National Coverage Analysis (NCA) Proposed Decision Memo

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

CAG-00460N

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Decision Summary

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

1)   A CMS approved randomized controlled trial may be extended to a prospective longitudinal study when the randomized controlled trial is completed, and the findings of the randomized controlled trial demonstrate a clinically meaningful benefit in cognition and function. Details of the prospective longitudinal study must be included in the same protocol as the randomized controlled trial.

2)    All studies for CMS approval must fully describe in the protocol how the following will be carried out:

(a)Patient Criteria
Patients must have:
  • A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
  • Evidence of amyloid pathology consistent with AD.

    Patients must not have:
  • Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
  • Expected death from any cause during the duration of the study.
  • Medical conditions, other than AD, likely to increase significant adverse events.

    (b) Research Questions
    CMS approved trials must address, at a minimum, the research questions below:
  • Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in a statistically significant and clinically meaningful difference in decline in cognition and function?
  • What are the adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?

    (c)Study Requirements
    The diversity of patients included in each trial must be representative of the national population diagnosed with AD.

    Additionally, any CMS approved trial must adhere to the following standards of scientific integrity:

    1. 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.
    2. The rationale for the study is well supported by available scientific and medical evidence.
    3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
    4. Anticipated number of enrolled subjects is sufficient to question(s) being asked in the National Coverage Determination.
    5. The study is sponsored by an organization or individual capable of completing it successfully.
    6. 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.
    7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
    8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
    9. 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.
    10. 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 Quality (AHRQ) Registry of Patient Registries (RoPR).
    11. 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 accessibly 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).
    12. 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.
    13. 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.

    Consistent with section 1142 of the Act, AHRQ supports clinical trials supported by NIH and other trials that CMS determines meet the above-listed standards and address the above-listed research questions.

    The principal investigator must submit the complete trial protocol, identify the relevant CMS research questions that will be addressed and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the trial 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]"

  • 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.

    Proposed 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: 	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

    1)   A CMS approved randomized controlled trial may be extended to a prospective longitudinal study when the randomized controlled trial is completed, and the findings of the randomized controlled trial demonstrate a clinically meaningful benefit in cognition and function. Details of the prospective longitudinal study must be included in the same protocol as the randomized controlled trial.

    2)    All studies for CMS approval must fully describe in the protocol how the following will be carried out:

    (a)Patient Criteria
    Patients must have:
  • A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
  • Evidence of amyloid pathology consistent with AD.

    Patients must not have:
  • Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
  • Expected death from any cause during the duration of the study.
  • Medical conditions, other than AD, likely to increase significant adverse events.

    (b) Research Questions
    CMS approved trials must address, at a minimum, the research questions below:
  • Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in a statistically significant and clinically meaningful difference in decline in cognition and function?
  • What are the adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?

    (c)Study Requirements
    The diversity of patients included in each trial must be representative of the national population diagnosed with AD.

    Additionally, any CMS approved trial must adhere to the following standards of scientific integrity:

    1. 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.
    2. The rationale for the study is well supported by available scientific and medical evidence.
    3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
    4. Anticipated number of enrolled subjects is sufficient to question(s) being asked in the National Coverage Determination.
    5. The study is sponsored by an organization or individual capable of completing it successfully.
    6. 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.
    7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
    8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
    9. 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.
    10. 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 Quality (AHRQ) Registry of Patient Registries (RoPR).
    11. 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 accessibly 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).
    12. 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.
    13. 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.

    Consistent with section 1142 of the Act, AHRQ supports clinical trials supported by NIH and other trials that CMS determines meet the above-listed standards and address the above-listed research questions.

    The principal investigator must submit the complete trial protocol, identify the relevant CMS research questions that will be addressed and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the trial 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]"

  • 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 

    Date Actions Taken

    July 12, 2021

    CMS opens an NCA for Initial 30-day public comment period begins.

    August 11, 2021

    First public comment period ends. CMS receives 131 comments

    January 11, 2022

    Proposed Decision Memorandum posted. 30-day public comment period begins.

    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 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 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 availablea

    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:

  • A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
  • Evidence of amyloid pathology consistent with AD.

