ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis.

The International Conference on Harmonization (ICH) stems from the initiative of three major world partners (Japan, USA, European Community) who composed a mutually accepted body of regulations concerning the safety, quality and efficacy requirements that new medicines have to meet in order to receive market approval. Documents on non-clinical safety pharmacology already composed by this organisation include two guidelines: the S7A adopted in 2000 and, its companion, the S7B guideline, in a draft form since 2001. The S7A guideline deals with general principles and recommendations on safety pharmacology studies designed to protect healthy volunteers and patients from potential drug-induced adverse reactions. The S7B recommends a general non-clinical testing strategy for determining the propensity of non-cardiovascular pharmaceuticals to delay ventricular repolarisation, an effect that at times progresses into life-threatening ventricular arrhythmia. In the most recent version of this document (June 2004), the strategy proposes experimental assays and a critical examination of other pertinent information for applying an 'evidence of risk' label to a compound. Regrettably, the guideline fails to deal satisfactorily with a number of crucial issues such as scoring the evidence of risk and the clinical consequences of such scoring. However, in the latter case, the S7B relies on the new ICH guideline E14 which is currently in preparation. E14 is the clinical counterpart of the S7B guideline which states that non-clinical data are a poor predictor of drug-induced repolarisation delay in humans. The present contribution summarises and assesses salient aspects of the S7A guideline as its founding principles are also applicable to the S7B guideline. The differences in strategies proposed by the various existing drafts of the latter document are critically examined together with some unresolved, crucial problems. The need for extending the objective of the S7B document to characterise the full electrophysiological profile of new pharmaceuticals is argued as this approach would more extensively assess the non-clinical cardiac safety of a drug. Finally, in order to overcome present difficulties in arriving at the definitive version of the S7B guideline, the Expert Working Group could reflect on the introduction of the S7B guideline recommendations in the S7A document, as originally intended, or on postponing the adoption of an harmonized text until the availability of novel scientific data allows solving presently contentious aspects of this and the E14 guidelines.