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

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A. The Centers for Medicare & Medicaid Services (CMS) covers Food and Drug Administration (FDA) approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) when furnished in accordance with Section B (Coverage Criteria) under coverage with evidence development (CED) for patients who have: A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia, both with confirmed presence of amyloid beta pathology consistent with AD. B. Coverage Criteria: 1) Monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of AD based upon evidence of efficacy from a change in a surrogate endpoint (e.g., amyloid reduction) considered as reasonably likely to predict clinical benefit may be covered in a randomized controlled trial conducted under an investigational new drug (IND) application. 2) Monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of AD based upon evidence of efficacy from a direct measure of clinical benefit may be covered in CMS approved prospective comparative studies. Study data for CMS approved prospective comparative studies may be collected in a registry. 3) For CMS-approved studies, the protocol, including the analysis plan, must include: A study population whose diversity of patients are representative of the national population with MCI due to AD or mild AD dementia. A neurocognitive evaluation and a description of the instruments used to assess cognition and function for the clinical diagnosis of MCI due to AD or mild AD dementia for study enrollment and outcomes assessment. A description of: The multidisciplinary dementia team and optimal medical management. Study sites with clinical expertise and infrastructure to provide treatments consistent with the safety monitoring outlined in the FDA-approved label. 4) CMS-approved studies of a monoclonal antibody directed against amyloid (antiamyloid mAb) approved by FDA for the treatment of AD based upon evidence of efficacy from a direct measure of clinical benefit must address all of the questions below: Does the antiamyloid mAb meaningfully improve health outcomes (i.e., slow the decline of cognition and function) for patients in broad community practice? Do benefits, and harms such as brain hemorrhage and edema, associated with use of the antiamyloid mAb, depend on characteristics of patients, treating clinicians, and settings? How do the benefits and harms change over time? 5) CMS-approved studies must adhere to the following standards of scientific integrity that have been identified by the Agency for Healthcare Research and Quality: The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects. The rationale for the study is well supported by available scientific and medical evidence. The study results are not anticipated to unjustifiably duplicate existing knowledge. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination. The study is sponsored by an organization or individual capable of completing it successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data. All aspects of the study are conducted according to appropriate standards of scientific integrity. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Research and Quality (AHRQ) Registry of Patient Registries (RoPR). The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessible manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results). The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. The principal investigator must submit the complete trial protocol, cite where the detailed analysis plan for the CMS CED questions occurs in the protocol, and provide a statement addressing how the study satisfies each of the standards of scientific integrity (a. through m. listed above), as well as the investigator’s contact information, to the email address below. The information will be reviewed, and approved trials will be identified on the CMS website. Email address for protocol submissions: clinicalstudynotification@cms.hhs.gov Email subject line: "CED Monoclonal Antibodies for the Treatment of Alzheimer’s Disease [name of sponsor/primary investigator]" C. Monoclonal antibodies directed against amyloid indicated for the treatment of AD are covered when furnished according to the FDA approved indication in National Institutes of Health (NIH)-supported trials. D. For any CMS approved study, or NIH-supported trial, that includes a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials or studies also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20). E. Monoclonal antibodies directed against amyloid for the treatment of AD provided outside of a FDA approved randomized controlled trial, CMS approved studies, or studies supported by the NIH, are nationally non-covered. Consistent with section 1142 of the Act, AHRQ supports Medicare coverage of FDA trials in Section B.1, NIH trials, and CMS-approved studies that meet all the standards identified above, and address the above-listed research questions. See Appendix B for the suggested manual language for the National Coverage Determination.