    We propose the above criteria because these reflect the general trend in antiamyloid mAb trials of enrolling patients at earlier stages of disease who also meet biomarker criteria. These were the patient inclusion criteria used in the latest antiamyloid mAb Phase 3 trials (EMERGE and ENGAGE).  The original, failed trials, such as for bapineuzumab and solanezumab in 2014, targeted primarily patients with dementia.  Recent trials have shifted their targets earlier in the disease process, primarily to patients with MCI.  This is because antiamyloid experts believe that interventions in later stages of disease (moderate to severe dementia especially) are too late: at that point amyloid has already triggered downstream processes such as pathologic tau accumulation, inflammation, and neurodegeneration.  Once triggered, these downstream processes likely cannot be reversed by clearing amyloid.

    The shift to earlier stages of disease directly impacts the consideration of benefits and harms.  While we are proposing that only patients with a clinical diagnosis of MCI due to AD or mild AD dementia should be included in approved trials, these same patients with early disease are generally high functioning, and thus the long-term sequelae of adverse events such as ARIA need to be determined and fully documented in the trials.  In assessing the presence of MCI or early onset of AD, validated tests to measure cognition and function must be used. Examples of such validated tests include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Exam (MMSE), and the Clinical Dementia Rating (CDR) scale, all of which are well-supported and widely used.

    Recent trials requiring biomarker evidence of amyloid pathology for patient enrollment generally have used PET Aꞵ brain scans.  The importance of this requirement is exemplified by early, failed solanezumab trials.  An analysis of secondary outcomes reported that roughly 25% of trial participants may never have had AD (Siemers 2016).  A treatment aimed at improving cognition and function for AD patients, precisely because it modifies underlying AD pathophysiology, is not likely to succeed if it is not AD that is causing the patients’ symptoms in the first place.  In addition to PET Aꞵ brain scans, other evidence-based methods to detect AD pathology will be considered if supported by the peer-reviewed, published medical literature.

    The CMS required inclusion criteria specified above reflect the minimum trial inclusion criteria. We anticipate that patient inclusion criteria in protocols submitted to CMS for CED consideration may be more extensive than the criteria we proposed above, based on our review of recent trials (e.g., the latest antiamyloid mAb trial report, Mintun 2021, had 7 inclusion criteria).

    Additionally, given the disappointing lack of inclusion of underserved populations in past trials (see health disparities section), we require enrollment of a representative patient population.

    Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (NCD 220.6.20)

    The CED criteria for the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (NCD 220.6.20) are met if the PET Aꞵ scan is included in a CMS-approved study under the proposed CED for antiamyloid mAbs.  One of the questions specified in the beta amyloid PET NCD for studies to address under CED is, “Does using PET Aß imaging in guiding patient management, to enrich clinical trials seeking better treatments or prevention strategies for AD, by selecting patients on the basis of biological as well as clinical and epidemiological factors, lead to improved health outcomes?” This question would be inherently addressed by any study approved under CED for this proposed decision because all approved CED studies for this current NCD on antiamyloid mAbs must aim to determine whether the treatment improves health outcomes for a specified AD population.  We note that the beta amyloid PET CED provides for a single lifetime use of a PET Aꞵ scan per Medicare beneficiary. This NCD does not change the frequency of the single lifetime PET Aꞵ scan per Medicare beneficiary. Thus, if a patient received a PET Aꞵ scan under the beta amyloid PET NCD, they are not eligible for an additional scan for any trial approved under this NCD.  However, the results of that scan may be used to determine whether the patient is eligible for a trial.

    Exclusion Criteria
    Trials must exclude patients with:

  • Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
  • Expected death from any cause during the duration of the study.
  • Medical conditions, other than AD, likely to increase significant adverse events.

    These patient exclusion criteria follow an approach similar to our inclusion criteria above.

    The first two bulleted requirements above are included because they reflect major exclusions commonly seen in AD trials generally.  They are notably similar to two of the exclusion criteria (of the original protocol’s exclusion list) from the Mintun 2021 NEJM trial publication, which is the most contemporary publication of an antiamyloid mAb (at the time of this writing), and incorporates lessons learned from past failed trials.

    The third bulleted requirement is to ensure patients are protected.  Enrolling patients with medical conditions that may lead to significant adverse events also may complicate or undermine the investigators’ ability to perform the trial and analyze a sufficient amount of completed trial data, which could compromise reliability of the results of the trial as a whole.

