Detection of QTc effects in small studies--implications for replacing the thorough QT study.

Background: ECG assessment with exposure response analysis applied to data from First-in-Man studies has been proposed to replace the thorough QT study for the detection of small QT effects.

Methods: Data from five thorough QT studies, three with moxifloxacin, one study with a drug with a large QTc effect (∼25 ms) and one with ketoconazole with a smaller QT effect (∼8 ms) were used. By subsampling, studies with 6-18 subjects on drug and six on placebo were simulated 1000 times per sample size to assess whether small QTc effects using ICH E14 criteria could be excluded and the impact of sample size on the estimate and variability of the slope of the concentration/QTc relation.

Results: With a sample size of nine or more on drug and six on placebo, the fraction of "false negative studies" was at or below 5% with data from the studies with moxifloxacin and from the drug with a large QTc effect. With the same sample size and no underlying QTc effect (placebo), the fraction of studies in which an effect above 10 ms could be excluded was above 85%. A treatment effect in the linear concentration-effect model resulted in a lower proportion of "false negatives." Sample size had little influence on the average slope estimate of the concentration/QTc relationship.

Conclusions: For drugs with a QTc effect of around 12-14 ms, exposure response analysis applied to First-in-Man studies with careful ECG assessment can be used to replace the through QT study.