Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease

A.    The Centers for Medicare & Medicaid Services (CMS) proposes to cover FDA approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) under Coverage with Evidence Development (CED) in CMS approved randomized controlled trials that satisfy the coverage criteria specified in Section C below, and in trials supported by the National Institutes of Health (NIH). All trials must be conducted in a hospital-based outpatient setting.

B.    For any CMS approved trials, or trials supported by the NIH, that include a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20), and one beta amyloid PET scan will be covered per patient, if the patient did not previously receive a beta amyloid PET scan.

C.    Covered Indications and Coverage Criteria for CMS Approved Trials

D.    Nationally Non-Covered Indications

Monoclonal antibodies directed against amyloid for the treatment of AD provided outside of the CMS approved randomized controlled trials and trials supported by the NIH are nationally non-covered.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act.

TO: 	Administrative File:  CAG-00460N

FROM: 	Tamara Syrek Jensen, JD
	Director, Coverage and Analysis Group
		
	Joseph Chin, MD, MS
	Deputy Director, Coverage and Analysis Group
		
	JoAnna Baldwin, MS
	Acting Director, Division of Policy and Evidence Review
	
	Andrew Ward, PhD, MPH
	Director, Evidence Development Division
	
	David Dolan, MBA
	Lead Analyst
		
	Karyn Kai Anderson, PhD, MPH
	Epidemiologist
		
	Joseph Dolph Hutter, MD, MA
	Lead Medical Officer

SUBJECT: 	Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease

DATE: 	January 11, 2022

I. Proposed Decision

A.    The Centers for Medicare & Medicaid Services (CMS) proposes to cover FDA approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) under Coverage with Evidence Development (CED) in CMS approved randomized controlled trials that satisfy the coverage criteria specified in Section C below, and in trials supported by the National Institutes of Health (NIH). All trials must be conducted in a hospital-based outpatient setting.

B.    For any CMS approved trials, or trials supported by the NIH, that include a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20), and one beta amyloid PET scan will be covered per patient, if the patient did not previously receive a beta amyloid PET scan.

C.    Covered Indications and Coverage Criteria for CMS Approved Trials

D.    Nationally Non-Covered Indications

Monoclonal antibodies directed against amyloid for the treatment of AD provided outside of the CMS approved randomized controlled trials and trials supported by the NIH are nationally non-covered.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act.

II. Background

Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations.  Please find below a list of these acronyms and corresponding full terminology:

AAN – American Academy of Neurology
AD – Alzheimer’s disease
AFA – Alzheimer’s Foundation of America
AfPA – Alliance for Patient Access
AGS – American Geriatric Society
AHIP – America’s Health Insurance Plan
BIO – Biotechnology Innovation Organization
CDC – Centers for Disease Control and Prevention
CED – Coverage with Evidence Development
CMS – Centers for Medicare & Medicaid Services
CSF – Cerebral spinal fluid
FDA – Food and Drug Administration
GAP – Global Alzheimer’s Platform
IAF – Infusion Access Foundation
IPA – Infusion Providers Alliance
mAbs/mABs – Monoclonal antibodies
MCI – Mild cognitive impairment
MITA – Medical Imaging & Technology Alliance
NAACOS – National Association of ACOs
NAMD – National Association of Medicaid Directors
NCA – National Coverage Analysis
NCD – National Coverage Determination
NDSS – National Down Syndrome Society
NHIA – National Home Infusion Association
NIA – National Institute of AgingNIH – National Institutes of Health
NMQF – National Minority Quality Forum
PCMA – Pharmaceutical Care Management Association
PhRMA – Pharmaceutical Research and Manufacturers of America
PET – Positron Emission Tomography
SNMMI – Society of Nuclear Medicine and Molecular Imaging
US – United States

Epidemiology

Alzheimer’s disease (AD) is a currently irreversible brain disorder that progressively degrades memory, cognitive function, and ability to carry out tasks of daily living.  AD is the number one cause of dementia in older Americans, contributing to 60-80% of cases.  Over 6 million older Americans are believed to have AD.  This prevalence is expected to rise to 14 million by 2060 barring effective interventions (such as lifestyle changes, treatment of risk factors, and possibly combinations of Alzheimer’s drugs).  AD is the sixth leading cause of death in the United States, but may rank from fifth to as high as third (after heart disease and cancer) as a cause of death for older Americans.  Older Black individuals are nearly two times as likely to have AD (and other dementias) as older White individuals, and Black patients with AD are more likely to have mixed disease (AD plus one or more other causes of dementia).  Older Hispanic individuals are nearly one and one-half times as likely to have AD as older White individuals. Women are more likely to have AD than men, although this is in part because women live longer.  (AA 2021, NIA 2021, CDC 2021, Rajan 2021, Brookmeyer 2018, 2019.)

