Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

I am writing as a radiologist and nuclear medicine physician active in neuroimaging in clinical and research settings.

I believe that the restrictive coverage decision for amyloid PET poorly serves many patients suffering from cognitive impairment as well as their families. Accurate and early diagnosis of serious medical conditions such as dementia is fundamental to making informed clinical decisions even in the absence of disease-modifying treatments. It is also critical to patients and their families as they make difficult decisions about personal, professional, financial, and legal matters. These issues are particularly urgent in patients in the early stages of Alzheimer's disease who have limited time to express in advance their preferences and to focus their attention on family, friends, and meaningful activities.

While not a panacea, amyloid PET is a valuable test that can help exclude or support the diagnosis of Alzheimer's disease. I am regularly approached by dementia specialists who would like to order amyloid PET to assist them with clinically challenging or atypical presentation of cognitive impairment. This test will remain unavailable to many of these patients under the current coverage with evidence proposal.

I agree with many of the commenters that the appropriate use criteria developed by the Society of Nuclear Medicine and Molecular Imaging in conjunction with the Alzheimer's Association are a reasonable and responsible approach to using amyloid PET. If implemented, these criteria would limit the use of amyloid PET to clinical scenarios likely to increase the accuracy of diagnosis. I strongly urge CMS to put the interests of patients, their families, and their caregivers first and to adopt a coverage policy for amyloid PET that will make this test available based on these guidelines.

Sincerely,

Jonathan McConathy MD, PhD
Assistant Professor of Radiology
Washington University School of Medicine

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I believe that proving more tools to the physicians to make a more accurate diagnosis will in the long run be cost effective. In the case for beta amyloid imaging, weighing the probability of AD or non-AD causes of MCI should allow the physician, family and social services to better plan for the management of the patient.

With the current trend of increasing longevity and the baby-boomers reaching the ages where MCI is more prevalent as is the prevalence of chronic disease such as cardiovascular disease and diabetes. We as a society do share the burden and costs, directly or indirectly, with the families of the effected persons. As almost 50% of patients with dementia are without definitive diagnosis, to these 50%, treatment is at best an educated guess. Surely the financial and non-financial resources could be better targeted if a diagnostic test could weigh the probability of, say AD or non -AD cause of the MCI. A non-diagnosis or a missed diagnosis of any disease is a cost not only to the individual and the family, but a definite cost to the society as a whole. Dementia is probably more costly in terms of the financial, and psychological burden to the family and society than other chronic diseases.

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Re: CAG-00431N - National Coverage Analysis for Beta Amyloid PET in Dementia and Neurodegenerative Disease

The proposal by CMS to cover one amyloid PET scan through coverage with evidence development (CED) in clinical studies that meet certain clinical endpoints is not reasonable given the recent recommendations by the SNMMI and Alzheimer's Association. Covering one PET scan under the appropriate use criteria (AUC) guidelines IS reasonable and will allow patients to be triaged to the most appropriate care, eliminating years of uncertainty and expense.

Patients with Alzheimer's disease or other forms of dementia have to be managed by a broad spectrum of health care professionals. Engaging these professionals in a timely manner has proven to be cost effective.

There is tremendous momentum building around dementia and neurodegenerative diseases in the public and private sectors. We are beginning to see strong longitudinal data from the ADNI and AIBL studies and there is very clear direction coming from the National Plan to Address Alzheimer's Disease. I believe it is important for CMS to make a coverage decision that will not hinder this momentum in any way. I am hopeful CMS will adopt the SNMMI and Alzheimer's Association appropriate use criteria and make coverage available to it's Medicare beneficiaries as soon as possible.

Thank you for the opportunity to comment.

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I am a practicing behavioral neurologist in a specialty dementia center, and a researcher using neuroimaging as a tool in my studies. In my role as a clinician, I am often in the position of providing highly specialized expert opinion about the cause of a patient's cognitive impairment or dementia. In many cases that are referred to my program, the clinical presentation is unusual. In the cases in which the presentation is commonplace, I can often be highly confident in my diagnostic opinion based on clinical assessment and do not require specialized diagnostic testing such as FDG-PET imaging or spinal fluid examination. In many other cases in which the presentation is unusual, my expert diagnostic opinion requires further information about the neurobiology of the disease from specialized diagnostic testing. I use FDG-PET and spinal fluid analysis for amyloid beta and tau proteins frequently in my clinical practice and find them both to be of great value in some such cases. Their value is in increasing my confidence in the diagnosis, which ultimately strongly influences my treatment decisions and my prognostic counseling of the patient and family. Based on this experience, I believe it would be of great value to make amyloid PET imaging more readily available through CMS reimbursement under special circumstances as recommended by the Alzheimer's Association/Society for Nuclear Medicine Amyloid Imaging Task Force. I believe that specialists such as myself will be able to make judicious and cost-effective use of this tool to improve our confidence in the diagnosis of atypical dementia cases. Spinal fluid examination is valuable, but not all patients can tolerate it and we need a non-invasive test that provides similar information, which amyloid PET imaging does.

In my medical opinion, this will impact patient/family outcomes by 1) avoiding further ambiguity in an already very difficult diagnostic process; 2) avoiding unneccessary treatments that are attempted empirically when it is not clear whether a patient is likely to harbor brain amyloid or not; 3) streamlining the process of treatment, care, and prognosis that is possible when an expert clinician is highly confident in the patient's diagnosis. This impact on outcome is not as obvious as it may be when one day we have disease-modifying therapies tied to the presence or absence of brain amyloid, but it is nevertheless quite meaningful in today's practice by dementia specialists and the patients and families we care for. I agree also that this is very much in the spirit of the President's NAPA.

Brad Dickerson, MD

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Today, CMS posted a comment submitted on behalf of the American Academy of Neurology (AAN). The AAN stands out among professional organizations submitting their comments in this forum, as having done an admirable job of responsibly sticking (nearly) exclusively to the facts in the face of an intimidating field of public comments asserted by many professional organizations or collaborative groups and displayed here, which have strayed far into the territory of largely opinion-based rather than fact-based positions (...and it is worth bearing in mind that even "consensus opinions" of organization-appointed "experts" are, after all, still only opinions... and that there will always remain a huge gulf between expert-based opinion and evidence-based facts... as Medicine is replete with numerous glaring examples of 'consensus expert opinions' that have fallen to the wayside, once the actual facts were established by the collection of prospective well-controlled data subjected to objective interpretation and subsequent peer-review.)

Thus, with all due respect to the AAN (and very much is due) for making a conscientious effort to provide a factually based position statement, it is worthwhile reviewing a couple of places in their posted statement where there may be some deviation from, or incomplete consideration of, the available scientific evidence, as follows (AAN statements are denoted by quotation marks; annotations regarding factual basis are denoted by square brackets):

"We agree that the current evidence is insufficient to conclude that the use of PET Aß imaging improves health outcomes in Medicare beneficiaries with dementia or other related neurodegenerative diseases, with the exception of a few circumstances. For example, we believe that the distinction between Alzheimer’s disease and frontotemporal degeneration (FTD) can be confirmed with amyloid imaging and that this distinction has a direct impact on patient care."
[This is at least partially true (although it fails to take into account that a negative amyloid scan does not mean that a patient has FTD, so unlike with FDG (which CMS does already cover for this indication), the imaging will provide no information on which of the numerous other potential causes besides AD the patient's cognitive decline is actually due to)... nonetheless, the differential diagnosis can be informed at least as accurately, and far more usefully and safely with FDG-PET, using a dose of an established tracer that is currently marketed at about one-tenth of the price of Amyvid, and for which over two decades greater experience have already been obtained... for a more detailed analysis of this issue, please see www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=26854&ReportType=nca ]

"In addition, other clinically difficult diagnostic dilemmas can be informed by amyloid imaging. Examples include conditions such as posterior cortical atrophy, logopenic aphasia, some dysexecutive syndromes..."
[This may or may not be true... peer-reviewed publications reporting amyloid imaging on people with gold-standard confirmation of these diagnostic entities are very few, and involve very small numbers of patients with confirmed diagnoses, even in aggregate... and there is certainly no evidence that these differential diagnoses can be made more effectively with amyloid imaging than with FDG-PET, for which the same considerations apply as were just mentioned in the context of differentiating AD from FTD.]

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Dear Dr. Jacques:

I am a practicing nuclear medicine physician in an academic health care center. My practice includes all aspects of nuclear medicine including brain imaging. We have had FDG PET available to our patients for many years to help sort out the challenging cases of fronto-temporal dementia vs. Alzheimer’s disease. While we do these studies occasionally, they are certainly used infrequently. Thus, I am quite puzzled by CMS very restrictive proposed coverage determination for the imaging of Beta Amyloid. The guidelines from the Alzheimer’s association and Society of Nuclear Medicine are quite conservative and if our experience from FDG holds true, the amyloid scan will be used in a small minority of difficult cases.

Moreover, I am puzzled by CMS willingness to pay for physical exams, cognitive testing, MRI scans in the diagnosis of AD, even though careful studies have not demonstrated that each of these elements clearly improves outcomes in demented patients. However, CMS quite willing pays for prescribed medications to treat presumed AD, even when it is abundantly clear that such diagnoses are not uncommonly flawed and the medication may be given to a population who may not benefit from the treatment.

Thus, an “amyloid negative” PET scan in a younger, questionably demented, individual could be very helpful in directing the diagnostic workup and subsequent therapy. Few of our tests have such good negative predictive value. Thus, I strongly support the conservative AUC put forth by the AA/SNM.

CMS suggests registry , or CED, studies could be done in patients who are to receive amyloid PET scans , with biopsy proof of brain amyloid deposition required. Such an approach is not necessary and unduly limits access to this valuable technology. It is clear from well designed and performed studies, some at my institution, that amyloid PET signals substantially reflect beta amyloid burden. This is settled science. A registry, or CED, specifically examining change in management, including decisions NOT to use expensive medications in patients who do not have AD by scan, could be more interesting in a subset of patients.

It is quite frustrating to have my hands tied as a physician and not be able to offer the most informative diagnostic imaging tests to my patients, especially when the tests are FDA approved. I strongly believe a limited subset of patients with cognitive decline as outlined in the AUC , should be able to receive beta-amyoid PET imaging, per the FDA approved labeled indication and would benefit.

I would be happy to work with CMS on strategies to rationally deploy this technology, which may indeed be resource conserving as opposed to resource consumptive. Quicker and more accurate diagnosis is a valuable health care outcome. I am hopeful CMS will revise and liberalize their coverage for this important scan in their revised documents.

Sincerely,

Richard L. Wahl, M.D
Director of Nuclear Medicine and PET Center
Johns Hopkins University School of Medicine
Henry N. Wagner, Jr. Professor of Nuclear Medicine

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I have read most of the comments for this proposed decision memorandum. After digesting many of the well thought out data driven comments, I would like to propose a way to move forward that could be more cost effective in the long run and, one that could provide patients appropriate access to this important procedure.

The draft decision memo recommends one PET scan. “ Therefore, we propose to cover one PET Aß scan per patient through coverage with evidence development (CED)”, if the CED meets certain conditions listed in the proposed memorandum.
CMS should consider instead allowing one PET scan for a patient meeting the conditions covered in the Appropriate Use Criteria, published by SNMMI and the Alzheimer’s Association. Then if warranted, other conditions could be considered under CED or a clinical trial. Establishing a CED for the use of one PET scan per patient for narrowly defined conditions seems unnecessary given that the AUC guidelines are well defined. If further data review regarding patient management is desired, CMS could simply provide a unique code (G code, CPT code or modifier) for the amyloid PET scan. This code would serve as a unique identifier so data mining activities could evaluate the use of procedures prior to and after the uniquely coded amyloid scan.

Further, if CMS were to follow their most recent PET coverage decisions, they could approve one PET scan under AUC guidelines, and then allow further indications to be decided by the regional Medicare Contractors.

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As President of SNMMI's Center for Molecular Imaging Innovation and Translation and a molecular imaging researcher, I appreciate the opportunity to comment on the Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. In issuing its approval, the FDA noted the clinical utility of Amyvid, and I believe that sufficient evidence exists to support immediate coverage by Medicare. The proposed coverage with evidence development is overly burdensome, as it would require patients be entered into a clinical trial in which postmortem autopsy is required, leading to long delays in data collection and complications in interpretation. The Alzheimer's Association and Society of Nuclear Medicine and Molecular Imaging have jointly developed appropriate use criteria that clearly define scenarios in which beta-amyloid PET imaging is clinically and scientifically justified.
As a molecular imaging researcher, I am concerned about the broader effect of this CMS decision on the development of molecular imaging techniques. These techniques provide great potential to provide early diagnosis, accurate staging, and monitoring of response to therapy that can lead to better health outcomes and more effective utilization of resources. Such burdensome standards for coverage risk stifling innovation in this important field. I urge you to reconsider your decision.

Respectfully submitted,
Todd E. Peterson, Ph.D.

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I applaud CMS in its decision to allow for the coverage of one Beta Amyloid PET scan per patient in approved clinical studies that focus on health outcomes. By allowing for reimbursement for PET scans, Alzheimer’s research will not be stifled. As CMS correctly determined, the field is not ready to handle the logistics of widespread testing. Many of Medicare’s beneficiaries will have a positive result, which could unnecessarily devastate one of our country’s most vulnerable populations…seniors who may have had limited educations. They will turn to their doctors for guidance & hope, and their doctors will either prescribe marginally effective medications or place them in clinical research trials. Our patients deserve more. CMS should not pay for a test that at best creates more questions than answers, and at worst assigns an incurable diagnosis that the patient might not even have.

Proponents of wide-spread Beta Amyloid PET scanning argue that the reason anti-amyloid therapies have not been effective is because they have not been provided early enough in the course of the disease. This has not been proven, and could lead to hundreds of thousands of people 1.) getting a diagnosis that they don’t necessarily have, 2) getting on a medication that may not be effective for the condition, and 3.) getting on disability when they may still have many more productive years left. Furthermore, this particular population (< 65 years old) is not generally covered by Medicare, so Medicare should not be determining such coverage.

The finality of a diagnosis is what Beta Amyloid PET scanning promises, but it might not be the right diagnosis. Memory problems may be attributed to cerebral amyloid, but that may not be the cause. Access to PET scanning and waiting to be scheduled/waiting for the results would actually increase, not decrease time to be started on therapy. It is not primary care providers, neurologists, neuropsychologists, or even patient’s that are clamoring for testing, it is those who have financial stakes in Beta Amyloid PET scanning approval.

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August 2, 2013

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Dr. Jacques,

As an Alzheimer’s disease brain imaging researcher, psychiatrist and executive director of an organization that serves the needs of patients and families with Alzheimer’s and related diseases, I urge CMS to reconsider its draft decision and approve reimbursement for beta-amyloid positron emission tomography (PET) under the Amyloid Imaging Task Force’s Appropriate Use Criteria (AUC).

Several factors merit this further consideration and support the Taskforce’s recommendations:

1. We have an inadequate standard of care for patients and family caregivers. Nearly two in every three patients with dementia do not receive an evaluation, diagnosis, or exclusion of potentially reversible contributors to their cognitive impairment. Most family caregivers feel isolated, helpless, exhausted and overwhelmed by the condition, and more than half become clinically depressed. There is much more that the field can do for patients and families today—even before treatments are available to slow down or stop the underlying disease. The AUC would encourage health care providers to ask patients about memory and thinking problems and to either conduct an appropriate medical evaluation or refer them to a specialist who can.

2. There is a lot one can do for patients and family caregivers after an Alzheimer’s diagnosis. Patients, families, health care providers, policy makers and payers need to understand what an effective management plan involves and what a difference the right kind of medical and non-medical management can make. Patients deserve to have their memory and thinking problems recognized and properly evaluated, to have potentially reversible contributors identified and treated, to learn whether they are appropriate candidates for an approved medication treatment, and to be informed of relevant clinical trials. They and their family caregivers should know more about the challenges they may face, decisions they may face regarding work, driving, safety, financial and even legal issues, the proactive steps they can take to mazimize their quality of life, and where they can turn for additional help. Under the AUC, stakeholders would be encouraged to consider the possibility of a beta-amyloid PET scan within the context of a more comprehensive management plan, a beta-amyloid PET scan would be limited to those circumstances that would have a meaningful impact on patient management, and our patients and families would receive better care.

3. A beta-amyloid PET scan can improve confidence in a patient’s diagnosis and clinical course. While ongoing longitudinal studies will further clarify the extent to which a beta-amyloid PET scan, alone or in combination with other factors, predicts a cognitively impaired person’s clinical course, the information already in hand indicates that there is a close correlation between ante-mortem PET measurements and post-mortem histopathological measurement of beta-amyloid plaque deposition (the “standard-of-truth”) and that beta-amyloid PET findings can improve confidence in the judgment about subsequent clinical course. When used in the appropriate way, this information will empower patients, families, and professional caregivers in the development and implementation of a comprehensive medical and non-medical management plan.

4. The AUC are appropriate, justified and crtically needed. Under the AUC, a beta-amyloid PET scan will maximize diagnostic value, minimize excessive use and cost, ensure that the scan is not substituted for thoughtful and thorough patient evaluation, and improve the current standard of care.

I urge CMS to consider each of the points and recommendations made by the Amyloid Imaging Task Force, to also consider broader context of what is needed to help establish a higher standard of a higher standard of care for our patients and families, and approve reimbursement for amyloid PET under the AUC.

Thank you for your consideration.

Sincerely,

Eric M. Reiman, M.D.
Executive Director, Banner Alzheimer’s Institute
CEO, Banner Research

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Dear Dr. Jacques,

I am a neurologist at an academic dementia center and care for patients with cognitive impairment and dementia. In practice and research, the utility of amyloid PET has proven useful in diagnosis and management of these patients. Cases in which I have found particular use is distinguishing between frontotemporal dementia and Alzheimer's disease. I believe the knowledge of having Alzheimer's disease pathology can also help quality of life for people who want to know their diagnosis and want to plan for the future. Additionally, the knowledge of having Alzheimer's disease pathology allows the clinician to offer known treatments (cholinesterase inhibitors, memantine). I am writing to urge CMS to reconsider its draft decision and approve reimbursement of amyloid PET imaging.

Sincerely,

Sharon J. Sha, M.D., M.S.

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Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’s) National Coverage Decision (NCD) Tracking Sheet for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N). America’s Health Insurance Plans (AHIP) is the national association for the health insurance industry. Our members provide coverage to more than 200 million Americans, offering a broad range of health insurance products in the commercial market and demonstrating a strong commitment to participation in public programs.

General Comments

AHIP and our member health plans encourage CMS to ensure that all patients receive safe, effective and evidence-based treatments. Our members agree with CMS’ conclusions outlined in the NCD that the evidence is insufficient to conclude that the use of positron emission tomography (PET) amyloid-beta imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease. Our members recognize the urgent need for improved therapeutics in the prevention or amelioration of dementia, and support the decision to cover one PET amyloid-beta scan per patient under coverage with evidence development, in qualified clinical trials as defined in the CMS Clinical Trial Policy.

Additional Information Is Needed

Safety and effectiveness of the radiopharmaceutical agent utilized in PETs have not been established for predicting the development of dementia or other neurologic conditions or monitoring responses to therapies. Radiopharmaceuticals can contribute to a patient's overall long-term cumulative radiation exposure; and studies have shown that long-term cumulative radiation exposure is associated with an increased risk of cancer. There are very few published clinical trials for PET scanning in dementia, such as Alzheimer’s disease. Most of the published studies are small prospective cohort studies (not randomized or blinded) which show low specificity of the imaging agent and a clear need for further study.

There is a need for definitive criteria (cut-off ranges) for use in the interpretation of these scans to determine what constitutes a positive study. There is also a need for specialized training related to interpretation of these scans (because the image-interpretation process differs markedly from that typically used in nuclear medicine), and the fact that beta-amyloid neuritic plaque have been detected in patients with a variety of neurological disorders, in addition to older people with normal cognition.

Clinical utility of diagnostic testing is of paramount importance and the impact on clinically relevant health outcomes must be considered. Therefore, our members agree that because this diagnostic test has marginal operating characteristics and no evidence of clinical utility at this time, this type of test should be limited to use in qualified clinical trials, as defined in CMS’ Clinical Trial Policy. Qualified clinical trials have the scientific rigor and control that better enable them to generate the evidence necessary to make definitive judgments as to whether an item or service meets the evidentiary standards for reasonable and necessary. These trials should be focused on addressing safety and efficacy so that usable information is collected and applied to the coverage determination process.

Thank you for the opportunity to comment on this important issue.

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I strongly support CMS in its decision to take a measured, informed and responsible position regarding Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease.

The U.S. government should not succumb to pressure from pharmaceutical manufacturers who prey upon the public’s fear of Alzheimer’s disease to rush to diagnosis of Alzheimer's and to treat it with drugs of unknown efficacy or safety in individuals who may or may not have the disease. The industry has cynically promoted atypical antipsychotic medications to nursing homes and assisted living facilities to sedate and chemically restrain persons with Alzheimer’s, although these drugs have FDA Black Box Warnings that they should not be used to treat elderly persons with dementia because they can cause serious illness and death. Any effort by the pharmaceutical industry to rush Alzheimer’s drugs to market should be considered against the backdrop of the way these companies have exploited people with the disease.

In addition to the U.S Justice Department, more than half the states have filed lawsuits alleging illegal marketing of antipsychotic drugs to treat persons with dementia by companies that have now joined with nonprofit organizations to promote the development of new and potentially unsafe medications for persons with dementia. The government should protect the public against exploitation and let Alzheimer’s research and drug development proceed with strong scientific safeguards.

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Thank you for the opportunity to comment on the CMS draft decision. I am a neurologist and a clinical researcher who has been working in Alzheimer’s disease (AD) for the past 20 years. I specifically remember the first presentation of PET amyloid imaging data at the International Conference on Alzheimer’s Disease in 2002 and the strong sense that this technology would greatly aid our field in bringing accurate diagnosis to our patients and ultimately in finding a successful disease-modifying therapy. Over the past decade, there has been remarkable progress in PET amyloid imaging research, particularly in providing evidence that this technology is indeed able to detect the presence of amyloid plaques—the hallmark pathology required for the neuropathological diagnosis of AD—in the living brain with very high accuracy.

Although I appreciate the thoughtful process of the committee, I strongly urge the CMS to reconsider the draft decision, as I am very concerned that the proposed CED will greatly hamper progress in the field and deny the opportunity for accurate diagnosis and appropriate treatment for patients currently suffering from dementia in whom there is diagnostic uncertainty. The Alzheimer’s Association and Society of Nuclear Medicine and Molecular Imaging brought together a group of experts in the field to develop Appropriate Use Criteria (AUC) for PET amyloid imaging ⁽¹⁾. These criteria are well considered, and I would urge CMS to consider adopting these criteria for limited coverage of clinical scans immediately.

I am a practicing clinician, and I particularly want to urge limited coverage for the small subset of patients with a progressive dementia syndrome that includes unusual or confusing clinical features. CMS has already acknowledged in a previous coverage decision that making the diagnostic distinction between Alzheimer’s disease and Fronto-temporal dementia (FTD) has important clinical consequences for the patient. PET amyloid imaging has already demonstrated superiority to FDG-PET in confirming the diagnosis of AD vs. FTD in several studies, with autopsy confirmation ^(2,3).

Although my own work has focused on research in the very early “preclinical” stages of AD, I certainly do not believe that PET amyloid imaging should be used clinically for screening normal individuals, those with subjective cognitive complaints, or even those with questionable mild cognitive impairment at this point, as I agree with CMS that more data needs to be gathered in these populations to determine the prognostic value and impact on treatment decisions. I do have one specific concern with the proposed CED regarding clinical trials, as the evidence already gathered from the Bapineuzumab and Solaneuzumab trials suggest that approximately 22% of mild AD dementia patients enrolled in these studies are “amyloid-negative” on PET amyloid imaging, and that these patients do not show clinical decline typical of AD ^(4,5). At this point, it would seem unethical to enroll amyloid-negative patients into clinical trials aimed at altering amyloid pathology, putting these patients at risk for adverse effects and subjecting them to the burden of a trial that is very unlikely to provide any benefit if they lack the target pathology.

Finally, I wish to strongly urge CMS to provide limited coverage according to the AUC criteria on the basis of fairness to their broad constituency of older citizens. Since florbetapir was approved by the FDA last year, patients who are fortunate enough to have the financial means have been able to obtain florbetapir scans through private payment. Patients from high education, high socio-economic (SES) strata (and unfortunately in our country, patients in these strata remain overwhelmingly Caucasian) are currently the only ones able to benefit from these diagnostic advances, while unfortunately patients from lower SES, who are actually disproportionately affected by dementia, will be denied access to technology to aid accurate diagnosis and appropriate treatment.

If we are to achieve the goal set forth by our government with the National Alzheimer’s Project Act (NAPA) in 2011, to find an effective treatment for Alzheimer’s disease by 2025, we must move forward quickly and avail ourselves of this important advance to improve the diagnosis and care of our senior citizens afflicted with this terrible disease.

1) Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, Karlawish JH, Rowe CC, Hedrick S, Pappas V, Carrillo MC, Hartley DM. Update on appropriate use criteria for amyloid PET imaging: Dementia experts, mild cognitive impairment, and education. Alzheimers Dement. 2013 Jul;9(4):e106-9. doi: 10.1016/j.jalz.2013.06.001; and J Nucl Med. 2013 Jul;54(7):1011-3.
2) Rabinovici GD, Rosen HJ, Alkalay A, Kornak J, Furst AJ, Agarwal N, Mormino EC, O'Neil JP, Janabi M, Karydas A, Growdon ME, Jang JY, Huang EJ, Dearmond SJ, Trojanowski JQ, Grinberg LT, Gorno-Tempini ML, Seeley WW, Miller BL, Jagust WJ. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology 2011;77(23):2034-2042.
3) Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, O'Keefe G, Ackerman U, Tochon-Danguy H, Chan JG, Reininger CB, Fels L, Putz B, Rohde B, Masters CL, Rowe CC. Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias. J Nucl Med 2011;52(8):1210-1217.
4) Sperling R, Salloway S, Raskind M, Ferris S, Honig L, Porsteinsson A, Sabbagh M, Yuen E, Liu E, Lu Y, Lull J, Miloslavsky M, Wang D, Tudor C, Nejadnik B, Guenzler V, Reichert M, Ketter N, Grundman M, Black R, Brashear R On Behalf of the Bapineuzumab Study Investigators Bapineuzumab Phase 3 trials in mild to moderate Alzheimer’s disease dementia in apolipoprotein E e4 carriers (Study 302) and non-carriers (Study 301). American Neurological Association October 2012.
5) Salloway S, Sperling R, Gregg K, Zhao X, Yu P, Joshi AD, Lu M Mintun MA, Pontecorvo MJ, Booth K, Wyman B, Sun J, Sundell K, Schmidt M, Margolin R, Skovronsky DM, Liu E, Siemers E, Brashear HR, for the bapineuzumab and solanezumab investigator groups. Characterization of the Clinical Course of Placebo-Treated Amyloid-Negative Subjects with Mild-Moderate Alzheimer’s Disease (AD): Results from the Phase 3 PET Sub-studies. Alzheimer’s Association International Conference Boston, July 2013.

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August 2, 2013

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

VIA ELECTRONNIC SUBMISSION

Re: CAG- 00431N Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear Dr. Jacques:

The American College of Radiology (ACR), representing more than 34,000 diagnostic radiologists, interventional radiologists, radiation oncologists, nuclear medicine physicians and medical physicists, is pleased to submit comments on the Centers for Medicare & Medicaid Services (CMS) Proposed National Coverage Decision for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. The ACR continues to support national coverage and would urge CMS to revise their proposed coverage criteria in implementing the final coverage decision.

The ACR recommends national coverage for the use of PET with a radiopharmaceutical to image beta-amyloid plaques, as beta-amyloid detection is invaluable to the multi-disciplinary armamentarium used to evaluate early dementia. We believe there is evidence to show the benefits in patient management when combined with the Appropriate Use Criteria (AUC) developed by the Alzheimer’s Association (AA) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). These criteria go a long way to addressing restricting imaging to those scenarios where there does appear to be sufficient evidence for imaging narrowly defined patients and clinically difficult differential diagnoses. The ACR feels the proposed CED coverage criteria would be difficult and costly to implement and would urge CMS to re-evaluate and consider alternative data collection approaches and approve national coverage of the three AUC indications.

Meaningful Patient Management
Earlier detection with beta-amyloid PET imaging, combined with following the Appropriate Use Criteria (AUC), is important in the management of patient care. Earlier detection with AUC allows the much needed time for physicians and their families to make meaningful management decisions. This may change the timing and increase of patient treatment and care, planning and preparation, therapies and medications, logistics and costs etc. Diagnosing as well as excluding Alzheimer’s disease is significant in making important decisions in patient management. This provides answers and direction with addressing the symptoms of the patient and treating differential diagnosis and significantly impacting the quality of care and management.

Appropriate Use Criteria
We agree and support SNMMI’s recommendations regarding the Appropriate Use Criteria (AUC) and urge CMS to evaluate their findings below.

The criteria demonstrated that for amyloid imaging to be considered appropriate, individuals must exhibit several characteristics. These include: (1) a cognitive complaint with objectively confirmed impairment; (2) Alzheimer's disease (AD) as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (3) knowledge of the presence or absence of amyloid-beta pathology is expected to increase diagnostic certainty and alter management.

We also believe when all of these criteria are met, amyloid PET imaging is appropriate in the following scenarios:

Coverage with Evidence Development
ACR does not support the proposed CMS Coverage with Evidence Development (CED) criteria trial design tied to autopsy, as this is a difficult end point to achieve in a CED framework. CED framework is more suited for observational studies. Almost no imaging trials or non-imaging trials for coverage have been tied to autopsy because of the difficulty in getting autopsies in large numbers of patients. This is especially true in a disease that may take many years and perhaps two decades to progress; death may occur from other obvious causes that may make it difficult for families to understand why autopsy is needed.

The ACR urges CMS to re-evaluate the proposed CED coverage and implement national coverage per AUC indications and refer to the FDA labeled indications and findings. Additionally, CMS may want to consider alternative data collection checklist approaches similar to the NCD structure previously placed on FDG PET for dementia. If CMS decides for a CED framework, ACR urges CMS to consider more appropriate short term criteria for patients with dementia such as actual management change and quality of life change as achievable end points under a CED framework.

ACR Procedure Guideline: Training and maintenance of skills of interpretation
The ACR is developing a collaborative Procedure Guideline with the American Society for Neuroradiology (ASNR) in an effort to put forth a collective document addressing indications, qualifications and responsibilities of personnel including physician training, skill maintenance, experience for interpretation, brain PET/CT examination specifications, equipment specifications, documentation, equipment quality control, radiation safety, radiopharmaceuticals quality control, and improvement/safety/infection control/and patient education. A draft guideline will be released for public comments in August 2013 and a final guideline release in 2014. Additionally, the ACR and Dartmouth has a PET/CT educational course available through the ACR’s Education Center located in Reston, VA. The ACR has the capacity and experience to expand topics and develop future educational programs in promoting brain PET/CT in dementia.

Conclusion
The ACR requests that CMS revise the proposed PET NCD and implement national coverage for the use of beta-amyloid PET scans as a diagnostic test for the purpose of estimating beta-amyloid neuritic plaque density in adult patients with documented cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline, as per the AUC and work with the societies and stakeholders in developing alternative checklist criteria tailored to Beta Amyloid imaging. If CMS decides for a CED framework, ACR urges CMS to consider more appropriate short term criteria for patients with dementia such as actual management change and quality of life change as achievable end points under a CED framework.

Thank you for the opportunity to comment on this important national coverage decision. If you have any questions, please contact Anita McGlothlin at 800-227-5463 extension 4923 or via e-mail at amcglothlin@acr.org.

Respectfully Submitted,

Harvey L. Neiman, MD, FACR
Chief Executive Officer
American College of Radiology

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The World Molecular Imaging Society (WMIS) appreciates the opportunity to comment on the Proposed Decision Memorandum on Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N).

WMIS recognizes that the Proposed Decision proposes an option for providing a limited number of Medicare beneficiaries with beta amyloid PET through coverage with evidence development (CED). However, WMIS is concerned that the Proposed Decision reflects unwarranted skepticism from CMS about both the current state of the evidence for beta amyloid PET and the value of the consensus Appropriate Use Criteria (AUC) developed by the Alzheimer’s Association (in partnership with the Society of Nuclear Medicine and Molecular Imaging). WMIS encourages CMS to adopt a more nuanced approach to both of these key issues—coverage and CED—in its Final Decision.

First, WMIS believes that for certain specific indications as reflected in the Appropriate Use Criteria, the clinical evidence for beta amyloid PET is sufficient to warrant coverage as reasonable and necessary. WMIS cautions that a final decision that simply denies coverage for all indications without distinguishing between them would be unwarranted and limit beneficiary access to beta amyloid imaging.

Second, if CMS nevertheless remains convinced that CED is warranted for certain uses of beta amyloid PET, WMIS is concerned that it will be exceptionally difficult for researchers to craft feasible CED studies that could ever meet the Proposed Decision’s proposed thresholds, particularly the use of “randomization and postmortem diagnosis as the endpoint.” If CMS is intent on requiring CED for the coverage of beta amyloid PET for certain indications, WMIS encourages CMS to provide significantly more flexibility in both the design of and beneficiary eligibility criteria for such studies.

Background

WMIS is an international scientific educational organization dedicated to the understanding of biology and medicine through multimodal in vivo imaging of cellular and molecular events involved in normal and pathologic processes, and the utilization of quantitative molecular imaging in patient care. At present, WMIS has over 1,000 members. WMIS was formed in 2011, as a result of the merger of two of the premier molecular imaging societies — the Academy of Molecular Imaging and the Society for Molecular-Genetic Imaging. Between 2006 and 2011, AMI was the sponsor of the original National Oncologic PET Registry (NOPR), and post-merger, WMIS continued to sponsor NOPR 2009 and NOPR (NaF-PET).

WMIS has been deeply involved in supporting the CMS effort to make evidence-based coverage decisions on PET imaging, and presented in support of the current beta amyloid PET reconsideration request at the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting on January 30, 2013.

General Comments

The burdens of Alzheimer’s disease are well known. The Alzheimer’s Association has reported that health care costs for people with Alzheimer’s disease and other types of dementias will reach $200 billion, with the majority of these costs borne by Medicare and Medicaid. An estimated 5.4 million people are living with Alzheimer’s disease. Far too many people with Alzheimer’s disease are not diagnosed until their symptoms have become severe. Today Alzheimer’s disease pathology only can be inferred through the recognition of a characteristic phenotype. By the time dementia is obvious, deficits often are so pervasive that the typical phenotype may be difficult to recognize.

It is precisely this crucial importance of early diagnosis of Alzheimer’s disease that makes the opportunities afforded by beta amyloid PET so compelling and important. Significant advances in the use of imaging have made it possible to detect the onset of Alzheimer’s disease, track its progression, and monitor the effects of treatment in people with the disease. One such major advance is the FDA-approved beta amyloid PET tracer florbetapir, whose FDA label states that a negative result is “inconsistent with a neuropathological diagnosis of AD at the time of image acquisition” and “reduces the likelihood that a patient’s cognitive impairment is caused by AD.” Empowered with increased knowledge of brain pathology through tools like beta amyloid PET, clinicians will be more likely to begin and maintain appropriate treatment. CMS currently pays for many diagnostic tests to diagnose or exclude AD. Rapid diagnosis of the absence of amyloid via imaging may lead to more appropriate treatments, thus limiting the expense and risks of inappropriate uses of AD drug therapies.

Coverage Based on Appropriate Use Criteria

In this context, and based on the clinical evidence submitted in support of the use of beta amyloid PET, WMIS encourages CMS to reexamine the benefits of establishing coverage in the final decision pursuant to the Appropriate Use Criteria (AUC) developed by the Alzheimer’s Association in partnership with the Society of Nuclear Medicine and Molecular Imaging. We believe that the AUC constitutes a thoughtful approach to provide access while limiting over-utilization, and that the existing clinical evidence for beta amyloid PET when used in accordance with the AUC parameters is more than sufficient to warrant coverage of beta amyloid PET as reasonable and necessary. Any trepidation on the part of CMS as to the sufficiency of the evidence for the use of beta amyloid PET for other indications should not restrict coverage for those indications where the evidence is compelling. Indeed, there is ample precedent for careful indication-based decisions on whether the same service should be covered outright or through CED. In the context of coverage for FDG-PET for Alzheimer’s, on which WMIS was deeply involved, CMS established coverage for the differential diagnosis of fronto-temporal dementia (FTD) and Alzheimer’s disease under specific requirements, and authorized coverage through CED studies for other indications.

WMIS recognizes that CMS may be concerned that coverage of beta amyloid PET for certain indications would lead to over-utilization of beta amyloid PET. We believe that this concern can be allayed by the adoption of a coverage standard that reflects the AUC, thereby establishing adequate and sufficient safeguards to prevent overuse of this technology, while still ensuring the availability of beta amyloid PET to beneficiaries for whom it is reasonable and necessary. As we stated in our previous comment letter, any such standards adopted by CMS should be rigorous ones. WMIS endorses CMS making explicitly clear in adopting any such criteria that beta amyloid PET scans should not be used for screening of asymptomatic patients or evaluation of those with no documentation of cognitive decline. Moreover, WMIS reiterates its belief that beta amyloid PET should not be considered reasonable and necessary in patients who present with symptoms and clinical profiles that make their diagnosis clear and confident without the scan, in the judgment of the treating physician.

Coverage with Evidence Development for Other Uses

To the extent that CMS nevertheless remains convinced that CED is warranted for certain uses of beta amyloid PET, WMIS and other stakeholders can provide technical assistance in developing registries or other similar approaches to collect evidence that would inform the eventual coverage of beta amyloid PET. WMIS has extensive experience in this context, having worked closely with CMS over many years in developing and sponsoring the various NOPR CED registries.

Precisely because of this experience, however, WMIS is concerned that researchers who wish to develop CED clinical studies of beta amyloid PET will find it exceptionally difficult and challenging to meet the proposed approval thresholds articulated in the Proposed Decision. For example, the Proposed Decision states that such studies must be “comparative, prospective and longitudinal, and use randomization and postmortem diagnosis as the endpoint where appropriate.” Few, if any, clinical studies can accomplish these aims without extraordinary or prohibitive expense, and it is not clear to WMIS whether any entity qualified to develop a beta amyloid PET study would find it feasible to do so under such parameters. In short, if CMS is intent on requiring CED for the coverage of beta amyloid PET for certain indications, WMIS encourages CMS to provide significantly more flexibility in both the design of and beneficiary eligibility criteria for such studies. As an example, if CMS wished to obtain more data on management changes (for instance, data on decisions—based on the results of a beta amyloid PET scan—to avoid administering expensive medications that may not be appropriate), it is possible that such data could be collected under CED.

PET Tracers and the CED Trend

Finally, WMIS does want to raise one overall concern regarding the relationship between PET and CED in general. There appears to be a growing trend—starting with FDG-PET, continuing with NaF-PET, and now with beta amyloid PET—of establishing CED as the default coverage status for new FDA-approved PET tracers. PET imaging itself is now a mature and commonplace medical technology, whose value and merit is beyond question in the clinical and scientific community. While each new PET imaging tracer will inevitably come with its own advantages and limitations—as does every drug, device, or technology that comes before CMS for coverage—WMIS advises against requiring every new PET tracer to navigate the lengthy and extensive CED process. We trust that the recent final decision to remove the national non-coverage decision for PET for FDA-approved oncologic applications, combined with the review with beta amyloid for Alzheimer’s, will create a foundation for future tracers that enables CMS to avoid proposing CED as a matter of course.

