Key result
Baseline-adjusted concentration-effect modeling enables unbiased placebo-corrected QTc drug effect predictions.
Why the study?
Concentration-response analysis in thorough QT studies was hampered in parallel group designs because a double difference of QTcF per subject cannot be calculated, prompting evaluation of a novel model based on change from baseline with fixed time and concentration effects.
Does concentration-effect modeling based on change from average baseline with a fixed time effect allow for placebo-corrected prediction of QTc prolongation and assay sensitivity compared to conventional difference-to-placebo analysis?
Does concentration-effect modeling based on change from average baseline with a fixed time effect allow for placebo-corrected prediction of QTc prolongation and assay sensitivity compared to conventional difference-to-placebo analysis?
This methodological study demonstrates a concentration-effect model based on change from baseline with a fixed time effect to evaluate drug-induced QTc prolongation and assay sensitivity, making concentration-response analysis applicable to parallel-group thorough QT studies.
Answers are grounded in this paper and cite their sources.
Concentration-response analysis may refine QTc assessment; leaves open its role replacing time-matched methods in regulatory submissions.
As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time-matched difference between (baseline corrected) QTcF or QTcI under the supra-therapeutic dose and placebo. A study is considered negative, if the two-sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration-response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo-corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration-response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect.
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Ferber et al. (2014) studied QTc interval prolongation assessment in thorough QT studies. Concentration-effect modeling based on change from average baseline with fixed time and concentration effects vs. Conventional concentration-response analysis based on the difference to placebo was evaluated on Placebo-corrected prediction of drug effect on QTc (QTcF or QTcI) and estimate of circadian time course for assay sensitivity. Concentration-effect modeling based on change from baseline with fixed time and concentration effects enables placebo-corrected QTc drug effect prediction with an unbiased standard error.
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