Design and Conduct of the Thorough Phase I ECG Trial for New Bioactive Drugs

Abstract

Drug-induced prolongation of the QTc interval, when excessive and in conjunction with the right risk factors, can degenerate into torsades de pointes (TdP), a frequently fatal form of polymorphic ventricular tachycardia. While it is clear that the QT interval on the electrocardiogram (ECG) may not be highly correlated with the risk of TdP, change in the QTc duration is the one relied upon by drug developers and regulatory authorities as the best predictor of a new drug’s cardiac safety. As commented on by Dr. Robert Temple from the Food and Drug Administration (FDA) in an FDA co-sponsored public meeting in Shady Grove, MD, in January 2003, if a drug prolongs the QT interval this effect is the commonest cause of new drug development delays, disapprovals, or removal from the market. Such drugs have come from many different therapeutic groups and from many different, related, and unrelated chemical structures. Some examples include the antihistamine terfenadine; the antibiotic grepafloxacin; the antispasmodic terodiline; the calcium channel blocker lidoflazine; the atypical antipsychotic sertindole; the opioid levomethadyl; and the gastric prokinetic agent cisapride.