Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

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A. The Centers for Medicare & Medicaid Services (CMS) has determined that the evidence is insufficient to conclude that the use of positron emission tomography (PET) amyloid-beta (Aβ) imaging is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member for Medicare beneficiaries with dementia or neurodegenerative disease, and thus PET Aβ imaging is not covered under §1862(a)(1)(A) of the Social Security Act (“the Act”). B. However, there is sufficient evidence that the use of PET Aβ imaging is promising in two scenarios: (1) to exclude Alzheimer’s disease (AD) in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD); and (2) to enrich clinical trials seeking better treatments or prevention strategies for AD, by allowing for selection of patients on the basis of biological as well as clinical and epidemiological factors. Therefore, we will cover one PET Aβ scan per patient through coverage with evidence development (CED), under §1862(a)(1)(E) of the Act, in clinical studies that meet the criteria in each of the paragraphs below. Clinical study objectives must be to (1) develop better treatments or prevention strategies for AD, or, as a strategy to identify subpopulations at risk for developing AD, or (2) resolve clinically difficult differential diagnoses (e.g., frontotemporal dementia (FTD) versus AD) where the use of PET Aβ imaging appears to improve health outcomes. These may include short term outcomes related to changes in management as well as longer term dementia outcomes. Clinical studies must be approved by CMS, involve subjects from appropriate populations, and be comparative and longitudinal. Where appropriate, studies should be prospective, randomized, and use postmortem diagnosis as the endpoint. Radiopharmaceuticals used in the PET Aβ scans must be FDA approved. Approved studies must address one or more aspects of the following questions. For Medicare beneficiaries with cognitive impairment suspicious for AD, or who may be at risk for developing AD: Do the results of PET Aβ imaging lead to improved health outcomes? Meaningful health outcomes of interest include: avoidance of futile treatment or tests; improving, or slowing the decline of, quality of life; and survival. Are there specific subpopulations, patient characteristics or differential diagnoses that are predictive of improved health outcomes in patients whose management is guided by the PET Aβ imaging? Does using PET Aβ 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? Any clinical study undertaken pursuant to this national coverage determination (NCD) must adhere to the timeframe designated in the approved clinical study protocol. Any approved clinical study must also adhere to the following standards of scientific integrity and relevance to the Medicare population. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org ). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The clinical research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or the study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment 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 on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with §1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. All other uses are noncovered.

Decision Memo: To: Administrative File: CAG-00431N Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease From: Louis Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group James Rollins, MD, PhD Division Director Brijet Burton Coachman, MPP, MS, PA-C Lead Analyst Stuart Caplan, RN, MAS Analyst Rosemarie Hakim, PhD Epidemiologist Jeffrey Roche, MD, MPH Medical Officer Joseph Hutter, MD, MA Lead Medical Officer Subject: Final Decision Memorandum for: CAG-00431N Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease Date: September 27, 2013 I. Final Decision A. The Centers for Medicare & Medicaid Services (CMS) has determined that the evidence is insufficient to conclude that the use of positron emission tomography (PET) amyloid-beta (Aβ) imaging is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member for Medicare beneficiaries with dementia or neurodegenerative disease, and thus PET Aβ imaging is not covered under §1862(a)(1)(A) of the Social Security Act (“the Act”). B. However, there is sufficient evidence that the use of PET Aβ imaging is promising in two scenarios: (1) to exclude Alzheimer’s disease (AD) in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD); and (2) to enrich clinical trials seeking better treatments or prevention strategies for AD, by allowing for selection of patients on the basis of biological as well as clinical and epidemiological factors. Therefore, we will cover one PET Aβ scan per patient through coverage with evidence development (CED), under §1862(a)(1)(E) of the Act, in clinical studies that meet the criteria in each of the paragraphs below. Clinical study objectives must be to (1) develop better treatments or prevention strategies for AD, or, as a strategy to identify subpopulations at risk for developing AD, or (2) resolve clinically difficult differential diagnoses (e.g., frontotemporal dementia (FTD) versus AD) where the use of PET Aβ imaging appears to improve health outcomes. These may include short term outcomes related to changes in management as well as longer term dementia outcomes. Clinical studies must be approved by CMS, involve subjects from appropriate populations, and be comparative and longitudinal. Where appropriate, studies should be prospective, randomized, and use postmortem diagnosis as the endpoint. Radiopharmaceuticals used in the PET Aβ scans must be FDA approved. Approved studies must address one or more aspects of the following questions. For