Limitations Reported in Evaluating Effectiveness of Risk Minimization Measures in the EU during 2018-2021: A Qualitative Analysis of Industry-Sponsored Post-Authorization Safety Studies.

Abstract

Marketing-authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post-authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry-sponsored PASS that did not render a conclusion. We conducted a thematic analysis of study limitations extracted from assessment reports and study reports finalized by the Pharmacovigilance Risk Assessment Committee between 2018 and 2021. In 39 (61.0%) of the PASS a conclusion on RMM effectiveness was drawn, where 25 (39.0%) PASS was inconclusive. Most PASS had a cross-sectional design with surveys as primary data sources (73.4% and 65.6% respectively). Four main themes emerged: (i) survey-specific limitations, (ii) limitations specifically related to secondary use of data, (iii) general limitations related to study design, and (iv) limitations not related to study design. In general, frequently reported limitations were survey-related, such as selection bias or information bias. Interestingly, well-known study limitations related to secondary use of data such as missing or misclassification of data were more often presented in inconclusive compared with conclusive PASS. Given that about 40% of PASS did not allow a conclusion on RMM effectiveness, our results suggest prioritization for strategies to mitigate limitations related to the secondary use of data at the protocol stage, for example, through feasibility assessments. Although many databases may have incomplete registration of some variables, feasibility testing prior to conducting a PASS could contribute to meeting study objectives and concluding on RMM effectiveness.