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By: Beatrice Setnik, Richard Dart, and Edward Cone

Acrichard-dart_photocedward-cone_photoording tobeatricesetnik_photo the National Survey on Drug Use and Health, an estimated 3.8 million people aged 12 or older in 2015 were current misusers of pain relievers, representing 1.4% of the US population (³12 years of age). With growing concern of prescription opioid abuse, abuse-deterrent formulations have been one approach to mitigate this epidemic. Such formulations are designed to be difficult or aversive to manipulate for the purposes of obtaining more opioid from the product (e.g., defeating an extended release mechanism) or to abuse by an alternate route of administration (e.g., intranasal, intravenous).  Abuse-deterrent opioid formulations vary in nature and mechanism, and approaches can include but are not limited to physical barriers (to prevent extraction of opioid), agonist-antagonist combinations, aversion, and prodrugs.  

Both the Food and Drug Administration  and Health Canada have issued regulatory guidances on the appropriate in vitro, clinical, and post-marketing testing of such formulations (Category studies), in order to demonstrate their ability to deter abuse. Laboratory (in vitro) evaluations (Category 1) require extensive testing of a formulation undergoing various chemical and physical manipulations to extract the opioid and defeat the abuse-deterrent features.

From a clinical perspective, Category 2 and 3 studies refer specifically to pharmacokinetic and human abuse potential studies, respectively. Category 2 studies are typically conducted in healthy volunteer populations and involve pharmacokinetic evaluations of either the intact or manipulated formulation. Category 3 studies involve a population of nondependent recreational opioid users and include pharmacodynamics measures that evaluate the “attractiveness” of a drug by measures that evaluate how much a drug is liked, the willingness to take the drug again, and how much of a “high” or other pleasurable effects it produces. Such studies are subsequently included in product labeling to provide a description of the products abuse-deterrent features.

Category 4 studies refer to epidemiological evaluation of the product’s performance (i.e., ability to deter abuse) in the real world. They are complex, requiring different study methods depending on the type of abuse-deterrent approach taken.

The purpose of such studies is to determine whether a marketed abuse-deterrent opioid results in meaningful reductions in abuse, misuse, and related adverse clinical outcomes, including addiction, overdose, and death in the population. Interpretation of signals across multiple studies will be one of the challenges faced in determining claims of real world abuse deterrence.

Designing Category 1-4 studies requires careful considerations of methodological details including the properties of the formulation itself and how best to replicate conditions of real world abuse in the laboratory and clinic setting. The design considerations and emerging post-marketing data will be reviewed at the upcoming AAPS Annual Meeting and Exposition in Denver. The symposium Abuse Deterrent Formulations: Testing Effectiveness from the Benchtop to the Real World will be held on November 16, 2016, from 9:40 am to 10:25 am. We hope you’ll join us there for a productive conversation.

Beatrice Setnik, Ph.D., has been active in CNS research, clinical drug development, and abuse potential assessment for over 16 years and is currently the VP of Scientific Affairs at INC Research.
Edward Jackson Cone, Ph.D., FTCB, is an employee of Pinney Associates and specializes in the assessment of abuse-deterrent formulations for the pharmaceutical industry. He is considered the lead authority on Food and Drug Administration approval requirements for Category 1 (in vitro laboratory testing) assessments of new pharmaceuticals with abuse-deterrent properties.
Richard C. Dart, M.D., Ph.D., is a physician specializing in emergency medicine and toxicology. Since 1992, he has served as the director of the Rocky Mountain Poison and Drug Center, and he is the executive director of Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System.