Genomic Tests For Warfarin Could Gain Coverage With Study Participation

Under a CMS proposal, genomic testing to predict warfarin response would receive Medicare coverage in the context of a clinical trial comparing the frequency of five kinds of adverse events with and without the tests.

CMS wants more evidence that genetic testing of individuals' responsiveness to the blood thinner warfarin actually improves health outcomes in Medicare populations, and the agency is using the national coverage process to call for randomized clinical trials.

In a proposed coverage decision issued May 4, CMS says Medicare cannot, based on available evidence, cover pharmacogenomics warfarin testing for routine use, but it can do so when employed as part of controlled clinical studies.

The proposal opens a 30-day public comment period on the coverage-with-study-participation plan. The Medicare agency opened the national coverage analysis last August, the first NCA for a pharmacogenomic diagnostic (¹ (Also see "Medicare Considers Coverage Policy For Genetic Warfarin Dosing Tests" - Medtech Insight, 11 Aug, 2008.), p. 11).

CMS defines pharmacogenomics as the study of how an individual's genetic makeup, or genotype, affects the body's response to drugs. During a Medicare Evidence Development and Coverage Advisory Committee meeting on the topic in February, several panelists suggested CMS use its authority to condition national coverage on additional evidence collection as a means to get more data on these types of assays, CMS reports.

As a general rule, coverage with study participation "is to be used in rare instances," CMS explains, but it may be appropriate where there is evidence of safety, a high potential to provide significant benefit to Medicare beneficiaries and significant barriers to conducting clinical trials otherwise.

CMS wants randomized data

Under the proposed decision, genomic testing to predict warfarin response would receive Medicare coverage only "in the context of a prospective, randomized, controlled clinical trial."

CMS aims to compare the frequency of adverse events between Medicare-aged patients whose warfarin therapy does and does not include genetic dosing tests.

The five types of adverse events CMS wants to monitor, particularly within the first month of warfarin therapy, are major hemorrhage, minor hemorrhage, thromboembolism related to the primary indication for anticoagulation, other thromboembolic events and mortality.

Used by more than a million people in the U.S. each year, warfarin - often sold under the brand name Coumadin - is indicated for patients with atrial fibrillation, venous thromboembolism, valvular heart disease, cerebrovascular disease and cardiac valve replacements.

A side effect of warfarin is excessive bleeding, which can be fatal. The risk can be mitigated with a dosage adjustment following regular PT/INR tests (prothrombin time/International Normalized Ratio).

Genomic tests, on the other hand, are used once to help predict a patient's initial response to the drug to help a physician find the most appropriate dose the first time, reducing the risk of bleeding.

CMS wants to learn whether genomic testing changes physicians' plans for their patients' therapy and whether those patients experience better health outcomes.

"Although pharmacogenomic testing would be used to better approximate the best starting dose of warfarin, it would not eliminate the need for periodic PT/INR testing," the agency writes in its proposal.

Current guidelines already recommend starting elderly warfarin patients with a low dose.

"Since the lower initiation dose recommendation is already relevant to [the] Medicare population in general, it is not clear that pharmacogenomic testing itself adds additional actionable information to further guide physician management," the agency writes.

Compared with their younger counterparts, older patients tend to "have multiple co-morbid conditions for which they take drugs of various classes known to interact with warfarin," the decision memo states.

FDA-cleared tests for the VKORC1 and CYP2C9 genetic variants associated with warfarin metabolism include Nanosphere's Verigene , AutoGenomics' INFINITI , ParagonDx Rapid Genotyping Assay , Osmetech's eSensor and TrimGen's eQ-PCR (² (Also see "Clinicians Split On Warfarin Gene Testing As A New Standard Of Care" - Medtech Insight, 4 Aug, 2008.), p. 6). Many clinical laboratories offer their own home brew assays as well.

Drug label cites but doesn't mandate genotyping

In 2007, FDA started requiring that information on testing for VKORC1 and CYP2C9 genetic variants be added to warfarin labeling (³ (Also see "Personalized Genetic Test Info Added To Warfarin Drug Labeling" - Medtech Insight, 20 Aug, 2007.), p. 9).

CMS stresses, however, that "the label does not require or explicitly recommend pharmacogenomic testing prior to the initiation of warfarin therapy."

Despite the updates to the FDA label, most insurance carriers do not cover genetic warfarin sensitivity tests, according to Washington Research Group analyst David Blaszczak. "However, Medicare national coverage decisions have shown to have impact on commercial payers in the past," he writes in a May 5 research note.

In its proposed decision, CMS says that professional societies differ on whether there is yet enough evidence to provide Medicare coverage for genomic testing for warfarin.

"Societies that represent providers who treat the patients with warfarin therapy note the need for more research on this issue," CMS writes, while those representing laboratory professionals "believe that there is sufficient evidence for coverage."

A 2008 technology assessment for CMS commissioned by the Agency for Healthcare Research and Quality found that no studies under the review addressed the Medicare agency's questions about subsequent therapeutic management after pharmacogenomic testing.

The assessment also noted nine ongoing clinical trials on pharmacogenomic testing of CYP2C9 and VKOCRC1 registered with clinicaltrials.gov.

Although the evidence is not yet conclusive, CMS says it believes "the addition of this technology may present the best alternative to current practice."

Comments are due by June 3, and a decision is expected by August 3.

-Monica Hogan ([email protected])

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