title: Statistical issues including design and sample size calculation in thorough QT/QTc studies.
abstract: After several drugs were removed from the market in recent years because of death due to ventricular tachycardia resulting from drug-induced QT prolongation (Khongphatthanayothin et al., 1998; Lasser et al., 2002; Pratt et al., 1994; Wysowski et al., 2001), the ICH Regulatory agencies requested all sponsors of new drugs to conduct a clinical study, named a Thorough QT/QTc (TQT) study, to assess any possible QT prolongation due to the study drug. The final version of the ICH E14 guidance (ICH, 2005) for "The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs" was released in May 2005. The purpose of the ICH E14 guidance (ICH, 2005) is to provide recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The guideline, however, is not specific on several issues. In this paper, we try to address some statistical issues, including study design, primary statistical analysis, assay sensitivity analysis, and the calculation of the sample size for a TQT study.
authors.affiliation: Division of Biometrics VI, Office of Biostatistics/Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA. Joanne.Zhang@fda.hhs.gov
authors.forename: Joanne
authors.initials: J
authors.lastname: Zhang
authors.forename: Stella G
authors.initials: SG
authors.lastname: Machado
mesh_terms: D015507:Drugs, Investigational / Q000009:adverse effects*; D004562:Electrocardiography / Q000706:statistics & numerical data*; D017408:Guidelines as Topic; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007391:International Cooperation; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size
chemical_list: D015507:Drugs, Investigational