Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

August 16, 2023

Joseph Chin, M.D.
Medical Officer for Coverage and Analysis
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services, mailstop: S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

RE: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG00431R)

Dear Dr. Chin:

The 35 undersigned organizations resolutely support the Centers for Medicare & Medicaid Services (CMS) proposal to end the 10-year coverage with evidence development (CED) requirements for Beta Amyloid (A?) Positron Emission Tomography (PET) imaging in dementia and neurodegenerative disease. We similarly support CMS’ proposal to cover more than one scan per patient’s lifetime and allow A? PET scan use outside the context of a CED CMS-approved study. Collectively, our organizations represent people living with Alzheimer’s disease and related dementias (ADRD); family caregivers; healthcare providers; researchers; coalitions and advocacy organizations focused on chronic disease, aging, and minority and women’s health; private-sector leaders; and clinical trial sites. Together, we strongly urge CMS to maintain and update the existing National Coverage Determination (NCD) to clearly cover A? PET (without CED or other conditions of coverage), rather than providing coverage at the discretion of Medicare Administrative Contractors (MACs) and Medicare Advantage (MA) plans. We are concerned that the transition from national to local coverage discretion would put beneficiaries at risk of coverage gaps.

Additionally, while we appreciate CMS’ proposal to increase timely and equitable Medicare access to Aß PET scans, we oppose the agency’s simultaneous CED restrictions to beneficiary access for the entire class of FDA-approved monoclonal antibody (mAb) disease-modifying therapies for the treatment of early Alzheimer’s (CAG-00460N) and the precedent established by the decision.[i] In 2013, Medicare decided to limit coverage of Aß PET scans under CED, citing insufficient evidence that the imaging findings would make a difference for patients with Alzheimer’s disease due to the lack of a disease-modifying therapy and limited symptomatic treatment. [ii] Today, there are two FDA-approved Alzheimer’s disease-modifying therapies, one on-label symptomatic treatment, and several other treatments in development. The painful irony of this contradictory policymaking will become increasingly apparent as more beneficiaries are accurately diagnosed with early Alzheimer’s by Aß PET scans but will be unable to realize the benefits of FDA-approved therapies to delay their decline or address neuropsychiatric symptoms that significantly impact their quality of life.

Statement of Interest

Many of the organizations listed here will present their own responses to CMS and will actively advocate for those positions. These comments are not intended to impact adversely the ability of individual organizations, alone or in combination, to pursue separate comments with respect to the proposed NCD for A? PET in dementia and neurodegenerative disease.

We Urge National Coverage Without CED or Other Conditions of Coverage

Under its current 10-year coverage policy, CMS’ NCD under CED limits Medicare coverage for Aß PET to a single scan per lifetime that occurs within the context of a clinical trial.[iii] Medicare beneficiaries who need a scan today have three flawed options : (1) pay for the scan out-of-pocket, (2) forgo the test, or (3) be forced into limited clinical trials under CED (however, there are currently no active trials). Published appropriate use criteria, which CMS adopted in its two designated CED studies, required that knowledge of Aß PET results was expected to change diagnosis and management and whether Aß PET is associated with improved clinical outcomes.

Extensive CED data collected on 18,000 Medicare beneficiaries validated the FDA’s original assessment of the therapeutic value of Aß PET imaging. The CMS-approved CED study, Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) data analysis, published in JAMA in April 2019, found that PET imaging has significantly helped in the diagnosis and monitoring the progression of AD as well as in identifying which patients are likely to benefit from a potential treatment.[iv] Just as importantly, a negative PET result rules the disease out—the study found approximately 36 percent of patients clinically diagnosed with AD were negative for amyloid plaque confirmed by an amyloid PET scan.[v] Overall, the data demonstrate that use of Aß PET scan resulted in changes in clinical management for more than 60 percent of patients who participated—most notably in the starting, stopping, or modification of AD drug therapy, but also in the use of other drug therapies and/or counseling about safety and future planning.[vi]

However, due to low participation among Medicare beneficiaries of color in the first CMS-approved CED trial, CMS required a second CED confirmatory study in 2020 to gather additional information. The New IDEAS study[vii] was a limited extension of the original IDEAS study for underserved populations, but CMS’ proposed decision memo states that, “One study (New IDEAS) has not been completed due to enrollment issues and is not active.”[viii]

National coverage and the removal of CED requirements for Aß PET imaging will be particularly significant for underserved communities who were not well-represented in CMS-approved clinical studies. A 2022 secondary cohort analysis of the original IDEAS study found lower odds of amyloid PET positivity in older Asian, Black, and Hispanic adults with MCI and dementia compared with non-Hispanic White individuals.[ix] These results have important implications for the diagnosis, treatment, and prevention of ADRD in groups that are at the highest risk of dementia, which further supports the proposed elimination of the CED restriction and CMS’ finding that these tests are reasonable and necessary.

Support for national Medicare coverage of A? PET scans was outlined in July 2022, when 20 of our organizations joined together in a comment letter to CMS.[x] In December 2022, 53 organizations shared a letter with President Biden urging him to direct the Secretary of the U.S. Department of Health and Human Services to reopen the Aß PET NCD for a full reconsideration.[xi]

While we greatly appreciate CMS' proposal to expand coverage of A? PET scans and end the one scan per beneficiary lifetime limit, we are concerned that leaving coverage to the discretion of local contractors could result in variability of coverage and beneficiary access delays to early diagnosis and intervention. An NCD finding the tests reasonable and necessary without CED or other conditions of coverage would provide consistent and clear coverage immediately once such a policy was finalized.

Our concern with claim-by-claim coverage is that Medicare Advantage (MA) plans frequently assert that, under chapter 4 sections 90.3 and 90.4 of the Medicare Managed Care Manual, they are not required to cover items and services in the absence of an NCD or Local Coverage Decision (LCD).[xii] If MA plans attempt to assert that coverage is not required for A? PET scans, there would likely be access issues that would disproportionately impact beneficiaries in lower-income communities who are more likely to have MA. A recent paper by Harvard Medical School and Inovalon found that MA enrollees are 50% more likely than FFS enrollees to be enrolled in a health maintenance organization (HMO). The same study found that MA enrollees have a lower average income are less likely to have attained a higher education degree or own a home or car.[xiii]

Conclusion

To ensure equitable access to Aß PET scans, we support the CMS proposal to end CED restrictions for A? PET scans. We further urge CMS to modify the existing A? PET NCD to end the lifetime scan coverage limit and provide national coverage without any other coverage requirements so that all Medicare beneficiaries with ADRD can access the tests they need and deserve.

Thank you for considering our views and for CMS’ commitment to improved detection and quality care for people with Alzheimer’s disease. If you have questions, please contact Sue Peschin, President and CEO of the Alliance for Aging Research, at speschin@agingresearch.org or the Alliance's Vice President of Public Policy and Government Relations, Michael Ward, at mward@agingresearch.org.

Sincerely,

_____________________________________________________

[i] Centers for Medicare and Medicaid Services. “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease.” 06 Jul 2023. https://www.cms.gov/medicare/coverage-evidence-development/monoclonal-antibodies-directed-against-amyloid-treatment-alzheimers-disease-ad.

[ii] Centers for Medicare and Medicaid Services. “Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease.” 27 Sep 2013. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&NCAId=265.

[iii] Ibid.

[iv] Gil Rabinovici et al. “Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia.” JAMA. 2019;321(13):1286-129., https://jamanetwork.com/journals/jama/fullarticle/2729371.

[v] Ibid.

[vi] Ibid.

[vii] American College of Radiology Bulletin. “A new trial is recruiting patients for its dementia imaging study focusing on underrepresented populations.” https://www.acr.org/Practice-Management-Quality-Informatics/ACR-Bulletin/Articles/March-2021/New-IDEAS.

[viii] Centers for Medicare and Medicaid Services. “Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease.” 17 Jul 2023. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=308.

[ix] Consuelo H. Wilkins et al. “Racial and Ethnic Differences in Amyloid PET Positivity in Individuals With Mild Cognitive Impairment or Dementia: A Secondary Analysis of the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) Cohort Study.” JAMA Neurol. 2022;79(11):1139-1147. https://jamanetwork.com/journals/jamaneurology/fullarticle/2796653#noi220059r63.

[x] Alliance for Aging Research. “Twenty Organizations Ask Medicare to End Coverage Restrictions for Alzheimer’s Disease Diagnostics.” 15 Jul 2022. https://www.agingresearch.org/news/twenty-organizations-ask-medicare-to-end-coverage-restrictions-for-alzheimers-disease-diagnostics/.

[xi]Alliance for Aging Research. “Alliance Leads More Than 50 Organizations Urging President Biden to Reevaluate Decision on Alzheimer’s Diagnostics.” 13 Dec 2022. https://www.agingresearch.org/news/alliance-leads-more-than-50-organizations-urging-president-biden-to-reevaluate-decision-on-alzheimers-diagnostics/.

[xii] Centers for Medicare and Medicaid Services. “Medicare Managed Care Manual Chapter 4 - Benefits and Beneficiary Protections.” 22 Apr 2016. https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/mc86c04.pdf.

[xiii] Scott Builder et al. “Harvard-Inovalon Medicare Study: Who Enrolls in Medicare Advantage vs. Medicare Fee-for-Service.” Inovalon. https://www.inovalon.com/resource/harvard-inovalon-medicare-study-who-enrolls-in-medicare-advantage-vs-medicare-fee-for-service/?utm_medium=email&utm_source=GranID20461-&utm_campaign=RH231334-&utm_content=harvard-inovalon-medicare-study.

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VIA ELECTRONIC DELIVERY

David Dolan and Joseph Hutter, M.D.
Center for Clinical Standards and Quality
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
U.S. Department of Health and Human Services
Attention: CAG-00431R
P.O. Box 8013
Baltimore, MD 21244–1850

Re: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease Proposed Decision Memorandum and National Coverage Analysis [CAG-00431R]

Dear Mr. Dolan and Dr. Hutter:

The Society of Nuclear Medicine & Molecular Imaging (SNMMI) appreciates the opportunity to comment on the Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease Decision Memorandum (CAG-00431R) posted on July 17, 2023. SNMMI and its more than 15,000 members set the standard for the practice of nuclear medicine and molecular imaging by creating guidelines, sharing information through journals and meetings, and advocating on key issues that affect molecular imaging and therapy, research, and practice.

We appreciate the decision by the Centers for Medicare & Medicaid Services (CMS) to open a national coverage analysis (NCA) and reconsider NCD 220.6.20. SNMMI agrees with the agency’s proposal to remove the NCD, ending coverage with evidence development (CED) for PET beta amyloid imaging and permitting Medicare Administrative Contractors to make determinations about coverage under section 1862(a)(1)(A) of the Social Security Act. That is an appropriate action given the importance of Medicare beneficiary access to this minimally invasive, essential procedure and the significance of dementia and neurogenerative disease in the Medicare population.

SNMMI has been concerned about elements of the current NCD. Specifically, we believe that maintaining patients to a single lifetime scan and solely under CED will only serve to hamper access. Indeed, NCD 220.6.20 is longstanding, and the clinical studies approved under the NCD have not expanded since 2016. And yet, as CMS acknowledges, other studies have been conducted outside the NCD, generating additional evidence, and obviating the need to maintain CED.

In addition, a single scan per lifetime is neither reasonable nor supported by evidence. Given that amyloid presence in the brain may change over time and accurate measurements of beta amyloid are important, Medicare should cover more than one amyloid PET scan in a patient’s lifetime. Accordingly, SNMMI agrees with CMS in its proposed assessment that “removal of NCD 220.6.20 will allow appropriate coverage of amyloid PET scans and will greatly reduce provider and patient burden from existing requirements and test limitation.”

SNMMI also shares CMS’ view that more recent and advanced treatments directed against amyloid, which require the confirmation of the presence of amyloid in the brain, make tests like amyloid PET even more critical to medical treatment and further justify the removal of NCD 220.6.20. PET scans provide crucial information that may affect the course of treatment. Anti-amyloid drug treatments for Alzheimer’s Disease are examples of interventions where diagnostic tests such as amyloid PET ensure that such therapies are used with appropriate patients, thereby reducing unnecessary exposure to potential harmful side effects. Removal of NCD 220.6.20 will ensure that such treatments can effectively be used and widen the options for diagnosis and assessment of disease progression.

Finally, we are pleased that CMS proposes in the decision memorandum to remove NCD and we urge the agency to retire or remove the other PET NCDs that inappropriately limit coverage. We believe that such NCDs are outdated and do not reflect current clinical evidence and practice. In particular, we recommend that CMS retire NCD 220.6.19 which essentially non-covers NaF-18 PET nationally. We believe that coverage of such scans should be left to contractor discretion.

Thank you for your consideration of our comments. Please feel free to contact Julia Bellinger, JBellinger@SNMMI.org if the Agency has additional questions about the topics discussed in our comments.

Sincerely,

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Administrator Chiquita Brooks-LaSure
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

RE: NCD Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear Administrator Brooks-LaSure:

The Alliance of Community Health Plans (ACHP) applauds the Centers for Medicare & Medicaid Services (CMS) for its commitment to establish national coverage policies with evidence based on safety and efficacy data. With promising but uncertain treatments of Alzheimer’s actively in development, testing and early usage, now is not the appropriate time to change a National Coverage Determination that has been in place and working since 2013 for beta amyloid pet scan in dementia and neurodegenerative disease patients. Let’s not walk away from what is working today.

ACHP represents the nation’s top-performing, nonprofit health plans that provide high-quality coverage and care to tens of millions of Americans across nearly 40 states and D.C. Our member companies serve diverse populations across all lines of business and support the development and coverage of testing and treatment that improve health outcomes.

The lack of evidence of efficacy for monoclonal antibodies directed against amyloid, unknown safety risks and the need for consistency in treatment and coverage necessitate maintaining the current national coverage policy. Revising the current policy of one scan per patient enrolled in clinical study will not meaningfully advance the available evidence and treatment of individuals with neurodegenerative disease.

ACHP’s comments are informed by top clinical leaders, such as member company medical directors and pharmacy leaders. Based on their extensive expertise and decades of experience in the field, there is consensus that beta amyloid positron tomography has not demonstrated effectiveness, safety or enough value to reconsider the current coverage decision. The current national coverage determination balances that admirable goal of advancing evidence and care while not giving individuals and families facing the everyday challenges Alzheimer's disease presents a false hope.

In 2013, CMS determined that the evidence is insufficient to conclude that the use of positron emission tomography (PET) beta amyloid imaging was reasonable and necessary for the diagnosis or treatment of illness or injury and issued a National Coverage Determination (NCD 220.6.20). The NCD covers one PET amyloid-beta scan per patient per lifetime in CMS-approved studies under coverage with evidence development. Since the issuance of the NCD, additional therapies were approved by the Food and Drug Administration (FDA) which target the reduction in beta-amyloid plaques in the brain. The FDA cited beta-amyloid plaques as a surrogate endpoint, a reduction of which “is reasonably likely to result in clinical benefit.” CMS agreed with ACHP member concerns and issued a National Coverage Determination (NCD 200.3) that limited coverage to those enrolled in clinical trials under a Coverage with Evidence Development. ACHP stands with our previous comments submitted during the NCD analysis and reiterates concerns about safety risks, beta-amyloids as a surrogate endpoint and emphasizes the need for consistency in coverage.

PET imaging is a high radiation examination involving the injection of a radioactive tracer into the body. Although fairly low risk, especially as compared to an invasive lumbar puncture, the impact of increased radioactive exposure over time is not well known. Studies of PET imaging was based on the use in diagnosis of neurodegenerative disease and not continued monitoring. Allowing coverage of additional tests per patient could increase the risk of unnecessary testing without appropriate clinical criteria, unlike what currently exists. Further, imaging should be limited to those for whom diagnosis or related treatment is needed.

Evidence is still inconclusive about the role of beta-amyloid plaques in the pathophysiology of Alzheimer’s Disease. Changing the NCD at this time would blunt CMS’s ability to continue evidence generation that will likely benefit our collective understanding of beta-amyloid plaques as it relates to the treatment of Alzheimer’s disease. Removing the coverage with evidence determination would create a patchwork of coverage nationwide with variation from local jurisdiction to local jurisdiction. For patients navigating an already complex diagnosis and treatment, this lack of consistency could unnecessarily create challenges to access.

We appreciate the continued engagement with you and members of your team. We should not change the National Coverage Determination at a time in which there are questions about the efficacy and population who could benefit from monoclonal antibodies targeting amyloid plaque. Please contact Michael Bagel, ACHP Associate Vice President of Public Policy, at mbagel@achp.org or (202) 897-6121 with any questions.

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August 16, 2023

VIA ELECTRONIC FILING

Centers for Medicare and Medicaid Services
Coverage and Analysis Group
7500 Security Blvd.
Baltimore, Maryland 21244

Re: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease.

The Pharmaceutical Research and Manufacturers of America (PhRMA) is pleased to submit these comments in response to the Centers for Medicare & Medicaid Services’ (CMS’) proposed reconsideration of the National Coverage Determination (NCD) ending coverage with evidence development (CED) for beta amyloid positron emission tomography (PET). PhRMA represents the country’s leading innovative biopharmaceutical research companies, which are devoted to discovering and developing medicines that enable patients to live longer, healthier, and more productive lives. Over the last decade, PhRMA member companies have more than doubled their annual investment in the search for new treatments and cures, including nearly $101 billion in 2022 alone.

PhRMA strongly supports CMS’ proposal to remove the NCD for beta amyloid PET scans. As noted in our prior comment letters to CMS, beta amyloid PET scans are an essential tool for physicians in detecting the presence and level of amyloid plaques, which result from the accumulation of the peptide amyloid-ß. As CMS itself acknowledged nearly nine years ago in its Final Decision Memo for this NCD, “[i]t is widely accepted that the presence of amyloid plaques in the human brain is virtually necessary for the diagnosis of [Alzheimer’s disease],” and the presence of such plaques is “built into the postmortem diagnostic gold standard” for Alzheimer’s disease.

Furthermore, as CMS notes in the Proposed Decision Memo, since 2013 “The advances in medical care and standards of practice and development of proven treatments have altered the application of amyloid PET scans in clinical practice and research.” New treatments, including anti-amyloid monoclonal antibodies (mAbs) have been approved by the FDA for treatment of Alzheimer’s disease. Beta amyloid PET scans are not only a critical diagnostic tool to accurately diagnose patients with Alzheimer’s disease (or to rule out a diagnosis of AD) but an important tool to evaluate whether and how certain treatment options may work for particular patients. Beta amyloid PET scans are critical to assessing and helping determine which patients may be appropriate candidates for potential treatment with anti amyloid mAbs. The availability of these treatments, combined with the widely acknowledged benefits of an accurate and timely diagnosis for patients and their caregivers , only adds to the urgency of CMS not just removing the NCD, but facilitating timely patient access to this critical diagnostic tool. Therefore, we recommend CMS make the removal of the NCD effective as soon as possible, ideally sooner than the 60 day period CMS has stated is usually reasonable. Furthermore, PhRMA urges CMS to closely monitor MAC coverage determinations and ensure there is consistent coverage of beta amyloid PET scans across Medicare Part B fee-for-service, as well as Medicare Advantage plans.

It is also clear that the standard for coverage in Medicare Part B has been met. Since the beta amyloid PET NCD was finalized in September 2013, significant additional evidence has been generated that further supports the importance of beta amyloid PET scans. For example, research published in JAMA several years ago reflected that beta amyloid PET scans are critical for appropriately managing Alzheimer’s patients, and significantly increases physician confidence in their diagnoses. CMS must cover interventions that fall within a Part B benefit category that meet the reasonable and necessary standard. In our view, given the robust collection of available evidence regarding the importance of these scans, it is clear that beta amyloid PET scans have surpassed the standard of “reasonable and necessary” for coverage in Medicare Part B, and therefore, removal of the NCD is appropriate. PhRMA strongly recommends CMS explicitly clarify that the standard for coverage has been met in its final decision memo.

PhRMA appreciates the opportunity to comment on the NCD analysis initiated by CMS for beta amyloid PET in Dementia and Neurodegenerative Disease. Please do not hesitate to contact us if we can provide additional information or answer any questions related to our comments.

—s—
Lauren Neves
Deputy Vice President, Policy and Research
PhRMA

—s—
Corbin Santo
Assistant General Counsel
PhRMA

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August 16, 2023

Joseph Chin, M.D.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

BY ELECTRONIC DELIVERY

Re: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Dr. Chin:

The Personalized Medicine Coalition (PMC), a multi-stakeholder group comprising more than 200 institutions from across the health care spectrum, thanks the Centers for Medicare & Medicaid Services (CMS) for the opportunity to comment on its Proposed National Coverage Determination (NCD) Reconsideration for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease.[1] Beta amyloid PET imaging is a critical tool for diagnosing Alzheimer’s disease (AD), ruling out a diagnosis of AD, and evaluating whether and how certain treatments may work for a patient. The emergence of new anti-amyloid treatments, some requiring multiple PET scans to inform an individual patient’s treatment course, makes timely and appropriate access to this imaging tool essential for individuals living with AD and their families.

PMC supports CMS’ proposals to remove the limit of one scan per lifetime and to end Coverage with Evidence Development (CED) for beta amyloid PET imaging for Medicare beneficiaries. This coverage approach is consistent with the evidence developed since NCD 220.6.20 was issued in September of 2013. Instead of finalizing its proposal to permit Medicare Administrative Contractors (MACs) to make coverage determinations independently, however, PMC urges CMS to keep a national coverage policy in place allowing more than one scan per lifetime without CED. We are concerned that in the absence of a national coverage policy, MACs and Medicare Advantage (MA) plans could develop inconsistent coverage policies that create new access barriers for Medicare beneficiaries.

PMC defines personalized medicine as an evolving field in which physicians use diagnostic tests to determine which medical treatments will work best for each patient or use medical interventions to alter molecular mechanisms that impact health. By combining data from diagnostic tests with an individual’s medical history, circumstances, and values, health care providers can develop targeted treatment and prevention plans with their patients.

Personalized medicine is helping to shift the patient and provider experiences away from trial-and-error toward a more streamlined process for making clinical decisions, which will lead to improved patient outcomes, a reduction in unnecessary treatment costs, and better patient and provider satisfaction. PMC’s members are leading the way in personalized medicine and recommend that patients who may benefit from this approach undergo appropriate testing and tailored treatment as soon as possible during their clinical experiences.

More than 6 million individuals are living with AD, which irreversibly degrades memory, cognitive function, and eventually motor function. AD is a primary cause of dementia in older Americans and, as CMS notes, it is one of the most burdensome diseases for the Medicare population. Abnormal levels of amyloid in the brain are one of the key pathologies found in patients with AD, and beta amyloid PET imaging is an essential tool for physicians in detecting the presence and level of amyloid plaques. Knowing amyloid status adds clarity for physicians managing the treatment of patients with suspected Alzheimer’s disease by helping them reduce adverse events from inappropriate treatment, thus improving the chances of directing appropriate care.

Statement of Neutrality

Many of PMC’s members will present their own responses to CMS’ Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease and will actively advocate for those positions. PMC’s comments are designed to provide feedback so that the general concept of personalized medicine can advance, and are not intended to impact adversely the ability of individual PMC members, alone or in combination, to pursue separate comments with respect to the proposed decision.

