Novel Approaches to Assessing Cardiac Safety —Proceedings of a Workshop

Current testing for proarrhythmic potential of drugs relies on determining their effect on the QT interval of the ECG. Because QT prolongation is frequently associated with blockade of the human ether-à-go-go related gene (hERG) channel, the International Conference on Harmonization (ICH) S7B guideline recommends an hERG inhibition assay as the first proxy for identifying such potential risk. Since hERG assays are relatively cheap and rapid, pharmaceutical companies invariably rely on them for early-stage triage of new compounds. The TQT (Thorough QT) study, the backbone of clinical cardiac safety testing under ICH E14, is a blunt instrument with a poor positive predictive value. Candidate compounds suspected or shown to prolong the QT interval may be rejected out of hand or attract restrictive labelling. However, a number of QT-prolonging drugs, such as sertindole or alfuzosin, appear in these tests to be proarrhythmic but do not necessarily lead to arrhythmias. The statistical power of laterphase clinical trials is generally insufficient to predict rare but serious proarrhythmic risks that can have huge public health and economic impacts. Regulatory and postmarketing experiences have shown that most serious adverse effects appear only when a large number of patients have been exposed over long periods of time. In addition, drugs are capable of proarrhythmic mechanisms other than those identified by the hERG channel. Given that the major cost of developing a new drug accrues during the clinical trials phase, there would be a huge economic and clinical benefit to identifying earlier, and more accurately, those drugs that are likely to cause arrhythmias.