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In Warfarin Labeling Update, FDA ‘Stopped Short’ to Await More Data

The US Food and Drug Administration had to “stop short” of recommending genotyped-based dosing information in warfarin’s prescribing information because it is awaiting more specific outcomes data from ongoing genetic studies with the anticoagulant, according to an agency official.
Many clinical studies have shown that patients with variations in the CYP2C9 and VKORC1 genes may need a lower warfarin dose than patients without those variations. However, the FDA said it needs further research to establish a genotype-based dosing algorithm for the drug, and to validate whether pharmacogenomic tools used to determine warfarin dosing will improve clinical and health economic outcomes over standard trial-and-error methods.
The FDA announced Aug. 16 that the labeling for warfarin, marketed by Bristol-Myers Squibb under the trade name Coumadin, has been updated with information explaining how genotypes may impact their response to the drug. 
The label “is not a directive to doctors that they should use [genetic testing.] We will await the results of outcomes studies for that type of label,” Janet Woodcock, deputy commissioner and chief medical officer of the FDA, said during a conference call accompanying the announcement. “This information in the label is more informational to doctors. It explains some of the sources of variability in the drug response.”
The ‘Precautions’ section of Coumadin’s updated label states: “Identification of risk factors for bleeding and certain genetic variations in CYP2CP and VKORC1 in a patient may increase the need for more frequent [international normalized ratio] monitoring and the use of lower warfarin doses.”
During the call, agency officials focused on the new label’s use of the word “may” to note that the agency is not requiring doctors to perform genetic testing. Agency officials repeatedly emphasized that more outcomes data are needed for more prescriptive labeling guidelines regarding genetic testing.
In the call, Dwaine Rieves, acting director of the FDA’s Center for Drug Evaluation and Research’s medical imaging and hematology products division, noted that with the labeling update the agency merely wanted to make physicians aware that genetic testing is a viable option to aid them in initiating patients on warfarin.
“These enzyme-type genetic tests, they provide somewhat more of an objective tool that physicians can use in their many considerations of choosing the dose,” Rieves said during the call. “The label does not say that the performance of these tests is required. In fact, the label emphasizes to a certain extent the unknowns with respect to the importance of these factors ultimately impacting outcomes.”

All existing warfarin tests are certified under CMS’ Clinical Laboratories Improvement Amendment. Kimball Genetics last year launched its warfarin sensitivity DNA test for research/investigational purposes along with the “Pharmacogenetics for Coumadin” study. Nanogen, Genelex, and Clinical Data also market home-brew tests in this area.

Although no FDA-cleared genetic test for this indication is currently available, “several tests are currently under consideration,” and some companies have said they intend to take their products through the FDA regulatory process, according to an FDA official.
Physicians currently use a trial-and-error method when monitoring warfarin’s effect on a patient, typically relying on the individual’s prothrombin time/international normalized ratio to dose the drug. But dosing is complicated by factors including diet, age, and other medical interactions. Patients who take too much warfarin can suffer life-threatening bleeding and those who take too little can suffer blood clots.
More Outcomes Data Needed
Rieves noted that since more clinical research is necessary, the FDA did not change the dosing recommendations or the monitoring process for warfarin.
The label recommends that Coumadin therapy be initiated within the range of 2 mg to 5 mg per day with dose adjustments based on the results of PT/INR determinations. Lower initiation doses “should be considered” for patients with genetic variations in CYP2C9 and VKORC1 enzymes, in elderly or debilitated patients, and in those with the potential to exhibit greater than expected PT/INR responses to Coumadin, the label states.
“We did have to stop short of recommending specific doses for specific genotypes,” Larry Lesko, director of the office of clinical pharmacology at the agency’s Center for Drug Evaluation and Research, said during the call. “That’s the kind of additional information that studies that would be conducted under the Critical Path would really focus on.”
Under the Critical Path Initiative, the FDA and the University of Utah are looking at the clinical outcomes of incorporating genetic testing into warfarin therapy [see PGx Reporter 06-27-2007]. 
According to Woodcock, this study has already given the FDA some “valuable” information “but there is a fair amount of work that would have to be done before the biomedical community would determine whether or not this would be part of standard therapy or not.
“We hope under Critical Path we will continue to collaborate with a number of groups … in nailing down the level of contribution of genotyping to management of patients for mediating anticoagulation,” she said.
Since variations in the CYP2C9 and VKORC1 genes account for between 35 percent and 50 percent of the dosing variability for warfarin, and because the drug has such a high and potentially fatal adverse-event profile, industry, academia, and insurers have been eager to investigate the utility of PGx strategies to reduce these AEs.
For instance, the Harvard Partners Center for Genetics and Genomics, Medco, the Mayo Clinic, and Clinical Data and PharmaCare are all researching the clinical and economic utility of PGx-based warfarin dosing [see PGx Reporter 11-29-2006, 12-06-2006, 09-20-2006].