1. PMC supports CMS’ proposal to remove the coverage limit of one beta amyloid PET scan per patient.

In addition to confirming the presence of beta amyloid in the brains of patients who are being evaluated for AD prior to the initiation of anti-amyloid treatments or enrollment in anti-amyloid clinical trials, beta amyloid PET scans have become an important tool for monitoring a patient’s response to anti-amyloid treatments and managing their treatment appropriately. Clinical trials for anti-amyloid treatments, for example, have utilized multiple beta amyloid PET scans to enroll patients and initiate amyloid targeting therapies, monitor reduction in beta amyloid levels during treatment, and potentially inform future decisions on treatment completion. In addition, while some patients with cognitive impairment may have a beta amyloid PET scan that does not indicate AD at one stage of their life, a repeat scan in future years could have a positive result as their disease progresses. CMS’ current policy to cover only one beta amyloid PET scan per patient can constrain patients’ choice of treatments and the appropriate management of anti-amyloid treatments.

PMC appreciates CMS' recognition in the proposed decision memo of the feedback it has received on how the use of beta amyloid PET scans has evolved to inform both treatment selection and treatment management and that its once in a lifetime limit is outdated and no longer clinically appropriate. We agree with CMS’ proposal to remove the coverage limitation of one beta amyloid PET scan per patient. We believe this decision will improve patient access to evolving personalized medicine approaches for initiating, monitoring and managing anti-amyloid treatments.

2. PMC supports CMS' proposal to end CED based on the available evidence.

For patients with progressive neurodegenerative diseases, timely access to beta amyloid PET scans is critical for providing patients with information regarding their disease and potential ways to manage and treat it. However, CMS’ existing NCD only covers beta amyloid PET scans in the context of CED studies for the purposes of “excluding AD in narrowly defined and clinically difficult differential diagnoses” and to “enrich clinical trials seeking better treatments or prevention strategies for AD, by allowing for selection of patients on the basis of biological as well as clinical and epidemiological factors.”[2] Since access to PET is currently limited to sites participating in an approved study, Medicare’s policy does not currently cover beta amyloid PET scans for patients who are unable to receive care at one of those sites. Thus, CMS’ CED requirement limits beneficiaries’ ability to access this important diagnostic tool.

In the decade since CMS finalized its existing NCD requiring additional evidence development, more than 30 academic manuscripts involving over 1,000 individual researchers have been generated demonstrating the benefits of beta amyloid PET imaging, with benefits including altered clinical management, changed patient diagnoses, and improved provider confidence.[3] Notably, this includes results of the Imaging Dementia – Evidence for Amyloid Scanning (IDEAS) study that was developed and conducted in response to CMS’ CED requirements for beta amyloid PET scans to assess the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with mild cognitive impairment (MCI) or dementia. The IDEAS study included 11,409 participants initially characterized as having MCI or dementia of uncertain cause. Ninety days after beta amyloid PET imaging, patient care plans changed in 60.2 percent of patients initially characterized as having MCI and 63.5 percent of patients initially characterized as having dementia of unknown cause. In some cases, changes to care plans helped patients avoid unnecessary additional testing such as neuropsychological testing, other imaging tests, and cerebrospinal fluid analysis.[4] An aggregated analysis of other studies found that beta amyloid PET scans contribute to a change in diagnosis for approximately 30 percent of patients and increased diagnostic confidence in approximately 60 percent of patients.[5] No new CED studies have been approved since 2016. In fact, a limited extension of the original IDEAS study for underserved populations, the New IDEAS study, lacks trial sites in 18 states,[6] and as CMS notes, is not active and has not been completed due to enrollment issues.

We appreciate CMS’ acknowledgement in its proposed decision memo that a number of relevant clinical studies have been conducted and new evidence has been developed outside the context of CMS’ CED requirement, specifically in the development of evidence for new anti-amyloid treatments. We support CMS’ determination that separate CED studies on beta amyloid PET scans are no longer needed. Furthermore, we appreciate CMS’ recognition that the use of beta amyloid PET scanning has changed and has become more individualized with the emergence of new treatments. We believe removing CED requirements will help expand access to care for patients who may benefit from a beta amyloid PET scan, but who also face geographical, institutional and other barriers to equitable participation in such clinical studies.

3. PMC urges CMS to keep a National Coverage Determination in place, without a one-time scan limit and without CED.

PMC shares CMS’ interest in reducing the burden placed on providers and patients by the agency’s existing test limitation and CED requirements. However, CMS proposes to remove its national coverage policy and allow local MACs to make coverage determinations regarding beta amyloid PET imaging, to include covering more than one scan per patient’s lifetime and use within or outside the context of a CMS approved study. As noted above, PMC is concerned that in the absence of a national coverage policy, MACs and MA plans could develop inconsistent coverage policies, such as by imposing varying utilization management controls in the face of increased utilization, that create new barriers and inequities in access to this important diagnostic tool.

To fully optimize Medicare beneficiaries' access to beta amyloid PET scans that enable personalized medicine approaches to managing and treating a patient’s disease, PMC encourages CMS to keep a National Coverage Determination (NCD) in place clarifying that beta amyloid PET scanning is “reasonable and necessary” without a one-time scan limit and without CED as conditions for coverage. If CMS chooses to move forward with removing its existing NCD, PMC encourages CMS to work with MACs and MA plans to ensure consistent coverage policies emerge in the absence of a national coverage policy.

PMC appreciates your commitment to ensuring that beneficiaries with dementia, Alzheimer’s and other neurodegenerative diseases have access to the diagnostic and imaging tools needed to address their medical needs. We look forward to working with you and your colleagues at CMS to ensure the Medicare program fosters patient access to personalized medicine and the technologies enabling this approach to care. If you have any questions about PMC’s comments, please contact me at 202-499-0986 or cbens@personalizedmedicinecoalition.org, or David Davenport, PMC’s Manager of Public and Science Policy, at ddavenport@personalizedmedicinecoalition.org or 804-291-8572.

Sincerely,

Cynthia A. Bens
Senior Vice President, Public Policy
Personalized Medicine Coalition

[1] Centers for Medicare & Medicaid Services. Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R). July 17, 2023. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=308. (Accessed August 10, 2023.)

[2] Centers for Medicare & Medicaid Services. Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease (NCD 220.6.20). September 27, 2013. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=356&ncdver=1. (Accessed August 10, 2023.)

[3] Partnership to Fight Chronic Diseases. Amyloid Beta PET Scans: By the Numbers. https://www.fightchronicdisease.org/sites/default/files/PFCD%20PET%20By%20The%20Numbers%20%281%29.pdf. (Accessed August 10, 2023.)

[4] Gil D. Rabinovici et al. “Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia.” JAMA. April 2, 2019. Vol. 321(13):1286–1294. https://pubmed.ncbi.nlm.nih.gov/30938796/. (Accessed August 10, 2023.)

[5] Enrico R. Fantoni et al. “A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease.” J Alzheimers Dis. 2018. Vol. 63(2):783-796. https://pubmed.ncbi.nlm.nih.gov/29689725/. (Accessed August 10, 2023.)

[6] The New IDEAS Study. Find a Site by State. https://www.ideas-study.org/Find-a-Site/Site-Locator-by-State. (Accessed August 15, 2023.)

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August 16, 2023

Joseph Chin, M.D.
Director, Coverage and Analysis Group
Center for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Dr. Chin:

On behalf of the Alliance for Patient Access (AfPA), thank you for the opportunity to offer comment regarding the Centers for Medicare & Medicaid Services (CMS) National Coverage Analysis (NCA) on Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. We are encouraged by the reconsideration of coverage determinations for PET beta amyloid imaging and urge CMS to ensure appropriate, patient-centered access to this type of test moving forward.

AfPA appreciates that CMS is proposing to withdraw the existing national coverage determination (NCD) that limits access to beta amyloid imaging. However, AfPA encourages CMS to update the NCD to allow for the broadest possible coverage for these scans, which will be valuable in ensuring patients have optimal care when navigating Alzheimer's.
If an NCD is removed at 220.6.20, ending the Coverage with Evidence Development (CED) requirement for PET beta amyloid imaging and permitting Medicare coverage to be made by Medicare Administrative Contractors (MACs), we respectfully ask CMS to provide strategic guidance that encourages equitable coverage for such scans.

About AfPA
Founded in 2006, AfPA is a national network of policy-minded health care providers who advocate for patient-centered care. AfPA supports health policies that reinforce clinical decision-making, promote personalized care and protect the physician-patient relationship. Motivated by these principles, AfPA members participate in clinician working groups, advocacy initiatives, stakeholder coalitions, and the creation of educational materials. AfPA hosts the Neurological Disease Working Group, a network of clinicians, which works to ensure that the clinician’s perspective informs policy discussions around care for patients living with neurological diseases.

Burden of Alzheimer’s Disease
An estimated more than 6 million Americans aged 65 and older are living with Alzheimer’s in 2023, with significant economic impact (1). The estimated total healthcare cost for the treatment of Alzheimer’s disease was $345 billion in 2023 (2). By 2050, this number is expected to rise to nearly $1 trillion (3). The effects of Alzheimer’s reach far beyond financial burden. One in three seniors dies of Alzheimer’s or dementia. While advances in medicine have helped mortality from other diseases to significantly decrease, deaths from Alzheimer’s disease have increased (4).

Caregivers also carry a unique burden with Alzheimer’s disease. More than 11 million Americans provided an estimated 18 billion hours of care, typically unpaid, for people with Alzheimer’s disease in 2023 (5). The financial, health, and societal cost of Alzheimer’s will only continue to climb, as this disease impacts more people. Therefore, tools that can help better diagnose and manage this disease are critically important.

Opportunity to Improve Care Through PET Coverage
Patients with Alzheimer’s disease have historically had few treatment options, limited to drugs purposed for symptom management. That has recently changed, as CMS has granted coverage of several monoclonal antibody treatments for patients diagnosed with early Alzheimer’s. A requirement of being prescribed monoclonal antibody treatment is a preliminary PET scan to observe the amyloid plaque buildup; however, it is also vital that patients have access to additional PET scans to monitor disease progression. PET scans are important diagnostic tools, and as noted in the Proposed Decision Memo the most comment used method for patient selection in trials for any AD therapy (6). The previous one-per-lifetime coverage determination is inadequate for patients who could benefit from new treatment options and accurate disease monitoring.

To better treat Alzheimer's and dementia patients, an updated NCD that includes coverage of scans, without CED, is crucial to combat this disease. Additionally, an updated NCD allowing for broad coverage will help support greater health equity, as CED requirements for these tests have hurt historically underserved Medicare patients, as well as people of color, who are statistically more likely to develop Alzheimer’s disease and less likely to participate in clinical trials (7). One widely cited study documented this, stating that “a number of barrier themes were identified in the study, including mistrust of researchers and the health care system, fear related to research participation, inadequate information about research and opportunities, [and] inconvenience…”(8). We share CMS’s goal of ensuring diverse clinical trials, but continued use of any CED, determined nationally or locally, will only serve to exacerbate the disparities that CMS’s priorities in diversity seek to ameliorate.

Providing Equitable Coverage under Medicare Administrative Contractors
As proposed by CMS, the removal of an NCD will leave coverage decisions to be made by MACs. AfPA is concerned this approach may lead to inconsistent, inequitable coverage across different coverage regions. However, should CMS move forward with the decision to allow MACs to determine PET beta amyloid imaging coverage, we urge CMS to provide clear and concise guidelines that would ensure that patient access is not determined by patient location.

Substantial data findings reported by CMS have found that amyloid scanning has significantly assisted in the diagnosis and monitoring of Alzheimer's and dementia, as well as is necessary for identifying which patients would benefit from treatment (9). If MACs make coverage determinations, they should do so with an expansive lens that provides the opportunity for the best possible care for patients.

Prioritizing Patient-Centered Care
Patient-centered care is rooted in the relationship providers foster with their patients, relationships built through trust and open communication. A key aspect of this is shared decision-making, which is crucial for patient confidence and adherence. When treatment coverage limits the tools at a clinician’s disposal, this can undermine the provider-patient partnership by interfering with the preferred course of treatment. Accordingly, we thank CMS for working to reduce barriers between patients and appropriate diagnostic tools and urge CMS to act to ensure broad access to PET beta amyloid imaging.

We recognize the challenges CMS is working to address and appreciate the opportunity to provide comments on this reconsideration. Thank you for your attention to this important topic. If AfPA can provide further details or be of assistance in this matter, please contact us at cmcpherson@allianceforpatientaccess.org or 202-951-7097.

Sincerely,
Josie Cooper
Executive Director
Alliance for Patient Access

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I support the removal of the NCD and the shift to local decisions rather than an NCD. By way of background, I am an MD PhD and the first part of my career was as a full time Alzheimer research in two medical schools as a faculty member.

There is one concern that could arise at the MAC level, however. All three tracers approved for Amyloid PET studies contain FDA language - from their approval, some years ago - "not shown to be safe and effective for therapeutic monitoring." This and other disclaimers on the legacy FDA PET test labeling, may be one reason the FDA current drug approvals are so vauge about required imaging. MACs should be assured they should use the most recent drug labeling, clinical trial studies, and review articles on best practices, to provide PET coverage. Outdated or ten year old remarks left standing on the FDA labeling should not preclude up to date coverage decisions.

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August 16, 2023

Ms. Tamara Syrek-Jensen
Director, Coverage and Analysis
Centers for Medicare & Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Dear Ms. Syrek-Jensen:

On behalf of GE HealthCare, thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS) proposed reconsideration of national coverage for Beta Amyloid Positron Emission Tomography (PET) in dementia and neurogenerative disease. GE HealthCare is a leading global medical technology, pharmaceutical diagnostics, and digital solutions innovator working to solve the greatest challenges in healthcare that patients and clinicians face today and in the future. GE Healthcare Pharmaceutical Diagnostics is the global leader in the production and supply of contrast media and molecular imaging agents used to enhance medical imaging exams for major disease area diagnostic and treatment pathways.

We commend CMS’ reconsideration of the NCD based on the evolution of the science and treatment options for patients with Alzheimer’s Disease (AD). Given the amount of clinical evidence that has accumulated since the original NCD, we believe that there is no need to gather additional data and agree that that Coverage with Evidence Development (CED) should end. We also agree that the one amyloid PET scan per lifetime rule should be lifted.

We recommend that CMS cover amyloid PET under an NCD to ensure access and to support patient selection for amyloid targeting therapies. We do remain concerned about the implications of deferring local coverage decision-making to the Medicare Administrative Contractors (MAC), particularly given that the robust clinical evidence warrants national coverage and the likely challenges for implementation of separate local coverage decisions. Further, there is no assurance that the MACs would all choose to develop coverage policies that would eliminate the one scan per lifetime rule.

Evidence
Based on the evidence published since the NCD in 2013, national coverage of amyloid PET is warranted for beneficiaries suffering from cognitive impairment who are being evaluated for Alzheimer’s disease or other causes of cognitive decline. Amyloid PET imaging should be considered reasonable and necessary for those patients that are evaluated for or undergoing treatment with an FDA-approved anti-amyloid therapeutic.

Following the NCD reconsideration request that GE HealthCare, together with other stakeholders, submitted to CMS in September 2020, we provided in December 2020, through the Medical Imaging & Technology Alliance (MITA), an extensive summary of the published evidence (with 65 unique citations). This evidence included the IDEAS study and the other collective evidence which showed change in diagnosis following amyloid PET scans in approximately one-third of patients, thereby demonstrating that the standard clinical work-up (without amyloid PET) for Alzheimer’s disease, does not reliably result in an accurate etiological diagnosis. Furthermore, the amyloid PET assessment resulted in increased diagnostic confidence as well as subsequent patient management changes.

Changes in patient management occurred in more than 60% of patients in the IDEAS study¹, with changes in medication being the most frequent type of change in 44% of patients. These results were again consistent with other studies reported in the literature.

In the meantime, GE HealthCare, MITA, and other stakeholders have provided CMS with updated evidence and publications gathered in subsequent clinical trials (including IDEAS), trials of therapeutics, and separate research to support our consistent contention that the growing amount of evidence was sufficient to end coverage with evidence development and demonstrates clinical utility to meet the standard of reasonable and necessary for the Medicare population.

Since that submission of evidence in 2020, more data has been published demonstrating the value of amyloid PET. Evidence from the Veterans Administration (VA) showed that in a tertiary memory disorder clinic, results from amyloid PET scans led to a change in diagnosis in 52.8% of cases and was associated, in the case of a positive test, with fewer further diagnostic testing.² Additional research from the same center looked at ordering practices (the VA covers beta amyloid PET scanning) to consider how scans might be ordered in an academic, tertiary memory disorders clinic. The study demonstrated that slightly more than one-third of patients received orders for a scan and that the orders largely adhered to appropriate use criteria (AUC). Given that fewer patients than were eligible under AUC received orders, the study authors concluded that physicians use clinical judgement when implementing AUC for ordering scans.³

Several studies have assessed the impact on caregivers, including the IDEAS CARE sub-study, highlighting the value of clear communication between physicians and their patients⁴, and development of coping strategies⁵ and end of life planning.⁶

In a long term follow up to the ABIDE study,⁷ van Maurik and coworkers revealed differences between those patients that accepted to have the amyloid PET scan versus those that chose not to. Rates of institutionalization, mortality and healthcare costs were all lower in those who had the amyloid PET, indicating the value of the scan in influencing longer term outcome measures.⁸

The European AMYPAD consortium completed a randomized controlled trial to investigate the value of an early amyloid PET scan in the diagnostic work-up of three subgroups of participants, those with subjective cognitive decline, mild cognitive impairment or dementia and compared the outcome of a patient receiving an etiological diagnosis with very high confidence to the group where the amyloid PET scan was later in the work-up of the patient. The rate of patients with an etiological diagnosis with high confidence at three months was 3.5 times higher in the arm with an early PET scan compared to the later PET arm and this effect was consistent over the clinical subgroups studied.⁹

The incremental value of amyloid PET and CSF (AB42, tau and p-tau) in the diagnostic work- up of mild cognitive or mild dementia patients following standard clinical work-up was evaluated by Ramusino and coworkers. The methodology included two dementia experts working through three rounds of diagnosis, where the initial round was based upon clinical, neuropsychological, and structural MRI alone. The second round of diagnosis included either CSF or amyloid PET and then in the final round the other biomarker was added. A negative PET scan led to more diagnostic changes than the CSF measure in both rounds two and three while diagnostic confidence was significantly higher for PET compared to CSF at each of these time points.¹⁰

All these studies further contribute to the evidence of the utility of PET amyloid imaging in the diagnostic work-up of patients with Alzheimer’s disease and other causes of cognitive impairment, even in the absence of disease modifying therapies. The availability of amyloid PET scans has changed the ability of clinicians to determine etiology with high confidence, resulting in disease-appropriate patient management.

Amyloid-targeting therapies
CMS recognizes that PET amyloid imaging “is the most commonly used method for patient selection in trials for any AD therapy as well as patient selection for eligibility for new FDA-approved anti-amyloid drugs, such as lecanemab.” Amyloid confirmation is required prior to initiating treatment as per the label of the approved anti-amyloid therapies¹¹ and Appropriate Use Recommendations state amyloid confirmation by amyloid PET or CSF as a requirement.¹² GEHC agrees with this observation and urges CMS to ensure there is clear coverage direction to ensure clinicians have the autonomy to follow the AUCs and make the reasonable and necessary diagnostic choice for each patient.

CMS has recently cross referenced the Prospective Study on Anti-Amyloid-ß Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease Coverage of Evidence Development (The Anti-Aß mAb CED Study), Temporary Clinical Trial # “99999999” on the Amyloid PET CED page¹³ to provide clarity that Medicare is currently covering amyloid PET scans for patients that are being evaluated for eligibility for treatment with lecanemab. Presumably, this resource would need to be updated based on whether CMS chose to cover nationally or, if MACs were to have coverage discretion, referencing local policies.

Biomarkers of amyloid become key to clinical definition of AD
As understanding of AD and related pathological changes progresses, biomarker confirmation, in addition to clinical assessment, is becoming increasingly important. In 2021, the International Working Group (IWG) revised their recommendations for the clinical diagnosis of AD¹⁴ and recommended that “Alzheimer’s disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer’s disease phenotypes” and defined Alzheimer’s disease as a “clinical–biological entity defined by a specific clinical phenotype associated with in-vivo evidence of Alzheimer’s pathology.”

While the intended use of the NIA-AA 2018 framework that proposes a purely biological (biomarker based) definition of Alzheimer’s disease based on biomarkers of amyloid, tau and neurodegeneration (ATN framework), was for research purposes, the NIA-AA recommendations on diagnostic guidelines for Alzheimer’s disease from 2011¹⁵ that precede availability of validated AD biomarkers are currently undergoing revisions to incorporate biomarker-based criteria as well.¹⁶

Finally, the appropriate use criteria¹⁷ for PET amyloid imaging are also undergoing revision with Amyloid PET imaging proposed to be rated appropriate for patients with MCI/dementia due to suspected AD with either typical or atypical clinical features and any age of onset, patients undergoing evaluation for anti-amyloid therapy, to inform prognosis of patients with MCI due to suspected AD, and for patients with MCI / dementia due to suspected AD with recent equivocal or inconclusive CSF biomarkers. Amyloid PET was also proposed as possibly appropriate for patients with subjective cognitive decline at elevated risk for AD and for monitoring response to anti-amyloid therapy.¹⁸

As revisions to the clinical guidelines recommending increased use of biomarkers in the clinic are finalized, CMS should ensure a uniform coverage policy that reflects these recommendations.

Beneficiary access

We are concerned that deferring coverage decision-making to MACs will impede beneficiary access to amyloid PET. While we understand the agency believes that MAC medical directors may be nimbler in making coverage decisions at the regional level, CMS has sufficient evidence to cover amyloid PET imaging in an NCD and to avoid regional variation in beneficiary access and other implementation challenges/timelines resulting from the local coverage determination process.

Although we generally agree with the statement that “the use of amyloid PET has changed and has become individualized with treatments,” we do not agree that “allowing local MAC discretion to make a coverage decision better serves the needs of the Medicare program and beneficiaries at this time.” CMS mentions that “individual patient factors need to be considered” as well as “local clinical environment and institutional factors” and the MACs ability “to promptly respond to the evidence on proven treatments for individual patients” as a rationale for local coverage decision-making. Even if one were to accept these premises, the implication appears to be coverage on a case-by-case basis rather than an LCD—or minimally the possibility of more restrictive and variable LCDs across the country.

An addition area of concern around such claim-by-claim coverage absent an LCD (or a Local Coverage Article) is that Medicare Advantage (MA) plans, based on their interpretation of the Medicare Managed Care Manual, do not be believe they are required to cover items and services in the absence of an NCD or LCD and do not cover services under an LCA.¹⁹ In the case of local coverage, CMS would need to issue guidance to the MA plans to ensure access to the majority of beneficiaries now receiving coverage through MA plans.

Since CMS has reviewed the evidence supporting amyloid PET for over ten years and now proposes to let MACs make coverage decisions, the proposal for local coverage could be construed that the evidence is not strong enough to support national coverage. The regional MAC medical directors may not have the same level of experience in reviewing amyloid PET evidence as medical directors in the Coverage and Analysis group. Since CMS cannot mandate coverage decisions at the local level, there is a reasonable risk that the MAC medical directors may view evidence differently across regions which would lead to inconsistent coverage for beneficiaries.

While CMS supports removal of the one scan per patient lifetime limit, we are concerned without an NCD, this recommendation is not binding on the MACs and would not be assured at the local level. This is particularly troubling for the reasons on which we have commented previously:

A lingering access issue for patients is a result of packaged payment for amyloid PET and the associated radiopharmaceuticals to hospital outpatient departments. While providing consistent, national coverage would increase access, the ability of hospital providers to provide these services at financial loss continues to impede access. CMS noted that “one study (New IDEAS) has not been completed due to enrollment issues” and they “encourage(s) completion of the remaining approved CED study.” The Government Accountability Office (GAO) reported²⁰ that several hospitals who participated in the original IDEAS study declined to participate in New IDEAS because of expiration of the payment pass-through and the subsequent lower packaged payment. We welcome the opportunity to comment on the 2024 Hospital Prospective Payment System (OPPS) proposed rule where input was solicited on how the OPPS packaging policy for diagnostic radiopharmaceuticals has impacted beneficiary access and recommend that CMS work expeditiously to resolve this payment issue.

GE HealthCare appreciates the opportunity to share our comments on the proposed reconsideration of national coverage for Beta Amyloid Positron Emission Tomography (PET) in dementia and neurogenerative disease. Our company is dedicated to the early evaluation and treatment of Medicare beneficiaries with Alzheimer’s disease. We believe that policies supporting equitable and uniform access to evaluation are essential to achieving this objective. We appreciate the effort that CMS has made in considering coverage and meeting with us and other clinical, commercial, and patient group stakeholders. We are happy to continue that dialogue. If you have any questions about these comments, please contact me or Anya Mett, Global Product Leader Neurology, at anja.mett@ge.com.

Sincerely,

Elizabeth A. Spurgin
Head, Reimbursement & Policy

References:

Rabinovici GD, Gatsonis C, Apgar C, et al. Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA. 2019;321(13):1286-1294. doi:10.1001/jama.2019.2000

Vives-Rodriguez AL et al., Impact of amyloid PET in the clinical care of veterans in a tertiary memory disorders clinic. Alzheimers Dement. (2022) Aug 17;8(1): e12320.]

Turk KW et al., Amyloid PET ordering practices in a memory disorders clinic. Alzheimers Dement. (2022) Aug 17;8(1):e12333

Gadbois et al., "Now at least we have something to call it": Patient and care partner experiences receiving an amyloid PET scan. J Am Geriatr Soc. (2022);70(10):2938-2947

Couch et al., I know that my role is going to change": a mixed-methods study of the relationship between amyloid-ß PET scan results and caregiver burden. Aging Clin Exp Res. (2023);35(2):387-397

Belanger E et al., Advance directives among cognitively impaired persons who had an amyloid PET scan and their care partners: a mixed-methods study. BMC Palliat Care 2022) 21(1):194

De Wilde A et al., Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort: The ABIDE project. AZ Dem (2019) 15(11): 1458-1467

Van Maurik I et al., A more precise diagnosis by means of amyloid PET contributes to delayed institutionalisation, lower mortality, and reduced care costs in a tertiary memory clinical setting. Alz Dementia (2023) May; 19 (5): 2006-2013

Altomare D et al., Clinical Effect of Early vs Late amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS randomised clinical trial. JAMA Neurology (2023) June 80 (6): 548-557

Ramusino CM et al., Incremental value of amyloid PET versus CSF in the diagnosis of Alzheimers Disease. Eur J Nuc Med Mol Imaging (2020). Feb; 47 (2); 270-280

Aduhelm Prescribing Information (www.accessdata.fda.gov version 4/2022, accessed August 2023)

Leqembi Prescribing Information (www.accessdata.fda.gov version 7/2023, accessed August 2023)

Cummings J et al., Aducanumab: Appropriate Use Recommendations Update. J Prev Alzheimers Dis. 2022;9(2):221-230.

Cummings J et. al., AUC Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2023;10(3):362-377

https://www.cms.gov/medicare/coverage/coverage-with-evidence-development/amyloid-pet accessed August 2023

Dubois B, Villain N, Frisoni GB, et al. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021;20(6):484-496. doi:10.1016/S1474-4422(21)00066-1

McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the

National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–69

Jack et al NIA-AA Revised Clinical Criteria for Alzheimer's disease. Presented at AAIC conference July 16th, 2023 and https://aaic.alz.org/downloads2023/NIA-AA-Revised-Clinical-Criteria-AAIC-2023.pdf

Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. Alzheimers Dement. 2013;9(1):e-16. doi:10.1016/j.jalz.2013.01.002

Rabinovici et al Updated Appropriate Use Criteria for Amyloid and Tau PET Presented at AAIC conference July 16th, 2023

https://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/mc86c04.pdf; §10.2, 90.3

United States Government Accountability Office. Medicare Part B: Payments and Use for Selected New, High-Cost Drugs. March 2021. https://www.gao.gov/assets/gao-21-252.pdf

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VIA ELECTRONIC DELIVERY TO: https://www.cms.gov/medicare-coverage-database/view/national-submit-public-comment.aspx?DocID=308&commentDocType=nca&fromPage=pmemo&proposed=Y&fromTracking=Y&=

August 16, 2023
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Attention: CAG-00431R
P.O. Box 8013
Baltimore, MD 21244–18

RE: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease,

The Biotechnology Innovation Organization (BIO) appreciates the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS’) proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. We support the proposed changes, as they will expand coverage of an important diagnostic tool in the fight against Alzheimer’s Disease (AD), dementia, and other neurodegenerative diseases.

BIO is the world's largest trade association representing biotechnology companies, academic institutions, state biotechnology centers, and related organizations across the United States and in more than 30 other nations. BIO’s members develop medical products and technologies to treat patients afflicted with serious diseases, to delay the onset of these diseases, or to prevent them in the first place. In that way, our members’ novel therapeutics, vaccines, and diagnostics not only have improved health outcomes, but also have reduced healthcare expenditures due to fewer physician office visits, hospitalizations, and surgical interventions. BIO membership includes biologics and vaccine manufacturers and developers who have worked closely with stakeholders across the spectrum, including the public health and advocacy communities, to support policies that help ensure access to innovative and life-saving medicines and vaccines for all individuals.

The Agency’s Reconsideration

Currently, the national coverage determination (NCD) at §220.6.20 covers one PET amyloid-beta (Aß) scan per patient in CMS-approved studies under coverage with evidence development (CED).

In 2022, CMS internally generated an opening of this NCD analysis based on stakeholder feedback, including public comments received during the finalization of the NCD for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease because clinical study protocols may involve more than one PET Aß scan per patient. The purpose of the NCD reconsideration is to determine if the current policy of one scan per patient per lifetime should be revised.

In the current proposed decision memo issued on July 17, 2023, CMS proposes to remove the NCD at § 220.6.20, ending CED for PET beta amyloid imaging and permitting Medicare coverage determinations for PET beta amyloid imaging to be made by the Medicare Administrative Contractors (MACs) under § 1862(a)(1)(A) the Act.

BIO supports the Agency’s proposal to end CED under the NCD and, while the Agency would allow coverage to be determined regionally by MACs, BIO encourages CMS to ensure appropriate coverage by the MACs going forward, ensuring robust coverage that aligns with the CMS’s own access and equity of care principles for dementia.

As CMS states in the July 17 proposed decision memo, “[t]he advances in medical care and standards of practice and development of proven treatments have altered the application of amyloid PET scans in clinical practice and research. For example, promising antiamyloid drug treatments to improve health outcomes such as cognition and function would not be expected to have a clinical impact in the absence of brain amyloid….Moreover, stakeholders and patients have specifically noted that the once in a lifetime limit on amyloid PET is outdated and not clinically appropriate due to the development of antiamyloid treatments and the need to confirm the presence of amyloid to start these treatments and to possibly discontinue treatments when brain amyloid has been completely removed to avoid unnecessary treatment harms.”

Given the extensive evidence development in this area, BIO believes the NCD to allow coverage of only one PET scan per lifetime was too narrowly scoped and failed to account for the current state of robust, existing evidence regarding the value and importance of PET beta-amyloid imaging for diagnosis as well as management of and potential treatment options for dementia and neurodegenerative disease.

Moreover, this decision comes in concert with the Agency’s announcement of “The Guiding an Improved Dementia Experience” (GUIDE) Model, announced on July 31. The GUIDE model will focus on dementia care management with a goal of improving quality of life for people living with dementia, reducing strain in unpaid caregivers and enabling individuals to remain in their homes and communities. According to the Administration, Black, Hispanic, Asian Americans, Native Hawaiian, and Pacific Islander populations have been particularly disadvantaged in receiving dementia care. The GUIDE Model will offer a comprehensive package of care coordination, management, caregiver education, support and respite services, and greater access to specialty dementia care in underserved populations and communities. CMS’s renewing focus on dementia care and improving access to new treatments to delay the effects of Alzheimer’s will provide significant value to patients with Alzheimer’s and their families, especially those historically underserved.

We therefore thank CMS for revising the NCD to remove the once-in-a-lifetime provision, which will allow beneficiaries to access PET scans as clinically appropriate, without set quantity limits. We believe subjecting amyloid PET scans to CED—particularly the requirement that patients be enrolled in a clinical trial to receive coverage—would only perpetuate existing challenges of care inequities in AD.

Demonstrated Value of PET

The value of amyloid PET scans has been proven through more than 25 Alzheimer’s disease studies conducted by a variety of healthcare providers in a wide range of healthcare settings. Specifically, the CMS-approved Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study has provided Phase 4 data to support the clinical utility of amyloid PET scanning. The study demonstrated that a patient receiving an amyloid PET scan had a change in treatment more than 60% of the time, and a change in diagnosis for 35% of patients based on their individual results.

PET radiotracers are FDA-approved tests to identify patients with one of the hallmark pathologies of Alzheimer’s disease: amyloid plaques. The use of Amyloid PET scans can assist clinicians in making a diagnosis for their patients who are suffering from symptoms of cognitive decline. With the availability of amyloid-targeted disease-modifying treatments, it’s even more critical that physicians have access to these types of diagnostic tools to help identify the right patients who may benefit from these types of therapies.

In a 2019 JAMA study, researchers questioned whether the use of amyloid PET was associated with subsequent change in management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. Based on their findings, Amyloid PET was associated with changes in the subsequent management of diagnostically challenging patients with cognitive disorders.

In this study, amyloid PET results were negative in a significant minority of patients with a pre-PET diagnosis of Alzheimer’s disease, and conversely, most patients with negative scan results had a pre-PET diagnosis of Alzheimer’s disease. This diagnosis and subsequent treatment may have persisted if these patients had no access to amyloid PET. As reported in previous studies , the use of amyloid PET was associated with frequent changes in diagnosis, improved diagnostic confidence, and reduced use of other diagnostic tests. There was also an increase in the proportion of amyloid positivity in patients referred to Alzheimer’s disease clinical trials, which would considerably improve the efficiency of screening for trials requiring positive amyloid PET results as an inclusion criterion.

Conclusion

Scientific and technological breakthroughs have led to the advancement of new biomarker-guided, targeted pathway-based medicines. BIO looks forward to engaging with CMS and other stakeholders throughout this process to ensure coverage is available to the right patients at the right time in accessible settings of care. We encourage CMS to continue to evaluate coverage of the most modern and up-to-date methods of confirming amyloid, including expanding coverage at this time for follow-up PET scans and other necessary diagnostic tests to guide patient treatment. This is an area where technology is rapidly evolving, and coverage flexibility is critical.

BIO appreciates the opportunity to provide feedback to CMS through this NCD Redetermination for comment. We look forward to continuing to work with the Agency to ensure Medicare enrollees can access care in an efficient and timely manner. Should you have any questions, please contact us at 202-962-9200.

Sincerely,

/s/
Crystal Kuntz
Senior Vice President
Healthcare Policy & Research
Biotechnology Innovation Organization

/s/
Andy Cosgrove
Senior Director
Healthcare Policy & Research
Biotechnology Innovation Organization

Notes:
PET beta-amyloid imaging is an essential tool for physicians in detecting the presence and level of amyloid plaques, which result from the accumulation of the peptide amyloid-ß. In 2013, CMS considered the NCD to allow coverage for diagnostic PET imaging for oncologic uses not already determined by an NCD, to be made at the discretion of local Medicare administrative contractors (MACs), due to ‘‘various improvements in the technical, regulatory and professional aspects of PET imaging for diagnosis.’’ CMS recognized that “it is widely accepted that the presence of amyloid plaques in the human brain is virtually necessary for the diagnosis of [Alzheimer’s disease (AD)],” and the presence of such plaques is “built into the postmortem diagnostic gold standard” for AD. Since the 2013 reconsideration, the Agency reports new non-oncologic PET agents have been approved by the FDA and multiple professional medical societies have published guidelines relevant to the appropriate use of these agents - reinforcing the clear diagnostic importance of PET beta-amyloid imaging.

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National Down Syndrome Society Comments to the Centers for Medicare & Medicaid Services (CMS)
Re: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease
(CAG-00431R)

August 16, 2023

The National Down Syndrome Society (NDSS) empowers individuals with Down syndrome and their families by driving policy change, providing resources, engaging with local communities, and shifting public perceptions. In collaboration with our colleagues at Down Syndrome Affiliates in Action (DSAIA), GiGi’s Playhouse Down Syndrome Achievement Centers, LuMind IDSC Foundation (LuMind IDSC), and the National Task Group on Intellectual Disabilities and Dementia Practices (NTG), and on behalf of the community we serve, NDSS writes today to respond to CMS’ proposed decision memo for the coverage of positron emission tomography (PET) beta amyloid imaging.

NDSS and the undersigned organizations wrote to CMS on July 15th, 2022, urging the agency to revisit the PET imaging coverage policy because the coverage regime does not provide sufficient access to PET imaging for the Down syndrome community, which has a demonstrable need for more than one scan per lifetime. We appreciate CMS’ consideration of ours and other’s input and the development of the proposed decision memo which removes the coverage with evidence determine (CED) and allows for coverage for more than one scan in a patient’s lifetime. As we shared in our original letter, the Down syndrome community is uniquely positioned in the Alzheimer’s landscape and subsequently in the need for PET imaging because the amyloid precursor protein (APP) gene, which is strongly associated with the formation of amyloid peptides and plaques, sits on the 21st chromosome. Because people with Down syndrome have three copies of chromosome 21 and thus three copies of the APP gene, they are at a higher risk for developing Alzheimer’s disease than people in the general population. In the real world, the somber reality is that individuals with Down syndrome face an estimated lifetime risk higher than 90% for developing Alzheimer’s disease, with the onset of symptoms coming earlier and progressing faster than their counterparts in the general public. Because people with Down syndrome are so likely to develop Alzheimer’s disease, it is critical that they receive access to high-quality medical care, including PET scans, an important method for evaluation of a patient, detection and diagnosis, efficacy of treatment for Alzheimer’s disease, and testing for adverse events.

We are concerned that the proposed decision memo permits Medicare coverage determinations for PET beta amyloid imaging to be made by the Medicare Administrative Contractors (MACs) under §1862(a)(1)(A) of the Social Security Act (the Act). If CMS determines that coverage should be determined through the MACs, it could result in some regions being covered for one scan per lifetime while another region may not impose these coverage limitations. This would be discriminatory to individuals in regions with limited coverage who could benefit from the more robust coverage determinations that other MACs offer. Variability in coverage and beneficiary access will result in delayed access to potential treatment that could drastically improve outcomes and quality of life for individuals with and without disabilities. Furthermore, while a CED authorizes coverage for individuals in the fee-for-service and Medicare Advantage programs, if the MACs make the decision about coverage, such coverage requirement does not apply to Medicare Advantage plans. This means that individuals with Down syndrome may not have choices regarding their coverage if it is inconsistent, thereby limiting access to potential therapies. We believe that Medicare coverage for PET imaging should be uniform for all beneficiaries, including individuals with Down syndrome, who are enrolled in Medicare and being assessed for potential treatment of amyloid plaques.

NDSS, along with our co-signing organizations, strongly urge CMS to establish a uniform coverage policy of PET scans based on medical necessity and without a one per lifetime limit. We value our discussions and work with CMS on positive efforts to ensure appropriate access to health care services for individuals with Down syndrome and we look forward to continuing to work with you on this important issue. For more information regarding these comments, please contact us at policy@ndss.org.

Sincerely,???
Kandi Pickard?
President and CEO
National Down Syndrome Society

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The Council on Radionuclides and Radiopharmaceuticals, Inc.

500 North Capitol Street, NW
Suite 210
Washington, DC 20001-7407
(202) 547-6582

VIA ELECTRONIC SUBMISSION

Ms. Chiquita Brooks-LaSure, Administrator
Centers for Medicare & Medicaid Services
Attention: CAG-00431R
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Ms. Chiquita Brooks-LaSure:

The Council on Radionuclides and Radiopharmaceuticals, Inc. (CORAR) is pleased to submit comments to the Centers for Medicare & Medicaid Services (CMS) on the above referenced proposed decision memorandum to remove the national coverage determination (NCD) at § 220.6.20. CORAR represents the developers and manufacturers of diagnostic and therapeutic radiopharmaceuticals, radionuclides, and other radioactive products primarily used in medicine and research, and also includes firms that operate nuclear pharmacies that prepare and dispense radiopharmaceuticals in patient-ready doses for administration to patients in healthcare facilities.

This proposed decision memorandum would end Medicare Coverage with Evidence Development (CED) requirements as well as remove the coverage limitation of one-lifetime limit on positron emission tomography (PET) beta amyloid imaging. Regarding the proposed decision memorandum you previously stated, “We know there is significant interest in the medical community about new treatments that may be effective in slowing the development of Alzheimer's disease. PET scans are an important part of diagnosis and treatment of Alzheimer's disease, and this decision is an important part of CMS' mission to help improve the lives of Americans we serve.”

Evidence continues to build over the last few years supporting the clinical utility of PET beta amyloid imaging to aid in diagnosis and treatment of disease and assist in the early identification of patients eligible for newly approved anti-amyloid monoclonal antibody treatment. For example, a recent study demonstrated the clinical value of identifying the amyloid status of patients to better inform clinical decision-making, including patient management, improved diagnostic accuracy, and reduced risk of adverse events(1). CORAR acknowledges the important step that CMS is taking as stated in the proposed decision memorandum, “We believe removal of NCD 220.6.20 will allow appropriate coverage of amyloid PET scans and will greatly reduce provider and patient burden from the existing requirements and test limitation.”

However, this proposed decision memorandum would permit Medicare coverage determinations to be made by the Medicare Administrative Contractors (MACs) under § 1862(a)(1)(A) of the Social Security Act (the Act). This provides the MACs with a Local Coverage Determination (LCD) for PET beta amyloid imaging. CORAR believes a further step is needed to reduce the risk of delays and avoid the potential for a patchwork of PET beta amyloid imaging coverage policies for Medicare beneficiaries. CORAR strongly recommends that CMS issue a National Coverage Determination (NCD) versus coverage at the discretion of MACs and Medicare Advantage (MA) plans. An NCD would provide clear and consistent national coverage immediately for PET beta amyloid imaging to benefit all eligible Medicare beneficiaries.

However, in the case that CMS finalizes an LCD policy for PET beta amyloid imaging, CORAR urges CMS to quickly coordinate its implementation through all the MACs. This to ensure clear and seamless coverage while also supporting immediate beneficiary access to PET beta amyloid imaging once the current NCD is removed. This is especially important for those beneficiaries under consideration for anti-amyloid therapy.

CORAR appreciates CMS’s consideration of our comments. I would be happy to answer any questions you may have and can be reached at (202) 547-6582 or michael.guastella@corar.org.

Sincerely,

Michael J. Guastella
Executive Director

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August 16, 2023

SUBMITTED ELECTRONICALLY

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Ms. Syrek Jensen:

AHIP appreciates the opportunity to provide input on the Centers for Medicare & Medicaid Services’ (CMS) Proposed National Coverage Determination (NCD) Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease, published July 17, 2023. AHIP is the national association whose members provide health care coverage, services, and solutions to hundreds of millions of Americans every day. We are committed to making health care better and coverage more affordable and accessible for everyone.

Alzheimer’s Disease and other forms of dementia and neurodegenerative disease take a heavy toll on patients, their caregivers, and their family members. AHIP and its member health insurance providers strongly support Medicare coverage of drugs and services that show clear evidence of net clinical benefit to patients by saving lives, reducing the burden of illness, and improving health and quality of life.

CMS is proposing to remove the current NCD which limits Medicare coverage to one beta amyloid positron emission tomography (PET) imaging scan per patient through coverage under evidence development (CED). Removal of the NCD would leave Medicare coverage determinations to the individual Medicare Administrative Contractors (MACs).

AHIP appreciates CMS’ comprehensive analysis of the clinical evidence that has been generated since 2013 when the current NCD became effective. In our comments to CMS on the NCD analysis pertaining to Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease, we recommended CMS may need to consider re-opening its NCD on beta amyloid PET scans, given the importance of confirming the presence of amyloid beta plaque in patients for the purpose of diagnosis. In addition to its importance as a diagnostic tool for Alzheimer’s Disease and other forms of dementia and neurodegenerative disease, beta amyloid PET scans may be needed to help determine eligibility for treatment with monoclonal antibodies (mAbs) for Alzheimer’s Disease, consistent with clinical study protocols. As CMS notes in the proposed decision memo, “One would not expect a therapy that removes brain amyloid in Alzheimer’s patients to work in patients who do not actually have brain amyloid and the disease in the first place.”

It is unclear whether beta amyloid PET scans may also be needed to track changes in a patient’s amyloid levels over time to assess their response to treatment and even terminate treatment if a patient’s amyloid levels are significantly reduced.

While there are other methods to confirm the presence of amyloid beta plaque, cerebral spinal fluid (CSF) testing is more invasive, requiring a lumbar puncture, and blood-based biomarker tests are still in their early stages. Beta amyloid PET scans remain a widely used tool for diagnosis and management of patient treatment.

A challenge for both treating clinicians and the MACs will be to strike a balance that is supported by clinical evidence and results in appropriate use of PET scans. Ensuring that beta amyloid PET scans are reasonable and necessary and not overutilized will avoid not only unnecessary costs but also exposure to harmful radiation for patients. PET scans are high radiation examinations that involve injecting a radioactive tracer into the patient. While the actual risk to the patient from one scan is low, the risk increases with repeated scans and exposure to radiation, particularly for vulnerable patients. In addition, without guidelines, there may be overutilization due to the difficulties non-specialist providers can experience when attempting to clinically distinguish Alzheimer’s Disease from age-expected memory loss and mild cognitive impairment.

We are also concerned that leaving decisions about coverage for beta amyloid PET scans to individual MACs may lead to inconsistent and potentially inequitable access across geographic areas and patient groups, result in confusion for beneficiaries and their providers, and make it difficult to develop consistent clinical guidelines for treatments that rely on or incorporate such scans. Therefore, while we support the proposed removal of the current NCD, we urge CMS to provide a single national coverage policy for beta amyloid PET scans. In doing so, CMS should consider the appropriate purpose and frequency for use of beta amyloid PET scans for diagnostic and monitoring purposes, and the extent to which other types of imaging might be used. A national approach can best ensure a coverage policy that balances the potential benefits and harms while providing clarity and consistency for Medicare beneficiaries and providers across the country.

Additionally, we request that CMS consider that expanded Medicare coverage of PET scans will increase costs associated with coverage of mAbs for Alzheimer’s Disease, as specified under the NCD for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. We request that CMS’ Office of the Actuary consider the combined costs of treatment and related imaging in its determination of whether an NCD will trigger the requirements of section 1852(a)(5) of the Social Security Act. Under that statutory provision, if CMS determines that an NCD would result in a significant change in costs, Original Medicare is required to assume the costs covered by the NCD for Medicare Advantage (MA) enrollees until the plan year for which the expected costs are appropriately reflected in MA benchmarks. We urge CMS to make this significant cost determination for plan years 2023 and 2024, as it pertains to MA plans, as quickly as possible after the final NCD is released.

We appreciate CMS’ consideration of these comments and share your commitment to providing Medicare enrollees access to treatments that save lives, reduce the burden of illness, and improve health and quality of life. For questions, please email kberry@ahip.org.

Sincerely,

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August 16, 2023

VIA ELECTRONIC SUBMISSION

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Ms. Jensen:

Eisai Inc. (“Eisai” or “the Company”) is pleased to submit these comments to the Centers for Medicare and Medicaid Services (CMS or “the Agency”) on the Proposed Decision Memorandum for the Reconsideration of the National Coverage Determination (NCD) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (“PET amyloid-beta scan NCD” or “NCD 220.6.20”) (CAG-00431R). The Company strongly supports CMS’ proposal to remove NCD 220.6.20 in its entirety, to allow appropriate and adequate coverage of amyloid PET scans. Removal of the NCD would be a major step forward for ensuring coverage is available for providers who utilize scans as necessary to identify patients for whom initiation of treatment is appropriate and monitor patient treatment thereafter. Eisai agrees with CMS that this action will significantly reduce burden on providers and patients from the existing requirements and limitations, keeping the patient population of need at the fore. With treatment options for dementia and neurodegenerative diseases (e.g., Alzheimer’s disease (AD)) rapidly evolving, Eisai believes this is the right step for CMS to ensure coverage is available for the most appropriate diagnostic tests for guiding Medicare patient treatment.

I. EISAI’S human health care MISSION IN ALZHEIMER’S DISEASE

Eisai is driven by our “human health care,” or hhc, mission in AD. Everything we do is guided by the principle that patients and their families come first, and we have a responsibility to listen and learn from them. Eisai has been listening, aligning, and understanding the needs of patients living with AD since well before the approval of our first AD therapy. This core principle began at Eisai more than 30 years ago and continues to drive our focus on patients, their families, and the public.

Eisai’s efforts to discover new treatments for AD began in the early 1980s through the Company’s relentless pursuit to understand the underlying causes of the disease. The Company has spent over a quarter of a century with people affected by this disease to better understand their needs. Eisai’s pioneering efforts in AD led to the landmark approval of Aricept® (donepezil) for treatment of dementia in AD in 1996, after nearly 13 years of research and development work.[1]

These efforts have led to AD therapy breakthroughs, including our monoclonal antibody, LEQEMBI® (lecanemab-irmb), which received accelerated approval from the Food and Drug Administration (FDA) on January 6, 2023, and subsequently received traditional approval on July 6, 2023. FDA approval is based on Phase 3 data from the CLARITY AD clinical trial, a trial included and referenced in this Proposed Decision Memorandum, in which lecanemab met its primary endpoint and all key secondary endpoints with statistically significant results. Lecanemab demonstrates clinically meaningful slowing of cognitive and functional decline (i.e., actual patient outcomes observed in the clinical trial) in a patient group generalizable to U.S. Medicare beneficiaries, including patients at the earliest stages of disease with low tau levels.[2] Importantly, the prescribing information for LEQEMBI states: Confirm the presence of amyloid beta pathology prior to initiating treatment. PET imaging is a key means of confirming amyloid beta pathology, and therefore identifying appropriate patients for therapy.

II. CMS SHOULD FINALIZE THE PROPOSAL TO RESCIND THE NCD FOR BETA AMYLOID PET IN DEMENTIA AND NEURODEGENERATIVE DISEASE

Eisai recommends that CMS finalize its proposal to rescind the NCD for Beta Amyloid PET in Dementia and Neurodegenerative Disease, thereby terminating Coverage with Evidence Development (CED) and permitting coverage decisions to be made by the local Medicare Administrative Contractors (MACs). We agree with the Agency that removal of the NCD will ameliorate provider and patient burden and enable the MACs to be more agile in providing coverage of PET scans, when reasonable and necessary, as new treatments and technologies are developed and approved by the FDA.

Removal of NCD 220.6.20 also will reduce complications for providers administering the treatment of monoclonal antibodies directed against amyloid under the current NCD for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. By limiting Medicare beneficiaries to a single amyloid PET scan in their lifetime, the current NCD hinders physicians’ abilities to order the most appropriate test for their patients. Additionally, the NCD for Beta Amyloid PET in Dementia and Neurodegenerative Disease could add coverage and access complications for future innovative treatments.

As the Agency states in this Proposed Decision Memorandum, research on amyloid PET has advanced, and with further developments in medical care and treatments, particularly in the area of anti-amyloid treatments, utilization of amyloid PET has evolved, becoming more individualized with patient treatments. The amyloid PET represents a useful diagnostic test that can aid the safe administration of anti-amyloid treatments to the targeted patient population, by detecting the presence of beta amyloid in each individual patient and providing a signal for the effectiveness of treatment when brain amyloid is removed. For these reasons, we support CMS’ swift actions to rescind the PET NCD to facilitate safe and accessible treatment for patients in need. We encourage CMS to finalize this decision as soon as possible following the close of the comment period, to help ensure patients and providers have access to the most appropriate diagnostic tools in a timely fashion.

III. CONCLUSION

As the leader in research, development, manufacturing and commercialization of multiple AD treatments, Eisai greatly appreciates the opportunity to comment on the Proposed Decision Memorandum for the Reconsideration of the PET amyloid-beta scan NCD Proposed Decision Memorandum. We strongly support CMS’ proposal to rescind NCD 220.6.20 in its entirety as rapidly as possible to ensure access to scans does not serve as a barrier to treatment for patients with AD. We would be pleased to answer any questions about these comments and look forward to continuing to work with CMS on ensuring uniform and equitable access to therapy for patients with AD.

Sincerely,

Lynn D. Kramer, MD, FAAN
Chief Clinical Officer, Neurology Business Group
Eisai Inc.

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BIOGEN
225 Binney Street
Cambridge MA 02142
Phone: 781-464-2000
www.biogen.com

August 16, 2023

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Attention: CAG-00431R
Mail Stop C4–26–05
7500 Security Boulevard
Baltimore, MD 21244–1850

Re: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Administrator Brooks-LaSure:

Biogen appreciates the opportunity to comment on CMS’ proposed decision to remove the national coverage determination (NCD) at § 220.6.20, ending coverage with evidence development (CED) for positron emission tomography (PET) beta amyloid imaging (the “NCD”).*1 Biogen commends and supports CMS’ proposal to remove the NCD, including the lifetime limit of one amyloid PET scan per beneficiary. We continue to strongly believe that current clinical evidence on the utility of PET beta amyloid imaging in the diagnosis and treatment of people with Alzheimer’s disease is sufficient to support this decision by the agency in its reconsideration.

Biogen is a leading global biotechnology company that has pioneered multiple breakthrough innovations since its founding in 1978, addressing some of medicine’s greatest challenges. Biogen’s innovative treatments include a co-developed treatment for postpartum depression, two co-developed treatments to address a defining pathology of Alzheimer’s disease, a therapy for a rare genetic form of amyotrophic lateral sclerosis (ALS), and the first approved treatment for spinal muscular atrophy (SMA). Biogen’s pipeline of novel therapies in neurology, neuropsychiatry, specialized immunology, and rare diseases have the potential to impact the lives of patients and families living with postpartum depression, lupus, and Alzheimer’s disease. Achieving health equity is one of Biogen’s strategic priorities. Biogen strives to include diverse patient populations in our clinical trials, and we partner with community organizations that are working to reduce health disparities. Biogen puts science to work in the service of humanity.

I. Background

The advancement of the clinical evidence on beta amyloid PET imaging demonstrates that it is appropriate, reasonable, and necessary to cover beta amyloid PET scans without CED. Biogen thus agrees with the Agency’s conclusions in the proposed decision memo regarding removal of the NCD with CED for PET amyloid beta imaging. Specifically, Biogen supports the following conclusions:

August 16, 2023

Joseph Chin, M.D.
Medical Officer for Coverage and Analysis
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services, mailstop: S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

SUBMITTED VIA ONLINE COMMENT PORTAL

Re: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease – CAG-00431R

Dear Dr. Chin:

We commend the Centers for Medicare and Medicaid Services (CMS’s) proposal to end the decade-old Coverage with Evidence Development (CED) requirements for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (Beta Amyloid PET). Updating this coverage policy to allow more than one scan per patient’s lifetime and to allow coverage outside CED-related, CMS-approved studies are critically important for people living with or suspected of having Alzheimer’s and other neurodegenerative diseases, their families, and clinicians who assist in diagnosis and treatment of their patients. Given the changing landscape of treatments for Alzheimer’s and other neurological diseases, this action is essential.

Removing the one-scan-per-lifetime limitation and other onerous CED requirements from Medicare coverage will also assist in addressing the significant health inequities relating to Alzheimer’s disease(1) and those relating to CED coverage restrictions, as well.(2) To assure the reduction of inequities, however, more is needed. Rather than removing the National Coverage Determination (NCD) entirely, as proposed, we urge CMS to maintain and update the current NCD to cover Beta Amyloid PET imaging without requiring CED or other unnecessary conditions of coverage. To remove the NCD altogether would grant regional Medicare Administrative Contractors (MACs) discretion on coverage, which could lead to differences in coverage based on where a beneficiary lives or which Medicare Advantage plan provides coverage. These differences would further exacerbate existing health inequities in treatment access and outcomes for Alzheimer’s disease and dementia. Disparities in access relating to differences in coverage decisions among MAC jurisdictions is well documented,(3) and almost one in three rural Medicare residents with early stage Alzheimer’s disease do not have access to a hospital outpatient department in their county.(4) Moreover, Medicare Advantage plans have used the lack of an NCD or Local Coverage Determination as support for denying coverage for enrolled beneficiaries or otherwise requiring more than Medicare fee-for-service does to cover a service.(5)

Access to timely diagnosis is one critical component in the fight against Alzheimer’s disease. The significance and benefit of the decision to expand access to Beta Amyloid PET is blunted, however, by CMS’s continued refusal to reconsider the CED restrictions on patient access for an entire class of FDA-approved monoclonal antibody therapies for the treatment of early Alzheimer’s disease (CEG-00460N). Enabling access to timelier diagnosis while imposing restrictions on coverage of treatments shown to delay progression and extend independence is cruel and incongruous policy. For many, the CED requirements imposed under CEG_00460N will mean denied access, unnecessary burden of illness, and loss for patients and caregivers. We strongly urge CMS to reconsider CEG-00460N, remove the CED requirements, and cover FDA-approved Alzheimer’s disease therapies in the same way Medicare covers all other FDA-approved therapies prescribed for their approved usages.

Alzheimer’s disease is an insidious, fatal illness that emotionally and financially devastates patients, their families, and their communities. People living with Alzheimer’s disease should receive the same compassion, attention, and, mostly importantly, Medicare coverage of testing and treatment as people living with fatal cancers, genetic diseases, and other serious, life-threatening illnesses do.

Sincerely,

Candace DeMatteis, JD MPH
Policy Director
Partnership to Fight Chronic Disease

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August 16, 2023

Joseph Chin, M.D.
Medical Officer for Coverage and Analysis
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services, mailstop: S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Re: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Dr. Chin:

Thank you for the Centers for Medicare & Medicaid Services (CMS) July 17 proposal (CAG-00431R) [1] to remove the national coverage determination (NCD) at § 220.6.20, ending Coverage with Evidence Development (CED) data collection requirements and the one scan per patient per lifetime limit for positron emission tomography (PET) beta amyloid imaging. CMS deserves credit for responding to the overwhelming evidence and consensus among diverse stakeholders who, for many years, have called for an end to these harmful restrictions. CMS should go father than the proposed decision memo. Rather than shifting Medicare coverage determinations for PET beta amyloid (Aß PET) imaging to the Medicare Administrative Contractors (MACs,) CMS now should provide full national coverage to all eligible Medicare beneficiaries to support detection, diagnosis, clinical treatment and supportive care. By acting now to provide full national coverage, CMS would avoid perpetuating a decade of delayed access for Medicare beneficiaries, avert fragmentation, prevent confusion among health care providers and their patients, and prevent health disparities that would arise for unequal coverage by the MACs. It is crucial that CMS work proactively and relentlessly to ensure that all beneficiaries – whether in traditional Medicare or Medicare Advantage (MA) Plans – have full, swift, unimpeded, and equal coverage for Aß PET scans. That means no CED study requirements, no lifetime limits, and no shifting responsibility to MACs and MA Plans.

As stated in the LEAD Coalition’s July 15, 2022 public comment letter when CMS originally opened a more limited reconsideration, CMS should provide full national coverage for all FDA-approved PET, cerebrospinal fluid (CSF), blood, and other technologies that may emerge to support detection, diagnosis, clinical management, and research studies, based on Aß, tau, or other biomarkers, for Alzheimer’s disease and other forms or causes of cognitive impairment.

As the LEAD Coalition [2] wrote to CMS in 2013:

"Nearly everything medical professionals do depends on an accurate diagnosis. Patients and families want, deserve and need to know the cause of cognitive impairment. Currently, far too few people experiencing symptoms of cognitive impairment receive a timely, accurate and clear diagnosis. Amyloid PET is a major advance in Alzheimer’s disease (AD) diagnosis and has the capacity both to facilitate appropriate treatment and avert inappropriate treatment.

"Amyloid PET allows more timely and precise advice on available courses of treatment, and gives patients and families greater clarity about what they face and the planning decisions to be weighed.

• reducing disease-related stigma;
• allowing the family to build a care team and seek out education and support services;
• providing access to approved medications and behavioral interventions;
• offering an opportunity for timely development of advance directives, financial planning and declaration of end-of-life wishes; and
• facilitating clinical trial enrollment."

In April 2013, the LEAD Coalition strenuously urged CMS to provide full national coverage within the appropriate use criteria (AUC) developed by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer’s Association;[3] we explicitly asked CMS not to impose Coverage with Evidence Development (CED). In August 2013, the LEAD Coalition responded to CMS’ Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N) and reiterated our unwavering opposition to CED. We wrote at the time that CED would be “essentially telegraphing that CMS does not intend to approve diagnostic advances for at least another five to ten years or more.” A full decade later, sadly, our fears proved to be well-founded. While the (Original) IDEAS Study [4] has been enormously valuable in confirming what many of us knew intuitively, and we are optimistic that the New IDEAS Study [5] also will advance the field, those studies could have occurred without the harms inflicted by the CMS CED through a decade of delay.

In mid-2022, CMS initiated an excruciatingly narrow and inadequate reconsideration limited to determining if the current policy of one scan per patient per lifetime should be revised, while not addressing the overarching CED restrictions on uses beyond CMS-approved clinical trials. Now, after another year of lost time, CMS proposes to remove the one scan per patient per lifetime limit and its own CED study requirement. The LEAD Coalition welcomes removal of this artificial, arbitrary, and harmful limit along with the CMS CED study requirement, and urges CMS is the strongest possible terms to ensure that coverage is guaranteed for all Medicare beneficiaries whose treating health care providers order these scans as part of clinical care or in furtherance of research studies. As the American Academy of Neurology (AAN) wrote in its July 7, 2022 public comment:

"…we believe beta-amyloid pet scans are a vital diagnostic tool and deference should be appropriately shown to clinical judgment. Restriction to one PET scan per lifetime is likely to negatively impact participation in trials under the NCD for mAbs directed against amyloid for the treatment of Alzheimer’s disease. The AAN also believes that current restrictions on beta-amyloid PET scans may negatively impact care by limiting the information that physicians need to make appropriate treatment decisions (e.g., to stop monoclonal antibody therapy). If Medicare coverage is limited to one scan per patient, the additional PET scans furnished during the trials will not be covered and those costs will have to be borne by the trial sponsors or beneficiaries. This limitation raises major health equity issues and may limit trial participation for low-income beneficiaries. Furthermore, the AAN believes that there may be circumstances in which the clinician believes an additional scan is warranted. Such circumstances include but are not limited to, technical issues with tracer, movement artifact, development of new cognitive symptoms, or the initial scan being done when the patient is not symptomatic."

As the American College of Radiology (ACR) wrote in its July 11, 2022 public comment:

"Patients who are potential candidates for monoclonal antibodies should have an amyloid PET scan immediately before determining whether they are a candidate for monoclonal antibody therapy and before entering a covered trial. Amyloid status observed in earlier scans may no longer reflect a patient’s current beta-amyloid status. Studies evaluating the use of blood biomarkers to determine amyloid status have noted that some patients who are positive by blood tests will initially be negative by PET but will ultimately “progress” to be positive by PET. [6] There is no evidence to suggest that a single amyloid PET scan per patient is appropriate or that an outdated scan can provide the diagnostic information needed to determine whether a patient is currently a candidate for therapy. Furthermore, ACR does not understand the scientific basis for limiting beta-amyloid PET to one scan per lifetime. Not only can CNS beta-amyloid status change over time, but ongoing clinical trials for monoclonal antibody therapies for AD have also used the results of post-treatment beta-amyloid PET to inform a decision on whether to continue monoclonal antibody therapy. … In addition to scans to determine a patient’s eligibility for therapy, CMS should require and cover post-treatment PET scans to determine whether beta-amyloid has been removed."

Any artificial lifetime limit on Aß PET scans not only undermines equitable participation in a single clinical trial, it potentially prevents individuals from volunteering for or participating in subsequent clinical trials.

Aß PET imaging — without CMS-imposed lifetime limits — is reasonable and necessary for clinical use among people experiencing cognitive impairments and for clinical trial participants. CMS already is aware (as noted extensively in the July 17 proposed reconsideration) of the persuasive results from IDEAS [7], and other public comments highlight more than 30 separate studies that further confirm the benefits of Aß PET. As stated in the August 8, 2023 public comment by the American Academy of Neurology:

"There is robust literature demonstrating that beta-amyloid PET influences clinical decision-making. In the IDEAS Study which included 11,409 participants with mild cognitive impairment (MCI) or dementia of uncertain cause, ninety days after beta-amyloid PET, patient care plans changed (compared with the pre-PET plan) in 60.2% of patients initially characterized as having MCI and 63.5% of patients initially characterized as having dementia of unknown cause. Similarly, Pontecorvo et al. found that immediate notification of beta-amyloid PET findings was associated with a change in patient management, particularly changes in AD medication. The information provided by the scan had a significant impact on prescribing patterns in that acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001)."

While the LEAD Coalition welcomes the new CMS proposal to end this CED, it is inadequate merely to shift decision-making to MACs. Instead, based on the robust existing evidence, CMS should act now to ensure full and equal national coverage. Shifting to the MACs would guarantee more delays, prolong uncertainty, invite unjustifiable regional disparities, and risk deepening health inequality for the most medically under-served Medicare beneficiaries who would struggle to navigate MACs’ case-by-case decision-making processes. If CMS were to shift decision-making and any MACs declined to provide coverage in their markets, it would pose a potentially existential threat to the New IDEAS Study and be counter-productive to our shared goal to overcome health disparities. As explained in the August 8, 2023 public comment by the Medical Imaging and Technology Alliance:

"An NCD would provide consistent and clear coverage immediately once such a policy was finalized, instead of months of uncertainty as MACs each determine their local coverage policy. Based on past experience with MAC coverage of diagnostics, many contractors opt to provide coverage on a claim-by-claim basis without a posted policy providing coverage. Other MACs have used Local Coverage Articles (LCAs) for imaging agents and advanced imaging for oncologic and nononcologic PET scans.

"A concern with either claim-by-claim coverage or an LCA is that Medicare Advantage (MA) plans frequently assert they are not required to cover PET in the absence of an NCD or LCD, nor are they required to cover items and services only included on LCAs. MA plans often point to section 90.3 of the Medicare Managed Care Manual, which allows MA plans to follow coverage for NCDs and LCDs but not articles or claim-by-claim coverage. If MA plans attempt to assert that coverage is not required for beta amyloid PET, there could be access issues for anti-amyloid therapies. This is particularly problematic in states like California, Florida, and Texas which have the highest MA enrollments in the country and a sizable portion of the Medicare population. CMS would need to issue guidance and transmittals to the MA plans to instruct them to follow the coverage established by the MACs.

"Even for MACs that decide to issue LCDs, this process could also take several months to establish final policies. Additionally, once a final LCD is issued, it is not effective for 45 days. During this time, there would be a lack of clarity for ordering physicians and coverage gaps for beneficiaries in need of beta amyloid PET imaging to receive anti-amyloid therapy."

A generation of people facing cognitive impairment have been denied the clinical and non-clinical benefits of Aß PET and a generation of research projects have been denied the utility of Aß PET in advancing scientific discovery. A lost decade has been too high a price, the continuation of which would be intolerable. As noted in the August 14, 2023 public comment by the Alzheimer’s Association:

"On the heels of the Food and Drug Administration (FDA) traditional approval of Leqembi ® and as new treatments advance, access to this diagnostic tool becomes even more important. In the new era of treatment and management of patients with Alzheimer’s, multiple amyloid PET scans may be necessary to test for eligibility, establish a baseline, track changes in a person's amyloid levels over time, and even to determine that treatment should be paused because lower amyloid levels have been achieved."

While this CMS proposed reconsideration process is limited to Aß PET by the underlying NCD 220.6.20, it stands as a stark reminder that other technologies for other biomarkers and other causes of cognitive impairment have been or will be approved by the FDA and those technologies equally deserve full national coverage. The scientific and clinical communities and – more important – people facing all forms or causes of cognitive impairment deserve ready and equitable access that is possible only through CMS full national coverage. While CMS non-coverage, CED, and other utilization management tactics harm all beneficiaries who stand to benefit from technologies to detect, diagnose and measure clinical progression, these CMS actions fall hardest on Medicare beneficiaries who experience socioeconomic and other health and healthcare access disparities. Medicare is meant to be an equalizer, to be a powerful tool to advance health equity and broader social justice. Ensuring (and insuring) full national Medicare coverage for all FDA approved technologies to detect, diagnose, and measure cognitive impairment is an essential first step toward empowering older adults to work with their clinicians to ascertain with greater accuracy what diseases they do and do not face and therefore what clinical and non-clinical supports are appropriate. The Administration’s commitment to health equity is on the line as is the foundational rationale for the Medicare program as articulated by President Lyndon B. Johnson in 1965 upon signing the Medicare bill (H.R. 6675, now Public Law 89-97, 79 Stat. 286) into law:

"No longer will older Americans be denied the healing miracle of modern medicine. No longer will illness crush and destroy the savings that they have so carefully put away over a lifetime so that they might enjoy dignity in their later years. No longer will young families see their own incomes, and their own hopes, eaten away simply because they are carrying out their deep moral obligations to their parents, and to their uncles, and their aunts.[8]"

Thank you for considering this public comment and for your commitment to overcoming Alzheimer’s disease and other forms of dementia. For any questions or additional information about this proposed NCD reconsideration or other issues, please contact LEAD Coalition Executive Director Ian Kremer at any time.

Sincerely,

Ian N. Kremer, J.D.
Executive Director
LEAD Coalition (Leaders Engaged on Alzheimer's Disease)
ikremer@leadcoalition.org

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Response to CMS Proposed Decision on PET Beta Amyloid Imaging Coverage:
Should CMS remove the current NCD for beta amyloid PET in dementia and neurodegenerative disease?

Daniel L. Alkon¹, David Morgan², Giulio Taglialatela³, and Alberto J. Espay⁴

1 Chief Scientific Advisor of SynapsDx, Rockville, Maryland
2 Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan
3 Mitchell Center for Neurodegenerative Disease, Department of Neurology, UTMB, Galveston, Texas
4 Department of Neurology, James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio.

We extend our appreciation to the Centers for Medicare & Medicaid Services (CMS) for their consideration of changes to the national coverage determination (NCD) for amyloid PET imaging. Upon thorough review, we respectfully propose that more impactful measures can ensure appropriate treatment of patients with Alzheimer’s disease (AD). Notably, at the diagnosis outset, a significant 50-70% of symptomatic patients are inaccurately diagnosed due to the absence of routine cognitive screening despite CMS coverage (Hansson et al., 2022). This issue exacerbates particularly in cases of subjective cognitive decline or mild cognitive impairment (MCI). Only approximately 25% of Medicare beneficiaries recall undergoing these tests (Jacobson et al., 2020). Given the progressive nature of AD, the absence of baseline cognitive assessment hampers the ability to monitor changes in a patient’s condition. Thus, we assert that directing resources toward cognitive testing, and proactive management of comorbidities and lifestyle upstream in the diagnostic pathway (Livingston et al., 2020; Rolandi et al., 2020) holds greater promise. Our stance discouraging amyloid PET coverage is rooted in the following key reasons:

Lack of Sufficient Evidence: The available evidence supporting the clinical utility and cost-effectiveness of amyloid PET imaging in routine clinical practice remains inconclusive. While studies suggest its role in identifying amyloid plaques in the brain, there is a lack of robust evidence demonstrating its impact on patient outcomes or treatment decision-making.

When Klunk et al., demonstrated amyloid PET in humans, both individuals with AD dementia and agematched controls had cerebral amyloid burden (Klunk et al., 2004). Since this time, various studies have shown that between 20-40% middle-aged and elderly individuals are amyloid positive without apparent signs of dementia (Katzman et al., 1988; Delaere et al., 1993; Price and Morris, 1999; Klunk et al., 2004; Pike et al., 2007; Aizenstein et al., 2008; Zolochevska and Taglialatela, 2016). In individuals 80 years of age or older, 60% presented at autopsy with AD neuropathology but no cognitive impairment during life (Jack et al., 2014, 2017, 2018; Jansen et al., 2015). In fact, in an Alzheimer's Association-supported study, “a major limitation of amyloid PET to support a diagnosis of AD dementia is the high prevalence of amyloid positivity in normal older individuals.” (Johnson et al., 2013b). Furthermore, amyloid PET can be observed in other medical conditions such as dementia with Lewy bodies or amyloid angiopathy (Johnson et al., 2007, 2013a; Gomperts et al., 2008) raising the possibility of misdiagnosis (Gomperts et al., 2008; Alakbarzade et al., 2021).

Roberts and colleagues observed that the likelihood of a positive PET scan increased from 0% in individuals aged 50-59 years to 16.4% in those aged 80-89 years with MCI – the population studied in the CLARITY trials (Roberts et al., 2018; van Dyck et al., 2023). Given that PET positivity peaks at 16.4% in the 80-89 year age group (Roberts et al., 2018), we question the value of using amyloid PET in a population with low prevalence of amyloid and no dementia. Multiple clinical trials employing positive amyloid PET scans for enrollment (Alzheimers trial unable to show significantly slower cognitive decline, n.d.; BWH Press Release - Brigham and Women’s Hospital, n.d.) have resulted in failure, leaving ambiguity regarding whether the cause lies in the treatment, patient selection, or the adequacy of amyloid for diagnosis. The utility of amyloid PET in predicting MCI to AD conversion is limited, as indicated in a study examining its use in MCI (Martínez et al., 2017). Over the long term, the adjusted annual conversion rates from MCI to AD in specialist settings and population studies are 8.1% and 6.8%, respectively (Mitchell and Shiri-Feshki, 2009). Less than half of all MCI patients will progress to AD over ten (10) years (Mitchell and Shiri-Feshki, 2009).

In the landmark IDEAS study, funded by the Alzheimer’s Association to develop a Coverage with Evidence Development program, amyloid PET altered diagnosis from AD to non-AD and non-AD to AD in 25% and 10.5% of cases, respectively (Rabinovici et al., 2019). The authors noted the need for further research on amyloid PET's impact on clinical outcomes. Balancing cost and value, amyloid PET averages $7,275 per scan (How much should your PET scan cost?, 2018), which in the context of a 10.5% switch to an AD diagnosis from non-AD due to PET seems disproportionate. While the 25% diagnosis shift from AD to non-AD holds value, we question whether the initial AD classification wasn't a broader term encompassing dementia without thorough diagnostic exclusion and use of other Alternative Diagnostic Modalities and appropriate cognitive testing during the annual wellness exam, covered by CMS, in order to first establish baseline and second to show progressive changes.

Based on the available evidence cerebral amyloid is a risk factor for AD, not a determinate. While the presence of amyloid increases the likelihood of developing Alzheimer's disease, it is essential to note that most individuals with brain amyloid will not develop AD. The idea that individuals with amyloid will eventually develop AD if they live long enough is a fallacy of composition. In this case, it would be fallacious to assume that just because amyloid is present in the brains of some individuals, all individuals with amyloid will eventually develop AD if they live long enough. We note that Jack et al. acknowledged this in the 2018 NIA-AA guidelines stating “because of increasing death rates with age and the long preclinical period of AD, it cannot be known if that person would have developed T, (N), or (C) had they lived longer” (Brookmeyer and Abdalla, 2018; Jack et al., 2018).

Considering these factors, it remains unclear how amyloid PET will improve outcomes, especially in the context of new anti-amyloid drugs with unclear clinical benefit and particularly when 40% of dementia cases are attributable to comorbid diseases such as diabetes, heart disease, and stroke, all of which are manageable (Rolandi et al., 2020), with 40% of all dementia preventable through 12 modifiable risk factors (Livingston et al., 2020).

Alternative Diagnostic Modalities: In alignment with CMS, we emphasize the significance of selecting appropriate patients to ensure that newly developed drugs offer more benefits than potential risks (CAG- 00431R, page 3). According to Leqembi's FDA labeling, establishing the presence of AD is a prerequisite before assessing amyloid positivity, as outlined in Section 2.1 Patient Selection of the USPI. [i] PET scans, as discussed earlier, fall short in simultaneously establishing both AD and amyloid. Additionally, a positive PET scan does not reliably indicate AD, nor does it strongly predict AD progression within ten (10) years in the presence of MCI.

Moreover, there are credible alternative diagnostic avenues available to assess cognitive impairment and rule out AD. Synapse loss, a direct driver of clinical dementia (Jack et al., 2010), is recognized in the CMS memo as a cause of AD symptoms (Jack et al., 2011, 2018). The DISCERN™ test deploys three biomarker assays targeting key AD factors: memory regulation, synaptic connections, amyloid plaques, and neurofibrillary tangles. Clinical trials have demonstrated DISCERN™'s remarkable sensitivity and specificity, exceeding 95%, validated against the NIH Gold Standard for AD, autopsy-validated dementia (Khan and Alkon, 2010). Based on our experience, over 40% of patients assessed using DISCERN™ suspected to have AD do not have this disease. This substantially saves costs by obviating invasive procedures like lumbar punctures and amyloid PET imaging.

Limited Accessibility and Equity Concerns: Recent articles in STAT, market research, and the U.S. Department of Energy (glennroberts, 2017; Trang, 2023; 2023 United States PET Imaging Market Report: Forecasts to 2026 with Focus on Market Trends in Hospitals and Imaging Centers, Including Procedure Volume, Use of OEM Vs. Third-Party Service Providers and More, 2023) highlight the concerning reality that the United States has only approximately 2500 PET scanners. These scanners are in high demand, with nearly 100% utilization for both clinical use and research purposes (Trang, 2023). The logistical challenges of time and travel further burden patients seeking access to PET scans. Additionally, the interpretation of PET images requires specialized training, restricting the availability of PET scanners primarily to major metropolitan areas making PET useful only in specialized clinics rather than primary and secondary care settings (Hansson et al., 2022). Moreover, the issue is compounded by the longstanding mistrust of the medical establishment within minority and historically underrepresented communities (Watson et al., 2014). In summary, granting coverage for amyloid PET imaging without addressing the accessibility and equity concerns may lead to significant disparities in access to care, particularly for older adults living in rural or underserved areas. The availability of facilities providing this imaging modality is limited, making it challenging for some Medicare beneficiaries to access the service, potentially exacerbating existing healthcare disparities.

Cost Implications: Including amyloid PET imaging as a covered service could create substantial financial challenges for Medicare, beneficiaries, and the healthcare system. At inpatient facilities, the average cost is $7,275 (How much should your PET scan cost?, 2018). Amyloid PET scans are necessary for Leqembi prescription and monitoring, potentially leading to three (3) scans per year per patient at a cost of $21,825. Assuming 3.25 million eligible Leqembi patients among the 6.5 million Americans aged 65 and older with AD dementia (2022 Alzheimer’s disease facts and figures, 2022), this adds a minimum of $71 billion to Medicare costs.

These numbers need context: Medicare payments for AD patients are already significantly high, nearly three times more than non-AD beneficiaries, totaling $321 billion in 2022 (2022 Alzheimer’s disease facts and figures, 2022). PET inclusion could escalate this to approximately $392 billion in the first year. These calculations exclude MRI costs, Leqembi expenses, infusion fees, and potential hospitalization and treatment costs due to ARIA and other drug side effects.

In summary, due to limited and inconclusive evidence on clinical benefits and potential financial strain, a thorough cost-benefit evaluation is imperative. It's crucial to balance potential advantages against expenses before deeming coverage reasonable and necessary (§1862(a)(1)(A) of the Medicare Act). We discourage the current changes allowing Medicare coverage for amyloid PET imaging, favoring equitable access to proven diagnostics. This includes the McKhann committee criterion of observing progressive cognitive decline post-dementia diagnosis (McKhann et al., 2011), ensuring superior care for Medicare beneficiaries.

Your consideration of these arguments is appreciated. We're committed to collaborative efforts with CMS and stakeholders, aiming for evidence-driven policies to enhance healthcare outcomes for all beneficiaries.

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Submitted electronically to the Medicare Coverage Database via CMS.gov.

August 16, 2023

Coverage and Analysis Group
Center for Medicare and Medicaid Services
Department of Health and Human Services
Administrative File CAG-00431R

RE: Proposed National Coverage Determination Reconsideration for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear members of the Coverage and Analysis Group,

We write to you today on behalf of BJC HealthCare (“BJC”), an integrated health system in St. Louis, Missouri, and its academic physician partners at the Washington University School of Medicine (“WUSM”), regarding the National Coverage Analysis Proposed Decision Memo (“the Memo”) reconsidering the National Coverage Determination for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (NCD 220.6.20). The Memo proposes to rescind NCD 220.6.20, ending Coverage with Evidence Development (“CED”) for Positron Emission Tomography (“PET”) beta amyloid imaging and instead permitting Medicare Administrative Contractors (“MACs”) to make local coverage determinations for this service. BJC and WUSM strongly support this proposal and thank the Agency for this opportunity to advocate publicly for its adoption.

In February of 2022, BJC and WUSM submitted public comment regarding Administrative File CAG-00460N, the NCA for Monoclonal Antibodies directed against Amyloid (“AA-mAbs”) for the treatment of Alzheimer’s Disease (“AD”). In our public commentary, we noted that NCD 260.6.20’s coverage limitation of one Amyloid PET scan per beneficiary lifetime would significantly curtail investigators’ ability to design longitudinal studies of the longer-term effects of mAb therapy on Medicare beneficiaries with AD. We therefore recommended the Agency consider revising NCD 220.6.20 to specify that additional Beta Amyloid PETs may be covered when part of a CMS-approved trial under a relevant CED protocol, e.g., mAbs for the treatment of AD. We believed the oversight inherent in a CMS-approved CED trial would ensure all such PETs are medically necessary and clinically appropriate for Medicare beneficiaries and otherwise consistent with NCD 220.6.20.

In April 2022 your Agency issued NCD 200.3 permitting national coverage of AA-mAbs for treatment of AD under a CED protocol, with two possible coverage modalities depending on the particular circumstances of an AA-mAb’s Food and Drug Administration (“FDA”) approval. In July the FDA granted full approval of Leqembi, an AA-mAb demonstrating efficacy from a direct measure of clinical benefit and therefore eligible for the most permissive coverage standard under NCD 200.3. The CAG’s proposed rescission of NCD 200.6.20 therefore coincides fortuitously with Leqembi’s (and soon, similar successor treatments’) more widespread availability, including for Medicare beneficiaries.

As noted in our prior commentary, CMS must expand coverage of PET beta amyloid imaging to ensure Medicare beneficiary access to these innovative therapies, and to facilitate the CED process under NCD 200.6. We therefore strongly recommend the CAG finalize the Memo’s proposed rescindment of NCD 200.6.20 and deferment of PET beta amyloid imaging to the local MACs. If possible, the CAG should finalize a retroactive effective date for the rescindment coinciding with one of the effective or implementation dates of NCD 200.3 (April 7, 2022 or December 12, 2022, respectively), or the effective date of the FDA’s approval of Leqembi (July 6, 2023). A retroactive effective date would help ensure seamless Medicare beneficiary access to both treatment via AA-mAb and investigation via PET beta amyloid imaging. We thank the CAG in advance for its consideration and look forward to a final decision.

Sincerely,

Mary C. Spencer, R.N., MSN
Vice President, Neuroscience Clinical Service Line
BJC Health Care & Barnes-Jewish Hospital

Bruce L. Hall, MD, PhD, MBA
Vice President and System Chief Medical Officer
BJC Healthcare, Center for Clinical Excellence
Professor of Surgery
Professor of Healthcare Management
Washington University in Saint Louis

David M. Holtzman, MD
Barbara Burton and Reuben M. Morriss III Distinguished Professor
Scientific Director, Hope Center for Neurological Disorders
Dept. of Neurology
Washington University School of Medicine

Pamela K. Woodard, MD, FACR
Radiologist-in-Chief, Barnes Jewish Hospital
Director, Mallinckrodt Institute of Radiology
Elizabeth E. Mallinckrodt Professor of Radiology
Professor of Internal Medicine, Pediatrics, and Biomedical Engineering
Washington University School of Medicine

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August 15, 2023

Joseph Chin, M.D.
Acting Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore, MD

Electronically Submitted: CMS_caginquiries@cms.hhs.gov

Re: Public Comment on NCA for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Dr. Chin:

The New Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) Study Team appreciates the opportunity to submit public comments in response to the Centers for Medicare & Medicaid Services’ (CMS) National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. The Study Team members include the Study Principal Investigator and chair, Dr. Gil Rabinovici, University of California, San Francisco; Dr. Bruce Hillner, Virginia Commonwealth University; Dr. Barry Siegel, Washington University, St. Louis; Dr. Constantine Gatsonis, Brown University School of Public Health; Dr. Rachel Whitmer, University of California-Davis; Dr. Consuelo H. Wilkins, Vanderbilt University Medical Center; Dr. Peggye Dilworth-Anderson, University of North Carolina, Chapel Hill; Dr. Sid O’Bryant, University of North Texas; Dr. Robert Rissman, University of Southern California; and Dr. Maria Carrillo, Chief Science Officer of Medical & Scientific Relations for the Alzheimer’s Association. New IDEAS is sponsored by the American College of Radiology, directed by the Alzheimer’s Association, and advised by the Centers for Medicare & Medicaid Services. New IDEAS Study leadership applauds CMS for reconsidering the National Coverage Determination (NCD) at 220.6.20, and supports the Proposed Decision Memorandum to retire the NCD, effectively ending CED data collection requirements for position emission tomography (PET) beta amyloid (Aß) imaging.

First and foremost, the Study Team wants to correct a statement made by CMS in the Proposed Decision memorandum for the reconsideration of Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease. The New IDEAS Study is in fact currently active and open to accrual for Medicare beneficiaries who meet study eligibility criteria. The study implemented a temporary enrollment pause in March 2022 for only one of its three patient cohorts. The decision to pause enrollment into the study’s fastest accruing cohort enables the study to collect contemporaneous data across all cohorts and ensure study generalizability through proportionate enrollment of traditionally minoritized populations who bear the greatest burden of dementia. The New IDEAS Study Team is committed to the completion of the study as originally developed with CMS to meet its objectives of understanding the association between beta amyloid PET and patient-centered outcomes in a diverse population, specifically Black/African American and Hispanic/Latinx populations. To date, the study has enrolled over 4,400 unique individuals (over 60% of the pre-specified accrual goal), 45% of who self-identify as Black/African American and/or Hispanic/Latinx.

In the Decision Memorandum, CMS proposes to end the Coverage with Evidence Development (CED) requirement along with the limit of one beta amyloid PET scan per patient per lifetime. The New IDEAS Study Team supports these policy changes to prevent significant barriers to this important diagnostic tool. While we support the removal of CED, we hold concerns about the proposal to leave coverage determinations for beta amyloid PET imaging to be made at the discretion of the Medicare Administrative Contractors (MACs) under 1862(a)(1)(A) of the Social Security Act.

The New IDEAS Study Team strongly urges CMS to reconsider leaving coverage determinations to the discretion of the local MACs and instead implement a national coverage determination ensuring coverage for Medicare beneficiaries with cognitive impairment who are being evaluated for Alzheimer’s disease. If left to local determination, coverage of beta amyloid PET could be significantly delayed and highly variable across geographic regions, further exacerbating existing inequities to access beta amyloid PET imaging. Swift and broad coverage of beta amyloid PET is imperative at this time when anti-amyloid therapies are being approved by the Food and Drug Administration (FDA) and sought after by patients and their families.

The proposed rule, as written, creates concern for an effective transition from coverage under CED. The New IDEAS Study Team wants to emphasize specific recommendations to CMS as outlined below. These recommendations are intended to further improve access to beta amyloid PET imaging as a diagnostic tool for Alzheimer’s disease (AD), to ensure the study team’s ability to complete the New IDEAS Study, and to foster equitable care for those most at risk.

Expedited and detailed communication:
Through nearly a decade of experience operating the IDEAS Study Program, the Study Team has found that Medicare Contractors, and especially Medicare Advantage Plans, often lack the necessary information and transmittal documentation for them to seamlessly provide coverage of PET for non-oncologic indications to beneficiaries eligible for coverage. The lack of awareness in their coverage obligations results in frequent denials that lead to increased burden placed on providers and patients to navigate the process. These challenges disproportionately impact Black/African American and Hispanic/Latinx Medicare beneficiaries because these groups are more likely to be enrolled in Medicare Advantage.[1] At the time of final ruling, we strongly encourage CMS to draft thoroughly detailed transmittal documents that are distributed in an expedited manner to MACs and MA plans. We believe that CMS should provide recommendation to the local MACs and MA plans and monitor determinations to ensure that variations in coverage do not result in health equity-related access differences.

Coverage for clinical diagnosis and utility in addition to therapeutic evaluation and management:
We strongly urge CMS to recommend coverage of beta amyloid PET not only for the purpose of therapeutic evaluation and management but also as a tool for early and accurate diagnosis. Recognizing that we are in a new era of treatment and management of Alzheimer’s disease, driven by recent FDA approvals of therapies, broad access and coverage to beta amyloid PET has become even more important. However, we strongly believe that coverage of beta amyloid PET should not be limited for use in evaluation and management of approved therapies but should also be covered widely as a diagnostic tool for providers to care confidently for their patients with cognitive impairment.

To remind CMS of published evidence highlighting the clinical utility of beta amyloid PET, we reiterate the published clinical utility of beta amyloid PET, which was assessed by the primary analysis of the IDEAS Study. The robust sample was comprised of 11,409 participants initially characterized as having mild cognitive impairment (MCI) or dementia of uncertain cause. Ninety days after beta amyloid PET, patient care plans changed (compared with the pre-PET plan) in 60.2% of patients initially characterized as having MCI and 63.5% of patients initially characterized as having dementia of unknown cause. Hence, beta amyloid PET was associated with substantial subsequent changes in the management of patients with diagnostically challenging cognitive disorders.[2]

Beyond the IDEAS Study, at least 30 published studies involving more than 4,000 patients have reviewed the utility of beta amyloid imaging for the diagnostic assessment of patients evaluated for cognitive impairment in memory clinics. Several meta-analyses and systematic reviews [3] confirm the consistent impact of beta amyloid PET in the evaluation of patients with cognitive impairment, demonstrating that beta amyloid PET contributes to diagnostic revisions in approximately 30% of patients and increases diagnostic confidence in approximately 60% of patients. Changes in management were observed in 32% to 87% of patients, with the most common type of change in management being either the initiation or discontinuation of planned Alzheimer’s disease medication. Medication changes were observed in approximately 40% of patients in the first IDEAS Study. Other types of management changes included referral to clinical trials, Alzheimer’s genetic testing, addition or removal of planned diagnostic tests, and counseling about safety and future planning.

Although the evidence supporting the use of beta amyloid imaging is compelling, studies have largely excluded or had limited enrollment of Black/African American and Hispanic/Latinx individuals, who are 1.5 – 2 times more likely to have dementia. This lack of inclusivity is the primary reason for our New IDEAS study, which aims to enroll 7,000 individuals including 2,000 Black/African American, 2,000 Hispanic/Latinx, and 3,000 from other racial and ethnic groups. The rationale for completing the New IDEAS study is stronger now than when it was approved 3 years ago. In 2022, our team published a secondary analysis of the original IDEAS study and found the odds of having a positive amyloid PET scan were lower for Asian participants (odds ratio [OR], 0.47; 95%CI, 0.37-0.59; P < .001), Black participants (OR, 0.71; 95%CI, 0.60-0.84; P < .001), and Hispanic participants (OR, 0.68; 95%CI, 0.59-0.79; P < .001) compared with white participants.[4] These racial and ethnic differences in amyloid PET positivity may indicate differences in underlying etiology of cognitive impairment, which has important implications treatment and prevention, particularly treatments focused on amyloid.

The Study Team is grateful to have partnered with CMS for more than eight years in the development and implementation of both the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) Study and the New IDEAS Study. To facilitate the completion of the work started by this program, we are hopeful that CMS will consider and implement our recommendations described above. It is essential that CMS find a mechanism to cover beta amyloid PET immediately and broadly so that all Medicare beneficiaries have easy and affordable access.