Medicare beneficiaries with cognitive impairment suspicious for AD, or who may be at risk for developing AD: Do the results of PET Aβ imaging lead to improved health outcomes? Meaningful health outcomes of interest include: avoidance of futile treatment or tests; improving, or slowing the decline of, quality of life; and survival. Are there specific subpopulations, patient characteristics or differential diagnoses that are predictive of improved health outcomes in patients whose management is guided by the PET Aβ imaging? Does using PET Aβ 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? Any clinical study undertaken pursuant to this national coverage determination (NCD) must adhere to the timeframe designated in the approved clinical study protocol. Any approved clinical study must also adhere to the following standards of scientific integrity and relevance to the Medicare population. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org ). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The clinical research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or the study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment 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 on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with §1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. All other uses are noncovered. II. Background Definitions The following radiopharmaceuticals are referenced in this decision memorandum (DM): Florbetapir is florbetapir F18 (or AV-45) Florbetaben is florbetaben F18 (or AV-1, or BAY-94-9172) Flutemetamol is flutemetamol F18 (or GE-067) FDDNP is FDDNP F18 AZD4694 is AZD4694 F18 (or NAV4694) PIB is Pittsburgh Compound B C11 FDG is fluoro-D-glucose F18 The terms “PET Aβ imaging,” “amyloid-beta PET,” “PET Aβ,” “amyloid imaging,” “amyloid PET,” “Aβ imaging,” “amyloid-beta imaging” and “beta-amyloid imaging” are used synonymously in the literature and in this DM. Dementia Dementia is a syndrome involving cognitive and behavioral impairment in an otherwise alert patient, due to a number of neurological diseases, alone or combined. It is not a specific cause or disease process itself. The impairment must involve a minimum of two domains (memory, reasoning, visuospatial abilities, language or personality behaviors); impact daily functioning; represent a decline from previous levels of functioning; not be explainable by delirium (a temporary state of mental confusion and fluctuating consciousness from various causes) or a major psychiatric disorder; and be objectively documented by a “bedside” mental status exam (e.g., the mini-mental status exam) or neuropsychological testing (McKhann 2011). Mild cognitive impairment (MCI) Increasingly, research has focused on early stages of cognitive impairment, which lie between the cognitive changes of normal aging and dementia. Mild cognitive impairment (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 without impairment of day-to-day functioning. The clinical work up for MCI is similar to that for AD and other causes of dementia (discussed below). Individuals 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. MCI has multiple subtypes, discussed in more detail later in this DM. These subtypes, and associated results from “bedside” mental status exams and neuropsychiatric testing, could, when combined with (1) other patient characteristics (e.g., age, genetics, cognitive reserve, comorbidities), and (2) biomarkers (for hypometabolism, plaque accumulation, synaptic dysfunction and neuronal loss), serve as the foundation for the development of objectively defined “risk pools,” or subpopulations of individuals who are at risk of progressing from MCI or even pre-symptomatic states to AD (Petersen 1999 and 2009, Wolk 2009, Hughes 2011, Ward 2012, Landau 2012, Sachdev 2012). Alzheimer’s disease (AD) Epidemiology, clinical criteria, causes and treatment AD is an irreversible dementia characterized by progressive, relentless cognitive and functional decline. It is the number one cause of dementia in older Americans (age 65 and over), contributing to 60-80% of cases. Over 5 million older Americans ( > 12.5%) have AD. This prevalence is expected to rise to 8.7 million by 2030, and could reach 13.8 million by 2050. AD is the 5th leading cause of death in older Americans (and the 7th leading cause of death overall). Older African-Americans are two times as likely to have AD (and other dementias) as older whites. Older Hispanics are 1.5 times as likely to have AD as older whites. Women are more likely to have AD than men, although this is in part because women live longer (NIA 2013, Brookmeyer 2011, CDC 2013, AA 2013). Clinical criteria for diagnosing AD are informed by the NIA-AA 2011guidelines (McKhann 2011). Core clinical criteria for “probable AD” dementia must first meet the criteria for “all-cause” dementia described above. Additionally, there must be: (a) insidious onset; (b) documented worsening of cognition; (c) exclusion of major concomitant cerebrovascular disease (as most individuals with AD have some level of this as well); and (d) exclusion of alternative diagnoses (such as dementia with Lewy bodies (DLB), behavioral variant frontotemporal dementia (FTD), progressive aphasia or other neurological disease associated with dementia). A clinical diagnosis of “possible AD” dementia would meet the criteria for “probable AD” above, with the exception of having an “atypical course” (e.g., sudden rather than insidious onset) or an “etiologically mixed presentation.” 