    Similar to the inclusion criteria previously described, the above patient exclusion criteria reflect the minimum trial exclusion criteria.  While we only specify a few key patient criteria, we believe that previously completed antiamyloid mAb RCT inclusion and exclusion criteria may be important to consider because it may help select appropriate patients for enrollment and treatment who would most likely respond and achieve meaningful clinical benefits with minimal harms.  Patient selection has been reported to be one of the most important factors in recent promising findings compared to the past many years of failed research.  Building upon the emerging evidence, a reconsideration of this NCD would likely be dependent on the results of these trials, including which patients achieved improved health outcomes and which patients did not.

    Health Disparities

    Significant differences in the prevalence of AD across racial and ethnic groups have previously been reported.  Research has shown that AD is more prevalent in Blacks and Hispanics when compared to Whites, with Blacks being up to two times more likely to have AD and other dementias when compared to Whites, and Hispanics being about one and a half times more likely than Whites to have AD and other dementias (AA 2020, Mayeda 2016).  Despite the higher prevalence of AD and other dementias in Blacks and Hispanics, they are less likely to have a diagnosis when compared to Whites.  In a recent survey by the Alzheimer’s Association (2021), it was found that Black, Hispanic, and Native Americans were twice as likely than Whites to say they would not see a doctor if experiencing thinking or memory problems.  This can partially be explained by differing racial and ethnic beliefs about AD.  Significantly more Black and non-White Americans believe that symptoms of AD, such as significant memory loss, are part of the normal aging process when compared to White Americans (AA 2021, Connell 2009). This may also be partially due to higher rates of discrimination when seeking dementia-related health care. Recent surveys reveal that Blacks reported the highest level of discrimination in dementia health care (50%), followed by Native Americans (42%), Asians (34%), and Hispanics (33%), compared to Non-Hispanic Whites (9%) (AA 2021). 

    Additionally, under-representation of members of racial and ethnic groups in research relating to AD further exacerbates disparities in our understanding, and ability to provide appropriate health care for all individuals CMS serves related to these conditions. Some barriers to the recruitment of under-represented patients can include language, logistical barriers (e.g., time, travel), and a long-standing mistrust of the medical establishment (Watson 2014).  In the same survey previously mentioned by the Alzheimer’s Association (2021), 62% of Black Americans believed that medical research is biased against people of color, and Black Americans expressed less interest in participating in clinical trials for AD than any other group surveyed (White and non-White).  Additionally, only 53% of Black Americans surveyed believed that a future cure for AD would be equally shared regardless of race and ethnicity.

    While these barriers can present a challenge when recruiting under-represented patients for AD research, they may also present challenges related to appropriate diagnosis, management, and care for populations and communities served by CMS. In order to address these barriers in coverage and care, it is critical that these patients are engaged, recruited, and retained in future trials. Due to the lack of diversity in previous trials, the higher prevalence of AD in Black and non-White Americans, and the directives in Executive Order 13985, Advancing Racial Equity and Support for Underserved Communities Through the Federal Government, CMS is proposing as a trial requirement that the diversity of patients included in each trial must be representative of the national population diagnosed with AD.

    Research Questions

    Questions that must be answered under CED:

    • Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in both a statistically significant and clinically meaningful difference in decline in cognition and function?
    • What is the frequency and clinical impact of adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?

    These questions for CED derive from our conclusion, discussed above, that despite numerous trials involving multiple antiamyloid mAbs, no trial has been able to demonstrate a clinically meaningful improvement in patient health outcomes. At the same time, these same trials that have resulted in uncertain clinical benefit have demonstrated at least some significant harms, principally ARIA (brain swelling and/or bleeding), as a result of antiamyloid mAbs.  More research is needed not just on potential benefits, but also on these harms, to include how to better predict and avoid ARIA, and better manage it when it occurs.

    Answers to these CED questions through timely completion of rigorous trials is essential for patients and clinicians to be able to adequately weigh the benefits and harms of using an antiamyloid mAb.  There is also benefit in assessing whether the results of successful trials can be replicated in broader community practice, outside the rigor of clinical trials performed in relatively few academic medical centers.

