论文标题
自适应试验设计的点估计II:实际考虑和指导
Point estimation for adaptive trial designs II: practical considerations and guidance
论文作者
论文摘要
在自适应临床试验中,治疗效果的常规终点估计值易于偏见,即一种偏离其真实价值的系统趋势。正如FDA有关自适应设计指南中所述,希望报告减少或消除这种偏见的治疗效果的估计。但是,可能不清楚哪个可用估计器是可取的,并且在实践中使用它们的使用仍然很少。本文是两部分系列中的第二本,该系列研究了自适应试验的点估计中的偏差问题。第一部分提供了方法学回顾,以消除或减少自适应设计的点估计中的潜在偏差。在第二部分中,我们讨论了偏见如何影响标准估计器并评估可能产生的负面影响。我们回顾了当前的报告点估计的实践,并使用真实的自适应试验示例(包括代码)说明了不同估计器的计算,我们将其用作模拟研究的基础。我们表明,尽管这些估计值的平均值可能相似,但对于特定的试验,它们可以显着给出估计的治疗效果的值明显不同。最后,我们为研究人员提出指南,围绕估计器的选择以及自适应设计后的估计报告。在自适应设计的整个生命周期中,应考虑偏见问题,并在统计分析计划中预先指定估算策略。如果有的话,应首选无偏见或减少偏差的估计。
In adaptive clinical trials, the conventional end-of-trial point estimate of a treatment effect is prone to bias, that is, a systematic tendency to deviate from its true value. As stated in recent FDA guidance on adaptive designs, it is desirable to report estimates of treatment effects that reduce or remove this bias. However, it may be unclear which of the available estimators are preferable, and their use remains rare in practice. This paper is the second in a two-part series that studies the issue of bias in point estimation for adaptive trials. Part I provided a methodological review of approaches to remove or reduce the potential bias in point estimation for adaptive designs. In part II, we discuss how bias can affect standard estimators and assess the negative impact this can have. We review current practice for reporting point estimates and illustrate the computation of different estimators using a real adaptive trial example (including code), which we use as a basis for a simulation study. We show that while on average the values of these estimators can be similar, for a particular trial realisation they can give noticeably different values for the estimated treatment effect. Finally, we propose guidelines for researchers around the choice of estimators and the reporting of estimates following an adaptive design. The issue of bias should be considered throughout the whole lifecycle of an adaptive design, with the estimation strategy pre-specified in the statistical analysis plan. When available, unbiased or bias-reduced estimates are to be preferred.