BACKGROUND: Mirabegron was approved by the US FDA and EMA in 2012 for the treatment of overactive bladder (OAB). Based on safety observations in the clinical development program, FDA requested PMRs to evaluate the risk of cardiovascular (CV) and cancer events in mirabegron users. EMA requested an NI-PASS to assess CV safety.
OBJECTIVES: To generate rigorous, long-term safety assessments of CV and cancer outcomes among mirabegron users and to submit the results to FDA and, for the CV study, to EMA by June 2019.
METHODS: A PMR / NI-PASS program using electronic health care databases from the US (Humana, Optum) and Europe (UK CPRD, Danish Registries, Swedish Registries). Analyses in each database followed a common core protocol.
RESULTS: Five academic and contract research organizations conducted the studies, analyzing these respective data sources. An independent scientific advisory board (SAB) provided input to the study design and interpretation of study results. Five initial database-specific validation studies were undertaken to assess the performance of algorithms to identify CV and cancer events, and to inform choice of comparator groups for the subsequent two core NI-PASS (CV and cancer). These seven studies (5 validation, 2 core) were registered on the EU electronic Register of Post-Authorization Studies (EU PAS Register). Five site-specific validation study protocols (combining CV and cancer outcomes) and respective interim and final reports were prepared. For the two core studies, the team developed two core protocols, 10 site-specific protocols (separate for CV and cancer outcomes in each site), two statistical analysis plans, two interim reports, two final reports, and 10 site-specific final reports. All these study documents were required for submission to FDA and/or EMA. After 7 years of follow up, the core studies included data from approximately 250,000 OAB medication users (mirabegron and comparators combined), and approximately 3,200 CV cases and 5,800 cancer cases. The target date of June 2019 was met for the cancer study; a 6-month extension was required for the CV study.
CONCLUSIONS: This PMR / NI-PASS program has been a large undertaking requiring long-term commitment from all parties, an effective coordinating center, and extensive scientific interactions across research partners, SAB, Marketing Authorization Holder and regulators. The results (presented elsewhere) have strengthened understanding of the safety profile of mirabegron, and the endeavor has delivered useful learnings related to the design and organization of multidatabase NI-PASS.
