Pharmacogenomic Testing for Warfarin Response

June 3, 2009

Dear CMS Panel Members,

Thank you for the opportunity to respond to the CMS memo: Proposed Decision Memo for Pharmacogenomic Testing for Warfarin Response. Osmetech Molecular Diagnostics asks the panel to consider the following in support of the value of pharmacogenetic guided dosing of warfarin as we believe pharmacogenomic guided dosing is indeed of benefit to and improves health outcomes in Medicare beneficiaries.

We believe everyone agrees that the objective of any clinician in initiating warfarin therapy is to get their patient onto a stable therapeutic dose as quickly as possible and to avoid complications, be they, multiple dose changes or adverse events.

Given this clear clinical goal one has to ask: "What is the dose?" The answer, as we all know is not an easy one. There are multiple approaches clinicians now take in trying to achieve the "stable therapeutic dose" such as trial and error, fixed-dose approach, rote experience, medical society suggested dose strategies, algorithms inclusive of patient clinical information, among others while, the Physicians Desk Reference (PDR) contains little to no guidance in respect to selecting the initial dose.

What is known and science has proven is the role a patient''''s CYP2C9 and VKORC1 genes play in the metabolism and activity of warfarin. The functionality of gene specific effects on warfarin metabolism is well documented in scientific communities and has been recognized by highly regarded institutions including the American Medical Association, the FDA, and the Joint Commission. Numerous publications can readily be found in the medical literature including journals such as Blood and The New England Journal of Medicine (NEJM). In fact, as you know, the February 19, 2009 issue of the NEJM includes a compelling article on the benefit of pharmacogenetic guided dosing.

The article entitled: Estimation of the Warfarin Dose with Clinicaland Pharmacogenetic Data authored by The International Warfarin Pharmacogenetics Consortium (IWPC) is clear in their conclusion based on clinical and genetic data from 4043 patients:

The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

I am sure the panel must find it difficult to gloss over the fact that nearly 50% of patients being dosed on warfarin would benefit significantly by pharmacogenetic guided dosing by achieving a stable therapeutic dose sooner than later. How can this evidence not be acknowledged by the panel?

Finally, we would argue that to only pay for the tests of Medicare patients enrolled in a recognized clinical study is to create discrimination against Medicare patients who for a variety of reasons cannot enroll in a clinical study. By doing so, precludes a group of Medicare recipients from receiving the clear benefit from better and more precise dosing of what is a very risky drug. And in turn, we all know patients who are knowledgeable and have the money will seek out the test as any human being wants to avoid drug side effects and to become stabilized on a therapeutic dose as quickly and as effectively as possible.

The use of relevant genetic information does not provide the complete answer to establishing a stable therapeutic dose, but we believe that its use significantly improves the prospects of establishing a safer therapeutic dose for vulnerable patients more quickly. The dangers of inappropriate dosing are all too apparent with 46.2% of patients benefitting from the use of genetic information for initial dosing. It seems illogical to deny any new warfarin patients the benefits of genetic testing.

We ask the panel to reconsider the proposed position, seek common ground with the FDA and recognize the value and benefits of warfarin genetic testing for all Medicare beneficiaries by paying for the test.

Thank you for your reconsideration, as it is the right thing to do.

Sincerely,

Osmetech Molecular Diagnostics
757 South Raymond Avenue, Pasadena, CA 91105
1-626-463-2000

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June 3, 2009

Tamara Syrek Jensen, JD
Acting Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Ms. Syrek Jensen:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services' (CMS's) proposed national coverage determination (NCD), Pharmacogenomic Testing for Warfarin Response (CAG-00400N). America's Health Insurance Plans (AHIP) is the national association representing nearly 1,300 member companies providing health insurance coverage to more than 200 million Americans. We are pleased to submit these comments on behalf of our members.

General Comments
We support CMS's efforts to review all current, available, and valid clinical evidence to determine appropriate coverage for diagnostic tests and treatments that are best shown to be safe, effective, and improve the health outcomes of Medicare beneficiaries. AHIP and our member plans support CMS's proposal to not provide open coverage for pharmacogenomic testing for warfarin response until there is enough evidence collected to show clinical utility and improved outcomes within the Medicare population. Additionally, our members support CMS's intent to provide coverage for these tests through the more rigorous Coverage with Evidence Development (CED) mechanism: Coverage with Study Participation. While current evidence on using genetic testing to guide initial warfarin dosing does show that these tests are effective at identifying those patients with gene variants that affect warfarin response, we remain concerned regarding the lack of sufficient clinical evidence to demonstrate improved patient outcomes, safety, and clinical utility.

