**Nationally Covered Indications**

Effective August 3, 2009, the Centers for Medicare & Medicaid Services (CMS)
believes that the available evidence supports that coverage with evidence
development (CED) under 1862(a)(1)(E) of the Social Security Act (the Act) is
appropriate for pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict
warfarin responsiveness by any method, and is therefore covered only when
provided to Medicare beneficiaries who are candidates for anticoagulation
therapy with warfarin who:

  1. Have not been previously tested for CYP2C9 or VKORC1 alleles; and
  2. Have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and
  3. Are enrolled in a prospective, randomized, controlled clinical study when that study meets the following standards.

A clinical study seeking Medicare payment for pharmacogenomic testing of
CYP2C9 or VKORC1 alleles to predict warfarin responsiveness provided to the
Medicare beneficiary who is a candidate for anticoagulation therapy with
warfarin pursuant to CED must address one or more aspects of the following
question:

Prospectively, in Medicare-aged subjects whose warfarin therapy management
includes pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict
warfarin response, what is the frequency and severity of the following
outcomes, compared to subjects whose warfarin therapy management does not
include pharmacogenomic testing?

  * Major hemorrhage
  * Minor hemorrhage
  * Thromboembolism related to the primary indication for anticoagulation
  * Other thromboembolic event
  * Mortality

The study must adhere to the following standards of scientific integrity and
relevance to the Medicare population:

  1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants' health outcomes.
  2. The research study is well-supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
  3. The research study does not unjustifiably duplicate existing studies.
  4. The research study design is appropriate to answer the research question being asked in the study.
  5. The research study is sponsored by an organization or individual capable of executing the proposed study successfully.
  6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the FDA, it also must be in compliance with 21 CFR Parts 50 and 56.
  7. All aspects of the research study are conducted according to the appropriate standards of scientific integrity.
  8. The research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards.
  9. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR  312.81(a) and the patient has no other viable treatment options.
  10. The clinical research study is registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject.
  11. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than 3 years after the end of data collection.
  12. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
  13. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

Consistent with section 1142 of the Act, the Agency for Healthcare Research
and Quality (AHRQ) supports clinical research studies that CMS determines meet
the above-listed standards and address the above-listed research questions.

**B. Nationally Non-Covered Indications**

The CMS believes that the available evidence does not demonstrate that
pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin
responsiveness improves health outcomes in Medicare beneficiaries outside the
context of CED, and is therefore not reasonable and necessary under
1862(a)(1)(A) of the Act.

**C. Other**

This NCD does not determine coverage to identify CYP2C9 or VKORC1 alleles for
other purposes, nor does it determine national coverage to identify other
alleles to predict warfarin responsiveness.

**(This NCD last reviewed August 2009.)**