Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations

Abstract

As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.

Keywords: Classification; Clinical trials; Prescription drug abuse; Prescription drug misuse; Systematic review.

Figure 1

Recommended MARE classification system For each event, one event category would be chosen, the severity of the event could be recorded, the dosage form and method of administration would be identified, and any supplemental designations providing further information about the event would be selected. Dosage forms: OS: Solid dosage form designed to be swallowed intact; TM: Solid dosage form designed for administration through oral mucosa (e.g., buccal, sublingual); TD: Solid dosage form designed for transdermal administration (e.g., patch); SS: Semisolid dosage form designed for transdermal administration (e.g., gel, ointment, lotion, cream); OL: Liquid dosage form designed for administration by swallowing (e.g., solutions, suspensions, emulsions); NL: Liquid dosage form designed for administration intranasally (e.g., metered sprays); NA: Aerosol dosage form designed for administration intranasally; PI: Inhalants or sprays designed for pulmonary administration; UNK: Dosage form unknown Administration method: Oral; Sublingual; Nasal insufflation (i.e., “snorted”); Vaporized and inhaled; Injected; Unknown Definitions of MARE categories: Misuse-event Indicator: Any intentional therapeutic use of a drug product in an inappropriate way. Misuse specifically excludes those events that meet the definition of an Abuse-event Indicator. Abuse-event Indicator: Any intentional, non-therapeutic use of a drug product or substance, even once, for the purpose of achieving a desirable psychological or physiological effect. Suicide-related Event: A self-injurious or potentially self-injurious behavior associated with at least some intent to die or that resulted in death. Evidence that the individual intended to kill him/herself, at least to some degree, can be explicit or inferred from the behavior or circumstance. A suicide attempt may or may not result in actual injury (adapted from Posner et al, 2007). Therapeutic Error: A mistake in a therapeutic regimen. None of the Above: Sufficient information exists to determine that none of the previous categories apply. Unknown: Insufficient information exists to determine which category applies. Definitions of supplemental designations: Tampering: The inappropriate manipulation of a drug product. Withdrawal: Symptoms or signs due to the decline in blood concentration of a drug substance (eg, after dose reduction, at the end of a dosing interval, after discontinuing treatment) or due to the administration of an antagonist. Addiction-related indicator: Behavioral, cognitive, and physiological phenomena that may develop after exposure to a substance (typically on a repeated basis), which may include a strong desire to take the drug, difficulties in controlling drug use, persistent drug use despite harmful consequences, intractable and distracting thoughts about the drug, or placing a higher priority on drug use than other activities and obligations. Diversion: Any intentional act that results in transferring a drug product from lawful to unlawful distribution or possession. Diversion can occur with all categories except Therapeutic Error. Overdose: Any act that results in drug exposure exceeding that which is generally recommended or medically accepted.