legal hurdles faced by stakeholders seeking to research, develop, invest in and bring-to-market psychedelic therapies.
Eric M. Kraus is a partner at Phillips Lytle LLP and member of the firm’s Psychedelics & Mental Therapeutics Practice Team. He can be reached at (212) 508-0408 or firstname.lastname@example.org.
Lisa L. Smith is a partner at Phillips Lytle LLP and leader of the firm’s Psychedelics & Mental Therapeutics Practice Team. She can be reached at (716) 847-8336 or email@example.com.
Julia M. Markov, Pharm.D., is a science specialist at Phillips Lytle LLP and member of the firm’s Psychedelics & Mental Therapeutics Practice Team. She can be reached at 716-847-5442 or firstname.lastname@example.org.
1 FDA, Psychedelic Drugs: Considerations for Clinical Investigations, Guidance for Industry, Draft Guidance (June 2023), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations.
2 For the purposes of the guidance, the FDA used the term “psychedelic” to refer to the classical psychedelics such as psilocybin and lysergic acid diethylamide (LSD), as well as entactogens or empathogens such as methylenedioxymethamphetamine (MDMA).
3 FDA News Release, FDA Issues First Draft Guidance on Clinical Trials with Psychedelic Drugs, Agency Recommendations Aim to Inform Psychedelic Drug Development (June 23, 2023), https://www.fda.gov/news-events/press-announcements/fda-issues-first-draft-guidance-clinical-trials-psychedelic-drugs.
4 FDA, supra note 1, at 2.
5 FDA, supra note 1, at 6.
6 FDA, supra note 1, at 2-3.
7 FDA, supra note 1, at 4.
8 FDA, supra note 1, at 8-9.
9 FDA, supra note 1, at 9.
10 FDA, supra note 1, at 9.
11 FDA, supra note 1, at 9.
12 FDA, supra note 1, at 10.
13 FDA, supra note 1, at 5.
14 FDA, supra note 1, at 4, 5, 10.
15 FDA, supra note 1, at 10-11.
16 FDA, supra note 1, at 5, 10.
17 FDA, supra note 1, at 10.
18 FDA, supra note 3.