Most individuals with AD become symptomatic after age 65.  Alzheimer’s can be fatal anywhere between 2 and 20 years of symptom onset, but 8 years on average (in those with onset before age 75 years).  However, pathophysiologic changes in the brain (including amyloid-beta [Aꞵ] plaques and neurofibrillary tangles of tau) may be evident up to decades before symptoms occur.  Among 70-year-olds, 61% of those with AD die within a decade (compared to only 30% of those without AD).  However, most persons who have evidence of AD pathology but are asymptomatic will not develop AD dementia during their lifetimes. (Ganguli 2005, Brookmeyer 2018, AA 2021, Dilworth 2008, Sperling 2011, CMS 2013, Jack 2010.)

Clinical presentation and progression

The first symptom of AD is usually memory loss (amnesia), due to synaptic dysfunction and loss of neurons in the hippocampus.  This leads to impairment of reasoning, judgment, behavior and communication, as well as motor function, as the disease spreads to other regions of brain. Rarely the initial (or “presenting”) symptoms can be nonamnestic, such as disturbances in language, visuospatial abilities or decision-making.

Categorizing the onset and progression of AD, and even the definition of AD itself, are subjects of intense debate (Dubois 2021, Jack 2018).  Currently there is no universally agreed upon classification system for the “stages” of AD.  For example, the Jack 2018 criteria in their Table 6 “bear a close resemblance” to the Global Deterioration Scale (GDS) / Reisberg Scale (seen at https://www.dementiacarecentral.com/aboutdementia/facts/stages/#reisberg).  The newer Jack 2018 proposed stages differ in part because they are intended for an amyloid-positive patient population.  A recent study by Petersen and colleagues “represents one of the first attempts to fit data into the numeric clinical staging proposed by the [Jack 2018] NIA-AA research framework,” and concludes that further modification of these stages is needed (Petersen 2021).

Thus, the categories discussed below: are not meant to resolve ongoing debates about the precise “stages” of AD; recognize that any categorization represents a continuum; and neither assert a particular definition of AD nor are meant to weigh in on the appropriate clinical work up and diagnosis of patients with suspected AD.

Asymptomatic persons with evidence of AD pathology.  Termed “preclinical AD” by some, and persons “at-risk for progression to AD” by others, and reflective of “stages 1 and 2” AD, these are persons who are cognitively normal (or at least unimpaired on cognitive tests), but have, at a minimum, pathologic brain amyloid levels as evidenced by PET amyloid, cerebrospinal fluid, or other emerging tests (Jack 2018, Dubois 2021).  If these persons have evidence of abnormal tau as well, progression of AD symptomology becomes more likely.

Persons with mild cognitive impairment (MCI) and evidence of AD pathology, termed “prodromal AD” by some, and reflective of “stage 3” AD.  MCI is a syndrome in which persons experience memory loss (amnestic MCI) or loss of thinking skills other than memory loss (non-amnestic MCI), to a greater extent than expected for age, but with “minimal impairment of instrumental activities of daily living (IADL)” (Petersen 2018). Risk factors for MCI include advanced age and lower educational status.  MCI has multiple subtypes, and while it can be “the first cognitive expression of Alzheimer disease (AD), it can also be secondary to other disease processes (i.e., other neurologic, neurodegenerative, systemic, or psychiatric disorders)” (Petersen 2018).  Persons with MCI are at increased risk of developing dementia (whether from AD or another etiology), but many do not progress to dementia, and some get better (those for whom MCI is due to a treatable or self-limiting cause). (Wolk 2009, Hughes 2011, Ward 2012, Landau 2012, Sachdev 2012, Mayo 2021, Petersen 1999, 2009, 2018.)

Persons with dementia and evidence of AD pathology.  When persons with MCI and evidence of AD pathology become impaired in performing daily activities, this may indicate onset of AD dementia (reflective of “stage 4” and higher AD). Dementia is a syndrome involving cognitive and behavioral impairment in an otherwise alert patient, due to a number of neurological diseases, alone or combined.  Like MCI, dementia is not a specific cause or disease process itself.  The dementia impairment must involve a minimum of two domains (memory, reasoning, visuospatial abilities, language or personality behaviors); impact daily functioning; meet other certain criteria; and be objectively documented by a “bedside” mental status exam (e.g., mini-mental status exam, Montreal cognitive assessment) or neuropsychological testing (McKhann 2011, Nasreddine 2005, Mitchell 2008, CMS 2013).  We recognize that only patients with mild (as opposed to more severe) dementia are included in contemporary trials; furthermore, trials increasingly focus on individuals who have MCI or are even earlier in the disease process.

Etiology and diagnosis

The underlying cause(s) of AD remain unknown.  The number one risk factor is age itself.  Other prominent risk factors include genetic predisposition (e.g., the apolipoprotein ε 4 allele, or APOE-ε4), family history of dementia, and risk factors for cardiovascular disease (e.g., high blood pressure, diabetes, obesity, smoking, lack of exercise) (CDC 2021, NIA 2021, AA 2021, CMS 2013.)  Investigators hypothesize that a wide range of factors may contribute to the development of AD, including genetic, metabolic, inflammatory and immune system, mitochondrial, environmental, and neuronal, to include both cytoskeletal (occurring within the neuronal cell itself, like tau) and synaptic (altering the connectivity among neurons, like Aβ plaques).  (McAlpine 2021, ECRI 2012, Pimplikar 2010, Herrup 2010, Sperling 2011.)

