The University of Rochester Medical Center will participate in a unique research partnership with the National Institutes of Health and the U.S. Food and Drug Administration (FDA) to develop new methods to assess the safety of drugs in clinical trials with greater speed and certainty.
The research, to be directed by Rochester researcher Jean-Philippe Couderc, Ph.D., will, for the first time, give scientists access to a huge FDA database of electrocardiograms (ECG) for the purpose of identifying early predictors of cardiac risk. This project is part of the "Critical Path" initiative launched two years ago by the FDA to accelerate the process of bringing medical breakthroughs to patients while at the same time ensuring safety and reducing drug development costs.
"Cardiac toxicity is a major issue for the pharmaceutical industry," said Couderc. "In recent years, many drugs have been pulled from the market because of concerns that they may cause adverse cardiac events. And this is not just limited to cardiac drugs; it also includes antibiotics, anti-psychotic, heartburn, and anti-histaminic drugs among others."
The most common form of this toxicity manifests itself in a drug's impact on cardiac repolarization – a split-second period between the heart's contraction and recovery phase. A drug-induced prolongation of this period, called the QT interval prolongation, can significantly increase risk for developing fatal arrhythmias and sudden cardiac death.
Beginning last year, the FDA required companies to submit ECG data from clinical trials in electronic form. The result has been the creation of a large – 500,000 and growing – electronic warehouse of ECGs. Couderc and his team will be the first outside researchers to gain access to this database.
Of particular interest to Couderc is a specific set of control data. The FDA requires drug companies to include ECGs from subjects who have been administered the drug moxifloxacin, an antibiotic that is known to prolong the QT interval. Because there is currently no standard measurement, the drug is used to demonstrate that the methods used by the drug companies to measure the QT interval are precise.
Couderc will use this and other data from the FDA to further refine a software program he has developed that enables researchers to precisely analyze ECG data. The software, called COMPAS (Comprehensive Analysis of Repolarization Signal), was designed to accurately identify ECG abnormalities, while taking into consideration other factors that may influence a person's heart activity, such as eating and stress. The goal of Couderc's research is to develop new measurements – or biomarkers – to identify cardiac risks associated with new drugs.
"The measurement of the QT interval is helpful but it is not a perfect surrogate marker of drug toxicity," said Couderc. "There is a crucial need for other ECG markers that would be more sensitive and more reliable and that is what we are aiming to provide with this technology."
Couderc believes that one potential new biomarker resides in the morphological analysis of the T-wave. Subtle changes in the shape or morphology of the T-wave – which comes at the end the QT or repolarization interval – could be a better indicator that a drug is interfering with ion channels in the heart's cells. The ion channels are protein structures that control the flow of ions responsible for producing the electrical activity of the heart. Interference with these structures diminishes the cells' ability to "recharge" between contractions, which, over time, may lead to lethal electrical dysfunctions of the heart.
Rochester is home to particular expertise in this field. The Heart Research Follow-up Program is an international leader in the science of heart arrhythmias and a rare genetic condition associated with an abnormal QT interval, called the congenital Long QT Syndrome (LQTS). The University keeps an International Registry for LQTS, and follows thousands of families who have this inherited condition. One of the genetic forms of the QT prolongation syndrome is similar to the drug-induced syndrome, and the University's work focuses on developing the tools to identify individuals with either condition.
Ultimately, more precise indicators of cardiac toxicity will not only improve the safety of new drugs, they will enable pharmaceutical companies to determine more quickly which new compounds pose a potential risk. This information could represent significant savings for drug companies; it is estimated that it costs, on average, $900 million to bring a new drug from the laboratory to the doctor's office.
Consequently, technology that is more precise and more consistent in detecting cardiac toxicity has a tremendous commercial potential. Earlier this year the University licensed the COMPAS software to iCardiac Technologies, Inc., a Rochester-based company founded by Couderc that is positioning itself as a leading provider of advanced cardiac safety analysis technologies.
Joining Couderc in the $1 million NIH-funding project will be Arthur J. Moss, M.D. and Wojciech Zareba, M.D., Ph.D. Norman Stockbridge, M.D., Ph.D., with the Center for Drug Evaluation and Research at the FDA, will serve as a consultant on the project.