FDA took warfarin one step into the world of personalized medicine Aug. 16 with labeling changes that inform patients and doctors about the usefulness of genetic testing before beginning therapy with the blood thinner.

"This marks the first time that such pharmacogenomics has been included in [the labeling of] a widely used drug," Office of Clinical Pharmacology Director Larry Lesko commented at a press conference to unveil the new ¹ label. "This means that personalized medicine ... has moved into the mainstream where it is recognized as a factor in a product used by millions of Americans every day."

The agency did not actually recommend that the tests be conducted, nor did it identify a specific dosing level based on a patient's genetic characteristics.

"The clinical data available today are not sufficient ... to actually alter the recommendations in the label such that we require ... or even strongly encourage ... the use of these tests," Acting Director for the Division of Medical Imaging and Hematology Products Dwaine Rieves explained.

Mandating the tests would require that they be widely available and that is not yet the case, noted Lesko, although major laboratories offer this service.

As for dosing, he pointed out that "more studies are needed to explore the precise starting dose" based on genetic factors. Those factors are variants in two genes - CYP2C9 and VKORC1. The former is involved in warfarin metabolism and the latter helps regulate the ability of the drug to prevent blood from clotting.

Currently, prescribing warfarin (Bristol-Myers Squibb's Coumadin and generics) is a delicate matter as physicians seek a dose that will thin the blood to prevent clotting, but not thin the blood so much that severe bleeding occurs.

Since the appropriate dose varies by patient, finding that dose often is a matter of trial and error. To inform users about the impact of genetics, FDA has altered the Precautions section of the warfarin label to note that "genetic variations in the CYP2C9 and VKORC1 enzymes" are one of the factors that "may influence the response of the patient to warfarin."

Other factors influencing dose include age, diet and medications being taken. Genetics can be responsible for 35 to 50 percent of the variability, Lesko pointed out. "One of the benefits of [genetic] testing ... is to get to the maintenance dose that's optimal for that patient quicker," he said.

The updated label retains the recommendation that initial dosing begin at 2 mg to 5 mg per day, with adjustments made on the basis of results from the prothrombin time test and how they compare to the International Normalized Ratio for healthy people. FDA does note, however, "Lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes."

The enzyme genetic tests "provide somewhat more of an objective tool that physicians can use in their many considerations" when selecting the initial dose, Rieves pointed out.

The suggestion of lower doses for people with the genetic mutations stems from studies that found such patients generally require less warfarin. A meta-analysis was conducted of three studies that assessed bleeding risks and eight that looked at daily dose requirements. The studies involved 2,775 patients (99 percent Caucasian).

The meta-analysis reports an increased bleeding risk for patients carrying either of two mutations of CYP2C9. "Patients with at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17 percent less than the mean daily dose for patients homozygous for the CYP2C9*1 allele," the label notes. For patients with at least one copy of the CYP2C9*3 allele, mean daily dose requirement was 37 percent lower.

In an observational study of 219 Swedish patients retrospectively grouped by CYP2C9 genotype, the relative risk of over anticoagulation during the first two weeks of treatment was about double for those classified as *2 or *3, compared to patients with the *1 allele, FDA notes.

With regard to the VKORC1 gene, certain single nucleotide polymorphisms have been associated with lower dose requirements for warfarin, as indicated by a study of 201 Caucasians, FDA points out. In this trial, about 30 percent of variance between optimal doses could be attributed to variations in the VKORC1 gene, while 40 percent variance could be seen when a patient had variations in both the VKORC1 and CYP2C9 genes.

FDA is supporting research to come up with answers on genetics-based dosing. The agency's Critical Path Initiative is funding research at the University of Utah and the Critical Path Institute to develop genetically based instructions for warfarin dosing and is contributing to a clinical study by Harvard Partners to derive personalized warfarin dosing algorithms for patients new to the drug.

C-Path Institute - an independent research firm created in 2005 to advance the initiative - helped create a consortium of investigators to share information from warfarin studies and look for similarities (² Also see "Warfarin Dosing Biomarkers Could Be Model For Genetic Tests In Labeling" - Pink Sheet, 8 May, 2006., p. 21).

In consultation with FDA, the National Heart, Lung and Blood Institute is supporting a 2,000-patient multi-center randomized trial studying the effect of a genotype-based dosing protocol. Proposals to lead the study, which will follow patients for one year, were due in June. According to Yves Rosenberg, program director in the division of cardiovascular diseases, enrollment is scheduled to begin in mid-2008. Results of the study are expected in 2011.

John Carlquist, technical director of molecular diagnostics at Intermountain Health Care in Salt Lake City, says it is still unclear how clinicians can use information derived from genetic testing.

"Everyone seems to be underestimating the complexity of the situation," Carlquist said in an interview. "They know that you have one genotype and you end up with one dose, but what happens in between is not as simple as you would think."

New studies suggest that the specific mutation and the timing of the initiation dose versus the maintenance dose could have an impact on reaching the target blood level of the drug, he explained.

Carlquist is co-principal investigator of the recently completed COUMA-GEN study at the University of Utah. Results from the 200-patient randomized trial will be presented at the American Heart Association annual meeting in November. The investigators worked closely with C-Path and examined how a mutation-driven dosing protocol compared with standard, non-genotype-based treatment in maintaining patients' target drug level over three months. Carlquist said the next step will be to conduct a larger study and look at the influence of different mutations in the genes to try to improve dosing predictability.

Work on changing warfarin labeling to incorporate genetic factors is seen as a start down the road to a regulatory approach for medicines that can be "personalized" based on a patient's genetic makeup.

"The idea is to use [warfarin] as a model for how to create the standards for getting genomic data to be useful in guiding therapy," C-Path CEO Raymond Woosley told "The Pink Sheet."

The warfarin label changes should increase demand for genetic tests at laboratories that have developed their own assays. But whether a label lacking actual recommendations for use will spur development by diagnostics companies remains to be seen.

Kimball Genetics launched a Warfarin DoseAdvise Genetic Test in June. AutoGenomics filed a 510(k) for a genetic test to screen for the mutations on its Infiniti system in October, and Nanogen announced earlier this year that it planned to submit an application for a warfarin dosing test on its NanoChip 400 platform by the end of 2007.

But other firms are taking a wait and see attitude. Luminex has developed a test but is awaiting FDA decisions about the analytical and clinical data that will be required before making a submission, the company says. Third Wave Technologies also recently said it was waiting to see what label changes were made before it submits a 510(k) for its Invader warfarin test.

To get the word out on warfarin and genetics, FDA is working with the American Medical Association and the Critical Path Institute to develop a brochure for patients and physicians; the Center for Devices and Radiological Health is preparing a video to be put on the Internet. These are expected to be available in the last quarter of 2007, Lesko said.

FDA estimates that 2 million people begin warfarin therapy in the U.S. each year to prevent blood clots, heart attacks and stroke. According to NIH, more than 21 million prescriptions for the drug are written annually. Warfarin is the second highest cause of emergency room visits for adverse drug reactions.

- Cathy Dombrowski (c.dombrowski@elsevier.com)

Warfarin Label Change Falls Short of Recommending Genetic Testing

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