Decision Memo: 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: National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease DATE: April 7, 2022 I. Decision A. The Centers for Medicare & Medicaid Services (CMS) covers Food and Drug Administration (FDA) approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) when furnished in accordance with Section B (Coverage Criteria) under coverage with evidence development (CED) for patients who have: A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia, both with confirmed presence of amyloid beta pathology consistent with AD. B. Coverage Criteria: 1) Monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of AD based upon evidence of efficacy from a change in a surrogate endpoint (e.g., amyloid reduction) considered as reasonably likely to predict clinical benefit may be covered in a randomized controlled trial conducted under an investigational new drug (IND) application. 2) Monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of AD based upon evidence of efficacy from a direct measure of clinical benefit may be covered in CMS approved prospective comparative studies. Study data for CMS approved prospective comparative studies may be collected in a registry. 3) For CMS-approved studies, the protocol, including the analysis plan, must include: A study population whose diversity of patients are representative of the national population with MCI due to AD or mild AD dementia. A neurocognitive evaluation and a description of the instruments used to assess cognition and function for the clinical diagnosis of MCI due to AD or mild AD dementia for study enrollment and outcomes assessment. A description of: The multidisciplinary dementia team and optimal medical management. Study sites with clinical expertise and infrastructure to provide treatments consistent with the safety monitoring outlined in the FDA-approved label. 4) CMS-approved studies of a monoclonal antibody directed against amyloid (antiamyloid mAb) approved by FDA for the treatment of AD based upon evidence of efficacy from a direct measure of clinical benefit must address all of the questions below: Does the antiamyloid mAb meaningfully improve health outcomes (i.e., slow the decline of cognition and function) for patients in broad community practice? Do benefits, and harms such as brain hemorrhage and edema, associated with use of the antiamyloid mAb, depend on characteristics of patients, treating clinicians, and settings? How do the benefits and harms change over time? 5) CMS-approved studies must adhere to the following standards of scientific integrity that have been identified by the Agency for Healthcare Research and Quality: The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects. The rationale for the study is well supported by available scientific and medical evidence. The study results are not anticipated to unjustifiably duplicate existing knowledge. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination. The study is sponsored by an organization or individual capable of completing it successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data. All aspects of the study are conducted according to appropriate standards of scientific integrity. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Research and Quality (AHRQ) Registry of Patient Registries (RoPR). The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessible manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results). The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. The principal investigator must submit the complete trial protocol, cite where the detailed analysis plan for the CMS CED questions occurs in the protocol, and provide a statement addressing how the study satisfies each of the standards of scientific integrity (a. through m. listed above), as well as the investigator’s contact information, to the email address below. The information will be reviewed, and approved trials will be identified on the CMS website. Email address for protocol submissions: clinicalstudynotification@cms.hhs.gov Email subject line: "CED Monoclonal Antibodies for the Treatment of Alzheimer’s Disease [name of sponsor/primary investigator]" C. Monoclonal antibodies directed against amyloid indicated for the treatment of AD are covered when furnished according to the FDA approved indication in National Institutes of Health (NIH)-supported trials. D. For any CMS approved study, or NIH-supported trial, that includes a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials or studies also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20). E. Monoclonal antibodies directed against amyloid for the treatment of AD provided outside of a FDA approved randomized controlled trial, CMS approved studies, or studies supported by the NIH, are nationally non-covered. Consistent with section 1142 of the Act, AHRQ supports Medicare coverage of FDA trials in Section B.1, NIH trials, and CMS-approved studies that meet all the standards identified above, and address the above-listed research questions. See Appendix B for the suggested manual language for the National Coverage Determination. 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 Aging NIH – 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 A monoclonal antibody directed against amyloid (antiamyloid mAb) for the treatment of AD, is a “biological,” which is a type of drug; the terms “biologicals” and “drugs” are used interchangeably throughout this NCD. 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/biologicals). 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 2009, 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 2009, 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 functioning 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 (gantenerumab, donanemab, and lecanemab) currently undergoing Phase 3 trials designed for FDA approval (ClinicalTrials.gov 2022). 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 drug or biological that may fall within the benefit categories under 1861(s)(2)(A) or 1861(s)(2)(B) of the Social Security Act. IV. Timeline of Recent Activities July 12, 2021 CMS opens an NCA for Initial 30-day public comment period begins. July 22, 2021 CMS National Stakeholder Calls July 27, 2021 CMS National Stakeholder Calls August 11, 2021 First public comment period ends. CMS receives 131 comments January 11, 2022 Proposed NCD and Decision Memorandum posted. 30-day public comment period begins. January 11-February 10, 2022 CMS meets with stakeholders. List of stakeholder meetings; https://www.cms.gov/medicare-coverage-database/view/ncacal-tracking-sheet.aspx?ncaid=305&ncacaldoctype=all&status=all&sortBy=status&bc=17 February 10, 2022 Second public comment period ends. CMS receives 10,025 comments. 