Forging a Path Forward for Substance Abuse Potential Studies With the Cross-Company Abuse Liability Council By Beatrice Setnik, PhD

Many of my colleagues and I are members of the Cross-Company Abuse Liability Council (CCALC), where I have been a co-chair for the past seven years, and a member for 15. The CCALC is a grassroots organization that was founded by several pharmaceutical industry members seeking clarity around the conduct of abuse and dependence potential assessments for novel drugs in development. This was in 2006, at a time when the FDA guidances on these topics had not yet been published. Over time, this group of professionals evolved and grew, having regular stakeholder interactions with the FDA and Controlled Substances staff to discuss requirements for drug developers.

I have spent the better part of my career working to make drugs safer. Having adapted clinical trial methods to establish safe and comfortable stimulus-controlled environments for study participants, and personally being involved in the development of a number of approved abuse-deterrent opioid formulations, I know first-hand how critical abuse and dependence potential evaluations are in assessing the safety risks of novel drug. 

Determining Scheduled Status Under the Controlled Substance Act 

Human abuse potential (HAP) and dependence assessments are required to determine whether a drug needs to be controlled and, if so, under what scheduled class. Drug scheduling in the United States, under the 1970 Controlled Substance Act, places drugs into either unscheduled or scheduled status. 

Scheduled drugs fall under classes I-V, correlated with decreasing abuse potential. Schedule I is reserved for drugs with abuse potential that are not approved for medical use in the United States, whereas Schedule II-V is for drugs with approved medical use. 

The evaluation of abuse potential involves investigating the pharmacological properties of a drug to determine if it produces effects that may become addictive. Physical dependence evaluation examines the manifestation of drug withdrawal symptoms when a drug is abruptly discontinued; both of these paradigms may occur in conjunction or independent of one another. For example, opioids are addictive and cause withdrawal symptoms, but withdrawal may also be noted for drugs without abuse potential (e.g. corticosteroids, beta-blockers, antidepressants). 

Addressing New Challenges in Human Abuse Potential Research

The CCALC has held face-to-face meetings in collaboration with industry, academia, and the FDA once every two to three years since inception, and has provided much of the industry perspective on the practical challenges and solutions to assessing abuse and dependence potential. Many of the meetings have focused on evolving methodology for preclinical and clinical studies. 

During the height of abuse-deterrent opioid development, the group included a focus on in vitro methods and epidemiology concerning opioids. Many of the group’s achievements have included raising critical challenges in study design and data interpretation, and providing feedback and suggestions to draft FDA guidance documents. 

Despite having a final FDA guidance issued in 2017, evolving drug development and treatment modalities continue to prompt important dialogue to adapt existing methods. One example is the recent interest in psychedelics for the treatment of psychiatric disorders, including major depressive disorder. Currently, psychedelics have not been approved for medical use but have recognized abuse potential and, therefore, are classed as Schedule I. 

Once approved, rescheduling will be required, prompting a need for abuse and dependence potential evaluation prior to the submission of a New Drug Application (NDA). Given their unique pharmacological characteristics, many of the existing study methods require further modification and adaptation to control for variables such as limited available positive controls, functional unblinding, and limitations in the use of supratherapeutic doses.

The topic of psychedelics has been, and is currently, an ongoing discussion to determine pragmatic solutions to evaluate their abuse potential, and the CCALC continues to have critical and relevant discussions with industry stakeholders (including the FDA), during CCALC-led dialogue session meetings and through various posters and publications.

Advancing Human Abuse Potential Studies at Altasciences

At Altasciences, I have been able to focus on abuse potential evaluation, and our team has conducted over 60 HAP, abuse-deterrent formulation (ADF), and substance abuse studies since 2008. I have also supported the 8-factor analyses of many new drugs submitted for NDA approvals. The 8-factor analysis is a structured method to evaluate the abuse and physical dependence potential of a novel drug using data collected throughout drug development and any post-marketing data (if available). 

We are the leading organization in conducting substance abuse clinical trials, with principal investigators who collectively bring over 50 years of experience in the field of substance abuse, and with a team of physicians who have extensive expertise in identifying participants for substance abuse studies.

Does your program require substance abuse studies? Get in touch to discover how me and my team can help.  And be sure to check out my three-part podcast series, “The Many Faces of Recreational Drug Use”—a series of candid interviews in which I allow clinical trial participants with a history of personal drug use to speak about their own experiences with recreational use or substance abuse disorder, with empathy and understanding.

About the Author

Beatrice Setnik, PhD, Chief Scientific Officer.

Beatrice Setnik, PhD, joined Altasciences in 2019, and has been working in clinical drug development and abuse potential assessment since 2005. She earned a doctorate in Pharmacology and the Collaborative Program in Neuroscience from the University of Toronto—where she currently holds an appointment as an Adjunct Professor.

Prior to joining Altasciences, Beatrice worked as a research scientist in Toronto, Canada, and was responsible for providing scientific input on various specialty Phase I/II clinical trials—including abuse potential studies for CNS drugs. She has published numerous research articles in internationally recognized peer-reviewed journals and is a peer-reviewer for manuscripts submitted to Pain Medicine and Drug and Alcohol Dependence. 

An active member and participant in several congresses, including the College on Problems of Drug Dependence, Beatrice has been engaged in many aspects of abuse potential assessment, including developing patient-reported outcome instruments and contributing to post-marketing surveillance studies.

In 2024, she was recognized as a PharmaVoice 100 honoree, and named one of the 30 Most Influential People in the Pharma Industry by The Medicine Maker.

^{Published in March 2025.}