83 FR 15572 - Medicare Program; Reconciling National Coverage Determinations on Positron Emission Tomography (PET) Neuroimaging for Dementia

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Centers for Medicare & Medicaid Services

Federal Register Volume 83, Issue 70 (April 11, 2018)

Page Range		15572-15576
FR Document		2018-07410
In accordance with the court order on July 19, 2016 (Kort v. Burwell), this notice provides further explanation on the National Coverage Determinations for positron emission tomography (PET) neuroimaging for dementia.
Federal Register, Volume 83 Issue 70 (Wednesday, April 11, 2018)
[Federal Register Volume 83, Number 70 (Wednesday, April 11, 2018)]
[Notices]
[Pages 15572-15576]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2018-07410]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Medicare & Medicaid Services

[CMS-3353-N]


Medicare Program; Reconciling National Coverage Determinations on 
Positron Emission Tomography (PET) Neuroimaging for Dementia

AGENCY: Centers for Medicare & Medicaid Services (CMS), HHS.

ACTION: Notice.

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SUMMARY: In accordance with the court order on July 19, 2016 (Kort v. 
Burwell), this notice provides further explanation on the National 
Coverage Determinations for positron emission tomography (PET) 
neuroimaging for dementia.

FOR FURTHER INFORMATION CONTACT: Linda Gousis, (410) 786-8616.

SUPPLEMENTARY INFORMATION:

I. Background

    On July 19, 2016, the United States District Court for the District 
of Columbia issued an order requiring the Secretary of Health and Human 
Services (HHS) to further explain one aspect of a National Coverage 
Determination (NCD) decision memorandum issued by the Centers for 
Medicare & Medicaid Services (CMS). Kort v. Burwell, 209 F.Supp.3d 98 
(D.D.C. 2016). In particular, the court called for CMS to explain how 
its 2013 NCD denying coverage for a beta amyloid positron emission 
tomography scan (amyloid PET) \1\ could be reconciled with an earlier 
2004 NCD relating to fluorodeoxyglucose (FDG) positron emission 
tomography (PET) (FDG PET).\2\ We issued the NCDs under our authority 
to interpret the ``reasonable and necessary'' statutory standard in 
section 1862(a)(1)(A) of the Social Security Act (the Act) as it 
applies to coverage of items and services in the Medicare program. In 
this notice, we describe the key differences between the two NCDs. We 
relied on the existing record in preparing this document.
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    \1\ CMS, Decision Memo for Beta Amyloid Positron Emission 
Tomography in Dementia and Neurodegenerative Disease (CAG-00431N); 
2013 September 27. Available from: https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=265 (accessed 
on June 22, 2017). Note that amyloid PET is referred to in the 2013 
NCD as ``[beta]A PET'' or ``amyloid PET'' interchangeably. In this 
document, we are using ``amyloid PET''; however, quotes may refer to 
it by the similar terms.
    \2\ CMS, Decision Memo for Positron Emission Tomography (FDG) 
and Other Neuroimaging Devices for Suspected Dementia (CAG-00088R); 
2014 September 15. Available from: https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=104 (accessed 
on June 22, 2017).
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II. Provisions of the Notice

    In accordance with the Court's order, we explain why CMS covers one 
diagnostic test for specific patients, while covering the other only in 
the context of a clinical study (Kort, 115). Briefly, the differences 
arose from the type of assessment the test provided; predictive value 
of the test; and consensus panels' conclusions about the use of the 
tests.

A. Summary of the NCDs

    The 2004 NCD for FDG PET resulted in narrow coverage of the 
diagnostic test for specific subpopulations of patients meeting 
narrowly defined criteria (CMS

[[Page 15573]]

2004, 32).\3\ We determined that the ``scan is reasonable and necessary 
in patients with documented cognitive decline of at least six months 
and a recently established diagnosis of dementia who meet diagnostic 
criteria for both Alzheimer's disease (AD) and fronto-temporal dementia 
(FTD), who have been evaluated for specific alternate neurodegenerative 
diseases or causative factors, and for whom the cause of the clinical 
symptoms remains uncertain'' (CMS 2004, 3).
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    \3\ In this document, page numbers for the decision memorandum 
citations are based off of the page number at the bottom of the page 
on the PDF version which is available for download from web page 
provided in the previous footnotes for this document. Click on the 
``Need a PDF?'' icon on the right side of the screen to obtain a 
PDF.
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    The 2013 amyloid PET NCD resulted in non-coverage of amyloid PET 
for dementia and neurodegenerative disease; however, coverage was made 
available in the context of a clinical study. There, one amyloid PET 
scan per patient would be covered through coverage with evidence 
development (CED) pursuant to section 1862(a)(1)(E) of the Act (CMS 
2013, 4). The diagnostic test is covered under certain research 
parameters ``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, by 
allowing for selection of patients on the basis of biological as well 
as clinical and epidemiological factors'' (CMS 2013, 4).