Thank you for the opportunity to comment. We appreciate CMS revisiting NCD 220.6.20 to expand access of gold-standard diagnostic imaging without CED requirements. If you have any questions or comments on our letter, please do not hesitate to contact Dr. Gil Rabinovici, New IDEAS Study Principal Investigator, at gil.rabinovici@ucsf.edu.

Respectfully Submitted,
The New IDEAS Study Team

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We are immensely grateful for the opportunity to comment on the Center for Medicare and Medicaid Services' (CMS) proposed National Coverage Determination (NCD) reconsideration for Beta Amyloid Positron Emission Tomography(PET) in Dementia and Neurodegenerative Disease.

At UsAgainstAlzheimer's, we welcome CMS's proposal to eliminate the highly-restrictive NCD at § 220.6.20, effectively ending coverage with evidence development (CED) for PET beta amyloid imaging.

The proposed decision to allow Medicare coverage determinations for PET beta amyloid imaging to be made by the Medicare Administrative Contractors (MACs) under § 1862(a)(1)(A) of the Social Security Act (the Act) is an important step in the right direction, but we urge you to make an affirmative, national decision that amyloid PET scans should be covered. Beneficiary access to this important diagnostic and monitoring tool should not vary from region to region or plan to plan.

Our organization had previously submitted detailed comments on July 15, 2022, in response to CMS's NCD Analysis for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease. In those submissions, we presented a compelling case for CMS to reconsider this NCD and provide coverage without CED for the FDA-approved use of an Aß PET scan.

Since that time, the case for taking this long-overdue action has only strengthened. On July 6th of this year, Leqembi, one of the class of monoclonal antibodies targeting amyloid, received traditional FDA approval due to trial data demonstrating clear clinical benefit and a meaningful slowing of the disease's progression. In response, CMS provided broad coverage for all eligible beneficiaries through a registry. As CMS acknowledges in the proposed decision, a diagnosis through PET amyloid-beta (Aß) imaging is one likely path for a patient to receive Medicare coverage of the drug.

We recognize that national coverage of PET will have cost implications for Medicare, and we are taking steps through our Blood-based Biomarker Initiative to advance lower-cost diagnostic and monitoring tools.

USAgainstAlzheimer's commends CMS for reevaluating this NCD, and we eagerly anticipate the elimination of the CED requirement. We stand ready to collaborate in our unwavering commitment to ending this dreaded disease, which has already devastated too many American lives.

Sincerely,

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Voices of Alzheimer's, an advocacy organization led by people living with Alzheimer's Disease and caretakers, supports action by the Centers for Medicare & Medicaid Services (CMS) to end Coverage with Evidence Development (CED) requirements for beta-amyloid PET in Dementia and Neurodegenerative Disease. We also support the CMS proposal to lift PET scan coverage limits, which currently cover virtually no scans, as patients are only eligible for one scan in their lifetime if participating in a CMS-approved clinical trial. There is only one such trial today.

While we applaud these proposals, we remain concerned that the transition to coverage at the discretion of Medicare Administrative Contractors (MACs) will result in uncertainty, confusion, and delays in coverage. We urge CMS to end CED and remove the limit on scan coverage while issuing a national coverage determination of beta-amyloid PET to ensure consistent, broad access.

Existing CED requirements and limits restrict the ability of people living with Alzheimer’s disease to access testing that is crucial in making decisions that shape their fight against the disease. Beta-amyloid PET imaging plays a vital role in the most critical care decisions, including determining a diagnosis of Alzheimer’s disease, deciding whether an individual is eligible for disease-modifying therapies, monitoring treatment response, and determining when to stop treatment. PET imaging is also equally important in ruling out people who do not have Alzheimer’s disease since many other dementias share symptoms with Alzheimer’s.

Since the 2013 CED determination, researchers have published considerable data showing that the knowledge gained from amyloid PET scans adds value to the management of patients, minimizes misdiagnosis, reduces the risk to patients of adverse treatment effects, and informs clinical decision-making [1]. Further, since 2013, the FDA has granted traditional approval to the first-ever approved disease-modifying therapy for the treatment of Alzheimer’s disease, making access to diagnostic tools more important than ever. In light of these developments, Voices of Alzheimer’s could not agree more with the CMS statement that “appropriate coverage of amyloid PET scans will greatly reduce provider and patient burden from the existing requirements and test limitation.”

To avoid delays in coverage, confusion, and uncertainty for the millions of Americans living with Alzheimer’s, we urge CMS to reconsider its proposal to transition coverage of amyloid PET scans to the discretion of Medicare Administrative Contractors and instead end CED and the limit on scans while maintaining national coverage. Given the progressive nature of Alzheimer’s disease, the uncertainty and delay caused by the transition to coverage at the discretion of Medicare Administrative Contractors (MACs) and Medicare Advantage (MA) plans will result in poor patient health outcomes and inequitable access.

Every day, it is estimated that more than 3,000 people transition to a more advanced stage of Alzheimer’s, where they are no longer eligible for existing treatments. Even in the best-case regional coverage scenario for people with Alzheimer’s, where MACs decide to cover PET scans, establishing final Local Coverage Determinations (LCDs) could take several months. Then, once a final LCD is issued, it does not go into effect for 45 days. These bureaucratic delays could cost hundreds of thousands of people the chance to access FDA-approved treatments. CMS can altogether avoid this outcome by issuing a national coverage determination that provides consistent and clear coverage nationwide.

Furthermore, in staying with CMS’s stated intent of ensuring broad coverage of FDA traditionally approved treatments for Alzheimer’s disease, the agency should not transition to coverage at the discretion of MACs. Currently, CMS requires that patients who are candidates for treatment with anti-amyloid therapies receive a diagnostic test for amyloid identification under the National Patient Registry Portal. Without national coverage, if specific regions do not provide adequate coverage for amyloid PET scans, people living with Alzheimer’s who are eligible for treatment could be effectively barred from receiving the diagnostic tests required to initiate treatment.

Voices of Alzheimer's, on behalf of our members living with Alzheimer’s and related neurodegenerative diseases, appreciate and support proposals by CMS to ensure broad access to beta-amyloid PET. We urge CMS to move forward with its proposals to end CED and the coverage limits on amyloid PET scans and call on the agency to maintain national coverage of beta-amyloid PET to avoid the delay and uncertainty that could harm hundreds of thousands of people living with these diseases.

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August 15, 2023

Joseph Hutter, M.D.
Lead Medical Officer
Centers for Medicare and Medicaid Services

Electronically Submitted: CMS_caginquiries@cms.hhs.gov

Re: Public Comment on NCA for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Dr. Hutter:

The American College of Radiology (ACR) representing more than 41,000 diagnostic radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians, and medical physicists, appreciates the opportunity to submit public comments in response to the Centers for Medicare and Medicaid Services (CMS) National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. Our organization fully supports CMS’ process to remove the national coverage determination (NCD) 220.6.20, ending coverage with evidence development (CED). We strongly support broader coverage of beta-amyloid PET imaging by removing the current CED and limit of one scan per patient. This change in coverage will allow patients greater access to amyloid PET scans for Alzheimer’s disease diagnosis, management, and evaluation of newly approved therapies.

Medicare coverage of amyloid PET scans fulfills CMS’ commitment to allow broader coverage of this diagnostic test, Administrator Chiquita Brooks-LaSure said in a statement. “We know there is significant interest in the medical community about new treatments that may be effective in slowing the development of Alzheimer's disease. PET scans are an important part of diagnosis and treatment of Alzheimer's disease, and this decision is an important part of CMS' mission to help improve the lives of Americans we serve.”

The ACR submitted comments to CMS in July 2022 regarding its reconsideration of NCD 220.6.20. We believe the evidence is sufficient to end the CED and allow national coverage of beta-amyloid PET. Additionally, CMS should require post-treatment beta-amyloid PET to be performed as needed to document the removal of beta-amyloid from the brain. While we support the removal of CED, we hold concerns about the proposed decision to permit coverage determinations for Aß PET imaging to be made by the Medicare Administrative Contractors (MACs) under 1862(a)(1)(A) of the Social Security Act.

ACR strongly urges CMS to reconsider leaving coverage determinations to the discretion of the local MACs and instead implement a national coverage ruling. If left to local determination, a final ruling for coverage of Aß PET could be significantly delayed and highly variable across geographic regions, further exacerbating existing inequities to access. Swift and broad coverage of Aß PET is imperative at this time when anti-amyloid therapies are being approved by the Food and Drug Administration (FDA) and highly sought after by patients and their families.

Since Sept. 27, 2013, CMS has covered beta-amyloid PET imaging under CED, the ACR has worked with CMS over the last decade to generate the evidence necessary to expand coverage and access to this critical diagnostic tool for patients suffering from cognitive decline. The hallmark molecular biomarker of Alzheimer’s disease, beta-amyloid protein, can be non-invasively detected by PET. The ACR serves as the sponsor and operating center for the Imaging Dementia – Evidence for Amyloid Scanning (IDEAS) Study and subsequent New IDEAS study. These studies were developed to address the CED requirements of CMS’s 2013 NCD 220.6.20. ACR requests CMS incorporate updates on the New IDEAS study in the final decision memo as the proposed decision lists this study as inactive. Building upon the momentum of the IDEAS Study, the research team launched the New IDEAS study in December 2020 to analyze the clinical utility of beta-amyloid PET imaging of the brain in a diverse cohort of individuals diagnosed with mild cognitive impairment (MCI) or dementia. Without the insights provided by a diverse cohort, the clinical utility and effectiveness of beta-amyloid PET is less likely to be fully understood. For example, genetic, medical, and lifestyle factors are known risks for dementia, although the evidence has been developed from mostly white cohorts. In contrast, racial adversity, vascular disease, education disparities, and inequitable health care access, all play important roles in the excess risk of AD in African Americans. [1] Hence, the inclusion of New IDEAS data is critical to ensure representativeness of the subject population, effective clinical management, and advancement of health equity within the cohort. As of July 27th, the study has enrolled a total of 4,414 participants, of whom over 3,539 have already received their beta-amyloid PET scan. The national site network for the study includes 146 dementia practices and 126 PET imaging facilities. Contrary to what was stated in the proposed decision memo, New IDEAS is still active and accepting applications to become a participating PET imaging facility or dementia practice.

In 2021, the Alzheimer's Association, the ACR, the American Society of Neuroradiology, and the Department of Biostatistics at Brown University School of Public Health, along with other dementia and clinical research experts, launched the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET). [2] ALZ-NET is a voluntary provider-enrolled patient registry that collects longitudinal real-world clinical, safety, and imaging data about patients being evaluated for or treated with novel FDA-approved Alzheimer’s therapies. ALZ-NET is sponsored by the Alzheimer's Association and managed by the ACR. This national registry is an FDA-approved, agent-agnostic approach to gathering routine clinical practice data and outcomes for sharing quickly and transparently with all stakeholders. The registry is designed to continuously collect routine clinical practice data over time from healthcare providers caring for patients diagnosed with Alzheimer's who are taking an FDA-approved treatment for Alzheimer’s disease. The registry is designed to grow with scientific and medical advancements. As new drugs are approved and implemented in care, these will also be captured by the registry. ALZ-NET is also a platform for patients and providers to access resources about Alzheimer’s, including locating ALZ-NET participating sites and educational resources applicable to the usage and monitoring of novel therapies. Recently, ALZ-NET registry was submitted to CMS for consideration of CED approval in July 2023.

Clinical research is currently focused on new treatments directed against amyloid, which requires confirmation of the presence and extent of brain amyloid. Recent treatment trials requiring biomarker evidence of amyloid pathology for patient enrollment generally have used PET scans. We concur with CMS’ analysis that appropriate patient selection is key to ensuring benefits outweigh the potential harms of newly developed drugs targeting amyloid. By including useful diagnostic tests that can detect beta-amyloid in the brain, some of the harms of anti-amyloid treatments would be avoided because the drug would not be given to patients who do not have brain amyloid and potentially stopped when brain amyloid was completely removed. It is essential that CMS consider practice guidelines in determining the use and frequency of amyloid PET scans. CMS may also consider referencing the appropriate use recommendations that outline safety monitoring schedules for the two currently FDA-approved treatments, Aduhelm and Leqembi. [3,4] ACR encourages the use of evidence-based and physician-developed guidelines to decrease inappropriate imaging use and ensure Medicare patients receive the right imaging tests at the right time. We recommend the ACR Appropriateness Criteria® (AC) and the ACR—ACNM—ASNR—SNMMI Practice Parameter for Brain PET/CT Imaging in Dementia topic, which discuss the use of MRI head, CT head, FDG PET/CT, and amyloid PET/CT brain. The AC provide evidence-based guidance to assist referring physicians and other providers in making the most appropriate imaging or treatment decision for a specific clinical condition. Employing this guidance helps providers enhance quality of care and contribute to the most efficacious use of radiology. The AC are not intended to be used as coding guidance for radiologic procedures. [5]

We encourage CMS to review the latest Practice Parameter for Brain PET-CT Imaging in Dementia, which was revised and approved by the ACR Council in 2020 with an effective date of October 2021 (Resolution 41). [6] This guidance document was authored by ACR in collaboration with other medical specialty societies (ACNM, ASNR, and SNMMI) and includes indications for beta-amyloid PET, personnel qualifications and responsibilities, and specifications for the examination. Amyloid PET studies should be performed at the request of physicians knowledgeable in the clinical diagnosis and management of dementia and under circumstances in which the results of the examination are likely to impact patient care. Work has already begun to review and update this document to reflect new evidence and literature by the scheduled date of 2025. All guidance documents are subject to final review and approval before available to the public.

During the 30-day comment period following the release of the tracking sheet in June 2022, CMS received 36 comments. Many comments expressed the opinion that the scope of the reconsideration should be broader and provide national coverage of PET beta-amyloid imaging, or have coverage determined by Medicare administrative contractors (MACs). Most of these commenters also believed that the current limit of one PET scan per patient should be removed if CED were to remain. An important consideration in this proposed coverage decision memorandum is to allow Medicare coverage determinations to be made by the MACs. From our experience working with CMS and the MACs, we understand once the final decision is rendered, CMS will notify the MACs of its decision. CMS will issue guidance through transmittals and change requests advising the MACs on the effective and implementation dates, and subsequently update the NCD manual text and claims processing instructions. From this, MACs will determine what is necessary to ensure Medicare payment for reasonable and medically necessary beta-amyloid PETs for dementia and neurodegenerative diseases. These options include:

We acknowledge that the MACs have experience with extending coverage for PET scans for non-oncologic indications; however, given the importance of the findings from beta-amyloid PET imaging studies, ACR is concerned about the potential delay in coverage decisions by MACs and variations in local coverage that may result in health equity-related access differences due to different coverage decisions by each MAC. A NCD allowing full coverage without CED would ensure swift and consistent coverage for all Medicare beneficiaries.

Additionally, as CMS explicitly stated, PET images obtained with amyloid-targeting radiopharmaceuticals should be interpreted only by readers who successfully complete a special training program, provided by the manufacturers of each of these radiopharmaceuticals. The U.S. Nuclear Regulatory Commission (NRC) also maintains training and experience requirements under 10 CFR Part 35 for physician-experts (i.e., Authorized Users) responsible for safe medical use of these agents. [7]

To expedite access to PET scans for patients with cognitive decline, the ACR requests that CMS ensures coverage for the use of beta-amyloid PET scans as both an initial diagnostic test in patients who are being evaluated for Alzheimer’s disease and other causes of cognitive decline, as well as a test to monitor/follow-up (as appropriate) in adult patients who are being treated with either existing or experimental new Alzheimer’s disease therapies.

The ACR appreciates the opportunity to submit recommendations to CMS on diagnostic imaging for MCI and Alzheimer’s Dementia. If you have any questions or comments on our letter, please do not hesitate to contact Alicia Blakey MS, Principal Economic Policy Analyst, at ablakey@acr.org.

Respectfully submitted,

References
1. Barnes LL. Alzheimer disease in African American individuals: increased incidence or not enough data? Nat Rev Neurol. 2022 Jan;18(1):56-62. doi: 10.1038/s41582-021-00589-3. Epub 2021 Dec 6. PMID: 34873310; PMCID: PMC8647782. 2. https://www.alz.org/professionals/health-systems-medical-professi
onals/management/alzheimers-network-for-treatment-diagnostics
3. Cummings J, Rabinovici GD, Atri A, Aisen P, Apostolova LG, Hendrix S, Sabbagh M, Selkoe D, Weiner M, Salloway S. Aducanumab: Appropriate Use Recommendations Update. J Prev Alzheimers Dis. 2022;9(2):221-230. doi: 10.14283/jpad.2022.34. PMID: 35542993; PMCID: PMC9169517.
4. Cummings, J., Apostolova, L., Rabinovici, G.D. et al. Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis 10, 362–377 (2023). https://doi.org/10.14283/jpad.2023.30
5. https://www.acr.org/Clinical-Resources/ACR-Appropriateness-Criteria
6. https://www.acr.org/-/media/ACR/Files/Practice-Parameters/Brain-PET-CT-Dementia.pdf
7. https://www.nrc.gov/reading-rm/doc-collections/cfr/part035/full-text.html

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August 16, 2023

BY ELECTRONIC DELIVERY (CAGinquiries@cms.hhs.gov)

Dr. Joseph Chin
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: National Coverage Determination (NCD) for Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease (220.6.20) (CAG-00431R)

Dear Dr. Chin:

Eli Lilly and Company (Lilly) appreciates the opportunity to comment on the proposed removal of the National Coverage Determination (NCD) for Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease (220.6.20) (Proposed Decision Memo).¹ Lilly has been committed to Alzheimer’s research for more than 30 years and remains determined to finding solutions for this unrelenting and fatal disease. Our company has advanced the science of Alzheimer’s disease (AD) diagnosis and treatment by discovering and commercializing imaging agents that visualize amyloid plaques and tau tangles—pathological hallmarks of AD—in the living brain. In addition, Lilly’s therapeutic pipeline includes a portfolio of molecules that hold the potential to meaningfully change the course of Alzheimer’s patient care. Just last month at the Alzheimer’s Association International Conference (AAIC), Lilly presented the results of TRAILBLAZER-ALZ 2, the Phase 3 study for donanemab, an amyloid-targeting therapy for patients with early AD. Donanemab is the first drug to replicate Phase 2 results, demonstrating a slowing of cognitive and functional decline well beyond what is broadly considered clinically meaningful. Donanemab is now under FDA review with traditional approval anticipated before the end of the year.

Lilly is proud of this scientific progress and the associated data, which has been published in the New England Journal of Medicine and the Journal of the American Medical Association. These data confirm the clinically meaningful benefits that donanemab can provide to early symptomatic AD patients, including significantly slowing cognitive and functional decline to give patients and their loved ones more time in the higher functioning, less impaired stage of the disease, as well as potentially prolonging independence. However, the potential benefits of amyloid-targeting therapies, including those approved in the future, can only be realized if patients have timely and equitable access to these therapies as well as the diagnostic tools necessary to properly support their use.

Lilly strongly supports the Centers for Medicare & Medicaid Services’ (CMS’) proposal to advance coverage for positron emission tomography beta amyloid (Aß PET) imaging by removing coverage with evidence development (CED) requirements and permitting Medicare coverage for this critical diagnostic tool. However, we believe CMS should retain national coverage to avoid further coverage delays and eliminate variability in coverage across Medicare beneficiaries.

We further urge CMS to (1) proactively support an efficient and smooth transition from national-to-local coverage discretion (if finalizing the decision to remove the Aß PET NCD); (2) finalize this decision within forty-five (45) days of the publication of the Proposed Decision Memo, rather than waiting the full ninety (90) days; and, (3) reconsider the NCD for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease based on the strong clinical evidence now available.

In the Proposed Decision Memo, CMS expresses optimism about “a number of advances in medical care and treatments for AD.” Lilly shares this excitement. Yet, despite the appetite to look ahead, it is also important to take note of the extensive evidence which has been generated to demonstrate the clinical value of Aß PET over the past decade. The body of evidence for Aß PET now spans more than 40 studies and well over 20,000 patients. Through this wide range of studies, both CED and non-CED, the clinical value of Aß PET has been demonstrated extensively and consistently. Evidence of clinical value includes improvements on standard diagnostic outcome measures such as change in diagnosis, physician confidence, and actual change in management, as well as advanced outcome measurements including time to institutionalization, healthcare resource utilization, and mortality. Most of this evidence was generated even in the absence of disease-modifying medications for Alzheimer’s disease. For convenience and comprehensiveness, Lilly has consolidated these studies into an “Amyloid PET Body of Evidence” document, which can be found in Appendix A.

Nonetheless, the next chapter of Alzheimer’s patient care is upon us, and Lilly agrees with CMS’s outlook on the important role that Aß PET will play. In the proposed decision memo, CMS writes: “The advances in medical care and standards of practice and development of proven treatments have altered the application of amyloid PET scans in clinical practice and research. For example, promising antiamyloid drug treatments to improve health outcomes such as cognition and function would not be expected to have a clinical impact in the absence of brain amyloid. Appropriate patient selection is key to ensuring benefits outweigh harms of newly developed drugs targeting amyloid.”

Aß PET has become a gold standard in patient selection, both for therapeutic and diagnostic clinical trials. As CMS noted, Aß PET is commonly used to support appropriate patient identification for enrollment in clinical trials for amyloid-targeting therapies. In addition, Aß PET is the standard comparison arm in trials for amyloid-focused diagnostics, including the emerging blood-based biomarker tests. Finally, in TRAILBLAZER-ALZ 2, the Phase 3 study for donanemab, Aß PET was utilized for treatment monitoring, becoming the primary mechanism to inform when a patient should complete treatment with the amyloid-targeting therapy. Fifty-two percent of patients were able to complete treatment within 12 months, which is important both clinically and economically. In sum, the existence and availability of FDA-approved therapeutics perforce renders Medicare coverage for Aß PET reasonable and necessary.

After a decade of collecting evidence to support the clinical value of Aß PET and the approval of novel Alzheimer’s therapeutics, CMS should formally recognize that Aß PET is reasonable and necessary.

In order to achieve this objective in the most effective and equitable manner, Lilly believes the best path forward is for CMS to use this reconsideration opportunity to establish national coverage for Aß PET imaging without CED and to remove the lifetime limit on the number of scans Medicare will cover.

While CMS’s positive commentary regarding the value of Aß PET imaging in the Proposed Decision Memo is helpful and encouraging, it is likely that the transition from national coverage to local coverage discretion would result in both delays in patient access and variability in coverage across Medicare beneficiaries. Each Medicare Administrative Contractor (MAC) will either consider coverage on a claim-by-claim basis or establish a local coverage determination (LCD). Establishing coverage on a claim-by-claim basis would create uncertainty for beneficiaries and providers about whether each scan would be covered, could delay beneficiaries’ access to care, and could increase administrative burdens on the MACs. An LCD would establish a clear coverage policy for the MAC’s jurisdiction, but each MAC would need to dedicate time to drafting an LCD, soliciting and responding to comments, and issuing LCDs. The MACs’ decisions also affect access to care for beneficiaries enrolled in Medicare Advantage (MA) plans, because those plans may be required to follow the relevant MAC’s policy or develop their own policy in the absence of an LCD. Relying on local contractor discretion, instead of a clear, positive NCD, thus would result in delayed or denied care due to uncertainty about coverage while these policies are developed.

Any delay in access to care is troubling. Simply put, with Alzheimer’s disease, any delay means loss in brain function. Data shows that amyloid-targeting therapies have the greatest impact for those earliest in disease. With one amyloid-targeting therapy having already achieved FDA traditional approval, regulatory action on donanemab expected by year’s end, and the recent opening of CMS’s very own Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease CED Study Registry, further delays in establishing clear Aß PET coverage policies will cause unnecessary patient harm and result in frustration for all stakeholders, including CMS. Imaging centers are already expressing confusion and hesitation regarding Aß PET coverage when used in conjunction with approved CED protocols for amyloid-targeting therapies. Transitioning to local coverage discretion will likely result in further delays among the imaging centers as they wait for clarity. It is important to be clear that we do not believe that CMS intends to cause further delay in Aß PET coverage.

Given the multitude of MACs and MA plans, we are also concerned that local discretion will result in variability in coverage across Medicare beneficiaries. As with coverage delays, such variability is likely to exacerbate access issues, especially for patients in rural or underserved communities. Patients and physicians already experience geographic disparities in access to Aß PET scans under the current NCD’s CED program. For example, a total of 18 states, many of which are rural, lack even a single New IDEAs trial site.²

Finally, we underscore the extent of data collected under the Aß PET NCD to date demonstrates the clinical value of Aß PET imaging. These data clearly demonstrate the value of Aß PET as described in CMS’s Proposed Decision Memo and support national coverage.

If CMS decides merely to remove the Aß PET NCD, then it will be important for CMS to proactively take steps to support an efficient and smooth transition from national-to-local coverage. In the Proposed Decision Memo, CMS stated “[w]e believe removal of NCD 220.6.20 will allow appropriate coverage of amyloid PET scans and will greatly reduce provider and patient burden from the existing requirements and test limitation.” For these benefits to become an immediate reality CMS should consider the following actions steps:

• In the Final Decision Memo, CMS should expressly affirm that Aß PET is “reasonable and necessary.”
• CMS should work with MACs and MA plans to have local guidance/bulletins in place at the time of publication of the Final Decision Memo clarifying that Aß PET will be covered while MACs and MA plans draft coverage policies.
• In the Final Decision Memo, CMS should encourage MACs and MA plans to move quickly (i.e., within 30 days) to publish guidance and/or coverage policies.
• CMS should issue an expedited program transmittal to MACs regarding the removal of the and set forth CMS’s expectations for efficient and smooth transition of coverage discretion.
• CMS should make Aß PET a priority agenda item during the monthly meetings with MAC Medical Directors.
• CMS should publicly state that their expectation is that Medicare contractors facilitate Aß PET coverage.
• CMS should explicitly state that Aß PET imaging is covered when utilized in conjunction with a CMS-approved CED protocol for the Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease NCD.
• CMS should share their perspective on the potential value of using Aß PET to support limited treatment duration with amyloid-targeting therapies, if appropriate.
• CMS should expeditiously provide MA plans with guidance on risk adjustments, if necessary, for 2023 and 2024.

For AD patients, we must increase the urgency for diagnosis as delays lead to loss of brain function. As a group, these patients and their care partners have been waiting decades for both an early and accurate diagnosis of the disease and effective and clinically meaningful treatments. Broader access to Aß PET scans is critical to achieving these twin goals. CMS should move quickly to finalize this coverage decision within forty-five (45) days of publication of the Proposed Decision Memo, rather than waiting the full ninety (90) days. AD Patients are waiting.

Patients and their care partners face a variety of obstacles in obtaining an early and accurate diagnosis of Alzheimer’s disease. First, diagnosis of Alzheimer’s disease is on average delayed by 2 to 3 years after the onset of symptoms.³ In addition, Alzheimer’s is often misdiagnosed. In a large study utilizing Aß PET scans, nearly 1 in 3 individuals clinically diagnosed with AD had no evidence of amyloid plaques, one of the hallmarks of the disease.⁴ Finally, Alzheimer’s disease is underdiagnosed.

Over 50% of patients with any form of dementia are never formally diagnosed with the disease.^{5,6 M}oving swiftly to finalize this reconsideration is an important step towards advancing the diagnostics ecosystem, especially as new FDA-approved amyloid-targeting therapeutics continue to enter the market.

Broader access to Aß PET scans is also critical for patients who may be eligible for new FDA-approved amyloid-targeting therapeutics that are reliant on confirmatory Aß PET scans. At an individual patient level, the longer the reconsideration process takes, the more likely it is that that the therapeutic window closes for a particular patient, as the threat of their moving to the next stage in their AD clinical progression increases. Indeed, according to a recent analysis of public and published research, each day, upwards of 3,000 Medicare-covered individuals with early-stage Alzheimer’s Disease may progress to moderate or severe Alzheimer’s disease and they will no longer be eligible for new FDA-approved treatments.⁷

Lilly appreciates that the Aß PET Proposed Decision Memo was prompted by stakeholder comments submitted in connection with the NCD for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease.⁸ We also appreciate CMS’s acknowledgement that the science has progressed. We would be remiss in this comment letter if we did not take the opportunity to urge CMS to, again, demonstrate its commitment to people with AD by promptly acknowledging that a class-wide NCD based on a single product approval and a literature review of inapposite clinical trial data is out of date, and that the commitments extracted by FDA for post marketing data development are sufficient to satisfy any remaining questions CMS might have.

In this proposed decision memo, CMS noted “[t]he advances in medical care and standards of practice and development of proven treatments have altered the application of amyloid PET scans in clinical practice and research.” We agree and we urge CMS to reopen or retire the NCD for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease to account for these new data.

Specifically, on November 30, 2022 the manufacturers of Leqembi® (lecanemab) published the full data from their Clarity AD global confirmatory Phase 3 placebo-controlled, double-blind, parallel-group, randomized study in 1,795 people with early AD. In that study, the primary endpoint was change from baseline at 18 months in the CDR-SB (Clinical Dementia Rating-Sum of Boxes), a global cognitive and functional scale; key secondary endpoints were the change from baseline at 18 months in amyloid PET using Centiloids, AD Assessment Scale - Cognitive Subscale 14 (ADAS-Cog14), AD Composite Score (ADCOMS) and AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL). In addition, longitudinal changes in brain tau pathology as measured by tau PET (n=257) and cerebrospinal fluid (CSF) biomarkers of AD pathology (n=281) were evaluated in optional sub-studies.

According to that study, the primary endpoint of the mean change of CDR-SB from baseline at 18 months was 1.21 and 1.66 for lecanemab and placebo groups, respectively. Lecanemab treatment resulted in highly statistically significant results, reducing clinical decline on the global cognitive and functional scale compared with placebo at 18 months by -0.45 (95% Confidence Interval (CI): -0.67, -0.23; p=0.00005), representing a 27% slowing of decline. Starting as early as six months (difference: - 0.17 [95% CI: -0.29, -0.05]; < 0.01), and increasing in absolute difference over time across all time points every 3 months, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all p-values are less than 0.01). All key secondary endpoints also showed highly statistically significant results compared with placebo (p<0.001).⁹

On July 17, 2023, Lilly published the full data from its TRAILBLAZER-ALZ 2 trial. TRAILBLAZER-ALZ 2, a randomized, double-blind, placebo-controlled study, evaluated the safety and efficacy of donanemab, an investigational amyloid plaque targeting therapy. The study enrolled people with early symptomatic AD, which includes mild cognitive impairment (MCI) and the mild dementia stage of disease, with the confirmed presence of AD neuropathology. Participants completed their course of treatment with donanemab once they reached a prespecified level of amyloid plaque clearance. Participants in TRAILBLAZER-ALZ 2 were stratified by their level of the brain protein tau, a predictive biomarker for Alzheimer's disease progression. The primary analysis population (n=1182) for which the study was powered was comprised of people with an intermediate level of tau and clinical symptoms of Alzheimer's disease. In this population, the primary endpoint (iADRS) showed 35% slowing of decline (p<0.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (p<0.0001) over 18 months. The results demonstrated that donanemab significantly slowed cognitive and functional decline in people with early symptomatic AD (either mild cognitive impairment or mild dementia). Additionally, the data demonstrated:

• The beneficial treatment effect continued to increase relative to placebo over the course of the trial, with the largest differences versus placebo seen at 18 months.
  
• Study participants at the earliest stage of disease had greater benefit, with 40-60% slowing of decline compared to placebo. Significant benefits were also seen in more advanced patients.
  
• 47% of participants on donanemab showed no decline on CDR-SB, a key measure of disease severity at 1 year (compared to 29% of participants on placebo, p <0.001).
  
• 52% of participants completed their course of treatment by 1 year and 72% completed by 18 months as a result of achieving plaque clearance.
  
• Participants on donanemab had 40% less decline in ability to perform activities of daily living at 18 months [as measured by Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iADL), p <0.0001].
  
• Participants on donanemab experienced a 39% lower risk of progressing to the next stage of disease compared to placebo (CDR-Global Score, HR=0.61; p<0.001).¹⁰

CMS has stated CED requirements should not be redundant of FDA requirements. Since April 2022, when the Alzheimer’s therapeutics NCD was finalized, FDA has demonstrated that its own post-marketing requirements and expectations for Alzheimer’s therapeutics render CMS’s evidence development paradigm wholly unnecessary. Specifically, in the approval letter related to lecanemab, FDA identified the post-marketing data development requirements and commitments as well as various pharmacovigilance. The expectations of the FDA strongly resemble those of CMS’s CED questions, rendering the CED a duplication.

Donanemab has not yet been approved so it is too early to predict what, if any, post-marketing requirements or commitments might exist in connection with our own potential therapy. However, it is clear that FDA is exercising clear and capable judgment in this space such that CMS should not seek to interfere or exert duplicative resources or impose duplicative obligations.

Practitioners and providers have already updated their appropriate use recommendations and are in the process of developing clinical practice guidelines that clearly contemplate the use of amyloid-targeting therapies. Specifically, recent “Appropriate Use Recommendation” (AUR) developed for lecanemab sets forth the dementia-expert consensus view, based on the integration of the FDA accelerated approval USPI and the Phase 3 CLARITY-AD study results, that is intended to “assist practitioners who have chosen to provide patients with the option of treatment…” and highlights the importance of amyloid PET for confirming the presence of brain amyloid and the role of anti-amyloid therapeutics in treating AD.¹¹

This AUR also serves as the foundation for the more recently published, pragmatic guidance for US clinical neurologists from the Quality Committee of the American Academy of Neurology, which states, “…data on lecanemab and other monoclonal antibody infusions targeting amyloid-ß protein make clear that new agents are highly likely to be part of the toolkit for clinicians caring for patients with AD.” This “Emerging Issues in Neurology” manuscript further describes appropriate patients for treatment as those with early clinical symptoms and evidence of brain amyloid demonstrated via PET imaging or CSF studies and recommends that providers incorporate this evidence in the prescription decisions.¹²

Moreover, the Alzheimer’s Association, the American Academy of Neurology, neurologists, and nearly 100 bipartisan members of Congress have called on CMS to revise the amyloid-targeting therapy NCD so that patients can access FDA-approved medicines in this class.^{13,14,15,16,17} Unfortunately, CMS has yet to heed the calls of Alzheimer’s patients, caregivers, their families, and countless experts, as well as Congress, by refusing to revise the NCD and provide a permanent and reasonable path to appropriate coverage of FDA-approved medicines in this class.

Most recently, CMS rejected both the Alzheimer’s Association’s December 2022 the American Academy of Neurology’s June 2023 requests for NCD reconsideration, despite multiple public statements from the agency that they would swiftly open reconsideration once a “high level of evidence” became available for one or more therapies in the class.^18,19 Importantly, there are now published Phase 3 studies for both donanemab and lecanemab that undoubtedly meet the “high level of evidence” CMS has described as the trigger for reconsideration of the NCD for amyloid-targeting therapies.

While we recognize CMS’ efforts to lessen the burden of its NCD for Alzheimer’s therapeutics, Lilly remains committed to a long-term solution so patients do not face uncertainty and unnecessary access barriers. By leaving CED in place and mandating patient enrollment in registries, additional access hurdles and uncertain scenarios for this class of medicines remain. The best way to permanently ensure timely and affordable access for the most appropriate patients is for CMS to open a reconsideration of its NCD - as it has promised to do in conjunction with new clinical evidence that is now available - and cover new Alzheimer’s medicines and diagnostics to FDA label.

To that end, in the short months ahead, Lilly plans to submit data to a peer-reviewed publication that demonstrates how the existing data from the TRAILBLAZER clinical trial program answers the three CED questions outlined in NCD 200.3.

In conclusion, Lilly appreciates this opportunity to present our comments on the proposed removal of the National Coverage Analysis (NCA) for Beta Amyloid Positron Tomography in Dementia and Neurogenerative Disease (220.6.20). We are hopeful about the future of Alzheimer’s care, and we urge CMS to revise its proposed coverage policy to allow timely and appropriate access to new amyloid-targeting therapies as well as to the diagnostic tools that are necessary to identify patients who could most benefit from these therapies. We appreciate the time CMS has dedicated to meeting with us and other stakeholders, and we would be happy to answer any questions you have about these comments. Please contact Adam Phipps at phippsad@lilly.com or 614-256-6099 to discuss this letter.

Sincerely,

Anne E. White
President, Neuroscience Business Unit, Eli Lilly and Company

Appendix A: Amyloid PET Body of Evidence (see separate file)

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The Alzheimer’s Association appreciates the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS) proposed decision memorandum on Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease for the diagnosis of Alzheimer’s disease. The proposed new policy will remove the Coverage with Evidence Development (CED) data collection requirements and lifetime one scan limit which create unnecessary barriers to this important diagnostic and patient safety tool.

An early and accurate diagnosis of Alzheimer’s has a positive impact on health outcomes, access to treatments, and eligibility for research trials, plus much-needed support and services. This draft policy will expand access to PET scans beyond clinical trials and removes the current limitation of one scan per lifetime. On the heels of the Food and Drug Administration (FDA) traditional approval of Leqembi® and as new treatments advance, access to this diagnostic tool becomes even more important. In the new era of treatment and management of patients with Alzheimer’s, multiple amyloid PET scans may be necessary to test for eligibility, establish a baseline, track changes in a person's amyloid levels over time, and even to determine that treatment should be paused because lower amyloid levels have been achieved.

The Alzheimer’s Association is grateful to have partnered with CMS in the development and implementation of amyloid PET scans in Alzheimer’s research, diagnosis, and care for more than eight years on both the Imaging Dementia — Evidence for Amyloid Scanning (IDEAS) Study and the New IDEAS Study to create better ways to diagnose and care for people with memory concerns by using brain imaging. We would like to correct the statement in the proposed decision memorandum that New IDEAS is "inactive" as, in fact, the study continues. The recruitment of non-Hispanic White participants has simply been paused in order to close a gap in the recruitment of Hispanic and African American populations, whose participation is the overall goal of New IDEAS.

With regard to the continuation of New IDEAS, we are also deeply concerned by the impact of local contractor discretion. The Alzheimer's Association and our study partners note for CMS how difficult it could be to complete this important study if Medicare Administrative Contractors (MACs) decide against coverage in a given market. Recruitment of key populations has been challenging, as discussed above. A patchwork of amyloid PET scan coverage will only compound those challenges and could compromise the successful completion of the study.

While we support the proposal to end CED data collection requirements, we are concerned that leaving coverage to the discretion of the local contractors could result in variability of coverage, the expansion of existing inequities in diagnosis and treatment, and delays in accessing anti-amyloid therapies. Additionally, many Medicare Advantage plans do not cover imaging if there is not an established National Coverage Determination (NCD) or Local Coverage Determination. Based on the extensive published evidence over the past decade, we recommend CMS establish national coverage of beta amyloid PET through an NCD. We ask that CMS explain in detail how it intends to ensure the necessary coordination with the Medicare Administrative Contractors who will cover PET scans through local coverage determinations, as the treatments themselves are covered under CMS's national coverage determination. Any disconnect between the payers could result in delayed access to treatments. Time is of the utmost essence with regard to individuals living with Alzheimer's disease.

Finally, the proposed decision memorandum cites a study, only indicated as "Pillar 2022," related to the beta amyloid hypothesis. The Alzheimer's Association is unfamiliar with this reference as written and respectfully requests that CMS publish the full citation so that we may read the paper.

Thank you for the opportunity to comment. We look forward to working with CMS to ensure all people living with Alzheimer’s disease have easy, affordable access to high quality diagnostic tools, treatments, and care.

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Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore, MD 21244

14 August 2023

RE: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431R)

Dear Ms. Syrek Jensen:

On behalf of the Roche Diagnostics Corporation (“Roche”), I am pleased to submit comments in response to the above-captioned proposed decision memo entitled “National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease”. We commend CMS for taking action to reconsider the original National Coverage Determination (NCD) for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease (220.6.20), finalized in 2013.

Roche Diagnostics is part of one of the world’s leading research-oriented healthcare organizations — the Roche Group. Roche develops innovative products and services that address the prevention, diagnosis and treatment of diseases and medical conditions. As a global leader in the fields of diagnostics and pharmaceuticals, we believe in the power of diagnostics to identify the best treatments for patients, transforming their lives, improving outcomes and reducing costs of care. Roche Diagnostics is committed to improving the treatment of Alzheimer’s Disease and expanding access to all diagnostic and therapeutic tools that can identify and treat patients throughout the Alzheimer’s Disease care continuum.

In summary, we support CMS’s proposal to remove the aforementioned National Coverage Determination (NCD) for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease, thus permitting Medicare coverage determinations for PET beta amyloid imaging to be made by the Medicare Administrative Contractors (MACs). By doing so, PET beta amyloid imaging would not be subject to the coverage restrictions imposed by the Coverage with Evidence Development (CED) framework in the existing NCD and the MACs may appropriately account for the breadth of evidence that has been generated since CMS originally finalized this determination in 2013. We believe that removal of the NCD is a positive first step towards enabling access to PET Aß imaging for Medicare beneficiaries, and hope that it will have positive ramifications for other emerging diagnostic technologies for Alzheimer’s Disease such as cerebrospinal fluid and blood-based biomarkers.

While we support CMS’s proposed decision, we also recognize that MAC discretion may result in coverage disparities for these technologies. We encourage the MACs to issue proposed coverage determinations in a timely manner to reduce coverage gaps among patients that may currently be eligible, and we encourage CMS to consider whether coverage determinations issued by the MACs are creating an equitable and appropriate coverage environment for all Medicare beneficiaries.

*****

In the aforementioned NCD 220.6.20 finalized in 2013, CMS determined that the evidence is “insufficient to conclude that the use of positron emission tomography (PET) beta amyloid (also referred to as amyloid-beta (Aß)) imaging is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member for Medicare beneficiaries with dementia or neurodegenerative disease, and thus PET Aß imaging is not covered under §1862(a)(1)(A) of the Social Security Act (“the Act”)”. In two scenarios, CMS determined limited coverage: “(1) to exclude Alzheimer’s disease (AD) in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD); and (2) to enrich clinical trials seeking better treatments or prevention strategies for AD, by allowing for selection of patients on the basis of biological as well as clinical and epidemiological factors.) However, since 2013, there has been additional research published to support the value of PET Aß scans in patients with dementia and neurodegenerative disease. If CMS’s proposal to remove the NCD is finalized, we recommend that the MACs account for the additional body of research published since 2013 supporting expanded coverage of PET Aß scans for patients with dementia and neurodegenerative disease. In particular, we urge the MACs to avoid the institution of a pre-specified limit of one scan per patient per lifetime on the number of PET Aß scans that may be covered.

While we support CMS’s proposed decision to remove the NCD, we also recognize that deferring discretion for coverage of these technologies to the MACs may result in access gaps for Medicare beneficiaries. The relatively small number of patients who are currently eligible to receive PET Aß scans under the national CED framework may lose their pathway to coverage after the NCD is removed while they await new coverage determinations in development at the local level - a process that takes multiple months, at minimum. Time is of the utmost importance for patients undergoing diagnosis and treatment for Alzheimer’s Disease and other forms of dementia, particularly as new therapeutics entering the market have the highest impact on patients in the early stages of disease progression. According to estimates from the Alzheimer’s Association, more than 2,000 individuals aged 65 or older may transition per day from mild dementia due to Alzheimer’s disease to moderate dementia due to Alzheimer’s disease, and therefore outside of the indicated population for currently approved disease modifying therapies. As such, if the NCD is removed as proposed, we recommend that CMS encourage the MACs to develop Local Coverage Determinations for PET Aß imaging in a timely manner.

Further, MAC discretion may result in access disparities for PET Aß imaging between geographies based on MAC jurisdictional areas, as well as coverage gaps as MACs individually establish final policies. With anti-amyloid disease modifying therapies requiring amyloid confirmation to be eligible for treatment, it is critical that all diagnostic tools are available, regardless of a patient’s geographic location. We applaud CMS’s continued commitment to improving health equity, and encourage that the CMS Framework for Health Equity act as a guiding document for CMS and the MACs as the coverage landscape for diagnostic and therapeutic tools for patients with Alzheimer’s Disease continues to evolve. We hope that further review of available evidence by MACs at the local level will result in a pathway to equitable coverage across the entire Medicare population.

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We appreciate the opportunity to submit comments on this National Coverage Analysis and thank you for your consideration. Please contact me at (202) 330-3298 or via e-mail at nicholas.halzack@roche.com if you have any questions. Thank you in advance for your review of our comments.

Sincerely,

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August 11, 2023

Chiquita Brooks-LaSure, Administrator
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Diseases (CAG-00431R)

Dear Administrator Brooks-LaSure:

Life Molecular Imaging (LMI) appreciates the opportunity to submit comments on the above-referenced proposed decision memo of the National Coverage Determination (NCD) for Beta Amyloid Positron Emission Tomography (PET), 220.6.20. LMI manufactures and markets Neuraceq® (florbetaben F18 for injection), an FDA-approved radiopharmaceutical agent that specifically identifies the presence of beta-amyloid (Aß) plaque when a PET scan of the brain is performed.

We support and appreciate your thoughtful consideration in removing the NCD for beta-amyloid PET (220.6.20) and allowing Medicare coverage determinations to be made by the Medicare Administrative Contractors (MACs) under §1862(a)(1)(A) of the Social Security Act.

LMI is confident that CMS has generated sufficient evidence from the CMS-approved clinical studies over the past 10 years to propose an NCD covering amyloid PET scans that excludes lifetime limitations and Coverage with Evidence Development (CED) requirements. Through these studies, data has been collected and analyzed to demonstrate that amyloid status confirmation with PET scans assists in the management of patients, reduces misdiagnosis, and decreases the risk of adverse events from inappropriate treatments. LMI is completing a value dossier that catalogs these studies, and we will be happy to share it with you when it is approved for distribution. Additionally, CMS has also determined that amyloid PET scans can be used to identify and monitor patients who may be treated for Alzheimer’s disease with newly approved anti-amyloid monoclonal antibodies.

