MolDX: Molecular Testing for Solid Organ Allograft Rejection

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS Internet Only Manuals, Pub 100-02 Medicare Beneficiary Policy Manual chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

This Medicare contractor will provide limited coverage for molecular diagnostic tests used in the evaluation and management of patients who have undergone solid organ transplantation. These tests can inform decision making along with standard clinical assessments in their evaluation of organ injury for active rejection (AR).

These tests may be ordered by qualified physicians considering the diagnosis of AR affiliated with a transplant center, helping to rule in or out this condition when assessing the need for or results of a diagnostic biopsy. They should be considered along with other clinical evaluations and results and may be particularly useful in patients with significant contraindications to invasive procedures.

Molecular diagnostic tests that assess a transplanted allograft for rejection status are covered when ALL of the following criteria are met:

• The test must provide information about at least one of the two following clinical status determinations:
• AR status
• Cellular or Antibody-mediated rejection (ACR or AMR) status
• The intended use of the test must be:
• To assist in the evaluation of adequacy of immunosuppression, wherein a non-invasive or minimally invasive test can be used in lieu of a tissue biopsy in a patient for whom information from a tissue biopsy would be used to make a management decision regarding immunosuppression, OR
• As a rule-out test for AR in validated populations of patients with clinical suspicion of rejection with a non-invasive or minimally invasive test to make a clinical decision regarding obtaining a biopsy, OR
• For further evaluation of allograft status for the probability of allograft rejection after a physician-assessed pretest, OR
• To assess rejection status in patients that have received a biopsy, but the biopsy results are inconclusive or limited by insufficient material.
• The test demonstrates analytical validity (AV), including an analytical and clinical validation for any given measured analytes, and has demonstrated equivalence or superiority for sensitivity or specificity (depending on intended use) of detecting allograft rejection to other already-accepted tests for the same intended use measuring the same or directly comparable analytes.
• Clinical validity (CV) of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population. The degree of validity must be similar or superior to established and covered tests (see associated coverage Articles). If conducted with concordance to tissue histologic evaluation the Banff Classification for renal allografts or other accepted criteria (if existing) for other organs must be used.
• The test is being used in a patient who is part of the population in which the test was analytically validated and has demonstrated CV.
• For a given patient encounter, only one molecular test for assessing allograft status may be performed UNLESS a second test, meeting all the criteria established herein, is reasonable and necessary as an adjunct to the first test.
• For minimally or non-invasive tests, the benefit to risk profile of the molecular test is considered by the ordering clinician to be more favorable than the benefit to risk profile of a tissue biopsy, or a tissue biopsy cannot be obtained. For example, this may be the case if a biopsy is considered medically contraindicated in a patient.
• The test successfully completes a Technical Assessment that will ensure that AV, CV, and clinical utility criteria set in this policy are met to establish the test as Reasonable and Necessary.

Covered tests with AV that is significantly below similar services may have coverage rescinded.

Allograft solid-organ transplantation has become a standard of care in patients with end-stage organ disease. In some patients, these treatments, along with other advances in care, have transformed fatal disease into treatable and preventable disease^1-3 After transplantation, patients are placed on immunosuppressant drug therapy and routinely monitored to prolong the survival of the donor allograft. The cost for managing a failed allograft may be 500% more than a patient with a functioning transplant.⁴ Early detection of AR has led to significant improvement in allograft survival in the first 12 months posttransplantation.⁵

The importance of graft rejection and immunosuppression was discovered early on following the development of transplantation, a challenge that started to be overcome with the availability of immunosuppressants, though with the current standard-of-care for managing solid organ transplant patients, rejection remains a common problem with a high frequency of graft failure at 5 and 10 years.^4,6-8 Acute rejection occurs as cellular rejection (ACR) or antibody-mediated rejection (AMR).⁹

Graft assessment is used clinically to assist in the management of immunosuppression; the clinical value it brings is that it allows modification of immunosuppressive therapy so as to maximize graft longevity, which is a focus of post-transplant care. Histology has traditionally been used, potentially in conjunction with serologic markers as a common graft assessment tool.^8,10-15 While histology is considered the gold standard of diagnosis at this point in time, this requires a biopsy, which is invasive and may be associated with significant risks and access to care barriers.

