EVALUATING POTENTIAL ABUSE-RELATED ADVERSE EVENTS IN CLINICAL STUDIES OF PSYCHEDELICS AND NOVEL CENTRAL NERVOUS SYSTEM ACTIVE DRUGS TO INFORM LABELING AND SCHEDULING RECOMMENDATIONS: ISSUES, METHODS, AND RECOMMENDATIONS

For CNS-active drugs, conducting an abuse potential assessment (APA) during development is a key component of the overall safety evaluation required by the United States Food and Drug Administration (FDA) and by law per the Controlled Substances Act (CSA) of 1970. The APA is conducted to assist with labeling and scheduling of approved medications, the latter of which serves to protect the public health by controlling the prescribing and use of drugs that may have abuse potential. Assessing the abuse potential of CNS-active drugs requires the evaluation of data from numerous sources, including nonclinical and clinical studies. Per FDA’s 2017 Assessment of Abuse Potential of Drugs guidance document, a full APA includes identifying potential abuse-related adverse events (AEs) in all clinical safety and efficacy studies of CNS-active drugs. Psychedelics and novel drugs that produce ambiguous signals in nonclinical and clinical abuse potential studies provide unique challenges to the APA, and thus particular focus on potential abuse-related AE assessment methods is paramount. The objectives of this presentation will be to review the issues involved with assessing potential abuse-related AEs in clinical studies of novel psychoactive compounds and provide recommendations on methods and strategies for collecting abuse-related AE data. Psychedelics and other novel CNS-active drugs may produce profound psychoactive effects that could be associated with the therapeutic response; regardless of their expectedness, these events should be collected and reported as potential abuse-related AEs. Proper abuse-related AE assessment requires a well-planned prospective, systematic methodology, starting with a prespecified list of AE terms that will be closely monitored as events of special interest. Terms related to euphoria, dissociation/psychosis, intoxication, CNS stimulation or depression, and others specific to the drug type or class should be included. Sponsors should review proposed lists of abuse-related AE terms and plans for collecting abuse-related information with FDA’s Controlled Substance Staff before implementation to ensure alignment with the Agency. Investigators and staff must be trained to identify and record information about abuse-related AEs when they occur so that detailed narratives can be written, and all Investigators in multi-site studies should be adequately and similarly trained to avoid variability in AE collection procedures across sites. Comprehensive narratives provide contextual information and help determine if psychoactive effects of the drug (e.g., hallucinations, euphoria, sedation, emotional lability) appear likely to motivate post-treatment recreational use or are instead aversive and unlikely to be sought out. Since no clear objective criteria for such differentiation exist, collecting detailed contextual information and summarizing potential abuse-related AE data in a clear and thorough manner will better inform the Sponsor and FDA and assist in scheduling and labeling decisions. It is imperative that Sponsors, Investigators, sites, and Contract Research Organizations conducting studies with CNS-active compounds work together in implementing a plan for collecting potential abuse-related AE data as these data are vital components of the APA and scheduling proposal submitted by Sponsors in the New Drug Application and provide the data FDA will need in its CSA scheduling recommendation and labeling development. Such data can also inform FDA’s potential requirement for post-marketing risk evaluation and mitigation strategies (REMS).