Molecular biomarkers considered hallmarks of AD are Aβ plaques, and neurofibrillary tangles of the protein tau. Neurodegeneration, evidenced by atrophy in specific brain regions on MRI, is a less specific marker, but correlates better with clinical progression of disease; as such, it is the downstream neuronal dysfunction and loss that appear to cause the symptoms of Alzheimer’s disease (Jack 2018, Jack 2011).

Abnormal amyloid is the first known physiological change, giving rise to the amyloid cascade hypothesis, which posits a causal role of amyloid as instigator or essential component of a common pathway (the “central event in the aetiology of Alzheimer's disease”) that leads to downstream changes including inflammation, tau pathology, and ultimately neurodegeneration (Alzheimer 1898, 1907; Glenner 1984, Goate 1991, Hardy 1991, Selkoe 1991, Beyreuther 1991, Selkoe and Hardy 2016). The “amyloid hypothesis” itself has evolved into a more contemporary, nuanced form that considers the complexity of newly discovered variables and pathways (Jack 2018, Selkoe and Hardy 2016).

The role of amyloid in Alzheimer’s disease remains complicated for at least three reasons. First, amyloid plaques are seen in other diseases, such as dementia with Lewy bodies, cerebral amyloid angiopathy, Parkinson’s disease, Huntington’s disease, and inclusion body myositis.

Second, amyloid is associated with normal physiologic processes.  One author recently summarized: “While Aβ protofibrils and oligomers are known to be toxic (Yakupova 2021, Johannesson 2021), it is now postulated that Aβ is also physiologically produced during neuronal activity (Haass 1992, Kent 2020), augments synaptic plasticity (Finnie 2020) and functions in memory formation (Kent 2020)” (Pleen 2021).  Normal function extends to disease prevention or response, such as protection against oxidative stress, regulation of cholesterol transport, and anti-microbial activity. Aβ protects the brain from infections, repairs leaks in the blood–brain barrier, and promotes recovery from injury. In this light, amyloid plaques might even play a protective role early in Alzheimer’s disease. (Esparza 2013, Makin 2018, Guglielmotto 2010, Zou 2002, Yao 2002, Soscia 2010, Puzzo 2015, Shokri-Kojori 2018, Huan 2020.)

Combining the research on amyloid function with the data across multiple anti-amyloid AD trials, one author concludes, “. . . plaque clearance alone does not explain clinical efficacy, and amyloid plaque formation may be a protective mechanism by which soluble oligomers are sequestered to limit their neurotoxicity [Gaspar 2010]” (Tolar 2020).  This last point is acknowledged, in part, by contemporary proponents of the amyloid hypothesis; as they state, evidence suggests that “plaques can effectively sequester oligomers in a non-diffusible, less neurotoxic state, at least up to a point” after which “excess oligomers can diffuse onto surrounding synaptic membranes and other hydrophobic cell surfaces (Hong 2014)” (Selkoe and Hardy 2016).

Third, amyloid plaques can be detected in cognitively normal older adults.  Autopsy studies demonstrate that approximately one-third of older individuals (20-65% depending on age) who are cognitively normal have amyloid accumulation at levels consistent with AD pathology (Hulette 1998, Price 1999, Knopman 2003, Rowe 2010).  Other research however suggests that “[cognitively unimpaired] individuals with abnormal amyloid biomarkers have more rapid progression of atrophy, hypometabolism, and clinical/cognitive decline than individuals without biomarker evidence of Aβ deposition” (Jack 2018).

When a finding of pathologic tau is added to pathologic amyloid (both of which can be detected by PET or in CSF), determination that the disease is consistent with AD becomes more certain. The specificity for diagnosis of AD by detection of both amyloid and tau pathology is still undergoing research (Dubois 2021, Jack 2018).  One guideline states unequivocally that “the only disorder that consistently shows an increase in CSF P-tau is AD [Olsson 2016], whereas this biomarker is normal in other neurodegenerative disorders” (Jack 2018). This same guideline further states, “Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia” (emphasis in the original).  This guideline also suggests that research could be effectively guided based on the amyloid + tau + neurodegeneration biomarker data profile of research participants, without presuming to answer definitively the bigger question of causality (Jack 2018).

Even with these advancements in evidence and research guidance since the 2011 NIA-AA guidelines, as a real world, practical matter, clinical diagnosis and possible interventions remain a challenge because most dementias are associated with mixed pathology.  The most prevalent co-contributor to cognitive decline (especially early mild decline) appears to be cerebrovascular disease, which includes small vessel ischemia in addition to strokes and microinfarcts.  Examples of other co-diseases include: Lewy body disease; frontotemporal lobar degeneration; Parkinson’s disease; and hippocampal sclerosis associated with TAR DNA binding protein 43 (TDP-43) proteinopathy (whether part of, or co-existing with, AD) (Nelson 2019, Brookmeyer 2018, AA 2021, Nag 2015).  Autopsy studies support that less than 20 percent of persons with AD have “pure” AD (no mixed pathology), lending credence to the comment that “the least common form of Alzheimer’s disease is Alzheimer’s disease” (Schneider 2007, Wilson 2010, Karlawish 2021a). The impact of these mixed diseases on cognition and function may be separate and additive, although “it is uncertain whether multiple mixed pathologies act independently or synergistically on risk of all cause dementia” (Brookmeyer 2018).  The implication is that any treatment targeting amyloid specifically may be less effective the greater the level of mixed disease in a given patient.

In sum: the etiology of AD is unknown and may be multifactorial; clinical diagnosis is poor (Beach 2012, Knopman 2001) and can be improved by biomarkers, but to a degree that is debated; the role of Aꞵ as cause vs marker of disease remains controversial.

Treatment

Currently, there is no effective treatment for AD.  Existing medications do not prevent, halt, or slow – let alone reverse – the disease. Care is therefore primarily supportive and increases as functional impairment progresses, eventually leading to round-the-clock supervision which can be needed for years.  Some medications, such as memantine and cholinesterase inhibitors, can temporarily improve cognitive and neuropsychiatric symptoms in some patients with AD (as well as certain other dementias) (Birks 2006, Reisberg 2003).  Addressing risk factors likely helps.  The 2020 Lancet Commission concludes that lifestyle changes and treatment of 12 modifiable risk factors associated with Alzheimer’s could potentially prevent or delay up to 40% of dementia cases (Livingston 2020).

Antiamyloid-beta monoclonal antibodies (antiamyloid mAbs), the treatment considered in this NCD, are laboratory-made proteins designed to bind a specific substance in the body, with the goal of marking it for destruction by the body’s immune system. Scientists design various mAbs as treatments with the goal of targeting and neutralizing or clearing infections (like the COVID-19 virus), cancer cells, and in the case of Alzheimer’s disease, amyloid accumulation in brain.

Aduhelm™ (aducanumab) is the first and only such antiamyloid mAb to be approved by the FDA, and was done so under FDA’s “accelerated approval” pathway.  At the time of this NCD analysis, CMS is aware of at least three other antiamyloid mAbs currently approaching Phase 3 trials. This NCD addresses antiamyloid mAbs as a class since the drugs have a similar function of reducing amyloid in the brain.

III. History of Medicare Coverage

Prior to this NCD analysis, CMS did not have an NCD specific to monoclonal antibodies directed against amyloid for the treatment of AD.  In the absence of an NCD, coverage decisions for monoclonal antibodies directed against amyloid for the treatment of AD have been made by local Medicare Administrative Contractors (MACs).

A.  Current Request

CMS opened this NCD analysis to complete a thorough review of the evidence to consider coverage of monoclonal antibodies directed against amyloid for the treatment of AD.

B. Benefit Category

Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act.

Monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s Disease may be considered a biological that may fall within the benefit categories under 1861(s)(2)(A) or 1861(s)(2)(B) of the Social Security Act.

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities 

V.  Food and Drug Administration (FDA) Status

Aduhelm is the only antiamyloid mAb approved by the FDA. On June 7, 2021, the FDA approved aducanumab (brand name Aduhelm) with an indication for use in the treatment of Alzheimer’s disease. On July 7, 2021, the indication for use was updated to clarify that treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of Alzheimer's disease, the population in which treatment was initiated in clinical trials. The letter is available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761178Orig1s003ltr.pdf

VI. General Methodological Principles

When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.  The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries.  An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will not be made available to the public. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination.

VII. Evidence

A.  Introduction

This section provides a summary of the evidence we considered during our review.  The evidence reviewed to date includes the published medical literature on pertinent clinical trials of monoclonal antibodies directed against amyloid for the treatment of AD.  Our assessment focuses on the key evidence question below.

B.  Discussion of Evidence

1.  Evidence Question

Is the evidence sufficient to conclude that the use of monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease improves health outcomes for Medicare beneficiaries?

2.  External Technology Assessments

CMS did not request an external technology assessment (TA) on this issue.

3.  Internal Technology Assessment

We searched the data bases Academic Search Premier, CINAHL, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, for English language articles in peer-reviewed journals, published from 2010 – 2021, using the search terms ‘Phase 3 Clinical Trials’, ‘beta-Amyloid’, and ‘monoclonal antibodies’. To ensure that we captured all the relevant articles, the search was conducted independently and concurrently by a NIH librarian, the contractor International Consulting Associates (ICA), and CAG. As the searches were completed, the NIH librarian first, ICA second, and CAG last, we incorporated all the distinct, relevant references into a single reference database. The final result was the identification of over 250 peer-reviewed documents relevant to the NCD analysis.

