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Serious Adverse Events Consortium Releases First Data Set on Genes Linked to Stevens-Johnson Syndrome

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The International Serious Adverse Events Consortium and the US Food and Drug Administration released the first set of genetic data linked to Stevens-Johnson syndrome, a serious skin rash associated with many drugs.

"The SAEC has fulfilled a key goal of the Critical Path Initiative by providing the research community with public access to new genomic data on adverse drug events," Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said in a statement last week.

The data, which was compiled and analyzed from biological samples donated by GlaxoSmithKline, is available through the SAEC's website for free to researchers who sign a data-use agreement. The SAEC also plans to publish later this year the genetic associations uncovered by the study.

"This consortium has taken a significant step forward by promoting open sharing of drug safety data," Woodcock said in a statement. "This type of cooperation has the potential to lead to more personalized approaches to medicine that can reduce a patient's risk for experiencing an adverse drug event."

The genetic data for Stevens-Johnson syndrome comes 16 months after a group of pharmaceutical companies, academic institutions, and regulatory bodies agreed to collaborate on research to identify genetic markers that predispose patients to experiencing adverse reactions when treated with certain drugs. The consortium's first two projects centered on drug-induced Stevens-Johnson syndrome and liver toxicities [see PGx Reporter 10-03-2007].

"We are pleased to be able to provide these invaluable data to the research community to both improve the productivity of drug development and to begin the critical process of developing validated biomarkers to forecast patients who may be at risk for drug-induced serious adverse events," SAEC Chairman Arthur Holden said in a statement.

Holden said the group used whole-genome studies to uncover the genetic abnormalities linked with Stevens-Johnson syndrome. Samples were genotyped on the Illumina Human 1M BeadChip, he added.

Despite the discovery of these gene associations, "it would be preliminary to develop a meaningful diagnostic chip off this data," Holden stressed. Previously published studies have linked various polymorphisms in the HLA region with Stevens-Johnson syndrome.

There are over 40 drugs associated with Stevens-Johnson syndrome, and patients whose samples were analyzed in the SAEC study were on a variety of these drugs. As a result, the FDA will not be able to make any "meaningful changes to drug labels" based on this data, he added.

Stevens-Johnson syndrome manifests in patients in the form of blisters and peeling. Patients who experience serious skin rashes such as Stevens-Johnson syndrome do so following treatment with nonsteroidal anti-inflammatory drugs for pain, sulfonamides and penicillins for infections, or anticonvulsants for seizures.

A decision by the FDA to change the label of these drugs "would require significant input from well-designed studies," Holden noted. By comparison, the SAEC's data "are collections of cases that right now go across enough drugs in the serious skin rash area that there would be no meaningful changes that they could make.

"I think the changes to some of these labels have been done prematurely on the back of relatively small cohorts that haven't been replicated," Holden added.

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Stevens-Johnson syndrome and subtypes of this reaction, such as toxic epidermal necrolysis, are rare in the general US population, affecting less than 200,000 people. Although uncommon, these types of reactions can be fatal. For example, approximately 30 percent of patients who experience toxic epidermal necrolysis die of the reaction.

Although the SAEC's findings will not likely inspire the FDA to change drug labels with gene-risk association data, the effort is in line with a growing PGx focus at the agency.

The agency most recently updated the labels of the anticoagulant warfarin and the HIV drug abacavir to include genetic-risk data. FDA officials plan to re-update warfarin's label with PGx-guided dosing information and update the anticoagulant clopidegrel with gene-risk data [see PGx Reporter 10-22-2008].

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