论文标题

在随机临床试验中剂量切换对切换的影响的有效,双重稳定的估计

Efficient, Doubly Robust Estimation of the Effect of Dose Switching for Switchers in a Randomised Clinical Trial

论文作者

Van Lancker, Kelly, Vandebosch, An, Vansteelandt, Stijn

论文摘要

由Janssen Pharmaceuticals进行的临床试验进行的,其中将灵活的给药方案与安慰剂进行了比较,我们评估如果将其切换器(即,切换到更高剂量的患者)如何将其保留在低剂量上。这是为了了解灵活的给药是否可能对他们有益。仅将这些患者的反应与在低剂量下保持低剂量的患者的反应进行比较,因为后者患者通常处于更好的健康状况。由于所考虑的试验中的可用信息太稀缺了,无法实现可靠的调整,因此我们将从同时在同一目标上同时进行的固定剂量试验中传输数据,尽管不是在相同的患者人群中。特别是,我们将提出一个依赖结果模型和研究与患者特征之间关联的倾向得分模型的估计器。如果正确指定了两个模型,则提出的估计器渐近公正(在两个模型定义的模型下,当两个模型正确指定时)。我们表明,使用外部研究结果的提议的方法通常适用于由于违反积极性而无法进行经典混杂调整的研究(例如,以确定性方式进行切换的研究)。蒙特卡洛模拟和对激励研究的应用表明表现足够的表现。

Motivated by a clinical trial conducted by Janssen Pharmaceuticals in which a flexible dosing regimen is compared to placebo, we evaluate how switchers in the treatment arm (i.e., patients who were switched to the higher dose) would have fared had they been kept on the low dose. This in order to understand whether flexible dosing is potentially beneficial for them. Simply comparing these patients' responses with those of patients who stayed on the low dose is unsatisfactory because the latter patients are usually in a better health condition. Because the available information in the considered trial is too scarce to enable a reliable adjustment, we will instead transport data from a fixed dosing trial that has been conducted concurrently on the same target, albeit not in an identical patient population. In particular, we will propose an estimator which relies on an outcome model and a propensity score model for the association between study and patient characteristics. The proposed estimator is asymptotically unbiased if at least one of both models is correctly specified, and efficient (under the model defined by the restrictions on the propensity score) when both models are correctly specified. We show that the proposed method for using results from an external study is generically applicable in studies where a classical confounding adjustment is not possible due to positivity violation (e.g., studies where switching takes place in a deterministic manner). Monte Carlo simulations and application to the motivating study demonstrate adequate performance.

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