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Abstract:
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The ICH E14 guidance, implemented in 2005, stipulated that new compounds in clinical development undergo a 'thorough QT/QTc' (TQT) study to detect drug-induced QTc prolongation potentially associated with increased risk of Torsade de Pointes (TdP). Since then, hundreds of TQT studies have been conducted, and no marketed drug has been associated with TdP. However, TQT studies have increasingly been viewed unfavorably due to their low cost-effectiveness. Several researchers have noted that a robust drug concentration versus QTc (C-QTc) modeling assessment in early phase clinical trials should obviate the need for a subsequent TQT study. We contrast two common modeling approaches for C-QTc assessment with a proposed new approach, focusing on single ascending dose alternating panel trials. A real example and stochastic simulations are used to illustrate the high reliability of the proposed modeling approach for deducing whether a given compound is associated with QTc prolongation of regulatory concern.
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