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Abstract:
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The ICH has recently issued a guideline (E14) to the pharmaceutical industry to address QT interval prolongation. The guideline proposed conducting a "Thorough QT/QTc Study (TQS)" and defined two criteria for a "negative TQS". Several methods have been proposed for the sample size calculation of the TQS. However, most methods only considered mean change instead of the maximum change as defined by the guideline, and the impact of the two criteria on the traditional framework of hypothesis testing was not examined. In this work, we examine the impact of these criteria on the hypothesis testing framework, derive the distribution of maximum change, propose a unified approach for the sample size calculation specifically designed to address the two criteria, calculate the sample size based on different assumptions, and compare our results with those using some other approaches.
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