Development of Novel Endpoints for Clinical Trials in Substance Use Disorders Working Group
Chairs: Tanya Ramey, MD, PhD; Martin Mumenthaler, PhD
Upcoming Activity: 21st Annual Scientific Meeting Session, 19-21 February 2025, Washington DC – Development of novel endpoints for clinical trials in substance use disorder
Working Group Meeting, 21st Annual Scientific Meeting, 19-21 February 2025, Washington DC
The Development of Novel Endpoints for Clinical Trials in Substance Use Disorders Working Group will meet to discuss the Commentary/position paper on the current state of the field in light of novel non-abstinence endpoints and statistical considerations, based on our recent meetings and session at the 21st Annual Meeting.
Most Recent Activity: Working Group Meeting, 2024 Autumn Conference, 12-13 September 2024, San Diego, CA – view summary – view slides
Inaugural Meeting: 17 May 2024, Virtual Meeting
Recent regulatory opinion regarding approval when demonstrating successful treatment of SUD has moved away from the requirement to demonstrate complete abstinence to being open to a reduction in substance use. Historically the shift from absolute abstinence to risk reduction position in regulatory realm became apparent when the FDA adopted the ‘percentage of subjects with no heavy drinking days’ as an acceptable endpoint for pharmacotherapy trials in alcohol use disorder (2015 FDA Draft Guidance). Within the Public-Private Partnership (ACTIVE)- Alcohol Clinical Trials Initiative-run trials, the analyses have demonstrated that a 2-level reduction of the WHO risk drinking level is associated with improved functional outcomes and can be used as a clinical trial endpoint (Witkiewitz et al., 2018). Going further, in 2018, the FDA issued a Draft Guidance “Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Medication-Assisted Treatment Guidance for Industry.” In October 2023, the FDA followed with the next Guidance document “Stimulant Use Disorders: Developing Drugs for Treatment”. The FDA also had several meetings involving the public and patient advocacy groups. Our proposal is to focus on such SUDs as Opioid Use Disorder, Stimulant Use Disorder, Cannabis Use Disorder, Polysubstance Use Disorder and other (not excluding alcohol use disorder). The purpose of this Workgroup is to review current thinking on endpoint selection for treating substance abuse and to summarize the strengths, weaknesses, and challenges of established and newly proposed endpoints. Insights from NIDA, NIAAA, clinicians, clinical trialists, and regulators will be discussed and the next steps in endpoint development proposed.
In addiction clinical trials, patient reported outcomes (PRO) have been a standard approach to clinical endpoint measurement, emphasizing attention paid to patient’s own voice and opinion. On the other hand, PRO present challenges in terms of reliability and validity. There are factors that can affect a patient’s response, e.g., memory problems, desire to please others, secondary gain. Most importantly, even if a medication provides a sustained decrease in drug use, this decrease must be reflected in functional improvement valued by patients, their families, and third-party payors to achieve general use and reimbursement. The array of symptoms that may serve as endpoints in clinical trials of SUD therapeutics development goes beyond consumption-focused endpoints. One of such symptoms that is central to addiction is ‘craving.’ Reduction in craving may translate into decreased drug use, improved self-control over its use, and/or a decreased propensity to relapse. There exist multiple scales to measure craving, but there is no unity of thinking as to which and how to best apply those to SUD therapeutics development. We plan to contribute to this topic as one of the key important areas of research.
We intend to develop a white paper summarizing the work of the group for a CNS journal by the end of the first year. In the next 2 years we plan publications on the topic of novel endpoints within a particular Substance Use Disorder category and transdiagnostically. We also plan to propose a future session for consideration for an ISCTM meeting.