November 12, 2004

FDA backs DNA database for drug-induced arrhythmia

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Lynette Gillis, M.D.

FDA backs DNA database for drug-induced arrhythmia

For 15 years, a team of Vanderbilt investigators has been collecting DNA samples from patients who suffer a rare adverse drug effect — an arrhythmia that can be fatal. Now the group's efforts will get some high-profile assistance from the Food and Drug Administration.

In a unique collaboration with the FDA, First Genetic Trust, and GlaxoSmithKline, Vanderbilt will serve as a primary referral site for physicians and their patients who suffer an adverse drug event called long QT syndrome. The prolongation of the QT interval on the electrocardiogram is what predisposes patients to a life-threatening arrhythmia, said Dan M. Roden, M.D., William Stokes Professor of Experimental Therapeutics and a principal investigator in the collaboration.

“We've been interested in this rare adverse drug effect for many years, with the idea that it is genetically determined,” Roden said. “The key first step in searching for genetic variants that may increase susceptibility is finding enough patients who have suffered this unusual event.”

Roden and Alfred L. George Jr., M.D., Grant W. Liddle Professor of Medicine and director of Genetic Medicine, have accumulated over 100 samples, Roden said. “This new collaboration will let us expand that collection by becoming a referral center for all the cases that are reported to the FDA,” he said.

When physicians report drug-induced long QT syndrome to the FDA, the FDA will refer the physician and patient to Vanderbilt for participation in the study. First Genetic Trust, a company whose mission is to develop DNA databases of patients with well-characterized clinical characteristics, will contribute its Web-based genetic banking and research technology to the effort.

“It's very exciting that the FDA not only thinks this is an important idea — because they're interested in mechanisms underlying rare drug effects — but also that they've agreed to serve as a conduit for collecting DNA samples,” Roden said. “It's the first time the FDA has done this. Other adverse drug effects are probably next on their list.”

Although QT interval prolongation and the resultant arrhythmias are uncommon, even one death may be too high a risk when there are other drug options, Roden said. The antihistamine Seldane, for example, was removed from the market after it was found to cause fatal arrhythmias in rare cases.

The FDA now requires that pharmaceutical companies assess the risk for this side effect in all drugs in development.

If genetic variants associated with susceptibility for drug-induced long QT syndrome can be identified, Roden said, it may be possible to develop diagnostic tests that can be used to prevent the side effect.

Vanderbilt is a member of the Pharmacogenetics Research Network, a National Institutes of Health-funded initiative to understand how genetic variation contributes to individual differences in drug responses. Roden is the leader of Vanderbilt's effort, which focuses on arrhythmia — especially discovering the genetic variants that affect electrical activity in the heart and understanding how those variants influence responses to drug therapy.