Human Medicines Evaluation Division, Scientific and Regulatory Management Department, European Medicines Agency, 30 Churchill Place, Canary Wharf, London, E14 5EU, UK.
Dutch Medicines Evaluation Board, PO Box 8275, 3503 RG, Utrecht, The Netherlands.
Drug Saf. 2018 Feb;41(2):191-202. doi: 10.1007/s40264-017-0604-4.
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.
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.
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.
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.
制药公司向欧洲药品管理局提交的风险最小化措施（RMM）效果评估研究是上市后监管要求的一部分，代表了涵盖一系列药物和安全性问题的重要数据来源。本研究对这些研究的目标、设计和相关监管结果进行了回顾，并得出了一些结论，这些结论可能有助于未来风险最小化评估的进展。
从风险管理计划、研究方案、临床研究报告和 157 种心血管、内分泌和代谢适应证药物的评估报告中获取信息。我们选择了观察性研究，以 RMM 实施情况和（1）实施措施（如临床知识或医生对 RMM 中建议的遵守情况）；以及（2）RMM 所要求的不良反应的发生或严重程度降低作为感兴趣的结局指标。
在 59 项合格研究中（24 项完成，35 项正在进行），44 项评估了实施措施，而仅有 15 项评估了安全性结局（1 项研究为单一结局，14 项研究有其他结局）。51 项研究采用非实验设计，25 项研究使用电子医疗数据库进行分析。在 24 项已完成的研究中，17 项被认为是令人满意的，支持立即进行监管决策，6 项被认为是不确定的，需要进行新的评估，1 项因需要新的安全性限制而提前终止，因此需要进行新的评估。在 24 项已完成的研究中，有 21 项研究认为符合同意的截止日期，24 项研究的平均提交时间为 37 个月（标准差±17），不同研究采用的数据源类型存在差异。
确定了 RMM 评估计划中的三个重要差距：缺乏对实施情况的早期反馈、对安全性结局评估的局限性，以及无法从一套风险最小化工具的不同元素的综合测量提供有效性信息。需要更有力的证据来推进监管科学，并根据需要更快速地调整风险最小化策略。
