title: Multiple comparisons of repeated measured response: issues of assessment of prolongation of QT interval in thorough QT trials.
abstract: The primary objective of a thorough QT clinical trial is to demonstrate the lack of QT prolongation induced by the test treatment. The ICH E14 guidance defined drug-induced prolongation of QT interval as evidenced by an upper bound of the 95% one-sided confidence interval around the mean effect on QTc of 10 ms. Furthermore, it defined a negative thorough QT/QTc study as one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms. Conventionally, this objective is tested with the intersection-union test by testing the mean difference between the test treatment and placebo of QTc changes from baseline at each of the matched time points. The multiple-comparison nature of the test leads to higher false positive rate when comparisons are made repeatedly at multiple time points. Many approaches have been proposed in the last 5 years in order to improve the efficiency of the test. In this article, we survey and discuss some of the approaches.
authors.affiliation: DBVI, Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, Food and Drug Adminisration, Silver Spring, Maryland, USA. yi.tsong@fda.hhs.gov
authors.forename: Yi
authors.initials: Y
authors.lastname: Tsong
authors.forename: Jinglin
authors.initials: J
authors.lastname: Zhong
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D015982:Bias; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D016001:Confidence Intervals; D003627:Data Interpretation, Statistical; D004562:Electrocardiography / Q000706:statistics & numerical data; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D015233:Models, Statistical; D015203:Reproducibility of Results; D018401:Sample Size; D013997:Time Factors