Conclusion

WMIS is committed to working with CMS to ensure that Medicare beneficiaries have access to this important new technology, and to work with physicians and patients to develop guidelines for appropriate use. We look forward to continuing to work collaboratively with CMS, and would be pleased to provide CMS with any additional information that it may find useful in reaching its final decision.

Sincerely,

/s/
Zaver M. Bhujwalla, PhD
President

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August 2, 2013
Louis Jacques, M.D.
Coverage and Analysis Group, Director
Centers for Medicare & Medicaid Services
Department of Health and Human Services
2500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

On behalf of the Alzheimer’s Foundation of America (AFA), a national nonprofit organization that unites more than 1,600 member organizations across the country with the goal of providing optimal care and services to individuals confronting dementia, and to their caregivers and families, I am writing to submit comments in response to the Centers for Medicare and Medicaid Services’ (CMS’) Proposed Decision Memo for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease (CAG-00431N).

AFA has concerns about the potential consequences of the proposal as drafted, including its effect on innovation and technology in the Alzheimer’s disease research space and its impact on individuals with Alzheimer’s disease and other dementias, and their family caregivers. Specifically, AFA believes CMS’ draft decision is too restrictive and urges the Agency to revisit its determination to allow for more expansive Medicare coverage of this FDA-approved diagnostic tool when appropriate in select populations, such as complex or inexplicable cases or individuals with progressive dementia at early age of onset.

Misdiagnosis of Alzheimer’s disease and related dementias is already rampant, leading to unnecessary costs and, most importantly, risks to individuals. Such misdiagnosis comes with fiscal costs, as individuals with Parkinson’s disease or vascular dementia who were originally diagnosed with Alzheimer’s disease spend thousands of dollars on potentially harmful medication and ineffective clinical care, when they could have been receiving effective treatment earlier in their disease progression.

As noted in the draft decision memo, an amyloid PET scan can be used to exclude Alzheimer’s disease “in narrowly defined and clinically difficult differential diagnoses, such as Alzheimer’s disease versus frontotemporal dementia (FTD).” Such a diagnostic tool is critical to ensure appropriate care for the thousands of individuals with FTD who would be physically harmed if they were misdiagnosed and treated with current drugs for Alzheimer’s disease that are actually detrimental to persons with FTD (memory.ucsf.edu/ftd/matters/memantine), in addition to suffering the emotional harm and unrealistic expectations that can result from misdiagnosis.

Confirmation of the presence or absence of amyloid plaques in the brain, while not an absolute indication of Alzheimer’s disease (at this point in scientific research), can be of value in both the research and clinical settings in trying to offer the most accurate possible diagnosis, especially in complex cases. Timely and proper diagnosis assists individuals with Alzheimer’s disease and their family caregivers in determining and planning for care management needs and meeting other challenges prior to advanced progression of dementia. Enabling families to better manage the immediate and future consequences of this disease can improve quality of life, change the trajectory of care and produce better outcomes over the long term. AFA recognizes, however, that specialized training is needed to accurately read and analyze scans and that access to amyloid PET scans is not a substitute for a full-scale clinical evaluation and follow-up.

Today, Alzheimer’s disease in the U.S. is already at crisis proportions. As our population ages, incidences of the number of persons affected by this brain disorder are expected to triple by 2050. Costs associated with Alzheimer’s disease are also growing at an unsustainable rate. A recent RAND study of adults aged 70 and older found that total economic cost of dementia in 2010 was estimated to be $109 billion for direct care—higher than heart disease and cancer; and $159 billion to $215 billion when cost of informal care is included.

Currently, there are no consistently effective pharmaceutical interventions to stop or slow progression of Alzheimer’s disease. Amyloid PET scans are used to assist clinicians in making a diagnosis, not as a direct treatment option. By limiting use of amyloid PET scans to clinical trials that find effective treatment in this context, CMS failed to correctly apply an “appropriate use” standard. Moreover, subjecting coverage to just one reimbursable PET scan in certain clinical trials “to enrich treatments or prevention strategies for Alzheimer’s disease” could result in a delay of many years before such effective treatments can be identified and could require millions of dollars in resources to conduct these clinical trials. This challenging financial burden could have a chilling effect and discourage investment in such promising diagnostic tools and pharmaceutical interventions.

AFA believes that appropriate use of an amyloid PET scan in specific populations is a critical tool to help properly confirm a diagnosis of possible Alzheimer’s disease and, thus, can play a significant role in ensuring effective care management, enabling appropriate planning and improving health outcomes. CMS approval of the use of this diagnostic tool, moreover, would send a strong message that the Agency recognizes the need for innovation in the fight against Alzheimer’s disease and for incrementally funding the new reality of Alzheimer’s disease care, while experts continue to advance scientific research into the precise cause of this illness. AFA sees CMS’ coverage decision as the first step in a process of appropriately expanding access to amyloid PET scans. AFA urges CMS to annually revisit amyloid PET coverage to ensure that access and usage are appropriate and effective, and that new technologies and the latest research are applied.

The benefits of early and proper detection of Alzheimer’s disease are many and varied. Even though there are no current treatments to cure, prevent or reverse the disease, or change the underlying Alzheimer’s disease process, available treatments can help slow progression of symptoms. The general rule of thumb is: the earlier, the better.

When diagnosed earlier in the progression of the disease, people have more cognitive functions intact and can provide input into their care throughout the progression of the disease. In addition, early and accurate diagnosis helps people with Alzheimer's disease and their families plan for the short- and long-term, including the ability to:

• inform family members, friends, and caregivers of their diagnosis;
• make living arrangements;
• address financial and legal matters;
• express end-of-life wishes;
• adopt healthy lifestyles (i.e., proper diet, mental activity, physical exercise);
• take advantage of support services; and
• develop care teams and other support networks.

Having a domino effect, this input helps relieve family caregivers of the burden of making these critical decisions for loved ones, which can mitigate the impact of Alzheimer’s disease on the physical and mental well-being of caregivers and, as a result, reduce related health care costs.

Documentation of Alzheimer’s disease in an individual’s medical record is critical for care coordination and is necessary for health care providers to address complications in the management of other co-morbidities, such as diabetes. It will also help ease transitions between care settings and help identify individuals with dementia to hospital emergency departments and first responders. Given the projected skyrocketing cost of dementia care, these preventive measures likewise can result in cost savings to families, government and society.

Additionally, accurate and timely diagnosis can provide greater opportunities for people with Alzheimer’s disease to participate in clinical trials. New drug therapies currently being tested focus on stopping progression in the early stages of the disease, requiring trial participants to have low to mild cognitive impairment. Greater participation in clinical trials is essential in order to accelerate drug development.

AFA has long supported efforts to increase awareness of Alzheimer’s disease and promote its early detection. Since 2003, we have held our annual National Memory Screening Day, providing free, confidential memory screenings and educating the public about the importance of proper detection of memory problems.

Similarly, the U.S. Department of Health and Human Services calls for “timely and accurate diagnosis” of Alzheimer’s disease in the “National Plan to Address Alzheimer’s Disease.” It notes that, “[T]imely diagnosis gives people with the condition and their family’s time to plan and prepare for the future, leading to more positive outcomes for both.” (NAPA Plan, Strategy 2.B).

Appropriate use of an amyloid PET scan in specific populations is a vital tool to help properly confirm a diagnosis of possible Alzheimer’s disease and, thus, can play a significant role in ensuring effective care management, enabling appropriate planning and improving health outcomes. As such, AFA respectfully urges CMS to revise the draft coverage decision to expand Medicare coverage of this important diagnostic tool.

AFA appreciates the opportunity to comment on this issue of importance to the Alzheimer’s community. If you have any further questions, please feel free to contact me or Eric Sokol, AFA vice president of public policy, at esokol@alzfdn.org or (202) 643-9601.

Sincerely,

Carol Steinberg
President

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This comment is in support of the use of Amyvid PET in the evaluation of dementia. I feel this agent can be efficacious in selected patients, and recommend approval. I have full confidence in my neurology and medical colleagues to use this agent judiciously, reserving testing for those patients who remain undiagnosed and/or problematic. My experience in nuclear medicine/PET for >30 years has convinced me that all radiopharmaceuticals and diagnostic tests are ultimately utilized based upon their value to our patients. At a minimum, CMS support of further clinical research is desperately needed.

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August 2, 2013

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Draft Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

On behalf of Lilly USA, LLC (Lilly), we are providing our second set of comments on the Centers for Medicare & Medicaid Services (CMS) Draft Decision Memorandum on Beta-amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease (CAG-00431N), published on July 3rd.[1] Pursuant to our original request, we request that CMS authorize appropriate Medicare coverage, outside the unnecessary and unreasonable constraints of the Coverage with Evidence Development (CED) construct, for the use of beta-amyloid Positron Emission Tomography (PET) imaging as a diagnostic test for the purpose of estimating beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline. The request is consistent with, and made in support of, the Appropriate Use Criteria (AUC) recommendations created by experts representing the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging.[2]

As you know, Lilly has been involved in beta-amyloid PET imaging discussions with the Coverage Analysis Group (CAG) at CMS for more than two years. Despite the commitment of this Administration to the fight against AD, the proposed decision memorandum provides no coverage to any Medicare patient in the normal course of their diagnosis and treatment. Under the proposed decision memorandum, no patient – regardless of his or her circumstances, the complexity of his or her clinical presentation or clarity of diagnosis, and/or his or her provider’s judgment of the need for amyloid imaging – is entitled to this innovative diagnostic coverage outside of a clinical trial. Further, as we discuss in greater detail below, the CMS proposed coverage with evidence development will not provide any meaningful coverage, and, in fact, represents a threat to innovation.

It is important to recognize that the standards to assess the “reasonable and necessary” nature of diagnostic and treatment agents are different. Significantly, the statute’s plain language refers to items and services that are “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”[3] If “improvement in health outcomes” is used as a coverage requirement for this or any other diagnostic tool, then CMS will have, in essence, required the statute to require both diagnosis and treatment. Such a decision would violate the plain language of the Medicare Act and threaten coverage for diagnostic services for patients living with many incurable diseases, including amyotrophic lateral sclerosis, muscular dystrophy, spinal muscular atrophy, CADASIL, and Kennedy’s disease – to name a few.

The proposed decision memorandum is inconsistent with the Administration’s public commitment to Alzheimer’s patients in the National Alzheimer’s Plan in such a way that, if other disease areas were held to a similar standard, it could jeopardize access for millions of Medicare beneficiaries who are living with many other diseases and dependent on the Medicare program.

CMS has articulated coverage principles that, if they were consistent with the Medicare Act, would necessarily mean that virtually no diagnostic service could be supplied to an Alzheimer’s patient. By CMS’ logic, the Medicare program is no more able to cover clinical neurologic evaluations, than it is able to cover amyloid imaging. Both would be equally vulnerable to the “health outcomes” test for coverage that CMS attempts to pull from a statute whose plain language, in fact, forecloses any such coverage requirement.

The CMS draft decision proposing coverage with evidence development for the use of beta-amyloid PET imaging agents is inappropriate given the current state of the evidence. To further build upon our original letter requesting this NCD sent in June 2012, as well as multiple public comments made during the 13 months that followed, this letter highlights recent scientific evidence that was not available at the time the draft decision was posted, as well as previously existing evidence supporting the value of more accurate and timely diagnoses for patients with Alzheimer’s disease or other forms of cognitive impairment, as made possible by beta amyloid imaging agents, such as Amyvid™ (Florbetapir F-18 Injection).

A. Executive Summary

• Improving the differential diagnosis of patients with Alzheimer’s disease and other forms of cognitive impairment is not just reasonable and necessary for CMS, but important for patients
  • Patients with Vascular Dementia or Parkinson’s Disease who are initially misdiagnosed as having Alzheimer’s disease undergo many avoidable medical procedures and tests while enduring uncertainty that could now be avoided in many cases[4]
  • Patients with Vascular Dementia or Parkinson’s Disease who are initially misdiagnosed as having Alzheimer’s disease incur substantial additional and avoidable costs until such time as they are correctly diagnosed[5]
  • Beta amyloid PET imaging has already been shown to significantly change the intended management of cognitively impaired patients[6]
  • A patient’s right to an accurate diagnosis is a meaningful and important outcome
  • A large majority of people have stated they would want accurate and specific information regarding their diagnosis if there was a clinical suspicion similar to that described in the Appropriate Use Criteria[7,8]
• The National Alzheimer’s Project Act is a call to action for steps forward; the recommended Coverage with Evidence Development approach is a step backward
  • The Department of Health and Human Services has stated that in the absence of a cure for Alzheimer’s disease, current medicines can improve patient quality of living and delay symptoms provided patients receive early and accurate diagnoses[9,10]
  • Coverage with Evidence Development has previously introduced long delays until a coverage decision
  • Patients for whom the evidence has already demonstrated definable value should not be forced to decide between joining clinical trials or waiting years to have access to innovative diagnostic technology that can help them today
  • The draft Coverage with Evidence Development approach for beta amyloid PET imaging is even more complex and restrictive to innovation than prior CEDs
  • The standards used for the denial of coverage within the draft decision are inconsistent with the standards used by CMS to justify coverage of similar diagnostics
  • Rather than moving forward in Alzheimer’s diagnosis and care, if the logic used to recommend Coverage with Evidence Development for beta-amyloid PET imaging were applied to other aspects of a patient’s diagnosis, it would mean dementia patients would receive no clinical evaluation or care services, including physician evaluation for their underlying condition
• Fortunately, a good solution exists for patients and their families
  • Adopt coverage based on the Appropriate Use Criteria developed by experts within the fields of Alzheimer’s disease and Molecular Imaging

B. The Proposed Decision Memo Fails to Appreciate and Recognize the Value in Ruling-Out the Presence of Beta-amyloid Plaques

Data presented during the January 2013 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting noted that approximately 20% of patients clinically diagnosed with AD during life (in vivo) are discovered to have no evidence of Alzheimer’s pathology upon autopsy.[11] As described in greater detail below, this means that in practice, an average of 1 out of every 5 patients are misdiagnosed and subject to potentially unnecessary, ineffective, or even harmful medicines and medical procedures. The ability to avoid improper diagnosis and treatment alone substantiates both the role of beta-amyloid testing and the value presented by a negative scan. Within the current draft coverage decision, however, CMS states that there is a lack of conclusive evidence that a negative scan could lead to more accurate diagnosis of non-Alzheimer’s dementias and related diseases, ultimately concluding that the related evidence “…is of limited persuasiveness, based almost entirely on clinical vignettes and case studies.”[12] As noted within several comments already posted, recent evidence developed from various non-vignette sources – clinical trials, CMS claims analyses, etc. – prove this assumption false by demonstrating the unique insight provided by a negative scan. Without repeating all of the valuable evidence identified by other comments, there are two additional recent studies that are germane to this question.

Initially, research presented by Noam Kirson and colleagues at the 2013 Alzheimer’s Association International Conference (AAIC) meeting utilized CMS claims data to demonstrate that patients with vascular dementia (VD) and Parkinson's disease (PD), who are first misdiagnosed as having AD, utilize substantially greater levels of medical resources and generate substantial excess costs until they are finally accurately diagnosed[13]. In talking about this research, Dr. Kirson was quoted as saying:

“We see that a considerable share of these Medicare beneficiaries with Parkinson's disease and vascular dementia have a history of misdiagnosis of Alzheimer's disease, and we also see that those who were misdiagnosed with Alzheimer's disease incur significantly higher medical costs up to and including the period of their correct diagnosis. No less important is the decline in costs after the correct diagnosis; that is where we think the policy relevance comes from, because that strongly suggests that if we could arrive at a correct diagnosis earlier, we could potentially eliminate at least some portion of those excess costs."[14]

Although the Medicare statute mandates coverage for items or services in the enumerated categories without regard to cost, the underlying avoidance of unnecessary medical procedures and interactions – highlighted below as being made up of clinician visits, outpatient visits, inpatient stays, emergency department visits, diagnostic imaging, and laboratory testing[15] – demonstrate a clear and documented value to a negative beta-amyloid PET scan using CMS’ own data that must not be overlooked.

The study by Kirson and colleagues[16] utilized de-identified administrative claims data for Medicare beneficiaries (5% Analytic Sample File) between 1999 and 2011. Using those claims, two mutually exclusive patient cohorts were created: one each for VD and PD diagnosed patients (defined as patients with 2 or more claims for either VD or PD, without claims for any other dementia type between, after, or in combination with their most recent VD/PD diagnoses). Within each cohort, patients were then classified as previously misdiagnosed with AD if they had 2 or more claims with AD diagnoses (either primary or secondary) in any of the three years preceding their first confirmed VD/PD diagnosis. Within each disease cohort, misdiagnosed patients were matched to similar patients with no prior AD misdiagnosis using well-established propensity score methods. The study then followed the matched patient sets from the date of their first AD diagnosis for misdiagnosed patients and the first confirmed VD/PD diagnosis for patients with no prior AD misdiagnosis, comparing annual medical resource use (e.g., inpatient visits/days, emergency department visits) and costs (amounts paid by Medicare in 2012 US dollars) during a four (4) year follow-up period. Comparisons between the matched patient pairs were reported in one-year intervals and stratified by time to correct diagnosis.

In addition to the over-arching findings described by Dr. Kirson above, the study also found the following[17]:

• 16.6% of patients ultimately diagnosed with VD and 8.4% of patients ultimately diagnosed with PD had prior AD diagnoses that appeared incorrect.[18]
• Regardless of whether patients were correctly diagnosed in the first, second, or third year following their AD misdiagnosis, avoidable medical procedures and related excess medical costs (not including Part D prescriptions) immediately declined and eventually dissipated.[19]
• Statistically significant differences in required medical procedures per misdiagnosed VD patient diagnosed in the first year following their misdiagnosis included: more inpatients days (14.4 vs. 10.3), more emergency department visits (6.6 vs. 4.6), more outpatient physician visits (42.5 vs. 35.8), and higher rates of diagnostic imaging (1.8 vs. 1.2). These same trends continued for patients whose diagnosis was corrected within 2 and 3 years, respectively, as well. In nearly all cases, no statistical difference was observed following correct diagnosis.[20]
• Statistically significant differences in required medical procedures per misdiagnosed PD patient diagnosed in the first year following their misdiagnosis included: more inpatients days (10.3 vs. 7.0), more emergency department visits (5.3 vs. 4.4), more outpatient physician visits (40.6 vs. 33.8), and higher rates of diagnostic imaging (1.3 vs. 1.0). These same trends continued for patients whose diagnosis was corrected within 2 and 3 years, respectively, as well. In nearly all cases, no statistical difference was observed following correct diagnosis.[21]
• Statistically significant cumulative excess costs per misdiagnosed VD patient averaged $11,967, $18,775, and $20,318 for patients whose diagnosis was corrected within one, two, or three years of their AD misdiagnosis, respectively.[22]
• Statistically significant cumulative excess costs per misdiagnosed PD patient averaged $12,738, $19,378, and $34,840 for patients whose diagnosis was corrected within one, two, or three years of their AD misdiagnosis, respectively.[23]

Taken as a whole, the significant and avoidable medical resources and related costs tied directly to a misdiagnosis of AD – and their dissipation following the correction of earlier misdiagnosed AD – represent an important and empirically-demonstrated value of ruling out Alzheimer’s disease, as well as the added benefits of enabling that rule-out as early as possible. Consistent with CMS’ interpretation of the “reasonable and necessary” standard, including avoided burdensome and/or futile treatment or tests[24], the ability to limit inpatient stays and keep patients out of emergency rooms offers clear justification for outright coverage of beta-amyloid PET imaging within the appropriate patient population. We ask only that CMS follow the science and data. If it does so, the agency will provide non-CED coverage for beta-amyloid PET imaging agents in appropriate circumstances.

In addition to the benefits of potentially-avoidable medical services, the draft decision gives insufficient consideration to the benefits that can be offered through the appropriate and targeted use of Alzheimer’s-indicated drugs that are deemed to be “reasonable and necessary” by CMS by virtue of their coverage for Medicare beneficiaries. In considering the impact of drugs, CMS poses the question, “…could a negative scan excluding AD avoid harm that would have otherwise occurred if patients were misdiagnosed with AD and given medications for symptoms that were in fact caused by other disease(s)?”[25] While this is an interesting question, it leaves an obvious gap by not asking: could a negative scan excluding AD also lead to potential benefits by preventing a potential misdiagnosis of AD, thereby directing patient management toward alternative and potentially reversible causes of cognitive impairment? Lilly presented multiple positive answers to this question during the January 2013 MEDCAC that do not appear to have been considered within the current draft decision.

One example is a 2002 study by Hejl, Høgh, and Waldemar[26] in which the authors examined the prevalence of potentially reversible causes of cognitive symptoms within a memory clinic setting among 1,000 patients with an average age of 66.1 years. The authors found that potentially reversible conditions were the primary underlying cause of observed impairment in 19% of cases, and were most often encountered in patients with mild cognitive impairment. Of those patients with potentially reversible conditions, depression, hydrocephalus, and alcohol dependence syndrome accounted for 82% of the primary diagnoses.[27] In these cases, a negative scan could have offered physicians more clarity and confidence in ruling out Alzheimer’s-related cognitive impairment and served to focus patient treatment and management more quickly and effectively to the benefit of the patients. Notably, the treatments in these cases would not likely be the same treatments given to Alzheimer’s patients (e.g., cholinesterase inhibitors and memantine). Since these were the only therapeutics examined within the draft decision, it is clear that there appears to be a gap in the potential therapeutic and surgical value considered by CMS. Even when expert testimony at the MEDCAC drew attention to this need (as noted within the draft decision), the experience was dismissed as being “…of limited persuasiveness, based almost entirely on clinical vignettes and case studies…”[28] despite being presented with peer-reviewed evidence during those same proceedings.[29]

Importantly, Hejl and colleagues emphasized the unique importance of enabling early and accurate treatment under these circumstances as “…potentially reversible conditions may progress into irreversible conditions if left untreated.”[30] This underscores the risk to patients created by CMS’ proposed decision memorandum.

C. Beta-Amyloid Imaging Can Change the Intended Management of Patients Suspected of Having Alzheimer’s Disease

A recurring theme in the memorandum is that examining patients for possible Alzheimer’s disease using beta-amyloid PET imaging will not change the management of patients.[31] CMS’ assumption that amyloid identification will never affect management is contradicted by the available evidence. Under the management standard that CMS itself articulates, it is not possible to sustain the proposition that beta-amyloid PET imaging has never been shown to contribute to the management of any Medicare patient, regardless of the patient’s condition.

In a study published in 2012 and conducted at CMS’ suggestion, Grundman and colleagues examined how the use of beta-amyloid PET imaging can change the intended diagnosis, treatment, and overall management of patients who may have AD. After receiving the results of the beta-amyloid scan[32]:

• The intended diagnosis changed in 125 (54.6%) of 229 studied cases.
• There was at least one change in the intended management plan for 199 (86.9%) of 229 subjects.
• In 31% of subjects (71 of 229), beta-amyloid testing led to an intended change in AD medications.
• In negative scan subjects, 26.7% (31 of 116) of patients have AD medications removed from their intended management plan.
• In 7.4% of subjects (17 of 229), the results led to an intended change in treatment with psychiatric medications.
• Intended plans for brain CT/MRI were reduced by 65% after a positive scan (17 of 26) and 40% after a negative scan (12 of 30).
• Intended neuropsychological testing was reduced by 85% after a positive result (23 of 27) and 48.5% after a negative result (16 of 33).
• FDG PET scan use was removed from the intended patient management plan in 91% of relevant cases (21 of 23) after the results of beta-amyloid testing.

These results went on to indicate that use of beta-amyloid testing could result in nearly a quarter of patients initially suspected of having AD avoiding unnecessary and potentially inappropriate medications, including anti-psychotics.

In arguing that amyloid testing has never, to date, contributed to management in any Medicare patient, CMS struggles to address the issue of the appropriate use of cholinesterase inhibitors (e.g., Aricept) and memantine (e.g., Namenda). According to the decision memorandum, when the diagnosis is unclear, providers should simply engage in what amounts to empiric therapy with AD drugs, observing that “no additional harm appears to result from a misdiagnosis that places patients on such dementia medications.”[33] Such empiric therapy could, in fact, be dangerous in the event that FTD is present. As noted by CMS, “cholinesterase inhibitors have been shown to exacerbate symptoms in some patients with FTD, and use of memantine has correlated with greater functional and cognitive decline.”[34] Finally, empiric therapy use that does not give consideration to minimizing patient exposure to unnecessary side effects from commonly used medications runs contrary to FDA’s focus on this topic.[35]

D. CMS’s Dismissal of the Value of Knowing Fails to Reflect the Available Data

The manner in which the draft decision handles the value of knowing an accurate diagnosis is erroneous and dismissive of a true public health threat.

CMS contends that many people don’t want to know their true diagnosis, quoting a study completed by the Harvard School of Public Health that, in fact, establishes that a clear majority of U.S. respondents (64.1%) reported that they would be “very likely” or “somewhat likely” to take a test that would tell them if they would develop Alzheimer’s in the time prior to the onset of symptoms.[36] This disconnect between the data and the assertion that people do not want to know their diagnosis becomes even more clear when it is considered that this study actually asked other questions that are more relevant to the proposed appropriate use of beta-amyloid PET imaging as an adjunctive diagnostic aid in the evaluation of cognitively impaired individuals, as opposed to a screening tool used in a cognitively healthy population. For instance, the study asked respondents, “If you were exhibiting confusion and memory loss, would you go to a doctor to determine if the cause of the symptoms was Alzheimer’s disease or not?” An overwhelming 88.8% of U.S. participants responded “yes” to this question.[37] Similarly, the study asked, “If you had a family member who was exhibiting confusion and memory loss, would you want the person to see a doctor to determine if the cause of the symptoms was Alzheimer’s disease or not?” A near unanimous 97.5% of U.S. participants responded “yes.”[38]

Since the focus of the original request – as well as that of the Appropriate Use Criteria – is for consideration focused on patients who are already being evaluated for observed cognitive decline, it seems clear that the majority of relevant US patients within this research do want to do everything they can to determine the underlying cause of dementia observed within themselves or their loved ones. The effort to use this study to justify that “many do not want to know” their diagnosis seems incongruent with the underlying data, resulting in a selective and inappropriate interpretation of the study.

The US Department of Health and Human Services (HHS) has also highlighted the importance of early and accurate detection by noting, “The earlier you detect Alzheimer's, the better chance you have of treatments possibly delaying certain symptoms. Early diagnosis also allows families to better plan for the course of the disease.”[39] That same website goes on to note, “There is no cure for Alzheimer’s, but there are medicines that may improve quality of living and delay some symptoms.”[40] Evidence provided by the Alzheimer’s Association[41] and cited during the MEDCAC meeting[42] offered further support for this value by noting that delayed detection can include, “...missed opportunities to prevent falls and injuries, including potentially fatal injuries; [and]…delays in planning for future functional declines.” This early and accurate identification becomes even more important when taken together with the Kirson et al. research noted above, in which the value of knowing an accurate, non-AD diagnosis translated to avoidable “reasonable and necessary” services for beneficiaries following a rule-out of AD as well.

Despite this overwhelming agreement between government, patients, advocates, and researchers, CMS’ draft decision states that “…a diagnosis of AD does not trigger access to items or services covered by CMS that a beneficiary could not otherwise obtain given a threshold of clinically documented functional impairment, regardless of the etiology of that impairment,”[43] thereby dismissing the value of a timely and accurate diagnosis. By taking this approach, CMS is forcing patients to needlessly progress in their disease – reaching a higher threshold of functional impairment – without the benefit of medications HHS has determined could improve their quality of life, and in doing so, potentially preventing patients from their best chance of delaying the crippling symptoms of Alzheimer’s disease for as long as possible.

CMS should value a patient’s right to an accurate diagnosis as a meaningful and important outcome, as government statements, research, and testimony provided at the MEDCAC have clearly shown it is meaningful to them. Even if CMS is unable or unwilling to take this into consideration, the evidence is clear that enabling Alzheimer’s-appropriate treatments for those with the disease, while avoiding unnecessary and avoidable medical services through accurate rule-out of the Alzheimer’s disease for those without, offers ample justification that it is “reasonable and necessary” under Section 1862 of the Social Security Act (42 U.S.C. § 1395y(a)(1)(A)) to provide AUC-consistent coverage without the undue burden of a Coverage with Evidence Development construct.

E. The CED Proposal Is Methodologically Unrealistic, Provides No Meaningful Coverage, and Represents a Threat to Innovation

The available evidence provides a strong case for limited, non-CED coverage of beta-amyloid PET tracers, consistent with the AUC recommendations. If CED remains within the final coverage determination, it should only do so as a complement to that covered population – a way in which to encourage additional therapeutic or pre-symptomatic prevention research above and beyond the coverage appropriately supported by experts and provided by CMS. If CED is put forward in this manner, there are still countless needed adjustments to the methods and directions suggested by CMS as requirements for its execution.

Most importantly, CED coverage provides no means by which to address the failure of the draft decision to recognize that coverage is justified within the existing evidence base. Within the current draft guidance for CED, CMS specifies 13 “…standards of scientific integrity and relevance to the Medicare population [that] should be demonstrated in all CED studies.”[44] The third of these standards states that, “The study results are not anticipated to unjustifiably duplicate existing knowledge.”[45] Given the evidence presented within these comments, as well as that which was previously available, it is clear that enacting CED for the AUC-appropriate population would violate CMS’ own standard of scientific integrity.

Additionally, the proposed CED coverage put forward within this draft decision is inconsistent with recent CED-related decisions, including the National Oncology PET Registry (NOPR) final decision that was released in June 2013.[46] Within that CED design and ultimate series of positive coverage decisions, there were never any indications or interests in mortality-confirmed endpoints, confirmed health outcomes of specific patients included within the registry, or confirmation that the reading of the scan was either consistent across geographies, or even correct. In this proposed decision[47], CMS has now asked for randomized clinical trials, autopsy-confirmed results to confirm in-study diagnosis, and even called into question the previously FDA-reviewed and approved reader training program – a quality assurance step that is not mandated for the now-covered FDG PET scans.

This inconsistency between the previous final PET-focused decision, and this current draft whose timing almost overlaps, simply cannot be justified. Beta-amyloid imaging safety has not been called into question with the draft decision, and the recent positive NOPR decision signals that CMS believes in the value and utility of PET imaging as a reasonable and necessary part of medical practice.

By factoring potential risks into its approval decision, the Food and Drug Administration (FDA) has already provided an important and informed perspective on the safe use of amyloid imaging. FDA, by approving the product, determined that a positive risk/benefit ratio was present. This heightened requirement associated with beta-amyloid imaging, as compared to standards employed to evaluate previously-approved non-proprietary tracers, should create confidence that new PET radiopharmaceuticals, like those used for beta-amyloid PET imaging, will not only be accurate and reliable, but will also have defined and accepted clinical benefits for the patients in whom they are used as specified in the FDA-approved label. It is inappropriate for CMS to ask for a reconfirmation of this previously evaluated and approved FDA requirement which is specifically committed to the jurisdiction of the FDA. Attempting to do so does nothing to improve the quality of the research, and instead is likely to discourage manufacturers from investing the significant resources necessary to bring innovative products to market. That, in turn, threatens innovation, not only with respect to Alzheimer’s disease, but more broadly as well. This threat to innovation is completely inconsistent with the Administration’s commitment to the fight against Alzheimer’s.

The onerous CED requirements proposed in the draft decision memorandum, if included within the final decision, will likely prevent sponsors from answering the questions CMS believes to be important. Randomization, for example, is preferred for determining clinical utility, but the FDA has already evaluated and positively answered that question with the approval of florbetapir. If CMS is genuinely interested in how well this diagnostic performs in real world settings, then designs that emphasize pragmatic and observational approaches should be prioritized. These naturalistic designs would enable CMS to gain additional insight if it seeks to further translate the existing well-controlled studies to practice settings.

Similarly, forcing studies that conflate reasonable diagnostic endpoints (e.g., change in patient management) with reasonable therapeutic endpoints (e.g., change in functional status or survival) reduces the ability for dedicated research sponsors to support a trial of reasonable size and scope. Indeed, if every diagnostic study had to be run at the size and inclusion level of a standard therapeutic clinical trial, very few – if any – innovative diagnostic interventions would ever make it to market.

Finally, the manner in which the draft decision calculates positive and negative predictive values (PPV and NPV) fails to account for both the characteristics of an adjunctively-used beta-amyloid PET imaging agent, as well as the population in which this request for coverage has specified that it be used. It is important to note that the goal of the scan is not to determine the presence or absence of clinical-pathological entity Alzheimer’s dementia. Instead, it is to determine the presence or absence of neuritic amyloid plaques – a determination of which can then be combined adjunctively to the results of a thoroughly completed patient evaluation to assist a physician in determining the likely etiology of a patient’s observed impairment. A determination of the presence or absence of beta-amyloid plaques should not be expected to directly correlate to an absolute positive decision independent of the consideration of other test results and patient factors. Additionally, the population assumptions used as the basis for the example calculations within the draft decision are not relevant to this request, as they assume a starting point of older Americans without cognitive impairment – a population inconsistent with both the AUC guidance and Lilly’s original request for coverage, specifying appropriate patients as those Medicare beneficiaries with objectively observed and confirmed cognitive impairment combined with diagnostic uncertainty following a thorough evaluation. Within this appropriate and well-defined population, the probability of moderate-to-frequent plaques is likely in the 50-60% range based on multiple studies noting 76-84% probability in clinically diagnosed AD patients and 38-45% probability in prodromal patients.[48] Using a 50% estimate, and applying the 90% sensitivity and specificity estimates used within the draft decision, then PPV and NPV are both 90% in an appropriate patient population, and further support this technology as reasonable and necessary for the appropriate Medicare patient.

F. The Proposed Decision Memorandum Is Fundamentally Inconsistent with CMS’ Practice and Policy of Covering Diagnostic Services for Diseases, Even Where There Is No Cure or Disease-Modifying Therapy

Although we dispute CMS’ characterization of the impact of amyloid imaging on the course of dementia patients’ disease, CMS’ proposed coverage decision rests and falls on the conclusion that the “evidence is insufficient to conclude that the use of positron emission tomography amyloid-beta (Aß) imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease.”[49] In its proposed decision memorandum, CMS incorrectly suggests that Medicare coverage cannot exist where there is no cure for a disease, or at least where there is no disease-modifying therapy. That standard, however, is not only inconsistent with the plain language of the statute, which specifically provides for coverage for “diagnosis *or* treatment,”[50] but it is also inconsistent with the Medicare program’s long-standing policy and practice in covering a host of diagnostic items and services across varying levels within the larger CMS structure. For this reason, the proposed decision memorandum represents not just a threat to Alzheimer’s patients, but to patients living with a broad range of illnesses who are dependent on the Medicare program for their care and for whom there is no cure or disease-modifying therapy.

For example, since 1985, CMS has provided coverage and reimbursement for brain MRI scans for use in the diagnosis of multiple sclerosis (MS).[51] MS is a neurological disorder for which there is no drug that modifies the course of disease. Following diagnosis, patients must endure a gradual decline, typically succumbing to death from the disease after a long course. While recent therapies offer some hope at ameliorating some of the symptoms of MS, none provide a cure, much like current drug therapies for AD.

Notwithstanding that, at the time coverage for brain MRI to diagnose MS was authorized, and for many years thereafter, there were no viable treatment options available. In keeping with the statutory mandate that CMS cover diagnostic services, the agency has covered the diagnostic (and has done so continually) since 1985. This was an entirely correct decision on the part of CMS, precisely because the Medicare statute promises coverage, not just for “treatment”, but for “diagnosis *or* treatment.”[52]

Testing for amyotrophic lateral sclerosis (ALS) – more commonly known as Lou Gehrig’s disease – via electromyography/nerve conduction studies provides yet another example. ALS is a progressive, debilitating neurological disorder for which no therapy or treatment can change the course of the disease; according to one longitudinal study, the average patient with motor neuron disease lives only 43 months following the onset of symptoms.[53] Despite the absence of viable disease modifying treatment options, the Medicare program has paid for the EMG study procedures that, when combined with clinical evaluation, are the basis of diagnosis.[54]

Another example is testing for Creutzfeldt-Jakob disease (CJD), which is a prion-based rapidly progressive neurological infection. There is no treatment for CJD and the disease is uniformly fatal. Yet, Medicare pays for diagnostic services that aid in the diagnosis of CJD. For example, two Part B carriers explicitly provide coverage for the brain MRI scans that show the characteristic changes associated with the disease.[55,56] In both instances, two independent ICD-9 codes in both LCDs support provide for coverage for the diagnostic services for CJD.[57]

Similarly, the Medicare program has covered genetic testing used in the diagnosis of Huntington’s disease, another condition for which there is no available cure.[58] One Medicare contractor, in confirming this coverage in its role as the agent of the Medicare program, performed an analysis of potentially applicable research that could cause it to reconsider its positive coverage decision and, upon completion of that analysis, found no relevant materials that prevented coverage for such testing, despite the lack of disease modifying treatments and the nature of Huntington’s disease.[59] The fact that the testing is covered for diagnostic purposes, and not on the basis of resulting management or observed health outcomes, is clear, as the policy ensures coverage for “Confirmatory testing by direct DNA analysis in an individual with clear symptoms of Huntington’s disease…” and “Diagnostic testing when an individual presents with clear neurological symptoms that appear to be Huntington's disease, but there is no family history….”

Testing within these diseases are just a few of the examples that can be listed to show that diagnostic coverage has not required that there be a cure for a given disease. Sadly for the affected patients, many diseases exist for which diagnostics cannot lead to a cure. Despite that, the Medicare program continues to cover diagnostic evaluations and testing within these settings on the apparent basis that arriving at the correct diagnosis is inherently “reasonable and necessary.”

Even if true, the suggestion that beta-amyloid PET imaging should not be covered because it cannot change health outcomes – a fact which the available evidence disputes – is an inappropriate standard. Putting aside in vivo beta-amyloid identification for the moment, Medicare covers many other services related to Alzheimer’s disease and other forms of cognitive impairment that, by CMS’ logic, should not be covered because they do not have evidence showing they improve the health outcomes. For example, Medicare covers Evaluation & Management services, including patient and family counseling provided under those codes, drug therapy with cholinesterase inhibitors and memantine, and mental health services for appropriate Alzheimer’s patients struggling to cope with the implications of their disease.[60,61] As indispensable as all of these services are, these services clearly do not alter the course of Alzheimer’s disease, but they are covered nonetheless, without controversy.

G. The Draft Decision Is at Odds with the Goals of the Administration’s National Alzheimer’s Plan

The proposed decision memorandum is all the more disappointing because it cannot be squared with the National Alzheimer’s Project Act (NAPA), which Congress unanimously passed and which President Obama signed into the law on January 4, 2011.[62] CMS cannot simultaneously stand by its proposed decision memorandum and say that it is committed to NAPA.

NAPA establishes within the Office of the Secretary of Health and Human Services the National Alzheimer’s Project, whose purpose is, among other things, to “...improve the early diagnosis of Alzheimer’s disease.”[63] The Act also calls for the creation of a National Alzheimer’s Plan, intended to guide implementation of the Act.[64] In May 2012, the first Plan was released.[65] As the Plan recognizes, “It is often difficult to distinguish between Alzheimer’s disease and other dementias in terms of clinical presentation and diagnosis.”[66] Accordingly, Strategy 2.B of the Plan urges “timely and accurate diagnosis” of Alzheimer’s disease in order to give afflicted patients and their families “…time to plan and prepare for the future, leading to more positive outcomes for both.”[67]

CMS’s proposed decision memorandum is fundamentally at odds with the goals of Congress and the Obama Administration, as expressed in NAPA. As Congress itself observed, one of the central aims of the Alzheimer’s Project is to “…improve the early diagnosis of Alzheimer’s disease.”[68] Because beta-amyloid PET imaging can help determine which patients suffer from Alzheimer’s versus other forms of dementia and cognitive impairment - particularly when the diagnosis is unclear – it is indisputable that it can, in appropriate patients, help with the early diagnosis of Alzheimer’s and other dementia patients.