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 that cannot be redacted 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 300 peer-reviewed documents relevant to the NCD analysis. These searches resulted in over 300 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 1 contains summary descriptive information about individual Phase 3 RCTs. 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 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 statistically significant results presented, and related author-attributed effect sizes, when available a VIII. Public Comment 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. Second Comment Period: 01/11/2022 – 02/10/2022 During the 30-day public comment period following the release of the proposed NCD and decision memorandum, CMS received over 10,000 comments. Of these comments, 68 were omitted from publication on the CMS website due to excessive personal health information content, for a total of 9,957 comments posted to the CMS website. None of the comments included new evidence that met our inclusion/exclusion criteria. However, Biogen’s recent publication of its EMERGE and ENGAGE trial results was reviewed as well as the new American Academy of Neurology (AAN)guidelines. All comments were considered for this final decision and are summarized in the comments and responses below. The majority of comments, approximately 65 %, stated that there was not enough evidence to cover antiamyloid mAbs. These commenters either supported the proposed CED decision for antiamyloid mAbs, or stated that antiamyloid mAbs should not be covered by CMS. Of these comments, over 5,000 were form letters, where at least part of the comment contained nearly identical language regarding the evidence and the request for CMS to exclude Aduhelm from coverage. CMS also received around 700 comments expressing support for coverage of antiamyloid mAbs, with many stating that CMS has previously covered treatments for conditions such as HIV and cancer that had been approved by the FDA under accelerated approval. Many of these commenters also mentioned the lack of alternative treatment options and that coverage limited to only randomized controlled trials would be duplicative of studies required for the FDA and would further limit patient access. The remaining comments (approximately 2,700) did not express clear support for coverage, non-coverage, or coverage under CED. About 60% of these comments were from stakeholders requesting that patients with Down syndrome and other intellectual and developmental disabilities (IDD) have the same access other patients would have to antiamyloid mAbs, while several other commenters mentioned that Medicare should negotiate drug prices. Some comments were also specific to the PET for beta amyloid requirement in the proposed decision. While CMS received a record number of comments on the proposed NCD and decision memorandum, many of these comments included very similar details and requests. All of the comments received are reflected in the comment and responses to the themes below: Lack of Evidence for Clinical Benefit Comment: The majority of public comments stated that that there is not enough evidence showing that these drugs/biologicals provide a clinical benefit in order to cover antiamyloid mAbs. Response: CMS appreciates these comments and believe that CED as modified in this final decision is the right balance of providing appropriate patient access and patient protections as well as generating evidence needed for patients, clinicians and caregivers. Monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of Alzheimer’s disease based upon evidence of efficacy from a change in a surrogate endpoint (e.g., amyloid reduction) considered as reasonably likely to predict clinical benefit Comment: Several commenters stated that CMS should not restrict access to an FDA approved treatment for AD, especially since there are no alternative options available. Response: We appreciate these comments and recognize that Alzheimer’s disease is a significant burden affecting the Medicare population. However, currently no Alzheimer’s drug of any type has succeeded, to date, in modifying disease progression. No trial involving any intervention, alone or combined, has yet demonstrated a meaningful improvement in health outcomes for patients treated with antiamyloid mAbs for the treatment of AD. More trials are needed, and the results of these trials will assist in providing answers to CMS, as well as to clinicians, patients, and caregivers, regarding the clinical benefits and harms of this treatment. Based on public comments, we balanced providing patient access, patient protections and generating evidence to answer the questions that are key to helping patients, caregivers, and clinicians making decisions about the best treatments for each individual. Coverage with Evidence Development (CED) Randomized Controlled Trial requirement Comment: Several commenters stated that the requirement of a randomized controlled trial for a drug that has been approved by the FDA is unprecedented, with some questioning CMS’ authority for such a requirement. Response: CMS, historically, has completed few NCDs for drugs or biologics. The reason for this is not because of a single factor. Most drugs/biologics are based on at least two RCTs or based on an intermediate/surrogate outcome that has shown a clear connection to a clinical benefit (e.g., lowering blood pressure reduces chance of stroke, reducing tumor size and mortality). As stated in the analysis, for these particular class of drugs/biologics, there is currently no Alzheimer’s drug of any type that has succeeded, to date, in modifying disease progression. No trial involving any intervention, alone or combined, has yet demonstrated a meaningful improvement in health outcomes for patients treated with antiamyloid mAbs for the treatment of AD. More trials are needed, and the results of these trials will assist in providing answers to CMS, as well as to clinicians, patients, and caregivers, regarding the clinical benefits and harms of this treatment. In proposing and finalizing this NCD and decision memorandum, CMS followed a long-standing process established by Congress in making an NCD under section 1862(l) of the Act. We have looked to the medical and scientific evidence and found that this treatment could not be covered under the reasonable and necessary standard in section 1862(a)(1)(A). However, we believe it is appropriate to support further research in this area given that AD is a particularly important condition affecting the aged Medicare population. We worked closely with AHRQ about the appropriate standards for the clinical studies that would be necessary to answer the remaining scientific and medical questions. The results of these studies may result in sufficient evidence to expand Medicare coverage in the future. Coverage in the context of ongoing clinical