As CMS notes within this proposed decision memo, several professional societies (American College of Chest Physicians (ACCP), American Society of Hematology (ASH) and American College of Medical Genetics (ACMG)) have concluded that the evidence is insufficient to support the use of pharmacogenomic testing to guide initial dosing or ongoing treatment of warfarin. Published technology assessments have also concluded that there is a need for clinical studies on the clinical utility and the ability to improve patient outcomes of pharmacogenomic tests for warfarin response. Within the May 2008 report published by the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS), Realizing the Potential of Pharmacogenomics: Opportunities and Challenges, the authors concluded that "…much of the valuable information about pharmacogenomics is in the form of early scientific discoveries. Although this information has the potential to be useful, its clinical utility is not yet well understood."¹

Additionally, a technology assessment published in March 2008 by the California Technology Assessment Forum (CTAF), Use of Genetic Testing to Guide the Initiation of Warfarin Therapy² , stated that current evidence has not demonstrated that the use of genetic information alters warfarin management nor reduces major bleeding. The primary benefit may be in reducing the number of blood draws to assess/adjust clotting time, as there is no consensus on the best method to integrate genotype information into the initial dosing and management of this therapy. It was also concluded that studies have not convincingly demonstrated a significant improvement in potential surrogate markers for bleeding such as the frequency of excessive anticoagulation or the time spent with INR values (the time it takes for blood to clot) outside of the therapeutic range.

Some of our member plans have chosen to cover this testing procedure 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. AHIP urges CMS to encourage clinical trial developers to develop studies that focus on more than one of the potential adverse patient outcomes (major and minor hemorrhage; thromboembolism related to the primary indication for anticoagulation; other thromboembolic events; and mortality) noted within this NCD. Trials should attempt to recruit as many patients as possible in order to achieve the highest level of statistical power and control groups should be genotyped to allow for genetic comparisons.

Our members also recommend that collecting the following outcome measures related to warfarin treatment are necessary within studies to be able to compare randomized populations: time to target international normalized ratio (INR); number of days spent at excess INR; number of days spent at inadequate INR; number of episodes of bleeding complications; number of episodes of clotting complications; and cost effectiveness. Finally, proposed studies should be designed to take into account and record the turnaround time necessary to receive pharmacogenomic test results and the importance of having these results prior to initiating warfarin therapy. Clinical studies approved for CSP coverage containing the above criteria and outcome measures, should significantly add to the current evidence base and help determine the clinical utility of these tests.

Thank you for the opportunity to comment on this important issue.

Carmella Bocchino
Executive Vice President, Clinical Affairs and Strategic Planning

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May 26, 2009

Ms. Maria Ciccanti
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Pharmacogenomic Testing to Predict Warfarin Responsiveness (CAG- 00400N)

Dear Ms. Ciccanti:

I am writing on behalf of Roche Diagnostics Corporation (Roche) to support the Centers for Medicare & Medicaid Services (CMS) proposed coverage under evidence development (CED) decision for pharmacogenomic testing to predict responsiveness to warfarin therapy. Pharmacogenomics uses powerful diagnostic tools to help determine the appropriate course of treatment for a specific patient based on his or her unique genetic characteristics. Part of the rapidly emerging field of personalized medicine, pharmacogenomic-based therapy includes both a pharmaceutical and a companion diagnostic that will help target that pharmaceutical’s use. The health care system must adapt to appropriately cover both the pharmaceutical and diagnostic elements to maximize the benefits to society of appropriate targeting of advanced pharmaceuticals. We believe use of CED is an appropriate first step to providing coverage for pharmacogenomic testing to predict responsiveness to warfarin therapy.

Roche is one of the world’s leading research-focused healthcare firms in both pharmaceuticals and diagnostics. We believe personalized healthcare holds great promise for individual patients and for society as whole as it improves the safety and efficacy of pharmaceutical therapy and thus improves patients’ health, quality of life, and survival. Diagnostic tests that enable fitting the treatment to the patient are key to fully realizing this promise.

