By Turna Ray
The Centers for Medicare & Medicaid Services has given the green light to a study sponsored by Iverson Genetics that will compare health outcomes for pharmacogenomics-based warfarin dosing to standard methods.
In approving the study, CMS will reimburse for the genetic testing conducted in the clinical trial, which involves more than 7,000 patients.
Iverson Genetics CEO Dean Sproles said that the warfarin study will use Genmark's eSensor Warfarin Sensitivity Test, which has been cleared by the US Food and Drug Administration.
"After evaluating various FDA-cleared platforms, we've chosen Genmark's eSensor XT-8 platform," Sproles told Pharmacogenomics Reporter this week. He added that the company decided to use an FDA-cleared test after discussions with CMS and experts in the steering committee for the study.
The two-year study, which garnered CMS approval this week under its "coverage with evidence development" scheme, will investigate whether adverse events are reduced when dosage for the highly variable anticoagulant is determined in first-time users based on genetic information. In the randomized, blinded, multi-center trial, researchers will compare patient outcomes when warfarin is administered with the help of PGx data and without.
Last year, when CMS found insufficient evidence demonstrating that PGx-guided warfarin dosing improves health outcomes for Medicare beneficiaries, the government payor decided not to cover such testing for Medicare recipients, except when it is performed as part of a prospective, randomized controlled trial (PGx Reporter 05/06/09).
The CMS approval "is for a clinical study under 'coverage with evidence development' and will cover pharmacogenetic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness," Iverson Genetics said in a statement. Iverson Genetics will provide laboratory services and oversee compliance issues for the study.
The FDA earlier this year updated the labeling for warfarin with PGx-guided dosing ranges. The agency first updated the anticoagulant's labeling in 2007 to inform healthcare providers of the heightened risk of adverse events for warfarin-treated patients harboring mutations in the CYP2C9 and VKORC1 genes.
Then on Jan. 22, the FDA updated the "Dosing and Administration" section in warfarin's label to state that a "patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose." The label further instructs healthcare providers to refer to a table containing stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 variants. "Consider these ranges in choosing the initial dose," the label advises (PGx Reporter 02/03/10).
Sproles said that the study will test for the gene mutations listed in the FDA-approved label for the drug.
Genmark, formerly known as Osmetech, received FDA clearance for its warfarin sensitivity test and its eSensor XT-8 platform in 2008. Tests from several other companies, including TrimGen, Nanosphere, Autogenomics, and Paragon Dx, have also received FDA approval.
It is estimated that more than 2 million patients are prescribed warfarin in the US annually, and between one percent and five percent of patients experience a major bleeding event due to incorrect dosing. Iverson Genetics cited an American Enterprise Institute-Brookings working paper that reported that the annual costs associated with warfarin-related adverse reactions are in the order of $1.1 billion.
Iverson Genetics' warfarin study will evaluate whether the use of genetic information can reduce side effects, such as major hemorrhagic or thromboembolic events, in the general population.
The study is being led by Elizabeth Ofili, chief of cardiology at Morehouse School of Medicine in Atlanta, Ga. The warfarin study steering committee is accepting clinical sites interested in participation. Further information is available here.
According to Sproles, CMS's approval of the study under CED has attracted the interest of several firms who have offered to provide various services for the trial, and the company is in discussions with various parties.
In conducting the study, Iverson Genetics aims to involve more than 50 sites, and ink partnerships with additional sponsors, health information technology providers, and express delivery providers to ensure fast turnaround times for genetic test results — a particularly significant detail, since lengthy turnaround times for genetic test results have hampered PGx studies involving warfarin in the past.
Many payors, unconvinced that genetic testing in the broad patient population to dose warfarin is clinically useful, have said that test results will have to be returned to physicians as soon as the same day that testing was done, if the intervention stands a chance at being cost-effective. Currently, typical turnaround times for genetic test results for warfarin sensitivity range from a few days to as long as a week.
A recent observational study conducted by the Mayo Clinic and the pharmacy-benefit manger Medco reported a 30 percent drop in hospitalizations when warfarin was dosed with the help of genetic information. Although the results of that study have convinced many doctors within Medco's system to adopt genetic testing to dose warfarin, some physicians and researchers have criticized those results as being inflated by physician bias, since the trial was not blinded. Furthermore, Medco acknowledged that long turnaround times for testing results also impacted the study results. The median time from warfarin initiation until the genotype was available to the prescribing physician was 32 days (PGx Reporter 03/17/10).
Even previously reported randomized-controlled PGx studies on warfarin dosing have failed to sway payors that the intervention improves patient outcomes and is cost-effective over standard methods.
One study, published in Circulation in November 2007, called Couma-Gen, was a much anticipated randomized-controlled trial conducted by researchers at the University of Utah and LDS Hospital of Intermountain Healthcare. It compared outcomes when patients were initiated on warfarin by genetic risk factors versus clinical factors only. The study did not reach its primary endpoint of a reduction in bleeding outcomes, but researchers concluded that "an algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation."
Iverson Genetics' study is the second PGx-guided warfarin dosing trial approved under CED since CMS issued its decision last May. The first such trial to receive CED coverage was a study looking at the utility of genetic testing to personalize warfarin dosing in orthopedic patients (PGx Reporter 04/14/10).
The five-year Genetics Informatics Trial of Warfarin, or GIFT, is being led by Brian Gage, an internist and health service researcher at Washington University School of Medicine, St. Louis, and involves 1,600 knee or hip replacement surgery patients. The study received $3.7 million from the National Heart, Lung, and Blood Institute and genotyping is reimbursed by CMS.
Gage was originally the principal investigator for Iverson Genetics' warfarin study but handed the job over to Ofili when he received NHLBI funding for GIFT. However, Gage remains on the steering committee for Iverson Genetics' study and has worked with Ofili and faculty at Duke University to help design the trial. Gage, the developer of warfarindosing.org, a website that calculates warfarin doses for healthcare providers using genetics and clinical factors, told PGx Reporter that both GIFT and Iverson's study will use the website to calculate dosages.
Iverson Genetics plans to begin recruiting patients in September after all 50 sites have garnered approval from institutional review boards.