QT/QTc prolongation in placebo-treated subjects: a PhRMA collaborative data analysis.

In an ongoing effort to try to understand the variability of QT/QTc data and determine how that variability would affect the design, analysis, and conclusions drawn from data collected in thorough QT/QTc studies, five Pharmaceutical Research and Manufacturers Association (PhRMA) companies recently performed retrospective analyses of placebo and nondrug 12-lead resting electrocardiogram (ECG) data. The data were obtained from five rigorously conducted studies in which the collection and analysis of QT/QTc intervals was a primary objective. Variables that are known to affect variability of QT/QTc intervals, such as adequate resting time before recording the ECGs, food, and consistency of lead placement, had been well controlled in each of the studies.

Performance characteristics for some typical QT study designs under the ICH E-14 guidance.

The International Conference on Harmonization (ICH) guidance for clinical evaluation of QT prolongation (E14) affected drug development by advocating that a thorough QT study (TQT) be conducted during development to assess the QT prolongation liability of a compound. The ICH E14 Statistics Group shortly thereafter recommended that a noninferiority intersection-union test (IUT) be used to exclude a clinically worrisome QT prolongation. Recent analyses have indicated that the IUT might be overly conservative with respect to excluding QT prolongation.