title: Impact of baseline ECG collection on the planning, analysis and interpretation of 'thorough' QT trials.
abstract: The current guidelines, ICH E14, for the evaluation of non-antiarrhythmic compounds require a 'thorough' QT study (TQT) conducted during clinical development (ICH Guidance for Industry E14, 2005). Owing to the regulatory choice of margin (10 ms), the TQT studies must be conducted to rigorous standards to ensure that variability is minimized. Some of the key sources of variation can be controlled by use of randomization, crossover design, standardization of electrocardiogram (ECG) recording conditions and collection of replicate ECGs at each time point. However, one of the key factors in these studies is the baseline measurement, which if not controlled and consistent across studies could lead to significant misinterpretation. In this article, we examine three types of baseline methods widely used in the TQT studies to derive a change from baseline in QTc (time-matched, time-averaged and pre-dose-averaged baseline). We discuss the impact of the baseline values on the guidance-recommended 'largest time-matched' analyses. Using simulation we have shown the impact of these baseline approaches on the type I error and power for both crossover and parallel group designs. In this article, we show that the power of study decreases as the number of time points tested in TQT study increases. A time-matched baseline method is recommended by several authors (Drug Saf. 2005; 28(2):115-125, Health Canada guidance document: guide for the analysis and review of QT/QTc interval data, 2006) due to the existence of the circadian rhythm in QT. However, the impact of the time-matched baseline method on statistical inference and sample size should be considered carefully during the design of TQT study. The time-averaged baseline had the highest power in comparison with other baseline approaches.
authors.affiliation: Biostatistics and Statistical Reporting (Oncology), Novartis Pharmaceuticals, Florham Park, NJ, USA. Venkat.Sethuraman@novartis.com
authors.forename: Venkat
authors.initials: V
authors.lastname: Sethuraman
authors.forename: Qiankun
authors.initials: Q
authors.lastname: Sun
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003198:Computer Simulation; D004562:Electrocardiography / Q000187:drug effects* / Q000592:standards; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012016:Reference Values; D012107:Research Design / Q000592:standards*; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents