AlloMap® Molecular Expression Testing For Detection of Rejection of Cardiac Allografts

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The Centers for Medicare & Medicaid Services (CMS) is not issuing a National Coverage Determination (NCD) for AlloMap® Molecular Expression Testing For Detection of Rejection of Cardiac Allografts. In the absence of an NCD, coverage determinations for AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts, under section 1862(a)(1)(A) of the Social Security Act (the Act) and any other relevant statutory requirements, will continue to be made by the local Medicare Administrative Contractors (MACs).

Decision Memo: Administrative File: CAG-00455N FROM: Tamara Syrek Jensen, JD Director, Coverage and Analysis Group Joseph Chin, MD, MS Deputy Director, Coverage and Analysis Group Melissa Evans, PhD, MSAE Director, Division of Policy and Evidence Review Lori Ashby, MA Deputy Director, Division of Policy and Evidence Review Heather Hostetler, JD Lead Analyst Joseph Dolph Hutter, MD, MA Lead Medical Officer SUBJECT: Final decision memorandum for AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts DATE: April 13, 2021 I. Decision The Centers for Medicare & Medicaid Services (CMS) is not issuing a National Coverage Determination (NCD) for AlloMap® Molecular Expression Testing For Detection of Rejection of Cardiac Allografts. In the absence of an NCD, coverage determinations for AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts, under section 1862(a)(1)(A) of the Social Security Act (the Act) and any other relevant statutory requirements, will continue to be made by the local Medicare Administrative Contractors (MACs). II. Background AlloMap® Molecular Expression Testing (“AlloMap”) is an FDA-approved In Vitro Diagnostic Multivariate Index Assay (IVDMIA) test service performed in a single laboratory, assessing the gene expression profile of ribonucleic acid (RNA) isolated from peripheral blood mononuclear cells (PBMC). AlloMap is intended to give physicians information on the risk of acute cellular rejection in their patients following heart transplant. AlloMap is one type of non-invasive diagnostic test that may be used to identify patients who have a low probability of moderate/severe acute cellular rejection at the time of testing. Physicians can use results of this test in conjunction with standard clinical assessment to identify which post-transplant patients should undergo heart biopsy. AlloMap received market authorization from the Food and Drug Administration on August 26, 2008 and is indicated for use in heart transplant recipients with stable allograft function who are 15 years of age or older and at least 2 months (≥55 days) post-transplant. Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations. Please find below a list of these acronyms and corresponding full terminology: ACR – Acute cellular rejection CMS - Centers for Medicare & Medicaid Services FDA - Food and Drug Administration IVDMIA - In Vitro Diagnostic Multivariate Index Assay MAC - Medicare Administrative Contractor NCA - National Coverage Analysis NCD - National Coverage Determination PBMC - Peripheral blood mononuclear cells RNA - Ribonucleic Acid US - United States III. History of Medicare Coverage Prior to this national coverage analysis, CMS did not have an NCD specific to AlloMap Molecular Expression Testing for Detection of Rejection of Cardiac Allografts. In the absence of an NCD, coverage decisions are made by local MACs. A. Current Request We received a complete, formal request in January 2013 from Marc Halushka MD, PhD, Department of Pathology, Johns Hopkins Medical Institutions to make a national coverage determination to non-cover AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts. The requestor stated that generally a blood-based assay to detect acute cellular rejection and antibody-mediated rejection in individuals would benefit patients and be a significant improvement in diagnosis and treatment, given the limitations and risks of the more invasive heart biopsy. However, the requestor believed based on the evidence included in the request that this particular assay “does not perform adequately.” Specifically, it has “poor sensitivity,” and “no intrinsic predictive capability.” The formal request letter can be viewed via the tracking sheet for this NCA on the CMS website at: https://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx?NCAId=302 . B. Benefit Category Medicare is a defined-benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Act. The benefit category is diagnostic laboratory tests IV. Timeline of Recent Activities Date Action 10/16/2020 CMS initiates this national coverage analysis and posts the proposed decision memorandum. A 30-day public comment period begins. 11/15/2020 30-day public comment period ends. CMS receives three comments. V. Public Comment Public comments sometimes cite the published, peer-reviewed medical literature and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for informing a coverage determination. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. All comments that were submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=302 . Comment Period: 10/16/2020-11/15/2020 During the public comment period, CMS received three comments. Each of these comments was published on the CMS website. There were two comments submitted by physicians, one of which was the requestor, and one comment submitted by the sponsor of the AlloMap test. Two of the commenters supported the proposed decision to not issue a national coverage determination, thereby continuing to allow coverage to be determined by the local MACs. One commenter opposed the proposed decision, requesting non-coverage of AlloMap. Comment : One commenter stated that AlloMap is helpful not only due to the COVID crisis (and patient concerns about coming to the hospital for a biopsy), but also in the non-COVID environment, for selected patients, such as those with poor venous access or severe scar tissue (making biopsy more difficult) and to reduce the need for biopsy generally in order to prevent biopsy related complications. Response : Thank you for your comment. Comment : One commenter, the developer of the AlloMap Molecular Expression Test, discussed the range of support, from medical society guidelines to examples of commercial payer coverage, for use of the test, along with a few additional publications since 2013. Response : Thank you for your comment and the included citations. Because we are not making a national coverage determination, the MACs may review any appropriate evidence, including medical society guidelines. Comment : The NCD requestor provided comments reiterating some of the arguments made in his initial request for non-coverage, and critiqued some of the more recent studies we cited in our decision. Response : We appreciate these comments. While the commenter did not present new information regarding his critique of predictive values, we agree that there are considerable limitations of the studies published since 2013, some of which the commenter points out. We would like to clarify that this decision does not provide