The Thorough QT Study: Is Its Demise on the Horizon?

Abstract

In response to concerns regarding the public health implications of drugs being approved that have a proclivity to cause the potentially lethal ventricular arrhythmia torsade de pointes (TdP), there was an international regulatory call to action in 2001. This culminated in the 2005 International Committee on Harmonization (ICH) ICH E-14 guidance “The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.”1,2 Since then, almost all new chemical entities with systemic exposure have undergone a dedicated study to determine the potential of the compound to prolong the QTc interval. A “positive finding” in this resource-intensive study can have a major impact on the remainder of a drug’s development (e.g., extensive ECG assessments during phase 3, potential approval delays, etc.) and, in some cases, has resulted in termination of the development program. The article by Darpo and colleagues3 in this Journal details a prospective study to test the hypothesis that using PK/QTc modeling in a single ascending dose design study, such as is typically performed in the first-in-human study (FIM), will be sufficiently sensitive to detect QTc effects, to be acceptable in lieu of the thorough QT (TQT) study. Reasons to be optimistic that this important effort is likely to be successful include the fact that careful core-lab analyzed ECG assessments in phase 1 is an approach that is already being