Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013–2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.

最近发生的埃博拉病毒病暴发肯定了对已证明具有疗效的治疗方法的迫切需求。随机对照临床试验仍然是金标准，但在疾病暴发期间，由于道德方面的考虑和充满挑战的现场条件，可能难以进行。在没有随机对照组的情况下，建立对照组的统计模型可能是可行的。这种基于模型的参考对照只有在与不进行治疗的情况下具有与实验组相同的死亡风险时，才是可信的。测试这种反事实假设的一种方法是评估来自不同临床研究的非随机对照组之间是否存在合理的相似性，这可能表明未来的对照组将具有相似的均质性。我们评估了2013-2016年西非埃博拉病毒病爆发期间进行的六项临床研究的相似性。这些研究评估了favipiravir，生物ZMapp，抗疟药amodiaquine或恢复性血浆或恢复性全血的给药。我们比较了这六项研究的非随机对照组，这些对照组包括1147名受埃博拉病毒感染的个体。我们发现相当多的异质性，在进行统计学建模以调整预后变量后，异质性并没有消失。在这六项研究的非随机对照组中，死亡率风险差异很大（31％至66％）。调整基线协变量（年龄，性别和周期阈值，代表病毒载量的模型）的模型未能充分地重新校准这些研究，并显示出异质性仍然存在。