Benefit-­Risk Re-­Assessment of Pharmaceuticals: A Retrospective Analysis of Safety-­Related Referral Procedures in the European Union in the Period 2001 -­ 2012

Background: As the benefit-­‐risk profile of a medicinal product is often not fully established at the granting of the Marketing Authorisation (MA), unexpected safety issues may emerge once a medicine is widely used by larger populations. Such safety issues are referred to the European Medicines Agency (EMA) for benefit risk re-­‐ assessment to gain an Opinion on whether the MA should be maintained, changed, suspended or withdrawn across the European Union. There is a call for more transparency and for a switch from implicit towards a well-­‐balanced decision-­‐making procedure. The understanding of the determinants relevant to the re-­‐assessment procedures may help to improve the transparency and may elicit some points for improvement in the process. Objective: The aim of this study is to determine the triggers, outcomes and timing within the product life cycle of referral procedures for both centrally and non-­‐centrally authorised medicines and to investigate the attributes that contribute to the EMA’s Opinion. Methods: A retrospective study of all available documentation issued by the EMA was performed including all safety-­‐related referral procedures concluded during 2001-­‐2012 included. The elapsed time between the year that the first Marketing Authorisation was issued and the year a referral procedure was initiated was determined. Characteristics of the product and safety issue under suspicion were identified and reviewed. Results: A total of 113 safety-­‐related referral procedures were concluded in 2001-­‐2012 included, concerning 106 active ingredients, or 119 product-­‐safety issue combinations. In 9% of the procedures the EMA Opinion recommended withdrawal of the product, in 10% a suspension and in 72% to change the Marketing Authorisation. Only in 6% of the cases the recommendation was to maintain the Marketing Authorisation unchanged. Referral procedures were initiated in all phases of the product life cycle, and in a broad variety of product classes. The Member states are key in notifying safety concerns, triggered most often by spontaneous case reports (31%) or clinical studies (37%). Conclusions: The seriousness of the adverse event under suspicion was the strongest if not the sole determinant in the decision-­‐making procedure. (Relative) effectiveness played a role in only a minority of procedures, and re-­‐assessments due to a safety-­‐ related referral procedure are more a unilateral risk-­‐assessment rather than a benefit-­ risk assessment.