Bayesian Approach of Assay Sensitivity Analysis of Thorough QT Trials

• Activity Number: 68
• Type: Topic Contributed
• Date/Time: Sunday, July 31, 2011 : 4:00 PM to 5:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Yi Tsong*+ and Xiaoyu Dong and Xiao Ding
• Companies: U.S. Food and Drug Administration/CDER and University of Maryland at Baltimore County and U.S. Food and Drug Administration/CDER
• Keywords: Bayesian ; Assay sensitivity ; QTc prongation ; Efficiency

Abstract

One of the analyses recommended in ICH-E14 Guidance after the test drug is shown to be negative in QT interval prolongation is an assay sensitivity analysis of a positive control drug with known effect on QT prolongation. One of the most frequently used positive control drug is moxifloxacin. In order to improve the efficiency of the study and to reduce the number of subject exposing to a positive control, moxifloxacin for example, we explore the potential sample size reduction with a Bayesian approach utilizing the data of historical TQT trials. Using a mixed effect model, we derived the distributions of QTc interval in placebo group and of moxifloxacin-induced prolongation based on fourteen crossover trials and six parallel arm trials. In considering the consistency/inconsistency between historical and current trials, we use a weighted prior distribution. For trials using moxifloxacin as positive control, we use a weighted prior of moxifloxacin QTc prolongation. The relative efficiency of the Bayesian to the frequentist approaches can be shown in large reduction of sample size requirement.