Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Cu
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Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan Kentaro Sakamaki1,2 · Yusuke Morita3,4 · Katsuhiro Iba3,5 · Toshifumi Kamiura3,6 · Seitaro Yoshida3,7 · Naoyuki Ogawa3,8 · Hideki Suganami3,9 · Satoru Tsuchiya3,10 · Satoru Fukimbara3,11 Received: 21 February 2019 / Accepted: 24 January 2020 © The Drug Information Association, Inc 2020
Abstract Background Two 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. Methods Eligible 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. Results Useable 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. Conclusions In 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. Keywords Multiple endpoints · Multiplicity adjustment · Sample size calculation · Survey of current practices
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Data Science Department, Nippon Shinyaku Co., Ltd., Kyoto, Japan
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Clinical Information & Intelligence Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
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Center for Data Science, Yokohama City University, Yokohama, Japan
Clinical Development Department, Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan
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Data Science Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan
Clinical Data Science Department, Kowa Company, Ltd., Tokyo, Japan
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Data Science, Sumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan
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Data Science, Ono Pharmaceut
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