A method for assessing and monitoring consistency of nonclinical ECG analysis.

Cardiovascular safety is a key area of concern for new drugs in development, and the collection and analysis of electrocardiograms (ECGs) is a standard and major component of nonclinical testing. Digital data capture technology allows for high-throughput and long-duration ECG collections, resulting in large volumes of data. Consistent analysis of these ECG data is critical for detecting meaningful changes during nonclinical drug development. We developed a method to assess the consistency of nonclinical ECG analysis for a group of analysts over time. Eight­lead ECGs were collected from conscious dogs using Ponemah (v5.2, DSI). Analysts placed Pstart, Qstart, Rpeak, Send, and Tend marks on six waveforms for each animal. The ECG files were randomized and re-marked under blinded conditions 4 to 14 days following initial mark placement. Averages of each parameter measured (RR interval, QRS duration, PR interval, and QT interval) were compiled for each marking session and analyst. A Gage R&R evaluation was completed. Graphical output from the Gage R&R evaluation showed distinct variability on group and individual analyst levels. Differences in inter- and intra-analyst variability (reproducibility and repeatability, respectively) were observed between trained analysts and analysts in training. The Gage R&R method is an effective tool for assessing consistency of digital ECG mark placement at a group level. Furthermore, it is able to identify areas of improvement for individual ECG analysts and to assess ECG analyst consistency during their training period. The assessment results are useful for facilitating discussions on best practices and maintaining consistency of mark placement.

Left thoracotomy surgical approach for chronic instrumentation in dogs and monkeys providing high-quality electrocardiogram signals.

INTRODUCTION: Assessment of cardiovascular parameters, including the electrocardiogram (ECG) is required by the regulatory guidelines. In safety pharmacology studies, this is typically done using chronically implanted radiotelemetry devices in non-rodent species. METHODS: We compared ECG signal quality from ten male beagle dogs and 10 male cynomolgus monkeys with telemetry transmitters implanted using two surgical approaches: i) epicardial ECG lead placement via single incision, left side thoracotomy or ii) subcutaneous ECG lead placement via laparotomy. In addition, epicardial leads and semi-automated scoring were used in combination to detect changes in ECG values caused by moxifloxacin. Telemetry-instrumented male beagle dogs (n=8) and male cynomolgus monkeys (n=8) were given moxifloxacin at 10, 30, or 100 mg/kg (dogs) and 10, 50, or 175 mg/kg (monkeys) as a single dose by oral gavage. RESULTS: ECG signals were of excellent quality with epicardial lead placement, and human activity in the room did not significantly alter signal quality. Administration of moxifloxacin was associated with prolongation of QTc interval, in both dogs and monkeys in a dose-dependent pattern. Dogs given 30 mg/kg and 100 mg/kg, the maximum QTcf interval prolongations were 22 ms (+9%, 8 h postdose) and 60 ms (+24%, 15 h postdose). In monkeys given 50 and 175 mg/kg, the QTcb interval was significantly prolonged from 1 to 6h postdose, and QTcb interval prolongation persisted in monkeys given 175 mg/kg through 19 h postdose. In monkeys given 175 mg/kg, the maximum QTcb interval prolongation was 43 ms (+12.9%, 16 h postdose). DISCUSSION: The present study demonstrated that placing leads directly on the epicardium drastically diminishes signal disruption due to room disturbances and subsequent animal excitement. This novel surgical model demonstrated adequate sensitivity to detect changes in ECG parameters, specifically QTc interval prolongation in both the dog and monkey.