Heart of the Matter
by Jessica Royer Ocken
January 2008
Guidelines and regulations regarding cardiac safety data require clinical investigators to conduct trials in new ways.
Since the May 2005 implementation of the landmark International Conference on Harmonisation (ICH) E14 guidance for cardiac safety in drug development, and its subsequent requirement by regulators worldwide, cardiac safety testing has been a growing component of clinical research on compounds that have non-cardiac applications.
“E14 [calls for] the clinical evaluation of QTc elongation, which is a very specific abnormality and only one part of an overall cardiovascular safety package,” notes Jeffrey Paul, Ph.D., senior director of clinical pharmacology for Wyeth Research, in Collegeville, Pa., USA. “This piece is required and regulated, but it has spawned an overall cardiac safety awareness. E14 has made us all more vigilant and aware.”
Evolving Trial Design
E14 also has changed the way clinical trials are designed and implemented. “The old way would [entail] good medical practice of collecting information to see how a patient is doing—minimal safety information, vital signs, labs, an ECG,” Paul says. “Now it’s much more intense.”
“Clinical trials are now designed to answer questions about cardiac safety over the long term,” says Dr. Peter Kowey, chief of cardiovascular disease for Main Line Health System and cardiac safety consultant, in Philadelphia, Pa., USA. This begins with collecting pre-clinical information before the trial even begins.
Careful evaluations early in studies help reveal the relationship of dose and blood level of the drug in question to changes in cardiac indices, Paul says. “We also have the thorough QT study, which is done to understand the potential pharmacology for a drug to change cardiac repolarization.”
This new intensity of study also has logistical effects. To meet E14 requirements, the ECG study of the QT interval must be very precise. “The effect to be measured is as little as 5 ms—one-eighth of a millimeter on a standard electrocardiogram,” says Dr. Dhiraj Narula, medical director for Quintiles ECG Services, in Mumbai, India. “Hence, the design focuses on the use of electronic data capture and measurement in a fully digital environment.”
And the need for precision doesn’t end after Phase I. As the trial progresses, the cardiac safety findings in one phase inform the continued testing that will be required for the next. “A lot depends on the class of drug, what’s known about that class, and what preclinical information you have that makes you believe there might be a problem,” Kowey says.
Selecting Participants
The patients for whom the compound is intended also help determine which testing will be appropriate. “If you think you will treat patients who have pre-existing cardiovascular disease with the compound, that places an even higher burden,” Kowey says. “For example, if you have a diabetes drug, obviously people with cardiovascular problems will be exposed, because those are frequent in people with diabetes.”
There also are classes of drugs, including those intended to treat depression, Parkinson’s and infectious diseases, that must be monitored more closely for cardiac effects. “Many drugs in these classes have been shown to be pharmacologically active on potassium channels”—which in turn affect the QT interval—“and given the regulatory risk, we have seen pharmaceutical companies opting to perform the thorough QT evaluation earlier in the drug development sequence,” Narula notes.
There are practical considerations as well. “Measurement of ECGs in patients with Parkinson’s is more difficult because of tremor, which can affect ECG quality,” Narula says. “Hence a larger number of ECGs is typically required in order to maintain accuracy through signal averaging.”
In addition to the structure of the clinical trial, the E14 regulation also has impacted the way subjects and patients are selected for study. “If you think you may have cardiac safety issues, you need to protect the subjects and patients in the course of the trial,” Kowey says.
“It goes both ways,” he continues. “If you don’t have at-risk patients, you can’t conclude much. You need to sequence in patients with higher cardiovascular risk. Study low-risk patients initially. If [the cardiac data] doesn’t show much, then you can study [the compound] in higher-risk individuals. It’s a process whereby you need to step up the intensity of clinical trial experience as patients go through it so at the end of the day, you have meaningful information.”
Challenge and Benefit
Other challenges presented by E14 include the added time and expense cardiac safety data collection adds to the clinical trial—and a simple learning curve. “Interestingly, it does require continuous education for people not in the cardiac area,” Paul says. Because these regulations relate to compounds intended for non-cardiac uses, ECG analysis is now working its way into areas of medicine where it has little other presence.
And, while inpatient participants in a trial may simply need a little education about the added ECGs they’ll experience, outpatients can be more difficult. “Collecting this data requires some doctor visits to be prolonged,” Paul says.
In other cases, collecting cardiac data is an especially heavy burden. “Oncology also has a very special set of problems or challenges because of the nature of the disease and the types of compounds being tested,” Paul says. “Getting cardiac information on top of trying to ameliorate the disease is especially challenging.”
But despite the added challenge (and the fact that it’s required), the experts agree that E14 is reaping benefits. “We think we have a much cleaner set of new compounds to work with that probably lack potential for these bad cardiovascular side effects,” Paul says.
Many compounds are eliminated now before they even reach clinical trials. “There are certain in vitro tests that measure electrophysical properties, so we can weed things out very early, and they never have to come to humans at all,” Paul says. Based on this early elimination of potential risk, “you’re much more confident in what you have when you get to Phase III and beyond.”
Looking Ahead
These sorts of discussions and continued evolution in the process of collecting cardiac safety data serve as reminders of the novelty of these regulations. But Narula sees improving efficiency and enhanced patient safety ahead.
“We are seeing a change in industry thinking similar to that over the acceptance of a central laboratory a decade ago,” he says. “Eventually all ECG data will be collected digitally and stored or reviewed centrally.” When this is done, the data are “available in real time to the study monitor, and the central ECG laboratory provides an expeditious and accurate interpretation of the ECG,” he says. “The costs are substantially lower than they initially appear to be, as line items for local interpretation of ECGs are reduced.”
And then there’s that learning curve. “In studies where the investigator is not well-acquainted with the nuances of ECG reading, such as in psychiatry drug studies, patient safety is enhanced by a centralized process.”
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