Principles of assessment of abuse liability: US legal framework and regulatory environment

Identifying the abuse potential of drug products in the premarketing and postmarketing environment has been a critical component in the implementation of drug abuse control laws worldwide. In the US, the Controlled Substances Act of 1970 (CSA) is a comprehensive federal law enacted to prevent the abuse or diversion of substances with abuse liability or addiction potential (for present purposes, these terms are used interchangeably). Under the jurisdiction of the Drug Enforcement Administration, the law applies to the manufacture and distribution of narcotics and other drug substances with potential of abuse. The CSA classifies substances with abuse potential into schedules I-V based on the substance's risk of diversion or abuse, and thus provides a legal framework for the assessment of abuse liability of New Molecular Entities. When the Food and Drug Administration reviews the safety and efficacy of a New Drug Application it also determines whether the drug has potential for abuse, and if so, will begin the process to schedule the drug under the CSA. As the assessment of abuse potential is a critical component of a marketing application, pharmaceutical companies (sponsors) bear the responsibility of generating a comprehensive preclinical and clinical data package for regulators to review and make decisions on labeling and the corresponding postmarketing surveillance. Recent regulatory guidelines adopted in the European Union (EU) (2006), Canada (2007), and USA (2010) provide recommendations to sponsors on preclinical and clinical methodologies for the assessment of abuse potential. This paper reviews the legal framework of the assessment of abuse liability and scheduling of controlled substances in the USA and describes the current global regulatory environment and the challenges that sponsors and regulators face when assessing abuse liability of New Molecular Entities, from the early stages of development through the late stages, review, and approval.