Sequential parallel comparison design (SPCD) clinical trials aim to adjust active treatment effect estimates for placebo response to minimize the impact of placebo responders on the estimates. This is potentially accomplished using a two stage design by measuring treatment effects among all participants during the first stage, then classifying some placebo arm participants as placebo non-responders who will be re-randomized in the second stage. In this paper, we use causal inference tools to clarify under what assumptions treatment effects can be identified in SPCD trials and what effects the conventional estimators target at each stage of the SPCD trial. We further illustrate the highly influential impact of placebo response misclassification on the second stage estimate. We conclude that the conventional SPCD estimators do not target meaningful treatment effects.

翻译：序贯平行对照设计临床试验旨在通过调整安慰剂反应对活性治疗效应估计的影响，以最小化安慰剂反应者对估计值的影响。这通常通过两阶段设计实现：第一阶段测量所有参与者的治疗效果，然后将安慰剂组部分参与者分类为安慰剂无反应者，在第二阶段进行重新随机化。本文运用因果推断工具，阐明了在何种假设下序贯平行对照设计试验中的处理效应可被识别，以及传统估计量在试验各阶段所针对的效应目标。我们进一步说明了安慰剂反应误分类对第二阶段估计值的显著影响。最终得出结论：传统序贯平行对照设计估计量并未针对有意义的处理效应。