These searches resulted in over 250 articles, including descriptions and assessments of Phase 3 clinical trials testing the efficacy and safety of using monoclonal antibodies for treatment of Alzheimer’s Disease (AD). Some of the studies, such as Konstantinos Avegerinos et al., “Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease,” a 2021 publication in Aging Research Reviews, were metanalyses that surveyed multiple clinical trials testing a variety of potential anti-amyloid drugs for treatment of AD. In addition to peer-reviewed articles, we reviewed reports from other agencies, including the FDA, the Guideline Development, Dissemination and Implementation Subcommittee of the American Academy of Neurology, the National Institute on Aging, and the National Institute for Health Care and Excellence.  We also reviewed the Institute for Clinical and Economic Review’s May 5, 2021 report “Aducanumab for Alzheimer’s Disease: Effectiveness and Value.”

4.  Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)

A MEDCAC meeting was not convened on this issue.

Below are two Evidence Tables.

Table 2 contains summary results from Phase 3 RCTs.

To ensure the public has access to the same information that CMS reviewed, we included the national clinical trial (NCT) numbers that uniquely identify all of the RCTs (12) for both tables.  To review the trials, go to clinicaltrials.gov and enter the NCT number into the search box under “Other terms.”  The tables also include, for each row, the author name and year.  The full citation for the publication can be found in the bibliography of this proposed decision memorandum which will allow anyone to find the information reviewed by CMS.

Evidence Table 1.  Individual Phase-3 RCTs of monoclonal antibodies versus placebo in Alzheimer’s Disease: Summary-level information

Evidence Table 2.  Individual Phase 3 RCTs, and meta-analyses, of monoclonal antibodies versus placebo in Alzheimer’s Disease: Random effects modeling results (standardized mean difference (SMD) and 95% confidence interval, unless otherwise noted) for all outcomes, with only statisticallysignificant results presented, and related author-attributed effect sizes, when available^a

VIII. Public Comment

Public comments sometimes cite the published clinical evidence and give CMS useful information.  Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.

CMS uses the initial public comments to inform its proposed decision.  CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum.  All comments that were submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-database/view/ncacal-public-comments.aspx?ncaid=305&ncacaldoctype=all&status=all&sortBy=status&bc=17.

Initial Comment Period: 07/12/2021 – 08/11/2021

During the 30-day comment period following the release of the tracking sheet, CMS received 131 comments. The majority of comments, approximately 77 commenters, did not support coverage or recommended coverage with evidence development (CED). Twenty-six comments did not state a clear position regarding coverage.

The comments included 58 from physicians, and eight from medical companies.  We also received 26 comments on behalf of national associations/professional societies, including the American Academy of Neurology (AAN), UsAgainstAlzheimer’s, Biotechnology Innovation Organization (BIO), Public Citizen, Value Based Care Coalition, National Home Infusion Association (NHIA), Medical Imaging & Technology Alliance (MITA), National Association of ACOs (NAACOS), National Association of Medicaid Directors (NAMD), America’s Health Insurance Plans (AHIP), Society of Nuclear Medicine and Molecular Imaging (SNMMI), Alzheimer’s Association, National Minority Quality Forum (NMQF), Alliance for Patient Access (AfPA), Global Alzheimer’s Platform (GAP), American Geriatrics Society (AGS), Infusion Providers Alliance (IPA), Alliance for Aging Research, National Down Syndrome Society (NDSS), Duke Margolis Center for Health Policy, Alzheimer’s Foundation of America (AFA), Infusion Access Foundation (IAF), Pharmaceutical Care Management Association (PCMA), Pharmaceutical Research and Manufacturers of America (PhRMA).

In addition to the above public comments, CMS held two stakeholder meetings and met with numerous patient advocates organizations, manufactures, payers, and think tanks. See the mAB Tracking Sheet (https://www.cms.gov/medicare-coverage-database/view/ncacal-tracking-sheet.aspx? ncaid=305&ncacaldoctype=all&status=all&sortBy=status&bc=17) for the stakeholder meeting transcripts and a full list of the organizations.

The themes from the comments included criticism of the evidence for Aduhelm™, citing conflicting results between EMERGE and ENGAGE, and the presence of adverse events (e.g., Amyloid Related Imaging Abnormalities (ARIA)). The commenters cited that these are reasons additional evidence is needed before the drug is coverable, or expressing that coverage should be limited to CED.  Commenters also expressed concerns over the price of Aduhelm™.  Commenters stated that CMS should cover Aduhelm™, and future anti-amyloid monoclonal antibodies, based on FDA approval and because of the lack of available effective treatments for AD. Commenters specified that diagnostic tests for beta amyloid should also be included in coverage.

IX. CMS Analysis

National coverage determinations are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§1869(f)(1)(B) of the Act).  In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage.  Moreover, with limited exceptions, the expenses incurred for items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§1862(a)(1)(A) of the Act).

In addition to §1862(a)(1)(A) of the Act, a second statutory provision may permit Medicare payment for items and services in some circumstances.  That statute, section 1862(a)(1)(E) of the Act, provides, in pertinent part, that:

(a) Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services—
. . .
(1)(E) in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section.

