The ICH E14 Guidance for Industry requires every new drug to be tested for QT prolongation to predict the risk of Torsades de Pointes (TdP), a lethal arrhythmia. Digital data and ECG waveforms are required for submission, and centralized ECG analysis is recommended (whether assessing QTc in a Thorough QT study or in Phase 1 with concentration effect modelling now allowed under recent ICH E14 revisions).
Trial sponsors who still rely on paper-based ECGs and site-based analysis may be jeopardizing data quality, which could extend study timelines, increase costs and, most importantly, place patients, trials and compounds at risk. There are significant differences between paper-based and centralized ECG data collection and analysis, so it’s critical that sponsors understand how their selected method could make the difference between success and failure as they develop new medical products.
PROTECT THE COMPOUND
1. Nearly 80% of the time, cardiologists and other physicians cannot recognize a long QT when they see one.
How proficient are site-based physicians at reading ECGs? A study of more than 900 physicians showed that while QT experts correctly recognized a long QT 96% of the time, cardiologists and other physicians only got it right 22% and 21% of the time, respectively (Figure 1).1 Morphology issues are also challenging to identify. By taking this gamble with data quality, sponsors may face inaccurate QT readings, which could put their compounds at risk of termination.
2. Paper-based ECG screening errors can later result in false positive QT signals.
If a site under-measures QTc at baseline, but the patient’s QTc is correctly measured later on in the trial, the compound will appear to be responsible for an increase in QTc. At a minimum, this may require further investigation and explanation to regulators. Worse, a false positive signal for drug-induced QT prolongation could lead to trial delays or termination of the compound.
IMPROVE PATIENT ENROLLMENT AND STUDY EFFICIENCIES
3. Site-managed ECG measurements can result in inaccurate patient enrollment.
A 2015 analysis of 270,000 ECGs from multiple oncology studies concluded that as many as 45% of the patients excluded due to prolonged QTc were actually eligible for enrollment when correctly evaluated through centralized ECG measurement.2 Similar data trends have been documented in therapeutic areas beyond oncology. In an environment where every day of clinical development averages $37,000 or more in operational costs,3 sponsors can’t afford to exclude suitable patients and delay meeting recruitment goals and trial completion.
PROTECT YOUR PATIENTS
4. Site-based ECG analysis leads to unnecessary interruptions in treatment.
The same analysis of ECGs from multiple oncology studies found that up to 77% of dosing interruptions based on site-managed QTc measurements were unnecessary, as the centralized QTc measurements were considerably lower.2 By making decisions about dose interruptions based on site-managed ECGs, sponsors may be denying cancer patients potentially life-saving medications and might even eliminate them from the trial.
5. Paper-based ECG data collection delays recognition of patient safety issues.
Because site-managed ECGs are paper-based, the measurements must be manually entered into the CRF or EDC system, risking transcription errors and query delays. Since the ECGs are not saved as digital files, they are not accessible for risk-based monitoring, which means study teams do not receive real-time alerts when a site finds a safety issue ― potentially jeopardizing patient safety across the trial. Furthermore, if site investigators are not experienced cardiologists, they may miss important safety findings entirely.
CENTRALIZING ECG DATA COLLECTION: THE BENEFITS ARE CLEAR
In today’s environment where drug development costs and timelines continue to escalate, sponsors cannot afford to gamble with clinical trial data collection methods and analysis that put their compounds and study patients at risk. Centralizing ECG data collection and analysis through trained and experienced QT experts provides confidence in ECG accuracy, optimizes patient enrollment, overcomes the challenge of inter-reader variability caused by site-managed readings, and yields the highest quality data so that compounds – and patients – have the greatest chance for success.
Learn how a centralized approach to ECG data collection, analysis and reporting helped a large global pharmaceutical company respond to unexpected regulatory requests and meet review requirements. Read the case study!
Dr. Robert Kleiman is the Chief Medical Officer and Vice President of Global Cardiac Safety at ERT.