H. Conclusion

Lilly believes in and supports the National Alzheimer’s Project Act (NAPA), and agrees that “Timely diagnosis gives people with the condition and their families time to plan and prepare for the future, leading to more positive outcomes for both.”[69] This draft coverage decision, if made final without substantial changes, runs counter to this concept and challenges the basic assumption inherent in that statement: that the right and timely diagnosis of Alzheimer’s disease and related forms of cognitive impairment are important even in a world currently lacking disease-modifying treatments. Appropriate patients for whom the evidence has already demonstrated definable value should not be forced to decide between joining clinical trials or waiting years to have access to innovative diagnostic technology that can help them today. Likewise, recent CMS-derived evidence provides empirical and real world data demonstrating meaningful health outcomes improvements for patients following a negative beta-amyloid PET scan by enabling fewer emergency room visits, days spent in a hospital’s care, and even outpatient office visits – all as a result of avoiding a misdiagnosis of AD. When combined with the rigorous framework of the AUC, national Medicare coverage for this new class of PET tracers for beta amyloid identification in this population without CED is feasible, reasonable, and necessary.

Lilly is committed to developing innovative technologies that improve the lives of patients. We look forward to continuing to work with CMS and Alzheimer’s disease stakeholders to ensure that Medicare beneficiaries have timely and appropriate access to this important technology. Should you have any questions regarding these comments or would like to discuss them further, please contact Craig Hunter at 317-500-2028 or craig.hunter@lilly.com.

Disclosures

The information and statements contained in these comments are not intended for any promotional purpose whatsoever. This letter is solely a communication to CMS regarding information that may be relevant to the coverage of PET scans using beta-amyloid imaging agents. This information has been supplied as contemplated by CMS' guidance on NCD requests and in response to CMS’ call for public comments. Providers should not base decisions regarding whether to use Lilly’s Food and Drug Administration (FDA)-approved beta-amyloid imaging agent Amyvid based on the information contained in comments. Amyvid has been approved for:

"Positron Emission Tomography (PET) imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates sparse to no neuritic plaques and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Amyvid is an adjunct to other diagnostic evaluations.

Limitations of Use:

• A positive Amyvid scan does not establish a diagnosis of AD or other cognitive disorder.
• Safety and effectiveness of Amyvid have not been established for: Predicting development of dementia or other neurologic condition; Monitoring responses to therapies" (Amyvid Prescribing Information).

Lilly refers the reader to Amyvid’s FDA-approved label for full prescribing information.

Sincerely,

Mark J. Nagy
Vice President
Global Patient Outcomes & Real World Evidence
Eli Lilly and Company
Craig A. Hunter
Senior Research Scientist
Global Patient Outcomes & Real World Evidence
Eli Lilly and Company

Notes and References

[1] Centers for Medicare & Medicaid Services. Proposed decision memo for beta amyloid positron emission tomography in dementia and neurodegenerative disease (CAG-00431N). http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265. Published July 3, 2013. Accessed July 3, 2013.
[2] Clinical thought leaders, patient advocates, and physician specialty societies have developed a rigorous and evidence-based set of appropriate use criteria (AUC) for the use of beta amyloid PET imaging. This group, representing many prominent U.S. experts in the clinical evaluation and treatment of cognitive disorders, was convened by the Alzheimer’s Association in partnership with the Society of Nuclear Medicine and Molecular Imaging. As CMS is aware, these expert stakeholders are widely accepted as leaders in developing and identifying best practices for patients with cognitive impairment and Alzheimer’s disease. The AUC emphasize that the use of beta amyloid imaging should be carefully targeted, and only utilized in patients who present with: “(i) a cognitive complaint with objectively confirmed impairment; (ii) AD as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and, (iii) when knowledge of the presence or absence of amyloid pathology is expected to increase diagnostic certainty and alter management.” (See: KA Johnson, S Minoshima, 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 & Dementia (2013) 1-15.) Moreover, the new criteria take the additional – and important – step of identifying a number of circumstances in which the use of beta amyloid PET is inappropriate, providing practitioners with clear and appropriate limitations on utilization.
[3] 42 U.S.C. §1395y(a)(1)(A)
[4] Kirson NY, Hunter CA, Desai U, et al. Excess costs associated with misdiagnosis of Alzheimer’s disease among US Medicare beneficiaries with vascular dementia or Parkinson’s disease. Data on File. Analysis Group, Boston, MA. April 29, 2013.
[5] Kirson NY, Hunter CA, Desai U, et al. Excess costs associated with misdiagnosis of Alzheimer’s disease among US Medicare beneficiaries with vascular dementia or Parkinson’s disease. Presented at: Alzheimer’s Association International Conference (AAIC); July 2013; Boston, MA.
[6] Grundman M., Pontecorvo M., Salloway S., et al. Potential Impact of Amyloid Imaging on Diagnosis and Intended Management in Patients With Progressive Cognitive Decline, Alzheimer Dis Assoc Disord 2013;27(1):4-15.
[7] Blendon RJ, Benson JM, Wikler EM, et al. The Impact of Experience with a Family Member with Alzheimer’s Disease on Views about the Disease across Five Countries. Int J Alzheimers Dis. 2012, Article ID 903645, 9 pages. [internet] Available at: http://www.hsph.harvard.edu/news/press-releases/alzheimers-international-survey/alzheimers_topline/. Accessed 26 July 2013
[8] KA Johnson, S Minoshima, 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 & Dementia (2013) 1-15.
[9] U.S. Department of Health & Human Services. http://www.alzheimers.gov/diagnosing.html. Electronically retrieved July 30, 2013.
[10] U.S. Department of Health & Human Services http://www.alzheimers.gov/medical_treatment.html. Electronically retrieved July 30, 2013.
[11] Mark Mintun, MEDCAC Meeting Transcript. pp. 42.. Electronically retrieved at http://www.cms.gov/Regulations-and-Guidance/Guidance/FACA/Downloads/id66d.pdf on July 26, 2013.
[12] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[13] Kirson NY, et al. July 2013.
[14] Jeffrey S. “The High Cost of Alzheimer’s Disease Misdiagnosis,” Medscape News Today, 18 July 2013. Electronically retrieved at http://www.medscape.com/viewarticle/808068 on July 26, 2013.
[15] Ibid.
[16] Kirson NY, et al. July 2013.
[17] In addition to the public presentation of findings, a manuscript reporting on the full results of this study is being prepared with imminent submission for peer reviewed publication planned. Based on the precedent set in the recent Decision Memo for Positron Emission Tomography (FDG) for Solid Tumors (CAG-00181R4), in which unpublished data was unitized to justify a change in CMS’ coverage determination between draft and final versions (See CAG-00181R4, VIII. CMS Analysis, “Concerns about FDG PET utilization”, 2nd paragraph), CMS should consider the data presented here as equally able to be considered within the final Decision Memo ahead of final publication.
[18] Kirson NY, et al. July 2013.
[19] Ibid.
[20] Kirson NY, et al. April 29, 2013.
[21] Ibid.
[22] Kirson NY, et al. July 2013.
[23] Ibid.
[24] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013
[25] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[26] Hejl A, Høgh P, Waldemar G. Potentially reversible conditions in 1000 consecutive memory clinic patients. J Neurol Neurosurg Psychiatry 2002;73:390-394.
[27] Ibid.
[28] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[29] Mintun M. The Impact of Beta-amyloid Imaging on Diagnosis and Intended Patient Management. Presentation as part of Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease MEDCAC Meeting. January 30, 2013. Electronically retrieved at http://www.cms.gov/Regulations-and-Guidance/Guidance/FACA/Downloads/01302013presentations.zip on July 26, 2013.
[30] Hejl A, et al. 2002.
[31] Although we discuss here the potential for beta-amyloid amyloid PET imaging to impacts patient management, we do not accept CMS’ suggestion that an impact on management is required by the Medicare Act. The statute is clear in providing coverage for “diagnosis or treatment”. The statute does not limit coverage to “diagnosis where the diagnosis changes management”. The plain language of the statute requires coverage for diagnosis.
[32] Grundman M., et al. 2012.
[33] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[34] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[35] Food and Drug Administration. FDA Targets Drug Side Effects. FDA Consumer Health Information. September 2012. Electronically retrieved at http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM317517.pdf
[36] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[37] Blendon RJ, et al. 2012.
[38] Ibid.
[39] U.S. Department of Health and Human Services. http://www.alzheimers.gov/diagnosing.html. Electronically retrieved July 30, 2013.
[40] U.S. Department of Health and Human Services. http://www.alzheimers.gov/medical_treatment.html. Electronically retrieved July 30, 2013.
[41] Alzheimer’s Association. 2012 Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2012;8(2):131-168.
[42] Mintun M. January 2013.
[43] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[44] Centers for Medicare & Medicaid Services. Draft Guidance for the Public, Industry, and CMS Staff Coverage with Evidence Development in the context of coverage decisions. November 29, 2012. Electronically retrieved at http://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=23 on January 8, 2013.
[45] Ibid.
[46] Centers for Medicare & Medicaid Services. National Coverage Analysis (NCA) for Positron Emission Tomography (FDG) for Solid Tumors (CAG-00181R4) http://www.cms.gov/medicare-coverage-database/details/nca-details.aspx?NCAId=263. Published June 11, 2013. Accessed July 26, 2013.
[47] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[48] Johnson KA, Sperling RA, Gidicsin CM, et al; AV45-A11 study group. Florbetapir (F18-AV-45) PET to assess amyloid burden in Alzheimer's disease dementia, mild cognitive impairment, and normal aging. Alzheimers Dement. 2012. [Epub ahead of print]
[49] Centers for Medicare & Medicaid Services. (CAG-00431N). Published July 3, 2013. Accessed July 3, 2013.
[50] 1862(a)(1)(A)
[51] Centers for Medicare & Medicaid Services. Medicare National Coverage Determinations Manual, CMS Pub. 100-03, Chap. 1, Pt. 4, Sec. 220.2 (Rev. 135, Sept. 26, 2011) available at http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/ncd103c1_Part4.pdf.
[52] 1862(a)(1)(A)
[53] Turner MR, Parton MJ, Shaw CE, Leigh PN, Al-Chalabi A. “Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002”. J Neurol Neurosurg Psychiatry 2003;74(7):995–997.
[54] Wisconsin Physician Service, Nerve Conduction Studies and Electromyography, Local Coverage Determination L31346 (effective Jan. 1, 2012), available at http://downloads.cms.gov/medicare-coverage-database/lcd_attachments/31346_6/L31346_NEURO005_CBG_010112.pdf.
[55] Noridian Administrative Services, MRI and CT Scans of the Head, Brain, and Neck, Local Coverage Determination L32848 (effective March 5, 2013), available at http://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=32848.
[56] Novitas Solutions, MRI and CT Scans of the Head, Neck, and Brain, Local Coverage Determination L32632 (effective Jan. 1, 2013), available at https://www.novitas-solutions.com/policy/jh/l32632-r5.html
[57] Novitas Solutions, 046.11: Variant Creutzfeldt-Jakob Disease; 046.19: Other and Unspecified Creutzfeldt-Jakob Disease. January 1, 2013, available at https://www.novitas-solutions.com/policy/jh/l32632-r5.html
[58] Healthnet National Medical Policy, Genetic Testing for Huntington’s Disease, NMP138 (Dec. 2011), available at http://www.healthnet.com/static/general/unprotected/pdfs/national/policies/Genetic_Testing_Huntington_Disease_Dec_11.pdf.
[59] Ibid.
[60] Centers for Medicare & Medicaid Services. Medicare National Coverage Determinations Manual, CMS Pub. 100-03, Chap. 1, Pt. 1, Sec. 70.1 (Rev. 155, June 14, 2013), available at http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/ncd103c1_Part1.pdf.
[61] Centers for Medicare & Medicaid Services. Medicare Claims Processing Manual, CMS Pub. 100-04, Chap. 12, Sec. 210.1(Rev. 2714, May 24, 2013) (excluding mental health treatments for Alzheimer’s Disease patients from limitations on CMS payments for mental health services) available at http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/clm104c12.pdf.
[62] National Alzheimer’s Project Act (NAPA), Pub. Law 111-375, 124 Stat. 4100 (Jan 4, 2011) available at http://www.gpo.gov/fdsys/pkg/PLAW-111publ375/pdf/PLAW-111publ375.pdf.
[63] NAPA, § 2(c)(4)(A)
[64] NAPA, § 2(c)(1)
[65] Department of Health and Human Services, National Plan to Address Alzheimer’s Disease, available at http://aspe.hhs.gov/daltcp/napa/NatlPlan.pdf.
[66] Ibid.
[67] Ibid.
[68] NAPA, § 2(c)(4)(A).
[69] Department of Health and Human Services, National Plan to Address Alzheimer’s Disease, available at http://aspe.hhs.gov/daltcp/napa/NatlPlan.pdf.

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For 25 years, I have directed the faculty outpatient Memory Diagnostic Center at an academic medical center. The opportunity to now detect the amyloid molecular pathology of Alzheimer disease in living patients by using beta-amyloid positron emission tomography (PET) is the most valuable clinical advance that has occurred during my years of practice. Although much remains to be refined with this technology in clinical settings (eg, sensitivity, specificity, reliability, reproducibility, access, cost/reimbursement), it already has meaningfully contributed to my clinical decision-making in two areas: 1) the cognitively impaired older adult who lacks the typical clinical phenotype of Alzheimer disease but for whom this illness remains a consideration; and 2) the young onset dementia patient. In each situation, knowing whether or not fibrillar beta-amyloid deposits are present is immensely valuable for the differential diagnosis of the cognitive impairment and hence translates directly into disease-appropriate management. The reimbursement of this technology by CMS will make it more accessible to more affected individuals, thus precluding expensive broad-based diagnostic testing for all suspected causes of cognitive impairment and accelerating the initiation of appropriate management.

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August 2, 2013

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard?Baltimore, MD 21244-1850

RE: Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dr. Jacques:

We thank the Centers for Medicare & Medicaid Services (CMS) for the opportunity to provide comment on its July 3 Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography (Aß PET) in Dementia and Neurodegenerative Disease (CAG-00431N). We write today on behalf of more than 5 million Americans who have Alzheimer’s disease and millions more who have vascular, Lewy body or frontotemporal dementia; many overcame enormous obstacles to receive their diagnosis, many others remain undiagnosed.

We reiterate the recommendation of our April 30 comment (http://www.leadcoalition.org/?wpfb_dl=103) and strongly encourage that CMS issue a final decision to provide full nationwide coverage of Aß PET imaging in the evaluation of progressive cognitive decline when its use is consistent with the appropriate use criteria (AUC) developed by the Alzheimer’s Association and Society of Nuclear Medicine and Molecular Imaging (SNMMI) and there should not be a requirement for Coverage with Evidence Development (CED).

Requiring CED is inconsistent with the overwhelming balance of scientific evidence provided in the FDA decision, the initial application for coverage, testimony before the MEDCAC, comments prior to the proposed decision and comments being submitted in response to the proposed decision. The proposed decision does not appear to account for the fact that, under the AUC, use would be limited to a modest number of the most difficult diagnostic cases and would provide scientifically rigorous, evidence-based, and clinically meaningful results for patients, caregivers and medical providers.

The proposed decision would dramatically and unnecessarily delay AUC availability of Aß PET imaging to make differential diagnoses that medical professionals need to diagnose these conditions and begin the much-needed therapies. This CED threatens to jeopardize patient safety for those otherwise misdiagnosed and erroneously subjected to the wrong treatments.

This misapplication of CED also threatens to retard the pipeline of scientific innovation in the imaging field and potentially in other fields concerned by CMS’ unprecedented, unnecessary and ill-defined seismic shift in coverage criteria. The proposed decision runs counter to our national economic policy that depends on scientific innovation and to the National Plan to Address Alzheimer’s Disease that calls for ensuring timely and accurate diagnosis, enhancing care quality and efficiency, and educating and supporting people with Alzheimer’s disease and their families. The Advisory Council on Alzheimer’s Research, Care, and Services specifically recommended that Congress and CMS redesign Medicare coverage and reimbursement to encourage appropriate diagnosis of Alzheimer’s disease and provide care planning to diagnosed individuals and their caregivers.

The proposed CED conveys to patients a perplexing message that the diagnostic tool somehow is good enough for clinical trials but not good enough for patients to know whether they have Alzheimer’s disease, frontotemporal degeneration, or some other dementing condition. It tells patients that coverage will be available in clinical trials but creates a potentially prohibitive environment for clinical trials by covering only one test and giving no clear indication of what trial designs would be approved. It tells patients that autopsy remains the only reliable means of diagnosis both undermining confidence in the value of participating in any such clinical trials and essentially telegraphing that CMS does not intend to approve diagnostic advances for at least another five to ten years or more.

This is not about one company’s product; it is about a generation of diagnostic tools, a generation of clinical trials, and a generation of patients and families. We urge CMS to reconsider its proposed ruling and issue a final ruling which removes the CED requirement in favor of full national coverage under the AUC.

Thank you for considering our views. Please contact Ian Kremer, the LEAD Coalition’s executive director, at ikremer@leadcoalition.org or (571) 383- 9916, with questions or for additional information.

Sincerely,

Academy of Radiology Research
Alzheimer's & Dementia Alliance of Wisconsin
Alzheimer’s Foundation of America
Alzheimers North Carolina
American Association for Geriatric Psychiatry
Assisted Living Federation of America
Banner Alzheimer’s Institute
Beating Alzheimer's by Embracing Science
BrightFocus Alzheimer’s Disease Research
Caregiver Action Network
Center for Alzheimer Research and Treatment, Harvard Medical School
Cleveland Clinic Foundation
Coalition for Imaging and Bioengineering Research
Cortica Neurosciences, Inc.
Jeffrey Cummings, MD, ScD (Cleveland Clinic Lou Ruvo Center for Brain Health*)
Cure Alzheimer’s Fund
Dr. Michael Devous Sr. (University of Texas Southwestern Medical Center*)
Rachelle S. Doody, MD, PhD (Baylor College of Medicine*)
Geoffrey Beene Foundation - Alzheimer's Initiative
Georgetown University Medical Center Memory Disorders Program
Global Coalition on Aging
Howard University, Aging and Memory Disorder Programs
Janssen Alzheimer Immunotherapy
Janssen Research & Development, LLC
Latino Alzheimer’s and Memory Disorders Alliance
Linked Senior, Inc.
Kostas Lyketsos, M.D., M.H.S. (Johns Hopkins Memory and Alzheimer's Treatment Center*)
Dave Morgan, PhD (USF Health Byrd Alzheimer's Institute*)
National Association of States United for Aging and Disabilities
National Down Syndrome Society
National Hispanic Council on Aging
National Task Group on Intellectual Disabilities and Dementia Practices
Neurotechnology Industry Organization
New York Academy of Sciences
NYU Langone Comprehensive Center on Brain Aging/NYU Langone Silberstein Alzheimer’s Institute
NYU Alzheimer's Disease Center
Thomas O. Obisesan, MD, MPH (Howard University Hospital*)
OWL-The Voice of Midlife and Older Women
Piramal Imaging
Project Lifesaver International
RemeGenix, Inc.
ResearchersAgainstAlzheimer’s
Stephen Salloway, M.D., M.S.?(The Warren Alpert Medical School of Brown University*)
Reisa A. Sperling, MD, MMSc (Center for Alzheimer Research and Treatment, Harvard Medical School*)
R. Scott Turner, MD, PhD (Georgetown University Memory Disorders Program*)
USAgainstAlzheimer’s
USF Health Byrd Alzheimer's Institute
Volunteers of America
Vradenburg Foundation
Michael W. Weiner, MD (University of California San Francisco*)
WomenAgainstAlzheimer’s
Wooten Laboratory for Alzheimer’s and Neurodegenerative Diseases Research

* Affiliations of individual researchers are for identification purposes only and do not necessarily represent the endorsement of the affiliated institution.

Leaders Engaged on Alzheimer’s Disease (LEAD) is a diverse and growing coalition of 61 member organizations including patient advocacy and voluntary health non-profits, philanthropies and foundations, trade and professional associations, academic research and clinical institutions, and biotechnology and pharmaceutical companies. The LEAD Coalition works collaboratively to focus the nation’s strategic attention on Alzheimer’s disease and related disorders and to accelerate transformational progress in care and support, detection and diagnosis, and research leading to prevention, effective treatment and eventual cure. One or more participants may have a financial interest in the subjects addressed.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology.

While there is not yet a cure, early and proper diagnosis can extend the quality of life for the patient and their loved ones. [PHI Redacted] was diagnosed w Mild Cognitive Impairment in 1997 @ the Institute for Memory Impairments and Neurological Disorders (UCI MIND). I believe that therapeutic and lifestyle interventions slowed the progression of the stages of the disease & allowed us to participate in clinical trials paving the way for better care for those who followed. He passed away last year and donated his brain for autopsy. One day there will be a cure, but until then, every day counts!

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August 2, 2013

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: CAG-00431N Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear Dr. Jacques:

Firstly I would like to thank you for the opportunity to provide comments on the Proposed Decision Memo for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease.

I respectfully disagree with the proposed Decision Memo and hope that significant revisions will be made before the release of the Final Decision Memo.

In my opinion there is a large body of high quality medical data to support immediate coverage, which would change patient management and lead to better health outcomes for patients. The proposed coverage with evidence development is not the right approach for beta-amyloid imaging. I strongly believe that amyloid-beta (Aß) PET imaging should be covered following appropriate use criteria for patients who would currently benefit from this technology. These patients' access to the best available evaluation is very important. In fact, appropriate use criteria already are in place as a result of the collaboration between the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI).

Sincerely,

Andrei H. Iagaru, MD, FACNM
Assistant Professor of Radiology - Nuclear Medicine
Co-Chief, Division of Nuclear Medicine and Molecular Imaging
Director, Nuclear Medicine Residency Program
Stanford University Medical Center

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

Over 5 years ago [PHI Redacted] began showing signs of something going wrong. He had behavioral changes and a once empathetic person became very self-centered. When our psychiatrist no longer felt he was able to help we turned to a neurologist. Unfortunately, the neurologist dismissed my concerns as being an overly nagging [PHI Redacted]. There was no test to validate my concerns. We went to a new neurologist and eventually we received the diagnosis of Pick's disease a form of frontal temporal dementia. The agony of no diagnosis and people telling me it was my problem was almost as unbearable as living with dementia.

A test which would help to make this diagnosis period easier would be a godsend to both the patient and the caregiver. Please reconsider permitting this test.

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I too urge CMS to adopt broader coverage consistent with the carefully defined Appropriate Use Criteria (AUC, Johnson et al., 2013) that reflect substantial evidence and expertise. The AUC are consistent with health care and cost benefits that result from more informed, efficient and effective patient care and management. Given that there are areas where sufficient evidence is clear, I urge CMS to allow this technology to be more accessible to all who could benefit from its responsible appropriate use and enable the health and cost benefits of PET amyloid imaging to be more fully realized sooner rather than later.

[Background: PET methodology research (20+ yrs) with expertise in amyloid imaging (10+ yrs)]

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ResearchersAgainstAlzheimer's

August 2, 2013

Louis B. Jacques, M.D.
Director
Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

VIA ELECTRONIC DELIVERY

Re: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

A little more than one year ago, our government set the bold, ambitious and necessary goal of preventing and treating Alzheimer’s disease by 2025. In the year-plus since our nation ratified the first-ever National Plan to Address Alzheimer’s disease, a number of departments and agencies throughout the government have demonstrated their commitment to the plan and its goals by the boldness of their actions. We applaud this effort.

As a group of more than 350 of the nation’s leading Alzheimer’s scientists and clinician researchers, we believe strongly this goal is within reach. However, to succeed, every resource and proven tool that is available in the public and private sector must be marshaled, toward this end. Although we all support the practice of evidence-based medicine, we need to advance the field even as we deliver the highest possible standard of care.

We write to you as members of ResearchersAgainstAlzheimer’s – a group of scientists, researchers, and clinicians who work on the front lines of the nation’s fight against Alzheimer’s. We are witnessing in our labs and clinics the progress that is underway to find a better means of treating or preventing this disease, and we are confident that many breakthroughs will materialize over the coming years. That said, we also recognize just how challenging today’s environment is for patients, who are entitled to the best care possible, and for physicians, who seek every means to bring diagnostic clarity, hope and appropriate, safe and effective treatments to aging Americans who face the onset of dementia.

Today, the Centers for Medicare & Medicaid Services (CMS )has a unique opportunity to advance the care and health outcomes of a narrow subset of patients who will benefit from an advanced imaging technology: Beta Amyloid Positron Emission Tomography imaging, or PET Aß. However, last month CMS issued a proposed coverage decision that runs counter to the goal of ensuring every patient receives quality and efficient care, another core goal of our National Plan. ResearchAgainstAlzheimer’s requests that CMS reconsider and revise this proposed decision. Specifically, we request that CMS issue a National Coverage Determination for PET Aß imaging for carefully defined patients with difficult-to-diagnose memory disorders, especially as described by the Appropriate Use Criteria (AUC) issued by the Amyloid Imaging Task Force (AIT).

Never has the need been greater to determine the underlying causes of dementia and to deliver the best evidence-based care to Medicare beneficiaries. According to current estimates, only about half of all dementia patients ever receive a diagnosis of dementia. An accurate diagnosis is fundamental to providing appropriate treatment and care for any condition, including those that may lack an abundance of, or even any, disease-modifying treatments. An accurate diagnosis is also vital to well-informed research efforts.

The Importance of Beta Amyloid

The question before CMS at present is what coverage level is appropriate for an FDA-approved diagnostic that when used with PET imaging technology is able to detect levels of beta amyloid in the brain of patients being evaluated for dementia. While not all researchers agree with the “amyloid hypothesis,” a definitive diagnosis of Alzheimer’s during autopsy is not possible absent the presence of beta-amyloid. Specifically, the radiopharmaceutical Amyvid before CMS is FDA-approved to:

Estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. A negative Amyvid scan indicates sparse to no neuritic plaques and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Amyvid is an adjunct to other diagnostic evaluations.

As CMS itself recognized in its proposed coverage policy, this drug and corresponding imaging technology can be quite valuable in aiding in the diagnosis of memory-impaired patients presenting with complex and difficult-to-diagnose cases where, absent such information, a physician is largely left to speculation. Unfortunately, despite recognizing this value and benefit, the agency proposed to provide coverage only to a narrow subset of patients under the highly restrictive Coverage with Evidence Development (CED) policy. Importantly, patients who are scanned under these circumstances will, in most cases, not be told the results of their testing. While we agree that additional data should and must be collected to better understand the value of the technology, restricting all coverage to CED is de facto non-coverage given the tremendous amounts of time, cost, and other resources necessary to implement a CED study.

If existing technologies were able to provide accurate and precise diagnoses of memory disorders today, this would be a non-issue. But the reality is that there is a dearth of such technologies, as evidenced by the unacceptably high numbers of patients who go undiagnosed or inaccurately diagnosed. One recent study by Kirson et al presented at the Alzheimer’s Association International Conference earlier this month, has found that substantial misdiagnosis of Alzheimer’s patients with other forms of dementia or Parkinson’s Disease results in “substantial excess costs.” By detecting a fundamental indicator of Alzheimer’s disease or the absence of such proteins, a beta amyloid imaging test is able to support superior diagnosis of a subset of dementia patients that otherwise present a confounding clinical presentation. And once such a diagnosis is made, the patient and his or her family should then have access to the latest evidence-based care and treatments available – appropriate to their underlying disease pathology.

It is particularly disappointing that in issuing its proposed coverage policy, CMS appears to have completely disregarded the consensus of a leading group of Alzheimer’s researchers and clinicians that, under the auspices of the AIT, developed an evidence-based set of Appropriate Use Criteria (AUC) that would limit use of the technology to a narrow cohort of patients. Specifically, the task force determined that PET Aß was appropriate only for:

• Patients with persistent or progressive unexplained MCI;
• Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation; and
• Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

In addition, the AUC also stipulates clearly a sizeable segment of the population for whom the use of such a diagnostic is inappropriate, making clear that the tool is to be used sparingly and judiciously.

Improving Diagnosis and Health Outcomes

If the proposed policy is not amended, we are concerned that the misdiagnosis of Alzheimer’s disease, as found in the recent immunotherapy phase 3 trials (20% not Alzheimer’s), will preempt non-Alzheimer’s patients from being properly treated. For example, vascular dementia, which is caused by stroke, and frontotemporal dementia, which is caused by atrophying of the brain’s frontal and temporal lobes, are very different than Alzheimer’s disease in how they are managed, and treated, yet can be hard to diagnose based solely on clinical presentation. The line between Alzheimer’s and frontotemporal dementia is one such case in point that speaks to the need for greater coverage of – and beneficiary access to – PET Aß. Absent access to more precise diagnostic tools, the situation could result in patients with frontotemporal dementia being treated as if they had Alzheimer’s despite evidence that some Alzheimer’s medications are potentially harmful to such patients.

If a PET Aß scan reveals little to no evidence of beta amyloid, the test results would help physicians to rule out Alzheimer’s as the cause of a patient’s dementia and direct their efforts toward other causes. For example, the absence of beta amyloid should result in consideration of alternate diagnoses including depression, and, in some cases of patients with atypical cognitive impairment who are amyloid negative, it may be appropriate to undertake a trial of antidepressant medication.

If the test indicates a high-level of beta amyloid, that result coupled with additional information, can aid a physician in making a diagnosis of likely Alzheimer’s disease and treating the patient accordingly. For some patients, this could include treatment with medications available today to address the symptoms of the disease, leading to improved overall health outcomes. Greater physician confidence in the diagnosis of or exclusion of Alzheimer’s disease can result in better medication management. An amyloid-positive PET result that raises confidence in the diagnosis of AD – coupled with additional information – is likely to result in early and appropriate use of specific medication for symptomatic treatment of AD.

Conclusion

ResearchersAgainstAlzheimer’s urges CMS to reconsider its proposed decision memo on PET Aß imaging and to issue a National Coverage Determination that covers the difficult-to-diagnose cohort of dementia patients as outlined in the Appropriate Use Criteria developed by the Amyloid Imaging Task Force. This action is warranted based on the science and available evidence, and is critical to improving care for dementia patients as well as enhancing and expanding our body of knowledge of all forms of dementia. We would be very pleased to discuss this course forward with you at any time and to provide any further information you may request or require. Thank you for your careful reconsideration of this decision.

Sincerely,

Paul Aisen, M.D., Alzheimer's Disease Cooperative Study
Marilyn Albert, Ph.D., Johns Hopkins University School of Medicine
David Bennett, M.D., Rush Alzheimer's Disease Center
Jeff Cummings, M.D., Cleveland Clinic Lou Ruvo Center for Brain Health
Steve DeKosky, M.D., University of Virginia School of Medicine
Rachelle Doody, M.D., Ph.D., Baylor College of Medicine
Howard Fillit, M.D., Alzheimer’s Drug Discovery Foundation
David Holtzman, M.D., Washington University, St. Louis
Bruce Lamb, Ph.D., The Cleveland Clinic Foundation
David Morgan, Ph.D., Byrd Alzheimer’s Institute, University of South Florida
Ron Petersen, M.D., Ph.D., Mayo Alzheimer’s Disease Research Center
Reisa Sperling, M.D., Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
Rudy Tanzi, Ph.D., Harvard Medical School
John Trojanowski, M.D., Ph.D., Alzheimer’s Disease Center of the University of Pennsylvania
Michael Weiner, M.D., University of California, San Francisco

*Affiliations are for identification purposes only and do not necessarily represent the endorsement of the affiliated institution.

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Louis Jacques, M.D.
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

August 1, 2013

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

The Alzheimer’s Association appreciates the opportunity to comment on the Center for Medicare & Medicaid Services (CMS) draft determination on coverage of positron emission tomography (PET) amyloid-beta (Aß) imaging for individuals with dementia or neurodegenerative disease. The Association is disappointed with the proposed determination of Coverage with Evidence Development (CED) given the sufficient evidence and corresponding clear, scientific consensus recommendations provided to CMS by the Association and the Society for Nuclear Medicine and Molecular Imaging (SNMMI) regarding appropriate, limited coverage, only in specific populations.

The Alzheimer’s Association is the leading voluntary health organization in Alzheimer care, support and research. Today, there are more than 5 million Americans with Alzheimer’s disease, half of which have never received a formal diagnosis. The majority of individuals with Alzheimer’s disease are age 65 or older and rely on the Medicare program for access to health coverage and services.

Background on Alzheimer’s
The Alzheimer's Association understands that CMS' evaluation of the impact of brain amyloid imaging on health outcomes is ongoing, however the needs of Alzheimer's community are acute and immediate. A study published in April 2013 in the New England Journal of Medicine found that Alzheimer’s disease is now the costliest disease in America, and set to increase like no other. According to this independent, NIH-funded study, the annual cost of Alzheimer’s care in 2010 was as high as $215 billion.(1)

In addition, Alzheimer’s and related dementia make treating comorbidities very difficult to manage and increase the costs of care. For example, 30 percent of individuals with Alzheimer’s have heart disease, while 29 percent have diabetes. A senior with heart disease and Alzheimer’s costs Medicare 61 percent more than a senior with only heart disease, while a senior with diabetes and Alzheimer’s costs Medicare 81 percent more.(2)

Complications from managing these other chronic conditions also increase the likelihood of hospitalizations. (3,4) To address the needs of those patients, Alzheimer’s needs to be detected, accurately diagnosed and recorded in the medical record. One way to address these costs is to have the diagnosis recorded so that additional comorbidities can be addressed and managed in the most efficient and appropriate manner.(5) Physicians face a greater difficulty in managing these conditions when over half of the five million Americans living with Alzheimer’s have not received a formal diagnosis.

The Alzheimer's Association strongly supports early and accurate diagnosis of Alzheimer's disease. An early and accurate diagnosis has been found to lead to better outcomes and higher quality of life for people living with the disease and their families by: enabling earlier access to appropriate treatments; allowing the family to build a care team and secure education and support services; enabling enrollment in Alzheimer's/dementia clinical trials; and, providing an opportunity for the development of advance directives and financial planning. This also includes allowing family members and caregivers to be alert to potential financial fraud targeting individuals with dementia. (6) For all these reasons, an accurate and early diagnosis is very important for ensuring the highest quality of life for both the individual and their caregivers.(7)

Issues of Misdiagnosis
By having amyloid PET imaging as a tool to help in the diagnostic process in difficult cases, the number of misdiagnosed cases would decrease, thereby reducing the unnecessary overutilization of the health care system and improving health outcomes for patients. This is particularly true in the case of distinguishing between Alzheimer’s disease and vascular dementia. Preliminary evidence recently presented at the Alzheimer’s Association International Conference (AAIC) shows that, based on Medicare claims data, Medicare beneficiaries with vascular dementia who were misdiagnosed with Alzheimer’s disease overutilize the health care system relative to those with vascular dementia who were correctly diagnosed. (8)

Specifically, the data show that over a four-year period following a misdiagnosis of Alzheimer’s, a misdiagnosed individual incurs, on average, about $15,000 more in health care costs than an individual who was correctly diagnosed with vascular dementia.(9) The data also show that once the misdiagnosed individual receives an accurate diagnosis, the excess costs – and therefore the overutilization of the health care system – are almost immediately eliminated. In other words, the overutilization of the health care system by misdiagnosed individuals is not attributable to the complexity of the individual cases, but rather to the misdiagnoses.

While we recognize that costs are not to be a factor in your decision, these data point to a problem greater than costs: individuals who are misdiagnosed in difficult cases are not receiving the best possible health care. They are receiving inappropriate medications, undergoing treatment courses that do not work, and continuing to have health issues that are not being properly identified and addressed. These problems could be avoided – and health outcomes could be improved – with an earlier accurate diagnosis through the use of a rule-out amyloid PET scan.

Spirit of the National Alzheimer’s Project Act (NAPA)
Recognizing the growing Alzheimer’s crisis, Congress unanimously passed the bipartisan National Alzheimer's Project Act (P.L. 111-375) in 2010. The purpose of the law includes, “improv[ing] the- (A) early diagnosis of Alzheimer's disease; and (B) coordination of the care and treatment of citizens with Alzheimer's.” Congress mandated through NAPA that the Secretary of Health and Human Services create a strong, accountable National Alzheimer’s Plan with an appropriate commitment to the fight against Alzheimer’s that advanced the purpose of the statute.

In keeping with NAPA, the Secretary released the first-ever National Plan to Address Alzheimer’s Disease in May 2012, with an updated version released in June 2013. As a federal member of the Advisory Council on Alzheimer’s Research, Care, and Services, and a partner in the formulation and update of the National Alzheimer’s Plan, CMS understands that, like NAPA, one of the goals of the National Plan is to ensure an early and accurate diagnosis of Alzheimer’s. Moreover, the Plan acknowledges that receiving a timely and accurate diagnosis helps ensure that individuals with Alzheimer’s and their families have time to plan and prepare for the future, leading to more positive outcomes for both.(10,11) Amyloid PET imaging is a vital tool physicians can use to provide an accurate diagnosis of Alzheimer’s in clinically difficult differential diagnoses for individuals displaying cognitive impairment.

Amyloid Imaging Taskforce - Acceptable Use Criteria (AIT-AUC)
Amyloid PET imaging can greatly benefit a limited but critical population of individuals displaying cognitive impairment with clinically difficult presentations that complicate differential diagnoses. The Association partnered with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) to develop a set of appropriate use criteria (AUC) to guide physicians on the best use of this novel technology. (12)

Appropriate use of Amyloid PET imaging, as an adjunct to other types of evaluation and in compliance with the AUC, will allow for a more certain diagnosis. Using this information, the physician can alter the medication management and prescribed diagnostic services for the patient.

While an early and accurate diagnosis is a significant benefit to those with Alzheimer’s, an early but inaccurate diagnosis is harmful and can add significant additional costs. Very important benefits from this test will result from accurately and definitively ruling out a diagnosis of Alzheimer’s. Test results that rule out Alzheimer’s will prompt physicians to examine other causes of cognitive impairment, some of which can be reversed when recognized and appropriately treated.(13) Furthermore, individuals with Frontotemporal Dementia, which mimics Alzheimer’s disease, do worse on Alzheimer’s medications indicating the value of this test. (14)

The Costs of Delay
The need to accelerate improved care and an early and accurate diagnosis today, when scientifically supported, is critical. Neither families directly impacted by this disease, nor our federal government, can afford to wait as much as seven years for a final decision about national coverage, as was the case with the National Oncology Patient Registry and the evaluation by CMS of FDG PET coverage.

Seven years ago, this imaging technology did not exist, and the timeframe at which CMS has conducted CED process is unsuited and unacceptable in light of both the pace of scientific and technological innovation in the Alzheimer’s field and, more importantly, the rapidly increasing needs posed by the escalating Alzheimer’s epidemic. If the federal government follows this example and timeline, it will hinder coverage of a badly needed, already FDA approved diagnostic tool in limited populations in which sufficient evidence has indicated this technology has a meaningful impact.

The Association urges CMS to weigh the hidden but significant societal cost represented by years in a CED process with extremely limited access throughout this period for those in the specifically defined populations who could most benefit from this diagnostic tool.

Coverage with Evidence Development (CED) Design
The Association’s position has always been and remains that CED can be highly appropriate for some populations. However, the CED mechanism that has been proposed in this instance has deep issues that are documented and discussed in other public comment submissions. Among them, the requirements would limit participation to a much smaller cohort of individuals who would benefit from amyloid PET imaging and sets postmortem diagnosis as an endpoint rather than changes to the quality of life of the individual. The Association believes, based on review of the current proposal, that CMS must engage with the expert community to define how best to implement CED for those populations where full coverage is inappropriate.