Molecular diagnostic methods have emerged in an attempt to address limitations in current diagnostics including the measurement of donor-derived cell-free DNA (hereon cfDNA) and gene expression profile (GEP) assays, which have been developed in a number of organ allografts including kidney, heart, liver, and lung.^16-24 The principle underlying cfDNA assays to assess rejection is that the transplantation of a new organ involves transplantation of new genetic material, and genetic material is shed into the bloodstream as part of rejection.²⁵ The fraction of donor-derived cell-free DNA in the blood-stream may serve as a marker of rejection.^18-21 While this is a straightforward principle, DNA concentration in the bloodstream is quite small, and therefore tests relying on cell-free DNA require sophisticated methods to accurately capture and quantify the presence of cfDNA specific to the allograft.^18,21,25 GEP tests tend to quantify expression of numerous genes in the allograft recipient and use these data in algorithms developed with sophisticated modeling or machine learning to determine whether rejection is occurring.^22,24,26 These tests can not only provide information about graft status in a minimally-invasive manner, but they can be sensitive enough to be able to detect AR before it is histologically evident.²⁷

However, these molecular tests have different strengths and weaknesses and can be leveraged for different populations. For example, some GEP tests have high negative predictive value for the likelihood of AR, but may be limited in their ability as a positive predictor for ACR or even detecting AMR, which may still be useful in a stable patient at low risk for rejection.²⁸ Other tests may have higher sensitivity or positive predictive value, suitable for higher-risk patients.^18,21

While these technologies are new, large and multicenter studies have supported their use in renal and heart transplantation as minimally and non-invasive methods to assess allograft status, modify immunosuppression regimens, and avoid unnecessary biopsies.^18,19,29-31 Evidence continues to develop for other transplant allograft organs and other analytes.^16,17,32-35 Additionally, there is evidence that while some cfDNA and GEP tests may have different intended uses, combining both may further improve graft rejection determination.³⁶

Numerous prior Medicare coverage decisions have considered the evidence in the hierarchical framework of Fryback and Thornbury³⁷ where Level 2 addresses diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses on whether the information produces change in the physician's diagnostic thinking; Level 4 concerns the effect on the patient management plan and Level 5 measures the effect of the diagnostic information on patient outcomes. To apply this same hierarchical framework to analyze an in vitro diagnostic test, we utilized the ACCE Model Process for Evaluating Genetic Tests.³⁷ The practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes. When a proven, well established association or pathway is available, intermediate health outcomes may also be considered. For example, if a particular diagnostic test result can be shown to change patient management and other evidence has demonstrated that those patient management changes improve health outcomes, then those separate sources of evidence may be sufficient to demonstrate positive health outcomes from the diagnostic test.

Graft assessment is a well-accepted part of solid organ transplant management. Evidence clearly shows that patients are living with functioning organs transplanted from immunologically and genetic distinct individuals using current transplant management techniques, which may demonstrate significant heterogeneity among centers or even among individual physicians.

It is also well accepted within the transplant community that immunosuppression management is an important component of post-transplant care to both optimize graft longevity while avoiding side effects and toxicity of immunosuppressive therapies. Graft assessment is an important decision tool used to help clinicians optimize immunosuppressive treatment. The gold standard for assessing rejection or injury has historically been and remains a biopsy in conjunction with serologic criteria. However, given the invasive nature and risks associated with a biopsy, tests that can potentially mitigate the need for a biopsy while still providing clinicians with actionable information that can be used to help optimize immunosuppressive therapy are reasonable and necessary. Additionally, ongoing studies have supported that cfDNA and GEP can accurately determine allograft status in several organ types, and that molecular characterization can both precede and enhance histologic findings. As such, these approaches, as a service type, are reasonable and necessary for graft assessment.

Non-invasive graft assessment remains an actively evolving area of medicine as does the assessment of graft rejection via histology. As such, this contractor will continue to monitor the evidence, and new developments may impact this coverage decision.

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