title: Validation testing in thorough QT/QTc clinical trials.
abstract: In order to validate the results of a thorough QT/QTc (the duration of depolarization and repolarization of ventricles or the duration corrected for heart rate) clinical trial, ICH E14 recommended to include a concurrent positive control treatment in the trial. It further recommended that validation is achieved if the positive control has an effect on the mean QT/QTc interval of about 5 ms. Zhang (2008) discussed the intersection-union test approach for testing the validation hypotheses and an alternative global average test approach. In this article, we further discuss the difference and relationship of the two sets of hypotheses and the difference in the efficiencies of the two approaches. We conclude that validation can be achieved if either one test rejects the null hypotheses without inflating the family-wise Type I error rate. However, using both approaches may improve the efficiency in validation assessment.
authors.affiliation: Office of Biostatistics/Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, USA. yi.tsong@cder.hhs.gov
authors.forename: Yi
authors.initials: Y
authors.lastname: Tsong
authors.forename: Jinglin
authors.initials: J
authors.lastname: Zhong
authors.forename: Wen Jen
authors.initials: WJ
authors.lastname: Chen
mesh_terms: D000890:Anti-Infective Agents / Q000009:adverse effects; D001372:Aza Compounds / Q000009:adverse effects; D035061:Control Groups; D004562:Electrocardiography / Q000592:standards*; D024841:Fluoroquinolones; D017408:Guidelines as Topic; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology; D000077266:Moxifloxacin; D010919:Placebos; D011804:Quinolines / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D054928:Validation Studies as Topic
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D010919:Placebos; D011804:Quinolines; D000077266:Moxifloxacin