对适应性试验的系统调查表明，方法上需要大幅改进。

A systematic survey of adaptive trials shows substantial improvement in methods is needed.

作者信息

Wang Yuning, Yao Minghong, Liu Jiali, Liu Yanmei, Ma Yu, Luo Xiaochao, Mei Fan, Xiang Hunong, Zou Kang, Sun Xin, Li Ling

机构信息

Institute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-based Medicine Center and Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, 610041, China; NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu, 610041, China; China Sichuan Center of Technology Innovation for Real World Data, Chengdu, 610041, China.

出版信息

J Clin Epidemiol. 2024 Mar;167:111257. doi: 10.1016/j.jclinepi.2024.111257. Epub 2024 Jan 11.

DOI:10.1016/j.jclinepi.2024.111257

PMID:38218461

Abstract

OBJECTIVES

To investigate the design, conduct, and analysis of adaptive trials through a systematic survey and provide recommendations for future adaptive trials.

STUDY DESIGN AND SETTING

We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases up to January 2020. We included trials that were self-described as adaptive trials or applied adaptive designs. We identified three frequently used adaptive designs and summarized their methodological details in terms of design, conduct, and analysis. Lastly, we provided recommendations for future adaptive trials.

RESULTS

We included a total of 128 trials in this study. The primary motivations for using adaptive design were to speed up the trials and facilitate decision-making (n = 29, 31.5%). The three most frequently used methods were group sequential design (GSD) (n = 71, 55.5%), adaptive dose-finding design (ADFD) (n = 35, 27.3%), and adaptive randomization design (ARD) (n = 26, 20.3%). The timing and frequency of interim analysis were detailed in three-fourths of the GSD trials (n = 55, 77.5%) and in half of the ADFD trials (n = 19, 54.3%); however, more than half of the ARD trials (n = 15, 57.7%) did not provide this information. Some trials selected a different outcome than the primary outcome for interim analysis (GSD: n = 7, 12.7%; ADFD: n = 8, 27.6%; ARD: n = 7, 50.0%), but the majority of these trials did not provide explicit reasons for this choice (GSD: n = 7, 100.0%; ADFD: n = 7, 87.5%; ARD: n = 5, 71.4%). More than half (n = 76, 59.4%) of trials did not mention the accessibility of supporting documents, and two-thirds (n = 86, 67.2%) did not state the establishment of independent data monitoring committees (IDMCs). Moreover, unplanned adjustments were observed during the conduct of one-sixth adaptive trials (n = 22, 17.2%). Based on our findings, we provide 14 recommendations for improving adaptive trials in the future.

CONCLUSION

Substantial improvements were needed in methods of adaptive trials, particularly in the areas of interim analysis, the establishment of independent data monitoring committees, and unplanned adjustments. In this study, we offer recommendations from both general and specific aspects for researchers to carefully design, conduct, and analyze adaptive trials.

摘要

目的

通过系统调查研究适应性试验的设计、实施及分析情况，并为未来的适应性试验提供建议。

研究设计与设置

我们系统检索了截至2020年1月的MEDLINE、EMBASE、Cochrane对照试验中央注册库和ClinicalTrials.gov数据库。纳入那些自称为适应性试验或采用适应性设计的试验。我们确定了三种常用的适应性设计，并从设计、实施和分析方面总结了它们的方法学细节。最后，我们为未来的适应性试验提供了建议。

结果

本研究共纳入128项试验。采用适应性设计的主要动机是加快试验进程并便于决策（n = 29，31.5%）。三种最常用的方法是成组序贯设计（GSD）（n = 71，55.5%）、适应性剂量探索设计（ADFD）（n = 35，27.3%）和适应性随机化设计（ARD）（n = 26，20.3%）。四分之三的GSD试验（n = 55，77.5%）和一半的ADFD试验（n = 19，54.3%）详细说明了期中分析的时间和频率；然而，超过一半的ARD试验（n = 15，57.7%）未提供此信息。一些试验在期中分析时选择了与主要结局不同的结局（GSD：n = 7，12.7%；ADFD：n = 8，27.6%；ARD：n = 7，50.0%），但这些试验中的大多数未提供对此选择的明确理由（GSD：n = 7，100.0%；ADFD：n = 7，87.5%；ARD：n = 5，71.4%）。超过一半（n = 76，59.4%）的试验未提及支持文件的可获取性，三分之二（n = 86，67.2%）的试验未说明是否设立了独立数据监测委员会（IDMC）。此外，在六分之一的适应性试验实施过程中观察到了计划外调整（n = 22，17.2%）。基于我们的研究结果，我们提出了14条建议以改进未来的适应性试验。