At Roche, we are committed to gathering the evidence necessary to document the clinical utility of these tests as we develop them. We recognize that personalized medicine is an emerging field and that patients and payers have a clear interest in the establishment of appropriate levels of evidence before a product is covered. These requirements may rightly vary for a variety of reasons. It is, however, vital that such evidence requirements balance the benefits of stronger evidence (e.g., reduced uncertainty) with the costs that may result from more extensive evidence development (e.g., delayed access to new products). It is also essential that questions of coverage for pharmaceuticals and companion diagnostics take into consideration the specific clinical context and concerns of the particular treatment.

In some instances, Medicare’s coverage under evidence development may be the appropriate approach. CED allows the Medicare program to provide coverage for a new item or service in a controlled environment and thus to support development of additional evidence. CED acknowledges the potential value of a new test and provides a means to gather additional data to confirm that potential.

We applaud CMS for recognizing both the potential contribution pharmacogenomic testing can make in effectively managing patients on warfarin therapy and the importance to Medicare beneficiaries and the program of avoiding or reducing the risks attendant on the narrow therapeutic window for the treatment. Especially given the interaction of warfarin with the patient’s diet and with other drugs, we recognize the complexity of managing patients receiving warfarin therapy. We understand that, in these circumstances, further randomized controlled studies may be appropriate for CED. However Roche urges CMS to consider the specific clinical contexts involved in any future decisions regarding pharmacogenomic testing and not assume that CED or, if CED is used, further randomized clinical trials are necessary or appropriate in all cases. In this instance, Roche supports covering pharmacogenomic testing relating to warfarin under CED and appreciates CMS’ targeted approach to allow coverage for innovative tests. We also look forward to working with CMS as it determines appropriate coverage of personalized healthcare for Medicare beneficiaries in a variety of circumstances.

Sincerely,

Tadd S. Lazarus, M.D.
Medical Director
Roche Diagnostics

TLS/bbs

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At this time, the current evidence regarding the use of genotyping tests for the determination of drug metabolizer status indicates that while the available testing methods accurately identify the genetic makeup of patients, there is insufficient data to demonstrate that such testing, and the clinical decisions made based on them, results in a significant impact on health outcomes. Specifically, there have not been any clinical trials that have adequately demonstrated that such testing results in decreased short-term or long-term adverse events.

Perhaps the most studied area regarding the use of genotype polymorphism testing involves genetic variations in enzymes key to the metabolism and operation of the drug warfarin. A significant amount of evidence has shown that the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase enzyme subunit C1 (VKORC1) have the most significant role in warfarin metabolic variability (Higashi, 2002; Kirchheiner, 2005; Osman, 2006; Sconce, 2005.) Some reports attribute approximately 55% of warfarin dose variability to these two variants (Wadelius, 2005; Sconce, 2005.)

A published report by McClain and colleagues (2007), conducted for the American College of Medical Genetics, evaluated the use of CYP405 and VKORC1 testing the use of patients receiving warfarin due to increased risk of thrombotic events. The authors concluded the following:

• Analytic validity: Nearly all available data for analytic validity refer to two variants in the CYP2C9 gene; fewer data are available for the variants in the VKORC1 gene. Based on these data, analytic sensitivity and specificity are likely near 100%. Depending on methodology, 1% to 10% of samples may experience repeated assay failures resulting in inconclusive test results.
• Clinical validity: CYP2C9 and VKORC1 genotypes contribute significant and independent information to the stable warfarin dose and compared to the most common combination, some individuals with other genotype combinations will need more than the usual dose, while others would require less. Time to steady state warfarin levels varies by CYP2C9 genotype (3 to 5 days vs. 5 to 8 vs. 12 to 15 for the three most common genotypes). CYP2C9 positive predictive value (PPV) for serious bleeding events is estimated to be 7%; the negative predictive value (NPV) is 96%. Similar information for VKORC1 was not available.
• Clinical utility: The purpose of genetic testing in this clinical scenario is to predict an individual''s likely stable warfarin dose by incorporating demographic, clinical, and genotype data (CYP2C9 and VKORC1), and initiate warfarin at that predicted dose as a way to limit high INR (International Normalized Ratio) values (over-anticoagulation) that are associated with an increased risk of serious bleeding events. No large study has yet shown this to be acceptable or effective. Several randomized trials are underway to determine the clinical utility. The number needed to treat to avoid one serious bleeding event is estimated to range from 48 to 385.