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 functions, 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. Most individuals with AD become symptomatic after age 60. Generally an indolent process, it is typically fatal within 8-10 years of onset but can be fatal anywhere between 2 and 20 years. Among 70-year-olds, 61% of those with AD die within a decade (compared to only 30% of those without AD) (NIA 2013, Dilworth 2008, AA 2013). The underlying cause of AD remains unknown. The number one risk factor is age itself. Investigators hypothesize that a wide range of factors may contribute to its development, including genetic, metabolic, inflammatory, mitochondrial, environmental, and neuronal, to include both cytoskeletal (within the neuronal cell itself) and synaptic (the connectivity among cells) (ECRI 2012, Pimplikar 2010, Herrup 2010, Sperling 2011). Currently, there is no effective treatment for AD. Existing interventions do not prevent, modify or cure the disease process. 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). Care is therefore primarily supportive and increases as functional impairment progresses, eventually leading to round-the-clock supervision which can be needed for years. Diagnostic work-up, integration of biomarkers, and their shortcomings The clinical work-up for patients presenting with symptoms of dementia or cognitive impairment, including MCI with possible AD, is extensive. It includes a medical history taken from the patient and from an informant who is well acquainted with the affected person, a physical examination comprising a mental status evaluation aided by quantitative scales and/or neuropsychological assessment, and laboratory testing and often structural neuroimaging such as MRI or CT to rule out other diseases. Clinical assessment is performed primarily using two sources: the National Institute on Aging and the Alzheimer’s Association (NIA-AA) 2011 criteria, which updates the NINCDS-ADRA 1984 criteria to “incorporate more modern innovations in clinical imaging and laboratory assessment” (McKhann 2011); and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for dementia of the Alzheimer’s type. The innovations in “imaging and laboratory assessment” above refer to biomarkers. There are two types: those detecting amyloid-beta (Aβ) protein deposition; and those detecting downstream neuronal degeneration or injury (Jack 2011). Examples of the former type include: direct imaging of amyloid plaques in living brain with florbetapir, PIB and other agents; and decreased Aβ42 in cerebral spinal fluid (CSF), resulting from accumulation of this molecule in the brain. Examples of the latter type include: atrophy of hippocampus and entorhinal cortex on MRI, reflecting neuronal loss; increased total tau protein in CSF, which correlates with neuronal damage; and increased phosphorylated-tau (p-tau) in CSF, which correlates with formation of neurofibrillary tangles (NFTs) (Jack 2008, Sperling 2011, Hampel 2008, Mattsson 2009). This distinction between amyloid deposition and neuronal degeneration becomes important in current theories of the role of amyloid in the development of AD (discussed below). Increasing use of biomarkers in clinical research has given rise to two new proposed classifications for AD in the NIA-AA 2011 criteria: “probable” or “possible” AD dementia “with evidence of AD pathophysiology.” These proposed classifications are explicit hypotheses to be assessed through further research. Currently, there are no established biological or neuroimaging markers for the diagnosis of AD or related disorders. Accordingly, the NIA-AA workgroup on dementia concludes that “the core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia” (McKhann 2011). Unfortunately, despite being the “cornerstone” of diagnosis, clinical assessment of AD remains poor. For example, a review of 919 subjects with both clinical and neuropathologic (autopsy) data collected from the NIA-sponsored National Alzheimer’s Coordinating Center Uniform Data Set between 2005-2010 demonstrated sensitivity of clinical diagnosis ranging from 70.9% to 87.3%, and specificity ranging from 44.3% to 70.8% (depending on the restrictiveness of the clinical criteria); this study also found that 39% of subjects with dementia not clinically diagnosed with AD actually had “minimum levels of AD histopathology” (Beach 2012). Other studies found the clinical diagnosis of AD by expert neurologists to be 81% sensitive and 70% specific compared to neuropathology (Knopman 2001, Grundman 2012). Clinical diagnosis is poor because several other neurological diseases can mimic the dementia seen in AD, including cerebrovascular dementia, dementia with Lewy bodies (DLB), behavioral variant frontotemporal dementia (FTD), Parkinson’s disease, Creutzfeld-Jakob disease, and normal pressure hydrocephalus (NPH). Accordingly, NIA-AA 2011 guidelines require exclusion of these diseases as one of the criteria for clinical diagnosis of “probable AD.” Also, one or more of these diseases, most commonly vascular disease, co-exist in the majority of individuals with AD, as seen at autopsy (Schneider 2007). So there are relatively few patients with “pure” AD. Finally, it is not possible to measure the partial contributions of various coexisting diseases, identified either during life with imaging or biomarkers, or at autopsy, to a patient’s symptoms of dementia. Pathophysiology and the diagnostic gold standard for AD The pathophysiological hallmarks of AD are Aβ plaques, neurofibrillary tangles (NFTs) of the protein tau, and neuronal dysfunction and loss. However, 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. Amyloid plaques can also be detected in cognitively normal older adults. Autopsy studies demonstrate that approximately 33% 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). Finally, amyloid is associated with physiologic processes of disease prevention or response, such as protection against oxidative stress, regulation of cholesterol transport, and anti-microbial activity (Guglielmotto 2010, Zou 