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.

Electrocardiographic identification of drug-induced QT prolongation: assessment by different recording and measurement methods.

BACKGROUND: Careful assessment of QT interval prolongation is required before novel drugs are approved by regulatory authorities. The choice of the most appropriate method of electrocardiogram (ECG) acquisition and QT/RR interval measurement in clinical trials requires better understanding of the differences among currently available approaches. This study compared standard and Holter-derived 12-lead ECGs for utility in detecting sotalol-induced QT/QTc and RR changes. Manual methods (digitizing pad and digital on-screen calipers) were compared for precision of QT and RR interval measurement. METHODS AND RESULTS: Sixteen hundred pairs of serial 12-lead digital ECGs were recorded simultaneously by standard resting ECG device and by continuous 12-lead digital Holter over 3 days in 39 healthy male and female volunteers. No therapy was given on the 1st day followed by 160 mg and 320 mg of sotalol on the 2nd and 3rd day, respectively. Holter-derived and standard ECGs produced nearly identical sotalol-induced QT/QTc and RR changes from baseline, as did the manual digipad and on-screen caliper measurements. The variability of on-screen QT measurement in this study was greater than that of digipad. CONCLUSIONS: Digital 12-lead Holter and standard 12-lead ECG recorders, as well as the manual digitizing pad and digital on-screen calipers, are of equal utility for the assessment of drug-induced change from baseline in QT and RR interval, although the variability of the on-screen method in this study was greater than of the digipad.