The time constraints prior to release of the final decision do not allow for this critical discussion. Consequently, for those populations where CED is appropriate, we urge CMS to preserve design flexibility in its crafting of the final decision so that implementation of CED can be informed in a timely way through consultation with experts both within and beyond the Alzheimer’s clinical community. It is important that any study that CMS requires be designed to be as expedient and reasonable as possible, and that CMS preserves the flexibility to engage with the stakeholder community to fit the mutual interests of the community and CMS.

Conclusion
The Alzheimer’s Association appreciates the opportunity to comment on this draft coverage determination. We urge you to consider the many positive health outcomes to receiving a definitive Alzheimer’s diagnosis, as well as to definitely ruling out the same, when developing the final coverage determination. Thank you for your consideration. Please contact Rachel Conant, Director of Federal Affairs at 202-638-7121 or rconant@alz.org if you have any questions.

Sincerely,

Robert Egge
Vice President, Public Policy
Alzheimer’s Association

1 Monetary Costs of Dementia in the United States, New England Journal of Medicine 2013; 368:1326-1334
2 Alzheimers Association, 2013 Alzheimer’s Disease Facts and Figures, Alzheimer’s & Dementia, Volume 9, Issue 2
3 Rudolph JL, Zanin NM, Jones RN, Marcantonio ER, Fong TG, Yang FM, et al. Hospitalization in community-dwelling persons with Alzheimer’s disease: Frequency and causes. J Am Ger Soc 2010;58(8):1542-8.
4 Alzheimers Association, 2013 Alzheimer’s Disease Facts and Figures, Alzheimer’s & Dementia, Volume 9, Issue 2.
5 Okonkwo OC, Griffith HR, Copeland JN, Belue K, Lanza S, et al. Medical decision-making capacity in mild cognitive impairment: A three-year longitudinal study. Neurology 2008;72(19):1474-80.
6 Triebel KL, Martin R, Griffith HR, Marceaux J, Okonkwo OC, et al. Declining financial capacity in mild cognitive impairment: A one-year longitudinal study. Neurology 2009;73(12):928-34.
7 Improving the quality of care for mild to moderate dementia:Int J Geriatr Psychiatry. 2007 Aug;22(8):782-8.
8 Kirson NY, Hunter CA, Desai U, Cummings AKG, San Roman AM, Faries, DE, et al. Excess Costs Associated with Misdiagnosis of Alzheimer’s Disease among US Medicare Beneficiaries with Vascular Dementia or Parkinson’s Disease. Alzheimer’s Association International Conference. Boston, MA. July 17, 2013.
9 Calculated by the Alzheimer’s Association by weighting data from Kirson, et al., op. cit.
10 Gaugler JE, Kane RL, Kane RA, et al. Unmet care needs and key outcomes in dementia. J Am Geriatr Soc. 2005; 53: 2098-2105.
11 Mittelman MS, Haley WE, Clay OJ, et al. Improving caregiver well-being delays nursing home placement of patients with Alzheimer disease. Neurology. 2006; 67: 1592-1599.
12 Update on appropriate use criteria for amyloid PET imaging: Dementia experts, mild cognitive impairment, and education Alzheimer's & Dementia: The Journal of the Alzheimer's Association Volume 9, Issue 4 , Pages e106-e109, July 2013.
13 Butler and Zeman. Neurological syndromes which can be mistaken for psychiatric conditions. J Neurol Neurosurg Psychiatry 2005;76:i31-i38 doi:10.1136/jnnp.2004.060459.
14 Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J

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usagainstalzheimersnetwork.org

VIA ELECTRONIC DELIVERY

August 02, 2013

Louis B. Jacques, M.D.
Director
Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

USAgainstAlzheimer’s (USA2) appreciates this opportunity to comment on CAG-00431N regarding the use of positron emission tomography (PET) amyloid-beta (Aß) imaging in the evaluation of Medicare beneficiaries who suffer from cognitive impairment and who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. We speak as the leader of a national mobilization network committed to stopping Alzheimer's disease by 2020, and we offer our comments on behalf of, and in the voice of, the Medicare beneficiary whose care and health outcomes will be directly affected by CMS’s final decision.

On behalf of the more than 5 million Americans currently suffering from Alzheimer's and the tens of millions more at risk to develop this disease in the coming years, UAS2 strongly opposes the proposed decision to cover PET Aß imaging tests through coverage with evidence development (CED). As discussed below, we request that CMS:

Provide immediate coverage without CED for use in the narrowly defined and clinically difficult cases to assist in making differential diagnoses of the causes of dementia, as defined by the Alzheimer’s Imagining Taskforce.

INTRODUCTION

The use of CED has a respected place in the context of CMS’s review of new technologies. Here, however, in the case of coverage of PET Aß imaging tests, we believe it is misplaced and is being misapplied in a manner that presents real and avoidable risk of adverse health outcomes for a limited and well-defined group of Medicare beneficiaries.

In its Proposed Decision Memo, CMS asks:

1. Do the results of PET Aß 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.
2. 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 Aß imaging?
3. Does using PET Aß imaging in guiding patient management, to enrich clinical trials seeking better treatment 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?(Emphasis supplied)

With respect to the first question, we submit that the results of PET Aß imaging will assist in making a differential diagnosis that meaningfully informs the management of a patient presenting with clinical signs of dementia, avoiding the use of medications that are either futile or potentially harmful. Based on a more informed diagnosis, and in particular in those cases where a diagnosis of AD is ruled out and appropriate care is delivered, a patient’s quality of life is placed on a very different trajectory. For these reasons, PET Aß imaging improves a patient’s health outcomes. For PET Aß, this should be the standard applied to determine whether, for the narrow subset of patients meeting the criteria established by the AIT, its use is reasonable and necessary for both the diagnosis and the treatment of their illness. To hold it to any other standard flies in the face of prior CMS decisions, published studies, expert analysis, clinical logic and common sense.

With respect to the second question, the Alzheimer’s Imaging Taskforce, an expert panel convened by the Society of Nuclear Medicine and molecular Imaging (SNMMI) and the Alzheimer’s Association (AIT), has issued comprehensive Appropriate Use Criteria (AUC) for PET Aß imaging. As a result of the work of the AIT, CMS has before it compelling, evidenced based expert consensus recommendations on the specific characteristics of the subpopulation of patients who present with dementia, where AD is a possible diagnosis but where this diagnosis remains uncertain after a comprehensive evaluation by a dementia expert, and where the knowledge of the presence or absence of Aß pathology is expected to increase diagnostic certainty and alter management. It is hard for us to imagine that more is needed to meet this second test set forth by CMS.

Regarding the third question, the use of PET Aß imaging to enrich clinical trials in order to seek better treatment or prevention strategies for AD and to guide patient management in those trials is already a widely accepted practice in the nation’s most important prevention trials. While we will not address this issue at length in our comments, we look forward to the substantial body of evidence that will be submitted to CMS to support appropriate coverage for the use of PET Aß imaging in these trials that are providing hope to millions of Americans.

SUMMARY

The use of CED in the coverage of PET Aß imaging tests will delay access to a new technology that offers critical information otherwise not available to skilled clinicians. The inability to use this tool today will cause predictable, evidence-based harm to a narrow subpopulation of patients who face the clinical trauma of not knowing if their dementia is a potential sign of Alzheimer’s disease or if they suffer from a very different cause of psycho-neurological disturbances, requiring a wholly different clinical regimen and presenting a very different life challenge for the patient, the clinician, the family and all involved. This set of patients is entitled to access to PET Aß imaging tests today to guide immediate treatment decisions, to avoid the potential, continued misuse of harmful medications, and to make life altering decisions armed with the best diagnosis the clinical field can offer using available technology.

For the qualifying beneficiary whose life is held in limbo by the trauma of not knowing the underlying cause of dementia, access to PET Aß imaging offers an otherwise unavailable tool to guide the clinician in making an accurate diagnosis and to prevent the risk of adverse health outcomes through the avoidable misuse of medications. Whether viewed through the lens of published studies, expert analysis or clinical and practical logic, these benefits fall squarely in the camp of improved health outcomes.

We urge CMS to issue a National Coverage Determination (NCD) that covers use of PET Aß imaging tests without the CED requirement as a critical tool for a clinician who is challenged to rule out a diagnosis of Alzheimer’s disease (AD) in narrowly defined and clinically difficult subpopulation of patients, defined by the AUC, who may in fact be suffering from frontotemporal dementia (FTD) or other psycho-neurological disorder.

We will be pleased to work with the Agency to refine the policy in a manner that will not delay access to PET Aß imaging tests for this well-defined set of Medicare beneficiaries.

In support of this request, our comments below will address each of the following:

1. CMS’s draft decision stands in direct opposition to the Administration’s commitment to find a treatment or means of prevention of Alzheimer’s by 2025 as well as the Administration’s National Bioeconomy Blueprint .


2. The available scientific evidence and consensus is adequate to warrant coverage without evidence development for the use of PET amyloid imaging in clinically difficult differential diagnoses and in so doing to avoid the avoid the risk of adverse outcomes through misdiagnosis and mistreatment.


3. PET Aß is reasonable and necessary for the narrow subset of beneficiaries defined by expert consensus opinion whose health outcomes will be put at risk and may suffer by delayed access to this tool if only covered in a clinical trial.


4. The fear and confusion that surrounds the plight of today’s CMS beneficiary faced with confounding clinical presentation of dementia and a difficult-to-diagnose cause should be placed squarely within the sights of CMS’s ultimate decision on PET Aß imaging.

DISCUSSION

I. CMS’s draft decision stands in direct opposition to the Administration’s commitment to find a treatment or means of prevention of Alzheimer’s by 2025 as well as the Administration’s National Bioeconomy Blueprint .

CMS operates within the context of as opposed to independent of the National Alzheimer’s Project Act and the Administration’s commitment to stop Alzheimer’s disease by 2025. It is tempting to say that CMS as a regulatory agency must operate independent of a larger legal, policy and societal context within which the challenge posed by the Alzheimer’s epidemic is being met head on by Congress and the Department of Health and Human Services. Certainly every ruling by the agency must be rigorously guided by data and evidence, and no one would suggest otherwise.

Today, however, every agency with regulatory oversight, having discretion in the interpretation and application of its legal obligations, operates within a larger legal and policy context. In this case, that context is provided by NAPA, the National Plan, and the National Bioeconomy Blueprint and the nation’s commitment to promote innovation. When this engine of innovation is kicked into high gear to meet a challenge head on, as it has been by the current Administration through the implementation of the National Alzheimer’s Project Act and the Blueprint on the Bioeconomy, context matters.

A little more than one year ago, our nation made an historic commitment to stop Alzheimer’s disease by 2025 pursuant to a unanimous act of Congress directing the development of a national strategic plan to address Alzheimer’s. To set this goal, our government assembled a panel of experts from within and outside of government. More than a dozen departments, agencies and offices participated in this effort to create the National Plan to Address Alzheimer’s Disease, including CMS. Disease funding through the National Institutes of Health (NIH), regulatory science and accelerated avenues for review through the Food and Drug Administration (FDA), and innovation-oriented, beneficiary-driven coverage decisions through CMS, all work in concert to assure that sound action and results flow from the Administration commitment to an aggressive goal to stop Alzheimer’s by 2025.

CMS’ final decision regarding coverage for PET Aß imaging tests will unfold under the penumbra of this commitment to take every step possible to meet the looming Alzheimer’s crisis. The expanded use of CED, which CMS is seeking to reflect in its PET Aß Decision Memo, emerges from the Blueprint on the Bioeconomy, released in April 2012. As re-stated by CMS in its Draft Guidance for the Public, Industry and CMS Staff Coverage with Evidence Development , in the context of coverage decisions:

The CED authority has existed for more than a decade but has been applied sparingly. [CMS] is poised to implement the next phase of CED by better defining the parameters and guidance for CED so that it can be used more widely and effectively as a driver of innovation. CMS believes that the lessons learned during the initial implementation of CED can inform its more frequent use and create predictable incentives for innovation while providing greater assurance that new technologies in fact fulfill their initial claims of benefit. (Emphasis supplied.)

The proposed CMS decision on PET Aß imaging tests is moving precisely in the opposite direction. It defeats rather than drives innovation and removes needed innovation-based incentives in this field. Use of CED in the case of PET Aß imaging telegraphs that CMS has no intention of approving diagnostic advances in Alzheimer’s disease treatment and management for at least another five years or more.

Today, a national commitment exists to address a grave and growing threat to the health of millions of Americans presented by Alzheimer’s, recognizing that few technologies and treatments are available to help enable differential treatment decisions for the patient presenting with cognitive impairments who may or may not face Alzheimer’s. Government agencies are challenged to work in concert to assure that every action that rests within their discretion not only respects all available science, data and evidence but also advances the practical availability of innovative diagnostic tools and treatment modalities, sending a signal that predictable incentives are in place to bring life-sparing technologies and treatments forward.

We recognize that some innovations may prove, through time, not to enhance patient health outcomes. For example, metal-on-metal hip transplants. But here we are dealing with a non-invasive diagnostic tool that meaningfully informs treatment decisions. The real risk before CMS is the risk posed to those beneficiaries who meet the criteria of the AUC but who may be deprived of access to this technology for many years due to the imposition of the CED requirement. The risk does not lie in the diagnostic tool but rather in the course currently proposed by CMS.

The nation is facing a crisis without precedent as it gears up to treat and care for the aging Americans who will suffer from Alzheimer’s. Decisions send messages to a community that is searching for reasons to invest, but will retreat when doors appear to close or barriers seem to be put in place. The crisis is personalized every day as increasing numbers of Medicare beneficiaries are diagnosed with dementia. This crisis becomes increasingly poignant when any beneficiary’s dementia progresses without the security of a timely and accurate diagnosis and both patient and provider are presented with treatment choices that differ markedly based on the understanding of the underlying causes of the presenting symptoms. In these tough cases, the patient may be suffering from FTD, depression, Parkinson’s or other non-AD causes of dementia, on one hand, or may be facing a possible diagnosis of Alzheimer’s disease, on the other. Few clinical questions are more daunting, more compelling or more important to Medicare beneficiaries and their loved ones.

In this narrow circumstance, CMS has the ability today to provide a new, more specific, more elegant tool PET Aß imaging to accelerate and clarify a differential diagnosis. This tool has been approved by the FDA as safe and effective for determining the presence of amyloid beta plaques – a core feature of Alzheimer’s disease pathology. It is a tool whose “clinical utility has been identified and placed in the proper clinical context” by the AIT.

Misdiagnosis of the cause of dementia leads to $5,000 to $10,000 in excess medical costs per year until the correct cause is identified. Of course the indirect costs incurred by the patient and family in this diagnostic odyssey are not captured in these numbers. A subset analysis of recent phase III clinical trials finds that 20 percent of cases diagnosed as mild to moderate Alzheimer’s disease did not have amyloid deposits and thus were not Alzheimer’s cases. The health outcomes of many of the beneficiaries whose disease experiences are reflected in these data would have benefited from the more accurate diagnosis made possible through PET Aß imaging. It is likely that ruling out Alzheimer’s would have redoubled a conscientious, caring physician’s efforts to work to identify less frequent and possibly treatable causes of cognitive dysfunction. And the potential adverse health outcomes to those beneficiaries without Alzheimer’s who were misdiagnosed and given Alzheimer’s treatments would have been avoided.

The balance of any close decision must be weighted in favor of the beneficiary and of encouraging rather than stifling innovation that will improve their care and health outcomes.

This is the context in which CMS must re-evaluate its decision on PET Aß imaging and this context matters.

I. The available scientific evidence and consensus is adequate to warrant coverage without evidence development for the use of PET amyloid imaging in clinically difficult differential diagnoses and in so doing to avoid the avoid the risk of adverse outcomes through misdiagnosis and mistreatment.

In making determinations in the case of diagnostic tools, CMS employs a “Preferred Road to Diagnostic Coverage.” These are the evidentiary factors that are required for coverage determinations for new diagnostic technologies. The evidentiary milestones on this Preferred Road to Diagnostic Coverage are findings that:

• There is adequate evidence
• That the incremental information obtained by this new diagnostic technology
• Will change physician recommendations
• Resulting in changes in therapy
• That will improve health outcomes.

In this section and in Section III that follows we examine these important evidentiary milestones in the context of coverage for PET Aß imaging.

1. Is there adequate evidence?

Today, CMS covers (without CED) the use of Fluorodeoxyglucose (FDG) PET imaging for differential diagnosis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) based on an evidentiary record consisting of expert opinion but no clinical studies. The CMS decision memo states:

“In sum, our analysis of the evidence on the use of FDG-PET in detecting AD in elderly patients with early dementia and its potential effect on patient management and health outcomes is consistent with that of the external TA report update recently published on this topic. No published studies evaluated whether FDG-PET can alter clinical decision-making and improve patient outcomes when added to the standard workup.” (Emphasis supplied.)

Instead, when approving FDG-PET, CMS relied upon expert consensus to reach a determination that the evidence was adequate to conclude that FDG-PET improves patient outcomes by assisting in the detection of FTD in patients who: (i) were recently diagnosed with dementia, (ii) present with six or more months of cognitive decline, (iii) have undergone a comprehensive AAN-recommended workup (conducted by a practitioner experienced in the diagnosis and assessment of dementia), and (iv) face a diagnosis that continued to remain uncertain despite the extensive medical evaluation. Based on this finding, CMS continues today to cover FDG-PET for the differentiation of AD and FTD.

Here the evidentiary record for PET Aß imaging is stronger. This lack of consistency regarding the required level of evidence for FDG-PET versus PET Aß elicits two important responses:

• In the current record, CMS has before it evidence-based expert consensus opinion and published studies that support the value of using PET Aß imaging to clarify and reach a differential diagnosis for those meeting the AUC. (We cite these studies in Section III below.) To erect a different and higher standard for PET Aß as opposed FDG-PET and to refuse to accept the evidence that augments the expert opinion represented by the AIT represents an action by CMS in this limited setting that is arbitrary and capricious, and one that creates, unnecessarily, real risk for the subset of Medicare beneficiaries who fall within the AUC guidelines.


• The CMS beneficiary with access to FDG-PET today should not be left without access to a higher quality imaging test. In the case of PET Aß, a breakthrough technology has been introduced to the marketplace, which – for patients with a clinically difficult differential diagnosis offers a clearly improved path to detect FTD and rule in or rule out a diagnosis of Alzheimer’s. For the patients who today have access to FDG-PET but not PET Aß imaging, and who fall squarely within the AUC, by not making this tool available, this narrow set of beneficiaries and their providers will be forced to rely on what an inferior technology and, again, for many this will be to their potential harm. This result is untenable.

2. Will the information provided by PET Aß imaging provide incremental information that will change physician recommendations resulting in changes in therapy that will improve health outcomes?

Let’s examine each of these factors associated with the CMS test for improved health outcomes in the case of PET Aß.

Incremental information

CMS covers FDG-PET to differentiate a potential diagnosis of AD from FTD. PET Aß imaging, through the elegant attachment of radio-active isotopes to the amyloid plagues in the brain, detects a molecular pathology that may be associated with a diagnosis of Alzheimer’s. FDG-PET ‘infers’ this pathology based on spatial patterns of hypometabolism. This new information produced by PET AB is more than incremental.

Changes in physician recommendations resulting in changes in therapy

In January 2013, the AIT issued appropriate use criteria for amyloid PET. The AIT presented a carefully crafted set of clinical guidelines for the identification of a subset of patients for whom for the use of PET Aß would be a superior diagnostic tool in limited and well-defined cases. Specifically, when a beneficiary has met each of the following criteria, amyloid PET imaging is recommended for use:

1. A cognitive complaint with objectively confirmed impairment;
2. AD as a possible diagnosis, but when diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and
3. When knowledge of the presence or absence of Aß is expected to increase diagnostic certainty and alter management.

The AUC continues to define this subset of qualifying patients as:

• Patients with persistent or progressive unexplained Mild Cognitive Impairment (MCI)
• Patient satisfying core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation
• Patient with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

As discussed more fully below, for these beneficiaries who meet the appropriate use criteria for PET Aß imaging, an accurate diagnosis is essential to appropriate care and to the avoidance of a harmful outcome resulting from a less than fully informed treatment decision. A physician who holds in his hands the results of the PET Aß imaging test will know not to treat a patient with FTD or other psycho-neurological cause of the patient’s dementia with the drugs used today to treat AD. That physician’s recommendations for treatment and prescribed therapy for this patient will change directly as a result of this information. As noted by the AIT:

Exclusion of AD should result in consideration of alternate diagnoses including depression, and in some cases of patients with atypical cognitive impairment who are amyloid negative, it may be appropriate to undertake a trial of antidepressant medication.

Making this patient wait is difficult to justify.

That will improve health outcomes.
PET Aß imaging is recognized today as a tool that, when introduced to the care of a Medicare beneficiary who meets the AUC, provides more than incremental information as it deciphers the presence or absence of amyloid beta plaques, increases the prospect of diagnostic certainty, and changes therapy and management decisions. In some cases this will mean a very different treatment for a very different underlying cause of persistent mental confusion, such as depression. The change in a treatment regimen may mean a dramatically altered health outcome as well as the avoidance of harm. For others, the health outcome may derive from the contribution of the imaging findings to an ultimate confirmed diagnosis of Alzheimer’s and, with this, the value of knowing, the ability to plan, the opportunity to hold on to the quality of the life that remains to be lived. Again, whether viewed through the lens of published studies, expert analysis, clinical observation or practical logic, these benefits fall squarely in the camp of improved health outcomes.

For the patients who fall within the appropriate use criteria, each of the milestones in the Preferred Road has been met. By meeting these tests, as supported in our discussion below, not only is CED not appropriate for PET Aß, but coverage of PET Aß is reasonable and necessary for beneficiaries falling with the AUC.

II. PET Aß is reasonable and necessary for the narrow set of beneficiaries defined by expert consensus opinion whose health outcomes will be put at risk and who may suffer by delayed access to this tool if it is only covered in a clinical trial.

Coverage for a new diagnostic such as PET Aß rests on a finding that the technology is reasonable and necessary for the diagnosis or treatment … of an illness. [Social Security Act 1862 (a)(1)].

Along with CMS, we ask:

• Given the available evidence, is the use of PET Aß reasonable and necessary for the differential diagnoses in patients meeting the appropriate use criteria?


• Is there sufficient evidence available to CMS today to demonstrate that the use of PET Aß is reasonable and necessary to inform the treatment of patient meeting the appropriate use criteria, thereby avoiding a risk to beneficiaries of the use medications that have been shown harmful to patients who, as an example, are suffering from FTD?


• Is it reasonable only to allow access to this tool to those who participate in a clinical trial designed to validate the tool, while those seeking care outside of a clinical trial are left to wait for access to this potentially life-sparing diagnostic tool?

In answering these questions, we rely in significant part upon studies that are also cited by others who have submitted comments to CMS in response to the draft Proposed Decision Memo CAG-00431N, including those comments submitted by Dr. Gil Rabinovici, Assistant Professor in Neurology, UCSF Memory & Aging Center, and Dr. Norman Foster, Professor of Neurology Director, Center for Alzheimer's Care, Imaging and Research, University of Utah.

These clinicians offer the following critical observations:

1. Clinicians are in a difficult place: Distinguishing AD and FTD on clinical grounds can be challenging, and misdiagnosis rates are high even at expert centers.


2. An accurate diagnosis is essential to appropriate care and to the avoidance of a harmful outcome resulting from a less than fully informed treatment decision. An accurate diagnosis has an impact on a beneficiary’s prognosis , the likelihood of heritability, and most importantly on therapy, since drugs that are used to treat AD (cholinesterase inhibitors and memantine) worsen outcomes in FTD.

The differential diagnosis of AD versus FTD typically arises in young-onset dementia patients, at an age in which the overall prevalence of amyloid in the normal population is low, making “false positives” less likely.

PET Aß imaging becomes a critical adjunct to the resources called upon by the skilled specialist in reaching or ruling out a diagnosis of AD. As noted by the AIT,

Greater physician confidence in the diagnosis of or exclusion of AD can result in better medication management. An amyloid-positive PET result that raises confidence in the diagnosis of AD is likely to result in early and appropriate use of specific medication for symptomatic treatment of AD. In contrast, a plan to commence or continue medications developed for the treatment of AD….in patients with a negative amyloid scan may be inappropriate. (Emphasis supplied.)

3. PET Aß is a tool to reduce the overuse of medications in the elderly. The risk of polypharmacy in the elderly has been widely recognized by the medical community. The coverage of PET Aß promises to be a tool that will help providers resist and avoid this harmful outcome by having the confidence to treat what may be real and verified, as opposed to throwing multiple medications at clinical symptoms without an understanding of their source or combined risk.


4. PET Aß is more definitive than FDG-PET in ruling out AD, offering a clear and significant improvement over currently available and covered technologies, preventing patient harm. Amyloid imaging detects neuritic plaques, a core feature of AD pathology that is not part of the FTD pathologic spectrum. CMS covers FDG-PET for the differentiation of AD and FTD; however, amyloid PET has the advantage of directly detecting molecular pathology, whereas FDG-PET infers the pathology based on spatial patterns of hypometabolism.

   Multiple studies from different centers have demonstrated the utility of amyloid PET in distinguishing AD from FTD. In a head to head comparison of amyloid and FDG-PET in over 100 patients, amyloid PET had higher overall diagnostic accuracy than FDG in differentiating AD from FTD, and showed higher inter-rater reliability.

   Rabinovici et al reported at the Alzheimer’s Association International Conference (AAIC), July 2013, on the clinical impact of amyloid imaging at the UCSF Memory & Aging as demonstrated by observed clinician behavior, focusing on the AD versus FTD scenario. Amyloid imaging led to a change in diagnosis in 38% of patients who presented a diagnostic dilemma, and was significantly associated with changes in treatment (initiation of AD symptomatic therapy). In contrast, FDG-PET did not impact diagnosis or treatment when controlling for amyloid PET results. These data are still unpublished but are results the authors are willing to share and discuss with CMS.

5. Post-mortem diagnosis data, such as that proposed by CMS in the proposed Decision Memo, is available today. At the AAIC, Rabinovici et al reported the accuracy of amyloid PET versus post-mortem diagnosis in 25 patients evaluated at the UCSF Memory & Aging Center (more than double the number in the initial published report). Amyloid imaging had 100% sensitivity and 93% specificity versus the pathologic gold standard of NIA-Reagan high-likelihood AD. These numbers replicate in a clinical population previous findings from the florbetapir end-of-life study.

   Again, these manuscripts are currently under review or in preparation; however, the authors have indicated that they will be pleased to share the manuscripts with CMS to support these assertions.

6. Making PET Aß imaging available to those who participate in a trial but not in the context of care for those who satisfy the appropriate use criteria results in a harmful irony and is unsupportable. If the CMS draft decision stands it will be signaling to the subset of beneficiaries who face a clinically- confounding differential diagnosis of Alzheimer’s disease, frontotemporal degeneration, or some other dementing condition that PET Aß imaging is good enough to use in clinical research to determine whether a patient should be included in a trial due to the presence of amyloid plague or treated as a control based on the lack thereof but is not good enough for patients who face a real crisis in their care. This is an unintended irony and avoidable consequence.

III. The fear and confusion that surrounds the plight of today’s CMS beneficiary faced with confounding clinical presentation of dementia and a difficult-to-diagnose cause should be placed squarely within the sights of CMS’s ultimate decision on PET Aß imaging.

The Value of Knowing.

In few circumstances are a vast number of Americans waiting and hoping for help from the medical enterprise in the way that Medicare beneficiaries experiencing signs of cognitive impairment or dementia and facing a diagnosis of Alzheimer’s are today. A recent survey conducted by the Harvard School of Public Health, commissioned by Alzheimer’s Europe through a grant provided by Bayer, together with other data reported by the AIT, finds the following:

1. Nearly 89% of Americans say that if they were exhibiting confusion and memory loss, they would want to know if the cause of the symptoms was AD.
2. Of those aged 60 years and older, 95% say they would want to know if they had AD.
3. More than 97% say that if they had a family member exhibiting problems with memory loss they would want him or her to see a doctor to determine whether the cause was AD.
4. The convergence of evidence from numerous sources indicates that as many as half of people with dementia have never received a diagnosis.
5. A formal diagnosis allows individuals and their caregivers to have access to available pharmacologic or non-pharmacologic courses of treatment, build a care team, participate in support services, and enroll in clinical trials.
6. Participating in planning early in the disease process allows individuals with AD to create advance directives regarding their care and finances so that their wishes can be carried out when they are no longer cognitively able to make such decisions.
7. Early diagnosis also allows individuals with the disease and their caregivers to manage medications more effectively, receive counseling, and address driving and safety issues in advance.
8. Undertaking the diagnostic process early potentially allows cognitive impairment to be reversed in some people. For nearly one in every four individuals who reported to a memory clinic with cognitive problems, their cognitive impairment was the result of a reversible cause, such as depression or a vitamin B12 deficiency.

Within the group of Medicare beneficiaries whose plight is described through these observations, rests a subset of patients with a dementia pathology that eludes diagnosis despite the best efforts of the most skilled and highly trained provider. Their struggle is poignant; it calls for special care and response by CMS.

To return to the place from which we began, this is the context that places a re-evaluation of the CMS proposed decision CAG-00431N on solid footing, allowing and calling for a very narrow finding providing coverage for PET Aß imaging tests for the subset of beneficiaries meeting the appropriate use criteria establish by the Alzheimer’s Imaging Taskforce. Indeed, when considered in reverse, a prolonged wait for the results of CED through a clinical trial is, in fact, neither reasonable nor necessary for the beneficiary who today is suffering from dementia with an unknown and confounding cause and whose treatment and life choices could be immediately altered and improved by the power of knowing their disease state as a result of coverage by Medicare of a single PET Aß imaging test.

CONCLUSION

For patients suffering from Alzheimer's (and other neurodegenerative diseases) and their families, the results of PET Aß imaging tests can mean access to the most appropriate treatment possible. A positive result can direct the physician to consider Alzheimer's as a possible diagnosis, while a negative result would help direct clinicians to pursue other reasons for a patient's cognitive decline. While no disease-modifying treatments for Alzheimer's and dementia exist today, interventions capable of mitigating the symptoms of the disease or non-pharmacologic courses of treatment, particularly in those patients suffering mild cognitive impairment, are available.

Patients and families benefit from a positive diagnosis of Alzheimer’s disease even without disease modifying therapies. This permits appropriate application of presently available symptomatic and non-pharmacologic treatments. It also permits families to anticipate continued cognitive decline and ascertain their loved one’s preferences before they are severely demented.

Coverage decisions by CMS are among the most important decisions made by the agency for American citizens. Always decisions must be grounded on the best science, data and evidence available. Where, as here, evidence exists and this evidence has been carefully reviewed and validated through expert consensus, to ask that a clinical trial be conducted to test and validate what is known by these experts and has been presented to CMS, places a barrier between the Medicare beneficiary for whom the test is appropriate and critical medical care that has been shown to improve health outcomes.

We propose that CMS take the following actions as part of its final proposal:

Provide immediate coverage without CED of PET Aß for use in the narrowly defined and clinically difficult cases to assist in making differential diagnoses of the causes of dementia, as defined by the Alzheimer’s Imagining Taskforce.

USAgainstAlzheimer’s looks forward to working with the agency to refine the policy in a manner that will not delay access to PET Aß imaging tests for this well-defined set of Medicare beneficiaries. Thank you for your consideration.

USAGAINSTALZHEIMER’S

DISCLOSURE: USA2 Network (here, USAgainstAlzheimer’s) is a 501 (c) (3) public charity and voluntary health organization devoted to Stopping Alzheimer’s by 2020. The organization has been founded and predominantly supported by George and Trish Vradenburg and the Vradenburg Foundation. USA2 accepts other contributions from the public in support of its mission, including from individuals, nonprofit organizations, foundations and industry. Industry support has come from, among others, Eli Lilly, the sponsor of Amyvid. All contributed funds are used for general administrative purposes and are neither tied to nor allowed to influence any position, program or advocacy activity conducted by USA2.

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August 2, 2013
Via Electronic Delivery

Louis Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

Navidea Biopharmaceuticals, Inc. is pleased to submit comments on the Centers for Medicare and Medicaid Services’ (CMS) proposed decision memorandum for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N), published on July 3, 2013.¹ Navidea Biopharmaceuticals is a biopharmaceutical company focused on the development and commercialization of precision diagnostics and radiopharmaceutical agents. Specific to the comments here, Navidea is developing NAV4694, a Fluorine-18 labeled precision radiopharmaceutical candidate intended for use with PET imaging in the evaluation of patients with signs or symptoms of cognitive impairment such as Alzheimer’s disease (AD). NAV4694 binds to ß-amyloid deposits in the brain so that they can be revealed by imaging, thus enabling an earlier and more accurate diagnosis for patients who may have AD. Navidea has an ongoing NAV4694 Phase 2b trial in patients with Mild Cognitive Impairment and a Phase 3 program for NAV4694 in AD patients. The company has a strong interest in Medicare coverage policy for innovative radiopharmaceuticals that can enable better diagnostic accuracy, more informed clinical decision-making and, ultimately, improved patient care and outcomes.

The magnitude of the problem and the need for urgent national action around Alzheimer’s disease are profound and clearly recognized, as demonstrated by implementation of the National Alzheimer’s Project Act in January, 2011, with the goal to “improve early diagnosis and coordination of care and treatment of Alzheimer’s disease.” According to the Alzheimer’s Association, there are more than 5 million Alzheimer’s patients in the United States, with estimates that by 2050 as many as 14 million Americans could have the disease. In 2012, 15.4 million caregivers provided more than 17.5 billion hours of unpaid care valued at $216 billion. In 2013, Alzheimer's will cost the nation $203 billion and this number is expected to rise to $1.2 trillion by 2050. ²

To meet the increasing need to improve early diagnosis, new technologies to image beta-amyloid plaque, such as florbetapir F-18 injection, have been approved by the U.S. Food and Drug Administration to help physicians rule out patients who may not have AD. Patients who have been ruled out from having AD may then be assessed for further diagnosis and appropriate care. These patients may be spared the cost and negative health repercussions that can result from inappropriate medication regimens. A positive Aß PET scan, in conjunction with other tests, can assist physicians in diagnosing AD, and aid in determining appropriate treatment options and care for those patients. In both instances, more effective differential diagnosis can better inform patient therapeutic regimens and prescribed diagnostic services. The cost burdens associated with misdiagnosis of AD are significant, as noted in a recent scientific presentation at the Alzheimer’s Association International Conference. Data from Medicare beneficiary records indicated that “when patients with vascular dementia or Parkinson’s disease-related dementia are initially misdiagnosed as having Alzheimer’s disease, their cost of care rises dramatically.” The analysis showed that of vascular dementia patients previously and incorrectly diagnosed with, and treated for, AD incurred average incremental Medicare claims of about $12,000 - $14,000 during the year of diagnosis change, over and above the costs recorded for individuals with unchanged vascular dementia diagnoses. Patients with Parkinson’s disease who were previously diagnosed with AD incurred average incremental Medicare claims of $9,500 to more than $14,000.³

With an aim to provide physicians with specific and useful clinical recommendations for the use of new and emerging Aß PET imaging agents, expert consensus-based Appropriate Use Criteria (AUC) for Aß PET imaging were developed jointly by the Alzheimer’s Association (AA) and the Society for Nuclear Medicine and Molecular Imaging (SNMMI) and published earlier this year.⁴ These evidence-based, peer-reviewed guidelines describe very clear and specific clinical situations in which there would be great diagnostic value in determining the presence of amyloid plaque. The clear and specific nature of these guidelines would prevent the inappropriate proliferation of Aß PET imaging in situations for which the value has not been established.

In summary, Navidea respectfully disagrees with CMS’ proposal. The company believes that:

• Sufficient evidence does exist to conclude that PET Aß imaging improves meaningful health outcomes and supports immediate coverage by Medicare.
• PET Aß imaging should be covered by Medicare based upon the expert consensus and evidence-based Appropriate Use Criteria developed by AA and SNMMI.
• Coverage with CMS’ proposed Coverage with Evidence Development (CED) criteria is inappropriate for Aß imaging for AD as it precludes the use of this important diagnostic tool for clinical use in any situation outside of a clinical trial, apparently disregarding the guidance of the AUC, and the documentation of efficacy from FDA required registration trial data.
• CMS should comply with the intent of the Congressionally-mandated National Alzheimer’s Project Act by seeking to protect access to innovative diagnostics and therapies for AD such as PET Aß imaging.

Navidea appreciates the opportunity to comment on the proposed decision memorandum for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N). As a company committed to improving clinical decision-making and the management and care of patients who may, or who do have Alzheimer’s disease, we look forward to working productively with CMS to ensure that Medicare beneficiaries have ready and appropriate access to Aß PET imaging.

Sincerely,

Thomas H. Tulip, Ph.D.
President and Chief Business Officer
Navidea Biopharmaceuticals, Inc.

REFERENCES

1 Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N), July 3, 2013, available at http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265
2 Alzheimer’s Association. Alzheimer’s Facts and Figures. Accessed 7/30/13. http://www.alz.org/alzheimers_disease_facts_and_figures.asp.
3 Gever, J. (2013, July 11). Misdiagnosed Dementia Adds $$$ to Healthcare Bill. MedPage Today. Accessed 7/30/13. http://www.medpagetoday.com/MeetingCoverage/AAIC/40540
4 Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force (AIT), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer Association (AA). Alzheimer’s & Dementia. 25 January 2013;1-15.

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August 2, 2013

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Dr. Jacques –

Cardinal Health is pleased to respond to the Centers for Medicaid and Medicare Services (CMS) request for comments on the reconsideration request of Section 220.6 of the National Coverage Determinations (NCD) Manual, dealing with Positron Emission Tomography or PET imaging. Cardinal Health’s Nuclear Pharmacy Services provides over 12 million nuclear medicine and PET radiopharmaceutical doses annually in the United States. We also provide support for more than 25 early phase clinical trials in nuclear medicine and PET.

We would like to thank CMS for the opportunity to comment on this important decision on beta amyloid PET imaging. We respectfully disagree with the proposed decision memorandum and would like to see changes. Specifically, Cardinal Health urges CMS to cover beta amyloid PET imaging utilizing the framework of the Appropriate Use Criteria (AUC) as developed by the Amyloid Imaging Task Force as convened by the Alzheimer’s Association and Society of Nuclear Medicine and Molecular Imaging. According to the AUC, there are limited situations in which beta amyloid PET imaging is appropriate, specifically:

“Amyloid imaging is appropriate in the situations listed here for individuals with all of the following characteristics:

Preamble: (i) a cognitive complaint with objectively confirmed impairment; (ii) AD as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (iii) when knowledge of the presence or absence of Ab pathology is expected to increase diagnostic certainty and alter management.

1. Patients with persistent or progressive unexplained MCI
2. Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation
3. Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).”

From http://jnm.snmjournals.org/content/early/2013/01/28/jnumed.113.120618.full.pdf

We feel that the AUC criteria, carefully developed by expert clinicians and imagers with the patient’s interest in mind, are indeed the appropriate framework with which to provide coverage for beta amyloid PET imaging.

Coverage of beta amyloid PET imaging under the AUC framework would provide Medicare beneficiaries and their referring physicians with an important tool to aid in the diagnosis of patients with suspected Alzheimer’s disease. The confirmation or dismissal of Alzheimer’s disease as a cause for a patient’s cognitive decline is valuable, particularly in challenging cases as defined by the AUC. In addition to ensuring patients are put on the correct therapy, the value of confirming the disease is beneficial to the patient and their caregivers. Some patients spend many years in limbo, not knowing the cause of their cognitive decline and unable to properly plan for the future; therefore, access to an important diagnostic tool to assist these patients in getting a more definitive diagnosis, and thereby appropriate treatment and access to services, is imperative.

