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

Lumanity and PHARMO are collaborating to deliver long-term post-authorisation safety studies (PASS).

Rivaroxaban is a factor Xa inhibitor with several cardiovascular indications. Between 2011 and 2020, PHARMO, Bayer and partners conducted a large rivaroxaban PASS programme comprising eight observational studies as part of the regulatory post-approval commitment to the European Medicines Agency (EMA).[1]

This unique PASS programme exemplifies an approach whereby the prescription of a medication and its safety and effectiveness can be evaluated in a single initiative, covering all indications to be assessed, and by using well-established and validated population-based European databases already familiar to researchers, industry, and regulators. Databases included in this PASS programme are the PHARMO Data Network in the Netherlands, BIPS in Germany, and electronic health records from UK and Sweden.

By using a cohort study design in the database studies, we were able to evaluate real-world patterns of rivaroxaban use including episode of use between treatment interruptions, and by performing nested case–control analyses, we were able to evaluate its safety and effectiveness, including by duration and recency of use. In the publication, PHARMO and its research collaborators describe opportunities and challenges experienced from the four pharmacoepidemiologic database studies included in the programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements.

Best practices identified include:

• • Maintain early, clear, continuous, and open communication with the regulator through the seeking of their scientific advice. Take a stepwise approach starting with a drug utilisation study to inform the regulator about the feasibility of a safety study for this indication, formulating potential scenarios, based on different assumptions of projected sample sizes and timelines, to inform when would sufficient sample size be obtained for a safety study

• • Set milestones for study review following an initial period of data collection including key discussions between the regulator and the marketing authorization holder to discuss additional study questions arising after PASS initiation and feedback on programme direction. Identify opportunities for premature study cessation will be considered whenever clinically justified to enable earlier regulatory review and dissemination of results

• • Allow adaptation of study protocols to enable the inclusion of additional, or changes in, study objectives as well as modifications of study designs to reflect evolving prescription behaviours. Maintain flexibility to address new and emerging safety questions using post-hoc analyses to address e.g., data gaps from Risk Management Plans concerning specific patient subgroups or changes in standard of care that impact comparability of populations

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[1] Brobert G, Ruigomez A, Schink T, et al Challenges and lessons learned from a long-term post-authorisation safety study programme of rivaroxaban in Europe. BMJ Open 2024;14:e081348. doi: 10.1136/bmjopen-2023-081348