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Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan

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.

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Figure 1.

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Acknowledgements

The authors would like to thank the JPMA members who responded to this survey.

Funding

The first author’s work was supported in part by Grants-in-Aid for Early-Career Scientists (19K19383) from the Japan Society for the Promotion of Science (JSPS).

Author information

Correspondence to Kentaro Sakamaki.

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The authors declare that there are no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Sakamaki, K., Morita, Y., Iba, K. et al. Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan. Ther Innov Regul Sci (2020). https://doi.org/10.1007/s43441-020-00126-2

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Keywords

  • Multiple endpoints
  • Multiplicity adjustment
  • Sample size calculation
  • Survey of current practices