Importantly, he AUC provides clear limits on the utilization of beta amyloid PET imaging. For example, an asymptomatic patient is never an appropriate candidate for the procedure. There is concern this diagnostic test could be used as a screening tool; however, the notion of screening should not enter into the decision. The appropriate patient in the AUC can be utilized in the coverage decision to ensure that only those patients who will truly benefit are scanned. CMS is no stranger to conditions of coverage for PET imaging and coverage of beta amyloid PET should be no different. A definitive set of criteria is already being utilized for the differential diagnosis of Alzheimer’s disease versus frontotemporal dementia using FDG-PET. The criteria presented in the AUC could be developed into a similar set of conditions for coverage of beta amyloid PET imaging.

In addition, relegating coverage of beta amyloid PET imaging to very narrow CED constructs is not in concert with the administration’s National Alzheimer’s Project Act (NAPA). NAPA was enacted to bring more attention to issues of diagnosis, support and treatment of patients suffering from Alzheimer’s disease. Providing access to beneficiaries for this important test could not only aid in more accurate diagnosis of Alzheimer’s disease, it would also assist in proper stratification of patients into clinical trials focused on the development and understanding the effects of different therapies for Alzheimer’s disease.

For these reasons, we urge CMS to provide access to this important new diagnostic test by covering it for the AUC indications. Medicare beneficiaries, their caregivers and physicians deserve access to this test to assist in identifying the cause of their cognitive decline when that cause is not clear.

In closing, we appreciate the opportunity to comment on this important reconsideration. Should you have any questions regarding our comment, please contact Terri Wilson at (407) 790-8287 or terri.wilson@cardinalhealth.com.

Sincerely,

Tiffany Olson
President, Nuclear Pharmacy Services
Cardinal Health

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August 2, 2013

BY ELECTRONIC DELIVERY

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dr. Jacques:

The Pharmaceutical Research and Manufacturers of America (PhRMA) appreciates the opportunity to comment on CMS’ proposed decision memorandum on Medicare coverage for beta-amyloid (Aß) positron emission tomography (PET) in dementia and neurodegenerative disease. PhRMA is a voluntary nonprofit organization that represents the nation’s leading research-based pharmaceutical and biotechnology companies devoted to developing medicines that allow patients to lead longer, healthier, and more productive lives.

PhRMA is concerned that CMS’ proposed decision to apply coverage with evidence development (CED) to PET Aß imaging technology for dementia and neurodegenerative disease will create a significant barrier to access to a medically beneficial diagnostic test option for patients with Alzheimer’s disease and other forms of cognitive impairment. PhRMA is committed to the application of the best available evidence in Medicare coverage policy as the basis for timely patient access to clinically important tests and treatments, and we support CMS’ goal of applying CED to expand beneficiary access to beneficial items and services. While we appreciate that the proposed decision memorandum would replace a non-coverage policy for this technology, we are concerned that it would leave in place significant barriers to patient access for an innovative diagnostic that involves use of an FDA-approved radiopharmaceutical, is supported by evidence-based practice guidelines developed by clinical experts in the field, and is viewed as an important diagnostic option by patients. We also are concerned that, if finalized, the proposed decision would discourage continued progress in the diagnosis and treatment of Alzheimer’s disease, undermining the goals of the National Alzheimer’s Project Act (NAPA).

With 5 million Americans living with Alzheimer’s and more than 15 million caregivers supporting them, the direct costs of caring for those with Alzheimer’s is estimated to be $203 billion in 2013. In light of the dramatic impact of this disease, the need for policies that support and accelerate development of improved diagnostic and treatment options for Alzheimer’s disease is widely recognized by researchers, physicians, patients, and policymakers. Innovative diagnostic and assessment tools such as PET imaging will play an important role in continued progress against this disease. Frederic H. Fahey, D.Sc., the Society of Nuclear Medicine and Molecular Imaging (SNMMI) president, stated that, “the information garnered from amyloid PET imaging will aid in diagnosis and play a pivotal role in the development of new treatments for Alzheimer's.”

As stated in prior CED comments, PhRMA strongly believes that CED should not be applied in ways that would restrict beneficiary access to drugs and biologics that have been approved by FDA based on rigorous prospective clinical research. Similarly, as noted by CMS in the draft decision memo, one of the radiopharmaceuticals used in PET Aß imaging (florbetapir) has been approved by FDA via the new drug application (NDA) process. Based on clinical information provided during the approval process, FDA established clear guidelines on the indications and usage of the radiopharmaceutical in its label, stating it can be used in PET Aß imaging technology for “adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline.” The policy proposed in the draft decision memo would lead to inappropriate coverage restrictions on radiopharmaceuticals supported by FDA approval and, as described below, by evidence-based practice guidelines and clinical experts in this field.

PET Aß imaging is strongly supported by evidence-based practice guidelines and by leaders in the clinical and patient advocate communities. Following FDA approval of florbetapir, the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) formed the Amyloid Imaging Taskforce (AIT) to develop “appropriate use criteria” (AUC) to guide clinical use of the technology. The AUC supports the use of PET Aß imaging in conjunction with other available evidence to help physicians make appropriate diagnoses and help patients make informed care management decisions. The AUC further notes that the use of beta amyloid imaging should be carefully targeted and establishes criteria for the patient populations and circumstances in which the use of this imaging is considered clinically appropriate. By restricting coverage to a single scan per patient in approved clinical trials, the CED would impose significant access for use in patient populations supported by the AUC.

Similar to the AUC, leading patient organizations have recognized the value of PET Aß imaging as a diagnostic tool that should be available to patients and physicians. The Alzheimer’s Association has expressed concern that the CED approach proposed by CMS “will hinder coverage of a badly needed, already FDA approved diagnostic tool” for the targeted populations in which availability of PET imaging is clinically important.

The use of a CED as proposed by CMS for PET Aß imaging would chill continued progress against AD and undermine with the goals of the National Alzheimer’s Project Act and the Department of Health and Human Services’ (HHS) National Plan to Address Alzheimer’s Disease, which has the goal of accelerating advances in prevention, detection, treatment of AD. The HHS plan’s initiatives specifically promote efforts to “improve the early diagnosis of Alzheimer’s disease” and “accelerate the development of treatments that would prevent, half, or reverse the course of Alzheimer’s”. By imposing narrow limits on coverage of PET Aß imaging technology, the proposed decision would discourage adoption and continued refinement and advancement of this and other important diagnostic tests for patients with Alzheimer’s and other forms of cognitive impairment.

CMS has published the proposed decision memorandum for PET Aß imaging at a time when it is operating without formal CED guidance in place. In any final coverage decision memorandum, CMS should delete the reference in the current draft to CED guidance, which cites to a prior guidance that was withdrawn by the agency in 2012 when it issued a broad solicitation for public input on CED policy. We urge CMS to move expeditiously to finalize a CED guidance document, and to consider doing so prior to finalizing any coverage policy for PET Aß imaging that includes CED.

The proposed CED decision for PET Aß imaging illustrates several of the concerns raised by PhRMA in comments on CMS’ revised, draft CED in January 2013 and in prior comments. In addition to withdrawing the proposed CED for PET Aß imaging, CMS should address these issues as it seeks to enhance its use of CED in support of timely beneficiary access to medically beneficial tests and treatments.

In finalizing a CED guidance document, CMS should address several important issues identified in prior comments by PhRMA and other organizations, including:

PhRMA appreciates CMS considering our comments on the agency’s draft decision memo on Medicare coverage for PET Aß imaging in dementia and neurodegenerative disease. Because the test is supported by an FDA-approved radiopharmaceutical, evidence-based guidelines, and leaders from the clinical and patient communities, CMS should withdraw the proposed CED and consider alternative approaches to generating desired additional evidence while ensuring beneficiary access to an important diagnostic testing option. In any national policy on PET Aß imaging, CMS should ensure that the test is broadly available for beneficiaries for indications consistent with FDA-approved labeling and Appropriate Use Criteria. In addition, CMS should move expeditiously to finalize its CED guidance document before issuing any final coverage policy for PET Aß that involves CED. In doing so, the agency should include provisions such as those identified above and in prior comments to protect and expand beneficiary access and support continued progress against serious diseases with unmet need such as Alzheimer’s.

Sincerely,

Randy Burkholder
Vice President, Policy & Research
PhRMA

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I urge CMS to reconsider the Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. There has been to date much experience with PET amyloid imaging agents, and with FDA approval of florbetapir there is opportunity to use this experience to benefit patients. The Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association have thoroughly evaluated the available research and have identified three scenarios where there is already strong evidence of benefit to patients, caregivers, and families (I refer you to the Johnson, et al. paper from the SNM journal, 2013, of which you are certainly familiar).

There may be additional uses beyond these for which amyloid imaging may benefit patients; for these purposes it is reasonable to include a provision for research development of amyloid agents.

The proposed decision memo effectively impedes progress and withholds a diagnostic test that has the potential to help the appropriate subset of patients with cognitive decline. Appropriate uses, as outlined in the SNMMI/Alzheimer’s Association consensus statement, should be covered immediately, with provision for adding additional indications as future studies prove their utility and effectiveness.

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As a geriatric psychiatrist (with neither industry nor academic strings attached), I appreciate the thoughtful and reasonable draft coverage decision on florbetapir. Although presentations at the Alzheimer’s Association’s International Conference last month didn’t change my mind, I was struck by the consistency on the merits of broader coverage: sponsorship by Lilly.

The amyloid imaging agents, including florbetapir are wonderful research tools. The CMS allowance of covering florbetapir scans as part of research may allow capture of data on difficult cases for study, and encourage participation in research.

In a broader perspective, truly exciting findings presented at the Alzheimer’s Association International Conference add to the evidence that it’s not all about amyloid. Researchers presented evidence (detailed in early online publications in The Lancet) that dementia rates are decreasing in developed countries, a decrease of 25% over 20 years in the U.K.

Paying even more attention and money to light up amyloid in the brain, may actually detract from investigation and institution of other measures, likely in the public health realm, that may do more to slow or prevent dementia on a population-wide basis.

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As the Co-chairs of the National Oncologic PET Registry (NOPR) Working Group, we appreciate the opportunity to comment on the Proposed Decision Memorandum on Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-0431N).

Because our expertise relates principally to the uses of PET in oncology, NOPR takes no position on the substantive merits of the Proposed Decision. However, we note that the Centers for Medicare & Medicaid Services (CMS) has identified Coverage with Evidence Development (CED) as a potential option for the coverage of beta amyloid PET for certain indications. Given NOPR’s extensive experience in developing and administering a large CED registry for oncologic PET (both FDG and NaF), we believe we are uniquely positioned to offer the following technical observations and recommendations on best practices for the implementation of a CED PET registry, in the event CMS elects to authorize such an option for beta amyloid PET.

Background

The NOPR was launched as a clinical study in 2006, in response to a CMS proposal to expand coverage for ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) to cancers and indications not previously eligible for Medicare reimbursement. CED allowed Medicare beneficiaries with cancer imaging indications that were not covered at the time to have equal access to PET in order to inform clinical management decisions, in conjunction with prospective data collection within the NOPR. The primary objective of the NOPR was to measure the impact of PET on the referring physician’s intended patient management by collecting questionnaire data before PET and again after the PET results are available for decision making. In June 2013, CMS issued a comprehensive National Coverage Determination (NCD) lifting the CED restriction and providing national coverage for FDG-PET for oncologic indications. Between 2006 and 2013, the NOPR managed the collection and processing of over 288,000 FDG-PET scans. The NOPR continues to provide services pertaining to the ongoing CED coverage for NaF-PET.

Comments

Informed by our experience with the NOPR, our comments focus on two main areas. The first is the critical importance of understanding what types of studies are and are not feasible within the context of a CED registry approach. The second is the importance of establishing protocols to ensure the consistent collection of uniform, high quality data by the CED registry itself.

First, we encourage CMS to consider what types of studies would not be appropriate for a registry-based approach. For instance, we do not believe that it is feasible to run a randomized control trial with a NOPR-like infrastructure, as the key strength of a registry is managing and processing externally-generated data for review, rather than providing oversight of the details of the RCT process. Such studies are probably best conducted by other entities or organizations. Our experience with the NOPR also suggests that using a registry as a tool for investigating intended changes in patient management has important limitations (as we have acknowledged in our peer-reviewed publications); accordingly, striving to track actual changes in patient management is likely to yield more robust data.

We also believe that a registry approach is not well suited to studies that seek to do more than, for instance, collect a limited and well-defined set of data about each participating patient (e.g., an evaluation of the patient to date, plus the treating physician’s intended treatment prior to imaging) and then collect the treating physician’s report of actual management changes following imaging. Note that as the complexity of the data collected increases, the likelihood decreases that the human subjects protection structure established for the NOPR (namely, that the NOPR was the only entity engaged in research) will remain adequate. If more elaborate human subjects protections are required, this could greatly complicate the implementation of a broad registry that provides access both to the service and to useful data. Our experience with the NOPR also leads us to the conclusion that such CED registry data is of real but comparatively limited value in the absence of a mechanism for establishing a prospectively-defined claims database for linkage to registry data. Such a database would enable researchers to evaluate longitudinally the impact of the scan (and any reported changes in management) on outcomes.

Nor, in our experience, do we believe it would be feasible to administer a CED study — whether through a registry or otherwise — that utilizes “postmortem diagnosis as the endpoint,” as proposed in the Proposed Decision. The complications and longitudinal scope of such a study simply exceed what we believe the CED mechanism can be reasonably expected to accomplish. Should CMS authorize CED for beta amyloid PET, we would strongly encourage CMS to clarify that postmortem diagnosis, while perhaps a worthy goal, is not the threshold requirement for approval by CMS of a given CED proposal.

In short, we emphasize that the parameters of any NOPR-like CED registry would need to be defined carefully, in order to capture the strengths that a registry approach can provide without exceeding the expectations of what a registry can reasonably deliver. In our experience, a registry infrastructure is best suited to observational studies that, ideally, would be run in parallel with other prospective studies.

Second, we would underscore the critical importance of ensuring that the data collected by a CED registry is of uniform high quality, given that the very purpose of a CED registry is to generate reliable data that can be utilized in making scientifically sound coverage determinations.

Our primary observation is that any CED registry for beta amyloid PET would need to ensure that the participating treating physicians are adequately trained in the management of patients with cognitive impairment/dementia (for example, those with specialized expertise in neurology, psychiatry, geriatrics, or a related discipline). It is possible that the operational definitions of a “qualifying expert” in the Alzheimer’s Association guidelines could be refined and further delineated for this purpose. Moreover, we believe any viable proposal for a CED registry must, at minimum, acknowledge the need for adequate training of interpreting physicians in reading beta amyloid PET scans, and explain how such expertise will be demonstrated and authenticated. In the context of oncologic PET, by the time the NOPR was established in 2006, there was a significant field expertise in the reading and interpretation of oncologic PET scans, thus minimizing the need to ensure that the physicians whose PET reports were submitted to the NOPR were appropriately qualified to interpret them. Even then, in our review of the PET reports submitted we found variable expertise in reporting FDG PET results.

In contrast, it is our understanding that there are significantly fewer physicians with experience interpreting beta amyloid PET scans, and that any CED registry would likely be commencing operation concurrent with the first usage of beta amyloid scans in many facilities. Indeed, it may be desirable—at least in the initial stages of any CED registry—to incorporate a quality control mechanism in which the scans themselves are submitted to an image archive and subjected to an additional “blind” reading by experienced reader(s) of beta amyloid scans, in order to confirm the accuracy of the initial scoring of the scan.

Although perhaps obvious, we are compelled to observe that there will likely be significant costs associated with a CED registry above and beyond those costs that would be reimbursed for the scan itself. For instance, there will be costs incurred for the training of interpreting physicians, as well as costs incurred by the treating physicians for the time they spend collecting and reporting the necessary patient evaluative data that will accompany the scan results. While we recognize that CMS may be constrained in its ability to reimburse for such costs, the viability of a CED registry for beta amyloid PET will be limited unless significant startup funding is obtained from industry, stakeholder groups, or through grants from CMS or other federal agencies such as the NIA.

Finally, ensuring high quality data collection extends not just to the training of the treating and interpreting physicians, but also to the instruments used for data collection and reporting. From our experience with the NOPR, we believe that it would be important for any CED registry to collaborate with CMS and the physician community to develop a uniform scan interpretation score sheet, with clear and non-overlapping categories. For amyloid imaging, current FDA guidelines indicate that beta-amyloid PET scans should be interpreted as positive or negative, with a positive scan indicating moderate to frequent amyloid neuritic plaques. While narrative qualitative dictations can provide valuable information, we believe that as a practical matter, it will be challenging to analyze significant quantities of CED data without capturing such data on a structured case report form.

Conclusion

The NOPR Working Group appreciates the opportunity to share its perspectives on the advantages and limitations of registry-based CED studies for PET, and would be pleased to provide any additional clarification or comments that may be valuable to CMS based on our experience in this regard.

Sincerely,

/s/
Bruce E. Hillner, M.D., Chair
/s/
Barry A. Siegel, M.D., Co-chair
/s/
Anthony F. Shields, M.D., Co-chair

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Louis B. Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard, Mail Stop S3-02-01
Baltimore, Maryland 21244

RE: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

On behalf of the Alliance for Aging Research, thank you for the opportunity to comment on the Centers for Medicare & Medicaid Services (CMS) proposed decision memo regarding coverage for positron emission tomography (PET) amyloid-beta (Aß) imaging in dementia and neurodegenerative disease. While we appreciate CMS’ recognition of the role PET Aß imaging plays in research and your desire to provide coverage to patients enrolled in a clinical trial, we strongly urge you to expand coverage for PET Aß imaging to all eligible Medicare beneficiaries who meet the criteria defined by the Alzheimer's Association/Society of Nuclear Medicine and Molecular Imaging (SNMMI) Amyloid Imaging Taskforce (AIT).

The Alliance for Aging Research, www.agingresearch.org, is the leading non-profit organization dedicated to accelerating the pace of scientific discoveries and their application to vastly improve the universal human experience of aging and health. As such, we support the recommendations of the Alzheimer’s Association/SNMMI AIT which state that appropriate candidates for PET Aß imaging include:

• Those who complain of persistent or progressive unexplained memory problems or confusion and who demonstrate impairments using standard tests of cognition and memory.
• Individuals meeting tests for possible Alzheimer's, but who are unusual in their clinical presentation.
• Individuals with progressive dementia and atypically early age of onset (before age 65).

As many as 5.2 million Americans currently have Alzheimer’s disease. In just 12 years the number of people age 65 and older with Alzheimer’s is expected to increase to 7.1 million and by the middle of this century there will be just under 14 million people with the disease. It would likely take 7-10 years to develop the health outcomes evidence satisfying CMS’ requirements in the draft decision memo for broader coverage. By that time there will be nearly 40% more people afflicted with this disease.

Current methods for diagnosing Alzheimer’s disease do not have the level of sensitivity and specificity PET Aß imaging provides. We feel this tool has considerable value now and is necessary to have it accessible outside of clinical trials because it can clarify diagnoses—especially for those misdiagnosed with Alzheimer’s disease when they may have a curable condition, inform treatment decisionmaking, empower people with Alzheimer’s disease to consider entering clinical trials, and allow families to engage in financial and care planning.

Thank you for considering our views. If you have any questions or would like additional information, please do not hesitate to contact us at (202) 293-2856 or via email (speschin@agingresearch.org and cbens@agingresearch.org).

Sincerely,

Susan Peschin, M.H.S
Chief Executive Officer

Cynthia Bens
Vice President, Public Policy

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As a board certified Radiologist/Nuclear Medicine Physician with a group that encompasses four large outpatient imaging centers in Florida servicing a patient base predominantly of Medicare patients, I have extensive experience with PET for cancer imaging and for assisting in the differential diagnosis of dementia. I work with my medical community in assisting in the care of patients with various degrees of memory loss and in aiding in the diagnosis of dementia. As you are aware, CMS provided coverage in 2004 for FDG PET to aid in the distinction of Alzheimer’s disease (AD) versus frontotemporal dementia (FTD). This positive decision did not result in large numbers of patients being referred for FDG PET scans of the brain, but is selectively applied in challenging cases. In not all cases of known or suspected dementia, however, are FDG PET plus other imaging and clinical exams definitive for a diagnosis.

An unclear diagnosis may lead to unnecessary or invasive tests (including cerebral angiography, brain biopsy, etc.) which can be considerably more risky than PET scans; it can also hamper decisions on management and prognosis.

Furthermore, there are several clinical scenarios in which a more definitive neuroimaging tool would clarify the diagnosis:

• AD features, both typical and atypical, are present, including the focal cortical syndromes of primary progressive aphasia, corticobasal syndrome and posterior cortical atrophy
• Differentiating AD vs FTD when FDG-PET is inconclusive
• Early onset dementia with no family history and/or no mutation found
• Early onset dementia and the patient is still working in some capacity so that objective documentation of AD would provide the proof needed to initiate disability
• Dementia with positive autoantibodies, and the differential diagnosis includes AD vs an autoimmune encephalopathy
• Dementia with enlarged ventricles, and the differential diagnosis includes AD vs NPH

These clinical problems would be better addressed with a beta amyloid PET agent than with FDG PET, or as a complement to FDG PET.
In general, FDA approved amyloid imaging agents have gray matter tracer uptake proportional to the beta amyloid burden in the gray matter. A negative beta amyloid PET scan read by expert trained physicians has high negative predictive value for amyloid deposition in the gray matter and for the intermediate term development of Alzheimer’s Disease. Positive scans support amyloid deposition. Such information is clinically useful in key decision making processes, especially when patients need to determine whether to continue to work or to make other life plans.

On April 6, 2012 the Food and Drug Administration (FDA) approved Florbetapir (Amyvid) for PET imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. We use this test clinically and have used it in research. It is a powerful test. Unfortunately, current CMS rules prohibit Medicare reimbursement for the test. Medicare beneficiaries should have access to this test. Much as our experience with FDG PET, it is improbable the scan will be overused.

Consideration of a registry as was done for FDG PET in oncology indications might also provide data for CMS regarding how this scan is utilized in broader practice settings if concerns regarding broad coverage remain, despite the unequivocal biological data supporting the mechanism of tracer uptake and the biology visualized. I believe that access to beta amyloid PET imaging is very important, and I hope that my comments and those of my colleagues will help CMS reconsider its decision.

Sincerely,
Anton Serafini, MD
Lake Medical Imaging & Vascular Institute

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Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. Sufficient evidence exists to support immediate coverage,according to the appropriate use criteria (AUC) devleoped by the Alzheimer’s Association and SNMMI jointly.

All Medicare eligible patients, and not just those in limited clinical trials, should have access to a valuable new tool that can assist physicians in better diagnosing patients with cognitive impairment.

CMS should reverse its proposed decision memo and cover the three indications of the AUC without inappropriate coverage with evidence development. I disagree with CMS that an Aß scan does not lead to better health outcomes for appropriately selected patients, particularly in the case of a differential diagnosis which can prevent patients from being subjected to inappropriate medications and costs.

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In a selected patient population, patients with documented cognitive impairment where AD is in the differential diagnosis, amyloid imaging has demonstrated its value to increase diagnostic accuracy and alter patient management. The importance or confirming or excluding amyloid deposition with PET in patients where diagnosis is otherwise uncertain is absolutely crucial for patients and their relatives, to better direct patient care. It remains a mistery to me why CMS has overlooked the importance of being able with PET to exclude AD in those cases where this remains a diagnostic possibility. For patients and their families, this is of the outmost importance, and certainly has an impact in health outcomes and certainly helps to better direct and reduce health care expenditures. CMS should strongly reconsider its decsion to cover amyloid imaging for those patients with cognitive impairment where AD remains in the differential diagnosis even after a through clinical investigation. The decision to cover amyloid under the CED program does not make sense when so much rigorous scientific data has already been collecteed to prove that in this selected patient population amyloid imaging is very helpful to make a better diagnosis.

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I appreciate the thoughtful and measured review of the existing literature regarding the clinical utility, efficacy, and safety of florbetapir amyloid PET imaging by CMS in drafting proposed coverage guidelines. In addition, I'm grateful for the opportunity for public comment where consideration of additional viewpoints may further illumine the final coverage decision for amyloid PET imaging in the diagnosis of Alzheimer's dementia.

In this regard, it strikes me that the positions of the scientific and clinical community, on one hand, as crystallized in the SNMMI-Alzheimer's Association Amyloid Imaging Task Force's Appropriate Use Criteria for Amyloid PET and the CMS proposed narrow coverage, on the other hand, may not be that far apart. Both positions recognize the value of PET amyloid imaging in the difficult to diagnose case. This acknowledges that making the accurate diagnosis is important; reducing the morbidity associated with inappropriate treatments or further needless diagnostic evaluations, and providing to family members, caretakers, and patients a solace that follows from diagnosisand structuring a suitable set of expectations for future planning. Hence, even in the absence of disease modifying therapies, accurate diagnosis matters.

This challenge of making an accurate diagnosis is underscored for me in the context of my group's imaging core lab reads of amyloid PET images for trial eligibility assessment in several large, multicenter therapy trials (altogether over 1500 research subjects with cognitive symptoms consistent with MCI or AD). On average 15% of these amyloid PET scans acquired at enrollment as part of the eligibility assessment are negative, with some studies having negative scan rates as high as 25%. Specifically, those patients who otherwise meet operationalized diagnostic criteria for enrollment as determined by a dementia specialist most likely do not have Alzheimer's disease. This is sobering when considering how often the diagnosis of Alzheimer's disease is made in the US- and by whom. I would venture that the great majority of Alzheimer's disease patients are diagnosed by primary care physicians and internal medicine specialists rather than geriatricians, geriatric psychiatrists, or neurological specialists. This must result in misdiagnoses at least as high as the rates seen in clinical therapeutic trials using the highest diagnostic standards and more expert diagnosticians.

I would commend CMS to give some further consideration, if not dialogue, to make the proposed narrow criteria at least slightly broader and more in keeping with the conservative and measured recommendations of the Appropriate Use Criteria. These criteria resonate with common clinical conundrums and CMS's current interest for beneficiaries, but with practical and understandable guidance for clinical implementation, bearing in mind our shared belief that diagnosis is important.

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Drs. Conway, Jacques and Ms. Tavenner

Centers for Medicare and Medicaid Services

We write this comment in opposition to the draft decision to use Coverage with Evidence Development as a way to consider amyloid imaging in the assessment of Medicare Beneficiaries with neurodegenerative disorders. We and our colleagues have previously submitted a letter to you detailing the value of amyloid PET imaging, and indeed it is widely endorsed by many scientists and clinicians knowledgeable about AD.

Within the range of the Appropriate Use Criteria (AUC) for Amyloid PET developed by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging there is already compelling evidence for the current and immediate coverage of amyloid PET imaging. Yet the draft decision fails to utilize the AUC to define the intended population for amyloid PET (and those for which amyloid PET is inappropriate), and thus ignores the clear and consistent advice of a vast array of dementia and neuroimaging experts. The draft decision also fails to outline a clear path to coverage approval and instead proposes impractical and unprecedented requirements for coverage with evidence development. The draft decision is also riddled with inaccuracies, misrepresentations, dogmatic errors, and conflicting statements. We do not delineate those here because others have done so thoroughly in previously posted comments, but it is important to recognize the substantial flaws in this draft decision.

Most importantly, the draft decision fails to recognize that amyloid imaging is valuable immediately in differential diagnosis, including distinguishing difficult differentials such as AD versus FTD. It is critically important to understand that numerous studies show a high rate of misdiagnosis of AD with resulting improper management decisions. Similarly, only about half of patients presenting with memory abnormalities have AD as the underlying cause. These patients with amyloid progress to AD at high rates whereas those without plaques on amyloid imaging may improve, stay stable, or progress to other dementias. Further, its usefulness without further evidence in patients meeting AUC criteria is consistent with NAPA and the Administrations dedication to improving care for AD patients.

This draft decision conflicts with the basic medical tenant that making the proper diagnosis must occur before appropriate informed management decisions can be made. Ignoring the value of accurate and early diagnosis falsely suggests that there are no useful medical treatments for Alzheimer's disease. It is also relevant that misdiagnosis results in unnecessary costs and risks to patients, leading to other unnecessary testing, or missing opportunities to treat the true cause of their impairment.

Patients and their families have for many years sought understanding of their cognitive decline, including extensive diagnostic workups. Medicare and insurance companies pay for this diagnostic workup that includes CT and laboratory tests that do not remotely approach the diagnostic accuracy of amyloid PET scanning. Yet, when presented with a method that is sensitive and specific, CMS is stating that the evidence is insufficient that amyloid imaging improves health outcomes. CMS is thus inconsistent in its approach and should reconsider its position. Unfortunately, the real impact of the draft CMS decision would be to restrict access to this important diagnostic tool to only those that can afford it, despite current FDA approval of Amyvid PET that was based on completely sound reasoning. Our patients and your Beneficiaries deserve access to the best diagnostic information available. If there was uncertainty regarding the accuracy, sensitivity or specificity of this technique in the populations clearly identified by the AUC, evidence development would be necessary. The evidence has already been developed. It is clear, well understood, and ready for clinical application today. There are some areas where further evidence development is needed, and the CMS draft decision correctly identifies some of these - as does the AUC. But withholding access to the current well-documented clinical utility of this technique is unwarranted, and harmful to the patients we and CMS serve. We request with the utmost urgency that this draft decision be withdrawn and revised to reflect the state-of-the art knowledge readily available to delineate its appropriate and immediate use without further evidence development.

Michael D. Devous, Sr., Ph.D.
Professor of Radiology
Director, Neuroimaging, Alzheimer's Disease Center
University of Texas Southwestern Medical Center

Stephen Salloway, M.D., M.S.
Director of Neurology and the Memory and Aging Program, Butler Hospital
Professor of Neurology and Psychiatry
The Warren Alpert Medical School of Brown University

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UT Southwestern Medical Center The future of medicine, today.

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August 02, 2013

Louis B. Jacques, M.D.
Director
Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

USAgainstAlzheimer’s advocates appreciate this opportunity to comment on CAG-00431N regarding the use of positron emission tomography (PET) amyloid-beta (Aâ) imaging in the evaluation of Medicare beneficiaries who suffer from cognitive impairment and who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. Below are the comments and personal stories of three hundred and sixty-three USAgainstAlzheimer’s advocates.

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Dear Dr. Hutter

As a clinical and academic geriatrician with thirty years of experience in caring for frail elders, I would like to strongly recommend that amyloid PET be approved for patients who meet accepted criteria for this imaging modality without Coverage with Evidence development (CED). In addition to clinical and laboratory evaluation, and MRI, patients in whom the cause of dementia is unclear, need to undergo neuropsychological testing. Many cannot undergo these tests which last up to three hours. Testing for AD markers in the cerebrospinal fluid also represents a significant burden in elders who have multiple co-morbidities including spinal stenosis and osteoarthritis.

It is known that over half of the individuals with dementia never receive an accurate diagnosis. Older adults and their caregivers now expect and are entitled to much more timely and accurate diagnostic information in order to engage in advance care planning, financial planning, determine appropriate living arrangements, build a support system, join support groups and clinical studies.

Moreover if AD is determined not to be the cause of dementia, a trail of antidepressant therapy may have much clinical utility. Amyloid PET can also be useful in individuals with MCI who may have other possible factors contributing to cognitive impairment, such as vascular disease, diabetes, trauma, ventricular enlargement, and other medical causes.

AD and other dementias take a huge toll on the lives of both patients and caregivers. It is often diagnosed too late when positive interventions have little benefit, and quality years have already passed.

Sincerely,
Naushira Pandya M.D., CMD
Professor and Chair
Department of Geriatrics
Director, Geriatrics Education Center
Nova Southeastern University College of Osteopathic Medicine
Ft. Lauderdale, Florida

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I urge CMS to approve the use of beta-amyloid PET agents for use by qualified clinicians as recommended by the Society of Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association Appropriate Use Criteria (AUC) guidelines. These AUC guidelines identified subjects who likely would benefit from this technology, as well as subjects who likely would not benefit. The use of this technology in the differential diagnosis of dementias will have a positive effect on patient outcomes, sparing non-AD cases from inappropriate treatment with cholinesterase inhibitors and memantine and assuring appropriate use of these treatments in AD cases. Early definitive diagnosis of AD will also save valuable Medicare resources by removing diagnostic uncertainty and the need for multiple and varied medical opinions and repetitive neuropsychological testing. Use of this technology is also clearly indicated for entry into AD clinical therapeutic trials. This imaging technology has the ability to clarify dementia diagnosis and direct therapy.

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A strong connection between Aß PET/CT imaging and the post-mortem diagnosis of Alzheimer's Disease has already been established by Clark et al. (Lancet Neurology 2012), Choi et al. (Alzheimer Disease and Associated Disorders 2012), and others (Ikonomovic et al., Brain 2008). The U.S. Food and Drug Administration (FDA) fully vetted this data and approved Florbetapir PET/CT imaging for clinical use. Yet despite the rigorous review and approval by the FDA, the decision by CMS to not routinely cover Aß PET/CT imaging essentially takes Aß PET/CT imaging away from clinical patients. The close correlation between Aß PET/CT imaging and the diagnosis of Alzheimer's Disease provides a highly impactful tool for helping to manage and more accurately characterize patients with cognitive impairment. Although medications to halt or reverse the Alzheimer's Disease are still unavailable, the medications that patients currently receive for cognitive decline do have a profound effect on their quality of life. Ruling out Alzheimer's Disease is as important as ruling it in. Taking a patient off powerful medications that were prescribed because of an erroneous diagnosis of Alzheimer's Disease certainly has a highly meaningful health outcome.

Certainly, the federal health care financial system should be treated and conserved as a highly precious resource. It is not appropriate to liberally use Aß PET/CT imaging as a screening tool. Therefore it is my strong belief that the CMS should adopt the reasonable and judicious guidelines determined by the Alzheimer's Association and Society of Nuclear Medicine and Molecular Imaging. Specifically, patients should at least exhibit: (1) a cognitive complaint with objectively confirmed impairment; (2) Alzheimer's disease (AD) as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (3) knowledge of the presence or absence of Aß pathology is expected to increase diagnostic certainty and alter management. Only after if these initial characteristics are met, then patients must fit the following specific clinical scenarios to qualify for Aß imaging:

• Patients with persistent or progressive unexplained mild cognitive impairment.
• Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either atypical clinical course or etiologically mixed presentation.
• Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

I very much appreciate the ability to comment on this decision memo and respect the careful consideration that the CMS will give to this very important ruling.

Andrew Quon, M.D.
Associate Professor of Radiology
Co-section Chief, Nuclear Medicine and Molecular Imaging
Stanford University School of Medicine
300 Pasteur Drive
Stanford, CA 94305

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Re: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

I urge CMS reconsider the recent decision regarding coverage of Amyvid for AD diagnosis and use in clinical trials. Having spent my entire career dedicated to development treatments for AD, I have witnessed the revolutionary developments in our understanding of AD based on molecular imaging. Innovative technologies should pave the way to effective new treatments, as is being done in many other complex diseases. In conjunction with judicious clinical judgment, noninvasive PET of amyloid is critical for enabling accurate diagnoses which is essential for enabling the success of future clinical trials. The daunting and costly failures of drug candidates in AD is having negative impact on future investments by all stakeholders. Yet if expanded investments do not occur in the immediate future, the devastating consequences of this disease globally will escalate even further. Effective treatments are urgently needed. The learnings from the recent costly negative trials, solanuzemab and bapineuzemab, illustrate that in at least in defined subsets of cases, approximately 1/3 of subjects did not have evidence of amyloid pathology, as revealed by amyloid PET imaging. And importantly, these represent the largest trials to date implementing amyloid biomarkers and also were conducted in patients at the mild to moderate stages of AD. No leading candidate drug, even with a large estimated effect size, would be expected to show significance in a population where so many patients do not have the underlying disease. We need to ensure that promising drug candidates do not fail for the wrong reasons and it is essential that we apply the learnings from the past to optimize the chances for success in the future. As the field eagerly moves into earlier patient populations, defining the target population based on clinical criteria alone is far less certain. Thus it is predicted that greater than 1/3 of subjects entering a clinical trial may not have the underlying disease without the implementation of biomarkers for patient selection. Amyloid biomarkers are an essential tool as part of the inclusion criteria to ensure patients treated with novel candidate therapies are more accurately defined. The reimbursement by CMS of amyloid PET imaging in AD clinical trials is essential so as to avoid future costly failures and to give promising new therapies the best chance of success. It’s essential that the reimbursement include all targets being advanced for AD at the pre-dementia stages, not just amyloid directed therapies. Requirement for postmortem confirmation of diagnosis is not appropriate given the large number of global examples (ADNI, AIBL) illustrating remarkable correlation of amyloid PET ligands with amyloid as detected postmortem and with different amyloid ligands. In my current role as executive director of the Coalition Against Major Diseases (CAMD), a consortium of industry, government agencies, academic experts and regulators, we aim to qualify AD biomarkers for use in enrichment of clinical trials at the pre-dementia stage. At the time in my career where I am presently witnessing the devastating impact of AD on my own family and loved ones, I urge CMS to alter their ruling so that drug candidates being tested in the future have the best chance of success.

Note: The views expressed in this summary are the personal views of the author may not be understood to reflect the views of Critical Path Institute or members of CAMD.

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I am a neurologist with over 30 years of experience in diagnosisng and treating patients with memory and cognitive disorders and am particlualry interested in the use of imaging technology in guiding the diagnostic process adn making treatment decisions. While I appreciate the careful review provided by CMS in making its draft decision regarding reimbursement of amyloid PET imaging

I am concerned that the decision was driven primarily by the perception that approval would result in a dramatic increase in costs for diagnosis. It appears to me that the extensive evidence (outlined by many others who have commented on this decision)supporting the utility of amyloid imaging in the diagnostic process, especially in the distinction between AD and other neurodegenerative diseases, such as FTLD, and other causes of cognitive impairment was not given given sufficient importance.

CMS, in its conclusive statements, agreed that amyloid imaging could be useful for distinguishing between AD and FTLD and that this was an important use of amyloid imaging technology. Yet rather than approving reimbursement for this purpose, CMS determined that approval for reimbursement would be restricted to research studies which presumably would be used to confirm what they had already concluded. Distinguishing conditions other than FTLD from AD, some of which require very different medical management, is also of great importance for those of us, in memory disorder centers, who are confronted daily with these issues.

I believe that a responsible decision by CMS would be to support the Appropriate Use Criteria as recommended by SNMMI and the Alzheimer's Association. Such a decision would allow responsible and efficient use of amyloid iamging and would most likely reduce overall diagnostic and treatment costs for patients presenting with memory disorders. Even more importantly, it is ethically the right thing to improve the care of patients with memory disorders.

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To
Louis Jacques, M.D.
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Dr Jacques,

As a practising physician in South Florida, I am only to aware of the great need for safe and reliable test to assist in medical diagnosis. This is especially true in the case of patients suspected of having Alzheimer's disease who are particularly at risk for being misled and subject to many diagnosis which leads to costly and unnecessary treatments. I wish to comment in opposition to CMS's proposed decision to restrict Medicare coverage of beta amyloid PET imaging for the management of dementia and neurodegenerative diseases to patients enrolled in CMS approved clinical trials. CMS's decision will deprive physicians and their patients of an effective tool for the management of many Medicare beneficiaries suffering the effects of neurodegenerative disorders. The current standard of care for AD and related dementia disorders is not only fundamental treatment and prevention, but also to provide quality of care and care arrangements. I am convinced that beta amyloid PET imaging substantially enhances the ability of physicians to accurately diagnose AD, avoid unnecessary testing and inappropriate drug regimens, and otherwise formulate targeted treatment and prevention strategies. And because it yields greater diagnostic uncertainty, it assists families and patients in weighing lifestyle changes and developing financial and other plans for future management. I recognize that, for now, quantifying the clinical utility of beta amyloid PET imaging is difficult in the absence of disease-modifying treatments for Alzheimer's Disease. However, the utility of the test for management and planning could and should be recognized more appropriately by the adoption of the appropriate use criteria advocated by the Alzheimer's Association and teh SNMMI rather than the highly restrictive criteria proposed by CMS. Additionally, broadening the pool of patients who will receive reimbursement for beta amyloid PET imaging likely will motivate the research community in its quest for effective treatment. In conclusion, I encourage you to reverse your decision regarding Medicare coverage of beta amyloid PET imaging and allow reimbursement consistent with the appropriate use criteria thoughtfully developed by the Alzheimer's Association and the SNMMI.