Section 1142 of the Act describes the authority of the AHRQ to conduct and support research on outcomes, effectiveness, and appropriateness of services and procedures to identify the most effective and appropriate means to prevent, diagnose, treat, and manage diseases, disorders, and other health conditions.  That section includes a requirement that the Secretary assure that AHRQ research priorities under Section 1142 appropriately reflect the needs and priorities of the Medicare program.

CED is a paradigm whereby Medicare covers items and services on the condition that they are furnished in the context of approved clinical studies or with the collection of additional clinical data.  In making coverage decisions involving CED, CMS decides after a formal review of the medical literature to cover an item or service only in the context of an approved clinical study or when additional clinical data are collected to assess the appropriateness of an item or service for use with a particular beneficiary.

The 2014 CED Guidance Document is available at https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=27.

When making national coverage determinations, we evaluate the evidence related to our analytic questions based on the quality, strength and totality of evidence presented in the reviewed literature.  As part of this evaluation, it is important to consider whether the evidence is relevant to the Medicare beneficiary population.  In determining the generalizability of the results of the body of evidence to the Medicare population, we consider, at minimum, the age, race and gender of the study participants.

Evidence Review Summary

For this NCD, CMS focused on the following question:

Is the evidence sufficient to conclude that the use of monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease improves health outcomes for Medicare beneficiaries?

The spectrum of AD therapies currently in various stages of investigation extends from antiamyloid, to antitau, neurotransmitter-modifying, cognitive-enhancing, antineuroinflammatory, and neuroprotective therapies (ClinicalTrials.gov 2021, Huang 2020).  In 2019 alone, there were a total of 41 trials of AD therapies, with 9 targeting amyloid (including four using antiamyloid mAbs), and 32 using non-antiamyloid therapies (Huang 2020).  In this spectrum, therapies that specifically target amyloid are the ones that most directly test the amyloid hypothesis itself (outlined in the Background section). That is, if amyloid is causative of AD, then treating amyloid early enough in the disease process should substantially delay or possibly halt progression of AD to severe dementia and premature death.

The mechanistic strategies of antiamyloid therapies include interrupting Aβ production and/or aggregation, or clearing existing Aβ in the brain.  Of these strategies, researchers have increasingly focused on clearing Aβ using antiamyloid mAbs; as one study summarizes, “passive immunotherapy using monoclonal antibodies against Aβ has been best tolerated and, given its mechanistic selectivity, has been widely considered as the therapeutic approach of choice (Panza 2019)” (Avgerinos 2021).

Quality and Strength of Evidence

Various dosages of five monoclonal antibody (mAb) drugs were studied in 12 unique trials (see Table 1, Section VII.B, Evidence section), some of which were followed up with post hoc analyses.  To date, no trial of an antiamyloid mAb has confidently demonstrated a clinically meaningful improvement in health outcomes (i.e., cognition and function) for AD patients. Thus, there is insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease under §1862(a)(1)(A) of the Social Security Act.  While we recognize that one individual trial (EMERGE) reportedly demonstrated statistical significance of a primary health outcome in a post-hoc, secondary analysis of data for patients receiving high-dose aducanumab, important questions remain regarding the reliability of those results.  We discuss the twin EMERGE and ENGAGE trials in detail below.

The trials listed in Table 1 in Section VII.B have demonstrated that some antiamyloid mAbs, such as the most recent FDA-market authorized antiamyloid mAb, aducanumab, effectively clear amyloid plaques.  We agree with the FDA that this is encouraging.  We also agree that the clinical benefit of Aꞵ clearance remains uncertain, given that no trial has convincingly demonstrated a clinically meaningful improvement in health outcomes, such as a substantial difference in a global assessment of cognition and function (which the primary outcome for the aducanumab trials, the Clinical Dementia Rating – Sum of Boxes, or CDR-SB does) compared to a control group.  Thus, we agree with the conclusion, published by one author reviewing all the trial data, that “no biomarker has achieved surrogate status in AD drug development with definite evidence that a change in the biomarker predicts a clinical benefit” (Cummings 2020).

Further, as shown in Table 2 (see Section VII.B, Evidence section), a recent meta-analysis of antiamyloid mAb Phase 3 trials, performed by scientists at the National Institute on Aging (NIA), found evidence of statistical significance, but not necessarily clinically meaningful differences in health outcomes, concluding that the existing research “provides moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.” However, the authors cautioned that the meta-analysis conclusion is preliminary and individual studies are strongly needed to determine the clinical effectiveness of these anti-Aβ monoclonal antibody treatments for AD.  Their meta-analysis stated, “The generated evidence [from their meta-analysis] cannot be used to substitute or supersede the analysis of individual trials.” Based on our review of the totality of the evidence (see Table 1 and 2, Section VII.B, Evidence section) we agree with the NIA meta-analysis that there is some preliminary research that shows promise, but it’s far from conclusive and more rigorous individual trials (i.e., RCTs) continue to be needed to determine the clinical benefit of antiamyloid mABs for the treatment of AD.

