Is the pharmaceutical industry managing and assessing electrocardiograms (ECGs) as rigorously as it could? As consistently as it should? Should the FDA transition away from paper ECGs?

Jeffrey Litwin has a delicate line to walk. On the one hand, as chief medical officer and executive vice president of ERT (until recently known as eResearch Technology), his company offers unique systems and personnel to manage ECGs in a centralized manner. On the other hand, he can't flatly say the existing burden of regulation on the industry is insufficient.

"Most of the focus has been on the QT interval," allows Litwin, a cardiologist. "It's great we have some guidance to do something for QT. There is not very much focus on other safety issues." One example is morphology in the ECG, or the displacement from a normal trace. Another is the variability between reviewers who are not rigorously trained to interpret ECGs in a standard and reproducibly consistent fashion.

Core Issues

A few years ago, when it was drafting the QT guidance, Litwin says, the FDA did propose a more sweeping requirement. That might have required electronic ECGs, centrally reviewed. As with the QT studies today, those might have been deposited in the FDA's online database for ECG data. The agency softened that proposed requirement after industry objected.

But Litwin isn't convinced the issue of centralized ECGs might not be reopened, particularly in the light of well-publicized cardiology-related drug safety controversies last year. Will new FDA leadership make a difference? The big safety quandaries, even after the passage of the FDAAA legislation in late 2007, do have the U.S. authorities on the defensive. It's hard to predict how the agency might try to appease politicians or the public if another safety issue appeared on the front page of the newspapers. "If the agency could do what it wanted in a vacuum, they would have all data submitted electronically," Litwin says.

"A new administration will likely focus more on safety," he says. "Cardiac safety issues are the number one issue in drugs being removed from the market."

Beyond QT

True enough. But as he notes, prolonged QT testing represents just one aspect of what ECGs can reveal about a patient or a medication. And paper ECG and paper-based case report forms related to such data are probably not the best way to assess thousands of squiggly lines and whether they indicate an ominous, population-wide pattern of heart attacks or something of no public or clinical significance.

There are other sources of potentially worrisome randomness in cardiac safety assessments when done manually. There are a large number of manufacturers of ECG equipment. Each has a unique algorithm to make the key ECG calculations; the algorithms change over time and render the heart's electrical activity in subtly different ways. Then there are the differences between human beings in different medical specialties. Their expertise and consistency are also variable. General internists may have relatively plastic diagnostic criteria over time; electrophysiologists and expert cardiologists may be more consistent but unable to read large quantities of paper ECGs.

"The trust in the site to look at this is not the wisest thing," Litwin says. "People have accepted the concept that every blood lab has different values. The same has not been done with cardiac safety." ERT estimates that perhaps a quarter or third of trials currently use a centralized core lab for cardiac data.

No Hedging

Some of the problem is contextual. A general internist may be reviewing an ECG to help patients choose therapies or interventions. A core lab like ERT, which does nothing but assess ECGs, knows that the main drug safety question can be more appropriately and narrowly framed in scientific terms: did the drug under study cause a change in the patient's heart?

Says Litwin: "We have very strict guidelines. When we read, it is very clear if there is a change on the ECG. A core lab like ERT doesn't hedge our bets. Sites and the cardiology sites are generally reading for health care. There is a lot of hedging."

When he came to the company in 2000, perhaps 95 percent of the ECGs at ERT were done on paper. ERT has since migrated completely—to 98 percent electronic. "It was a huge switch in a relatively short period of time," Litwin says. He concedes the industry adopts all new technologies slowly for a host of appropriate reasons.

No matter what Washington does, he sounds cautiously hopeful that pharmaceutical manufacturers could begin to see the cost of centralized ECGs as worth the benefit in data quality. Among other things, electronic ECGs would potentially allow regulators more panoramic epidemiological perspectives, seeing across a decade of research or a whole class of similar drugs from different manufacturers.

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ERT's Jeffrey Litwin

Aside from the diagnostic and medical expertise that can be brought to bear by central ECG efforts, Litwin stresses the more mundane aspects of project management that can be harder to appreciate. ERT has roughly tripled the size of its project management team during the switch from paper to electronic. "These studies have their own nuances," Litwin says.

There are myriad details. Special adapters are needed to transmit data over phone lines. Detailed shipping and customs timetables to make sure all of the equipment arrives when needed. Calls from investigators at any hour of the day or night. And sophisticated edit checks to generate and resolve queries.

All of that can result in cleaner, better scientific data at the end of the trial. But some sponsors mainly see the bill, and mentally categorize the expense as an administrative or "optional" budget item. "In today's day and age, no one likes additional cost," concedes Litwin. Having said that, on a large Phase III project, a centralized program for ECGs might cost a few hundred thousand dollars. It may work out to less than one percent of the overall budget, he estimates.

Site Help

Litwin speculates that a broader usage of centralized ECGs might actually be able to move costs and work burdens away from sites, especially if the sponsor community provided ever-cheaper ECG machines to the sites. Part of the idea there is to just have one standardized piece of equipment doing all the studies, much as Southwest Airlines only uses one type of jetliner.

If a psychiatrist, surgeon or dermatologist is examining the patient, Litwin points out, there is all the more reason to have the ECG read by centrally by a specialist. "Eighty to ninety percent of the sites don't know how to read the ECG anyway," says Litwin. "They are sending it to someone in the hospital and getting the tracing back a few days later."

And while the pennies are pinched, to some degree, when trials are being planned, the opposite is true when a drug has turned up on Jay Leno's monologue. At that point, most sponsors urgently request a full portrait of the drug's safety profile, and are less worried about cost. "When things go amiss in a decentralized fashion, in a later phase study, no fee is too great to figure out what went wrong," Litwin notes.

ERT is having some success pointing out that a better time to ask the questions and build a rigorous and useful database is at the start of big trials, not after plaintiffs' lawyers have begun sniffing around. Contract research organizations often have early access to protocols, and ERT is trying to work with them to understand the advantages of its centralized ECG approach.

Litwin is fairly persuasive on centralized cardiac testing being of benefit to society at large. "There is a way out there for not a lot of cost to get really good data in the area where most drugs have had approvability issues or remaining on the market issues," says Litwin. "Only 25 percent of the studies are proceeding on to get the highest quality data. We are all going to be taking these drugs. It could give myself and others comfort to know that the best clinical work that can be done has been done."

Editor's note: In a recent series of articles on cardiac safety, Icon and New Cardio reviewed their plans and sense of the direction of the industry.

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