    To ensure that the CED results are based on reliable evidence, and recognizing that there may be different types of clinical trial designs that can answer these questions, we remain flexible in allowing investigators to propose the primary outcome in their CED trial protocol.  The “primary outcome” for a trial is the result that, if achieved (according to some pre-specified difference between the intervention group and the control group) determines that the trial is successful, and the intervention actually works – at least for those patients included in the trial.

    Validated Cognitive and Functional Instruments in CED Trials

    Measurement instruments to be used in the CED trials must have been independently validated and used in prior trials. The rationale for the choice of validated cognitive and functional instruments must be documented in the trial protocol. As part of our evidence review, a CMS contractor (ICA) conducted an environmental scan and identified validated cognitive and functional instruments. They reported: “Among the identified 16 trials included in the environmental scan (ES), 78 total instruments (26 unique) were used. The most often cited were the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog, includes 11-13 item version; n=16, 20.6%), the Mini-Mental State Examination (MMSE; 12, 15.4%), and the Clinical Dementia Rating-Sum of Boxes (CDR-SB; n=9, 11.5%).” As shown in our evidence table 1, the EMERGE and ENGAGE trials used CDR-SB while other drug trials have used ADAS-Cog.

    Clinically Meaningful Improvement

    We require that any proposed threshold for what constitutes a “clinically meaningful” improvement for a given trial’s primary outcome (which may be over and above statistical significance) be supported by the peer-reviewed, published medical literature.

    We will use the CDR-SB to exemplify what constitutes a clinically meaningful improvement in a primary outcome.  As discussed before, the CDR-SB is a widely-used outcome measure combining cognition and function globally, and was the primary outcome for the EMERGE and ENGAGE trials of aducanumab.  An often-cited publication, Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials, concludes: “On average, a 1-3 point decrease in Mini Mental State Examination, 1-2 point increase in Clinical Dementia Scale sum of boxes, and 3-5 point increase in Functional Activities Questionnaire were indicative of a meaningful decline” (Andrews 2019).  The paper provides further detail on how thresholds depend on disease severity (e.g., MCI v. mild AD), such that a meaningful threshold for one AD subpopulation is not the same as for another AD subpopulation.

    Prospective Longitudinal Study

    We recognize that waiting for published results of an RCT may limit access. However, it is appropriate access that matters and we have real concern about potential harms to Medicare patients, especially since patients in these trials have early or mild disease (MCI or mild AD) and are relatively high functioning. It is important to first demonstrate that the benefits outweigh the harms within the patient protections and controlled settings of RCTs. CMS believes that appropriate access to antiamyloid mAbs should be maintained if findings in the respective trials are positive.  CMS proposes that RCTs for antiamyloid mAbs for the treatment of AD that have been approved by CMS may extend their trial to a prospective longitudinal study when the RCT is completed, and the findings of the RCT demonstrate a clinically meaningful benefit in cognition and function. This proposal strikes an appropriate balance of providing patient access while also ensuring both protections for patients from harms and the appropriate data collection and analysis to address CMS’ questions to determine whether CMS should undertake an NCD reconsideration.  The details of the prospective longitudinal study must be included in the same protocol as the initially submitted RCT.

    Summary

    We are proposing CED for antiamyloid mAbs because we strongly support rigorous clinical trials that will answer whether this treatment will benefit Medicare beneficiaries with AD.  None of the trials completed as of the publication of this NCA has convincingly demonstrated that use of antiamyloid mAbs result in a meaningful improvement in health outcomes for AD patients.  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.

    IX. Conclusion

    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

    1)   A CMS approved randomized controlled trial may be extended to a prospective longitudinal study when the randomized controlled trial is completed, and the findings of the randomized controlled trial demonstrate a clinically meaningful benefit in cognition and function. Details of the prospective longitudinal study must be included in the same protocol as the randomized controlled trial.

    2)    All studies for CMS approval must fully-describe in the protocol how the following will be carried out:

    (a)Patient Criteria
    Patients must have:
    • A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
    • Evidence of amyloid pathology consistent with AD.
    Patients must not have:
    • Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
    • Expected death from any cause during the duration of the study.
    • Medical conditions, other than AD, likely to increase significant adverse events.

