Work

Impact of safety monitoring on error probabilities of binary efficacy outcome analyses in large phase III group sequential trials

Year: 2012

Type: article

Abstract: In phase III clinical trials, some adverse events may not be rare or unexpected and can be considered as a primary measure for safety, particularly in trials of life-threatening conditions, such as stroke or traumatic brain injury. In some clinical areas, efficacy endpoints may be highly correlated with safety endpoints, yet the interim efficacy analyses under group sequential designs usually do not consider safety measures formally in the analyses. Furthermore, safety is often statistically monitored more frequently than efficacy measures. Because early termination of a trial in this situation can be triggered by either efficacy or safety, the impact of safety monitoring on the error probabilities of efficacy analyses may be nontrivial if the original design does not take the multiplicity effect into account. We estimate the actual error probabilities for a bivariate binary efficacy-safety response in large confirmatory group sequential trials. The estimated probabilities are verified by Monte Carlo simulation. Our findings suggest that type I error for efficacy analyses decreases as efficacy-safety correlation or between-group difference in the safety event rate increases. In addition, although power for efficacy is robust to misspecification of the efficacy-safety correlation, it decreases dramatically as between-group difference in the safety event rate increases.

Source: Pharmaceutical Statistics

DOI: 10.1002/pst.1520

Authors: Yanqiu Weng, Wenle Zhao, Yuko Palesch

Institution: Medical University of South Carolina

Language: English

Topic: Statistical Methods in Clinical Trials

Subfield: Statistics and Probability

Field: Mathematics

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute of Neurological Disorders and Stroke