Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual – yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.

中文翻译：

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用于容纳多个控制臂的逆向选择设计


在随机对照试验中评估新疗法需要与现有疗法进行比较。如果存在几种具有相似益处的现有疗法，则可能难以确定单一的对照方案。针对这种情况，我们提出了一种逆向选择设计，其最简单的形式包括一个实验治疗组和两个对照组。与其在整个试验中都使用两个对照组，不如在早期中期分析中比较对照组，理想情况下是在应计进行时进行比较。此时，性能最差的对照组被丢弃，其余的对照组继续随机化。在研究结束时，我们将治疗与其余对照组进行比较。当现有疗法没有可用或可行的头对头比较时，这种设计需要比传统的三臂设计或两个序贯试验更小的样本量，在这些试验中，比较现有的疗法，并在随后的试验中使用更好的治疗方法作为对照组。这是因为最终比较仅在两个组之间进行，并且因为早期中期分析发生在应计结束之前——但有足够的信息，因此可以选择任何明显更好的对照组。我们通过模拟评估了逆向选择设计的操作特性，并表明它减少了将处理与最佳对照进行比较所需的样本量，控制了 I 型错误，并可能选择正确的控制臂用于最终分析。