ECGs are in used in clinical trials for many purposes, including inclusion/exclusion decisions (often based on ECG measurements such as QTc), dosing/withholding dosing decisions, detection of drug related adverse events, and detection of cardiac events related to a subject’s underlying cardiac disease.
The method by which ECGs are analyzed during a clinical trial has significant implications for the accuracy of the ECG measurements. Clinical trial sponsors have three options for the analysis of ECG analysis:
- Rely on investigative sites for ECG machine algorithm measurements and interpretations
- Rely on external, local cardiologists for overread of machine algorithm measurements
- Rely on a centralized ECG core lab for ECG processing / overread
It’s important to note that most clinical trials are for non-cardiac drugs, and investigative site personnel are not cardiologists, nor are they experts in ECG analysis. When sites manage ECG readings by themselves, they almost always rely on the paper measurements produced by the ECG machine algorithm. And, unfortunately, it’s quite common to find ECG machine measurements that are falsely low (false negatives) or falsely elevated (false positives).
Even if a local cardiologist performs overread of the site’s machine measurements, the paper-based ECG readings won’t deliver the high levels of precision seen with high-resolution, on-screen measurements.
In contrast, when ECG analysis is performed by a centralized ECG core lab, dedicated ECG specialists conduct the assessments using very high-resolution, on-screen measurements of ECG parameters, delivering the most precise measurements possible.
Assessing the Difference: Comparison Study Results
I’m often asked by pharma teams “How different can centralized ECG measurements be from ECG machine measurements?” And more often than not, they are surprised with my answer, which is based on a comparison we recently ran.
We examined the reliability of ECG machine-reported QTcF values for more than 270,000 consecutive digital ECGs collected during 299 clinical oncology trials, comparing the QTcF values reported by the ECG machine to those measured by a centralized ECG core lab. Our comparison found that 31% of the ECGs had a ≥ 10 ms difference between the ECG machine reported QTcF and the centrally measured QTcF, as shown in Table 1 below. 1
The rates of false negative ECG machine reports, (ECG machine QTcF value below categorical threshold value measured centrally) were 46% and 52% for >470 ms and > 500 ms (Table 2). False negative QTcF results may lead to the inappropriate inclusion of a subject in a trial, may lead to inappropriate dosing of subjects who actually have prolonged QTcF ─ increasing the risk of Torsades de Pointes and sudden death ─ and may jeopardize the safety both of the patient and of the drug development program.
The rates of false positive ECG machine reports (ECG machine QTcF values above the categorical threshold measured centrally) were 45% and 77% for > 470 ms and > 500 ms (Table 3). False negative QTcF results may lead to unnecessary subject exclusions, may lead to unnecessary withholding of doses, and can jeopardize study recruitment as well as study integrity.
Our research demonstrated that ECG machine QTcF measurements have significant rates of false negative and false positive results. When investigators rely on machine -read ECGs, false negatives may result in the inappropriate inclusion of a subject in a trial or inappropriate dosing when the QTcF is actually prolonged, with potentially grave consequences. Conversely, false positive ECG machine readings may result in unnecessary exclusion of subjects from a clinical trial or unnecessary withholding of doses during a trial.
These data suggest that reliance entirely on ECG machine QTcF measurements for clinical trial decisions may have critical consequences for clinical trial integrity as well as for patient safety. Use of centralized ECG analysis may protect the interests of both patients and drug developers.
Discover how centralizing cardiac safety data collection and analysis gives you confidence in ECG accuracy and yields the highest quality data so your compounds have the greatest chance for success. Get the guide here!
Robert Kleiman, MD is the Vice President, Cardiology and Chief Medical Officer at ERT