By Beatrice Setnik
Earlier this year, the FDA finalized their guidance related to the abuse liability evaluation of CNS-active drugs. [1] The guidance is intended to assist sponsors of investigational new drugs and applicants for approval of a new drug in evaluating whether the drug has abuse potential.
Included in the FDA guidelines are:
- Key definitions related to abuse potential
- A discussion as to which studies it is recommended are included in the assessment in order to satisfy FDA regulatory requirements
- Timing of when these studies should be initiated in the context of drug development
- General administrative recommendations for obtaining advice from the FDA
- A discussion regarding the abuse potential components of an NDA (new drug application)
The guidance offers key decision points as to whether a novel drug will require further abuse and dependence potential evaluation. The framework for drug scheduling is also discussed. The guidance focuses on CNS-active drugs and does not include considerations for anabolic steroids.
Compared to the draft guidance issued in 2010, the FDA makes more concise recommendations for pre-clinical evaluation of abuse and dependence potential. Sections cover receptor-ligand binding studies, as well as pre-clinical animal studies, including methodological considerations for conducting self-administration, conditioned place preference, drug discrimination, and physical dependence studies.
The guidance also covers the many components of evaluating abuse and dependence potential in the clinical setting. Pharmacokinetic and abuse-related adverse event (AE) data are presented in terms of how these types of data can be informative of abuse and dependence potential.
The FDA guidelines provide a list of AEs that are of special interest in such evaluations. The human abuse potential study is covered in greater methodological detail with novel insights into the statistical analysis of these studies that was not previously covered in the draft guidance.
Studies of cognition and performance, to evaluate a drug’s impairing effects, are mentioned. In addition, the clinical evaluation of physical dependence has been expanded in this version of the guidance, with more information regarding design considerations for such studies.
Lastly, post-marketing and illicit drug abuse data are described, as collected post drug approval. Substantial revisions have been made to the guidance, with new additional studies and details provided that were not previously addressed.
Some of the new revisions will impact the design and statistical analysis of studies moving forward and, in some cases, further discussion of these recommendations is warranted. On Thursday, March 30, 2017, a team of experts will be discussing the guidance and reviewing some important considerations for the recommendations provided by the FDA.
The experts will include Dr. David Heal (RenaSci), Dr. Jack Henningfield (Pinney Associates), and Dr. Beatrice Setnik at Syneos Health™. Copies of the guidance can be downloaded from the FDA at: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm198650.pdf
[1] https://www.fda.gov/downloads/drugs/guidances/ucm198650.pdf
About the Author
Dr. Setnik is Vice President, Clinical Pharmacology, Syneos Health Early Phase. She oversees medical and scientific affairs. Setnik earned her doctorate in pharmacology and the Collaborative Program in Neuroscience from the University of Toronto. As former Senior Director of Clinical Sciences at King Pharmaceuticals and Pfizer, Inc., she led clinical development and life cycle management, including abuse potential evaluation of pain compounds, such as abuse deterrent opioid formulations. Setnik also served as a research scientist at Ventana/Decisionline Clinical Research, where she provided scientific input on clinical trials, including abuse potential studies. Setnik chairs the clinical sub-team within the Cross Company Abuse Liability Consortium and is a member of the College on Problems of Drug Dependence.
