title: Statistical consideration in testing for assay sensitivity in a "thorough" QT study.
abstract: The current guidelines, ICH E14, for the evaluation of non-antiarrhythmic compounds recommends a "thorough" QT study (TQT) to be conducted during clinical development. Typically the treatment arms in the TQT study should include study drug at therapeutic and supra-therapeutic doses, placebo and a positive control such as Moxifloxacin (Avelox). The current hypothesis for assay sensitivity involves testing at pre-selected time points, where electrocardiograms (ECG) are obtained, if the mean baseline adjusted differences between positive control and placebo are greater than 5 ms. Since multiple time points are tested, the overall type I error rate should be adjusted using an appropriate multiple comparison procedure. In this article, we consider some recently proposed tests (Zhang, 2008) and explore the use of some standard global test procedures such as O'Brien's ordinary least squares (OLS) and Lauter's standardized sum (SS) tests for testing sensitivity of positive control. The powers of several test procedures are evaluated using simulation. The simulation shows that Zhang's method performs quite well in general but the OLS and SS tests have higher power when the coefficient of variations of QTc intervals have high heterogeneity.
authors.affiliation: Biometrics and Data Management, Novartis Pharmaceuticals, Florham Park, New Jersey, USA. Venkat.Sethuraman@novartis.com
authors.forename: Venkat
authors.initials: V
authors.lastname: Sethuraman
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.forename: Jixian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000890:Anti-Infective Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D001372:Aza Compounds / Q000009:adverse effects*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004562:Electrocardiography / Q000706:statistics & numerical data; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016018:Least-Squares Analysis; D015233:Models, Statistical; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin