Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Dutch Medicines Evaluation Board, Utrecht, The Netherlands.
Clin Transl Sci. 2021 Jul;14(4):1566-1577. doi: 10.1111/cts.13027. Epub 2021 May 1.
We aimed to determine whether uncertainties identified by the European Medicines Agency (EMA) were associated with negative relative effectiveness assessments (REAs) and negative overall reimbursement recommendations by national health technology assessment (HTA) agencies. Therefore, we identified all HTA reports from Haute Autorité de Santé (HAS; France), National Institute for Health and Care Excellence (NICE; England/Wales), Scottish Medicine Consortium (SMC; Scotland), and Zorginstituut Nederland (ZIN; The Netherlands) for a cohort of innovative medicines that the EMA had approved in 2009 to 2010 (excluding vaccines). Uncertainty regarding pivotal trial methodology, clinical outcomes, and their clinical relevance were combined to reflect a low, medium, or high level of uncertainty. We assessed associations by calculating risk ratios (RRs) and 95% confidence intervals (CIs), and agreement between REA and overall reimbursement recommendation outcomes. We identified 36 medicines for which 121 reimbursement recommendations had been issued by the HTA agencies between September 2009 and July 2018. High versus low uncertainty was associated with an increased risk for negative REAs and negative overall reimbursement recommendations: RRs 1.9 (95% CI 0.9-3.9) and 1.6 (95% CI 0.7-3.5), respectively, which was supported by further sensitivity analyses. We identified a lack of agreement between 33 (27%) REA and overall reimbursement recommendation outcomes, which were mostly restricted recommendations that followed on negative REAs in case of low or medium uncertainty. In conclusion, high uncertainty identified by the EMA was associated with negative REAs and negative overall reimbursement recommendations. To reduce uncertainty and ultimately facilitate efficient patient access, regulators, HTA agencies, and other stakeholders should discuss how uncertainties should be weighed and addressed early in the drug life cycle of innovative treatments.
我们旨在确定欧洲药品管理局（EMA）确定的不确定性是否与负面相对疗效评估（REA）和国家卫生技术评估（HTA）机构的负面总体报销建议相关。因此，我们确定了 Haute Autorité de Santé（HAS；法国）、国家卫生与保健卓越研究所（NICE；英格兰/威尔士）、苏格兰医学联合会（SMC；苏格兰）和 Zorginstituut Nederland（ZIN；荷兰）为 2009 年至 2010 年 EMA 批准的创新药物队列报告的所有 HTA 报告（不包括疫苗）。关键试验方法、临床结果及其临床相关性的不确定性被结合起来，以反映低、中或高水平的不确定性。我们通过计算风险比（RR）和 95%置信区间（CI）以及 REA 和总体报销建议结果之间的一致性来评估相关性。我们确定了 36 种药物，这些药物在 2009 年 9 月至 2018 年 7 月期间由 HTA 机构发布了 121 项报销建议。高不确定性与负面 REA 和负面总体报销建议的风险增加相关：RR 分别为 1.9（95%CI 0.9-3.9）和 1.6（95%CI 0.7-3.5），这一结果得到了进一步敏感性分析的支持。我们发现 33 项（27%）REA 和总体报销建议结果之间存在不一致，这些结果主要是在低或中不确定性的情况下，针对负面 REA 的限制建议。总之，EMA 确定的高不确定性与负面 REA 和负面总体报销建议相关。为了降低不确定性，并最终促进患者获得高效治疗，监管机构、HTA 机构和其他利益相关者应讨论如何在创新治疗药物的药物生命周期早期权衡和解决不确定性。
