Development of safety concerns within RMPs after approval: A cohort study of biologicals

Abstract

Background: Risk management plans (RMPs) form an integral part of the regulatory approval of new drugs in Europe. The RMP details all safety concerns and associated pharmacovigilance activities, facilitating postapproval knowledge increase. The process of knowledge incorporation in the RMP during a medicine's life cycle is currently unknown, and requires study. Aim: To explore the development of RMPs of biologicals after approval, by quantifying changes in safety concerns over time, and analyzing reasons for change. Methods: For a cohort of 17 biologicals (approved 11/'05-12/'09) initial RMPs and subsequent updates until 12/'12 were retrieved from EMA. Information on baseline safety concerns and associated pharmacovigilance activities was extracted from initial RMPs and follow-up information from RMP updates. In RMPs safety concerns are classified as identified risks, potential risks, and missing information (e.g. use in children). Incidence rates of transitions between these three classes, additions after approval and “omissions” (issue resolved or sufficiently studied) were calculated. Results: The median number of safety concerns was 15 (range 7-23) per product at approval: 3 identified and 6 potential risks, and 5 missing information. Median follow-up was 59 months per product, involving a median of 8 RMP updates. During follow-up, 43/251 (3/49 identified risks, 29/99 potential risks, 11/103 missing information) of the concerns changed (0.045/year overall, and 0.014/year, 0.084/year, 0.027/year for respective concerns). Among the 43 changes, 20 concerned omissions (3 identified and 9 potential risks, 8 missing information), resulting from completion of committed studies (9/20) or other studies (3/20), no new data (4/20), or unknown (4/20). 59 concerns were newly added (21 identified and 23 potential risks, 15 missing information), originating from studies (20/59), spontaneous reports (10/59), new indications (9/59), or other/combination (20/59). Conclusion: The observed development of RMPs after approval supports their role in a medicine's life cycle. Five years post-approval, the emphasis seems to be on newly emerged concerns, rather than on changes in baseline concerns.