title: Multiple comparisons of repeatedly measured response: issues of validation testing in thorough QT/QTc clinical trials.
abstract: In order to validate the results of a thorough QT/QTc clinical trial, ICH E14 recommended that a concurrent positive control treatment be included in the trial. Zhang (2008) recommended that the study results are validated if the positive control establishes assay sensitivity, i.e., has an effect on the mean QT/QTc interval of 5 ms or more. Zhang (2008) and Tsong et al. (2008) discussed the intersection-union test approach and an alternative global average test approach for testing assay sensitivity during the validation process. In this article, we further discuss the multiple comparison issues of the repeatedly measured QT difference between positive control treatment and placebo in the validation test. We describe and discuss several approaches for type I error rate adjustment that are applicable to the situation.
authors.affiliation: Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. yi.tsong@fda.hhs.gov
authors.forename: Yi
authors.initials: Y
authors.lastname: Tsong
authors.forename: Lihan K
authors.initials: LK
authors.lastname: Yan
authors.forename: Jinglin
authors.initials: J
authors.lastname: Zhong
authors.forename: Lei
authors.initials: L
authors.lastname: Nie
authors.forename: Joanne
authors.initials: J
authors.lastname: Zhang
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004562:Electrocardiography / Q000706:statistics & numerical data; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D015233:Models, Statistical; D015990:Placebo Effect; D015203:Reproducibility of Results; D013997:Time Factors