2002, Yao 2002, Soscia 2010). Because clinical diagnosis is poor, and amyloid pathology is seen in other diseases as well as in cognitively normal older persons, the “gold standard” for diagnosis requires both (a) the presence of moderate to frequent Aβ plaques and neurofibrillary tangles on autopsy, and (b) clinical documentation of progressive dementia during life (NIA-Reagan Institute 1997, Hyman 1997). Competing views on the role of amyloid Acknowledging that there are competing views on the role of amyloid in the pathophysiology of AD is key to interpreting the significance of trials on AD prognosis, diagnosis and clinical utility. It is widely accepted that the presence of amyloid plaques in human brain is virtually necessary for the diagnosis of AD. It is built into the postmortem diagnostic gold standard, and reflected in the FDA-approved label for florbetapir (Sperling 2011, NIA-Reagan 1997, FDA 2012). However, whether a threshold level of amyloid plaques in a patient is sufficient for diagnosing AD is a subject of much debate. One hypothesis is that patients with symptoms of cognitive impairment and evidence of brain amyloid have AD, and it is just a matter of time before this manifests clinically as AD dementia. A competing hypothesis is that “Aβ accumulation is necessary but not sufficient to produce the clinical manifestations of AD. It is likely that the cognitive decline would occur only in the setting of Aβ accumulation plus synaptic dysfunction and/or neurodegeneration” (Sperling 2011). In this light, the NIA-AA criteria authors conclude that “at this point, it remains unclear whether it is meaningful or feasible to make the distinction between Aβ as a risk factor for developing the clinical syndrome of AD versus Aβ accumulation as an early detectable stage of AD because current evidence suggests that both concepts are plausible” (Sperling 2011). PET Aβ imaging PET is a minimally invasive diagnostic imaging procedure used to evaluate normal tissue as well as diseased tissues in conditions such as cancer, ischemic heart disease and some neurologic disorders. A ligand that binds to a given targeted substrate (e.g., Aβ plaque aggregates) is labeled with a radioisotope (e.g., fluorine F18). The injected radiopharmaceutical (or “tracer”) emits positrons when it decays. PET uses a positron camera (tomograph) to measure the decay of such tracers within human tissue. The relative differences in the rate of tracer decay among anatomic sites provide biochemical information on the tissue being studied. PET Aβ imaging detects amyloid plaque density in vivo in human brain. While several Aβ imaging agents exist, including Pittsburg compound B (PIB C11), and several F18 labeled agents (florbetapir; florbetaben; flutemetamol; AZD469; and FDDNP, which images both amyloid and tau), the longer half-lives of the F18-labelled agents render them more practical in clinical settings. As the only FDA-approved agent for PET Aβ imaging to date is florbetapir, it is the primary focus of our review. III. History of Medicare Coverage CMS did not previously cover PET Aβ imaging. FDG PET is nationally covered for either the differential diagnosis of FTD versus AD under specific requirements; or, its use in a CMS-approved practical clinical trial focused on the utility of FDG PET in the diagnosis or treatment of dementing neurodegenerative diseases. FDG PET for dementia and neurodegenerative diseases and other specific covered uses of particular PET radioactive tracers (N13 ammonia, Rb82 and F18 sodium fluoride (NaF-18) are found in detail in Section 220.6 of the National Coverage Determination Manual available at http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/ncd103c1_Part4.pdf . A. Current Request In July 2012 Lilly USA, LLC, manufacturer of the PET amyloid radiopharmaceutical florbetapir (Amyvid™), requested that CMS reconsider its non-coverage decision for PET scans and provide coverage for the use of PET amyloid imaging as a diagnostic test to “estimate amyloid neuritic plaque density in adult patients with documented cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive impairment” (Requestor Letter, at http://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx?NCAId=265&fromdb=true ). B. Benefit Category Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage (§1812 (Scope of Part A); §1832 (Scope of Part B) and §1861(s) (Definition of Medical and Other Health Services) of the Act. PET is considered to be within the following benefit category: other diagnostic tests §1861(s)(3) of the Act). IV. Timeline of Recent Activities Date Action October 9, 2012 CMS accepts the formal request for the coverage of PET Aβ imaging in the diagnosis of AD and other causes of cognitive decline. A 30-day public comment period begins. November 8, 2012 The 30-day public comment period ends. CMS received 27 timely comments. July 3, 2013 CMS posts the proposed decision memorandum for 30 days of public comment. August 2, 2013 The public comment period on the proposed decision memorandum closes with 202 comments received. V. FDA Status The FDA has reviewed and approved one radiopharmaceutical for PET Aβ imaging, florbetapir (Amyvid™), in April 2012, to estimate Aβ neuritic plaque density in adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive decline. In the FDA-approved label for florbetapir there is no definition of “cognitive impairment,” but the label does reference studies whose cognitively impaired patient populations range from MCI to dementia. The label states that although a negative florbetapir scan reduces the likelihood of AD, a positive florbetapir scan does not confirm the diagnosis of AD or any other cognitive disorder. This is because a positive florbetapir scan, which indicates the presence of moderate to frequent amyloid plagues in the brain, may be seen in persons with AD or other causes of cognitive decline as well as in persons with normal cognition. The FDA-approved label for florbetapir indicates that it was not evaluated by the FDA as a screening tool to predict the development of dementia (including AD) or other cognitive disorders, nor to monitor the therapeutic response to treatment of these neurological conditions. Additionally, the label indicates that florbetapir images should only be interpreted by readers who successfully complete a special training program, which has been provided by the manufacturer through an in-person tutorial or electronic process. The FDA-approved label for florbetapir can be viewed in its entirety at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether the evidence is sufficient 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 CMS uses to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. Public commenters sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based 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 comment period to inform its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum. VII. Evidence A. Introduction The purpose of this evidence review is to summarize the published literature on whether PET Aβ imaging is beneficial to patients with symptoms of AD. The evidence reviewed here includes the published medical literature as of August 31, 2013, on pertinent clinical trials, focusing on florbetapir, as it is the only clinically-relevant, FDA-approved PET Aβ imaging tracer. Additional supporting evidence from other studies and sources are cited below. B. Summary of Evidence 1. Questions: Is the evidence adequate to conclude that PET Aβ imaging improves meaningful health outcomes in beneficiaries who display signs or symptoms of AD? Is the evidence adequate to conclude that PET Aβ imaging results inform the treating physician's management of the beneficiary to improve meaningful health outcomes? Those outcomes may include reasonably considered beneficial therapeutic management or the avoidance of unnecessary, burdensome interventions. 2. External Technology Assessment CMS did not request an external technology assessment (TA) on this issue. 3. Internal technology assessment Literature search methods Literature searches performed on PubMed included combinations of the following terms: amyloid, beta-amyloid, PET imaging, dementia, Alzheimer’s disease, neurodegenerative disorders, and mild cognitive impairment. Searches were also performed, using the same search terms, in ClinicalTrials.gov, the National Guideline Clearinghouse, the Cochrane Library, EMBASE, and other sources such as Trip Database. Additional articles were selected from citations from key clinical trials, recent review articles, the NCD request, expert speaker talks at the MEDCAC meeting, MEDCAC panel members and public comments. A review of the medical literature failed to reveal any pertinent meta-analysis or systematic reviews evaluating specifically the use of PET Aβ imaging in patients with signs and symptoms of AD. Although no randomized clinical trials were found exploring the use of PET Aβ imaging in this population, most studies found were prospective longitudinal studies. One study employed the use of a cross-sectional design (Landau 2012). Prospective Longitudinal Studies Wong D, Rosenberg P, Zhou Y, Kumar A, Raymont V, Ravert H, et al. In Vivo Imaging of Amyloid Deposition in Alzheimer’s Disease using the Novel Radioligand [18F]AV-45 (Florbetapir F 18). J Nucl Med. 2010 June;51(6):913–920. Wong and associates performed a study designed to explore brain imaging properties in cognitively healthy patients and those with AD by using PET florbetapir imaging. This open-label, multicenter, study involved 16 patients with Alzheimer’s disease, as well as 16 cognitively healthy controls; both groups received florbetapir and PET imaging (in AD patients the mean age was 75.8 +/- 9.2, in healthy controls (HC) the mean age was 72.5 +/- 11.6). Patients with AD had to be greater than 50 years of age and have a probable diagnosis of AD according to NINCDS-ADRDA criteria, with a mini-mental status examination (MMSE) score between 10 and 24 inclusive. All healthy control subjects also had to be greater than 50 years of age, have no evidence of cognitive impairment by history and psychometric testing, and had to have an MMSE score of ≥ 29. Subjects who showed evidence of any other significant neurodegenerative or psychiatric disease on clinical examination or MRI, or clinically significant medical comorbidities, were excluded from the study. In the study, standard uptake values ratios (SUVR) were calculated using cerebellar grey matter as the primary reference region, and centrum semiovale white matter as an alternative reference region, and a parametric mapping approach employing the cerebellum as a reference region was used to calculate distribution/volume ratios (DVR). Looking at the demographics of the two groups, though the baseline average MMSE was lower in the AD subjects than in the HC subjects (19.1 +/− 3.1 vs. 29.8 +/− 0.45), both groups were similar in age, weight, and education. A review of baseline data also revealed that there were a slightly higher proportion of males in the healthy control group than in the AD group (10/16 versus 8/16, respectively). Results of the study revealed that accumulation of florbetapir tracer was found in cortical target areas such as the frontal cortex, temporal cortex and precuneus, areas that were expected to be high in amyloid deposition, while in healthy control subject tracer accumulation predominantly was distributed in the white matter areas. The cortical to cerebellar SUVR values remained much longer in AD patients than in healthy controls, reaching a plateau within 50 minutes. Using the 10 minute period from 50–60 minutes post administration as a representative sample, the cortical average SUVR for this period was 1.67 +/− 0.175 for patients with AD vs. 1.25 +/− 0.177 for healthy control subjects. The study also revealed that spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r = 0.58–0.88, p < 0.005) and were significantly greater for AD patients than for healthy control subjects in cortical regions, but not in subcortical white matter or cerebellar regions. The authors concluded that florbetapir PET imaging showed significant discrimination between clinically diagnosed AD patients and healthy control subjects using either a parametric reference region method (DVR) or a simplified SUVR method. Camus V, Payoux P, Barré L, Desgranges B, Voisin T, Tauber C, et al. Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. Eur J Nucl Med Mol Imaging. 2012 Apr;39(4):621-31. doi: 10.1007/s00259-011-2021-8. Epub 2012 Jan 18. Camus and associates performed a prospective study to evaluate the clinical usefulness of florbetapir. The purpose of the study was to assess the feasibility of using PET imaging with florbetapir in three-level clinical settings to differentiate patients with mild to moderate AD or MCI patients from normal healthy control subjects in three PET centers. They also wanted to assess the safety of a florbetapir injection immediately after injection and during the follow-up period. Subjects included consecutive patients referred from the three participating memory clinics associated with the study center in France, and who met specific criteria as stated in the NINCDS-ADRDA criteria set for probable AD and DSM-IV criteria for Alzheimer’s type dementia or diagnostic criteria for amnestic MCI. All participants had to be at least 55 years of age, be able to speak French fluently, have completed at least seven years of education and have neither unstable somatic disease nor psychiatric comorbidities. Healthy subjects who acted as controls were recruited through a community advertisement and evaluated in the same clinical settings. The diagnosis of AD was confirmed using a mini-mental state examination (MMSE), as well as meeting the guidelines for global neuropsychological testing and an evaluation of verbal episodic memory (Free and Cued Selective Reminding Test, FCSRT), language (verbal fluency, naming, comprehension), gnosis, praxis, visuospatial functions and executive functions. Patients were excluded if they had any past or current symptomatic treatment with acetylcholinesterase inhibitors or memantine or had participated in any experimental study investigating Aβ-lowering agents. For MCI patients, a subjective memory complaint associated with isolated impairment in episodic memory had to be present, and assessed by a free recall total based on FCSRT. Healthy controls used in the study could not have any past history of or current major depressive episodes and/or antidepressant treatment, cognitive impairment in the diagnostic neuropsychological battery, memory complaints, or MRI brain scan abnormalities. A total of 46 subjects (20 men, 26 women, mean age 69.0 ± 7.6 years) were included in the study, including 13 AD patients, 12 MCI patients and 21 healthy control subjects. A brain MRI scan, a whole-body hybrid PET/CT scan and florbetapir PET imaging was performed on all subjects. PET images were assessed visually by blinded inspectors to any clinical information and quantitatively via the standard uptake value ratio (SUVR) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region. Results of the study revealed that the PET scan procedures were well tolerated, and no serious adverse events were reported during the immediate follow-up period, though at the 1-year follow-up, two patients did had medical problems unrelated to the study and were excluded from the analysis. The mean values of SUVR were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in healthy control subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and in all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with healthy control subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55 – 0.98) and a specificity of 38.1% (95% CI 0.18 – 0.62) for discriminating clinically diagnosed AD patients from healthy control subjects; however, the quantitative assessment of the global cortex SUVR showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894). Based on the results of the study, the authors felt that PET with florbetapir was suitable for routine use to improve the accuracy of AD diagnosis in the clinical setting, because the quantitative analyses showed a higher global SUVR and SUVR in several cortical regions (precuneus, anterior and posterior cingulate, frontal median, temporal, parietal and occipital cortex) in AD patients than in healthy control subjects. It also showed that the SUVR in the posterior cingulate and frontal median regions was significantly higher in AD patients than in MCI patients. The authors also note the following: the pattern of florbetapir cortical uptake found in the present study is similar to that found in previous studies conducted by Wong et al. and Clark et al.; the pattern also appears to be similar to those found with other amyloid-labeling compounds, such as PIB C11 and its flutemetamol F18-derived molecule, 11C-BF-227, FDDNP F18 and BAY94-9172 F18; and these patterns closely match the neuropathological stages of AD progression, which was strengthened by the high correlation found between florbetapir PET imaging and autopsy results. The authors concluded that PET with florbetapir should become a routine clinical procedure because it improves the reliability of AD diagnosis and the detection of typical or atypical forms of pre-dementia