Benefits and Harms

Any assessment of patient health outcomes must weigh harms and benefits. We know antiamyloid mAb trials have demonstrated harms such as headaches, dizziness, falls, and amyloid-related imaging abnormalities (ARIA).  At the time of this writing, there is ongoing assessment of whether the use of an antiamyloid mAb has caused or contributed to death.

Amyloid-Related Imaging Abnormalities (ARIA): Detected on brain MRI scans, ARIA has two principle forms: vasogenic edema (ARIA-E; essentially swelling of the brain) and intracerebral hemorrhage (ARIA-H; bleeding in the brain).  Specific drug type and dose, as well as patients’ apolipoprotein (APOE) ɛ4 carrier versus non-carrier status (Salloway 2018), appear to be associated with occurrence of ARIA. In a recent analysis of safety data of two phase 3 clinical trials (EMERGE and ENGAGE), ARIA was found in “approximately 40% of participants in the phase 3 studies of aducanumab, and approximately one-quarter of these patients experienced symptoms” (Salloway 2021).

While many cases of ARIA in the clinical trials have been subclinical (producing no symptoms), severe cases causing for example, malignant hypertension and epileptiform activity, have been documented (VandeVrede 2020, Scherlek 2020).

Due to the lack of a clear clinical benefit and the frequency of adverse events like ARIA, the evidence does not support that the benefits outweigh the harms for mAbs directed against amyloid for the treatment of AD.  Adverse events are more closely monitored and treated in the context of a clinical trial compared to general practice.  We have additional concerns at this time about harms in patients that would be treated outside the context of the safety monitoring of a controlled trial.

Biogen’s EMERGE and ENGAGE Trials, and Secondary Analysis

Since Aduhelm™ (aducanumab) is the only monoclonal antibody directed against amyloid for the treatment of AD that has been approved by the FDA at this time, we have reviewed the available evidence on aducanumab in more depth.  As we noted above, the research to date has not demonstrated a clinically meaningful benefit from the use of antiamyloid mAbs.  Recently, there has been early but inconclusive evidence that there may be a relation between clearing Aꞵ plaques and improving health outcomes for patients with AD.

After the Phase 1 PRIME trial of 197 patients (NCT01677572), Biogen launched two identically-designed Phase 3 multicenter, double-blind, randomized controlled trials with a total of 3285 patients: ENGAGE (Study 301, NCT02477800) and EMERGE (Study 302, NCT02484547).  The trials included patients with a positive PET Aꞵ brain scan, and either MCI due to AD (>80% of trial participants) or mild AD (determined by general patient inclusion criteria of a global Clinical Dementia Rating [CDR] score of 0.5, and a Mini–Mental State Examination score ranging from 24 to 30).  (FDA 2021, Rabinovici 2021, ClinicalTrials.gov 2021.) Patients were randomized 1:1:1 to low-dose aducanumab, high-dose aducanumab, or placebo.
*In the final protocol version, while the low-dose varied by APOE e4 positive or negative, all patients in the high-dose groups received 10 mg/kg.

The primary outcome (or endpoint) of both trials was a change from baseline in the CDR Sum-of-Boxes score (CDR-SB). A CDR-SB is “an 18-point scale measuring cognition (memory, orientation, judgment, and problem solving) and function (community affairs, home and hobbies, personal care)” (Rabinovici 2021). It is unclear what the baseline CDR-SB scores, or the changes, were in the EMERGE and ENGAGE trials because to date there has not been peer-reviewed publication of the trial design, results or secondary analyses.

According to the FDA, “Both studies were stopped prior to completion by the independent data monitoring committee (IDMC) after meeting pre-specified futility criteria based upon an analysis of pooled study data (with approximately 57% of patients completing the 78-week treatment period).  After the studies were unblinded, it was discovered that Study 302 [EMERGE] had met criteria for statistical significance for the primary endpoint, while Study 301 [ENGAGE] showed no suggestion of an effect of drug on the primary endpoint” (FDA 2021).

Specifically, for Study 302 [EMERGE], the additional data collected after official halting of the trials (due to prespecified futility criteria) found that “the primary endpoint, evaluating the high dose, was statistically significant with a CDR-SB change from baseline relative to placebo of -0.39 (p=0.0120); the low dose had a non-statistically significant numerical reduction (p = 0.0901)” (FDA 2021). The FDA reports that Biogen’s post-hoc, secondary analysis also demonstrated that Study 302 [EMERGE] met statistical significance for other, secondary outcomes assessing cognition and function: ADAS-Cog-13 and ADCS-ADL-MCI.

