Data Science Department, Taiho Pharmaceutical Co, Ltd, Tokyo, Japan.
Center for Research and Administration and Support, Biostatistics Division, National Cancer Center, Chiba, Japan.
JAMA Netw Open. 2020 Jun 1;3(6):e208633. doi: 10.1001/jamanetworkopen.2020.8633.
Group sequential designs allow potential early trial termination at the interim analysis, before study completion. Traditional maximum likelihood estimate is commonly used to quantify the treatment effect in group sequential design trials; however, in published clinical trials, a bias-adjusted estimator has rarely been reported.
To emphasize the need for considering overestimation of treatment effect by applying 2 bias-adjusted estimators to previously published, early-terminated oncology clinical trials.
Trials published from 2013 to 2017 were identified by searching MEDLINE and Embase on February 23, 2018. This review was restricted to oncology clinical trials using group sequential designs with a single preplanned interim analysis as well as 2-arm randomized clinical trials that were subsequently stopped for efficacy reasons. Each article was independently reviewed by 3 biostatisticians during text screening, and differences in opinion were resolved by discussion. This report presents the unadjusted hazard ratio (HR) of an experimental arm to a reference arm and 2 bias-adjusted HRs calculated by using the conditional mean-adjusted estimator (CMAE) and weighted CMAE (WCMAE).
In total, 198 abstracts were screened for eligibility, of which, 19 eligible clinical trials were identified as applicable to the bias-adjusted estimators. Unadjusted HRs ranged from 0.203 (95% CI, 0.150-0.276) to 0.71 (95% CI, 0.60-0.84), number of events at the interim analysis from 58 to 540, and information time from 48% to 82%. In each study, the HRs adjusted by CMAE and WCMAE were higher than the unadjusted HR. Bias-adjusted estimates in large trials (243 and 414 events at the interim analysis) were similar to the unadjusted HR. However, in small trials (eg, with 58 events at the interim analysis), bias-adjusted estimates were highly disparate from the unadjusted HR. In trials with large treatment effects (eg, HRs of 0.20 and 0.22), the difference between unadjusted and bias-adjusted HRs was small even though the number of events at the interim analysis was small; larger differences were observed when the unadjusted HR was greater than 0.5.
In this systematic review of oncology clinical trials that were stopped for efficacy at the interim analysis, relatively large differences were noted between the unadjusted and adjusted HRs when the number of events at the interim analysis was small or when the unadjusted HR was close to the boundaries. These findings suggest presenting the 2 bias-adjusted HRs along with the unadjusted HR in the data monitoring committee meeting.
群组序贯设计允许在研究完成之前，在中期分析时提前终止潜在的试验。传统的最大似然估计常用于群组序贯设计试验中量化治疗效果；然而，在已发表的临床试验中，很少有报道使用经过偏差校正的估计量。
强调需要考虑通过应用 2 种偏差校正估计量来校正对治疗效果的高估，这 2 种估计量曾应用于之前发表的、因疗效而提前终止的肿瘤学临床试验中。
2018 年 2 月 23 日，通过在 MEDLINE 和 Embase 上搜索，确定了 2013 年至 2017 年发表的试验。本综述仅限于使用群组序贯设计且仅进行一次预先计划的中期分析的肿瘤学临床试验，以及因疗效原因而随后停止的 2 臂随机临床试验。每位作者均由 3 位生物统计学家在文本筛选过程中进行独立审查，意见分歧通过讨论解决。本报告介绍了实验臂相对于参照臂的未经调整的风险比（HR），以及通过使用条件均值校正估计量（CMAE）和加权 CMAE（WCMAE）计算的 2 种偏差校正 HR。
总共筛选了 198 篇摘要以确定其是否符合纳入标准，其中有 19 项符合纳入标准的临床试验适用于偏差校正估计量。未经调整的 HR 范围为 0.203（95%CI，0.150-0.276）至 0.71（95%CI，0.60-0.84），中期分析时的事件数为 58 至 540，信息时间为 48%至 82%。在每项研究中，CMAE 和 WCMAE 校正后的 HR 均高于未经调整的 HR。大型试验（中期分析时有 243 个和 414 个事件）的偏差校正估计值与未经调整的 HR 相似。然而，在小型试验（例如，中期分析时有 58 个事件）中，偏差校正估计值与未经调整的 HR 存在较大差异。在治疗效果较大的试验（例如 HR 为 0.20 和 0.22）中，即使中期分析时的事件数较小，未经调整和偏差校正 HR 之间的差异也较小；当未经调整的 HR 大于 0.5 时，观察到更大的差异。
在这项对因疗效而提前终止的肿瘤学临床试验的系统综述中，当中期分析时的事件数较少或未经调整的 HR 接近边界时，未经调整和校正后的 HR 之间存在较大差异。这些发现表明，在数据监测委员会会议上，应同时呈现未经调整和 2 种偏差校正后的 HR。