research protocols or with additional data collection can expedite earlier beneficiary access to innovative technology while ensuring that systematic patient safeguards, including assurance that the technology is provided to clinically appropriate patients, are in place to reduce the risks inherent to new technologies, or to new applications of older technologies. While this is the first time CMS had proposed to cover a drug/biologic through Coverage with Evidence Development (CED) with a randomized controlled trial requirement, CMS has finalized other National Coverage Determinations (NCDs) for drugs/biologics with CED. For example, under the NCD for Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease (NCD 220.6.20), the CED requirement for positron emission tomography beta amyloid imaging (which uses radiopharmaceuticals) can be met by comparative and longitudinal clinical trials. Another example is that the NCD for Stem Cell Transplantation (NCD 110.23) requires prospective clinical studies. Randomized controlled trials are not required under those NCDs, but CMS has required randomized controlled trials in other NCDs, including for FDA-approved uses in some cases. For example, the NCD for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD) (NCD 160.18) provides coverage under CED in a CMS approved, double-blind, randomized, placebo-controlled trial. Comment: Many commenters suggested covering antiamyloid mAbs only in randomized controlled trials is duplicative of trials required by the FDA that are designed to answer the question of clinical benefit. CMS should not require the same RCTs as the FDA. Response: Informed by public comments, our current approach to CED for antiamyloid mAbs is similar to, but has evolved from, our January 2022 proposed NCD and decision memorandum. Many commenters agree with the FDA (and the CMS proposed decision) that there needs to be clear (nonconflicting) evidence of clinical benefit associated with use of an antiamyloid mAb for patients with early AD. We recognize that confirmatory trials required by the FDA for antiamyloid mAbs are designed to determine whether that drug/biologic provides a clinical benefit. Therefore, CMS has agreed to modify the final decision to specify that monoclonal antibodies directed against amyloid that are approved by FDA for the treatment of AD based upon evidence of efficacy from a change in a surrogate endpoint (e.g., amyloid reduction) may be covered in a randomized controlled trial conducted under an investigational new drug (IND) application. CMS does not require a separate RCT that duplicates an RCT conducted for FDA approval. We removed the "CMS-approved trial" language to further avoid any confusion with regard to CMS’ intent to support FDA required RCTs. At the time of this writing, Aduhelm would be eligible for Medicare coverage in any FDA approved trial. As part of coverage, routine items and services would also be coverable without any further action by CMS. Comment: Many commenters did not agree with the requirement that all trials must be conducted in a hospital-based outpatient center, stating that this would further restrict access for patients in underserved areas and discriminates against independent outpatient infusion centers. Response: The final decision reflects the public comments requesting CMS to expand the place of service beyond hospital-based outpatient centers. CMS is not restricting the place of service in the final NCD. In the proposed decision, we expressed that approved clinical trials should remain in hospital-based outpatient facilities to ensure integrated and coordinated care, availability of advanced imaging or other diagnostic tests, and rapidly-available advanced care if needed. These continue to be important factors for optimized patient health outcomes. Based on public comment, we do not restrict the place of setting in this final decision to ensure that antiamyloid mAbs that have received FDA approval based upon evidence of efficacy from a direct measure of clinical benefit may be given to a broader patient population which is important to answer the first CED question regarding Medicare patient outcomes in broader community settings. To ensure there continues to be integrated and coordinated advanced care, if needed, CMS is requiring that any clinical study protocol submitted for CMS-approval include a description of the multidisciplinary dementia team and optimal medical management of patients, and the study sites with clinical expertise and infrastructure to provide treatments consistent with the safety monitoring outlined in the FDA-approved label. This protocol requirement will ensure the highest level of appropriate clinical care, and to reassure patients and their caregivers that further research with antiamyloid mAbs will be conducted in a rigorous setting to minimize potential harms from the treatment. We believe all FDA-approved randomized controlled trials and NIH trial have the all appropriate safeguards for patients. Comment: Some commenters stated that the CED requirement would hurt future innovation for Alzheimer’s disease treatments. Response: CMS does not agree with these comments. We believe by defining the criteria by which a forthcoming therapy for Alzheimer’s disease could be covered would actually facilitate innovation. The CMS final decision gives the public a clear definition of where the goal line is for what constitutes success in a trial (and thus what meets the standard for "reasonable and necessary" required by law). Medical innovation must include clinical trials that demonstrate benefit to patients. Conversely, covering a drug that has not been shown to be effective may incentivize production, marketing and sales of similarly ineffective drugs, at the cost of hard research to find ones that do provide a clinical benefit to patients. Antiamyloid mAbs as a Class Comment: Many commenters stated that the proposed CED NCD should be specific to Aduhelm only. Response: This NCD takes a class approach, similar to other NCDs, in order to create a predictable pathway to national coverage that applies to every drug in this antiamyloid mAb class. As discussed in the Analysis of this decision memorandum, the antiamyloid drugs/biologicals have a similar function of reducing amyloid in the brain in the hopes it will slow down the progression of AD. There are other antiamyloid mAbs currently conducting Phase 3 trials (see clinicaltrials.gov). While the evidence based on published trials (Phase 2 and 3) has failed to establish a meaningful clinical benefit associated with the use of any monoclonal antibody directed against AD, the nature of the evidence regarding health outcomes is the same for all mAbs described in the literature. In particular, what is common to all monoclonal antibodies directed against AD (aducanumab, donanemab, lecanemab, and other