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July 31, 2013

Dear Dr. Hutler, Ms. Burton and Mr. Caplan:

I would like to comment on the coverage decision made by the Centers for Medicare and Medicaid Services (CMS) regarding the use of beta amyloid positron emission tomography (PET) in dementia and neurodegenerative diseases. Currently, I am the Director of the Neurological Institute of Alabama (NIA), and have over 30 years of experience in clinical neurology and neuroimaging. Throughout my career, I have had the opportunity to diagnose and treat hundreds of patients with dementing illnesses, including Alzheimer's disease. I have also extensively lectured on the subjects of neuroimaging and dementia, both together and separately, to audiences all over the world. Finally, I have had the opportunity to use different modalities of PET (including Florbetapir F18) in the context of managing patients afflicted by these conditions.

I have serious reservations about the first half of the CMS coverage decision as it is expressed, and I find it unreasonable and based on faulty logic. Respectfully, I offer the following points for consideration:

1. The statement that there is insufficient evidence to conclude that amyloid PET imaging improves the outcome of patients with dementia or neurodegenerative diseases makes absolutely no clinical sense. In fact, the usefulness of any diagnostic study cannot be summarily attached to its impact on the outcome of treatment, a variable that depends on many factors that include the natural history of the illness been diagnosed. From this point of view, the ultimate outcome of patients with neurodegenerative diseases is always the same, irrespective of what diagnostic tools are used to arrive at the diagnosis. And so, the diagnostic application of magnetic resonance imaging (MRI) and neuropsychological testing (NPT) in no way influences the ultimate demise of patients with Alzheimer's disease or any other of similar conditions, making these diagnostic strategies no different than the use of amyloid PET imaging.

2. Once we admit that the relationship between a diagnostic test (any test) and the outcome of the patient is not one of cause and effect, we cannot help but ask ourselves: What benefit does that particular test confer the patient? The answer to this question is often very difficult, and one that cannot be easily derived from looking at large populations comprised by patients who share a diagnosis without necessarily having comparable clinical circumstances. In other words, the concepts of public health do not apply in a practical or ethical way to each and every bedside situation. Therefore, those of us who have spent considerable amount of years taking care of patients realized long time ago that the less speculative a diagnosis (any diagnosis), the more likely we will be in a position to assist the patient affected by a relentlessly progressive illness in improving his quality of life. Conversely, the more speculative the diagnosis is, the greater the risk of using incorrect therapeutic strategies that can result in additional clinical problems, or even haste the ultimate outcome of the primary illness. In regards to Alzheimer's disease and other similar illnesses, any expert is likely to admit that tremendous progress has been made in attempting to secure ante mortem diagnoses and, in this context, amyloid PET imaging is simply the latest addition to our diagnostic armamentarium.

3. Based on the concepts expressed above, it is easy to take issue with the statement that amyloid PET imaging is not "reasonable and necessary". Let's begin by pointing out that the way in which section 1862(a)(1)(A) of the Social Security Act (SSA) is written sets CMS beneficiaries for failure, by combining two attributes that cannot be easily fulfilled without some degree of regulatory slide of hands. There are many instances in current clinical practice in which a test is reasonable but not to necessary (e.g. MRI testing for every headache patient), and vice versa (e.g. temporal artery biopsy for giant cell arteritis). Yet, the majority of these tests are not only approved for payment by CMS, but they are also widely utilized. Thus, to hold amyloid PET imaging to a standard that requires meeting both attributes, is unfair and likely to negatively impact the care of CMS beneficiaries.

4. Moreover, the decision obtusely ignores the fact that amyloid PET imaging represents the first instance of performing microscopic neuropathologic assessment at the bedside. The technique is geared at identifying “neuritic plaque burden”, a term borrowed from the pathology literature, and which implies that the test is akin to a noninvasive brain biopsy. I am sure there are those who would argue that there is a percentage of false negatives and false positives, but I submit that the existing data show a very strong correlation with postmortem microscopic pathology. From this point of view, amyloid PET imaging is taking us through a threshold of a new era in neurologic diagnosis, and every day its utilization is delayed will negatively impact the entire population of patients with neurodegenerative conditions.

5. A final point worth mentioning stems from the existing data I quoted earlier, and their application to specific clinical situations. If one looks carefully at the pathology data used to correlate amyloid PET imaging, it is possible to quickly realize that the individuals from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) where sufficiently astute to take into consideration the age of the patients and their interpretation of neuritic plaque burden. As such, this type of consideration should be also applied to the use of amyloid PET imaging. Therefore, the use and interpretation of this test in patient less than 50 years of age cannot be equated to those in patients above the age of 70. The implication for this differentiation is that the CMS decision is also flawed due to its "one side states all" approach to the subject.

I hope this information is useful. Please feel free to contact me if I can be of further assistance.

Respectfully,

Camilo R. Gomez, MD, MBA
Neurological Institute of Alabama
509 Brookwood Blvd
Birmingham, AL 35209

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As an investigator for the amyloid imaging compounds that hold such potential with Alzheimer’s disease, I have participated in the development of these products from an early stage of testing to completion of the clinical pathological correlations. However, my comments here are offered as a clinical neurologist who cares exclusively for dementia patients.

Until now, clinical assessment, management of patients with cognitive decline, memory loss and dementia has been mired in diagnostic uncertainty. The exclusionary tests available (CT, MRI, B12, TSH) simply indicate what the patient does NOT have; they cannot confirm the underlying cause of symptoms, whether Alzheimer’s or another form of dementia. Amyloid imaging would provide new and critical information. A negative scan would be highly informative to both patients and clinicians that the cause of a memory complaint is not amyloid build-up and, by inference, Alzheimer’s related. A positive scan would also be informative in suggesting that cognitive decline might be Alzheimer’s related. The consequence of delayed diagnosis is inaction and, in many cases, deferred planning and care that only heightens families’ anxiety and increases long-term costs. Any improvement in our diagnostic abilities and consequent improvement in care might actually reduce net costs.

Moreover, the proposed coverage limitations for amyloid imaging seem inexplicably arbitrary. CMS often pays for tests of low diagnostic utility despite evidence that they do not affect health outcomes for patients. A person with suspected metastatic melanoma will likely undergo an expensive FDG PET, for example, even though the data to date suggest that the scan will not change the individual’s course. In fact, studies show that approximately 30 scans are ordered for every actionable one. A promising test for a disease like Alzheimer’s should not be required to meet a markedly higher standard.

Our current advances in diagnostics for dementia have surpassed our advances in therapeutics. Yet the lack of an approved treatment for Alzheimer’s disease should not preclude an important diagnostic from being utilized. Indeed, we can now detect AD-related changes through biomarkers years ahead of symptoms – but we still have only a few drugs that at best relieve symptoms temporarily in some patients. These are developed on separate but parallel tracks, and both must continue to move forward.

I encourage CMS to reconsider its position and adopt the consensus recommendation as put forth by Dr. Johnson and colleagues¹.

Sincerely,

Marwan Sabbagh, MD

Marwan Sabbagh, MD, FAAN
Director, Banner Sun Health Research Institute
Research Professor of Neurology, University of Arizona College of Medicine-Phoenix
10515 W. Santa Fe Drive, Sun City, AZ 85351
623-832-6500

1. Johnson KA, et al. Update on appropriate use criteria for amyloid PET imaging: Dementia experts, mild cognitive impairment, and education. Alzheimers Dement. 2013 Jul;9(4):e106-9. doi: 10.1016/j.jalz.2013.06.001. PubMed PMID: 23

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As Speaker of the National Council of Representatives of the SNMMI Technologists section, as a technologist, as a professional and patient advocate I submit this letter in regards to Beta Amyloid Imaging. The importance of this material in the diagnosis in demetia and neurogenerative disease is paramount. The following points though provided by the society I belong to and believe in make this case. I apprecaite your review of this as well as hopefully changing ones ruling on this issue.

SNMMI appreciates the opportunity to comment on the Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. Sufficient evidence exists to support immediate coverage, which would change patient management, lead to better health outcomes for patients and assist families making care decisions. Coverage with evidence development (CED), as proposed, is not appropriate for Aß imaging, which the U.S. Food and Drug Administration (FDA) has already approved, noting its clinical utility.

Earlier this year the Alzheimer’s Association and SNMMI jointly developed appropriate use criteria (AUC). The end result concluded that Aß PET imaging demonstrates more than adequate evidence exists for Medicare to cover Medicare beneficiaries without additional onerous CED.

The AUC determined that for Aß imaging to be considered appropriate, individuals must exhibit several characteristics. These include: (1) a cognitive complaint with objectively confirmed impairment; (2) Alzheimer's disease (AD) as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (3) knowledge of the presence or absence of Aß pathology is expected to increase diagnostic certainty and alter management.

Should all of these criteria be met, Aß PET imaging is appropriate in the following scenarios:

• Patients with persistent or progressive unexplained mild cognitive impairment.
• Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either atypical clinical course or etiologically mixed presentation.
• Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

CMS did conclude “there is sufficient evidence that the use of Aß PET imaging could be promising to exclude AD in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD).”

What criteria represent a meaningful health outcome for a patient with mental cognitive decline? For a patient, being taken off powerful medications that are not indicated for their condition is most certainly a meaningful health outcome. For a patient who has a diagnosis of AD, and is being treated as having AD, having a test which can rule out AD certainly has a meaningful health outcome. Current standard care for AD and related dementia disorders is not only to attempt fundamental treatments or prevention, but also to provide quality of care and care arrangement. The outcome goes beyond a patient's quality of care and the Medicare beneficiary expenditure of care resources, but also for their family and caregivers. And yet, CMS is proposing that evidence is insufficient to conclude that the use of Aß PET imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease and thus is not reasonable and necessary; we disagree.

While CMS decided to cover one scan, it did so under CED which is so onerous, in our opinion and experience, that it is in effect a non-coverage decision. CMS states that the gold standard diagnosis for AD remains postmortem autopsy. Therefore, any CED trial design will need to be tied to autopsy. However, the challenge is the significant time lapse from the initial Aß scan to autopsy of patients who may benefit from Aß PET imaging defined in the AUC. These elderly patients might carry comorbidities that affect their cognitive status and outcome through the course. This is particularly true for early-stage and atypical patients for whom Aß PET imaging is recommended in the AUC. The FDA already set the rigorous standards for the approval of Aß PET imaging. They required that the abnormalities seen on PET closely correlate with neuritic amyloid pathology seen postmortem. The results of imaging vs. postmortem studies with florbetapir met those rigorous standards, leading to FDA approval of Amyvid. Why does the CED need to be tied to autopsy?

CMS states in the proposed decision memo, “Given that the gold standard diagnosis for AD remains postmortem, creating the building blocks of evidence-based appropriate use criteria, and establishing clinical utility on firm ground, will unfortunately take time.” How long should patients wait? Amyvid has already met the rigorous imaging versus postmortem studies, the SNMMI and Alzheimer’s Association Amyloid Imaging Taskforce has firmly established AUC and the FDA established clinical utility with approval. SNMMI is disappointed with the proposed decision memo because we believe Aß PET imaging is a medical advance that meets the major goal of the National Plan to Address Alzheimer’s disease to make major strides in the diagnosis and treatment of AD by 2025.

All Medicare eligible patients, and not just those in limited clinical trials, should have access to a valuable new tool that can assist physicians in better diagnosing patients with cognitive impairment. CMS should reverse its proposed decision memo and cover the three indications of the AUC without inappropriate coverage with evidence development. We disagree with CMS that an Aß scan does not lead to better health outcomes for patients, particularly in the case of a differential diagnosis which can prevent patients from being subjected to inappropriate medications and costs. We believe that additional information provided by the Aß PET study would be helpful assisting physicians to better manage their patients and therefore recommend implementing checks and balances.

Thank you for the opportunity to comment.

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August 1, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244
Submitted via email: CAGinquiries@cms.hhs.gov

RE: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques,

The American Academy of Neurology (AAN) is the premier national medical specialty society for neurology representing more than 26,000 neurologists and clinical neuroscience professionals, and is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a physician with specialized training in diagnosing, treating, and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, epilepsy, Parkinson’s disease, migraine, multiple sclerosis, and brain injury.

The AAN understands that the Centers for Medicare & Medicaid Services (CMS) has proposed coverage for one position emission tomography (PET) amyloid-beta (Aß) scan per patient through coverage with evidence development (CED). We are writing to express our general support for this decision, but we do have some suggestions. We agree that the current evidence is insufficient to conclude that the use of PET Aß imaging improves health outcomes in Medicare beneficiaries with dementia or other related neurodegenerative diseases with the exception of a few circumstances. For example, we believe that the distinction between Alzheimer’s disease and frontotemporal degeneration (FTD) can be confirmed with amyloid imaging and that this distinction has a direct impact on patient care. In addition, other clinically difficult diagnostic dilemmas can be informed by amyloid imaging. Examples include conditions such as posterior cortical atrophy, logopenic aphasia, some dysexecutive syndromes and mild cognitive impairment. Would the ruling include these clinical entities?

We are also concerned about the delay in time for the CED process. Since CED exercises not infrequently take many years to complete, we are concerned that our patients with neurodegenerative diseases might not benefit from emerging technologies. We would propose that if data, such as those generated by the evidence-based medicine reviews of literature commonly performed by the AAN, were used to inform the field, such data could be acted upon swiftly and expedite the CED process. Although still at an early stage, I am pleased to tell you that the Guidelines Development Subcommittee of the AAN is actively discussing the feasibility of developing an evidence-based systematic review of available literature on beta amyloid imaging.

The AAN also agrees that clinical studies evaluating the medical necessity of PET Aß imaging for Medicare beneficiaries with cognitive impairment suggestive of AD, or who may be at risk for developing AD should address the questions articulated in the proposed decision memo:

• Do the results of PET Aß imaging lead to improved health outcomes? We believe that there needs to be more specific guidelines with regard to the definition of outcomes as this information is not included in the decision memo.
• Does patient management guided by PET Aß lead to improved health outcomes?
• Can PET Aß imaging be used to guide the management of individual patients or specific diagnoses?

In addition, the AAN respectfully offers a series of questions for consideration in future clinical studies.

1. What is the quantitative description of the diagnostic accuracy of PET Aß imaging?

What is the sensitivity and specificity of PET Aß imaging for determining that AD is the cause of a patient’s symptoms? Without this information, a clinician will not be able to interpret the results of a positive or negative study in a meaningful way. Have such studies been done in the general population as well as in specialist settings?

2. How strong is the quality of evidence supporting the diagnostic accuracy of PET Aß imaging?

What is the Class of evidence in studies of diagnostic accuracy for PET Aß imaging? Physicians should be provided a measure of confidence when interpreting the quantitative measures of the diagnostic accuracy of PET Aß imaging.

3. How does the diagnostic accuracy of PET Aß imaging compare to common imaging modalities already in routine use such as CT or MRI?

This information will help clinicians put the role of PET Aß imaging into perspective. What is the added value of PET Aß imaging over MRI and CT imaging?

4. Are there other ways to make this distinction that do not involve imaging? If so, how does their performance compare to that of PET Aß imaging?

This information will help clinicians put the role of PET Aß imaging into perspective. What is PET Aß imaging’s added value over non-imaging modalities such as MRI and cerebrospinal fluid examinations?

5. Is the diagnostic accuracy of amyloid PET high enough to obviate the need to search for reversible causes of dementia?

This information will serve to guide future studies regarding treatment of different causes of dementia. It must also be recognized that in many neurodegenerative diseases, despite an inevitably progressive course, information gained from amyloid imaging may still affect management in important ways.

The AAN appreciates the opportunity to provide comments on CAG-00431N. Should you have questions about our comments or require further information, please contact Daneen Grooms, Manager of Regulatory Affairs, at dgrooms@aan.com or (202) 525-2018. Thank you for your consideration.

Sincerely,

Timothy A. Pedley, MD, FAAN
President, American Academy of Neurology

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I reiterate the comments made by the SNMMI and could not state the case better. See below. However I can add that as someone approaching the age where early or confirmative diagnosis of AD, I do not agree with the current coverage plan. CMS should not take this valuable tool from patients. Let's move forward in imaging, not backward!

SNMMI appreciates the opportunity to comment on the Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. Sufficient evidence exists to support immediate coverage, which would change patient management, lead to better health outcomes for patients and assist families making care decisions. Coverage with evidence development (CED), as proposed, is not appropriate for Aß imaging, which the U.S. Food and Drug Administration (FDA) has already approved, noting its clinical utility.

Earlier this year the Alzheimer’s Association and SNMMI jointly developed appropriate use criteria (AUC). The end result concluded that Aß PET imaging demonstrates more than adequate evidence exists for Medicare to cover Medicare beneficiaries without additional onerous CED.

The AUC determined that for Aß imaging to be considered appropriate, individuals must exhibit several characteristics. These include: (1) a cognitive complaint with objectively confirmed impairment; (2) Alzheimer's disease (AD) as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (3) knowledge of the presence or absence of Aß pathology is expected to increase diagnostic certainty and alter management.

Should all of these criteria be met, Aß PET imaging is appropriate in the following scenarios:

• Patients with persistent or progressive unexplained mild cognitive impairment.
• Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either atypical clinical course or etiologically mixed presentation.
• Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

CMS did conclude “there is sufficient evidence that the use of Aß PET imaging could be promising to exclude AD in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD).”

What criteria represent a meaningful health outcome for a patient with mental cognitive decline? For a patient, being taken off powerful medications that are not indicated for their condition is most certainly a meaningful health outcome. For a patient who has a diagnosis of AD, and is being treated as having AD, having a test which can rule out AD certainly has a meaningful health outcome. Current standard care for AD and related dementia disorders is not only to attempt fundamental treatments or prevention, but also to provide quality of care and care arrangement. The outcome goes beyond a patient's quality of care and the Medicare beneficiary expenditure of care resources, but also for their family and caregivers. And yet, CMS is proposing that evidence is insufficient to conclude that the use of Aß PET imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease and thus is not reasonable and necessary; we disagree.

While CMS decided to cover one scan, it did so under CED which is so onerous, in our opinion and experience, that it is in effect a non-coverage decision. CMS states that the gold standard diagnosis for AD remains postmortem autopsy. Therefore, any CED trial design will need to be tied to autopsy. However, the challenge is the significant time lapse from the initial Aß scan to autopsy of patients who may benefit from Aß PET imaging defined in the AUC. These elderly patients might carry comorbidities that affect their cognitive status and outcome through the course. This is particularly true for early-stage and atypical patients for whom Aß PET imaging is recommended in the AUC. The FDA already set the rigorous standards for the approval of Aß PET imaging. They required that the abnormalities seen on PET closely correlate with neuritic amyloid pathology seen postmortem. The results of imaging vs. postmortem studies with florbetapir met those rigorous standards, leading to FDA approval of Amyvid. Why does the CED need to be tied to autopsy?

CMS states in the proposed decision memo, “Given that the gold standard diagnosis for AD remains postmortem, creating the building blocks of evidence-based appropriate use criteria, and establishing clinical utility on firm ground, will unfortunately take time.” How long should patients wait? Amyvid has already met the rigorous imaging versus postmortem studies, the SNMMI and Alzheimer’s Association Amyloid Imaging Taskforce has firmly established AUC and the FDA established clinical utility with approval. SNMMI is disappointed with the proposed decision memo because we believe Aß PET imaging is a medical advance that meets the major goal of the National Plan to Address Alzheimer’s disease to make major strides in the diagnosis and treatment of AD by 2025.

All Medicare eligible patients, and not just those in limited clinical trials, should have access to a valuable new tool that can assist physicians in better diagnosing patients with cognitive impairment. CMS should reverse its proposed decision memo and cover the three indications of the AUC without inappropriate coverage with evidence development. We disagree with CMS that an Aß scan does not lead to better health outcomes for patients, particularly in the case of a differential diagnosis which can prevent patients from being subjected to inappropriate medications and costs. We believe that additional information provided by the Aß PET study would be helpful assisting physicians to better manage their patients and therefore recommend implementing checks and balances.

Thank you for the opportunity to comment.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] was diagnosed with Parkinson's disease due to a tremor in her hand. For ten years she was took medication for Parkinson's disease and when she started to have issues with dementia, we were told that this commonly occurs over time with Parkinson's. After 10 years of treatment, my sister and I noted that [PHI Redacted] Parkinson's disease was not getting worse and her medication requirements weren't increasing as is normal with that disease.

Only after approaching [PHI Redacted] doctor with our observations was she given a brain scan, determining that her tremor was due to a stroke she had unknowingly had. With that new information, her dementia diagnosis was reanalyzed and determined to be middle-stage Alzheimer's.

If a brain scan had been performed a decade earlier, [PHI Redacted] would not have been taking unnecessary Parkinson's medication for 10 years and her dementia would not have been written off as a progression of that disease. We wonder if her Alzheimer's had been diagnosed at an earlier stage, if the earlier treatment options would mean that her dementia would not have progressed as quickly and she would still have more of her mind and memory function.

My family's experience highlights the need to use the tools available to provide more accurate diagnosis and treatment of brain disease. Please, don't make numerous families suffer the consequences of misdiagnosis like ours did.

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August 1, 2013

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: CAG-00431N Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear Dr. Jacques:

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) appreciates the opportunity to comment on the Proposed Decision Memo for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. SNMMI disagrees with the Proposed Decision Memo and believes that significant revisions are needed before release of the Final Decision Memo.

SNMMI believes that sufficient evidence exists to support immediate coverage, which would change patient management, leading to better health outcomes for patients and assisting families who are making care decisions. SNMMI believes that coverage with evidence development (CED), as proposed, is not appropriate for beta-amyloid imaging, which the U.S. Food and Drug Administration has already approved, noting its clinical utility. We urge that the Final Decision Memo cover amyloid-beta (Aß) PET imaging following appropriate use criteria for patients who currently would benefit from this technology to improve the accuracy of determining the cause of their condition and their management. These patients cannot wait to have access to the best currently available evaluation and treatment. While we agree that more information is needed, the proposed CED is impractical, fails to advance the field, would significantly delay translation of significant advances to clinical care, and would fail to include those who are most in need and simultaneously least likely to qualify or be able to participate in such a study. Furthermore, the standards for judging the adequacy of evidence needed and the potential number of covered CED trials is ambiguous. A Final Decision should provide greater clarity and provide a clear path for future coverage.

SNMMI’s comments will focus on the following areas:

• Evidence supporting amyloid imaging
• CED challenges
• Alternative CED recommendations

Evidence supporting amyloid imaging
Earlier this year the Alzheimer’s Association (AA) and SNMMI jointly developed appropriate use criteria (AUC). The end result concluded that Aß PET imaging demonstrates more than adequate evidence exists for Medicare to cover Medicare beneficiaries without additional onerous CED. The criteria demonstrated that for amyloid imaging to be considered appropriate, individuals must exhibit several characteristics. These include: (1) a cognitive complaint with objectively confirmed impairment; (2) Alzheimer's disease (AD) as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (3) knowledge of the presence or absence of amyloid-beta pathology is expected to increase diagnostic certainty and alter management.

Should all of these criteria be met, amyloid PET imaging is appropriate in the following scenarios:

• Patients with persistent or progressive unexplained mild cognitive impairment.
• Patients satisfying core clinical criteria for possible Alzheimer's disease because of unclear clinical presentation, either atypical clinical course or etiologically mixed presentation.
• Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

CMS states in the Proposed Decision Memo that the evidence is not adequate to conclude that PET amyloid-beta imaging improves meaningful health outcomes in beneficiaries who display signs and symptoms of AD. SNMMI respectfully disagrees with that statement under the criteria and scenarios laid out in the AUC. CMS also states the evidence is not adequate to conclude that PET Aß results inform the treating physician’s management of the beneficiary to improve meaningful health outcomes. Again, SNMMI disagrees with this assessment under the criteria and scenarios laid out in the AUC, particularly with regard to a differential diagnoses and the avoidance of futile treatment or tests. CMS did conclude “there is sufficient evidence that the use of PET Aß imaging could be promising to exclude Alzheimer’s disease in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD),” yet still declined to cover the procedure under these circumstances. This evidence was carefully reviewed and assessed by the Alzheimer’s Imaging Taskforce (AIT) convened by the Alzheimer’s Association and SNMMI to write the AUC.

CMS should consider what a meaningful health outcome for a patient with mental cognitive decline should look like. In our experience, for a patient, being taken off powerful medications that are not indicated for their condition is most certainly a meaningful health outcome. For a patient who has a diagnosis of Alzheimer’s disease, and is being treated as having Alzheimer’s disease, having a test which can exclude AD certainly has a meaningful health outcome. Current standard care for Alzheimer's disease and related dementia disorders is not only to attempt fundamental treatments or prevention, but also to provide symptom treatment, quality of care and care arrangement. The outcome goes beyond a patient's quality of care and the Medicare beneficiary expenditure of care resources, but also for their family and caregivers. And yet, CMS is proposing that evidence is insufficient to conclude that the use of PET amyloid-beta imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease and thus is not reasonable and necessary. We disagree.

CED challenges

While CMS decided to cover one scan, it did so under coverage with evidence development which is so onerous, in our opinion and experience, that it is in effect a non-coverage decision. CMS states that the gold standard diagnosis for AD remains postmortem Therefore, it indicates any CED trial design will need to be tied to autopsy. However, a challenge is a significant time lapse from the initial amyloid scan to autopsy of patients who may benefit from amyloid PET imaging defined in the AUC. These elderly patients might carry comorbidities that affect their cognitive status and outcome through the course. This is particularly true for early-stage and atypical patients for whom amyloid PET imaging is recommended in the AUC. While performance of an autopsy is admirable, and under certain circumstances appropriate, CMS does not currently reimburse for the arrangement or performance of an autopsy. Access to brain autopsy is impossible for outpatients in large areas of the United States and outside the means of most families or a registry to arrange or pay for. The FDA already set the rigorous standards for the approval of amyloid PET imaging. They required that the abnormalities seen on PET closely correlate with neuritic amyloid pathology seen post-mortem. The results of imaging vs. post-mortem studies with Amyvid™ met those rigorous standards, leading to FDA approval of Amyvid™. So why does the CED need to be tied to autopsy? To do so makes any CED impractical, grossly delays access to important, new diagnostic technology and assures that the results will be from grossly unrepresentative populations. Furthermore, the questionable ethics of coverage only for CED with autopsy would place coercive pressure on vulnerable populations, who have cognitive decline, and their families to enter into research as subjects in order to accrue the medical benefit of imaging evidence for absence of or moderate to frequent neuritic plaque.

CMS states in the proposed decision memo, “Given that the gold standard diagnosis for AD remains postmortem, creating the building blocks of evidence-based appropriate use criteria, and establishing clinical utility on firm ground, will unfortunately take time.” How much time should patients wait? Amyvid™ has already met the rigorous imaging versus postmortem studies, the AIT has firmly established appropriate use criteria and the FDA established clinical utility with approval. SNMMI is disappointed with the Proposed Decision Memo because we believe amyloid PET imaging is a medical advance that meets the major goal of the National Plan to Address Alzheimer’s Disease to make major strides in the diagnosis and treatment of AD by 2025. Alzheimer’s disease is a major and growing public health problem. The proposed decision admits that amyloid PET would provide more accurate diagnosis in the context of clinical drug trials. Why then, not allow patients not in clinical trials similar advantage of more accurately and specifically knowing the cause of their illness?

Our experience with CED has been widespread with the NOPR and many lessons have been learned. CED has an important role and can be extremely helpful to expand access, while collecting data for more informed “short term” evidence based decisions. However, CED should not be employed for studies that are intended to be long term as the logistics are not practical or reasonable from the point of view of patients. Those long range clinical trials should be left to the academic and clinical research centers with the data collection rigor, difficult end points, and prospective, randomized, blinded studies. Evidence needed for coverage decisions should be based upon pragmatic study principles, including disadvantaged, underrepresented, and medically complex patient populations that are unable to participate in rigorous, long-term clinical trials. In our experience, the target population of patients with difficult to diagnose cognitive deficits and who have a variety of socioeconomic environments often would be unable to adhere to randomized trial protocols and, likewise, would compromise the analysis of outcomes due to large drop-out rates and large amounts of missing data.

If we look to the National Oncologic PET Registry (NOPR) which is viewed by many, including CMS, as a very successful coverage with evidence (CED) program, there are some facts that we cannot escape or overcome. The CED program was burdensome and required prolonged and sustained effort. In fact, CMS allowed for the initial CED coverage to begin on January 28, 2005. However, setting up the structure and CMS approved measures were not completed for implementation by both CMS and NOPR until May 8, 2006, one year and 3 months later. Data collection began for Medicare beneficiaries with a PET study on or after May 8, 2006. Subsequently, the published literature reporting on the NOPR data occurred on January 15, 2009, NOPR requested reconsideration based on the new evidence from the CED, and CMS granted a slightly expanded coverage policy, allowing continued coverage only under the CED model. The second phase of NOPR opened in 2009; more papers from the previous NOPR were published, as well as published literature from the second phase of NOPR 2009. All this significant work by many dedicated individuals resulted in a final CMS decision to end the data collection on June 11, 2013. The NOPR experience for CED, from official start to finish, lasted 8 years and 4 months and 15 days. While there are many more lessons to learn from the NOPR experience, this timeline of more than 8 years for a CED with far less requirements to end points, supports our notion that the endpoint of autopsy that has been proposed is not appropriate for CED.

Alternative CED approach

As an alternative to the proposed CED, CMS should consider a similar approach to the information collected on FDG PET for dementia. Prior FDG PET imaging approval by CMS for dementia evaluation (Alzheimer's disease versus frontotemporal dementia) with an appropriate checklist and prior medical workup requirements has been successfully operationalized and guided effective, but a limited use of the national resources. We would like to advocate a similar approach for amyloid PET imaging. We recommend immediate coverage for the three indications of the appropriate use criteria with an enhanced checklist similar to the FDG checklist. Data collected from billing records could then be used to assess the effectiveness of the program applying appropriate use guidelines.

All Medicare eligible patients, and not just those in limited clinical trials, should have access to a valuable new tool that can assist physicians to better diagnose patients with cognitive impairment. SNMMI recommends CMS reverse its proposed decision memo and cover the three indications of the appropriate use criteria without inappropriate coverage with evidence development. We disagree with CMS that a beta amyloid scan does not lead to better health outcomes for patients, particularly in the case of a differential diagnosis which can prevent patients from being subjected to inappropriate medications and costs. We believe that additional information provided by the PET study would be helpful assisting physicians to better manage their patients and therefore recommend implementing checks and balances, such as an enhanced FDG checklist. We do not share CMS’s belief that this needs to “unfortunately take time.”

We welcome the opportunity to discuss this further and would be happy to meet with you at a date and time of your choosing.

Sincerely,

Gary Dillehay , MD, FACNM, FACR
President, SNMMI

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The Centers for Medicare and Medicaid Services (CMS) announced in September 15, 2004 that the evidence was adequate to conclude that a 2-deoxy-2- [F-18] fluoro-D-glucose Positron Emission Tomography (FDG-PET) scan was 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). The test was approved by FDA, which has a rigorous approval process. CMS also determined that the test from the referring and billing providers, once having appropriate documentation of evaluation of the Medicare beneficiary, would be eligible for coverage.

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Asian Americans and Pacific Islanders (AAPI) are included in the 4 million individuals with Alzheimer Disease (AD) in the U.S. However the detection and management of AD among AAPI is ten fold more difficult due to cultural and linguistic barriers. AAPI families tend to overlook or minimize signs of AD, afraid of the stigma put on it and once being detected, the disease would be in a too advanced stage. They also tend to care for their family members with AD at home. All these factors affect the treatment and management of AAPI with AD and impact on their quality of life, not to mention of their care givers’ as well.

The information this technology provides can be important in the diagnosis and in the development of treatment plans for such patients and their caregivers. It reinforces the need for them to get appropriate medical treatment and management with the overall result of an improved quality of life of AAPIs with AD.

With the above comments, the National Council of Asian Pacific Islander Physicians (NCAPIP) urge that CMS reconsider their decision of requiring the technology to be approved for reimbursement under “Coverage with Evidence Development” (CED) criteria, which would limit coverage to only those patients enrolled in a clinical study to generate the additional benefit and safety information for CMS to determine if it can be covered more widely. It will limit access through inclusion of our AAPI patients with AD to the clinical study for the reasons provided. Therefore, our AAPI patients with AD will not benefit of the restricted coverage proposed.

Along with a broad group of stakeholders, medical experts and patient advocates, NCAPIP medical provider members strongly support Medicare coverage and believe that CED is not appropriate for this FDA-approved technology, especially for our AAPI communities.

Best regards,

Ho Luong Tran, M.D., M.P.H.
President and CEO
National Council of Asian Pacific Islander Physicians

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] was 83 when she was diagnosed with Alzheimer's. She refused to accept that there was anything wrong with her but I was constantly receiving phone calls of concern from her friends and neighbors, acquaintances, & the police. I arranged for her to have a life line bracelet - she put it in a drawer. I arranged for a care giving service to keep her in her home - she cancelled visits and then called with last minute requests. She often locked herself out of her house and could never find her car keys.

I am very mindful of this disease because [PHI Redacted] died from it after long illnesses. [PHI Redacted]

[PHI Redacted] I do not know what the Amyloid test would cost but I am sure it will be less than the cost of treatment and care for people who come down with Dementia. Please make this diagnostic test available to those who want it and their families.

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In response to the Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N), I would first like to thank the member of the committee for what appears to be a well thought-out and comprehensive evaluation of the topic of CMS coverage of amyloid-base PET imaging. That being said I would like to provide the perspective of practicing Behavioral Neurologist faced with the often-difficult task of accurately identifying the cause of cognitive decline in the adult population.

I would argue against the decision based on a few considerations. The first being the assertion by the committee (in response to the Grundman 2012) that in the case of an uncertain diagnosis that an extensive evaluation would proceed whether the amyloid PET scan is available -Conversely, if you did not have such a convincing clinical picture, 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. Although this is the often the case, having a positive scan would significantly decrease the risk of repeated, frequently invasive, testing which will typically result in thousands of dollars being spent. A positive scan early in the process would significantly curtail such diagnostic explorations. Furthermore, in the case of an atypical presentation of someone that has a scan consisting with amyloid plaque deposition- i.e. consistent with Alzheimer Dementia, this would greatly limit and focus the necessary decisions to other causes for the patient’s symptoms. Again, facilitating accurate and rapid diagnosis with limited exposure to additional testing and treatments.

Additionally, the availability of this technology would likely benefit patients and families that have limited access to dementia specialist. Given the difficulty in diagnosing Alzheimer’s in a small, but significant number of patients, having access to an amyloid PET scan, when interpreted by an appropriately trained professional, would likely decrease the number referrals needed to specialist, which often results in a significant burden to patients in the sense of excess travel-which often accounts for decreased productivity (time loss from work) for care-givers, delayed diagnosis, and the risk of repeated testing. The financial and emotional impact of this should not be overlooked.

Lastly, it could be argued that fundamentally there is little difference in the use of FDG -PET for determining a diagnosis of AD from FTD in regards to the arguments used against the use of amyloid PET scans. Yet, thankfully, FDG- PET is approved and has proven to be very helpful in the evaluation of elderly persons with dementia. At a minimum, it would seem that like with the use of FDG-PET a specific set of criteria would need to be met in order to have the amyloid PET scan covered, thus limiting inappropriate utilization. Unfortunately, as the amyvid PET scan is already approved, the current decision to restrict coverage by CMS, and thus commercial insurance agencies, will help to reinforce a stratified diagnostic system whereby those with the financial means will have the benefit of pursuing the test, whereas those without the discretionary funds will be denied access. This is certainly an unfortunate circumstance.

Sincerely,

Eric McDade D.O.
Assistant Professor
University of Pittsburgh School of Medicine
Department of Neurology
Associate Director-Clinical Core, Alzheimer Disease Research Center

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Louis B. Jacques, M.D.
Director, CMS Coverage and Analysis Group
Office of Clinical Standards and Quality (CMS/OCSQ)
Centers for Medicare & Medicaid Services
Louis.Jacques@cms.hhs.gov

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N) Submitted on behalf of The Amyloid Imaging Taskforce

Dear Dr. Jacques:

President Obama signed the National Alzheimer’s Project Act (NAPA) into law in 2011. The goals of NAPA, including treatment and prevention by 2025, care, support and public engagement, are highly dependent upon identifying and providing an early and accurate diagnosis to those with cognitive impairment. Improving the accuracy and specificity of diagnosis is an essential step to improving the quality of care for dementing diseases. Twenty-five years of neurochemistry and neuroimaging research has delivered on its promise to assist in accurate diagnosis during life through the ability to detect one of the major molecular pathologies underlying Alzheimer’s disease dementia. Patients and caregivers deserve to benefit from this success.

In early 2013, the combined efforts of the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging produced appropriate use criteria (AUC) for amyloid PET, which detailed a responsible and cost-sensitive roadmap toward making this technology available (1, 2). The AUC defined the populations that would benefit from this diagnostic technology and, perhaps more importantly, identified individuals for whom this technology would not be beneficial or useful. The foundation of the recommendation is to utilize the skills of dementia experts, specially trained and experienced physicians who occasionally encounter a diagnostic dilemma, an atypical patient whose diagnosis is uncertain even after comprehensive evaluation (3). Such patients are uncommon but well known to exist, and the diagnostic challenge they pose has been acknowledged by CMS: Coverage for such patients’ care currently includes both the services of the dementia expert and additional diagnostic testing, such as FDG-PET and SPECT imaging, when explicitly justified.

The AUC require that a dementia expert, following documentation of a standardized clinical evaluation, determine the need for an amyloid PET scan to improve the certainty that a patient’s impairment is or is not due to amyloid pathology, and that this increased certainty would improve patient treatment, care and support. Amyloid PET is not useful to detect or exclude the clinical syndrome of dementia, nor in several other clinical scenarios that represent inappropriate use detailed in the AUC report (1,2). The use of amyloid PET imaging should be strictly limited according to the AUC to circumstances in which knowing the pathologic basis of established impairment, as being either amyloid-based or non-amyloid-based, would improve clinical care.

Since accurate, consequential diagnosis is enabled by the AUC, the rejection of the AUC as a basis for CMS coverage will reduce the likelihood of reaching the goals of the National Plan to Address Alzheimer’s Disease. The history of progress in treating diseases with gradual onset has taught us that to fight Alzheimer’s disease we need to arm expert clinicians with the best diagnostic tools available. We cannot expect progress in caring for patients with Alzheimer’s disease without accurate, timely diagnosis. We need to know who is living with the disease and who is not, and when there is doubt, primary care providers need to be able to consult dementia experts with the ability to utilize validated methods to detect underlying pathology to determine the cause of symptoms. As is true with all serious medical illnesses, knowing the cause of illness empowers patients, families and health providers alike to make appropriate management decisions. In the case of dementing diseases, these management decisions are not easy; they are life altering and often critical to avoiding costly care crises.

The proposal by CMS to use Coverage with Evidence Development, without a limited approval for those restricted populations that will benefit from this diagnostic tool today, will hinder our progress toward reaching the goals of the National Plan by 2025. There is no question that better empirical evidence of improved health outcomes should continue to be sought, and several such studies are now underway. However, the outlined terms of the CED fail substantially to recognize key elements of the current state of knowledge and fail to provide a pathway to approve appropriate use.