B. Kort v. Burwell Summary

    The plaintiffs in Kort were beneficiaries who exhibited symptoms of 
cognitive impairment but did not have a diagnosis for their illness. 
They wanted amyloid PET scans because they thought the scans would help 
their doctors make a differential diagnosis. The court determined that 
the amyloid PET NCD failed to adequately explain how the decision 
denying coverage for amyloid PET could be reconciled with the earlier 
decision approving coverage of FDG PET in certain contexts. The court 
noted, ``[t]he similarities between FDG PET and BA scans are manifest. 
Both are diagnostic tests that involve the use of a PET scan and a 
radiopharmaceutical tracer. Both are indicated for use on overlapping 
patient populations exhibiting symptoms of cognitive impairment. And, 
although neither test can affirmatively diagnose a disease, both have 
diagnostic value as a tool for differentially diagnosing patients who 
exhibit symptoms associated with several different diseases'' (Kort, 
114-115). Without vacating the 2013 NCD, the Court remanded ``the 
Decision Memo so that the agency can evaluate in the first instance 
whether its coverage decisions can be reconciled'' (Kort, 115).

C. Analytic Framework for Reviewing Clinical Evidence

    We evaluated the relevant clinical evidence to determine whether or 
not the evidence is sufficient to support a finding that an item or 
service is reasonable and necessary for the Medicare population, which 
consists largely of adults 65 years of age and older (CMS 2004, 13 and 
CMS 2013, 13). This process was discussed in the methodological 
principles for both NCDs. The critical appraisal of the evidence 
enables CMS to determine to what degree the agency is confident that 
the intervention will improve health outcomes for beneficiaries (CMS 
2004, 13 and CMS 2013, 13).
    Specifically for diagnostic imaging tests, the overall assessment 
focuses on whether use of the test to guide patient management and 
treatment improves health outcomes (also referred to as clinical 
utility). Before appropriately reaching a consideration of outcomes, 
two fundamental properties of diagnostic tests need to be established: 
(1) the test accurately and reliably measures the intended analyte, 
factor, or component (also referred to as analytic validity); and (2) 
the test accurately and reliably identifies the condition or disorder 
of interest (also referred to as clinical validity). Outcomes such as 
change in patient management due to diagnostic tests and accuracy, 
sensitivity, and specificity are also of interest to CMS (CMS 2004, 14 
and CMS 2013, 30).

D. Review of the Clinical Evidence for FDG and Amyloid PET

    While both diagnostic tests use a PET scan, there is a distinction 
in the tracers used for the scans: FDG provides a physiologic 
(functional) assessment of the brain since it highlights glucose 
metabolism; meanwhile, beta amyloid tracers such as florbetapir 
(Amyvid[supreg]) and flutemetamol (Vizamyl[supreg]) provide a molecular 
(anatomic) assessment since they bind to amyloid [beta] plaques (CMS 
2004, 5 and CMS 2013, 11). In both coverage analysis, we focused on 
whether the PET scans can accurately and reliably identify dementias, 
including AD, and whether use of the scans to guide management and 
treatment improves meaningful health outcomes (CMS 2004, 14 and CMS 
2013, 14). We focused on these because numerous mechanism of action 
studies have shown that PET scans can accurately and reliably detect 
radionuclide tracers that tag nitrogen, oxygen, glucose, and 
amyloid.\4\
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    \4\ Petersen et al. Practice parameter: Early detection of 
dementia: Mild cognitive impairment (an evidence-based review), 
Report of the Quality Standards Subcommittee of the American Academy 
of Neurology. Neurology. May 2001; Neuroimaging in the Diagnosis of 
Alzheimer's Disease and Dementia. Expert panel convened by the 
Neuroscience and Neuropsychology of Aging Program, National 
Institute on Aging (NIA), HHS. April 5, 2004. https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id104d.pdf 
(accessed on August 9, 2017); and D Matchar, S Kulasingam, B 
Huntington, M Patwardhan, L Mann. Technology Assessment: Positron 
emission tomography, single photon emission computed tomography, 
computed tomography, functional magnetic resonance imaging, and 
magnetic resonance spectroscopy for the diagnosis and management of 
Alzheimer's disease. Duke Center for Clinical Health Policy Research 
and Evidence Practice Center. December 2001. https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id9TA.pdf (accessed 
August 9, 2017). (CMS 2004, 43 and 46)
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    Ultimately, we determined that evidence for FDG PET for 
differential diagnosis of dementias was more compelling and 
substantiated than for amyloid PET when the same analytic framework was 
applied to these diagnostic imaging tests. There were several reasons 
for CMS finding FDG PET more compelling. The ability of the FDG PET 
test to accurately and reliably identify the disorder of interest is 
better established and accepted than for molecular PET scans, such as 
beta amyloid (CMS 2004, 8). Since the 1980s, functional assessment of 
the brain using one of a number of tracers, such as ones for blood 
flow, oxygen utilization, and glucose metabolism, has been used to 
diagnose dementia. Among these, FDG is a glucose analog and behaves 
similar to glucose in the cell. Glucose metabolism may be viewed as an 
indicator of cell activity. Used as a PET tracer, FDG will indicate the 
cell activity. In the brain, function as shown by cell activity 
(glucose metabolism or FDG tagging) may be used to differentiate causes 
of dementia (CMS 2004, 7). For example, in frontal lobe dementia, 
imaging tests have shown marked hypometabolism (darker areas) of the 
frontal or temporal lobes with sparing of parietal lobes. In patients 
with Alzheimer's disease, there is typically hypometabolism bilaterally 
in the temporal and parietal lobes (CMS 2004, 5, 7, and 33). 
Additionally, ``the presumed higher specificity of FDG PET for 
detecting metabolic patterns correlated with FTD could decrease the 
number of false positive results for AD and consequently increase the 
number of true positives for FTD to inform

[[Page 15574]]

patient management and caregiver counseling'' (CMS 2004, 35).
    In contrast to the evidence supporting use of FDG PET, there were 
uncertainties regarding the use of amyloid PET. The presence or absence 
of amyloid in the brain has been considered in diagnosis of AD, but it 
is not diagnostic because some normal individuals also have amyloid 
plaques (CMS 2013, 10). Amyloid tracers bind to and statically mark 
amyloid plaque providing an anatomic or structural assessment (location 
and concentration) but do not provide information on cell activity or 
brain function. This is an inherent limitation of anatomic assessments 
compared to functional assessments because the hallmark of dementia is 
an abnormal decline in cognitive function (CMS 2013, 7). Thus, the 
premise that the test accurately and reliably identifies the disorder 
is reduced in amyloid imaging compared to functional imaging, such as 
FDG, due to the different mechanisms of action. Additionally, the 
ability of amyloid PET scans to diagnose AD is inherently reduced by 
the pathophysiologic characteristics of AD since the presence 
extracellular amyloid [beta] is only one of two specific findings 
required for the diagnosis of AD. The second key factor is the presence 
of intracellular neurofibrillary tangles (NFTs) consisting of abnormal 
tau proteins. Amyloid tracers do not show the presence of NFTs or 
abnormal tau proteins, which are not detected by any commercially 
available radionuclide tracer (CMS 2013, 10). In addition, findings 
based on postmortem investigation and studies (pathophysiologic 
alternations in brain biopsies) may not directly translate to factors 
that may be used to make a clinical diagnosis of patients with 
dementia.
    The FDG PET NCD acknowledged that AD-type physiology may be present 
in normal individuals with normal cognitive function; therefore, a 
positive amyloid PET scan does not necessarily mean the individual has 
AD (CMS 2004, 5). As subsequently noted in the amyloid PET decision 
memo nine years later, ``[A]myloid 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)'' (CMS 2013, 10).
    The reliability of test is a necessary component for determining 
health outcomes or clinical utility. The foundation of clinical utility 
for functional PET scans, like FDG PET, is better established than 
anatomic PET scans, like amyloid PET. While direct, high quality 
evidence on clinical utility of FDG PET for dementia was not found in 
published literature at the time of the 2004 decision, there were 
related studies that showed clinical utility of FDG PET for other 
treatable causes of cognitive impairment or dementia such as 
cerebrovascular disease, certain inherited diseases, and metabolic 
conditions that could possibly be diagnosed with FDG PET, and then 
treated with proven therapies to improve health outcomes (CMS 2004, 32, 
37). At the time of the amyloid PET NCD, there was no published 
evidence of clinical utility similar to what was reviewed for FDG PET, 
and there were no related studies suggesting that amyloid PET would be 
helpful in the differential diagnosis of AD and FTD (CMS 2013, 14). 
Further, because amyloid PET does not specifically diagnose other 
conditions, the clinical utility or improved health outcomes associated 
with other diseases is not applicable.
    Since the mid-2000s, a number of clinical trials of different 
therapies that target amyloid have failed to produce results of 
improvement in health outcomes (CMS 2013, 61).\5\ FDG PET did not have 
the same negative trials at the time of our 2004 decision.
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    \5\ See also Peterson RC. Early Diagnosis of Alzheimer's 
Disease: Is MCI Too Late? Current Alzheimer Research. 2009; 
6(4):329; Petersen RC, Smith G, Waring S, et al. Mild cognitive 
impairment: clinical characterization and outcome. Archives of 
Neurology. 1999;56:303-8; National Institute on Aging (NIA) and the 
Reagan Institute. Consensus recommendations for the postmortem 
diagnosis of Alzheimer's disease. The National Institute on Aging, 
and Reagan Institute Working Group on Diagnostic Criteria for the 
Neuropathological Assessment of Alzheimer's Disease. Neurobiology of 
Aging. 1997 Jul-Aug;18(4 Suppl):S1-2; and Technology Evaluation 
Center (TEC), Blue Cross Blue Shield. Beta Amyloid Imaging with 
Positron Emission Tomography (PET) for Evaluation of Suspected 
Alzheimer's Disease or Other Causes of Cognitive Decline. 2013 
February;27(5).
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E. Determining the Predictive Value of Amyloid PET Compared to FDG PET

    We did not have the same concerns regarding false positives using 
FDG PET to differentially diagnose AD as we did with amyloid PET. The 
predictive value of the amyloid PET scan cannot be based solely on its 
capability to ``rule out'' AD, because there is also the risk of 
positively diagnosing patients with Alzheimer's when they do not have 
it. Conversely, for a patient faced with the possibility of having 
Alzheimer's, a negative amyloid PET result could be reassuring (CMS 
2013, 52-53). However, such reassurance would not change clinical 
management because the patient may still have AD. If a clinician did 
not have ``a convincing clinical picture [of AD], work up to exclude 
other diagnosable and potentially treatable diseases should proceed 
anyway (as it would if an amyloid scan were negative). The 
unavailability of an amyloid scan does not change that logic'' (CMS 
2013, 52).
    At the same time, the amyloid PET scan portends great risk because 
there is no evidence for what a positive scan means in specific 
patients since they can have amyloid plaques but not have AD. At the 
Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) 
meeting held specifically on amyloid PET on January 30, 2013, one 
expert speaker mentioned that he believed that a patient with mild 
cognitive impairment (MCI) and a positive amyloid PET scan had 
Alzheimer's disease and that many other experts agreed with him (MEDCAC 
2013, 31, 53).\6\ However, no published clinical trials, studies, 
consensus publications, or further MEDCAC discussions identified 
whether, for amyloid PET, ``objectively-defined subpopulations of 
patients with cognitive impairment for which the scan (alone or 
combined with other tests) may be more or less appropriate. Yet there 
are many subtypes of MCI, and some (e.g., amnestic MCI) may be more 
relevant than others. Furthermore, there is evidence that the same 
level of amyloid burden detected by a scan may mean something very 
different in say, a 66 year-old compared to an 86 year-old (e.g., Le 
Couteur 2013, Laforce 2011). Yet the [Amyloid Imaging Task Force] AIT 
is silent about such potentially important distinctions'' (CMS 2013, 
33). (The AIT was a consensus panel that developed recommendations for 
use of amyloid PET.)
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    \6\ Medicare Evidence Development & Coverage Advisory Committee 
(MEDCAC), Meeting: Beta Amyloid Positron Emission Tomography (PET) 
in Dementia and Neurodegenerative Disease, Meeting Transcript; 2013 
January 30. Available from: https://www.cms.gov/Regulations-and-Guidance/Guidance/FACA/downloads/id66d.pdf (accessed on June 22, 
2017). (CMS 2013, 79, 80, and 82)
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    We concluded in the amyloid PET NCD that ``widespread clinical use 
of the scan both in many types of patients with unexplained MCI, and to 
make a positive diagnosis of Alzheimer's disease (despite insufficient 
evidence on

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the clinical meaning of a positive scan) has great potential to lead to 
over-diagnosis of Alzheimer's disease. Such misdiagnosis of Alzheimer's 
disease portends real harm to our beneficiaries (La Couteur 2013), and 
this must be considered in our coverage decision'' (CMS 2013, 33).
    ``False positive'' test results, widely considered by radiologists 
as the bane of diagnostic imaging, are of special concern for amyloid 
PET. The following are scenarios that contrast the impacts of negative, 
positive, and false positive test results. For example, if a patient 
were to get a computed tomography (CT) study of the chest, abdomen, and 
pelvis to ``rule out'' cancer, and if the CT study were negative, that 
indeed would be reassuring to the patient. However, if the study were 
positive for an enlarged lymph node, liver lesion, or some questionable 
pulmonary nodule, these findings could be followed up by biopsy, 
surgical resection, or assessing for progression of disease on a close 
follow-up CT. In contrast, a completely different clinical scenario 
follows amyloid PET. Those options to further explore findings common 
for other ``positive'' diagnostic tests do not exist. Providers cannot 
do a biopsy, resection, or close follow up of amyloid imaging after a 
positive amyloid scan.
    Concern about false positive test results was not a major factor in 
the 2004 decision memorandum on FDG PET. Based off of an external 
technical assessment that helped inform the 2004 decision memorandum, 
we concluded that ``FDG-PET testing would reduce the number of false 
positive results'' (CMS 2004, 16). FDG PET has the ability to diagnose 
patients with disease (dementias, not only Alzheimer's) since it is a 
functional test and measures glucose metabolism (activity) as noted 
earlier. Based on the patterns of uptake (cellular function indicating 
activity), a differential diagnosis between FTD (characteristic 
hypometabolism in the frontal lobe of the brain) versus AD 
(characteristic hypometabolism in temporal and parietal lobes of the 
brain) versus normal patterns (no hypometabolism) may be made. In our 
FDG PET decision, we noted, ``Patients with FTD generally tend to show 
bifrontal and bitemporal hypoperfusion in single photon emission 
computerized tomography (SPECT) or glucose hypometabolism in FDG PET 
scans. In contrast, temporoparietal defects are predominant in AD'' 
(CMS 2004, 7).
    In contrast, the false positive results were a greater concern with 
amyloid PET (CMS 2013, 48-50), since amyloid plaques may be present in 
many individuals with normal cognitive function. As noted earlier, the 
presence of amyloid (positive test) by itself does not diagnose AD 
since the diagnosis of AD is based on the presence of both amyloid and 
tau proteins on autopsy. A positive amyloid PET does not allow a 
differential diagnosis between FTD versus AD versus an individual with 
normal cognitive function since amyloid is a structural component and 
does not indicate function.

