Opioid analgesics are essential to the management of pain in many patients, but they are also associated with potential risks for abuse, overdose, and diversion, concerns which must be considered in the planning and execution of clinical trials studying these controlled substances.
In this paper, we discuss the challenges of conducting clinical trials of controlled substances, specifically Schedule II and III opioid analgesics, and provide recommendations on addressing regulatory and clinical hurdles on the opioid analgesic development pathway.
Sponsors who undertake development of controlled substances or novel agents that may eventually be subject to control are often unaware of the amount of effort and planning involved in conducting these types of clinical trials. Faced with a variety of logistical challenges ranging from appropriate protocol design and site selection to careful management of the drug supply chain and clinical supplies, sponsors must take great care in navigating the regulatory requirements and clinical considerations that govern studies involving controlled substances.
Regulations
Internationally, the International Narcotics Control Board (INCB), a United Nations (UN) entity, monitors enforcement of restrictions on controlled substances. The INCB’s authority is defined by three international UN treaties – the Single Convention on Narcotic Drugs of 1961, the Psychotropic Convention of 1971, and the Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988, which contains provisions related to the control of controlled substance precursors. European Union (EU) Member States that have agreed to abide by the provisions of these treaties each create responsible agencies and enact laws or regulations to implement the requirements of these conventions.
In the U.S., clinical trials involving opioid analgesics, whether as a study drug or a comparator, must adhere to the Controlled Substances Act of 1970 (CSA) and its implementing regulations, which are enforced by the Drug Enforcement Agency (DEA), as well as the requirements of the Federal Food, Drug and Cosmetic Act of 1938. The provisions of the Uniform Controlled Substances Act, which have been passed by most of the 50 states, are similar to the CSA. However, each state has its own legislative, regulatory, and enforcement structure and process. State regulations of controlled substances frequently change, so it is important to be aware of the regulatory nuances of each state in which a trial is conducted.