Assessing abuse liability in clinical trials.

In this article, the use of data collected in registration-focused clinical trials to provide information concerning abuse liability of compounds under development is discussed. Registration-focused trials are limited by the small and select sample chosen for study participation and design constraints. However, most compounds under development are first administered to humans during the conduct of registration-focused trials, so this presents an opportunity to collect potentially important information about the effects of drugs in humans. At present, information concerning subjective effects and symptoms associated with drug discontinuation are not collected systematically. Reports are generally considered as adverse events (AEs) and are recorded on the case report forms (CRFs) in the investigators own language. There is generally no rating of drug "liking". The authors suggest strategies that could be implemented in registration-focused clinical trials to improve the information gathered with regard to subjective effects, abuse liability and discontinuation-emergent symptoms. Importantly, there remains much groundwork to be done in developing and validating appropriate assessment instruments and determining "threshold" levels for concern. Under the best of circumstances, registration-focused clinical trials have limited potential to detect abuse liability because of the small number of patients seen and the exclusion of many subjects who might be particularly vulnerable to the abuse of marketed compounds (i.e. individuals with substance use disorders). In cases where there are reasons to suspect that a drug under development has abuse potential, systematic exploration with a series of studies specifically designed to assess abuse potential must be conducted.