The Centers for Medicare and Medicaid Services earlier this month launched an investigation to determine if the nation’s Medicare program should cover pharmacogenomic testing for the widely-prescribed anticoagulant warfarin.
The agency’s determination could play a significant role in shaping the policies of private insurers, most of which remain unconvinced of the technology’s clinical utility and have so far not covered it.
On Aug. 4, CMS announced that it is “internally opening [a] National Coverage Analysis (NCA) to complete a thorough review of the evidence to determine if the use of pharmacogenomic testing for warfarin is reasonable and necessary under the Medicare program.”
According to the agency, it initiated the NCA in light of limited clinical evidence that warfarin dosing guided by pharmacogenomic testing yields positive health outcomes.
A year ago, the US Food and Drug Administration updated the label for warfarin to note that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. The agency did not require physicians to genetically test their patients, however, noting that additional outcomes studies would be necessary [see PGx Reporter 9-5-2007].
Since then, the FDA has approved a handful of warfarin sensitivity test kits from several companies, including ParagonDx, Nanosphere, Autogenomics, and Osmetech, but gene-based warfarin testing has not been widely adopted by physicians, and insurers have been slow to cover PGx-guided warfarin testing [see PGx Reporter 09-26-2007].
“Clearly, an individual patient's initial response to warfarin therapy may be influenced by a multitude of factors well beyond genetic variation,” CMS said in a statement announcing its NCA. “We are concerned by the paucity of evidence available to determine what effect on overall health outcomes, if any, can be confidently attributed to treatment strategies that include pharmacogenomic testing in the determination of dosing.”
To help guide its coverage decision, CMS is inviting the public to comment on the issue until Sept. 3. A decision from the agency is expected on Feb. 4, 2009.
Many private insurers look to CMS’ coverage decisions when determining what they will cover. Although industry observers have noted that a positive NCA from CMS can help spur coverage from private insurers, CMS refused to recognize the connection.
“Our decisions are not bearing on private insurers,” a CMS spokesperson told Pharmacogenomics Reporter this week.
It appears CMS launched the NCA because it is skeptical about existing evidence backing PGx-guided warfarin dosing. For instance, CMS said that the clinical trials the FDA used to update warfarin’s label were too small, and the resulting labeling language does not definitively support PGx-guided warfarin dosing.
In the most recent label for Bristol-Myers Squibb’s Coumadin, updated in August 2007, under the “Pharmacogenomics” section, the agency cited a meta-analysis of nine qualified studies including 2775 patients it used to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients. And in a study of 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses, FDA reported in the label.
“The trial investigators suggest that pharmacogenomic testing may contribute to the identification of patients who may be more likely to over- or under-respond to warfarin,” CMS noted in its statement. “The dosing information in the label does not require or explicitly recommend pharmacogenomic testing prior to the initiation of warfarin therapy.”
NHLBI’s COAG trial “should provide an unbiased measure of how VKORC1 and CYP2C9 genotyping affects INR control and adverse events.”
However, according to Brian Gage, medical director of the Barnes-Jewish Hospital's Blood Thinner Clinic, currently available data might just be enough for CMS to cover genotyping for warfarin dosing under certain conditions.
“It seems reasonable for CMS to reimburse for genetic testing only when such testing would be cost neutral or cost saving,” Gage, who is also an associate professor of medicine at Washington University in St. Louis, told Pharmacogenomics Reporter this week. He said these instances could include using the test “perhaps in patients who require intravenous or low-molecular-weight heparin while their INR is subtherapeutic.”
Gage’s research has focused on pharmacogenomic-based warfarin testing, and he helped develop WarfarinDosing.org, a free site designed to help doctors estimate warfarin doses by applying an algorithm that uses clinical factors and patients’ genotypes.
He said the warfarin-dosing algorithms have “worked well” in “prospectively validated” trials of patients beginning warfarin. Although Gage acknowledged that previous studies have been too small to determine if genotyping can prevent major adverse events associated with warfarin, he noted that his research shows that under specific conditions PGx-based warfarin dosing can be clinically useful.
In a July 7 article he co-authored in the Journal of Thrombosis and Haemostasis, Thacker et al. argue that genotyping is likely to be beneficial if the following criteria are met: (1) the patient is starting warfarin; (2) the genotype results will be available before the fourth dose is prescribed; and (3) the patient would be at high risk of hemorrhage if the INR is elevated.
Also, in the March issue of Personalized Medicine, Gage and Lawrence Lesko, director of FDA’s Office of Clinical Pharmacology, co-authored a commentary outlining the lessons future clinical researchers can glean from the controversial Couma-Gen Study, which did not reach its primary endpoint of reducing bleeding outcomes [see PGx Reporter 03-19-2008].
The Couma-Gen study was conducted by researchers at the University of Utah School of Medicine and LDS Hospital and Intermountain Healthcare, and was published in the Nov. 7 issue of Circulation. It enrolled more than 200 patients initiated on warfarin and randomized them to receive either PGx-guided dosing or standard dosing protocols that rely only on clinical factors.
Although the study did not reach its primary endpoint, the researchers concluded that “an algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation.” Furthermore, subset analyses indicated that “pharmacogenetic guidance showed promise for wild-type and multiple-variant genotypes.”
The results of the Couma-Gen study “have been reported to deny the value of genotyping, but [in fact] they were intriguing,” Lesko and Gage wrote in the Personalized Medicine commentary. “The trial has important implications … for the design, randomization, blinding, and end-point definition of future studies.”
Lesko has been publicly urging the healthcare community to embrace PGx-guided warfarin dosing. Shortly after the Couma-Gen study appeared, Lesko rebuked participants at a healthcare conference for focusing on the negative aspects of the study and overlooking the positive findings, particularly the discovery that PGx-guided dosing was more accurate than standard dosing methods [see PGx Reporter 12-07-2007].
“There was actually very positive news coming out in the article which people didn’t really focus on,” Lesko said at the time. “There is a sort of bias in the way we look at personalized medicine to kind of look for reasons why not, instead of the reasons why.”
Payors looking for larger trials supporting the use of genotyping in warfarin dosing can look to the Clarification of Optimal Anticoagulation through Genetic trial. The study, funded by the National Heart, Lung, and Blood Institute, will enroll 1,400 patients starting warfarin on doses determined by clinical factors versus genetic-based algorithms.
This trial “should provide an unbiased measure of how VKORC1 and CYP2C9 genotyping affects [international normalization ratio] control and adverse events,” Gage said.
CMS said that when it looks to assess the strength of clinical research to make a coverage decision, it considers the scientific validity of whether healthcare interventions yield positive health outcomes, and looks for trials with limited bias.
For a positive coverage analysis, study findings for a particular intervention must also be the generalizable to the Medicare population and impart a risk/benefit ratio acceptable to CMS.
Despite FDA’s approval of several diagnostic tests that gauge genetic variants associated with increased risk of adverse events with warfarin, large national insurers like Aetna, WellPoint, and Cigna have not yet said they would cover PGx-guided warfarin dosing.
However, there have been reports that United Health Group and CMS plan to reimburse for an FDA-approved test, which currently cost between $300 and $500 [see PGx Reporter 10-10-2007].