The use of electrocardiograms in clinical trials: a public discussion of the proposed ICH E14 regulatory guidance

Abstract

This meeting, jointly sponsored by the FDA, Drug Information Association and Heart Rhythm Society, examined crucial issues on nonclinical and clinical evaluation of the potential of new drugs to prolong the QT interval of an electrocardiogram (ECG). It gathered ∼ 350 attendees from pharmaceutical industry, academia, core ECG analysis laboratories, regulatory agencies (FDA, European Medicines Agency, Japanese Ministry of Health, Labour and Welfare, and Health Canada) and the International Conference on Harmonisation (ICH). Key issues discussed included the reliability of the S7B guideline strategy, design and usefulness of the ‘thorough QT/QTc study’ recommended by ICH E14 guideline, choice of 5 ms QTc prolongation as a threshold for regulatory concern, ECG reading, and statistical analysis. This report is restricted to the two main presentations dealing with the predictability of nonclinical tests for clinical outcomes – one defending the prognostic value of nonclinical tests and the other, from the FDA, which casts reservations on the predictive value of nonclinical studies. Commentary on the recent finalisation of ICH S7B and E14 guidelines are also provided.