This article has been updated from an earlier version to include additional comments.
Finding insufficient evidence demonstrating that pharmacogenomics-guided warfarin dosing improves health outcomes for Medicare beneficiaries, the Centers for Medicare & Medicaid Services this week determined that pharmacogenomic testing to predict warfarin responsiveness is "not reasonable and necessary."
Instead, CMS proposed a more "appropriate" alternative, employing a "coverage with evidence development" strategy, in which it would pay for PGx-based warfarin dosing only for Medicare beneficiaries who are part of a prospectively designed, randomized-controlled trial showing pharmacogenomics-guided dosing strategies improve health outcomes over standard dosing methods.
CMS is soliciting comments on this proposal until June 3.
Most major insurers do not yet cover genetic testing to gauge warfarin responsiveness for their beneficiaries. However, many private payors follow CMS' lead when determining whether to cover new technologies. A CED decision from CMS on genetic testing for warfarin could signal private payors to hold off on covering genetic testing in this area until large, randomized, prospective studies are completed, yielding more convincing outcomes data.
At least one large, national insurer, Aetna, told Pharmacogenomics Reporter that it does not currently cover PGx testing for warfarin and suggested that CMS' CED proposal will not inspire any policy changes in the near term.
"Aetna currently does not cover diagnostic genetic tests for warfarin because the clinical value of this type of genetic testing has not been established," an Aetna spokesperson said. "Aetna would not currently cover them in a clinical trial setting either."
According to Bruce Quinn, senior health policy specialist at the law firm Foley Hoag, while CMS' proposal is consistent with the majority of private insurers, it does open up new debates surrounding design of acceptable studies that would garner Medicare coverage.
Under the CMS proposal, coverage for Medicare beneficiaries will be granted only when a prospective, randomized trial finds that PGx-guided warfarin dosing compared to standard methods lessens the frequency and severity of hemorrhage and thromboembolism, or reduces mortality. In order to receive payment, studies must adhere to "appropriate standards of scientific integrity," and relate to the Medicare population, according to the standards laid out by CMS.
CMS' draft position opens "the question of what trials would be appropriate, at what cost, scale, and time," said Quinn, who was formerly the contractor medical director for California’s Medicare Part B program. "A very tightly managed trial, for example, might have little relevance to average test use.
"What if CMS wants an [randomized-controlled trial], for example, but the IRB at [the] Mayo [Clinic] were to find it unethical?," Quinn posited. "The next moves ... [leading up] to the final process put a lot of issues in play."
Meanwhile, at least one diagnostic firm with its hat in the warfarin genetic testing space expressed disappointment over CMS' proposal.
"The coverage for patients in a prospective, randomized, controlled clinical study is ... puzzling as these studies are generally covered by grants," said Ramanath Vairavan, senior VP of sales and marketing for AutoGenomics, one of several companies marketing a genetic test for warfarin sensitivity.
The Carlsbad, Calif.-based firm's Infiniti Warfarin XP dose-response assay for identifying patients with CYP450 2C9 and VKORC1 genetic variants received 510(k) clearance from the FDA last January [see PGx Reporter 01-30-2008].
"This illogical decision perhaps has been influenced by the lobbying of big pharma, that in spite of numerous prospective studies and publications that have clearly shown the benefit for genetic testing and the FDA relabeling of the drug, CMS has succumbed into making a contradictory decision that will certainly impact patient well being and the cost of healthcare," Vairavan told Pharmacogenomics Reporter this week. "As a manufacturer of the test we appeal to CMS to revisit this controversial decision at the earliest."
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The CED proposal follows a national coverage assessment notice that CMS issued last August, asking the public to weigh in on whether the government agency should pay for tests that determine which patients are genetically predisposed to experience an adverse reaction to warfarin [see PGx Reporter 10-29-2008].
In response to CMS' NCA, around 75 percent of respondents said CMS should cover such tests because there is sufficient clinical evidence showing that PGx-based warfarin dosing would reduce adverse events and save healthcare dollars in the long run. However, around 18 percent of respondents, mostly professional organizations, payors, and some healthcare providers, said they did not want CMS to cover genetic testing for the widely prescribed anticoagulant.
However, at the time, a few doctors and academics suggested in public comments that CMS should cover genetic testing for warfarin under certain circumstances or employ a conditional coverage scheme to spur research and gather clinical evidence.
While CMS was considering the public's comments and making its decision, a meta-analysis from the University of Cincinnati concluded that it may not be cost-effective to perform genetic tests to guide initial warfarin dosing in "typical" patients with atrial fibrillation, but it may be cost-effective to test individuals at high risk for hemorrhage. The study was published in the Annals of Internal Medicine in January [see PGx Reporter 01-21-2008].
"Although there is little doubt that warfarin dosing should be more cautious in patients known to have certain genetic variants, the cost effectiveness of routine testing is uncertain," Brian Gage, associate professor of medicine at Washington University in St. Louis and an author of the Annals of Internal Medicine study, told Pharmacogenomics Reporter this week.
Gage, developer of WarfarinDosing.org, a free site designed to help doctors estimate warfarin doses by applying an algorithm that uses clinical factors and patients' genotypes, has been a longtime proponent of a CED strategy for PGx-guided warfarin dosing.
Previously, Gage recommended that CMS should provide coverage under several scenarios: if the patient is starting warfarin for the first time; if the genotyped results will be available before the fourth dose is prescribed; if the patient would be at high risk of hemorrhage if the INR is elevated; and if the patient requires parental anticoagulation therapy while his or her INR is subtherapeutic.
Gage attributed the uncertainty around whether genetic testing improves outcomes in warfarin-treated patients to the prevalence of randomized trials that are too small and thus have yielded heterogeneous results of pharmacogenetic testing. "As evidence from additional studies becomes available, Medicare should re-evaluate their coverage decision," Gage said.
There are several large outcomes studies evaluating PGx-guided warfarin dosing.
The Agency for Healthcare Research and Quality and the National Heart, Lung, and Blood Institute are funding randomized controlled trials that will enroll more than 1,500 patients starting on warfarin. In addition, the University of Washington in Seattle, the University of Utah, the US Food and Drug Administration, the principal investigators of the Harvard Creating an Optimal Warfarin Nomogram Trial, and the Warfarin Pharmacogenomics Consortium are enrolling 5,000 patients in a study to develop a PGx-based dosing algorithm for warfarin.
Since the FDA updated warfarin's label with genetic risk association information in 2007, agency officials have been urging greater adoption of genetic testing in this field. However, genetic test developers have maintained that more convincing guidance from the FDA could very well be the missing key in changing the coverage policies of private payors and CMS with regard to warfarin testing.
In August 2007, the FDA updated the label for warfarin to note that people with variations of the genes CYP2C9 and VKORC1 may respond adversely 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 09-05-2007].
Lawrence Lesko, director of FDA's Office of Clinical Pharmacology, previously told Pharmacogenomics Reporter that the agency is reviewing newly published retrospective and prospective data and considering updating the anticoagulant's label once again with genetically guided dosing information.