    (b) Research Questions
    CMS approved trials must address, at a minimum, the research questions below:
    • Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in a statistically significant and clinically meaningful difference in decline in cognition and function?
    • What are the adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?
    (c)Study Requirements
    The diversity of patients included in each trial must be representative of the national population diagnosed with AD.

    Additionally, any CMS approved trial must adhere to the following standards of scientific integrity:

    1. 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.
    2. The rationale for the study is well supported by available scientific and medical evidence.
    3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
    4. Anticipated number of enrolled subjects is sufficient to question(s) being asked in the National Coverage Determination.
    5. The study is sponsored by an organization or individual capable of completing it successfully.
    6. 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.
    7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
    8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
    9. 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.
    10. 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 Quality (AHRQ) Registry of Patient Registries (RoPR).
    11. 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 accessibly 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).
    12. 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.
    13. 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.

    Consistent with section 1142 of the Act, AHRQ supports clinical trials supported by NIH and other trials that CMS determines meet the above-listed standards and address the above-listed research questions.

    The principal investigator must submit the complete trial protocol, identify the relevant CMS research questions that will be addressed and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the trial 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]"

    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.



    APPENDIX A
    General Methodological Principles of Study Design

    (Section VI of the Decision Memorandum)

    When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is 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 patients.

    We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

    The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.

    Assessing Individual Studies

    Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:

    • Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
    • Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
    • Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
    • Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an unlikely explanation for what was found.
    • Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

    Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:

    • Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
    • Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
    • Differential assessment of outcome (detection bias).
    • Occurrence and reporting of patients who do not complete the study (attrition bias).

    In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

    Randomized controlled trials
    Non-randomized controlled trials
    Prospective cohort studies
    Retrospective case control studies
    Cross-sectional studies
    Surveillance studies (e.g., using registries or surveys)
    Consecutive case series
    Single case reports

    When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

    Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

    Generalizability of Clinical Evidence to the Medicare Population

    The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.

    The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

    The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

    Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

    A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

    If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

    Assessing the Relative Magnitude of Risks and Benefits

    Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.



    APPENDIX B
    Medicare National Coverage Determinations Manual

    Draft
    We are seeking public comments on the proposed language that we would include in the Medicare National Coverage Determinations Manual. This proposed language does not reflect public comments that will be received on the proposed decision memorandum, and which may be revised in response to those comments.

    Table of Contents
    (Rev.)

    [XXX.X]

    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

    1)   A CMS approved randomized controlled trial may be extended to a prospective longitudinal study when the randomized controlled trial is completed, and the findings of the randomized controlled trial demonstrate a clinically meaningful benefit in cognition and function. Details of the prospective longitudinal study must be included in the same protocol as the randomized controlled trial.

    2)    All studies for CMS approval must fully-describe in the protocol how the following will be carried out:

    (a)Patient Criteria
    Patients must have:
    • A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
    • Evidence of amyloid pathology consistent with AD.
    Patients must not have:
    • Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
    • Expected death from any cause during the duration of the study.
    • Medical conditions, other than AD, likely to increase significant adverse events.
    (b) Research Questions
    CMS approved trials must address, at a minimum, the research questions below:
    • Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in a statistically significant and clinically meaningful difference in decline in cognition and function?
    • What are the adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?
    (c)Study Requirements
    The diversity of patients included in each trial must be representative of the national population diagnosed with AD.

    Additionally, any CMS approved trial must adhere to the following standards of scientific integrity:

    1. 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.
    2. The rationale for the study is well supported by available scientific and medical evidence.
    3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
    4. Anticipated number of enrolled subjects is sufficient to question(s) being asked in the National Coverage Determination.
    5. The study is sponsored by an organization or individual capable of completing it successfully.
    6. 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.
    7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
    8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
    9. 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.
    10. 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 Quality (AHRQ) Registry of Patient Registries (RoPR).
    11. 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 accessibly 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).
    12. 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.
    13. 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.

    Consistent with section 1142 of the Act, AHRQ supports clinical trials supported by NIH and other trials that CMS determines meet the above-listed standards and address the above-listed research questions.

    The principal investigator must submit the complete trial protocol, identify the relevant CMS research questions that will be addressed and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the trial 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]"

    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.

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