Since its release 10 years ago, ICH Guideline E141 has governed the clinical proarrhythmic cardiac safety regulatory landscape: it has been adopted by the United States Food and Drug Administration (FDA), Health Canada, the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). The goal of premarketing proarrhythmic cardiac safety investigation is to determine to the greatest degree possible whether a non-cardiac drug (a drug for a non-cardiac indication) has the propensity to lead to a rare but potentially fatal polymorphic ventricular dysrhythmia, Torsades de Pointes,2 in patients who may be prescribed the drug should it subsequently receive marketing approval. The guideline addresses the Thorough QT/QTc (TQT) Study, a dedicated trial designed to prospectively exclude an unacceptable degree of drug-induced QTc interval prolongation or to identify the need for more intensive and extensive electrocardiogram (ECG) monitoring in Phase III trials than would usually be the case for a drug in the same class.

J. Rick Turner, PhD, FCMPI,Margaret Britto, PhD, Christopher H. Cabell MD, Dilip Karnad, MD, Snehal Kothari, MD, Jared Schettler, MS