用非随机真实世界证据研究模拟随机临床试验,Circulation

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用非随机真实世界证据研究模拟随机临床试验
Circulation ( IF 35.5 ) Pub Date : 2020-12-17 , DOI: 10.1161/circulationaha.120.051718
Jessica M Franklin ₁ , Elisabetta Patorno ₁ , Rishi J Desai ₁ , Robert J Glynn ₁ , David Martin ₂ , Kenneth Quinto ₂ , Ajinkya Pawar ₁ , Lily G Bessette ₁ , Hemin Lee ₁ , Elizabeth M Garry ₃ , Nileesa Gautam ₁ , Sebastian Schneeweiss ₁

Affiliation

背景：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（使用前瞻性纵向保险索赔重复的随机对照试验：应用流行病学技术）使用结构化过程来设计模拟随机对照试验 (RCT) 的 RWE 研究并比较结果。我们报告了前 10 项试验模拟的结果，评估了抗糖尿病或抗血小板药物的心血管结局。方法：我们选择了 3 项积极对照和 7 项安慰剂对照 RCT 进行复制。使用来自美国商业和医疗保险支付者的患者级别索赔数据，我们实施了纳入和排除标准，选择了主要终点，和比较人群来模仿每个相应的随机对照试验的人群。在模拟试验人群中，我们进行了倾向评分匹配以控制 >120 个暴露前混杂因素。所有研究措施都是前瞻性定义的，并且在计算风险比和 95% CI 之前注册了方案。每次复制都预先指定了主要分析的成功标准。结果：尽管尝试尽可能地模仿 RCT 设计，但 RCT 和相应的 RWE 研究人群之间的差异仍然存在。监管结论在 10 项中有 6 项是等效的。在 10 项研究中的 8 项中，RWE 模拟的风险比估计值在相应 RCT 的 95% CI 范围内。在 10 个中的 9 个中，满足了监管或估计协议的成功标准。在使用第二代磺脲类药物作为安慰剂替代心血管效应的随机对照试验中，发现效应估计值的最大差异。10 次重复中有 9 次在效果估计值之间有一个标准化差异 <2，这表明预期随机变异内的差异。结论：RCT 和 RWE 发现之间的一致性取决于使用的一致性度量。中期研究结果表明，选择具有相似适应症和使用模式的主动比较疗法可以提高 RWE 的有效性。即使在积极比较的情况下，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被准确地模拟。需要更多的试验模拟来了解 RWE 研究结果与 RCT 匹配的频率和情况。注册：URL：https://www。临床试验.gov；唯一标识符：NCT03936049、NCT04215523、NCT04215536、NCT03936010、NCT03936036、NCT03936062、NCT03936023、NCT03648424、NCT04237935、NCT04237922。

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Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies

Background:Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.Methods: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 and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication.Results: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 hazard ratio 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.Conclusions: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.Registration:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.

更新日期：2020-12-17

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