In a more recent publication from the College of Medical Genetics, Flockhart and colleagues describe the conclusions of a review of the currently available evidence for VKORC1 and CYP2C9 allele testing (2008). In this document the authors conclude:

• The analytical validity VKORC1 and CYP2C9 allele testing has been met.
• There is strong evidence to support association between VKORC1 and CYP2C9 variants and therapeutic dose of warfarin.
• There is insufficient evidence to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients.
• Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing.

Several published articles describing warfarin dosing models indicate that several clinical trials are underway to address these issues (Millican, 2007; Zhu, 2007.)

A study by Anderson and colleagues (2007) indicates some promise for the use of genetic polymorphism testing for patients receiving warfarin therapy. In their randomized blinded study of 206 patients, the investigators compared pharmacogenic-guided therapy vs. standard dosing methodology. While the results indicated that the pharmacogenic-guided therapy more closely approximated stable doses, resulting in significantly smaller and fewer dosing changes, the primary endpoint of reducing out-of-range INRs was not significantly different. However, in a post-hoc subset analysis, the authors reported that in wild-type patients and those with multiple variant carriers the differences were significant between groups. The authors indicate that additional research is warranted based upon their findings.

While the potential of pharmacogenomics is intriguing for many clinical applications, it is not yet clear which are most likely to yield clinical benefit in the near future. As this field evolves and matures, and if pre-prescription testing is shown to be of clinical utility for specific drugs, it will be important to establish evidence-based guidelines for health care professionals delineating the most effective courses of action based on genotype testing results.

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May 11, 2009

Centers for Medicare & Medicaid Services
Via online comment posting
Re: Pharmacogenomic Testing for Warfarin

The Blue Cross and Blue Shield Association (BCBSA), an association of 39 independent Blue Cross and Blue Shield Plans that collectively provide health insurance benefits to 102 million Americans, appreciates the opportunity to comment on the national coverage determination proposed by the Centers for Medicare and Medicaid Services (CMS) on the Proposed Decision Memo for Pharmacogenomic Testing for Warfarin Response. We believe the proposed Decision Memo is fair, in agreement with the existing evidence, and promotes the collection of the necessary evidence to make an eventual determination of the clinical utility of such testing.

Although a full-scale randomized, comparative clinical trial may not be appropriate or feasible to determine the clinical utility of a genetic test in every case, we believe it is highly appropriate in this case given the large population potentially affected and therefore the large public health impact, the existence of easily measurable outcomes, and the relatively short duration needed to attain those outcomes. This Decision Memo would promote enrollment in already ongoing clinical trials and ensure their timely completion. We look forward to the results.

Thank you for the opportunity to provide comments. We hope that you will consider them in your decision.

Sincerely,

Allan M. Korn, MD
Senior Vice President and Chief Medical Director
Blue Cross and Blue Shield Association
Chicago, Illinois

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Your proposed ruling on genetic testing for warfarin says, “we do believe the available evidence suggests that Coverage with Evidence Development (CED) under §1862(a)(1)(E) of the Social Security Act is appropriate.” I oppose this proposed coverage of further research of this test and submit as evidence two of my articles that have been published in the medical literature:

• A Systematic Review of Cochrane AnticoagulationReviews.¹
• Clinical Evidence For Rebound HypercoagulabilityAfter Discontinuing Oral Anticoagulants For VenousThromboembolism ²

The first article challenges the efficacy in reducing morbidity and mortality from clotting for warfarin and other vitamin K antagonists for all FDA approved and off-label indications. If warfarin is not efficacious, the bleeding risks are not justified. For 4.1 million Americans using warfarin and other VKAs in 2008,³ 94,000 –490,000 (2.3% – 12%)^4-8 had major bleeds and 33,000 – 49,000 (0.8% – 1.2%)^4-8 bled to death.

The second article documents that warfarin withdrawal causes clinical rebound hypercoagulation events in about 2% of patients with venous thromboembolism. In most trials of warfarin use, adverse events are not monitored after the drug is stopped, so these adverse events are not considered in efficacy analysis. Since 1 -2 million Americans discontinue warfarin per year,20,000 - 40,000 warfarin-withdrawal adverse events occur per year.

Thank you for considering the evidence in these articles.

Best wishes,

David K. Cundiff, MD

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