As described in a publication by one of the members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, “Study 301 [ENGAGE] detected no difference from placebo in either the high-dose or the low-dose group, with participants in the high-dose group having nominally worse cognitive function after 18 months than those in the placebo group.  Study 302 [EMERGE] was retrospectively deemed partially successful because a statistically significant, but very small absolute, difference was detected on the primary clinical outcome measure between the high-dose group and the placebo group, with no such difference in the low-dose group” (Alexander 2021).  The Advisory Committee’s vote on aducanumab on November 6, 2020 was: 10 against approval, 0 for approval, 1 abstention.  The additional trial data collected by Biogen also reportedly revealed that ARIA occurred in roughly 35% of patients who received high-dose aducanumab, compared to 10% of patients who received placebo (FDA 2021, Rabinovici 2021). As of this writing, Biogen’s secondary analysis has not been published in a peer-reviewed medical journal for CMS to review, nor have the original trials been published separately.  We strongly encourage such publications.

Many published expert opinions and reports have questioned Biogen’s secondary analysis of trial data and its conclusions regarding aducanumab’s effectiveness.  Most experts believed there was little, if any, reliable evidence to answer the key question of clinical benefit.  Some experts highlighted possible alternative explanations for why the two RCTs, EMERGE and ENGAGE, had conflicting outcomes based on a post-hoc analysis.  (Knopman 2020, Howard 2020, Lin 2021, Rubin 2021, Mullard 2021, Liu 2021, Alexander 2021, Rabinovici 2021, Karlawish 2021, Dunn 2021, FDA 2021).  For example, some experts have stated that:

• The conflicting outcomes between EMERGE and ENGAGE could be explained by differences in the placebo groups. The known heterogeneity of patients in early stages of AD could have resulted in chance differences between the placebo (control) groups of the two trials.  As such, in the EMERGE trial, the slight but statistically significant difference between the intervention and placebo groups could have been due to chance worsening of the placebo group, rather than a positive effect of the drug in the intervention group.
  
  
• Analysis based on selective (nonrandomized) data is prone to bias and is at best hypothesis-generating (exploratory) only.  Thus, the result of any post-hoc secondary analysis is insufficient to declare “success” in the face of conflicting trials.

Our conclusion is that Biogen’s secondary analysis cannot overturn, definitively confirm, or substitute for, the RCT evidence.  With conflicting results from two RCTs (EMERGE and ENGAGE), and a secondary analysis that did not resolve the difference between the two RCTs, CMS believes that the available evidence is insufficient to establish that the treatment is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act.

Coverage with Evidence Development (CED)

While there is insufficient evidence that antiamyloid mAbs  are reasonable and necessary for the treatment of AD, we acknowledge that AD is a particularly important disease that affects many Medicare beneficiaries.  We believe that the CED paradigm provides the most appropriate pathway to provide Medicare coverage while additional evidence is developed.  Latest-generation/emerging antiamyloid mAbs have demonstrated ability to significantly reduce amyloid plaque burden, and there are preliminary but promising clinical results from the high-dose aducanumab group in the EMERGE trial (albeit on post-hoc, secondary analysis).  We also consider the burden AD poses for our beneficiaries (it is the most burdensome disease in our Medicare population) and for society as a whole.  As discussed in the Background section of this NCD, over 6 million older Americans are believed to have AD, and this prevalence is expected to rise to 14 million by 2060 barring effective interventions. Effective treatments are needed, and because of the early but promising evidence and the immense burden of this devastating disease on the Medicare population, we are proposing CED to support rigorous trials to answer whether antiamyloid mAbs improve health outcomes for patients.  We propose to cover the antiamyloid mAbs in RCTs under Section 1862(a)(1)(E) of the Social Security Act using CED.

Under CED, we propose that a trial must be a multicenter RCT, with an appropriate control representing the standard of care.  This is consistent with the designs of large, pivotal Phase 3 trials for antiamyloid mAbs, including the most recent ones for aducanumab. In addition, to ensure the CED requirements do not assume the NIH’s role in fostering, managing, or prioritizing clinical trials, this CED will cover NIH-sponsored studies of antiamyloid mAbs. The purpose is to provide coverage for Medicare beneficiaries who participate in NIH studies in order to further grow the evidence base for antiamyloid mAbs.

We also propose that the setting for CMS approved clinical trials remain in hospital-based outpatient facilities as this ensures integrated and coordinated care, availability of advanced imaging or other diagnostic tests, and rapidly-available advanced care if needed. We propose these settings out of an abundance of caution, to ensure the highest level of clinical care, and to reassure patients that further research with antiamyloid mAbs will be conducted in a rigorous setting to minimize any potential harms from the treatment.

Coverage Criteria for CMS Approved Trials

Consistent with the CED requirements, to ensure the safety of research participants, federal regulations require provisions to monitor data collected in the course of a research study, where appropriate (see 45 CFR 46.111(a)(6); 21 CFR 56.111(a)(6)). Data and safety monitoring aims both to protect participants and ensure the integrity and validity of research data. All studies involving human subjects require some level of data and safety monitoring. This includes physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); and efficacy, effectiveness, and comparative trials (phase III). The specific monitoring strategy will depend on the risk, size, and scope of the study, and may involve individuals or groups.”https://catalyst.harvard.edu/wp-content/uploads/regulatory/DSMB-P_Guidance.pdf

Patient Criteria

Inclusion Criteria
To enroll, patients must have:

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