That being said, a new or revised NCD would remove the inefficiencies of individual MAC and Medicare Advantage (MA) plan claims and coverage considerations. MACs and MA plans each cover approximately half of Medicare beneficiaries, and we are concerned about inadequate and inconsistent coverage for the respective patient constituencies. Coverage by MACs may allow patients to receive amyloid imaging; however, there are regional variations between the MACs. Moreover, educating individual MACs and MA plans on the removal of the NCD will take considerable time, and the resulting LCAs (Local Coverage Analyses) and possibly LCDs (Local Coverage Determinations) will each undergo review cycles, hindering immediate access for patients. Some MA plans may determine that they are not required or compelled to cover this service without actual NCDs or LCDs. Again, this could hinder access for greater than 40% of Medicare beneficiaries participating in Medicare managed care plans.

If CMSs’ final decision on the coverage pathway is indeed through the MACs and MA plans, we trust that CMS will provide clear and strong recommendations to the MACs and MA plans to cover amyloid PET imaging. LMI is willing to partner with you to educate and inform these contractors and we will work diligently with the MACs and

MA plans to ensure they receive and implement the instructions and information in transmittals for the new coverage pathway.

Please know that LMI is happy to meet with CMS to discuss the optimal path forward to provide broad coverage for this technology, and to educate all stakeholders involved in the care of patients burdened with this disease.

For questions please contact Cynthia Herring, Head of Market Access, at c.herring@life-mi.com

Andrew Stephens, MD
Chief Medical Officer
Life Molecular Imaging

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August 8, 2023

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Attention: CAG-00431R
Mail Stop C4–26–05
7500 Security Boulevard
Baltimore, MD 21244–1850

Dear Administrator Brooks-LaSure:

The Medical Imaging Technology Alliance (MITA) is writing in support of the Centers for Medicare & Medicaid Services' (CMS) Proposed Decision Memorandum to end Coverage with Evidence Development (CED) requirements and remove the one lifetime limit for Beta Amyloid Positron Emission Tomography (PET) in dementia and neurodegenerative disease. MITA believes the published clinical evidence and scientific data over the past decade warrant national coverage of amyloid imaging for Medicare beneficiaries. We believe that coverage of beta amyloid in a National Coverage Determination (NCD) is preferable to coverage at the discretion of Medicare Administrative Contractors (MACs) and Medicare Advantage (MA) plans. The transition from national to local coverage discretion would risk coverage gaps due to delays with local coverage decision-making and inconsistent coverage by region. This would result in limiting Medicare beneficiaries’ access to beta amyloid PET imaging and anti-amyloid therapies.

MITA represents companies whose sales comprise more than 90 percent of the global market for medical imaging technology and we are the collective voice of PET and SPECT radiopharmaceutical developers, manufacturers, and distributors. Advances in nuclear medicine allow clinicians to more effectively identify and target disease, thereby providing more and potentially earlier options for treatment resulting in better patient outcomes.

MITA supports CMS’ reconsideration of the NCD 220.6.20 for beta amyloid PET scans to end CED data collection requirements. Beta amyloid PET scans are a critical tool that enable clinicians to identify the presence of amyloid plaques and ensure appropriate treatment. We agree with CMS that “appropriate coverage of amyloid PET scans will greatly reduce provider and patient burden from the existing requirements and test limitation.”

MITA and its members have a long history in the development of evidence on the clinical utility of beta amyloid PET imaging to aid diagnosis, help identify patients for treatment with monoclonal antibodies for Alzheimer’s disease, and even inform ongoing treatment decisions in clinical trials. Beta amyloid PET supports the appropriate utilization of amyloid-targeting therapies by identifying patients for the therapies with early and accurate diagnoses. Since the NCD took effect in 2013, a considerable amount of published evidence has been developed that demonstrates that the use of beta amyloid imaging positively impacts patient management and leads to changes in diagnosis, even in the absence of a disease modifying therapy. For example, data from the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) Study support the importance of beta amyloid PET scans. The IDEAS investigators concluded that the use of Alzheimer’s drugs was linked to amyloid status, finding that among patients with positive PET results, the overall use of Alzheimer’s drugs in the population increased significantly.¹ Beyond the IDEAS study, at least 30 published studies involving thousands of patients have reviewed the utility of beta amyloid imaging for the diagnostic assessment of patients evaluated for cognitive impairment in memory clinics.²

CMS notes in the Proposed Decision Memorandum that “when the 2013 CED questions were created, advances in the application of amyloid PET scans and the importance of patient selection for promising treatments were not known.” However, data has been developed over the past several years that demonstrates that the knowledge of amyloid status adds value to the management of patients, minimizes misdiagnosis, reduces the risk of adverse events due to inappropriate treatment, and informs clinical decision-making.³ Data also demonstrates that the utilization of amyloid PET scans positively impact long-term health outcomes, including delays in institutionalization, improved utilization of healthcare resources, and delays in mortality.⁴ CMS confirmed in the Proposed Decision Memorandum that “amyloid PET scans can be used to confirm presence of brain amyloid to select appropriate patients for proven anti-amyloid treatments.” We appreciate CMS’ recognition that it is appropriate for beta amyloid PET scans to be used to identify patients for treatment with monoclonal antibodies for Alzheimer’s disease.

Similarly, MITA supports removing the coverage limitation of one-lifetime beta amyloid PET scan per patient to reflect clinical practice and patient management with new anti-amyloid therapies. We appreciate that CMS noted in the Proposed Decision Memorandum that “stakeholders and patients have specifically noted that the once in a lifetime limit on amyloid PET is outdated and not clinically appropriate due to the development of anti-amyloid treatments.” Deferring coverage decision-making to the MACs will not ensure that each MAC will agree to cover more than one scan, will likely result in variability across MACs and Medicare Advantage plans, so we, therefore, support CMS making a national coverage decision.

As CMS also stated in the Proposed Decision Memo, “it is anticipated that clinical study protocols may involve more than one PET Aß scan per patient.” For example, amyloid confirmation could be required as an inclusion criterion, or follow-up amyloid PET scans could also be used to monitor treatment response and determine when to end treatment in a study. Patients could also be removed from amyloid-targeting therapies upon reaching a target level of reduced amyloid. Recently announced Phase 3 study results for an amyloid-targeted therapy showed that over 50% of patients were able to stop therapy within 12 months.⁵ The stopping criteria was primarily supported by amyloid PET.

Given that the one lifetime scan limit has been in place for over a decade, beneficiaries who had negative beta amyloid PET scans prior to approval of amyloid therapies—yet have legitimate reason to be retested—could face barriers to accessing treatment. More broadly, limitations on the number of beta amyloid PET scans covered should be considered in the context of the rapidly evolving evidence around amyloid-targeted therapies, with the goal of ensuring that beneficiaries will not be denied access to reasonable and necessary amyloid-targeted therapies because of outdated restrictions on the number of PET scans covered.

Based on the extensive effort to collect and publish evidence to meet the CED requirements over the past decade, MITA recommends that CMS maintain national coverage of beta amyloid PET based on the body of evidence that has accumulated from CMS-approved and other clinical studies. Numerous published studies involving thousands of patients clearly support that beta amyloid PET scans improve the clinical management of patients with cognitive impairment.

Within the IDEAS Study, the data has shown that beta amyloid PET scans led physicians to change their management in more than 60% of patients, whether they had mild cognitive impairment (MCI) or dementia. Moreover, 35.6% of patients with MCI and dementia received a change in diagnosis following the PET scan and 36.1% of patients that were considered to have Alzheimer’s disease after the clinical assessment and before the PET scan turned out to be amyloid negative.⁶ This underlines the important role that beta amyloid PET scans play in the diagnostic workup of patients with cognitive impairment, especially for ruling out an incorrect etiologic diagnosis.

Beyond the IDEAS study, as stated earlier, the more than thirty published studies⁷ involving thousands of patients have reviewed the utility of beta amyloid imaging for the diagnostic assessment of patients evaluated. Several meta-analyses and systematic reviews⁸ confirm the consistent impact of beta amyloid PET in the evaluation of patients with cognitive impairment, demonstrating that beta amyloid PET contributes to diagnostic revisions in approximately 30% of patients and increases diagnostic confidence in approximately 60% of subjects. Changes in management were observed in 32% to 87% of patients, with the most common type of change in management being either the initiation or discontinuation of planned Alzheimer’s disease medication. Medication changes were observed in approximately 40% of patients. Other types of management changes included referral to clinical trials, Alzheimer’s genetic testing, addition or removal of planned diagnostic tests, and counseling.

As described earlier, this published evidence shows that beta amyloid PET imaging changes diagnosis and treatment management plans. With this information, which can provide a more accurate and earlier diagnosis, beta amyloid PET imaging is able to improve patients’ health outcomes by providing physicians with better diagnostic information resulting in appropriate treatment.

While MITA appreciates CMS' proposal to expand coverage of beta amyloid PET scans, we are concerned that leaving coverage to the discretion of local contractors could result in variability of coverage and beneficiary access delays to anti-amyloid therapies. Patients that are candidates for treatment with anti-amyloid therapies are required to have a diagnostic test for amyloid identification under the National Patient Registry Portal. If CMS finalizes the Decision Memorandum to leave coverage to contractor discretion, there would be significant uncertainty with whether those scans are covered at the local level.

An NCD would provide consistent and clear coverage immediately once such a policy was finalized, instead of months of uncertainty as MACs each determine their local coverage policy. Based on past experience with MAC coverage of diagnostics, many contractors opt to provide coverage on a claim-by-claim basis without a posted policy providing coverage. Other MACs have used Local Coverage Articles (LCAs) for imaging agents and advanced imaging for oncologic and nononcologic PET scans.

A concern with either claim-by-claim coverage or an LCA is that Medicare Advantage (MA) plans frequently assert they are not required to cover PET in the absence of an NCD or LCD, nor are they required to cover items and services only included on LCAs. MA plans often point to section 90.3 of the Medicare Managed Care Manual, which allows MA plans to follow coverage for NCDs and LCDs but not articles or claim-by-claim coverage.⁹ If MA plans attempt to assert that coverage is not required for beta amyloid PET, there could be access issues for anti-amyloid therapies. This is particularly problematic in states like California, Florida, and Texas which have the highest MA enrollments in the country and a sizable portion of the Medicare population. CMS would need to issue guidance and transmittals to the MA plans to instruct them to follow the coverage established by the MACs.

Even for MACs that decide to issue LCDs, this process could also take several months to establish final policies. Additionally, once a final LCD is issued, it is not effective for 45 days. During this time, there would be a lack of clarity for ordering physicians and coverage gaps for beneficiaries in need of beta amyloid PET imaging to receive anti-amyloid therapy.

In the event that CMS finalizes a policy to give MACs the discretion to cover beta amyloid PET at the local level, we would urge CMS to coordinate with the MACs to ensure that there is transparency and clarity to ensure seamless coverage for all Medicare beneficiaries. In particular, for patients who are already under consideration for treatment with anti-amyloid therapy, these patients would need to obtain access to amyloid imaging once the NCD is no longer in place but before MACs finalize their policies. We would welcome the opportunity to assist CMS and the MACs to support appropriate coverage of beta amyloid PET imaging in this context.

Thank you for your consideration of our comments. If you have any questions or request any additional information, please contact Sue Bunning at 703-340-4100 or by email at sbunning@medicalimaging.org.

Sincerely,

Patrick Hope
Executive Director, MITA

MITA is the collective voice of manufacturers of medical imaging equipment, radiopharmaceuticals, contrast media, and focused ultrasound therapeutic devices. It represents companies whose sales comprise more than 90 percent of the global market for medical imaging innovations. These products include magnetic resonance imaging (MRI), medical X-Ray equipment, computed tomography (CT) scanners, ultrasound, nuclear imaging, radiopharmaceuticals, and imaging information systems. MITA Member company technologies are an important part of our nation’s healthcare infrastructure and are essential for the screening, diagnosis, staging, managing and effectively treating patients with cancer, heart disease, neurological degeneration, and numerous other medical conditions.

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The American Academy of Neurology (AAN) is the world’s largest neurology specialty society representing more than 40,000 neurologists and clinical neuroscience professionals. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a physician with specialized training in diagnosing, treating, and managing disorders of the brain and nervous system. These disorders affect one in six people and include conditions such as multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, stroke, migraine, epilepsy, traumatic brain injury, ALS, and spinal muscular atrophy.

The AAN appreciates that the Centers for Medicare and Medicaid Services (CMS) has proposed the retirement of the national coverage determination (NCD) for beta-amyloid positron emission tomography (PET) in dementia and neurodegenerative disease (NCD 220.6.20). The AAN believes it is appropriate that this NCD be retired given the recent FDA approval of monoclonal antibodies (mAbs) products directed against amyloid for the treatment of Alzheimer’s disease (AD). We strongly urge the agency to finalize this proposal expeditiously. The AAN, along with the American Geriatric Society (AGS) and the Society for Nuclear Medicine and Molecular Imaging (SNMMI) , sent a letter to the administrator in 2021 recommending that this NCD be retired in order to expand access for patients that may be candidates for mAbs, as detection of amyloid presence is a critical tool for neurologists when considering the use of these therapies. Retirement of this NCD would mean that beta-amyloid PET would be covered at the discretion of Part A/B Medicare Administrative Contractors (MACs) just like every other PET scan, including Tau PET, furnished for non-oncologic indications.

The AAN requests that CMS clarify that, along with removing limitations on the reimbursement of these scans, the radiopharmaceuticals required to complete them will also regain covered status. The AAN believes this should be explicitly clarified in the final policy to ensure that the MACs are advised the radio pharmaceutical is an essential requisite injected medication for every study, and needs to be covered, as without coverage there cannot be a PET scan.

There is robust literature demonstrating that beta-amyloid PET influences clinical decision-making. In the IDEAS Study which included 11,409 participants with mild cognitive impairment (MCI) or dementia of uncertain cause, ninety days after beta-amyloid PET, patient care plans changed (compared with the pre-PET plan) in 60.2% of patients initially characterized as having MCI and 63.5% of patients initially characterized as having dementia of unknown cause. Similarly, Pontecorvo et al. found that immediate notification of beta-amyloid PET findings was associated with a change in patient management, particularly changes in AD medication. The information provided by the scan had a significant impact on prescribing patterns in that acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group ( p < 0.0001). Based on the evidence demonstrating the clinical utility of amyloid PET, CMS should retire NCD 220.6.20 and allow coverage at contractor discretion for beta-amyloid PET, similar to coverage for other non-oncologic PET indications.

While the AAN understands that CMS has an interest in controlling costs and protecting program integrity, we believe beta-amyloid PET scans are a vital diagnostic tool and deference should be appropriately shown to the judgment of the treating clinician. Restriction to one PET scan per lifetime is likely to negatively impact participation in Coverage with Evidence Development requirements under the NCD for mAbs directed against amyloid for the treatment of Alzheimer’s disease. The AAN also believes that current restrictions on beta-amyloid PET scans may negatively impact care by limiting the information that physicians need to make appropriate treatment decisions, including whether to stop monoclonal antibody therapy. If Medicare coverage is limited to one scan per patient, the additional PET scans furnished under the mAb CED requirements will not be covered, and those costs will have to be borne by the trial sponsors or directly by beneficiaries. With multiple products now approved by the FDA, requiring confirmation of amyloid pathology prior to initiating treatment and a clearly demonstrated interest on the part of CMS of better understanding the safety and efficacy of these products, pre-existing policy is no longer necessary.

Additionally, the AAN notes that limiting amyloid PET scans to one per lifetime raises major health equity issues and may limit CED participation for low-income beneficiaries. Doing so would also run counter to CMS’ stated goal of generating data that is generalizable to the broader Medicare population. Furthermore, the AAN believes there may be circumstances in which the clinician believes an additional scan is warranted. Such circumstances include but are not limited to, technical issues with tracer, movement artifact, development of new cognitive symptoms, or the initial scan being done when the patient is not symptomatic. Additionally, given the approval and growing availability of mAbs for the treatment of AD, further amyloid testing may be reasonable and necessary for ensuring optimal care for patients, especially if a treatment were to be approved with a “treat to clear” regimen wherein confirmation of cleared amyloid could serve to reduce or end the course of treatment which will benefit patients clinically and economically.

The AAN would like to reiterate our gratitude to CMS for heeding our recommendations and our approval of this proposed retirement. Coverage of these scans, and the agents required for them, will assist our members in diagnosing and treating their patients. If you have any questions regarding these comments or seek further input, please contact Matt Kerschner, Director, Regulatory Affairs and Policy at mkerschner@aan.com or Max Linder, Senior Government Relations Manager at mlinder@aan.com.

Sincerely,
Carlayne E. Jackson, MD, FAAN
President, American Academy of Neurology

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As one of a small number of U.S. neurologists solely dedicating his “New Patient” appointment slots to
1) MCI
or
2) Mild Dementia, (likely of Alzheimer’s type)

I can tell you w/o doubt that amyloid PET is the only current appropriate choice for diagnosing “highly likely Alzheimer’s” (ie., MCI/mild dementia “w/ an amyloid basis”). Spinal fluid is not a clinically reasonable choice not sufficiently accurate for using LEQEMBI(or similar agent) given the risks. Blood assays for amyloid & tau are similarly not sensitive nor specific enough either.

I have 5 years of neurology training (1993-1997) and 26 + years of general neurology clinical practice (1997 to present) as the basis for my judgement on the above. For the past 3 1/2 years, I have accepted only New Patients w/ the above stated profile while maintaining care of my 6000 + continuity patients I have cared for over the past 26 + years.

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Amyloid PET is an effective non invasive tool to determine the presence and burden of amyloid in the brain. The PET amyloid study was utilized in the trials for the approved agents and is vital to the succesful utilization of amyloid reduction therapy. We need to know about amyloid deposition.

In addition to removing the Non coverage determination and need CED with development AND coverage for the isotope. Only changing the coverage for the scan does not support the procedure. The procedure reimbursement does not cover the cost of the isotope.

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It is a terrible idea to retire the current NCD without any guidelines for coverage in place to replace it other than the proposed "decision by the MAC." The MACs have not developed LCDs and that will leave providers simply guessing as to what the MACs, who often do not agree with each other, will decide if they review the claim. I would also recommend, if you choose to leave this to the MACs, that you require the MACs convene the multi-contractor advisory committee and develop one LCD model for all MACs to avoid the need to cross state lines to get coverage.

CMS needs to consider the complexity of this disease and the treatment. For example, imagine the patient with memory loss who is thought to have Alzheimers and may be a candidate for Leqembi. First, they cannot enroll in the registry since they are not yet diagnosed. Is a PET covered under CED? Next, if they get the PET and it is positive, the next step would be screening for APOE4 (another CMS coverage mess). If that is positive, the patient may decline treatment, and therefore would not be enrolled in CED. Will that negate coverage for the PET that was done? And even if the PET is positive and APOE4 negative, the patient may realize they cannot afford the coinsurance costs once they are informed and decline treatment. Again, no CED coverage.

I would propose that, rather than removing 200.6.20 that CMS modify that by removing the clinical trial or CED requirement and then adopt the provisions of NCD 220.6.13 (b)(1) (a) to (g), with minimal modifications, to ensure that the diagnosis of Alzheimer's is clinically supported prior to allowing an amyloid PET scan. It's really that easy.

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In an age where we appreciate preventative care and early detection to save costs and more importantly lives, it should be understood offering these PET exams in conjunction with the treatment needs to be standard of care. From the Alzheimer's Association: "1 in 3 seniors dies with Alzheimer's or another dementia. It kills more than breast cancer and prostate cancer combined."

I fully support CMS coverage of these FDA approved and proven drugs. The debate of efficacy is settled by the FDA (not CMS) - now coverage needs to follow.

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My [PHI Redacted] died at 84 after 15 years of non-diagnosed dementia. My [PHI Redacted] died at 81 with vascular dementia and Alzheimer’s diagnosed at autopsy. My [PHI Redacted] is 96 and is in a dementia nursing home unit. Her dementia began around 2010. It’s assumed that she has Alzheimer’s but she’s never had a PET scan.

I had a PET scan during a research project that I was in. [PHI Redacted]

My [PHI Redacted] is 88 and has been showing signs of dementia for the past year. He has had extensive memory testing resulting in a diagnosis of mild cognitive decline. I wish that Medicare would pay for a PET scan for him. In light of the current FDA approval for plaque removing drugs, it may be required for him to receive them.

I’m asking that Medicare begin approval of PET scans for those who have had memory testing showing declining memory in order to aid in diagnosing and slow the progression of Alzheimer’s disease. The earlier it’s diagnosed, the better. Thank you.

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We really need the amyloid PET scans approved for clinical practice. Many patients require the PET scans before they can be consider for antiamyloid therapy.

I would recommend that the PET scans go through an authorization process that verifies need. This should include previous neurological consult and work-up that is required before ordering the PET scan.

The protocol would be similar to what clinical research companies and the new ideas clinical trial follows as prerequisite before doing the PET scan.

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The American Geriatrics Society (AGS) supports the Centers for Medicare & Medicaid Services (CMS) proposal to remove the national coverage determination (NCD) at § 220.6.20, ending coverage with evidence development (CED) for positron emission tomography (PET) beta amyloid imaging and permitting Medicare coverage determinations for PET beta amyloid imaging to be made by the Medicare Administrative Contractors (MACs) under § 1862(a)(1)(A) of the Social Security Act. We urge CMS to finalize this proposal and retire NCD 220.6.20 in its entirety. The AGS commented to CMS in July 2022 on its reconsideration of NCD § 220.6.20 and we continue to believe that this NCD inappropriately limits coverage of beta amyloid PET for Medicare beneficiaries, including beneficiaries who may be candidates for monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s Disease (AD).

There is robust literature demonstrating that beta amyloid PET supports clinical decision-making. In the IDEAS Study which included 11,409 participants with mild cognitive impairment (MCI) or dementia of uncertain cause, ninety days after beta-amyloid PET, patient care plans changed (compared with the pre-PET plan) in 60.2% of patients initially characterized as having MCI and 63.5% of patients initially characterized as having dementia of unknown cause.(1) Similarly, Pontecorvo, et al found that immediate notification of beta amyloid PET findings was associated with a change in patient management, particularly changes in AD medication. The information provided by the scan had a significant impact on prescribing patterns in that acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). (2)

Retirement of the NCD would mean that beta amyloid PET would be covered at the discretion of Part A/B Medicare Administrative Contractors (MACs) just like every other PET scan, including Tau PET, furnished for non-oncologic indications.

(1) Rabinovici GD, Gatsonis C, Apgar C, et al. Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA. 2019 04 02;321(13):1286-94. doi: https://dx.doi.org/10.1001/jama.2019.2000. PMID: 30938796.

(2) Pontecorvo MJ, Siderowf A, Dubois B, et al. Effectiveness of Florbetapir PET Imaging in Changing Patient Management. Dement Geriatr Cogn Disord. 2017;44(3-4):129-43. doi: https://dx.doi.org/10.1159/000478007. PMID: 28787712.

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I just read the AD article and it had me thinking. Why are we not running these tests at regular intervals like we do for vaccinations, colon screening, prostate screening, mammograms, and PAP smears. You would think our neurological health is vital and should have a schedule automatically approved by all insurance companies. Cognitive function is critical to life and we should be in the business of ensuring that everyone lives well. When restrictions and limitations are placed on healthcare, we do a disservice. We really should be looking at things wholistically and individually according to the individual and their needs. If you don’t obtain a baseline, you are not able to track progress or declines. That leaves me asking the question, what have you truly learned if you don’t have enough evidence to compare? Thank you for the information and allowing me to provide my feedback.

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