F. Expert Consensus in Making Evidence-based NCDs

    Two expert panels, in 2002, the Medicare Coverage Advisory 
Committee (MCAC) \7\ Diagnostic Imaging Panel,\8\ and, in 2004, the 
National Institute on Aging (NIA) agreed on a narrow conditioned 
clinical use for the FDG PET scan (MCAC-DIP 2002, 122, 196-197 and CMS 
2004, 35). The expert panel convened by NIA believed the existing 
evidence warranted use of FDG-PET for a limited number of cases 
including differential diagnosis of AD and FTD (NIA 2004, 32, 35, 45, 
48, and 51-52). For these reasons, in 2004 we had confidence in the 
plausibility of downstream health outcomes for a narrow indication for 
FDG PET for differential diagnosis of AD and FTD.
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    \7\ The MCAC was the predecessor to the MEDCAC.
    \8\ MEDCAC, Meeting: Positron Emission Tomography (FDG) for 
Alzheimer's Disease/Dementia (Diagnostic Imaging Panel), Meeting 
Transcript; 2002 January 10. https://www.cms.gov/Regulations-and-Guidance/Guidance/FACA/downloads/id2a.pdf (accessed June 22, 2017).
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    In contrast to the uniform consensus for FDG PET, in 2013, two 
expert panels, the AIT \9\ and MEDCAC,\10\ manifestly disagreed about 
the clinical use of the amyloid PET scan (CMS 2013, 33 and MEDCAC 2013, 
55). While the AIT noted amyloid imaging may be appropriate in 
progressive unexplained or unclear clinical presentations (Johnson 
2013, e6), the MEDCAC did not find sufficient evidence for CMS to 
support outright coverage of amyloid PET (MEDCAC 2013, 248, 250). This 
different degree of consensus between 2004 and 2013 was a contributing 
factor in our decisions. However, our evidence-based approach to 
coverage determinations does not rely on consensus alone. As explained 
in the 2013 NCD, ``two credible expert panels--the AIT and the MEDCAC--
produced differing consensuses. That's why, in the well-established 
process of scientific evaluation, evidence must be evaluated to 
determine the strength of the consensus opinion'' (CMS 2013, 33). At 
the time the amyloid PET NCD was finalized, there was no evidence to 
support or refute the consensus opinions. CED for amyloid PET supported 
the needed development of evidence for future evaluation. Therefore, 
based on the evidence reviewed as described above and the conclusions 
of the expert panels, we came to differing conclusions because the 
evidence for FDG PET for a narrowly defined patient population was 
better established than for amyloid PET.
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    \9\ Johnson et al., Appropriate use criteria for amyloid PET: A 
report of the Amyloid Imaging Task Force, the Society of Nuclear 
Medicine and Molecular Imaging, and the Alzheimer's Association, 
Alzheimer's and Dementia; 2013 January. http://www.alz.org/research/downloads/appropriate_use_criteria_for_amyloid_PET_Alz_and_Dem_January_2013.pdf
 (accessed June 22, 2017).
    \10\ MEDCAC, Meeting: Beta Amyloid Positron Emission Tomography 
(PET) in Dementia and Neurodegenerative Disease; 2013 January 30. 
https://www.cms.gov/medicare-coverage-database/details/medcac-meeting-details.aspx?MEDCACId=66&year=2013&bc=AAAIAAAAAAAAAA%3d%3d& 
(accessed June 22, 2017).
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G. Summary

    As required by the court order that accompanied the Kort opinion, 
this document further explains why we reached different conclusions 
with respect to section 1862(a)(1)(A) of the Act in the NCDs for FDG 
PET and amyloid PET. Both decisions were based on the available 
evidence according to our analytic framework described herein. Based on 
that evidence, we created narrow coverage for a small patient 
population with extensive patient eligibility criteria and provider 
requirements for FDG PET. For amyloid PET, the totality of the evidence 
available was not sufficient to demonstrate that the test produced 
diagnostic value as a tool for differentially diagnosing patients who 
exhibit symptoms associated with AD or FTD. Therefore, we established 
coverage for amyloid PET in the context of a clinical study setting 
with patient and provider eligibility criteria under the authority of 
section 1862(a)(1)(E) of the Act.