stages, such as amnestic MCI and MCI associated with multi-domain deficits or neuropsychiatric symptoms (e.g., depression). But the authors also note that more studies testing the feasibility and tolerability of consecutive scans with florbetapir are needed to better document the accuracy of PET imaging with florbetapir in the AD diagnostic process at the dementia or pre-dementia stages, and that comparisons (or combinations) with other biomarkers, such as FDG PET, MRI and CSF dosages of tau and protein, are also needed. Clark CM, Sneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA. Use of Florbetapir PET for Imaging Aβ Pathology. JAMA 2011 Jan 19;305(3):275-83. Clark and associates performed a prospective clinical evaluation study to determine the qualitative and quantitative relationship between the florbetapir PET image and postmortem-amyloid pathology. This phase 3 multicenter study had two cohort groups. One group involved individuals at the end of life who consented to both florbetapir PET imaging and brain donation after death. In the other group, PET images were also obtained from younger individuals presumed to be free of brain amyloid to better understand the frequency of a false positive florbetapir PET image. The study enrolled 152 individuals who were at least 51 years of age and approaching the end of their life, to obtain 35 postmortem brain evaluations from those who received PET imaging 12 months or less prior to death. Inclusion criteria for this group included a physician’s assessment that the individual was likely to die within six months of study enrollment, absence of any known destructive lesion in the brain (e.g., stroke or tumor), and the individual’s willingness to have florbetapir PET imaging followed by a brain autopsy at the time of death. The study also involved a second group of 74 young, cognitively normal, healthy individuals (aged 18-50 years). In both groups, physical, neurological, and cognitive evaluations that included assessments of memory, language, and constructional praxis were obtained. Participants were imaged at 23 sites using clinical PET and PET/computed tomographic scanners, and florbetapir PET images were visually assessed by three board-certified nuclear medicine physicians, using a semi-quantitative score ranging from 0 (no amyloid) to 4 (high levels of cortical amyloid). A semi-automated quantitative analysis of the ratio of cortical to cerebellar signal (SUVR) also was performed for florbetapir PET images from all study participants. The main outcome measure of the study was correlation of florbetapir PET image interpretation (based on the median of 3 nuclear medicine physicians’ ratings) and semi-automated quantification of cortical retention with postmortem Aβ burden, neuritic amyloid plaque density, and neuropathological diagnosis of Alzheimer disease in the first 35 participants autopsied (out of 152 individuals enrolled in the PET pathological correlation study). Autopsied brain tissue was obtained to identify and quantify Aβ aggregation using an automated immunostainer following established immunohistochemistry methods, and PET image quantification was performed using image processing and analysis software. Aβ neuritic plaque density was determined, and the mean density for both neuritic and diffuse plaques, using silver stain, was summarized by anatomical region using a 4-point semi-quantitative scale (0 = none, 1 = sparse, 2 = moderate, 3 = severe). Also, a neuropathological diagnosis was made using standardized criteria as described by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and the National Institute on Aging (NIA) and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease (NIA/Reagan Institute criteria). Results of the study revealed that there were significant correlations between the two measures of amyloid on florbetapir PET (SUVR versus semiquantitative visual score: 0.82 [95% CI, 0.64 - 0.87]; p < .001) and the two measures of amyloid aggregation at autopsy (immunohistochemistry vs. silver stain: 0.88 [95% CI, 0.76 - 0.94]; p < .001). The strengths of the inter-method correlations (e.g., PET visual read to immunohistochemistry) were similar to that for the intra-method correlations (e.g., PET visual read to PET SUVR, pathology immunohistochemistry to pathology plaque score). The study also revealed that 15 participants in the primary analysis autopsy cohort met pathological criteria for AD (CERAD: probable or definite AD; NIA/Reagan Institute criteria: intermediate to high likelihood of AD) and of these 15 participants, 14 had florbetapir PET scans that were interpreted as visually positive (median read 2), giving a sensitivity of 93% (95% CI, 68% - 100%). Finally, 14 participants in the autopsy cohort had low levels of Aβ aggregation on the postmortem examination and did not meet CERAD or NIA/Reagan Institute pathological criteria for AD. All 14 had florbetapir PET scans that read as negative, yielding a specificity of 100% (95% CI, 76.8% - 100%). The authors noted that the reviewers who read results for the florbetapir PET images agreed with the final autopsy with respect to the presence or absence of neuropathological criteria of AD in 28 of 29 cases. The authors concluded that florbetapir PET imaging performed during life in this study correlated with the presence and density of Aβ at autopsy, and felt that this study provides evidence that a molecular imaging procedure can identify Aβ pathology in the brains of individuals during life. Clark C, Pontecorvo M, Bench T, Bedell B, Coleman R, Doraiswamy P. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic Aβ plaques: a prospective cohort study. Lancet Neural 2012;11:669-78. This second study by Clark and associates was a continuation of the 2011 discussed above. Like the original study, this prospective cohort study’s purpose was to determine the qualitative and quantitative relationship between florbetapir PET imaging and postmortem-amyloid pathology. Patients who were alive at the end of the first study were followed up to autopsy, or for an additional year after the PET scan. Images and histopathological results from the original cohort study were used and extended to follow-up and were analyzed together to test the diagnostic accuracy of binary visual interpretation of florbetapir PET scans by comparison with the reference standard of neuritic plaque density at autopsy. The original study enrolled 152 individuals and obtained 35 postmortem brain evaluations from those who had received PET imaging 12 months or less prior to death. Autopsy results of the original Clark article was based on this cohort of 35 subjects. The second Clark study used the same inclusion and exclusion criteria as the original study, as well as the same physical, neurological, and cognitive evaluations that included assessments of memory, language, and constructional praxis. The second study also had three board-certified nuclear medicine physicians read the florbetapir PET images, using a semi-quantitative score ranging from 0 (no amyloid) to 4 (high levels of cortical amyloid). And as before, a semi-automated quantitative analysis of the ratio of cortical to cerebellar signal (SUVR) was performed for florbetapir PET images from all study participants. Autopsied brain tissue was examined to identify and quantify Aβ aggregation, and neuritic plaque density was determined using a 4-point semi-quantitative scale (0 = none, 1 = sparse, 2 = moderate, 3 = severe). The main outcome measure of the study was correlation of florbetapir PET image interpretation and semi-automated quantification of cortical retention with postmortem Aβ burden, and neuritic amyloid plaque density. The neuropathologic diagnosis of AD was made using standardized criteria as described by the CERAD and the National Institute on Aging (NIA) and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease (NIA/Reagan Institute criteria). In the original Clark study, 35 participants died and had a postmortem exam. The remaining participants were followed up to 1 year, or a maximum of two years after the original PET scan. During this period an additional 24 autopsy results became available, leaving a combined total of 59 participants with a valid florbetapir PET scan and autopsy results within 24 months which comprised the primary efficacy analysis population. The mean age of this group was 79.4 years, and male as well as female genders were equally represented in this study. According to inclusion criteria, 12 subjects had no cognitive impairment, five had mild cognitive impairment that did not meet the criteria for dementia, 29 had AD, and 13 had other forms of dementia (e.g., dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal dementia, unspecified dementia, and mixed dementia). The secondary efficacy analysis population, which consisted of patients in the 12 month autopsy cohort, had similar demographic and characteristics as the primary efficacy analysis population. Results of the study revealed that 39 of the 59 patients included in the study in the primary efficacy analysis population had moderate or frequent neuritic plaques at autopsy and were categorized as positive for Aβ according to histopathological assessment. Most readers rated the florbetapir PET scans as positive in 36 of these 39 subjects, giving this a sensitivity rating of 92%. All 20 subjects with no or sparse neuritic plaque at autopsy were categorized as negative by the majority of readers of the florbetapir PET scan, resulting in a specificity of 100%. The overall accuracy for the primary efficacy analysis population was 95%. The sensitivity, specificity, and overall accuracy of the 46 participants included in the secondary efficacy analysis population were 96%, 100% and 98% respectively. Visual semi-quantitative ratings of Aβ by use of florbetapir PET imaging showed a positive correlation with postmortem levels of Aβ measured via immunohistochemistry in subjects who had autopsies within two years of PET scan (Spearman ρ = 0.76; p < 0.0001), as well as subjects who had autopsies within one year of PET scan (Spearman ρ = 0.79; p < 0.0001). The authors concluded that the results of the study showed correlation between florbetapir PET imaging and postmortem amyloid burden, and the authors concluded that florbetapir might be useful for imaging of Aβ neuritic plaques in the brains of patients with cognitive impairment. Fleisher AS, Chen K, Liu X, Roontiva A, Thiyyagura P, Ayutyanont N. Using Positron Emission Tomography and Florbetapir F 18 to Image Cortical Amyloid in Patients With Mild Cognitive Impairment or Dementia Due to Alzheimer Disease. Arch Neurol. 2011;68(11):1404-1411. Fleischer and associates used multiple research imaging centers in their study to characterize quantitative florbetapir PET measurements of fibrillar Aβ burden in a large clinical cohort of participants with probable AD or mild cognitive impairment and older healthy controls. The study used pooled data from the four registered phase I and II trials of florbetapir PET imaging, using standard dosing of florbetapir and non-dynamic PET acquisitions. The study evaluated both continuous and binary measures of florbetapir PET activity to assess global differences between clinical diagnostic groups, to confirm expected patterns of regional distributions of fibrillar Aβ, and to determine proportions of positive scans using cut-off thresholds for global cortical florbetapir activity. During the course of the study, researchers predetermined SUVR threshold levels for defining florbetapir PET positivit