Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA.
Clin Trials. 2023 Dec;20(6):689-698. doi: 10.1177/17407745231193137. Epub 2023 Aug 17.
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.
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).
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.
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.
背景/目的：人们越来越关注更好地理解观察性研究方法在医学产品评估和监管决策中的潜力。此前，我们使用链接的索赔和电子健康记录数据来模拟两个正在进行的随机对照试验，在公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，我们的目的是比较模拟试验和现已公布的随机对照试验的人群和结果。
本研究比较了模拟试验和已公布的 PRONOUNCE 和 GRADE 试验参与者的人口统计学和临床特征和研究结果。首先，我们检查了使用 OptumLabs Data Warehouse 的真实数据实施已公布的 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公布的随机对照试验的基线患者特征（使用标准化均数差值 <0.20 确定一致性）和主要和次要终点的结果（通过效果估计和统计意义的方向确定一致性）。
PRONOUNCE 试验纳入了 544 名参与者，模拟试验纳入了 2226 名倾向评分匹配的参与者。在 PRONOUNCE 试验的出版物中，32 个基线参与者特征之一被列为 ClinicalTrials.gov 的排除标准，但最终未被使用。在其余 31 个特征中，9 个（29.0%）是可确定的，11 个（35.5%）是部分可确定的，10 个（32.2%）是不可确定的，使用 OptumLabs 的结构化数据。对于另一个变量，PRONOUNCE 试验没有提供足够的细节来确定其是否存在。在 9 个可确定的变量中，模拟试验和已公布的随机对照试验的值有 6 个（66.7%）不一致。随机分组至首次主要心血管不良事件的时间和次要终点非致死性心肌梗死和中风的主要终点在模拟试验和已公布的随机对照试验之间是一致的。GRADE 试验纳入了 5047 名参与者，模拟试验纳入了 7540 名参与者。在 GRADE 试验的出版物中，34 个基线参与者特征中有 8 个（23.5%）是可确定的，14 个（41.2%）是部分可确定的，11 个（32.4%）是不可确定的，使用 OptumLabs 的结构化数据。对于一个变量，GRADE 试验没有提供足够的细节来确定其是否存在。在 8 个可确定的变量中，模拟试验和已公布的随机对照试验的值有 4 个（50.0%）不一致。主要终点为血红蛋白 A1c≥7.0%的时间在模拟试验和已公布的随机对照试验之间基本一致。
尽管存在挑战，但观察性方法和真实世界的数据可以在某些重要情况下得到利用，以便在更具代表性的患者群体中更及时地评估药物的有效性和安全性。
