Current Rational for the Telemetric and Holter ECG Warehouse (THEW)

On October 17, 2005, the FDA published an official guidance for industry as it relates to ICH (International Conference on Harmonization) E-14 guidance “Clinical Evaluation of QT/QTc Interval Prolongation and Pro-Arrhythmic Potential for Non-Arrhythmic Drugs” describing a battery of non-clinical studies to evaluate a drug's potential to prolong ventricular repolarization. According to the FDA, “problems arise from the inability to confidently predict safety performance in a timely and efficient manner. Current tools are not only cumbersome, they are also imprecise and thus leave considerable residual uncertainty. Consequently, there is a consensus on the limited value of current surrogate marker of drug cardiotoxicity, but there is no alternative method available today. The FDA has identified cardiac safety as a potential platform technology for addressing the critical development challenges faced by the pharmaceutical industry.   We need new tools that can eliminate problem products early and can better predict ultimate safety performance.”  More specifically, “there is an urgent need to develop tools to accurately assess the risk of new drugs causing heart rhythm abnormalities.” 
The propensity of drugs to cause a potentially fatal arrhythmia, torsade des pointes (TdP,) is a significant public health issue.  It has been estimated that as many as 86% of all new chemical entities tested in pharmaceutical development show specific inhibitory activity and thus have a potential to prolong the heart’s ventricular repolarization (VR), which in some cases can lead to TdP and potentially to sudden cardiac death (SCD).

The University of Rochester (UR) has a unique position to address the issue related to the development of improved ECG markers:

• First, the UR has developed strong relationship with the Agency and the Center for Drug Evaluation and Research. The UR is involved in a $1M research program to analyze a large set of digital ECG signals from the FDA XML ECG repository. More...
• Second, the THEW is hosted at the Heart Research Follow-up Program funded in the late sixties by Dr. AJ Moss and directed today by Dr. W. Zareba. This group has more than 30 years of research experience in quantitative analysis of ventricular repolarization involving animals, normal subjects and patients with genetic (Long QT Syndrome ) and acquired (coronary disease and hypertension) cardiac disorders. Some of these works also include patients exposed to drugs that affect the QT/U waves of the ECG. Our group has extensive experience in the design, conduct, and analysis of world-wide, multicenter, clinical research studies ranging from 100-3,500 subjects. Finally, this group has published extensively in major journals on factors influencing ventricular repolarization.
• Third, the UR has started the implementation of the Telemetric and Holter ECG Warehouse (THEW) Initiative.

The overarching goal of the THEW is to provide access to continuous electrocardiographic data to for-profit and not-for-profit organizations for the design and validation of analytic methods to advance the field of quantitative electrocardiography with a strong focus on cardiac safety. We belive that sharing data reinforces open scientific inquiry, encourages diversity of analysis and opinion, promotes new research, makes possible the testing of new or alternative hypotheses and methods of analysis, supports studies on data collection methods and measurement, facilitates the education of new researchers, enables the exploration of topics not envisioned by the initial investigators, and permits the creation of new datasets when data from multiple sources are combined.

To promote cross-fertilization of scientific knowledge, resources and ideas that will advance the field of quantitative electrocardiography and to meet the aforementioned goal, the THEW will strive to:

• Develop specific projects to implement and to grow the repository of ECG information in the THEW;   
• Facilitate scientific projects toward the development, testing and validation of ECG-related technologies and platforms;
• Leverage expertise and resources toward the implementation of collaborative projects among  FDA, UR, and other public and private stakeholders;
• Identify, develop and evaluate new electrocardiographic markers of cardiovascular risk related to management of patient care and evaluation of new molecular entities;
• As appropriate, incorporate scientific findings from the THEW into the premarket evaluation process for electrocardiographic devices and associated methodologies, and into the total product life cycle.

This center will provide services to researcher’s world-wide by fostering and distributing resources (data and tools) needed to conduct ECG-related activities (technology development and ECG metrics). We expect this initiative to spawn various collaborative research projects to not-for-profit entities and to facilitate the development of improved ECG technologies for cardiac safety.

As today, the THEW already contains several terabytes of ECG data and it is expected to grow significantly in the next couple of years.