Effects of ECG Summarization Methods on the Characterization of Drug‐Induced QT Prolongation – a Demonstration of Need for Standard Methods of ECG Beat Summarization6.3.6

A vital aspect of drug‐development is the pre‐clinical screening of drug‐induced cardiotoxicity. The effect a drug has on the ECG QT‐interval (QTi) is an especially vital screening due to the positive relationship between QT prolongation and arrhythmic events, such as Torsade de Pointes. Consequently, the accurate recording, measurement, and calculation of QTi and heart rate corrected QTi is necessary for cardiotoxicity studies. However, many aspects of these processes are subjective, and techniques vary greatly between researchers and across studies. Examples of subjective aspects of QT prolongation (QTp) characterization include, but are not limited to: the method of heart rate correction for QT (QTc), the number of data points considered, the number of ECG beats or amount of time averaged per data point, and the specific time points evaluated. While the effects of different QTc methods has previously been explored in the literature, the efficiency and accuracy of various ECG summarization methods still warrants further refinement. We evaluated the effects of different methods in order to begin identifying potential industry standards that can minimize the number of data points needed without compromising model prediction. In order to demonstrate the effect different summarization methods have on the identification of drug‐induced QTp, we used Ponemah software to analyze previously collected ECG telemetry data from non‐human primates. The subjects were administered vehicle, three doses of dofetilide, vehicle again, and three doses of quinidine, with a week between each dose. Data was summarized using various methods, including 1, 15, 30, 60 and 120 minute continuous averages as well as 1‐minute averages taken at 1‐hour intervals. We then quantified the effect size of the doses on QTi using restricted maximum likelihood (REML) estimation. Using these estimates, differences in results between the summarization methods were then compared. After finding dramatic differences, we performed power analyses on each summarization method to identify the most accurate and efficient methods. Results suggest that characterization of the dose response and power varied depending on the ECG summarization method used. Using continuous interval averages was more consistent and had greater power than selecting a 1‐minute average at various intervals. Further improvement is achieved by taking pharmacokinetics into account when selecting time intervals. These results confirm the need for careful consideration of ECG summarization methods during study design in order to avoid missing vital data or introducing researcher bias. It also provides evidence to support the recommendation for the introduction of a uniform industry standard for analyses of cardiovascular data. 6.3.6 Support or Funding Information This work was funded in part by a research grant from Eli Lily and Co, Indianapolis, IN