FDA issues draft guidance for clinical investigations of psychedelic drugs
Against the backdrop of evolving state regulatory landscapes for controlled substances, including psychedelics for therapeutic uses, the US Food and Drug Administration (FDA) recently released a draft guidance entitled Psychedelic Drugs: Considerations for Clinical Investigations – Guidance for Industry. FDA is soliciting comments to this draft guidance through August 25, 2023.
This draft guidance represents a tremendous step toward possible FDA approval of psychedelics as drug products. Although states have begun to regulate psychedelics (see our alert State psychedelic regulation: Oregon and California taking the lead), federal agencies have been much slower to act. In fact, most, if not all, psychedelics are US Drug Enforcement Administration (DEA) Schedule I controlled substances, which are illegal under federal law. While this is a step forward by FDA, it is not without regulatory hurdles and significant clinical and nonclinical requirements.
In issuing this draft guidance, FDA explains it is providing general considerations to sponsors developing psychedelic drugs for treatment of medical conditions (eg, psychiatric disorders, substance use disorders). The scope covers “classic psychedelics,” which typically include 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD), and “entactogens” or “empathogens,” including methylenedioxymethamphetamine (MDMA).
The guidance discusses general considerations for drug development programs that would evaluate the therapeutic potential of psychedelic drugs and that applies to clinical trials that will be conducted under an investigational new drug application (IND). However, FDA recognizes that since this is an emerging area of drug development, there is limited experience as to the configuration of programs that may support approval of a psychedelic drug. The agency specifically highlights a few “unique challenges” associated with designing clinical studies to evaluate the safety and efficacy of psychedelic drugs. In light of these challenges, FDA notes that its guidance presents foundational constructs that all sponsors, including academic sponsor-investigators, studying the therapeutic potential of psychedelic drugs should consider.
Chemistry, manufacturing, and controls (CMC)
For all phases of clinical trials, FDA requires sufficient CMC information to ensure proper identification, quality, purity, and strength, and drugs must be manufactured in compliance with current good manufacturing practice requirements. Further, FDA clarifies that the use of plant material, algae, macroscopic fungi, or any combination, may be considered a botanical, while drug products that are genetically modified, produced by fermentation of yeast, bacteria, or plant cells, or highly purified substances from naturally occurring substances are not considered botanicals.
FDA recommends consulting its December 2016 guidance on Botanical Drug Development for consideration of whether a product would be considered a botanical.
FDA refers to its recommendations set out in the 2010 guidance regarding M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. FDA also identifies considerations unique to psychedelic drugs, including:
- Human exposure: Since FDA notes that there may be extensive human exposure and information available from previously conducted clinical studies when no serious safety concerns were identified, the agency recognizes that it may be reasonable for clinical studies with certain psychedelic drugs to be initiated under an IND in the absence of typical animal toxicology. It clarifies that sponsors should plan to conduct nonclinical studies to support further drug development (unless adequate published data is available), and psychedelic drugs without a history of adequate clinical exposure should not be tested in humans until safety has been established in nonclinical studies.
- Dosing: FDA identifies that most of the conditions being studied with psychedelics to date are chronic, and sponsors should provide nonclinical studies to support chronic or chronic-intermittent dosing if the treatment effect is not durable and repeat dosing is expected.
- Serotonin (5-HT) receptor subtype evaluations: Because psychedelic drugs have serotonin (5-HT) activity, FDA expects a thorough evaluation of binding to 5-HT receptor subtypes and assessment of potential for negative effects on the heart.
Clinical pharmacology and considerations
FDA recommends adequate characterization of the pharmacokinetics and/or pharmacodynamics of a psychedelic drug both in vitro and in vivo. It identifies unique considerations of psychedelic drugs, including analyzing impacts of a high-fat meal and cardiac effects of long-term exposure to certain agonists, potential drug-drug and drug-disease interactions, known pharmacodynamic interactions, and dose-response relationships.
Further, the guidance notes a number of considerations unique to psychedelic drugs when establishing effectiveness by the substantial evidence standard, a few of which are summarized as follows:
- Adequate and well-controlled clinical studies are required, but the use of a traditional placebo as a control could be problematic in assessing efficacy.
- Use of a blinding questionnaire for both subjects and investigators/raters to evaluate the impact of functional unblinding to minimize bias.
- Clear informed consent to inform subjects of changes in perception, cognition, and judgment that may persist for many hours, as well as increased vulnerability and suggestibility during the treatment session.
- Address mitigation of adverse events or serious risks during the clinical studies and if similar strategies could be implemented post marketing.
Abuse potential assessment
Because many psychedelic drugs are Schedule I controlled substances with high abuse potential, FDA notes that the abuse potential assessment is required to be included in a new drug application submission. The agency notes that sponsors should propose the use of scientifically valid, published investigations to support the abuse potential assessment and refers sponsors to its 2017 guidance on Assessment of Abuse Potential of Drugs before submission of a new drug application. Further, FDA advises on the use of a human abuse potential study, recording of all adverse events, including psychedelic ones, assessment of the potential for physical dependence, and determination of dose range.
Not surprisingly, FDA encourages sponsors to discuss their plans for an abuse potential assessment with FDA early in the IND stage of drug development.
FDA’s draft guidance represents a significant consideration at the federal level for potential regulation of psychedelic drugs. While no more onerous than typical drug development guidance to sponsors, this guidance highlights what FDA views as “unique challenges” posed by psychedelic drugs. Any final guidance issued by FDA on this topic could become the standard that other regulators, including states, rely upon in developing and updating psychedelic drug regulation.
For this and other reasons, sponsors, researchers, state-licensed psychedelic drug providers, and other stakeholders should carefully review and consider commenting on this proposed guidance in light of current practice and experience as well as the medical and therapeutic benefits of psychedelics for treatment of behavioral health conditions.
For more information about these developments, please contact your DLA relationship partner or the authors of this alert.
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