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Harvard's Warfarin Dose Study Will Analyze Cost/Benefit of Using Gene-Based Dosing

The pharmacoeconomic component of ta warfarin outcomes study at he Harvard Partners Center for Genetics and Genomics may help justify to physicians, payors, and patients that there is some value in incorporating genomic data into prescribing decisions.
The HPCGG trial, begun Oct. 1, is divided into two parts. The first component will investigate whether incorporating genomic data will help determine the right warfarin dose for patients. The second portion, overseen by Jerome Avorn, chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, will determine whether incorporating such information yields an economic benefit.
According to Avorn, the real-world impact of the study will ultimately depend on the extent genetic testing saves health care dollars.
The pharmacoeconomic portion of the trial is “based on the idea that these days in health care if something works, it still needs to demonstrate that it’s cost-effective if it’s going to be taken up in a health care system,” Avorn told PGx Reporter.
“If the trial demonstrates that there is a better outcome, given that such [genetic] tests are often not cheap, payors and health care systems around the world and governments and insurers are going to want to know, ‘Well, if it is better than routine care, how much better is it in relation to how much extra cost it is?’” Avorn said. “I think the uptake of this or any pharmacogenetic approach is going to depend heavily on not just ‘does it work’ but also ‘how much benefit is there for how many dollars.’”
HPCGG Scientific Director Raju Kucherlapati told Pharmacogenomics Reporter that the first component of the trial will aim to improve the accuracy of warfarin dosing, currently estimated to be between 55 to 60 percent [see PGx Reporter 11-15-06].
The dosing portion is divided into two parts: an ongoing 500-patient prospective trial that will develop an algorithm for warfarin dosing, and a 1,200-patient trial, still in the planning stages, which will compare patients on warfarin with and without the aid of genomic data.
Five sites under the aegis of the Partners HealthCare System will be involved in the study, including Massachusetts General Hospital, Brigham and Women’s Hospital, Faulkner Hospital, North Shore Medical Center, and Newton-Wellesley Hospital.
Initial data from the trial are slated to be released at the end of 2007 or the beginning of 2008. Data from the pharmacoeconomic analysis will be released “shortly following” completion of the efficacy portion of the clinical trial, Avorn said.
Organizers will officially unveil the clinical trial at the HPCGG personalized medicine conference being held this week in Boston, HPCGG said.  
Cost v. Benefit
The economic analysis will approach costs and benefits from a global perspective, comparing all of the initial costs associated with using the test with all of the expected clinical benefits. The study “will not be looking at the specific cost of this particular test,” Avorn noted.
“If it’s not an off-the-shelf test, we’re going to look at what the test [would] cost in routine use rather than what is the cost of the test in the context of the study,” Avorn said. “We would total up the differences in benefit and compare it with the differences in the cost in the two arms of the study and see how many dollars need to be spent to obtain what increment in clinical effectiveness.”
According to Avorn, the cost component will “be of great interest to insurers or government programs as they think about how enthusiastic they want to become about supporting the cost of these tests,” but it may not engage the US Food and Drug Administration right away.
When the study ends, Avorn and Kucherlapati will discuss whether to release the pharmacoeconomic data to FDA ahead of publication. “FDA generally tends to not care about cost-effectiveness issues. I don’t think FDA will be beating down my door to ask about the cost-effectiveness piece. I think they will very curious to know about the efficacy part,” Avorn said.
HPCGG’s trial comes at a time when the FDA is in the process of incorporating genetic information to warfarin’s label, which has made industry keen on developing CYP2C9 and VKORC1 genetic tests.

“I think the uptake of this or any pharmacogenetic approach is going to depend heavily on not just does it work but also how much benefit is there for how many dollars.”

In November 2005 the FDA Clinical Pharmacology Subcommittee of Pharmaceutical Science Advisory Committee recommended testing for variations in the CYP2C9 and VKORC1 genes in patients requiring warfarin therapy.
During the most recent meeting of the Clinical Pharmacology Subcommittee on incorporating genetic information in tamoxifen’s label, Office of Clinical Pharmacology and Biopharmaceutics Director Lawrence Lesko provided an update on warfarin [see PGx Reporter 11-15-06].
Although no FDA-approved CYP2C9 and VKORC1 genetic tests are available at the time, several companies are stepping into the field. Kimball Genetics recently launched its warfarin sensitivity DNA test for research/investigational purposes along with the “Pharmacogenetics for Coumadin” study. The warfarin sensitivity DNA test determines the presence of variations in CYP2C9 and VKORC1 genes and Kimball expects to offer the DNA test for routine clinical use in early 2007. 
In addition, Nanogen is planning a test for resistance to warfarin based on mutations in the CYP2C9 gene. Potential competitors in this area include Genelex and Clinical Data, which both recently launched tests in this area, as well as Roche’s AmpliChip, made by Affymetrix, which identifies CYP2D6 and CYP2C19 genotypes.
Additionally, some form of physician education regarding the use of genetic tests in warfarin therapy may be another positive result of HPCGG’s study. “Once we have something to educate about, [physician education] will be a key component. I guess the best way to start that is to have a good article appear in a respected peer-reviewed journal … and take if from there on what to educate physicians about,” Avorn said. 

Physician adoption of genetic tests is one area of concern for genetic test developers. Affymetrix CEO Steve Fodor recently told BioArray News, a Pharmacogenomics Reporter  sister publication, that FDA’s recommendation for genetic tests in tamoxifen’s labeling is necessary to foment demand from physicians who had been reluctant to adopt the AmpliChip.

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