A definitive or thorough phase 1 QT ECG trial as a requirement for drug safety assessment

Prolongation of the QT interval by noncardiac drugs is the commonest cause of drug delays in development, nonapprovals and withdrawal from after marketing. The new regulatory guidance issued by the FDA-Health Canada ECG Concept document, requires irrespective of preclinical cardiac findings a definitive or thorough Phase I trial for all bioactive agents powered to exclude a 5-ms QTc effect (upper confidence interval = 10 ms) since such resolution is usually not possible with the variability inherent in ECG data from the usual trials in the target population. To design a definitive QT trial attention must be given to the sources of QTc duration spontaneous variability. The sources include the proper selection of the sample size, frequency of and method to analyze ECGs, proper correction formula for QT duration, choice of the supratherapeutic dose (required since the trail must be conducted in healthy volunteers rather than the target population) and proper use of a placebo and positive control groups. The positive control group is essential to define the sensitivity of the trial to detect a drug's effect on cardiac repolarization. An approach to interpretation of the resulting ECG data from the trial is provided.