In particular, the draft decision wrongly conflates the question of amyloid PET clinical utility with controversies about the amyloid cascade hypothesis of Alzheimer’s disease causation. Whether or not the initiating event in pathogenesis is the formation of amyloid, tau or other processes, Alzheimer’s disease dementia is by definition associated with amyloid deposition. This definition of the molecular pathology is universally recognized, and was re-emphasized in 2012 by an NIA consensus panel.

As a practical matter, the CED mechanism as outlined in the draft decision is not sufficiently or consistently detailed to permit a judgment as to how it could be applied, and therefore should be re-evaluated. As a matter of record, the CED mechanism applied previously to dementia diagnosis has proven impractical and produced no substantial contribution of empirical evidence for any level of coverage or non-coverage despite many years of effort.

For these reasons, we here call upon CMS to reconsider the proposed decision and work with the research and caregiving community to seek a better answer. Just as dementia expert services and advanced imaging and diagnostic services for dementing disease are a covered benefit under specific circumstances, the CMS should seek to implement a mechanism by which amyloid PET, acquired under carefully and highly restricted circumstances, could also be a covered benefit. Patients living with an inaccurate diagnosis, especially when reversible causes or harmful treatments are involved, cannot wait for CED.

Sincerely,

Submitted on behalf of The Amyloid Imaging Taskforce (undersigned)
Keith A. Johnson, MD (Co-Chair)
Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Satoshi Minoshima, MD, PhD (Co-Chair)
Department of Radiology, University of Washington, Seattle, WA, USA
Nicolaas I. Bohnen, MD, PhD
Departments of Radiology and Neurology, University of Michigan, and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
Kevin J. Donohoe, MD
Beth Israel Deaconess Medical Center, Boston, MA, USA
Norman L. Foster, MD
Department of Neurology, University of Utah, Salt Lake City, UT, USA
Peter Herscovitch, MD
PET Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
Jason H. Karlawish, MD
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Christopher C. Rowe, MD
Department of Nuclear Medicine and Centre for PET, Austin Health, Victoria, Australia
Saima Hedrick
Society of Nuclear Medicine and Molecular Imaging, Reston, VA, USA
Virginia Pappas
Society of Nuclear Medicine and Molecular Imaging, Reston, VA, USA
Maria C. Carrillo, PhD
Division of Medical and Scientific Relations, Alzheimer’s Association, Chicago, IL, USA
Dean M. Hartley, PhD
Division of Medical and Scientific Relations, Alzheimer’s Association, Chicago, IL, USA

References

(1) Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, Karlawish JH, Rowe CC, Carrillo MC, Hartley DM, Hedrick S, Pappas V, Thies WH; Alzheimer's Association; Society of Nuclear Medicine and Molecular Imaging; Amyloid Imaging Taskforce. 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. Alzheimers Dement. 2013 Jan;9(1):e-1-16; and J Nucl Med. 2013 Mar;54(3):476-90.
(2) Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, Karlawish JH, Rowe CC, Hedrick S, Pappas V, Carrillo MC, Hartley DM. Update on appropriate use criteria for amyloid PET imaging: Dementia experts, mild cognitive impairment, and education. Alzheimers Dement. 2013 Jul;9(4):e106-9. doi: 10.1016/j.jalz.2013.06.001; and J Nucl Med. 2013 Jul;54(7):1011-3. doi: 10.2967/jnumed.113.127068. Epub 2013 Jun 10.
(3) McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s dis- ease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263–9.

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August 1, 2013

BY ELECTRONIC DELIVERY

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

The Biotechnology Industry Organization (BIO) appreciates this opportunity to comment on the Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N).¹ Specifically, our comments oppose CMS' draft decision to apply coverage with evidence development (CED) to beta-amyloid Positron Emission Tomography (PET Aβ) imaging. Instead, we express support for Medicare coverage of this innovative and promising technology used in the early detection and treatment of Alzheimer's disease (AD) or cognitive impairment.

BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial, and environmental biotechnology products.

Aβ the representative of an industry that is devoted to improving health care through the discovery of new diagnostics and therapies, BIO supports the Department of Health and Human Services' (HHS') initiatives to accelerate research on detection, treatment, and prevention of AD through its National Plan to Address Alzheimer's Disease released by the Assistant Secretary for Planning and Evaluation (ASPE) on January 9, 2012.² The Plan's initiatives include expanding research and tools for clinicians, especially in the realm of emerging technologies and new approaches in clinical testing.³ In comments submitted February 8, 2012,⁴ BIO emphasized that any framework for improving diagnosis and care for serious, complex illnesses, such as AD, must include measures to provide access to innovative diagnostic and treatment options. Aβ such, BIO has a particular concern with actions by the Centers for Medicare and Medicaid Services (CMS) that may continue to limit patient access to PET Aβ imaging.

PET Aβ imaging technology represents a significant advancement in AD care, as it aids in the early diagnosis of AD or cognitive impairment by detecting amyloid-β deposition in the brain.one of the two defining pathologic lesions of AD. The status quo for differentiating definitive causes of AD and other cognitive decline has historically been post-mortem exams; thus, PET Aβ imaging allows for greater opportunity to manage clinical treatment earlier, potentially improving quality of life and health outcomes in patients living with the disease. Furthermore, the technology can help target therapeutic interventions in early stages of the illness, as well as avert unnecessary treatments. In addition to guiding existing treatment options, early diagnosis of AD allows patients to explore candidacy for clinical trials and helps patients and their caregivers seek out planning and support services.

Aβ we have expressed in previous comment letters, BIO supports the use of CED when it is used to help patients gain access to otherwise unavailable drugs, biologicals and other therapies. Our members invest billions of dollars each year in clinical research to develop and disseminate evidence to help guide the effective use of their therapeutics and diagnostics. However, BIO does not believe CED is appropriately used when it narrows the uses of FDA-approved drugs and biologicals.

Despite receiving approval by the Food and Drug Administration (FDA) last year, CMS proposed CED for PET Aβ imaging. Specifically, CMS proposes to cover one PET Aβ scan per patient only for those patients enrolled in a clinical trial whose objective meets one of two predefined aims: to develop better treatments or prevention strategies for AD, or as a strategy to identify subpopulations at risk for developing AD; or, to resolve clinically difficult differential diagnoses where the use of PET Aβ imaging appears to improve health outcomes. A trial must be preapproved by CMS and is subject to many other criteria including that it must: involve subjects from appropriate populations; be comparative, prospective, and longitudinal; and use randomization and postmortem diagnosis as the endpoint. If finalized, this decision will continue to exclude this technology from Medicare coverage, and therefore, it will remain inaccessible to most Medicare beneficiaries. Instead, BIO urges CMS to provide immediate Medicare coverage for the use of PET Aβ imaging in the evaluation of progressive cognitive decline. BIO specifically supports Medicare coverage for PET Aβ imaging when its use adheres to the criteria developed by the Alzheimer's Association and Society of Nuclear Medicine and Molecular Imaging's Amyloid Imaging Taskforce (AIT). These guidelines ensure appropriate use of this technology for intended populations only, as indicated by its appropriate use criteria (AUC) released earlier this year.⁵ Thus, CED is inappropriate for the "medically accepted" AUC population.

BIO appreciates the opportunity to submit these comments. CMS should endeavor to develop coverage policies that are flexible and that allow for innovative diagnostics and therapies to get to the right patients, at the right time. We urge CMS to provide coverage for PET Aβ imaging immediately, in concurrence with guidelines supported by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging. It is critical that the appropriate Medicare beneficiaries gain access to this and other innovative technologies that detect and treat this debilitating disease earlier in its progression. Please contact me if you have any questions about these comments. Thank you for your attention to this very important matter.

Sincerely,

/s/
Laurel L. Todd,
Managing Director,
Reimbursement and Health Policy

1 Centers for Medicare and Medicaid Services (CMS). 2013. Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N). Baltimore, MD: CMS, Available at: http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265.
2 Department of Health and Human Services (HHS). 2013. National Plan to Address Alzheimer's Disease: 2013 Update. Washington, DC: HHS. Available at, http://aspe.hhs.gov/daltcp/napa/NatlPlan2013.shtml.
3 HHS Press Office. 2012. News release: Obama administration presents national plan to fight Alzheimer's disease. Washington, DC: HHS, Available at: http://www.hhs.gov/news/press/2012pres/05/20120515a.html.
4 Biotechnology Industry Organization (BIO). 2012. Comments on the Draft Framework for the National Plan to Address Alzheimer's Disease. Washington, DC: BIO, Available at: http://www.bio.org/advocacy/letters/alzheimer%E2%80%99s-disease-bios-comments-draft-framework-national-plan-address-alzheimer%E2%80%99s.
5 Johnson, K. A., S. Minoshima, N. I. Bohnen, K. J. Donohoe, N. L. Foster, P. Herscovitch, J. H. Karlawish, et. al. 2013. 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 & Dementia 5(1):1-15, Available at: http://www.alz.org/research/downloads/appropriate_use_criteria_for_amyloid_pet_alz_and_dem_january_2013.pdf.

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I have been a practicing adult neurologist for 30 years with my practice limited to the evaluation and treatment of people with memory disorders. I have seen our evaluation and treatment of these people evolve over the years and have shared with them and their loved ones the frustration and sadness from our inability to confirm specific diagnosis which if we could would very likely allow us to develop effective disease targeted treatments rather than the very limited symptomatic treatments we now have available.

I have been utilizing the Amyvid PET scan regularly in the appropriate patients in my memory clinic since it has been FDA approved and probably have as much if not more experience with this diagnostic tool than any other "front line" practicing neurologist in the country. It has allowed me to increase my diagnostic certainty in the patient where this degree of certainty would not be attainable short of brain biopsy or autopsy. It certainly is not necessary or appropriate in the majority of the patients we evaluate on a daily basis and is not a substitute for the standard indicated testing but does allow the avoidance of some costly and sometimes invasive testing that the patient would be exposed to if we did not have the information of the presence or absence of cortical neuritic plaques that the Amyvid scan supplies. I can confirm from personal experience that the information from the Amyvid scan has allowed several of my patients to avoid the discomfort and risks of a lumbar puncture, many costly "esoteric" blood tests, EEGs, very extensive Neuropsych testing( standard cognitive testing is obtained on all patients) and sometimes psychiatric consultation and unnecessary drugs. Likewise it has allowed me to stop the long term use of anti-AD medication when it is not needed...these positive changes in management would not be possible without the information supplied by the scan. It certainly is more specific than FDG-18 PET. The Amyvid scan also allows structural imaging with the accompanying CAT scan. We typically obtain MRI prior to any molecular imaging but I have had 2 patients with no insurance who had to pay out of pocket for evaluation. These were very young patients who had normal blood studies and abnormal cognitive testing where the information from the Amyvid scan would be very helpful. Structural imaging also was needed and the Amyvid scans supplied both the needed structural and molecular imaging at 1 cost. MRI is more sensitive than CAT and of course CAT scan or MRI is obtained prior to any consideration of Amyvid but in these 2 specific situations the work up had to be tailored to the patient's needs.

Our patients and their families deserve the availability of the Amyvid scan if they require it for evaluation and management decisions.

Thank you.
Ira Goodman, MD
Compass Clinic

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Amyloid scans have really improved clinicians ability to differentiate between Alzheimer's dsiease and other types of diseases, especially in atypica lpresentation such as logopenic aphasia, posterior cortical atrophy, early-onset Alzheimer's dsiease and differentiating from FTD. I think there needs to be a braod coverage of Amyloid scans as it is an invaluable tool for clinicians diagnostic accuracy. In my practice so far, I have had to rely on research obtained amyloid scan to verify diagnoses and it OFTEN changed the management of my patients.

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I write in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] was a dynamic individual. A salesman all his life, he started a small electronic surplus business in New York City in 1945. He realized that the end of WW2 would result in an incredible amount of stuff appearing on the surplus markets and specialized in radio tubes. He operated that business for over a quarter century in the City and out on Long Island, where we wound up living. His relative success enabled us to move to suburbia and enabled me to attend engineering school and my brother to become a physician.

[PHI Redacted]

I would not wish this on my worst enemy or maybe I would. I support anything that will relieve the agony of dementia patients and their families.

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August 1, 2013

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: CAG-00431N Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear Dr. Jacques:

The American College of Nuclear Medicine (ACNM) appreciates the opportunity to comment on the Proposed Decision Memo for Beta Amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease. ACNM is comprised of physicians and other nuclear medicine professionals dedicated to enhancing the practice of nuclear medicine through the study, education and improvement of clinical practice. ACNM disagrees with the Proposed Decision Memo and believes that significant revisions are needed before release of the Final Decision Memo.

ACNM believes that there is enough evidence to support immediate coverage, which would change patient management and lead to better health outcomes for patients. ACNM believes that the proposed coverage with evidence development (CED) is inappropriate for beta-amyloid imaging. We ask CMS to make edits to the Final Decision Memo to cover amyloid-beta (Aß) PET imaging following appropriate use criteria for patients who would currently benefit from this technology. It is imperative that these patients have immediate access to the best available evaluation and treatment. While more data is needed, the current proposed CED is impractical and would delay necessary advances to clinical care. ACNM believes that the Final Decision should provide greater a clear path for future coverage.

Recently, the Alzheimer’s Association (AA) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) worked together to develop an appropriate use criteria (AUC). ACNM strongly agrees with their conclusion that Aß PET imaging reveals that evidence exists for Medicare to cover Medicare beneficiaries without additional burdensome CED.

ACNM respectfully disagrees with the Proposed Decision Memo’s view that there insufficient evidence to determine that PET amyloid-beta imaging improves meaningful health outcomes in beneficiaries who display signs and symptoms of Alzheimer’s disease (AD). The Proposed Decision Memo also states the evidence is not adequate to conclude that PET Aß results inform the treating physician’s management of the beneficiary to improve meaningful health outcomes. Again, ACNM disagrees with this opinion, especially as it relates to a differential diagnoses and the avoidance of futile treatment or tests. While CMS concluded that “there is sufficient evidence that the use of PET Aß imaging could be promising to exclude Alzheimer’s disease in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD),” they still declined to cover the procedure under these circumstances.

ACNM would like CMS to consider what a meaningful health outcome for a patient with mental cognitive decline is and how it should be better understood. In our view, a patient being taken off medications that are not indicated for their condition is a meaningful health outcome. Additionally, a test to exclude an Alzheimer’s diagnosis is certainly a meaningful health outcome to a patient who has been diagnosed and treated for AD. ACNM strongly disagrees with CMS’s proposal that evidence is insufficient to conclude that the use of PET amyloid-beta imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease and thus is not reasonable and necessary.

CMS’s decision to cover one scan under coverage with evidence development is burdensome and is effectively a non-coverage decision. CMS believes that the best and most accurate diagnosis for AD remains post-mortem which would result in a CED trial linked to autopsy. However, there is a considerable time lapse from the initial amyloid scan to autopsy of patient. In our view, tying CED to autopsy is impractical and delays access to new diagnostic technology.

ACNM is disappointed because we believe amyloid PET imaging is a medical advancement that meets the National Plan to Address Alzheimer’s Disease’s major goal to “Prevent and Effectively Treat Alzheimer’s Disease by 2025.” The proposed decision admits that amyloid PET would provide more accurate diagnosis in the context of clinical drug trials. For that reason, patients not in clinical trials should be allowed a similar advantage of more accurately diagnosing the cause of their illness. While CED has an important role and can be helpful to expand access for “short term” evidence based decisions, it should not be used for studies that are intended to be long term. In our view, long term clinical trials should be left to the academic and clinical research centers.

Alternatively, CMS should consider an approach similar to the information collected on FDG PET for dementia. Prior FDG PET imaging approval by the CMS for dementia evaluation with an appropriate checklist and prior medical workup requirements has been effective. Consequently, we would like to support a similar approach for amyloid PET imaging. We recommend immediate coverage for the three indications of the appropriate use criteria with an enhanced checklist similar to the FDG checklist. Data collected from billing records could then be used to determine the effectiveness of the program applying appropriate use guidelines.

All Medicare eligible patients should have access to a valuable new tool that can assist physicians in better diagnosing patients with cognitive impairment. ACNM recommends CMS reverse its proposed decision memo and cover the three indications of the appropriate use criteria without inappropriate coverage with evidence development. We believe that a beta amyloid scan does lead to better health outcomes for patients, especially in the case of a differential diagnosis which can prevent patients from being subjected to inappropriate medications and costs.

We welcome the opportunity to discuss this important issue further.

Sincerely,

Hossein Jadvar, MD, PhD, MPH, MBA, FACNM
President, ACNM

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

My family and I moved in with [PHI Redacted] when she was diagnosed with this horrofic disease 3 years ago and the days are etched into my heart as I watch [PHI Redacted] slide away from everything she ever knew. [PHI Redacted].
My son sees this in her, and the anguish in me and he is much too young for any of this!
If you have someone you hold dear you best take the time to cherish the moment now, for if you are ever diagnosed with this memory grabbing, wretched disease, you'll forget that person and wonder why they hang around.

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I am the director of Nuclear Medicine at Las Vegas Radiology which is an outpatient imaging facility. Our imaging site works with the local physicians providing health care to some of the underprivilaged communities. We had the privilege to offer amyvid PET scans to some of our patients under a clinical trial. In my opinion which is based on the input I received from the referring physicians, a negative Beta amyloid PET scan has a powerful impact on patient management, most often leading to change in diagnosis and treatment. Not providing coverage would lead to misdiagnosis and unnecessary treatment regimen in a sub group of population. It also causes unnecessary emotional and financial hardship to the patients and their families.

CMS decision to offer this study as a reginally based clinical trial will make it almost impossible for underprivileged communities to offer this test where such resources and infrastructer is lacking. If further evidince is required, I recommend that the coverage be offered undre NOPR. NOPR was very effective in Oncology whcih lead to approval of FDG PET for several malignancies. I request CMS to reconsider their decision not to provide coverage or atleast offer it under NOPR.

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I am a neurologist with sub-speciatly board certification in Behavioral Neurology. I mostly see patients with cognitive disorders. In patients that are rapidly progressive or have other atypical features, the diagnostic question of whether their impairment is related to neurodegenerative pathology versus non-degenerative pathology is a pressing clinical matter, generally more so than defining which neurodegenerative disease a patient has. Autoimmune/paraneoplastic limbic encephalitis is in the differential for a rapid amnestic syndrome - this usually requires lumbar puncture and potentially expensive testing such as paraneoplastic panels and CT imaging of the chest/abdomen/pelvis. Non-invasive imaging to confirm AD may prevent the need for further testing. Coverage for amyloid imaging can therefore be important even in the absence of a clinical trial.

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I am a cognitive neurologist at Beth Israel Deaconess Medical Center and an Assistant Professor of Neurology at Harvard Medical School. I run an active memory disorders group and can attest to how useful amyloid scanning would be in specific circumstances. For instance, patients who develop early onset memory impairment with some degree of behavioral symptoms pose a real challenge. I am often forced to do lumbar punctures to measure CSF Tau/Abeta to help distinguish between frontotemporal dementia and Alzheimer's disease. Amyloid imaging would certainly be less invasive and likely at least as accurate in this distinction. There are a number of other circumstances, as well, where amyloid imaging would be truly helpful. For instance, patients can present with a syndrome called "posterior cortical atrophy" which can be due to either Alzheimer's disease or to cortical basal degeneration. The former would have a positive amyloid scan and the later would not. For patients with these difficult conditions, accurate diagnosis can help with prognosis and treatment. I readily acknowledge that there is a risk of excessive use of this study, for instance in healthy elderly. I favor reasonable restrictions on patients. Having said that, I care for at least a dozen patients where this scan would truly allow me to give a much more accurate diagnosis, a more accurate prognosis, and would likely alter my current treatment.

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July 31, 2013

Louis Jacques, MD,
Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Request for Public Comment for Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

GE Healthcare (GEHC) appreciates this opportunity to comment on the proposed decision memo for Beta Amyloid Positron Emission Tomography (PET) in dementia and neurodegenerative disease which the Centers for Medicare and Medicaid Services (CMS) published on July 3, 2013 (1).

GEHC, a division of General Electric Company, has expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, performance improvement, drug discovery, and biopharmaceuticals manufacturing technologies. Our broad range of products and services enables healthcare providers to offer patients earlier and more accurate diagnosis and treatment of cancer, heart disease, neurological diseases, and other conditions that threaten the quality and length of life. Worldwide, we employ more than 53,000 people committed to serving healthcare professionals and their patients in more than 100 countries.

GEHC is disappointed in the conclusions of the proposed decision, and especially with the proposed requirement of coverage with evidence development (CED). We respectfully disagree with the proposed decision for several reasons:

1. The proposed CED is restrictive and would not address the questions of reasonable and necessary.
2. The proposed endpoints required to demonstrate that beta amyloid imaging is reasonable and necessary are inconsistent with previous CMS statements.
3. The proposed decision does not acknowledge the patients described under the Appropriate Use Criteria as defining a clinically difficult differential diagnosis(2) and appropriate for coverage.
4. CMS’ proposed decision is in conflict with the National Alzheimer’s Plan.

____________________________________

1.The proposed CED is restrictive and would not address the questions of reasonable and necessary.

The proposed decision recommends that studies to be performed as part of CED “must be approved by CMS, involve subjects from appropriate populations, be comparative, prospective and longitudinal, and use randomization and postmortem diagnosis as the endpoint where appropriate.” While GEHC agrees with CMS that appropriate patient populations should be included as part of any clinical study, we are concerned with other requirements. Longitudinal, comparative, randomized studies may not be feasible given the potential harm to patients who may be misdiagnosed. Additionally, these types of studies with post-mortem endpoints would likely be time and resource intensive, thereby limiting access to patients who may benefit from beta amyloid imaging.

Post-mortem examination is referenced as the ‘gold-standard’ for diagnosis of Alzheimer’s Disease (AD). However, post-mortem examination is not the standard of care and is not part of standard clinical practice to confirm a diagnosis of AD or dementia. The Food & Drug Administration (FDA) required that all clinical trials for beta amyloid imaging agents approved or under review provide post-mortem data as the standard of truth to be used in the efficacy analyses (3). Published data on beta amyloid imaging tracers shows high levels of sensitivity and specificity in detecting beta amyloid versus post-mortem pathology examination(4,5).

Although it is within the scope of CMS’ authority to consider whether new healthcare technologies are reasonable and necessary, post-mortem data is not necessary to answer these questions. This is because it will only confirm the diagnosis and not answer questions of impact on patient outcomes. The requirement of this type of data is also inconsistent with previous coverage decisions for similar technologies such as the National Coverage Determination (NCD) for PET FDG for the differential diagnosis of AD and frontal-temporal dementia (FTD) where there is a greater deficiency of evidence, but no additional post-mortem data were required for that coverage determination (6).

GEHC appreciates CMS’ willingness to cover beta amyloid imaging in a research environment. While studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) and similar studies have value from a research perspective, they do not answer questions regarding the potential impact of amyloid imaging in clinical management and clinician decision making. Therefore, we feel post-mortem data is an inappropriate requirement in CED.

2.The proposed endpoints to demonstrate that beta amyloid tracers are reasonable and necessary are inconsistent with previous CMS statements.

In addition to our disagreement with the proposed CED methodology, GEHC also disagrees with the recommended endpoints. The endpoints included in the proposed decision are inconsistent with other CMS guidance and evaluation of diagnostic technologies. While we agree that avoidance of futile treatments or tests may be appropriate health outcomes for a new diagnostic technology, we do not agree with the inclusion of survival and quality of life. CMS has acknowledged that the impact on clinical management is an appropriate endpoint for evaluating coverage of a new diagnostic technology (7). For example, in the NCD for the use of PET FDG in solid tumors, it was noted that the repeal of CED and the positive coverage that resulted was based on the impact of PET FDG on clinical management. In fact, over the course of the multi-year National Oncology PET Registry (NOPR), CMS noted that there were limited data demonstrating an impact on patient outcomes (8). Accordingly, we believe that CMS should be consistent in the endpoints that have been accepted for other diagnostic technologies.

3.CMS does not acknowledge the patients described under the Appropriate Use Criteria as defining a clinically difficult differential diagnosis and appropriate for coverage.

The draft decision recognizes the potential of a negative beta amyloid image to avoid harm of misdiagnosis and inappropriate treatment with AD medications such as memantine and cholinesterase inhibitors. It notes that these therapies have demonstrated efficacy in Dementia with Lewy Bodies (DLB), Huntington’s disease and vascular dementia. This infers that there is no harm in misdiagnosing these conditions. Additionally, differentiating between FTD and AD seems to be the only area where it is believed that treatment could cause harm and where beta amyloid imaging would be of value to patients.

We feel this represents a very limited view of treatment decisions and focuses on the treatment of a single ailment rather than the full patient picture. Although patients with DLB, Huntington’s disease and vascular dementia may not be harmed by side effects of treatment, they could be harmed otherwise by misdiagnosis. In the patient population covered by Medicare, most patients have comorbid conditions that require medication management. Any unnecessary medications may complicate patient management and cause harm. Additionally, failure to identify dementia or AD in patients may exacerbate chronic conditions and increase costs to Medicare and the patients (9).

The proposed decision overlooks other syndromes beside dementia that may present with cognitive impairment as the primary complaint. The AUC as outlined by the Alzheimer’s Association (AA) and Society of Nuclear Medicine and Molecular Imaging (SNMMI) Amyloid Imaging Taskforce (AIT) identifies a narrow group of patients and criteria for use of beta amyloid imaging (10). The AUC specifically recognize that in this narrow patient population, physicians should expect that these results would affect management of patients. In this subset of the patient population with cognitive impairment, there is clinical utility and potential to avoid harm. Therefore, we support coverage of beta amyloid imaging for the patient population meeting the AUC criteria.

4.CMS’ proposed decision is in conflict with the National Alzheimer’s Plan.

The National Alzheimer’s Plan includes several important strategies to accelerate development and use of diagnostics for dementia, including, accelerating the effort to identify early and pre-symptomatic stages of AD (Strategy 1.C) (11); and ensuring timely and accurate diagnosis (Strategy 2.B) (12). The proposed coverage decision fails to recognize the role of beta amyloid imaging and its potential role in the National Alzheimer’s Plan. Moreover, the proposed decision has the potential to prevent access to beta amyloid imaging for those who would benefit (the AUC patient population).

Conclusion

In summary, GEHC is disappointed in the proposed decision that would significantly restrict access to beta amyloid imaging.

Our support for coverage is based on rigorous FDA-approval requirements for PET radiopharmaceuticals and the recent publication of evidence-based neuroimaging guidelines which recommend several clinical scenarios where beta amyloid imaging may be useful in adult patients with cognitive impairment who are being evaluated for AD or other causes of cognitive decline.

CMS should consider broader coverage of beta amyloid imaging in order to be consistent with the National Alzheimer’s Plan’s strategy of ensuring timely and accurate diagnosis. The CED as outlined in the proposed decision is not only unduly burdensome, but also inconsistent with previous CMS coverage decisions and does not appropriately address the questions of reasonable and necessary.

GEHC appreciates the opportunity to submit comments on this important issue. If you have any questions on our comments, please do not hesitate to contact me by email at jane.majcher@ge.com or by phone at (609) 514-6701.

Sincerely,

Jane Majcher
Director, Reimbursement

References

1 Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N), July 3, 2013, available at http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265 (hereinafter “Proposed Decision”).
2 Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force (AIT), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer Association (AA). Alzheimer’s & Dementia. 25 January 2013;1-15.
3 Food and Drug Administration Center for Drug Evaluation and Research, Summary Minutes of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting October 23, 2008.
4 Amyvid Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf.
5 Salloway S, Gamez J, Curtis C et al. “[18F] Flutemetamol PET Imaging: Predictive Values, Sensitivity, and Specificity of Blinded Visual Interpretations” Presented at the 11th International Conference on Alzheimer’s and Parkinson’s Diseases. Florence, Italy. March 6-10, 2013.
6 National Coverage Determination (NCD) for FDG PET for Dementia and Neurodegenerative Diseases (220.6.13), April 3, 2009, http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=288&ncdver=3&bc=AAAAgAAAAAAAAA%3d%3d&.
7 Hillman BJ, Frank RA, Rodriguez GM. New Pathways to Medicare Coverage for Innovative PET Radiopharmaceuticals: Report of a Medical Imaging & Technology Alliance (MITA) Workshop. J Am Coll Radiol 2012;9:108-114.
8 National Coverage Analysis (NCA) for Positron Emission Tomography (FDG) for Solid Tumors (CAG-00181R4), June 11, 2013, http://www.cms.gov/medicare-coverage-database/details/nca-details.aspx?NCAId=263
9 Lin PJ, Fillit HM, Cohen JT, and Neumann PJ. Potentially Avoidable hospitalizations among Medicare beneficiaries with Alzheimer’s Disease and related disorders” Alzheimer’s and Dementia 9 (2013): 30-38.
10 Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force (AIT), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer Association (AA). Alzheimer’s & Dementia. 25 January 2013;1-15.
11 National Plan to Address Alzheimer’s Disease, http://aspe.hhs.gov/daltcp/napa/NatlPlan2013.shtml
12 Ibid

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

I knew something wasn't right with [PHI Redacted] over 10 years ago. We went through expensive testing and he had to sit through hours of psychological testing over the course of several days only to be told he was fine. I knew that wasn't the case; however, it took a couple of years for me to insist on more testing. This time he was diagnosed with mild cognitive impairment.

[PHI Redacted]

Please consider helping those of us who are caregivers. We need the best and most accurate diagnostic tools available. Perhaps I don't want to hear the diagnosis emotionally but realistically I MUST know!!

Thank you.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

PET imaging isn't the same as a CT Scan, it shows different things, it can give a clearer picture, it measures different activities in the brain than CT scans. [PHI Redacted] died of Alzheimers' and it was a long 10 year demise that affected [PHI Redacted] health and our family's well-being. I, my sister, and two brothers live in daily fear of this terrible disease as we age. Please make the best diagnostic tools and most advanced medicine available to understand, slow, and stop the progress of Alzheimers'.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] suffered from dementia the last years of her life. She was not prepared for that event, nor was our family. I'm sure events could have unfolded more smoothly had we more notice and time to prepare. [PHI Redacted] I am concerned that I could go down that path with no preparation and no one to watch out for me. I will be the first person in line for this new testing so that I could remove some of the uncertainty and allow me to adequately prepare for that outcome, should it be the case.

We need to error on the side of quick action to help lessen the events of the future.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] had Dementia. At first one doctor said she had "sundowner's syndrome". The next time it was Dementia. Finally, when pressed by Social Security when I applied to take over handling her SS income (she had become completely irresponsible) they got a FAX from her doctor saying she had Alzheimer's. [PHI Redacted] She would have given up altogether if she would have had to leave her home. She was on Aricep for a few years. If she had been diagnosed sooner she may have had a better life her last few years.

My once very loving, understanding little [PHI Redacted] turned into an angry, cruel person. She could no longer add simple numbers. She hallucinated frequently. About the only thing she didn't do that most with Alzheimer's do is wonder off and get lost.

[PHI Redacted] Early detection by tests could help tremendously. When [PHI Redacted] finally had a major stroke and was taken to the hospital, the ER doctor showed me via computer the tests he did on her brain that showed layers at a time and all the white areas were basically dead. She died that night. I know she was confused most of the time, and she would say inappropriate things to people when away from her house. It was awfully embarrassing. She had few lucid moments, and when she did, she cried. [PHI Redacted]

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] had Alzheimers before she passed away. But figuring that out was was ridiculously hard. I had taken her in to get examined and all that happened was a question and answer session. Afterwards they told us she was fine, just a little confused I think was the word they used. Two weeks later, she burned down her house with candles and killed her two dogs and two cats and almost killed herself trying to get back in to the home. [PHI Redacted] If you have any type of tool that helps in any way, it needs to be out there and available for use to the public. Figuring this out using questions falls way short of a safe way to care for any of us that might be susceptible to these diseases. Thank you for caring.

Scott Rayborne

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted]
She has always been physically active and an amazing teacher. In the past 3 years we have all noticed a decline in her ability to organize, remember events and even has had panic attacts where she could not remember where she was or what she was doing. It is stressful for the whole family, her daughter was in denial for years and the lack of being able to get a diagnosis has been an challenge. She has not been able to hold a decent paying job because of her condition so she needed to go to the State hospital for testing. They drug it out for 2+ years, putting her off, not really trying to find the cause of her memory loss. After much insistance and 2.5 years they did an MRI and came up with a diagnosis of early onset dementia. Earlier detection would have meant earlier treatment. The appalling lack of urgency was and is of great concern.

Please consider addressing this issue.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story: [PHI Redacted] has dementia or alzheimers - we don't know which- but is being treated for the alzheimers since we don't have a firm diagnosis. If there had been a test for him earlier, he could have started on some of the newer alzheimers medication sooner thus delaying the progress of the disease. He is now unable to communicate with us or his caregivers. [PHI Redacted] Thank you for listening to my story.

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The current CMS decision, while presented under the banner of "more clinical trials needed" is at odds with recommendations made by the Amyloid Imaging Task Force, a collaborative effort by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). I am not a member of this task force, but a community-based clinical neurologist who has spent 25 years in a practice focused on dementia patients. Out of the several hundred probable AD patients currently under my care, I have perhaps 12-15 who would meet the Task Force's criteria for florbetapir imaging. They desperately need to have confirmation (as best we can), in vivo, of their underlying pathology. The Task Force's recommendations on whom should be scanned and who should order them are well thought out and reflect current state of practice. Frankly, I suspect fears of unleashing a costly flood of testing during times of cost containment is at least, in part, a motivation behind the CMS decision. If that is the case, consider cumulative saved costs of meds (such as memantine, cholinesterase inhibitors) in patients in whom AD is excluded by florbetapir testing. The Task Force would limit the circumstances for ordering this test and limit ordering to appropriately experienced and trained physicians. Why not keep track of utilization, and reconsider if abused? I am appalled at the CMS decision on this, and frankly, enraged by it, as an advocate for my patients. I have no personal financial gain here... I just abhor lousy public policy decisions. How dare you!!!

Donald S. Marks, M.D.
Board-Certified Neurologist

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story: Alzheimer's medications are still very expensive and probably ineffective for other types of dementia (i.e. Lewy Body, Vascular, etc.). Other studies show that approximately 50% of Alzheimer's diagnoses are incorrect. If there is any interest within the Medicare community to ensure economically effective medical care, this decision should never be implemented.

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This is a response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here are my comments:

Delaying the more definite diagnosis of Alzheimer's versus another condition by requiring more evidence seems odd when Alzheimer's used to only be a tentative diagnosis until after an autopsy is done - AFTER DEATH - like when [PHI Redacted] was tentatively diagnosis in the mid-70's and not definitely diagnosis under her autopsy. is that the type of evidence you want the USA to return to? This test will allow for the appropriate mediation, treatment plan, life planning etc... to be done by the pt, providers and family. Stress is bad knowing for sure the pt's diagnosis is a tremendous stress reliever and has its own health benefits not only for the pt but for the pt's family.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] has attained the age of 100 years...about 6 years ago she began having short-term memory problems....at that time no physician suggested any tests to decide if she had dementia or Alzheimer's. One physician asked her a few questions: who's the president, what year is it, when were you born, etc. and prescribed Alzheimer's medication. As her family we hoped to keep her living alone(which is what she wants, she hates to feel dependent on anyone) because of this medication. After 2 or 3 years, [PHI Redacted] began to complain that she didn't think anything was wrong with her and that she didn't need the medication and went to another physician who didn't ask her anything except one question did you ever receive a diagnosis of Alzheimer's? Her answer was no and he took her off her medication. All of us (friends and family) have seen a decline to the point where carrying on a conversation is difficult because she repeats herself so often, doesn't remember if she ate a meal, doesn't remember what she ate, if she took her pills or not, etc. A test to rule out Alzheimer's would be a Godsend to families who worry about their loved ones,want to see them stay functioning as long as possible, and who live far away like I do (2000 miles away!).

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] primary care physician kept telling her that her first signs of memory loss were a "normal part of aging". I knew better......Normal aging does NOT include calling me several times a day to tell me the EXACT same thing! I argued with this doctor and other members of my family who were in denial about this for YEARS before she was finally referred to a neurologist for testing. They did a 3-hour neuropsych test and claimed she had MCI. I couldn't believe they only diagnosed it as MCI! This woman couldn't remember what what said 5 minutes ago and repeated herself constantly. But at least at that point, I had some grounds to get her on Aricept. Over the next year and a half she got to the point where she couldn't live on her own anymore so I had to move her from her house in the middle of the WOODS IN MASSACUSETTS to a senior living community. NOONE ALONG THE WAY THOUGHT TO TEST FOR LYME DISEASE even though she lived in a remote location in the woods and walked her dogs twice a day, rain or shine. Long story short, I finally insisted when she moved to NY that the neurologist test her for Lyme disease. It came back negative. But, if you know about Lyme disease you know that the lab test is INSUFFICIENT to diagnose Lyme disease especially in the late stagees of the disease. It had been YEARS since symptoms first appeared. Lyme disease researcher Alan MacDonald diagnosed the Lyme disease bacteria in 7 out of 10 brains he recieved from the Alzheimer's Brain Bank! I believe that HUNDREDS OF THOUSANDS OF cases of Alzheimer's disease are being MISDIAGNOSED and this is only ONE of the ways! Untold numbers of people are suffering and dying when they could be treated because accurate tests are not available to the average doctor. WE NEED TO BE ABLE TO ACCURATELY DIAGNOSE ALZHEIMER"S AND LYME DISEASE. With Lyme disease being the fastest growing vector-borne disease in the U.S., THIS PROBLEM IS ONLY GOING TO GET WORSE UNLESS WE HAVE ACCURATE TEST METHODS FOR BOTH DISEASES. If Medicare wants to CUT COSTS, THEY NEED TO SUPPORT ACCURATE TESTING FOR A VARIETY OF DISEASES, NOT THE LEAST OF WHICH IS ALZHEIMER"S.

Sincerely,
Amy Duffield
847-462-1802

P.S. The Infectious Diseases Society of America needs to be PART OF THE SOLUTION, NOT PART OF THE PROBLEM as is currently the case!

Amy Duffield

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I am writing to urge the Centers for Medicare and Medicaid not to delay in coering the cost of the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease. [PHI Redacted] suffered from progressive dementia for over 12 years. Her doctors could not tell us if the dementia was caused by Alzheimer's disease or another form of neurodegenerative disease. With new research and discovery in the causes of dementia, I believe it is important to diagnose and properly treat persons with Alzheimer's disease. With early detection of Alzheimer's, science can move forward in new research for neurodegenerative diseases.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story: [PHI Redacted], a genius and a very talented artist, was gripped by Alzheimer's disease a full ten years before it finally took his life. It's a horribly demeaning disease, and deflates the patient's entire family. [PHI Redacted] and my family would have been better equipped to deal with his disease if only a PET scan had been available to us as a diagnostic tool. It seems inconceivable that this wouldn't be less expensive than the ten years of care that Medicare and Medicaid ultimately paid for on his behalf. It's also inconceivable to me that everyone, including those in the decision-making process at Medicare, knows at least one person who is battling this brutal disease and yet fails to make PET scans available. If a cure isn't found soon for Alzheimer's, then the incidence of it will increase exponentially - and when it includes you or your family, this diagnostic tool won't be available. To me, this is a travesty. Pleaser make the RIGHT decision as regards PET imaging, and make this crucially valuable tool available to the broad spectrum of patients. Thank you for your attention.

