Study Design and Evaluation of Risk Minimization Measures: A Review of Studies Submitted to the European Medicines Agency for Cardiovascular, Endocrinology, and Metabolic Drugs

Introduction: Studies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation.

Methods: Information was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes of interest, the relationship between the RMMs in place and (1) implementation measures, such as clinical knowledge or physicians` compliance to recommendations contained in the RMMs; and (2) occurrence or reduced severity of the adverse drug reactions for which the RMMs were required.

Results: Of 59 eligible studies (24 completed, 35 ongoing), 44 assessed implementation measures, whereas only 15 assessed safety outcomes (1 study as a single endpoint and 14 studies with other endpoints). Fifty-one studies used non-experimental designs and 25 studies employed electronic healthcare databases for analysis. Of the 24 completed studies, 17 were considered satisfactory and supported immediate regulatory decision making, 6 were considered inconclusive and required new evaluations, and 1 was terminated early because new safety restrictions were required, thereby necessitating a new evaluation. Compliance with agreed deadlines was considered acceptable in 21 of 24 completed studies; the average time for a submission was 37 months (standard deviation ± 17), with differences observed by type of data source employed.

Conclusions: Three important gaps in the evaluation plans of RMMs were identified: lack of early feedback on implementation, limited evaluation of safety outcomes, and inability to provide information on the effectiveness from an integrated measurement of different elements of a set of risk minimization tools. More robust evidence is needed to advance regulatory science and support more rapid adjustment of risk minimization strategies as needed.