Implications of Individual QT/RR Profiles—Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes

Marek Malik (), Christine Garnett, Katerina Hnatkova, Jose Vicente, Lars Johannesen and Norman Stockbridge
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Marek Malik: National Heart and Lung Institute, Imperial College
Christine Garnett: Center for Drug Evaluation and Research, US Food and Drug Administration
Katerina Hnatkova: National Heart and Lung Institute, Imperial College
Jose Vicente: Center for Drug Evaluation and Research, US Food and Drug Administration
Lars Johannesen: Center for Drug Evaluation and Research, US Food and Drug Administration
Norman Stockbridge: Center for Drug Evaluation and Research, US Food and Drug Administration

Drug Safety, 2019, vol. 42, issue 3, No 7, 415-426

Abstract: Abstract Introduction In studies of drug-induced corrected QT (QTc) changes, fixed universal heart rate (HR) corrections (e.g., the Fridericia correction) are potentially misleading when assessing the effects of drugs that change HR. When data-specific corrections are designed, tests of their validity are needed. The proposed tests include zero correlations between QTc and corresponding RR values in the complete study data (pooling on-treatment and off-treatment interval measurements). Objective To document that this approach is potentially highly misleading, a statistical modeling study was conducted based on the full profiles of QT/RR data of 523 healthy subjects—254 females, mean age 33.5 years. Methods In each of the subjects, 50 baseline QT/RR readings were selected to model baseline data. In repeated experiments, groups of ten and 50 subjects were randomly selected and drug-induced HR increases between 0 and 25 beats per minute combined with QTc changes between − 20 and + 20 ms were modeled. In each experiment, subject-specific as well as population-specific HR corrections were designed so that the QTc interval data were uncorrelated to the corresponding RR interval data. Results The simulation experiments showed that when zero correlations of QTc data with RR data are combined with more than trivial HR increases, the HR corrections are substantially biased and underestimate or fully eliminate any drug-induced QTc interval changes. This result is in full agreement with theoretical considerations of HR correction principles. Conclusions The lack of correlation of QTc versus RR durations including on-treatment data does not prove any validity of HR corrections. Correlations of QTc versus RR in study data pooling on- and off-drug measurements should not be used to prove the appropriateness of HR corrections.

Date: 2019
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DOI: 10.1007/s40264-018-0735-2

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