Cardiac safety is one of the more challenging hurdles in the research and development of new chemical entities and biotechnology-derived products, and FDA says significant opportunities exist to improve the testing process and identify better markers of cardiac risk.

In response, iCardiac Technologies Inc., a privately held clinical technology company focused on the development of advanced electrocardiogram-based cardiac safety biomarkers, recently entered a multi-year research alliance with Pfizer Inc. (pfizer.com) to develop and validate advanced biomarkers using its COMPAS technology platform.

The aim of the research alliance is further development of iCardiac’s COMPAS platform and advanced electrocardiogram markers for use in the safety testing of in-development and on-market drugs. It includes a cross-licensing arrangement by which iCardiac will receive rights to electrocardiogram analysis technologies developed within Pfizer.

The companies will collaborate on a research program comprising a multitude of studies, which include retrospective and prospective electrocardiogram data analyses. ICardiac will receive an equity investment and technology license payment, plus research and development funding over the term of the alliance. The company will retain commercial rights to the validated technology platform and new biomarkers for future application in cardiac safety clinical trials and technologies.

"This alliance is a major vote of confidence in the advanced technology that iCardiac is developing," says Sasha Latypova, executive VP, iCardiac (icardiac.com). "Having Pfizer as a scientific and business partner gives iCardiac an immense resource to achieve its goals. In addition, this alliance moves the entire field of cardiac safety testing forward toward improved, more precise, and more cost-effective methods of cardiac risk evaluation, ultimately leading to safer drugs on the market."

The COMPAS — COMPrehensive Analysis of repolarization Signal — technology was developed at the University of Rochester within its heart research follow-up program and was exclusively licensed to iCardiac. The platform contains two types of electrocardiogram markers.

The first type is known as "Thorough QT Plus" — software that is used for measuring the FDA-required QT/QTc intervals from standard 12-lead and Holter electrocardiograms.

FDA requires nearly all drugs pass a thorough QT test to determine the risk of dangerous arrhythmias. The prolongation of the QT interval in electrocardiograms is often associated with dangerous and life-threatening arrhythmias which can lead to sudden cardiac death. Although this type of arrhythmia is very infrequent, it can not be tested for in a clinical trial. Consequently, FDA has accepted the QT interval measure as a proxy endpoint for studying the drug effects on the heart.

"This set of COMPAS tools provides the most precise way to measure QT interval compared to other commercial software packages, because of its advanced functionality," Ms. Latypova says.

One example of advanced functionality is the semi-automated identifying and eliminating from analysis the periods of electrocardiograms that contain noisy data or periods when heart repolarization intervals are at a non-steady state. These are the periods when heart rate goes up or down. Excluding such periods from analysis is important when comparing QT interval on study medication and on placebo at the same steady heart-rate level to identify any drug-induced changes.

"Many advanced features are either fully automated or semi-automated, leading to significant cost reduction for analysis with COMPAS compared to other software packages," Ms. Latypova says.

The second set of COMPAS tools — "Beyond QT" — contain advanced electrocardiogram biomarkers. These markers are based on highly sophisticated quantitative analyses of the T-wave and its morphology. The morphology can be described as the area on the electrocardiogram that represents a short period between heartbeats, when the heart repolarizes, preparing for the next beat.

Studies show the heart state is most susceptible to dangerous arrhythmias within this period. According to iCardiac executives, the "Beyond QT" tools have already demonstrated a much higher sensitivity and specificity than the QT interval measure in pilot studies. This improvement has been shown to reduce the required number of subjects by up to 42% to achieve the same level of statistical confidence as currently prescribed by FDA in a "Thorough QT" study.

This reduction will allow pharmaceutical companies to significantly reduce the costs of cardiac safety studies and reduce the false-positive and false-negative results of the QT-based cardiac safety analyses.

In addition, the "Beyond QT" tools show promising results for identifying the patients who are more likely to develop drug-induced arrhythmias. This would enable physicians to prescribe medicines with greater confidence to patients who would benefit most from a given medicine.

"As the Pfizer-iCardiac alliance is non-exclusive, iCardiac hopes to convince other pharmaceutical companies to join this effort by contributing historic electrocardiogram data and participating in prospectively designed studies to accelerate the development of advanced electrocardiogram-based cardiac safety assessment tools that will benefit the entire industry, and, most importantly, ensure safer medicines for patients," Ms. Latypova says.

This technology could mean changes for other fields of study as well. ICardiac executives say the COMPAS is an important tool for drug researchers and developers, and that the company will continue its pursuit to find more effective ways to conduct this type of research.

"ICardiac’s field of use for COMPAS technology is not limited to cardiac safety of drugs," says Ms. Latypova. "It also includes efficacy testing as well as device and diagnostic use. So iCardiac is currently pursuing all fields of use for its technology."