III. Collection of Information Requirements

    This document does not impose information collection requirements, 
that is, reporting, recordkeeping or third-party disclosure 
requirements. Consequently, there is no need for review by the Office 
of Management and Budget under the authority of the Paperwork Reduction 
Act of 1995 (44 U.S.C. 3501 et seq.).


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    Dated: March 16, 2018.
Seema Verma,
Administrator, Centers for Medicare & Medicaid Services.
    Dated: April 5, 2018.
Alex M. Azar II,
Secretary, Department of Health and Human Services.
[FR Doc. 2018-07410 Filed 4-10-18; 8:45 am]
BILLING CODE 4120-01-P
15574 Federal Register / Vol. 83, No. 70 / Wednesday, April 11, 2018 / Notices

patient management and caregiver 1998, Price 1999, Knopman 2003, Rowe of positively diagnosing patients with
counseling’’ (CMS 2004, 35). 2010)’’ (CMS 2013, 10). Alzheimer’s when they do not have it.
In contrast to the evidence supporting The reliability of test is a necessary Conversely, for a patient faced with the
use of FDG PET, there were component for determining health possibility of having Alzheimer’s, a
uncertainties regarding the use of outcomes or clinical utility. The negative amyloid PET result could be
amyloid PET. The presence or absence foundation of clinical utility for reassuring (CMS 2013, 52–53). However,
of amyloid in the brain has been functional PET scans, like FDG PET, is such reassurance would not change
considered in diagnosis of AD, but it is better established than anatomic PET clinical management because the patient
not diagnostic because some normal scans, like amyloid PET. While direct, may still have AD. If a clinician did not
individuals also have amyloid plaques high quality evidence on clinical utility have ‘‘a convincing clinical picture [of
(CMS 2013, 10). Amyloid tracers bind to of FDG PET for dementia was not found AD], work up to exclude other
and statically mark amyloid plaque in published literature at the time of the diagnosable and potentially treatable
providing an anatomic or structural 2004 decision, there were related diseases should proceed anyway (as it
assessment (location and concentration) studies that showed clinical utility of would if an amyloid scan were
but do not provide information on cell FDG PET for other treatable causes of negative). The unavailability of an
activity or brain function. This is an cognitive impairment or dementia such amyloid scan does not change that
inherent limitation of anatomic as cerebrovascular disease, certain logic’’ (CMS 2013, 52).
assessments compared to functional inherited diseases, and metabolic At the same time, the amyloid PET
assessments because the hallmark of conditions that could possibly be scan portends great risk because there is
dementia is an abnormal decline in diagnosed with FDG PET, and then no evidence for what a positive scan
cognitive function (CMS 2013, 7). Thus, treated with proven therapies to means in specific patients since they
the premise that the test accurately and improve health outcomes (CMS 2004, can have amyloid plaques but not have
reliably identifies the disorder is 32, 37). At the time of the amyloid PET AD. At the Medicare Evidence
reduced in amyloid imaging compared NCD, there was no published evidence Development & Coverage Advisory
to functional imaging, such as FDG, due of clinical utility similar to what was Committee (MEDCAC) meeting held
to the different mechanisms of action. reviewed for FDG PET, and there were specifically on amyloid PET on January
Additionally, the ability of amyloid PET no related studies suggesting that 30, 2013, one expert speaker mentioned
scans to diagnose AD is inherently amyloid PET would be helpful in the that he believed that a patient with mild
reduced by the pathophysiologic differential diagnosis of AD and FTD cognitive impairment (MCI) and a
characteristics of AD since the presence (CMS 2013, 14). Further, because positive amyloid PET scan had
extracellular amyloid b is only one of amyloid PET does not specifically Alzheimer’s disease and that many
two specific findings required for the diagnose other conditions, the clinical other experts agreed with him
diagnosis of AD. The second key factor utility or improved health outcomes (MEDCAC 2013, 31, 53).6 However, no
is the presence of intracellular associated with other diseases is not published clinical trials, studies,
neurofibrillary tangles (NFTs) consisting applicable. consensus publications, or further
of abnormal tau proteins. Amyloid Since the mid-2000s, a number of MEDCAC discussions identified
tracers do not show the presence of clinical trials of different therapies that whether, for amyloid PET, ‘‘objectively-
NFTs or abnormal tau proteins, which target amyloid have failed to produce defined subpopulations of patients with
are not detected by any commercially results of improvement in health cognitive impairment for which the scan
available radionuclide tracer (CMS outcomes (CMS 2013, 61).5 FDG PET (alone or combined with other tests)
2013, 10). In addition, findings based on did not have the same negative trials at may be more or less appropriate. Yet
postmortem investigation and studies the time of our 2004 decision. there are many subtypes of MCI, and
(pathophysiologic alternations in brain some (e.g., amnestic MCI) may be more
E. Determining the Predictive Value of relevant than others. Furthermore, there
biopsies) may not directly translate to Amyloid PET Compared to FDG PET
factors that may be used to make a is evidence that the same level of
clinical diagnosis of patients with We did not have the same concerns amyloid burden detected by a scan may
dementia. regarding false positives using FDG PET mean something very different in say, a
to differentially diagnose AD as we did 66 year-old compared to an 86 year-old
The FDG PET NCD acknowledged that
with amyloid PET. The predictive value (e.g., Le Couteur 2013, Laforce 2011).
AD-type physiology may be present in
of the amyloid PET scan cannot be Yet the [Amyloid Imaging Task Force]
normal individuals with normal
based solely on its capability to ‘‘rule AIT is silent about such potentially
cognitive function; therefore, a positive
out’’ AD, because there is also the risk important distinctions’’ (CMS 2013, 33).
amyloid PET scan does not necessarily
(The AIT was a consensus panel that
mean the individual has AD (CMS 2004, 5 See also Peterson RC. Early Diagnosis of developed recommendations for use of
5). As subsequently noted in the Alzheimer’s Disease: Is MCI Too Late? Current amyloid PET.)
amyloid PET decision memo nine years Alzheimer Research. 2009; 6(4):329; Petersen RC, We concluded in the amyloid PET
later, ‘‘[A]myloid plaques are seen in Smith G, Waring S, et al. Mild cognitive
impairment: clinical characterization and outcome. NCD that ‘‘widespread clinical use of
other diseases, such as dementia with
Archives of Neurology. 1999;56:303–8; National the scan both in many types of patients
Lewy bodies, cerebral amyloid Institute on Aging (NIA) and the Reagan Institute. with unexplained MCI, and to make a
angiopathy, Parkinson’s disease, Consensus recommendations for the postmortem positive diagnosis of Alzheimer’s
Huntington’s disease, and inclusion diagnosis of Alzheimer’s disease. The National
Institute on Aging, and Reagan Institute Working disease (despite insufficient evidence on
body myositis. Amyloid plaques can
Group on Diagnostic Criteria for the
amozie on DSK30RV082PROD with NOTICES

