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T-27: MADDERS: A Systematic Approach to Meeting Regulatory Requirements for Evaluating Abuse-Related Events in Clinical Trials

Poster Presenter

Ryan Lanier

Associate Director, Consulting
Analgesic Solutions
United States

Objectives

To review the development and implementation of a system (MADDERS) designed to prospectively identify, record, and classify abuse-related events in clinical trials to meet FDA regulatory requirements for the assessment of abuse potential of central nervous system (CNS)-active drugs.

ORAL PRESENTATION: 1:40PM

Method

Development of the system included identifying triggering events suggestive of possible abuse consisting of adverse events (AEs) or drug accountability discrepancies (DADs), development and testing of an event adjudication and classification process, and clinical trial implementation.

Results

In initial testing, triggering events were shown to have content validity, and consist of AEs such as drug abuse, misuse, diversion, and euphoria, and DADs such as missing pills and tampering. Supplemental AE and DAD forms were developed to collect additional contextual and patient-reported information about triggering events, which are classified into event categories based on definitions set forth by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, an FDA initiative. The forms were designed to be completed by trained staff as a guided interview, and were shown to be easy to use, the questions clear, and the information sufficient for classifying triggering events. Adjudication of mock cases by a panel of independent drug abuse experts showed a high level of consistency in classifying events. Following feasibility testing, the system was successfully implemented in multiple Phase 3 clinical trials including two different cannabinoids for pain and seizure disorders, and a new chemical entity opioid for chronic pain. Results showed a high level of agreement in event classifications between study staff and the expert panel. Adjudicators were able to reliably and prospectively classify events as Abuse, Misuse, Therapeutic Error, Diversion, Overdose, Tampering, Withdrawal, and Addiction-related Behavior. A key finding was that MADDERS adjudicators were able to effectively differentiate between commonly confused terms such as Misuse (intentional therapeutic use of a drug product in an inappropriate way) and Abuse (intentional, nontherapeutic use of a drug product or substance, even once, for the purpose of achieving a desirable psychological or physiological effect) and apply them appropriately. Review of the literature found that MADDERS results from these clinical trials were compatible with previously published findings on the abuse potential of these compounds.

Conclusion

In early testing, MADDERS was found to be a feasible approach with initial validity for prospectively identifying, classifying, and quantifying potentially abuse-related events in patient populations during clinical trials. The system has now been successfully implemented in at least 10 Phase 3 multicenter clinical trials and 1 Phase 4 post-marketing trial involving adult and pediatric patients, testing analgesic and non-analgesic CNS-active medications. Assessing abuse potential in humans includes identifying potentially abuse-related events in clinical trials and reporting those events to FDA to assist in approval, labeling, and scheduling recommendations. Per FDA guidance, abuse-related events from clinical trials should be “systematically categorized, tabulated, and analyzed,” however, there are currently no validated tools to assess drug abuse potential during Phase 2 through 4 studies. Customary methods of assessing abuse potential in clinical trials are flawed and can cause misclassification of events. Additionally, many of these tools do not take into consideration drug use discrepancies (e.g., administration of higher dose than prescribed, tampering with medication or dispensing device, difference in expected amount of unused medication in patient’s possession, etc.), and do not use standardized definitions of abuse and misuse related events. An initial working-group meeting convened by ACTTION and FDA led to the consensus classification system and terminology that MADDERS is based upon, and a second meeting acknowledged that MADDERS is the only available system that meets FDA needs for assessment of abuse-related events in clinical trials. Thus, MADDERS was created based on and following recommendations made by ACTTION and FDA and is intended to assist sponsors in meeting their regulatory requirements for assessing the abuse potential of drugs in clinical development. Continued refinement of the system and additional validation work are ongoing.