BACKGROUND/AIMS There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. METHODS This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). RESULTS The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. CONCLUSION Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.

中文翻译：

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评估观察方法和真实世界数据的使用，以模拟正在进行的随机对照试验。

背景/目标 人们对更好地了解观察研究方法在医疗产品评估和监管决策中的潜力越来越感兴趣。此前，我们使用链接的索赔和电子健康记录数据来模拟两项正在进行的随机对照试验，在发布其结果之前描述每个随机对照试验的人群和结果。在这里，我们的目标是将模拟试验的人群和结果与现已发表的随机对照试验进行比较。方法 本研究比较了参与者的人口统计和临床特征以及模拟试验（使用 OptumLabs 数据仓库的结构化数据）与已发表的 PRONOUNCE 和 GRADE 试验之间的研究结果。首先，我们使用真实世界数据检验了实施已发表的 PRONOUNCE 和 GRADE 试验中包含的基线参与者特征的可行性，并将每个变量分类为可确定、部分可确定或不可确定。其次，我们比较了模拟试验和已发表的随机对照试验的基线患者特征（使用标准化平均差异<0.20确定的一致性）以及主要和次要终点的结果（通过效果估计和统计显着性的方向确定的一致性）。结果 PRONOUNCE 试验招募了 544 名参与者，模拟试验包括 2226 名倾向得分匹配的参与者。在 PRONOUNCE 试验出版物中，32 个基线参与者特征之一被列为 ClinicalTrials.gov 的排除标准，但最终没有被使用。在其余 31 个特征中，使用 OptumLabs 的结构化数据，9 个（29.0%）可确定，11 个（35.5%）可部分确定，10 个（32.2%）不可确定。对于另外一个变量，PRONOUNCE 试验没有提供足够的细节来确定它。在可确定的九个变量中，模拟试验和已发表的随机对照试验中的值有 6 个（66.7%）不一致。模拟试验与已发表的随机对照试验之间的主要终点（从随机化到首次主要不良心血管事件的时间）以及非致命性心肌梗塞和中风的次要终点是一致的。GRADE 试验招募了 5047 名参与者，模拟试验包括 7540 名参与者。在 GRADE 试验出版物中，使用 OptumLabs 的结构化数据，34 名基线参与者特征中的 8 名 (23.5%) 是可确定的，14 名 (41.2%) 是部分可确定的，11 名 (32.4%) 是无法确定的。对于一个变量，GRADE 试验没有提供足够的细节来进行确定。在可确定的 8 个变量中，模拟试验和已发表的随机对照试验中的值有 4 个变量 (50.0%) 不一致。血红蛋白 A1c ≥7.0% 的主要终点时间在模拟试验和已发表的随机对照试验之间基本一致。结论 尽管存在挑战，但在某些重要情况下可以利用观察方法和真实世界数据，以便更及时地评估更加多样化和具有代表性的患者群体中的药物有效性和安全性。