Challenges and lessons learned from a long-term postauthorisation safety study programme of rivaroxaban in Europe.

To describe opportunities and challenges experienced from the four pharmacoepidemiological database studies included in the rivaroxaban post authorisation safety study (PASS) programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements. PASS programme of rivaroxaban carried out as part of the regulatory postapproval commitment to the European Medicines Agency. Clinical practice in Germany, the Netherlands, Sweden and the UK (electronic health records)-undertaken by pharmacoepidemiology research teams using country-specific databases with different coding structures. 355 152 patients prescribed rivaroxaban and 338 199 patients prescribed vitamin K antagonists. Two major challenges that were encountered throughout the lengthy PASS programme were related to: (1) finalising country-tailored study designs before the extent of rivaroxaban uptake was known, and (2) new research questions that arose during the programme (eg, those relating to an evolving prescribing landscape). We advocate the following strategies to help address these major challenges (should they arise in any future PASS): conducting studies based on a common data model that enable the same analytical tools to be applied when using different databases; maintaining early, clear, continuous communication with the regulator (including discussing the potential benefit of studying drug use as a precursor to planning a safety study); consideration of adaptive designs whenever uncertainty exists and following an initial period of data collection; and setting milestones for the review of study objectives.

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Competing interests: GB was an employee of Bayer AB, Sweden, at the time the PASS programme was conducted and has received consultancy fees from Bayer AG, Germany, thereafter as an external consultant. YB, CT, KS-W, MS-G, PV, TD, GN and PA are current employees of Bayer AG, Germany. MH was an employee of Bayer AG, Germany, at the time the PASS programme was conducted. AR and LAGR work for Spanish Centre for Pharmacoepidemiological Research, Spain, which received research funding for the study carried out within the rivaroxaban PASS programme. TS is an employee of Leibniz Institute for Prevention Research and Epidemiology, Germany, which received research funding for the study carried out within the rivaroxaban PASS programme. AV was an employee at BIPS at the time when the study was conducted. RH, ES and KMAS work for PHARMO Institute for Drug Outcomes Research, Netherlands, which received research funding for the study carried out within the rivaroxaban PASS programme. LF works for Friberg Research AB, Sweden, which received research funding for the study carried out within the rivaroxaban PASS programme.