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Public Comments Favoring CMS Coverage of Warfarin PGx Dosing May Not Be Enough

Although the majority of public comments submitted to a recent Centers for Medicare and Medicaid Services notice favors coverage for pharmacogenomic-guided warfarin testing, such opinion, without convincing clinical utility data to back it up may not be enough to affect a change in CMS’ coverage policy.
Payor groups, professional organizations, academia, industry, healthcare providers, and patients submitted around 70 responses to a national coverage assessment notice CMS issued in 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. 
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 (see chart below).
However, responses from around 18 percent of respondents, mostly professional organizations such as the American Heart Association, America’s Health Insurance Plans, and the Anticoagulation Forum; the insurer Blue Cross and Blue Shield Association; and some healthcare providers, showed they did not want CMS to cover genetic testing for the widely prescribed anticoagulant.
Although the majority of public opinion seems to weigh in favor of CMS coverage, at least one industry observer knowledgeable of CMS’ inner workings is not optimistic that the agency will issue a positive decision for gene-based warfarin dosing.
“Most insurer policies I am aware of do not yet cover warfarin genetics, and since CMS follows similar principles, I would not expect full coverage at CMS either,” said Bruce Quinn, senior health policy specialist at the law firm Foley Hoag, where he focuses on Medicare coverage and payment matters for new technologies. 
However, “CMS does have other options such as [providing] coverage within a trial,” added Quinn, who was formerly the contractor medical director for California’s Medicare Part B program.
Similarly, 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.
Having gauged public sentiment on the matter, CMS will now sift through the evidence in published studies and treatment guidelines issued by professional organizations, and issue its final decision on Feb. 4.
“We, of course, consider all the public comments, but our own staff does an exhaustive study of all the evidence, particularly clinical trials,” CMS spokesperson Donald McLeod told Pharmacogenomics Reporter this week. “What we look for is valid scientific evidence.”
Enough Evidence?
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]. 
Despite the update, most national insurers have decided to not cover genetic tests for warfarin dosing, maintaining that there is insufficient evidence confirming the clinical utility of the technology.
Reflecting this sentiment, America’s Health Insurance Plans, a national association representing nearly 1,300 health insurance plans, told CMS in public comments that some of its member payor organizations have decided to cover testing, but “many have not, as there still remain questions about the effectiveness of improving patient outcomes and the clinical utility of pharmacogenomic testing of warfarin response.”
The Blue Cross Blue Shield Association, an association of local insurers serving 100 million customers nationwide, also issued comments against CMS coverage, noting that while the assessments by the American College of Medical Genetics and the California Technology Assessment Forum have been able to establish the clinical validity of genetic testing to dose warfarin, these reviews did not conclude that the technology helps improve patient outcomes.
For instance, the ACMG’s review, conducted last August, found no studies that showed that the intervention reduced high INR values, the time-to-stable INR, or the occurrence of serious bleeding events. However, based on assumptions of clinical utility, ACMG estimated that the number of people who had to be genetically tested and warfarin-dose adjusted to avoid one serious bleeding event ranged from 48 to 385, with a cost-per-serious bleed event ranging from between $14,500 to $95,900.

“CMS does have other options, such as [providing] coverage within a trial.”

“Key assumptions that strongly influence this cost estimate are the effectiveness of reduced warfarin dose in avoiding serious bleeding (range 80 percent to 20 percent in a sensitivity analysis) and the cost of genetic testing (range $300 to $500),” the ACMG stated in its review.
Meanwhile, only one payor, Medco, wrote in support of CMS coverage. The pharmacy-benefits manager argued that based on pharmacological mechanisms, clinical data, and physician, patient, and payor demand for PGx testing for warfarin within its own system, the intervention “is reasonable and necessary” under the Medicare program.
Medco, the second-largest PBM in the US with 60 million beneficiaries, in December 2006 partnered with the Mayo Clinic to study the clinical and economic utility of using molecular diagnostics to help physicians dose warfarin [see PGx Reporter 12-06-2006].
In this study, nearly half of all patients contacted agreed to participate and 75 percent of doctors ordered the test, Medco said in comments to CMS. When the PBM offers the test commercially to its customers, nearly 99 percent of patients take the test and 50 percent of the physicians contacted ordered the test, according to the firm.
All industry representatives, as well as most patients and patient advocates who commented on CMS’s NCA were in favor of CMS coverage of warfarin testing. Industry commentators included warfarin test developers and testing service providers, including Genelex, Applied Biosystems, Genomas, DNA Direct, ParagonDx, and Kimball Genetics.
Meanwhile, healthcare providers were evenly split on the matter (four in favor; four against), with one doctor from Marshfield Clinic advocating for conditional coverage of the technology. Marshfield Clinic is one of the research collaborators in the recently launched Wisconsin Genomics Initiative, which aims to study 20,000 patient samples for one million genetic markers, and ultimately, translate personalized healthcare research into real-world medical practice (see related article, in this issue).
Two academics similarly urged conditional coverage.
“It is premature to encourage widespread testing for CYP2C9 and VKORC1 genetic variants through national coverage,” Jeffrey Tice, assistant professor of medicine at the University of California – San Francisco, wrote to CMS. “However, given the promise of the technology, it would be an ideal candidate for coverage with evidence development in support of ongoing trials.”
Brian Gage, associate professor of medicine at Washington University in St. Louis, also suggested CMS cover the intervention under certain circumstances: if the patient is starting warfarin for the first time; the genotyped results will be available before the fourth dose is prescribed; the patient would be at high risk of hemorrhage if the INR is elevated; and the patient requires parental anticoagulation therapy while his or her INR is subtherapeutic.
Gage’s research has focused on pharmacogenomic-based warfarin testing, and he helped develop, a free site designed to help doctors estimate warfarin doses by applying an algorithm that uses clinical factors and patients’ genotypes. In his comments to CMS, he noted that prior trials on PGx warfarin dosing have been too small and further study is needed.
Among commentators who told CMS to not provide coverage for warfarin testing, several noted the agency should reassess the matter after some large prospective trials are completed.
For instance, the AHRQ and the NHLBI are funding randomized controlled trials that will enroll more than 1,500 patients starting on warfarin. Additionally, several academic and government institutions, including the University of Washington in Seattle, the University of Utah, the FDA in partnership with 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.
FDA Push
Since the FDA updated the warfarin label with genetic risk association information over a year ago, Lawrence Lesko, director of FDA’s Office of Clinical Pharmacolog,y has been publicly urging greater adoption of genetic testing in this field.
In the March issue of Personalized Medicine, Gage and Lesko 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, whose name is a take on warfarin’s brand name Coumadin, 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, 2007, 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.” 
In recent comments to Pharmacogenomics Reporter, Lesko suggested that after some of the studies on PGx warfarin dosing are completed, FDA may revisit the warfarin label, and update it with more convincing data.
Since the labeling update last year, “more prospective and retrospective studies have been reported in the literature,” Lesko said. “We are actively looking into these data to determine if it would be possible and feasible to link label recommendations on dosing with genotypes of 2C9 and VKORC1.”
Although public opinion in favor of PGx-guided warfarin testing alone may not be enough to garner a positive coverage decision from CMS, genetic test developers maintain 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.

Public Comments to CMS National Coverage
Assessment for PGx Warfarin Testin
Professional Organizations
Healthcare Providers
Patients/Unknown Affiliation
Total Comments

SOURCE: CMS Public Comments

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