Scientific Publications by FDA Staff

Drug Saf 2013 Jun;36(6):441-53

Baseline Correction in Parallel Thorough QT Studies.

Zhang J, Dang Q, Malik M

BACKGROUND: In parallel thorough QT (TQT) studies, it has been speculated that either baseline correction should be omitted, under the assumption that it only adds noise to the data, or a time-averaged baseline instead of a time-matched baseline correction should be considered in order to reduce the study variability. OBJECTIVE: This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review. DATA AND METHODS: 57 parallel TQT studies conducted between 2002 and 2009 in 5591 healthy volunteers were evaluated. Only moxifloxacin and placebo arms, including their baselines, were considered. The options of using no baseline correction, time-averaged baseline correction, and time-matched baseline correction were examined and compared. RESULTS: QTc values exhibited a diurnal pattern, with longer QTc intervals during sleep preserved when correcting for a time-averaged baseline. Post-dose and baseline QTc values were highly correlated (mean rho = 0.80, range 0.56-0.98 and mean rho = 0.79, range 0.50-0.96 in the placebo and moxifloxacin groups, respectively). The variability of raw QTc values was substantially larger than that of baseline-adjusted QTc values. The difference in the point estimate of QTc differences between moxifloxacin and placebo differed by up to +/-4 ms between the time-averaged and the time-matched baseline corrections. Statistical tests indicate that assumptions of time-averaged baseline and no baseline correction are not appropriate. CONCLUSIONS: Baseline correction in parallel TQT studies leads to more precise QTc estimates. Because of possible inaccuracy introduced by time-averaged baseline correction, the time-matched baseline correction appears to be preferable for a parallel TQT study to both reduce the intrinsic variability due to circadian patterns and obtain more accurate point estimates.