Methodological considerations in the design of trials for safety assessment of new drugs and chemical entities

The heightened safety concern was precipitated by repeated reports on torsade de pointes (TdP) and other arrhythmias occurring in patients treated with an antihistamine drug (terfenadine) [1]. ECG measurements performed during the clinical development process by cardiologists (allegedly using "eyeball/calliper" techniques), have failed to identify drug-related QT prolongation. The false-negative conclusions consequently provided have resulted in a number of serious adverse events and, ultimately in the removal of terfenadine from the US market [2].