national coverage of AlloMap; instead it allows the MACs to continue to make coverage determinations at the local level. The MACs may use all of the evidence provided in this decision memo, as well as additional information such as the latest medical society guidelines to make a decision at the local level. Comment: The requestor states that “leading hospitals” choose not to use this test currently because they believe it offers no predictive benefit to patients. Response: The requester argues that the “leading hospitals” don’t use this test. However, we note that we received a public comment from a physician affiliated with The Cleveland Clinic who claims that the test “is invaluable in patients who have no venous access or who have such severe scar tissue that biopsies become dangerous and very painful.” Additionally, this physician states that the “test is essential during this COVID crisis when patients are fearful to come to hospitals for a biopsy and when hospitals may not have the capacity to perform routine invasive testing.” Also, both the requestor and this commenter from the Cleveland Clinic acknowledge that there are risks and complications associated with heart biopsy that having a non-invasive alternative can help avoid. Our decision to allow the MACs to continue making coverage decisions allows these patients to continue to receive the test. At the same time, the decision allows those other “leading hospitals” to continue to not use the test if they so choose, as there is no requirement or added incentive for them to now use the test as a result of this decision. VI. CMS Analysis The term “national coverage determination” is defined by statute and means a determination by the Secretary of the Department of Health and Human Services (Secretary) with respect to whether or not a particular item or service is covered nationally under Title XVIII of the Act. NCDs are controlling authorities for Medicare contractors and adjudicators as described more fully in 42 CFR 405.1060 . In the absence of an NCD, Medicare contractors may establish a local coverage determination (LCD) (defined in section 1869(f)(2)(B) of the Act) or adjudicate claims on a case-by-case basis. The case-by-case adjudicatory model permits consideration of a beneficiary's particular factual circumstances described in the medical record. The case-by-case model affords more flexibility to consider a particular individual's medical condition than is possible when the agency establishes a generally applicable rule. With relatively few exceptions, the statute provides in section 1862(a)(1) of the Act that no payment may be made under Part A or Part B for any expenses incurred for items or services which “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” The Supreme Court has recognized that “[t]he Secretary's decision as to whether a particular medical service is ‘reasonable and necessary’ and the means by which she implements her decision, whether by promulgating a generally applicable rule or by allowing individual adjudication, are clearly discretionary decisions.” Heckler v. Ringer, 466 U.S. 602, 617 (1984). See also, Almy v. Sebelius, 679 F.3d 297, 303-04 (4 th Cir. 2012) (“The Medicare statute preserves this discretion for the Secretary, leaving it to her judgment whether to proceed by implementing an NCD, by allowing regional contractors to adopt an LCD, or by deciding individual cases through the adjudicative process.”); International Rehabilitative Services Inc. v. Sebelius, 688 F.3d 994, 1001 (9 th Cir. 2012) (“But while the agency may make coverage determinations via up-front rules, it is not required to do so; rather, the agency has discretion in whether to make coverage determinations by up-front rulemaking or by case-by-case adjudication.”) We believe the decision to continue to allow MACs to determine coverage of AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts is clinically appropriate and in the best interest of beneficiaries. Since 2013, when we received the request to open an NCD to non-cover AlloMap, there have been several new studies published in the peer-reviewed medical literature evaluating the test (e.g., Deng 2014, Kobashigawa 2015, Crespo-Leiro 2015 and 2016, Fujita 2017, Moyayedi 2019), focusing on predictive value and clinical utility. [1] While each study has limitations, collectively they demonstrate that use of the test may better allow physicians to select patients who should undergo post-transplant heart biopsy. Specifically, the evidence indicates that the test may add value to selected patients, especially those for whom invasive biopsy poses greater risk due to poor venous access, scar tissue or other factors. Due to the very low volume of tests and affected beneficiaries, and the need for careful patient selection, CMS believes that coverage of AlloMap is an appropriate determination made by the Medicare Administrative Contractors (MACs). The MACs are structured to be able to take into account local patient, clinician and institutional factors, which are important when the overall prevalence is low. IX. Conclusion The Centers for Medicare & Medicaid Services (CMS) is not issuing a National Coverage Determination (NCD) for AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts. In the absence of an NCD, coverage determinations for AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts, under section 1862(a)(1)(A) of the Social Security Act (the Act) and any other relevant statutory requirements, will continue to be made by the local Medicare Administrative Contractors (MACs). [1] Deng MC, Elashoff B, Pham MX, et al. Utility of Gene Expression Profiling Score Variability to Predict Clinical Events in Heart Transplant Recipients. Transplantation. 2014;97(6). Kobashigawa J, Patel J, Azarbal B, et al. Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant: early invasive monitoring attenuation through gene expression trial. Circ Heart Fail. 2015;8(3). Crespo-Leiro MG, Stypmann J, Schulz U, et al. Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients. BMC Cardiovasc Disord. 2015;15(120). Crespo-Leiro MG, Stypmann J, Schulz U, et al. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. Eur Heart J. 2016;37(33). Moayedi Y, Foroutan F, Miller RJH, et al. Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients. J Heart Lung Transplant. 2019;38(1)’ Fujita B, Prashovikj E, Schulz U, et al. Predictive value of gene expression profiling for long-term survival after heart transplantation. Transpl Immunol. 2017;41. Decision Summary: The Centers for Medicare & Medicaid Services (CMS) is not issuing a National Coverage Determination (NCD) for AlloMap® Molecular Expression Testing For Detection of Rejection of Cardiac Allografts. In the absence of an NCD, coverage determinations for AlloMap® Molecular Expression Testing for Detection of Rejection of Cardiac Allografts, under section 1862(a)(1)(A) of the Social Security Act (the Act) and any other relevant statutory requirements, will continue to be made by the local Medicare Administrative Contractors (MACs). Related Material: Literature Review FDA Material Other Material 1 Federal Coverage Denial Notice