Testing for positive control activity in a thorough QTc study.
The ICH E14 guidance (ICH, 2005) recommend that a concurrent positive control should be included in a thorough QTc clinical trial to validate the study. The ICH E14 guidance (ICH, 2005) state that "The positive control should have an effect on the mean QTc interval of about 5 ms (i.e., an effect that is close to the QTc effect that represents the threshold of regulatory concern, around 5 ms)". This task may be carried out through some statistical tests. The current practice is to test at each time point where QT measurements are collected. This method is usually not efficient. In this article, I discuss two types of statistical procedures. The first one is a local statistical test to make a time-point-specific claim, i.e., to claim a mild QTc effect due to the positive control at some specific time points. A different approach, named as a global test, is also proposed, to make a general claim that the mean difference of the positive control and placebo after baseline adjustment will be about 5 ms without specifying at which time points. An example will be used to illustrate how to apply the two procedures. How to best allocate sample size in a parallel QTc study is also discussed in this paper.
Zhang
Joanne
J
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
D035061:Control Groups; D004562:Electrocardiography / Q000592:standards*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; 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*