Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan
Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan
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多终点临床试验中的多重性调整和样本量计算：日本当前实践的行业调查
DOI：
10.1007/s43441-020-00126-2
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发表时间：
2020
影响因子：
1.5
通讯作者：
Fukimbara Satoru
中科院分区：
文献类型：
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作者：
Sakamaki Kentaro;Morita Yusuke;Iba Katsuhiro;Kamiura Toshifumi;Yoshida Seitaro;Ogawa Naoyuki;Suganami Hideki;Tsuchiya Satoru;Fukimbara Satoru
背景综述了多终点临床试验中的两个问题：（1）多终点的术语、罕见事件与终点的关系、地区间多重性调整的差异;（2）多重性调整和样本量计算的现行做法。本文总结了调查结果的第二个issue.MethodsEligible试验本次调查满足以下条件：（1）确证性3期试验;（2）使用多个主要终点，共同主要终点，关键次要终点（S）或复合终点（S）;（3）纳入日本参与者;（4）在2010年或以后创建的协议。该调查于2017年10月至2017年11月在日本药品制造商协会的成员公司中进行。结果从日本13家公司和其他国家9家公司的78项试验中获得了可接受的答复。Bonferroni程序主要用于具有多个主要终点的临床试验，而考虑终点层次或假设结构的多个检验程序用于具有关键次要终点的临床试验。在样本量计算中，我们可以考虑研究成功的概率，例如在至少一个主要终点比较中具有统计学意义的概率;但是，也考虑了其他概率。本次调查显示，多重性调整和相关性的终点并不总是考虑在样本量calculation.ConclusionsIn多个终点的临床试验，临床重要性时，考虑确定多个测试程序。挑战仍然存在于功效的定义、多个检验程序的考虑以及样本量计算中终点之间的相关性。
BackgroundTwo issues in clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, the relationship between rare events and endpoints, and the differences in multiplicity adjustment between regions, and (2) the current practice on multiplicity adjustment and sample size calculation. This article summarizes the results of the survey on the second issue.MethodsEligible trials for this survey fulfilled the following conditions: (1) confirmatory phase 3 trial; (2) use of multiple primary endpoints, co-primary endpoints, key secondary endpoint(s) or composite endpoint(s); (3) inclusion of Japanese participants; and (4) protocols created in 2010 or later. The survey was conducted at member companies of the Japan Pharmaceutical Manufacturers Association from October 2017 to November 2017.ResultsUseable responses were obtained from 78 trials in 13 companies based in Japan and 9 companies based in other countries. The Bonferroni procedure was mostly used in clinical trials with multiple primary endpoints, while multiple testing procedures that consider a hierarchy of endpoints or a structure of hypotheses were used in clinical trials with key secondary endpoint(s). In sample size calculation, we can consider the probability of study success, such as the probability of statistical significance in at least one comparison of primary endpoints; however, other probabilities were also considered. This survey reveals that multiplicity adjustment and the correlation of endpoints were not always considered in sample size calculation.ConclusionsIn clinical trials with multiple endpoints, clinical importance was considered when determining multiple testing procedures. Challenges remain with the definition of power, the consideration of multiple testing procedures and the correlation between endpoints in sample size calculation.