Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative.
Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative.
复制标题
DOI：
10.1161/circulationaha.120.051718
复制
发表时间：
2021-03-09
期刊：
影响因子：
37.8
通讯作者：
Schneeweiss S
中科院分区：
文献类型：
--
作者：
Franklin JM;Patorno E;Desai RJ;Glynn RJ;Martin D;Quinto K;Pawar A;Bessette LG;Lee H;Garry EM;Gautam N;Schneeweiss S
监管机构正在评估使用非干预性真实世界证据（RWE）研究来评估医疗产品的有效性。RCT-DUPLICATE倡议使用结构化过程设计RWE研究，模拟随机对照试验（RCT）并比较结果。在这里，我们报告了前10个模拟试验的结果，评估抗糖尿病或抗血小板药物的心血管结局。我们选择了3个活性对照和7个安慰剂对照的随机对照试验进行复制。使用来自美国商业和医疗保险支付者的患者水平索赔数据，我们实施了纳入/排除标准，选择了主要终点和对照人群，以模拟每个相应的RCT。在试验模拟人群中，我们进行了倾向评分匹配，以控制>120个暴露前混杂因素。在计算风险比（HR）和95%置信区间（CI）之前，前瞻性定义所有研究参数并注册方案。为每次重复试验预先规定了主要分析的成功标准。尽管尝试尽可能接近地模仿RCT设计，但RCT和相应RWE研究人群之间的差异仍然存在。6/10例的监管结论等同。在10项研究中的8项中，RWE模拟实现了HR估计值，该估计值在相应RCT的95% CI内。在9/10例中，符合监管或估计一致性成功标准。在RCT中发现效应估计值的最大差异，其中第二代磺脲类药物用作安慰剂对心血管效应的替代。10次重复中有9次的效应估计值之间的标准化差异<2，这表明在预期的随机变异内存在差异。RCT和RWE结果之间的一致性取决于使用的一致性指标。中期结果表明，选择具有相似适应症和使用模式的活性对照药物治疗可增强RWE的有效性。即使在活性对照药物的背景下，也不能保证RCT和RWE结果之间的一致性，部分原因是试验没有完全模拟。需要更多的试验模拟来了解RWE发现与RCT匹配的频率和背景。
Regulators are evaluating the use of non-interventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT-DUPLICATE initiative uses a structured process to design RWE studies emulating randomized controlled trials (RCTs) and compare results. Here, we report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion/exclusion criteria, selected primary endpoints, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 pre-exposure confounders. All study parameters were prospectively defined and protocols registered before hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. Success criteria for the primary analysis were pre-specified for each replication. Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a HR estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation. Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs.