Comparison of conditional bias‐adjusted estimators for interim analysis in clinical trials with survival data
Comparison of conditional bias‐adjusted estimators for interim analysis in clinical trials with survival data
复制标题
临床试验中中期分析的条件偏倚调整估计量与生存数据的比较
作者：
M. Shimura;M. Gosho;A. Hirakawa
分组序贯设计广泛应用于临床试验中，以确定是否应提前终止试验。在此类试验中，最大似然估计通常用于描述实验治疗和参考治疗之间的疗效差异；然而，众所周知，它们表现出有条件和无条件的偏见。已建立的偏差调整估计器包括条件均值调整估计器（CMAE）、条件中值无偏估计器、条件均匀最小方差无偏估计器（CUMVUE）和加权估计器。然而，他们的表现并没有得到充分的调查。在本研究中，我们回顾了这些偏倚调整估计量的特征，并通过模拟研究将临床试验中的条件偏倚、总体偏倚和条件均方误差与生存终点进行比较。还评估了四个估计量的置信区间的覆盖概率。我们发现，当试验在中期分析终止时，CMAE 减少了条件偏差，并显示出相对较小的条件均方误差。条件中值无偏估计量的条件覆盖概率远低于名义值。在未提前终止的试验中，与其他估计量相比，CUMVUE 的偏差较小，条件覆盖概率也可接受。总之，在计划中期分析时，我们建议对不提前终止的试验使用 CUMVUE，对提前终止的试验使用 CMAE。版权所有 © 2017 约翰威利父子有限公司
Group sequential designs are widely used in clinical trials to determine whether a trial should be terminated early. In such trials, maximum likelihood estimates are often used to describe the difference in efficacy between the experimental and reference treatments; however, these are well known for displaying conditional and unconditional biases. Established bias‐adjusted estimators include the conditional mean‐adjusted estimator (CMAE), conditional median unbiased estimator, conditional uniformly minimum variance unbiased estimator (CUMVUE), and weighted estimator. However, their performances have been inadequately investigated. In this study, we review the characteristics of these bias‐adjusted estimators and compare their conditional bias, overall bias, and conditional mean‐squared errors in clinical trials with survival endpoints through simulation studies. The coverage probabilities of the confidence intervals for the four estimators are also evaluated. We find that the CMAE reduced conditional bias and showed relatively small conditional mean‐squared errors when the trials terminated at the interim analysis. The conditional coverage probability of the conditional median unbiased estimator was well below the nominal value. In trials that did not terminate early, the CUMVUE performed with less bias and an acceptable conditional coverage probability than was observed for the other estimators. In conclusion, when planning an interim analysis, we recommend using the CUMVUE for trials that do not terminate early and the CMAE for those that terminate early. Copyright © 2017 John Wiley & Sons, Ltd.
影响因子：
2.1
作者：
Zhong, Hua;Prentice, Ross L.
通讯作者：
Prentice, Ross L.