Drugs, QTc interval prolongation and final ICH E14 guideline : an important milestone with challenges ahead.

Regulatory concerns on the ability of an ever-increasing number of non-antiarrhythmic drugs to delay ventricular repolarisation, prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in the adoption of two, internationally harmonised, regulatory guidelines. On 12 May 2005, the International Conference on Harmonisation (ICH) reached an important milestone when it adopted the final texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies by which drugs should be investigated for their potential to induce these effects during their development.ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation. Specifically, it calls for a clinical 'thorough QT/QTc study' (typically conducted in healthy volunteers), which is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc interval prolongation. The E14 recommendations are generally applicable not only to new drugs that have systemic bioavailability but also to approved drugs when a new dose, route of administration or target population that may result in an increased risk is explored. The guideline provides for exceptions when this study may not be required.Recognising the fractious relationship between ICH E14 and ICH S7B, and the persistence of a number of issues that may require clarity and/or the emergence of other new scientific issues in the future, the ICH Steering Committee has formed an Implementation Working Group that is charged with providing clarity on aspects of the guideline that are ambiguous and responding to issues on which the sponsors are uncertain. This paper provides a commentary on some of the challenges that are likely to be faced by the sponsors of drugs during the next few years of application of these two guidelines. The adoption of these guidelines has left a number of questions unanswered and raised some new ones. When in doubt, the sponsor should seek formal regulatory clarity before making key decisions that may impact further development, assessment and approval of a new chemical entity. Although the goal of developing drugs with much lower torsadogenic potential and without inappropriate restriction in the use (or even rejection) of potentially beneficial drugs is within sight, it is questionable whether the risk of drug-induced pro-arrhythmia will be eliminated completely.