OBJECTIVES: FDA guidance requires that REMS include assessment plans describing how drug manufacturers will evaluate whether each REMS is meeting its stated goals and objectives at specified points in time.  Our primary goal is to highlight aspects of an experience developing and evaluating a RiskMAP for more effective REMS evaluations.  The RiskMAP focused on two endpoints: (1) Conveying key messages about appropriate use of a new medication to three stakeholder groups: Physicians (generalists and specialists), pharmacists, and patients; (2) Assessing the understanding and impact of those messages on co-prescribing, co-dispensing, and concomitant use of contraindicated drugs. METHODS: The multi-year study used:  (1) Pharmacy data (including cash payments) to confirm existence of a suspected risk, identify targets for risk mitigation interventions, and assess changes in risky prescribing over time; (2) Focus groups to obtain baseline insights into stakeholder knowledge and practices; and (3) Multiple telephone surveys to assess knowledge, attitudes and behaviors of the three stakeholder groups at different points in time. RESULTS: Analysis of pharmacy claims data for nearly 300,000 initiators of the new drug confirmed co-prescribing of contraindicated drugs. Small focus groups (general physicians N=9; specialty physicians N=9; chain pharmacists N=10; independent pharmacists N=7; patients N=15) allowed for open-ended discussion of stakeholder practices and generated ideas for survey questions.  Two waves of telephone surveys identified knowledge discrepancies and a rich array of attitudes regarding potentially dangerous concomitant drug use between and within physicians (generalists total N=358; specialists total N=365), pharmacists (total N=779) and patients (total N=216). CONCLUSIONS: Our broad approach facilitated achievement of the desired outcome.  Using complementary modes of assessment provided insight about several layers of behavior, including different prescribers, and prescribers of interacting drugs. Surmounting unanticipated challenges provided helpful insights for future REMS evaluations.