“Doctors can still practice good medicine without doing these tests, but the tests are available and that’s one of the major points we hope to make with making the change there.”

Besides illustrating the differences between using PGx-based tools and traditional methodologies to dose warfarin, these ongoing studies could affect insurers’ decision to cover these diagnostics, and impact physician adoption rates of the products.
Though few major insurers cover genetic testing for warfarin, this initial nod from the FDA may help change that. Large insurers have indicated that their decision to pay for genetic tests is contingent in part on whether such a test is mentioned in a drug’s label and if published data supports the value of such tests. Genetic tests for warfarin currently available on the market cost between $125 and $500, the FDA said.
Although additional studies are necessary, currently available data supports the FDA’s decision to update warfarin’s label, agency officials said. Initial results from the University of Utah study have indicated the feasibility of conducing randomized pharmacokinetic-based dosing trials with warfarin, and have established “prospectively the superiority of the PGx-guided warfarin dose selection,” Lesko said.
Also, data from a two-year outcomes study published in the July 25 issue of Clinical Pharmacology & Therapeutics, links the VKORC1 1173C/T and CYP2C9 genotypes with an increased risk of hemorrhage in African American and European American patients.
However, in the absence of more prescriptive data regarding genotype-based dosing, doctors should regularly check if warfarin is working properly and safely by ordering a prothrombin time test to evaluate the blood’s ability to clot properly, FDA officials emphasized during the call.
“Doctors can still practice good medicine without doing these tests, but the tests are available and that’s one of the major points we hope to make with making the change there,” Rieves said.
“INR monitoring should continue to be the cornerstone of anticoagulation monitoring,” Lesko added.
‘Abstract Concept’ Now ‘Mainstream’
During the FDA conference call Lesko hailed the labeling update as a milestone that brings “personalized medicine to the mainstream.” However, this is not the first time the agency updated a drug’s label with genetic testing information.
The FDA has updated the labels of several older drugs — the acute lymphatic leukemia therapy 6-mercaptopurine and Pfizer’s colorectal cancer agent Camptosar (irinotecan) — to recommend that doctors use genotypic data to modify doses for patients with specific genetic variations that put them at increased risk for developing adverse reactions.
The labels of newer oncologics such as Herceptin and Erbitux also mention companion diagnostics to determine the tumor type and predict patient response before starting the drugs.
Still, the new warfarin label is significant because it “marks the first time that such pharmacogenomic information has been included in a widely used drug,” Lesko said. “This means that personalized medicine is no longer an abstract concept, but has moved into the mainstream, where it is recognized as a factor in a product used by millions of Americans.”
Approximately 2 million people are initiated on warfarin therapy each year to prevent blood clots, heart attacks, and stroke. According to the FDA’s adverse events reporting database, complications from warfarin are the second-most common reason for emergency room visits, behind adverse reactions from insulin.

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