Abstract
The most recent International Conference on Harmonisation E14 Q&A document states that a separate positive control would not be necessary provided sufficiently high exposures are achieved in the early-phase studies. Realistically, a phase 1 study is unlikely to include a pharmacological positive control, and in cases in which plasma levels of the drug exceeding therapeutic levels are not achieved, the lack of a positive control can constitute a limitation when excluding an effect of regulatory concern. It has been proposed to use the effect of a standardized meal on the estimate of the diurnal time course of QTc to show assay sensitivity. We conducted simulations by subsampling subjects from a 3 different studies and could show that the effect on food on QTc can be reliably prove assay sensitivity for sample sizes as low as 3 × 6 subjects with a power greater than 80%.