QTc – "Time-series data"

Oral presentation

A considerable number of drugs have the ability to delay cardiac repolarisation, an effect that is reflected on the surface electrocardiogram (ECG) as prolongation of the QT interval. QT interval prolongation is a clinical surrogate marker for an electrophysiological cardiac environment that favours the development of life threatening cardiac arrhythmias, most commonly a polymorphic ventricular tachycardia denoted "torsade de pointes" (TdP), but possibly other ventricular arrhythmias as well. Interference of drugs with specific cardiac voltage-gated potassium- (e.g. HERG) and – less frequently - sodium-channels has been shown to be the underlying subcellular mechanism of QT interval prolongation and the corresponding proarrhythmia.

Because of the increased awareness on this serious drug safety issue, and as a result of scientific progress and growing preclinical and clinical evidence, regulatory authorities issued from the year 1996 until now various preclinical and clinical guidelines and "discussion papers" with several suggestions how QT prolongation should be properly addressed in development plans of new chemical entities (NCE).

A recent discussion fostered by the US-FDA under the headline "Time series data", attempted to define uniform requirements on structure, content and the electronic format for the submission of ECG safety databases. It appears, however, that the request for just one uniform standard in this regard is no longer pursued by the FDA, as indicated by a preliminary concept paper as of November 15, 2002 ("The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs"). Based on this most recent reference, the purpose of the workshop is to present and to discuss what is currently considered "state-of-the-art" in the evaluation of QT/QTc interval prolongation as well as analysis and presentation of the data. The workshop includes lectures on the in-vitro assessment of drug-induced HERG-channel blockade, the clinical methodology of the QT/QTc assessment, trial design issues, ECG data formats for submission and practical ECG-exercises.

Acknowledgement

We thank F. Haverkamp and J. Maus for their contributions to this abstract.

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