A New Approach to Evaluate the Drug Effect on the QTc Interval in Thorough QT/QTc Study

• Activity Number: 246
• Type: Contributed
• Date/Time: Monday, July 30, 2012 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Shui He*+
• Keywords: QT prolongation ; order statistics ; thorough QT/QTc study

Abstract

QT interval analysis has received more and more attention from regulatory and industry. It is recognized in clinical practice that QT prolongation related to drug-induced cardiac repolarization can potentially lead to life threatening arrhythmia. A thorough QT/QTc study for potential drug-induced cardiotoxicity is recommended by regulatory and ICH for the new drug development. Currently, the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval is tested against pre-specified constant, 10ms. It is well known that the current approach is very conservative and the maximum of observed mean treatment differences is not an unbiased estimate of the maximum of the true mean differences, but an estimate of the maximal order statistics from a multivariate distribution with the true mean differences. Several existing approaches have been proposed to improve the estimate. However, they work well in some scenarios and not as well in other scenarios where the adjustment is needed most. A new method is proposed by utilizing the order statistics of correlated non-i.i.d. random variables. The simulations are performed.