also be detected in cognitively normal Neuropathological Assessment of Alzheimer’s 6 Medicare Evidence Development & Coverage
older adults. Autopsy studies Disease. Neurobiology of Aging. 1997 Jul-Aug;18(4 Advisory Committee (MEDCAC), Meeting: Beta
demonstrate that approximately 33% of Suppl):S1–2; and Technology Evaluation Center Amyloid Positron Emission Tomography (PET) in
older individuals (20–65% depending (TEC), Blue Cross Blue Shield. Beta Amyloid Dementia and Neurodegenerative Disease, Meeting
Imaging with Positron Emission Tomography (PET) Transcript; 2013 January 30. Available from:
on age) who are cognitively normal have for Evaluation of Suspected Alzheimer’s Disease or https://www.cms.gov/Regulations-and-Guidance/
amyloid accumulation at levels Other Causes of Cognitive Decline. 2013 Guidance/FACA/downloads/id66d.pdf (accessed on
consistent with AD pathology (Hulette February;27(5). June 22, 2017). (CMS 2013, 79, 80, and 82)

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15576 Federal Register / Vol. 83, No. 70 / Wednesday, April 11, 2018 / Notices

Dated: March 16, 2018. discharging responsibilities as they DEPARTMENT OF HEALTH AND
Seema Verma, relate to helping to ensure safe and HUMAN SERVICES
Administrator, Centers for Medicare & effective drugs for human use and, as
Medicaid Services. required, any other product for which Food and Drug Administration
Dated: April 5, 2018. FDA has regulatory responsibility. [Docket No. FDA–2018–N–0981]
Alex M. Azar II, The Committee reviews and evaluates
Secretary, Department of Health and Human data on the safety and effectiveness of Preparation for International
Services. marketed and investigational human Cooperation on Cosmetics Regulation
[FR Doc. 2018–07410 Filed 4–10–18; 8:45 am] Twelfth Annual Meeting; Public
drug products for use in the practice of
BILLING CODE 4120–01–P Meeting
osteoporosis and metabolic bone
disease, obstetrics, gynecology, urology, AGENCY: Food and Drug Administration,
and related specialties, and makes HHS.
DEPARTMENT OF HEALTH AND
appropriate recommendations to the ACTION: Notice of public meeting.
HUMAN SERVICES
Commissioner.
SUMMARY: The Food and Drug
Food and Drug Administration The Committee shall consist of a core Administration (FDA or we) is
[Docket No. FDA–2017–N–4561] of 11 voting members including the announcing the following public
Chair. Members and the Chair are meeting entitled ‘‘International
Advisory Committee; Bone, selected by the Commissioner or Cooperation on Cosmetics Regulation
Reproductive and Urologic Drugs designee from among authorities (ICCR)—Preparation for ICCR–12
Advisory Committee, Renewal knowledgeable in the fields of Meeting.’’ The purpose of the public
osteoporosis and metabolic bone meeting is to invite public input on
AGENCY: Food and Drug Administration,
HHS. disease, obstetrics, gynecology, urology, various topics pertaining to the
pediatrics, epidemiology, or statistics regulation of cosmetics. We may use
ACTION: Notice; renewal of advisory
and related specialties. Members will be this input to help us prepare for the
committee.
invited to serve for overlapping terms of ICCR–12 meeting that will be held July
SUMMARY: The Food and Drug up to 4 years. Almost all non-Federal 10 to 12, 2018, in Tokyo, Japan.
Administration (FDA) is announcing the members of this committee serve as DATES: The public meeting will be held
renewal of the Bone, Reproductive and Special Government Employees. The on June 7, 2018, from 2 p.m. to 4 p.m.
Urologic Drugs Advisory Committee by core of voting members may include one See the SUPPLEMENTARY INFORMATION
the Commissioner of Food and Drugs technically qualified member, selected section for registration date and
(the Commissioner). The Commissioner by the Commissioner or designee, who information.
has determined that it is in the public is identified with consumer interests ADDRESSES: The public meeting will be
interest to renew the Bone, and is recommended by either a held at the Food and Drug
Reproductive and Urologic Drugs consortium of consumer-oriented Administration, Center for Food Safety
Advisory Committee for an additional 2 organizations or other interested and Applied Nutrition, 5001 Campus
years beyond the charter expiration persons. In addition to the voting Dr., Wiley Auditorium (first floor),
date. The new charter will be in effect members, the Committee may include College Park, MD 20740.
until March 23, 2020. one non-voting member who is FOR FURTHER INFORMATION CONTACT:
DATES: Authority for the Bone, identified with industry interests. Jonathan Hicks, Office of Cosmetics and
Reproductive and Urologic Drugs Further information regarding the Colors, Food and Drug Administration,
Advisory Committee will expire on 5001 Campus Dr. (HFS–125), College
most recent charter and other
March 23, 2020, unless the Park, MD 20740, jonathan.hicks@
information can be found at https://
Commissioner formally determines that fda.hhs.gov, 240–402–1375.
www.fda.gov/AdvisoryCommittees/
renewal is in the public interest.
CommitteesMeetingMaterials/Drugs/ SUPPLEMENTARY INFORMATION:
FOR FURTHER INFORMATION CONTACT:
ReproductiveHealthDrugs I. Background
Kalyani Bhatt, Division of Advisory
AdvisoryCommittee/ucm107572.htm or
Committee and Consultant The intention of the ICCR multilateral
by contacting the Designated Federal
Management, Center for Drug framework is to pave the way for the
Officer (see FOR FURTHER INFORMATION
Evaluation and Research, Food and removal of regulatory obstacles to
CONTACT). In light of the fact that no
Drug Administration, 10903 New international trade while maintaining
Hampshire Ave., Bldg. 31, Rm. 2417, change has been made to the committee
name or description of duties, no global consumer protection. The
Silver Spring, MD 20993–0002, 301– purpose of the meeting is to invite
796–9001, email: BRUDAC@fda.hhs.gov. amendment will be made to 21 CFR public input on various topics
14.100.
SUPPLEMENTARY INFORMATION: Pursuant pertaining to the regulation of
to 41 CFR 102–3.65 and approval by the This document is issued under the cosmetics. We may use this input to
Department of Health and Human Federal Advisory Committee Act (5 help us prepare for the ICCR–12 meeting
Services pursuant to 45 CFR part 11 and U.S.C. app.). For general information that will be held July 10 to 12, 2018, in
by the General Services Administration, related to FDA advisory committees, Tokyo, Japan.
FDA is announcing the renewal of the please check https://www.fda.gov/ ICCR is a voluntary international
amozie on DSK30RV082PROD with NOTICES

Bone, Reproductive and Urologic Drugs AdvisoryCommittees/default.htm. group of cosmetics regulatory
Advisory Committee (the Committee). Dated: April 5, 2018. authorities from Brazil, Canada, the
The Committee is a discretionary European Union, Japan, and the United
Leslie Kux,
Federal advisory committee established States of America. These regulatory
to provide advice to the Commissioner. Associate Commissioner for Policy. authority members will engage in
The Committee advises the [FR Doc. 2018–07437 Filed 4–10–18; 8:45 am] constructive dialogue with their
Commissioner or designee in BILLING CODE 4164–01–P relevant cosmetics industry trade

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Document Created: 2018-04-10 23:59:05
Document Modified: 2018-04-10 23:59:05
Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice.
Contact		Linda Gousis, (410) 786-8616.
FR Citation		83 FR 15572
83 FR 15572 - Medicare Program; Reconciling National Coverage Determinations on Positron Emission Tomography (PET) Neuroimaging for Dementia

DEPARTMENT OF HEALTH AND HUMAN SERVICESCenters for Medicare & Medicaid Services

Federal Register Volume 83, Issue 70 (April 11, 2018)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Centers for Medicare & Medicaid Services
