Design, Conduct and Analysis of Thorough QT Studies

Torsades de Pointes (TdP) is a type of polymorphic ventricular tachycardia that can result in fainting and death. While there are genetic causes for TdP, such as ion channel mutations, drug-induced TdP can occur, an event that first gained prominence with the interaction between terfenadine and ketoconazole. While TdP itself cannot be studied in clinical trials due to its low rate of incidence, a biomarker for TdP is prolongation of the QT interval on an ECG. Today, almost every drug is expected to be evaluated for its potential to prolong QT interval. This chapter discusses measurement of QT intervals in clinical trials, the design and analysis of “thorough” QT studies, including the intersection–union test and concentration-QT modeling, as well as practical matters related to the International Conference on Harmonisation’s E14 guidance.