Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings

Abstract

The QT interval from the ECG cannot be measured precisely. The relationship of the QT interval to the RR interval within individuals across time and different RR values, and across individuals eludes complete understanding. Intrinsic beat-to-beat variability in QT interval corrected for heart rate (QTc interval) is not trivial. Therefore, it is difficult to determine a valid and reliable estimate of the time for ventricular repolarization based on the QTc interval. Yet, it must be demonstrated that a drug does not result in an increase in the QTc interval that exceeds 5 ms with some reasonable degree of certainty to be quite confident that the drug does not convey some risk of ventricular tachydysrhythmia due to delayed ventricular repolarization. This demonstration can be a Herculean task due to the magnitude of variability in the QTc interval. Design features and analytical methods that might be used in the thorough QT study to improve the chances of demonstrating the true relationship between a drug and QTc interval are reviewed.

Keywords::

• cardiac safety
• drug development
• International Conference on Harmonization
• ICH E14
• QT
• QTc
• QT study
• thorough QT study
• Torsade de Pointes
• ventricular repolarization

Acknowledgements

The authors would like to thank Corina Loghin, Lu Zhang and Roy Tamura for their valuable comments.

Financial & competing interests disclosure

All authors are full-time employees of Eli Lilly and Company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.