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First I watched [PHI Redacted] die of Alzheimer's. Then [PHI Redacted]. Then an [PHI Redacted]. When I began going to the doctor with [PHI Redacted], they would not say the words "Alzheimer's" but they would prescribe drugs to combat it. [PHI Redacted] thought the doctors were crazy and refused to take the drugs. I was [PHI Redacted] caregiver for 8 years before she died of Alzheimer's. I have a cousin with it now. I have a [PHI Redacted] with early onset Alzheimer's who will not live out this year. She is 58. I am 57. If we only KNEW early enough of an Alzheimer's diagnosis - we could be treated aggressively and early - thereby giving us more "good" years and perhaps even being less of a burden on society. I went through [PHI Redacted] life savings in 4 years for her care. How many others are unable to contribute to society - or need financial assistance from the government? Combatting this disease early is a key to keeping this disease from both impoverishing families and this nation. Early PET scans can be the key to early diagnosis. We need this!

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

The side-effects of drugs to treat [PHI Redacted] cognitive condition are devastating and enough to make one not want to live any longer just because of how unpleasant it is everyday. If the illness she is suffering from is not Alzheimers, and she would not have to take medications as damaging as the disease, then [PHI Redacted] life, and all the people who care for her, would be immeasurably improved. Please consider adding this option to Medicare so that people who do not need these medications do not take them. Thank, Chris Lura

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As current Past-President of the Center for Molecular Imaging Innovation and Translation of the SNMMI and a molecular imaging researcher, I am very concerned regarding the decision by CMS to restrict the use use of florbetapir for positron emission tomography imaging of Alzheimer's disease (AD). Florbetapir has been FDA approved and shown in several clinical trials to validate the presence of beta amyloid plaques, allowing for the appropriate diagnosis and treatment options for patients with this devastating disease. As a researcher, I am extremely concerned that this decision by CMS will stifle innovation and research into the design and development of effective, state-of-the-art molecular imaging agents that have the potential to provide a highly specific diagnosis for patients with diseases such as cancer, cardiovascular disease and neurological disorders. Molecular imaging is a powerful tool that can provide an early diagnosis, assist with drug discovery and clinical trials into evaluating the effectiveness of new drugs, as well as determining the correct patient population for a specific drug. Molecular imaging probes such as florbetapir can save lives and precious resources by making sure that AD drugs are given to patients who will benefit most from them. I respect CMS' careful review of florbetapir, but respectfully request that they reconsider their decision, based on the data that led to the FDA approval of this molecular imaging agent.

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I am writing in supprt of making diagnostic testing available quickly to families that may have members with Alzheimer's.

[PHI Redacted] had Alzheimer's. For the first years, her friends and family thought she was a secret alcoholic. She got a lot of criticism from all of us, instead of getting support in helping her deal with her disease.

Prior to that, [PHI Redacted] also had Alzheimer's. This took a long time to diagnose as it was thought he was just combative and "ornery." It turns out, he was very upset that things just didn't make sense to him as his short-term memory was fading.

Please make bring new breakthroughs in diagnostic testing to the market ASAP so we can have accurate diagnoses and take appropriate, rather than well-intended but erroneous, actions.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] Medicare needs to cover this procedure. It is beyond the means of most individuals, isn't covered by most private insurance for diagnosis of Alzheimer's, yet is a valuable tool for diagnosis.

Read the statistics on the number of people who will have Alzheimer's in the US in 20 years. Without a major breakthrough, we will be in real trouble. But for those diagnosed, an early and accurate diagnosis means early access to proper treatment. Lack of that means death: [PHI Redacted], 12 years my senior, began to exhibit signs of dementia at the age of 51, just a few years before [PHI Redacted]. Lacking financial resources, and having insufficient medical coverage, she and her husband had a very difficult time getting a correct diagnosis. She had a delay of more than two years before getting her diagnosis, and for those two years, she received no medication that could have slowed the progress of the disease. As a result, it advanced rapidly. Within ten years, [PHI Redacted], formerly a vibrant, fun-loving mother of three, was dead. Her grandchildren remember "Grandma [PHI Redacted]" only as the woman in the nursing home who could no longer speak due to aphasia, and who cried when they left, trying to hold on to them.

[PHI Redacted], being so much younger than [PHI Redacted], was more like my big sister, and we more or less grew up together, living in the same home until [PHI Redacted] married. As I grew up and reached adulthood, [PHI Redacted] was not only my "big sister" but one of my closest friends. We had a special bond that nothing has been able to replace.

How many [PHI Redacted] have to die because they can't afford the tests necessary for an accurate diagnosis? If [PHI Redacted] had had access, she might well be alive today. [PHI Redacted]

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

[PHI Redacted] was diagnosed with Alzheimer's several years ago. He went from being the vice president of the 2nd largest meat packing company in the US to picking up leaves in the yard. [PHI Redacted] is 100% his care provider as he is still living at home, but the daily work and stress is taking it's toll.

I've often read that most all cancers can be cured if caught early. In fact,[PHI Redacted] is a 2 time breast cancer survivor and [PHI Redacted] survived prostate cancer in his late 50s, and they have been cancer free ever since. I believe that the only reason [PHI Redacted] beat cancer was because they had early detection of their respective cancers. Neither of them had to undergo any chemo-therapy, but rather just surgery to treat their cancers.

I bring up the early detection of cancer and the success of early treatment, because I believe strongly in early treatment of disorders & diseases as being a successful strategy. Although there is no cure for Alzheimer's, I believe that early detection of the disease would go a long way to ease the suffering of Alzheimer's patients & families, and eventually lead to early treatments, which would hopefully lead to cures, similar to cancer.

Alzheimer's is a viscous disease that decimates families, and effective detection and treatments are sorely lacking.

Nobody who has not been, or is not currently experiencing a family member with Alzheimer's disease would have any idea of the devastating effect of the disease on the patient as well as the family members. The people making this decision apparently have not experienced a close family member diagnosed with Alzheimer's disease, otherwise I would not have to write this letter.

Sincerely,

Todd Kofford

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

Both [PHI Redacted] suffer/ed from dementia related diseases. We still aren't sure that [PHI Redacted] had Alzheimer's; [PHI Redacted] has never been formally diagnosed, other than with dementia. The proper test could have helped get them the proper medications to help with their quality of life. [PHI Redacted] Please allow this test so that others don't have to suffer needlessly, and can instead get the proper care for their disease.

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I understand Medicare is declining to offer coverage for an FDA approved PET imaging technique that could potentially help seniors with Mild Cognitive Impairment. I am distressed about this as many people with MCI can get help faster if they were properly diagnosed which would 1. Improve the quality of life for those affected and 2. Lessen the cost for families, insurance, state insurance in the long run if proper diagnosis and treatment were determined earlier. Please make sure that medicare offers this important option for diagnostic purposes. Thank you.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story:

I am a Dementia Care Giver Survivor. [PHI Redacted] was diagnosed with Parkinson's with diffused Lewy bodies. Her dementia was frightening and extremely difficult to deal with. My entire family is shattered from [PHI Redacted] illness.

[PHI Redacted] passed on Valentine's Day this year. She had a tough 5 years. We all did.

Today, we are picking up the pieces and making the best of everything. I wish we could have had an earlier diagnosis. [PHI Redacted] was misdiagnosed with having Alzheimer's when she had a different form of dementia. More research on alternative solutions needs to be funded.

Please do something to help others from having to suffer the deep losses my family and I have experienced. It doesn't have to be the way it is today. Please. Help.

Warmly,

Susan Higgins

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I am a clinical neuroradiologist and Alzheimer's disease (AD) researcher. The ability to perform Amyvid scans in the setting of complex dementia would offer an important improvement in the care of my patients. I am dismayed that the current CMS proposal will limit the use of this test to my patients who are wealthy or those who are willing to join particular clinical trials. In my clinical practice, I receive daily consultations for the workup of patients with complex dementias. Sadly, the MRI findings of neurodenerative diseases in the both the early and late stages are not specific for definitive diagnosis in most cases. When considering a diagnosis of AD versus normal pressure hydrocephalus, for example, we have many patients who could potentially be spared an invasive and expensive neurosurgical procedure (shunting)if the diagnosis of AD could be ascertained non-invasively. Conversely, many of us have personal experiences with relatives or patients who were inappropriatly placed in independent senior apartments when early AD was misdiagnosed as delirium -- resulting in kitchen injuries, wandering, etc -- all of which cost the medical system and caregivers time and money. I fully support the Appropriate Use Criteria for amyloid PET developed by the Society for Nuclear Medicine and Molecular Imaging the Alzheimer's Association, and the statements from the American Society for Neuroradiology. As we move forwards with national health care coverage, let us not step backwards in the work for improved opportunities for care of our senior citizens.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is.

My very close relative is suffering. Her dementia is worsening and I am slowly loosing her. Amyloid PET imaging would have helped us very much. The Alzheimer medications on the market have failed to keep her dememtia stable. She takes Aricept and Namenda and yet we continue to see her worsening. The first thing when she started down the path of diagnosis that would have helped us know we were treating the correct disease would have been a diagonistic test. I have heard of various tests, but none are available to her on Merdicare. We need this test and I believe even as she worsens she could still benifit from this.

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I am writing in response to your proposed decision to require more evidence development before you make PET imaging available to people who may have Alzheimer's. This is the wrong decision. The FDA has approved this technology. People who face a diagnosis of Alzheimer's deserve to have it brought to their care. I want to tell you how difficult this is here is my story: [PHI Redacted] was a smart, energetic nurse practitioner, one of the first in the state of Massachusetts. In her late 50s she began to behave strangely, repeating herself, forgetting things, becoming a little paranoid. Frightened by the prospect of Alzheimers Disease she wanted nothing more than to deny there was anything wrong. We, however, wanted to fight this disease aggressively. This entailed hour long drives into the convoluted maze of Boston streets, parking fees, MRIs, memory tests, blood draws and questionnaires - only to be repeated again in 6 months or a year. And our answer? [PHI Redacted] MAY have Alzheimers - since there was nothing else they could find. The theory today is the drugs we have may need to be started at a much earlier stage in order to produce any benefit. Delaying diagnosis will do nothing but hurt the patient and ultimately cost so much more, both in emotional pain and real dollars. It is expensive to care for someone who can no longer dress themselves, go to the bathroom unassisted or be trusted not to wander. [PHI Redacted]

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July 31, 2013

Joseph Hutter, MD, MA
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Hutter:

As a board certified Radiologist with Lake Medical Imaging, which serves a patient base comprised primarily of Medicare patients, I have extensive experience with PET for cancer imaging and for assisting in the differential diagnosis of dementia. I am writing to ask you to support the request that CMS revise Section 220.6 of the National Coverage Determination (NCD) Manual and potentially cover PET tracers that image beta-amyloid plaques in the context of the diagnosis of dementia and neurodegenerative disease.

As you are aware, CMS provided coverage in 2004 for FDG PET to aid in the distinction of Alzheimer’s disease (AD) versus frontotemporal dementia (FTD). This positive decision did not result in large numbers of patients being referred for FDG PET scans of the brain, but is selectively applied in challenging cases. In not all cases of known or suspected dementia, however, are FDG PET plus other imaging and clinical exams definitive for a diagnosis.

An unclear diagnosis may lead to unnecessary or invasive tests (including cerebral angiography, brain biopsy, etc.) which can be considerably more risky than PET scans; it can also hamper decisions on management and prognosis.

Furthermore, there are several clinical scenarios in which a more definitive neuroimaging tool would clarify the diagnosis:

1. AD features, both typical and atypical, are present, including the focal cortical syndromes of primary progressive aphasia, corticobasal syndrome and posterior cortical atrophy
2. Differentiating AD vs FTD when FDG-PET is inconclusive
3. Early onset dementia with no family history and/or no mutation found
4. Early onset dementia and the patient is still working in some capacity so that objective documentation of AD would provide the proof needed to initiate disability
5. Dementia with positive autoantibodies, and the differential diagnosis includes AD vs an autoimmune encephalopathy
6. Dementia with enlarged ventricles, and the differential diagnosis includes AD vs NPH

These clinical problems would be better addressed with a beta amyloid PET agent than with FDG PET, or as a complement to FDG PET.

In general, FDA approved amyloid imaging agents have gray matter tracer uptake proportional to the beta amyloid burden in the gray matter. A negative beta amyloid PET scan read by expert trained physicians has high negative predictive value for amyloid deposition in the gray matter and for the intermediate term development of Alzheimer’s Disease. Positive scans support amyloid deposition. Such information is clinically useful in key decision making processes, especially when patients need to determine whether to continue to work or to make other life plans.

On April 6, 2012 the Food and Drug Administration (FDA) approved Florbetapir (Amyvid) for PET imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. We use this test clinically and have used it in research. It is a powerful test. Unfortunately, current CMS rules prohibit Medicare reimbursement for the test. Medicare beneficiaries should have access to this test. Much as our experience with FDG PET, it is improbable the scan will be overused.

Consideration of a registry as was done for FDG PET in oncology indications might also provide data for CMS regarding how this scan is utilized in broader practice settings if concerns regarding broad coverage remain, despite the unequivocal biological data supporting the mechanism of tracer uptake and the biology visualized. I believe that access to beta amyloid PET imaging is very important, and I hope that my comments and those of my colleagues will help CMS reconsider its decision.

Sincerely,

Manoj Bhatia, MD
Lake Medical Imaging & Vascular Institute

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July 31, 2013

Joseph Hutter, MD, MA
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Hutter:

I am writing to ask you to support the request that CMS revise Section 220.6 of the National Coverage Determination (NCD) Manual and potentially cover PET tracers that image beta-amyloid plaques in the context of the diagnosis of dementia and neurodegenerative disease.

As a board certified Radiologist with Lake Medical Imaging, which serves a patient base comprised primarily of Medicare patients, I have extensive experience with PET for cancer imaging and for assisting in the differential diagnosis of dementia. As you are aware, CMS provided coverage in 2004 for FDG PET to aid in the distinction of Alzheimer's disease (AD) versus frontotemporal dementia (FTD). This positive decision did not result in large numbers of patients being referred for FDG PET scans of the brain, but is selectively applied in challenging cases. In not all cases of known or suspected dementia, however, are FDG PET plus other imaging and clinical exams definitive for a diagnosis.

An unclear diagnosis may lead to unnecessary or invasive tests (including cerebral angiography, brain biopsy, etc.) which can be considerably more risky than PET scans; it can also hamper decisions on management and prognosis.

Furthermore, there are several clinical scenarios in which a more definitive neuroimaging tool would clarify the diagnosis:

• AD features, both typical and atypical, are present, including the focal cortical syndromes of primary progressive aphasia, corticobasal syndrome and posterior cortical atrophy
• Differentiating AD vs FTD when FDG-PET is inconclusive
• Early onset dementia with no family history and/or no mutation found
• Early onset dementia and the patient is still working in some capacity so that objective documentation of AD would provide the proof needed to initiate disability
• Dementia with positive autoantibodies, and the differential diagnosis includes AD vs an autoimmune encephalopathy
• Dementia with enlarged ventricles, and the differential diagnosis includes AD vs NPH

These clinical problems would be better addressed with a beta amyloid PET agent than with FDG PET, or as a complement to FDG PET.

In general, FDA approved amyloid imaging agents have gray matter tracer uptake proportional to the beta amyloid burden in the gray matter. A negative beta amyloid PET scan read by expert trained physicians has high negative predictive value for amyloid deposition in the gray matter and for the intermediate term development of Alzheimer's Disease. Positive scans support amyloid deposition. Such information is clinically useful in key decision making processes, especially when patients need to determine whether to continue to work or to make other life plans.

On April 6, 2012 the Food and Drug Administration (FDA) approved Florbetapir (Amyvid) for PET imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline. We use this test clinically and have used it in research. It is a powerful test. Unfortunately, current CMS rules prohibit Medicare reimbursement for the test. Medicare beneficiaries should have access to this test. Much as our experience with FDG PET, it is improbable the scan will be overused.

Consideration of a registry as was done for FDG PET in oncology indications might also provide data for CMS regarding how this scan is utilized in broader practice settings if concerns regarding broad coverage remain, despite the unequivocal biological data supporting the mechanism of tracer uptake and the biology visualized. I believe that access to beta amyloid PET imaging is very important, and I hope that my comments and those of my colleagues will help CMS reconsider its decision.

Sincerely,

George E. Kainz, MD
Lake Medical Imaging & Vascular Institute

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July 31, 2013

Joseph Hutter, MD, MA
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Hutter:

As a board certified Radiologist with Lake Medical Imaging, which serves a patient base predominantly comprised of Medicare patients, I am writing to ask you to support the request that CMS revise Section 220.6 of the National Coverage Determination (NCD) Manual and potentially cover PET tracers that image beta-amyloid plaques in the context of the diagnosis of dementia and neurodegenerative disease.

As you are aware, CMS provided coverage in 2004 for FDG PET to aid in the distinction of Alzheimer's disease (AD) versus frontotemporal dementia (FTD). This positive decision did not result in large numbers of patients being referred for FDG PET scans of the brain, but is selectively applied in challenging cases. In not all cases of known or suspected dementia, however, are FDG PET plus other imaging and clinical exams definitive for a diagnosis.

An unclear diagnosis may lead to unnecessary or invasive tests (including cerebral angiography, brain biopsy, etc.) which can be considerably more risky than PET scans; it can also hamper decisions on management and prognosis.

Furthermore, there are several clinical scenarios in which a more definitive neuroimaging tool would clarify the diagnosis:

• AD features, both typical and atypical, are present, including the focal cortical syndromes of primary progressive aphasia, corticobasal syndrome and posterior cortical atrophy
• Differentiating AD vs FTD when FDG-PET is inconclusive
• Early onset dementia with no family history and/or no mutation found
• Early onset dementia and the patient is still working in some capacity so that objective documentation of AD would provide the proof needed to initiate disability
• Dementia with positive autoantibodies, and the differential diagnosis includes AD vs an autoimmune encephalopathy
• Dementia with enlarged ventricles, and the differential diagnosis includes AD vs NPH

These clinical problems would be better addressed with a beta amyloid PET agent than with FDG PET, or as a complement to FDG PET.

In general, FDA approved amyloid imaging agents have gray matter tracer uptake proportional to the beta amyloid burden in the gray matter. A negative beta amyloid PET scan read by expert trained physicians has high negative predictive value for amyloid deposition in the gray matter and for the intermediate term development of Alzheimer's Disease. Positive scans support amyloid deposition. Such information is clinically useful in key decision making processes, especially when patients need to determine whether to continue to work or to make other life plans.

On April 6, 2012 the Food and Drug Administration (FDA) approved Florbetapir (Amyvid) for PET imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline. We use this test clinically and have used it in research. It is a powerful test. Unfortunately, current CMS rules prohibit Medicare reimbursement for the test. Medicare beneficiaries should have access to this test. Much as our experience with FDG PET, it is improbable the scan will be overused.

Consideration of a registry as was done for FDG PET in oncology indications might also provide data for CMS regarding how this scan is utilized in broader practice settings if concerns regarding broad coverage remain, despite the unequivocal biological data supporting the mechanism of tracer uptake and the biology visualized. I believe that access to beta amyloid PET imaging is very important, and I hope that my comments and those of my colleagues will help CMS reconsider its decision.

Sincerely,

Cathrine E. Keller, MD
Lake Medical Imaging & Vascular Institute

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July 30, 2013

Joseph Hutter, MD, MA
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Hutter:

I am writing to ask you to support the request that CMS revise Section 220.6 of the National Coverage Detennination (NCD) Manual and potentially cover PET tracers that image beta-amyloid plaques in the context of the diagnosis of dementia and neurodegenerative disease.

As a board certified Radiologist with Lake Medical Imaging & Vascular Institute, which encompasses four large outpatient imaging centers in Florida serving a patient base predominantly comprised of Medicare patients, I have extensive experience with PET imaging for cancer imaging and for assisting in the differential diagnosis of dementia. As you are aware, CMS provided coverage in 2004 for FOG PET to aid in the distinction of Alzheimer's disease (AD) versus frontotemporal dementia (FTD). This positive decision did not result in large numbers of patients being referred for FDG PET scans of the brain, but is selectively applied in challenging cases. In not all cases of known or suspected dementia, however, are FDG PET plus other imaging and clinical exams definitive for a diagnosis:

An unclear diagnosis may lead to unnecessary or invasive tests (including cerebral angiography, brain biopsy, etc.) which can be considerably more risky than PET scans; it can also hamper decisions on management and prognosis.

Furthermore, there are several clinical scenarios in which a more definitve neuroimaging tool would clarify the diagnosis:

• AD features, both typical and atypical, are present, including the focal cortical syndromes of primary progressive aphasia, corticobasal syndrome and posterior cortical atrophy
• Differentiating AD vs FTD when FOG-PET is inconclusive
• Early onset dementia with no family history and/or no mutation found
• Early onset dementia and the patient is still working in some capacity so that objective documentation of AD would provide the proof needed to initiate disability
• Dementia with positive autoantibodies, and the differential diagnosis includes AD vs an autoimmune encephalopathy
• Dementia w/enlarged ventricles, and the differential diagnosis includes AD vs NPH

These clinical problems would be better addressed with a beta amyloid PET agent than with FDG PET, or as a complement to FDG PET.

In general, FDA approved amyloid imaging agents have gray matter tracer uptake proportional to the beta amyloid burden in the gray matter. A negative beta amyloid PET scan read by expert trained physicians has high negative predictive value for amyloid deposition in the gray matter and for the intermediate term development of Alzheimer's Disease. Positive scans support amyloid deposition. Suchinformationn is clinically useful in key decision making processes, especially when patients need to determine whether to continue to work or to make other life plans.

On April 6, 2012 the Food and Drug Administration (FDA) approved Florbetapir (Amyvid) for PET imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline. We use this test clinically and have used it in research. It is a powerful test. Unfortunately, current CMS rules prohibit Medicare reimbursement for the test. Medicare beneficiaries should have access to this test. Much as our experience with FDG PET, it is improbable the scan will be overused.

Consideration of a registry as was done for FDG PET in oncology indications might also provide data for CMS regarding how this scan is utilized in broader practice settings if concerns regarding broad coverage remain, despite the unequivocal biological datasupportingg the mechanism of tracer uptake and the biology visualized.

Sincerely,

Romil Y. Patel, MD
Lake Medical Imaging & Vascular Institute

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As several comments posted here have implied or asserted that Amyvid (florbetapir) and other amyloid imaging radiotracers have diagnostic specificity that can be used to assess whether a patient's cognitive symptoms are due to Alzheimer's disease, it is worthwhile to examine what the peer-reviewed published literature actually has reported concerning this assertion.

It turns out despite explicit statements made in this forum claiming that amyloid imaging "can provide sensitive and specific information concerning whether or not a patient’s memory problems, cognitive decline, or dementia is due to Alzheimer’s disease(AD)," and that, "we finally have a method which is sensitive and specific" that there is not a single peer-reviewed published study of original research demonstrating that florbetapir has clinical diagnostic specificity... as indicated by a PubMed search current as of this morning (July 31, 2013). And this actually should not be considered surprising, since even the manufacturer/distributor of Amyvid has made it clear in its own literature accompanying their product that (regardless of apparently high biochemical specificity, as well as clearly high sensitivity, both reported to be >90%) diagnostic specificity for AD is entirely lacking... such that a positive scan can occur in a patient whose cognitive impairment is due to AD, or in a patient whose cognitive impairment is due to a neurodegenerative disease other than AD, or in a patient whose cognitive impairment is not due to any neurodegerative disease at all (really, is there any statement from any manufacturer that could possibly make it any clearer, that this is a tracer for which clinical specificity for AD is lacking? What actually might be considered surprising, is that very knowledgeable people would make implications about specificity to the contrary, not only in the absence of evidence for clinical diagnostic specificity since, after all, it could be argued that absence of evidence is not the same thing as evidence of absence but even in light of compelling evidence that has demonstrated that this radiotracer simply lacks clinical specificity.)

By the way, there is one paper that the PubMed search this morning retrieved that probably should be specifically mentioned here, since the unfortunate sensitivity/specificity terminology that it employed may otherwise create some confusion. Last year, a study published by Newberg et al. ("Initial clinical comparison of 18F-florbetapir and 18F-FDG PET in patients with Alzheimer disease and controls," J. Nucl. Med., 2012;53:902-907) found (again unsurprisingly, given the prior literature on this subject) that PET with FDG was a much better quantitative biomarker of cognitive dysfunction in AD patients (r=0.90, p < 0.0001; text on page 904, and Figure 3, panel B... incidentally, please note that these numbers were mis-stated in the paper's own abstract) than was florbetapir (r=0.26, p=0.34; text on page 904 and Figure 3, panel D... and numbers for florbetapir were also mis-stated in the paper's own abstract as r=0.12, p=0.66). The part of the paper that could cause confusion is that the authors talked about a "specificity" for florbetapir of 95% (i.e., amyloid-negative studies in 20 of 21 subjects who were not clinically diagnosed with AD) and a "specificity" for FDG of 86% (18 of 21). However, it is critically important to note that the values for neither "sensitivity" nor "specificity" reported in this paper were actual diagnostic sensitivity or specificity values, as no diagnostic gold standard was available for this study, but rather only dichotimization of subjects clinically suspected of either having AD, or of meeting criteria as controls. Thus, what the "sensitivity" and "specificity" terminology actually refers to in this paper is simply clinical concordance of imaging i.e., concordance with the clinical suspicion of AD vs. the clinical criteria for controls, respectively as no measure of diagnostic accuracy was possible. Moreover, what the results that these authors found actually demonstrate was that amyloid imaging with florbetapir has virtually no incremental diagnostic value above a competent clinical evaluation alone (which according to the revised "appropriate use" criteria, all imaged patients should get first anyways), since the florbetapir test results and the clinical abel were concordant in 95% of cases (...while, in contrast, the authors found that FDG had an incremental diagnostic value beyond clinical evaluation of up to 12.5%.)

The essence of the florbetapir specificity problem can be succinctly viewed as follows: the older a patient gets, the more false positives that the amyloid imaging test will yield due to the increasing likelihood that an amyloid imaging test will be positive even among patients who are clinically unaffected by Alzheimer's disease. On the other hand, the younger a patient is, the more false positives that the amyloid imaging test will yield due to the increasing likelihood that the patient's problem is caused by a cognitively impairing process other than AD. This begs the question of how narrow is the window of age in which reasonable clinical diagnostic specificity and positive predictive value for amyloid imaging could be expected even under the best performance circumstances (if such a window exists at all)?

Finally, it may be worth briefly considering what other tests besides florbetapir imaging are available that are capable of yielding very high diagnostic sensitivity in the face of low (to absent) specificity? One easy way such a test profile can be achieved, is by flipping a two-headed coin, i.e., one upon which "AD" is imprinted on both sides. Alternatively, if a more quantitative test is desired, one can roll a pair of dice, and define any sum of the values of the dice greater than or equal to 4 as indicative of the diagnosis of AD (a "test" that would have a sensitivity of 92% and a specificity of 8%). There are likely many imaging facilities that would be willing to flip a two-headed coin for considerably less reimbursement than the billing charges of "$3000-$10,000" that have been estimated for amyloid imaging (or patients and their families could simply be prescribed two-headed coins, and then flip them by themselves in the comfort and privacy of their own homes… especially since the interobserver concordance and reproducibility of test results from two-headed coins is known to be very high) and, of course, it was already long ago established that the manufacturer/distributor of Amyvid is more than willing to "roll the dice" from the time they acquired the company that held patent rights to florbetapir for $300 million, even in the context of an evidentiary situation that the SNMMI and the Alzheimer's Association joint Taskforce has summarized by concluding, "direct evidence linking amyloid PET to health outcomes is currently lacking." And this is, after all, a good thing, as we certainly need great risk-takers in society, to propel forward scientific and commercial progress... we just don't need them in the Medicare office charged with deciding whether American taxpayers should be compelled to pay for other people's elective procedures of unproven clinical benefit... especially without the concomitant collection of evidence that would enable a more informed decision to be made about this at some future point in time.

Dan Silverman, MD, PhD
Head, Neuronuclear Imaging Section
Ahmanson Translational Imaging Division
Professor, Department of Molecular and Medical Pharmacology
Executive Committee, UCLA Alzheimer's Disease Research Center
David Geffen School of Medicine, University of California, Los Angeles

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As a 20-year, non-medical,provider of assisted living care to many hundreds of seniors with both diagnosed and undiagnosed forms of dementia, and as one who lost [PHI Redacted] to Alzheimer's disease, I am writing to urge your most thorough reconsideration of the draft CMS decision to withhold Medicare coverage for florbetapir F18 PET in dementia and other neurodegenerative diseases.

The waste and tragedy of dementia is compounded by the failure to diagnose it, even for individuals with early-stage Mild Cognitive Impairment (MCI); and it is commonly mis-diagnosed at later stages of the disease's progression. The poverty of diagnostic tools to ascertain the most fundamental distinctions in the forms and root causes of dementias suffered by INDIVIDUAL Americans is striking to me and all of my non-medical colleagues in the Alzheimer's care community nationally. Absent a serious diagnostic tool, there is little likelihood of a confident physician diagnosis, and absent a diagnosis there is little likelhood of any treatment program being offered to the average dementia sufferer (or often-times their greater-suffering families). It is worth noting, and my experience is typical in the field, that of the hundreds of dementia victims who come to reside in our Compass Memory Support assisted living communities annually - nearly all of whom have been seen by a PCP and some by neurological specialists - almost none have ever received any advice as to the possibility of a treatment program related to any particular form or diagonsis of their dementia. Surely, this cannot be acceptable as a current condition or for our future.

I do not know much about the technical aspects of amyloid imaging techniques, but I do know that the FDA has approved this particular tool for patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline, and in the absence of a better coverage option available to the Centers for Mediare and medicaid Services RIGHT NOW, I urge you in the strongest possible terms to reverse the position adopted in the Decision Memo and take the first step to reverse as well the dearth of diagnostic muscle available to help individuals and families who are trying to find a path toward the treatment of MCI and Alzheimer's disease.

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Louis Jacques, M.D.
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

Thank you for the opportunity to comment on the Center for Medicare & Medicaid Services (CMS) draft determination coverage of positron emission tomography (PET) amyloid-beta (Aß) imaging for individuals with dementia or neurodegenerative disease. We are the Alzheimer’s Association’s National Early-Stage Advisory Group, a cohort of individuals from across the United States living in the early stage of Alzheimer’s disease and other dementias. As advisors, we are leaders and spokespeople for the Alzheimer’s Association and the cause. We provide guidance on appropriate programs for people living with early-stage Alzheimer’s, raise awareness about early-stage issues and advocate with legislators to ensure a strong, accountable National Alzheimer’s Plan supported by the resources necessary to change the trajectory of the disease. Our members have presented at Social Security Administration (SSA) hearings to include younger-onset Alzheimer’s disease in the SSA’s Compassionate Allowances Initiative, and currently two alumni advisors sit on the Food and Drug Administration’s (FDA) Patient Representative Program.

We strongly urge CMS to reconsider the draft determination of Coverage with Evidence Development, which would limit access to this important diagnostic tool. As individuals living with early stage Alzheimer’s, we understand first-hand the value of an early and accurate diagnosis. For many of us, obtaining the diagnosis was a long, costly and emotionally exhausting process; one filled with stress, anxiety and a feeling of helplessness.

We are disappointed that CMS would limit access to the PET Aß imaging test within the specific populations identified by the Amyloid Imaging Taskforce convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). While this test cannot definitely determine if an individual has Alzheimer’s disease, it can definitely rule it out. For individuals like us whose clinical presentations are not clearly diagnosable as Alzheimer’s disease or are otherwise atypical, this test provides valuable information to our physicians.

An early and more definitive diagnosis has allowed us to move forward and begin taking the steps necessary to prepare ourselves and our families for the future. This includes working with physicians to consider the most appropriate medical and non-medical treatments and supports, participating in clinical trials and creating a care plan to better manage medications and other conditions.

Additionally, we have been able to make financial and long-term plans and benefit from resources available to us such as Social Security Disability Insurance. Because of the disease progression an individual’s ability to participate in these important decisions may be impacted by the delay that would occur in obtaining an accurate diagnosis.

Perhaps the greatest benefits from this test, however, will be for those who can rule out a diagnosis of Alzheimer’s. Test results that rule out Alzheimer’s will prompt physicians to examine other causes of cognitive impairment, some of which can be reversed when recognized and appropriately treated. Furthermore, individuals with Frontotemporal Dementia, which mimics Alzheimer’s disease, do worse on Alzheimer’s medications indicating the value of this test.

An early and accurate diagnosis is a tremendous benefit to those of us with Alzheimer’s. An early but inaccurate diagnosis is extremely harmful and can add significant additional costs. Access to the amyloid PET imaging test will give physicians the opportunity to more accurately diagnose the cause of cognitive impairment, and empower those with this accurate diagnosis to seek the appropriate treatment and plan for their future based on the true underlying cause.

We thank you for the opportunity to comment on the draft decisions. Amyloid PET imaging is a vitally important tool for physicians to diagnose the most difficult cases of cognitive impairment. We are hopeful that CMS will reconsider the final determination to ensure that there are no barriers to access this new technology for those limited populations where its use is indicated by experts in the field.

Sincerely,

The Alzheimer’s Association National Early-Stage Advisory Group

[PHI Redacted]

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As a physician who has utilized beta amyloid PET imaging as part of multiple research projects, I am writing to ask CMS to reconsider the Coverage with Evidence Development (CED) requirements in the Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. It has already been clearly established that this exciting technology can make a significant impact on patient management decisions in the correct clinical settings and it is not appropriate to limit the availability of these scans to one scan per patient for those involved in a CMS-approved clnical study. The Appropriate Use Criteria published earlier this year by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging establish very reasonable and limited clinical circumstances for the use of beta amyloid PET which would ensure that this technology is only used in the appropriate diagnostic settings. Beta amyloid PET can make a meaningful impact in the lives and treatment of patients in 2013 and I would urge you to adopt the above referenced Appropriate Use Criteria rather than the draft CED decision. Thank you for the opportunity to comment on this important issue. Richard Noto, MD

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Alzheimer’s Disease (AD) is an increasingly important health problem in the US. Amyloid beta is the most widely recognized marker of Alzheimer Disease (AD), and many even believe it is a causal factor. Amyloid plaques are associated with neuronal damage that can eventually lead to profound dementia in a subset of patients. Positron Emission Tomography (PET) using imaging agents designed to measure amyloid plaque deposition has been shown to be an accurate, safe, and effective method for early diagnosis of Alzheimer’s disease (Clark, J Am Med Assoc. 2011, 305: 275) and has received FDA approval for the indication of AD diagnosis. There is considerable experience in the use of PET amyloid imaging agents, representing years of research (Rowe CC, Med Clin North Am. 2013 97:377) and leading to consensus guidelines on appropriate use (Johnson, J Nucl Med. 2013 54:1011).

Despite scientific and clinical evidence strongly in support of the utility of amyloid PET imaging for the diagnosis of AD, the CMS draft decision “Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease” has concluded that PET amyloid imaging is not considered part of current clinical care and should be covered only under CED, namely CMS-approved research protocols to provide evidence of Amyloid PET’s utility and impact. While I applaud CMS’s desire to support research to refine the use of Amyloid PET imaging, prior research has already established its utility for 3 indications listed the recent consensus guidelines cited above:

1. Patients with persistent or progressive unexplained mild cognitive impairment (MCI)
2. Patients satisfying core clinical criteria for possible AD, but requiring further clarification of diagnosis because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation
3. Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age)

I strongly urge CMS to provide coverage for patients meeting the consensus criteria above. While CED could be applied to other indications, the aforementioned criteria are supported by compelling evidence and expert consensus regarding the role of PET amyloid imaging in the diagnosis of Alzheimer’s disease. Withholding coverage for these established, consensus indications for use will deny Medicare recipients an FDA-approved method for early and specific diagnosis of AD that could significantly impact their lives and medical care.

Thank you for considering my input.

Sincerely,

Jacob G. Dubroff, MD, PhD
Assistant Professor of Radiology
Division of Nuclear Medicine and Clinical Molecular Imaging
Perelman School of Medicine
University of Pennsylvania

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As a board certified diagnostic and nuclear radiologist who practices in the community setting, I was very disappointed by the recent CMS decision on PET Amyloid Imaging. My patients, and possibly loved ones in the future, will be denied access to this ground breaking technology that for the first time can non-invasively diagnose the presence of Amyloid plaques in the brain. Currently the diagnosis of Alzheimer's disease is made incorrectly about 20% of the time; and this new test would improve the ability to accurately diagnose this disease. Without coverage for this test more repeat MRIs and CT scans will be unnecessarily performed on patients with progressive cognitive impairment. Moreover, this decision will decrease funding for future research on additional novel radiotracers which will limit technologic advancement which is crucial to the advancement of medicine and our society. Not only will patients suffer today because of lack of access to this technology, but patients in the future, may not have access to life-saving technologies which would have been developed if the CMS appropriately covered validated, accurate tests which address an important and growing public health concern.

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As a front line neurologist with sub-specialty training and interest in AD, I'd like to write a letter in support of your decision on PET imaging.

1. Many academics seemingly have no clue how tests in general are over-utilized, and seem particularly blind to the potential over-utilization of amyloid molecular imaging. Once this test is paid for by society at large, it will be massively overused and will not be tethered to clinical trials. Instead it will be pushed by those in the business of medicine. Can you imagine how many scans a single doctor (with a stake in a PET scanner, who's salary depends on filling the slots) could possibly order?

2. The results will not change outcomes (how could it without a disease modifying medication?), but when positive in mild or even asymptomatic patients, will create a great deal of distress. When negative, then it might cause false reassurance in patients without amyloid proteiopathies (who have other progressive disorders). I assure you that even well meaning doctors have not thought out these possibilities, which will add to the general confusion.

3. We know that about 30% of healthy and cognitively normal elderly have amyloid. Many of these patients will have a positive scan predictive of nothing, but distressing nonetheless. So I reject that these findings will help people prepare for dementia. Those with mild AD can prepare for dementia just as well as a cognitively normal person.

4. We know from clinicopathologic studies, that clinical AD has 94% diagnostic certainty in experienced hands.

5. Once we have a drug that is disease modifying, then these tests will become very important, but not until then.

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I provide public comment as a Professor of Radiology at the University of California, San Francisco who has been performing clinical research concerning Alzheimer’s disease for the past 25 years, as the Principle Investigator of the NIH funded Alzheimer’s Disease Neuroimaging Initiative, and as [PHI Redacted] with advanced dementia probably due to Alzheimer’s disease.

I’m extremely disappointed that “The Centers for Medicare & Medicaid Services (CMS) proposes that the evidence is insufficient to conclude that the use of positron emission tomography (PET) amyloid-beta (Aß) imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease, and thus PET Aß imaging is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (“the Act”).”

My disappointment stems from the simple observation that patients, and their families, suffering from memory problems, cognitive impairments, and dementia often wish to understand the cause of their problem. Patients and their families seek medical attention for these problems. The currently approved diagnostic approach includes obtaining a medical history, performing a physical examination including a neurological examination, performing laboratory tests, and the performance of brain scans including CT and MRI. All of these tests are currently approved and reimbursed by CMS as part of the workup of cognitive decline and dementia. Unfortunately none of these tests identify the presence of Alzheimer’s disease with a high level of sensitivity and specificity.

Until recently, the only way to determine if a patient had Alzheimer’s disease was to wait for autopsy, and the results of pathological examination to detect the presence of widespread amyloid plaques and tangles, the hall marks of Alzheimer’s disease. During the past decade, amyloid imaging with PET scanning has been developed to detect the presence of Alzheimer’s pathology. Several well-conducted studies have validated amyloid PET scanning with Alzheimer’s pathology at autopsy. It is now generally accepted that an amyloid PET scan, such as florbetapir and others can reliably detect Alzheimer’s pathology in living people. In other words, amyloid PET scanning can provide sensitive and specific information concerning whether or not a patient’s memory problems, cognitive decline, or dementia is due to Alzheimer’s disease.

Putting this in other words, for many years patients and their families have sought medical attention including extensive diagnostic workup to understand the cause of their memory and cognitive problems. Medicare and insurance companies pay for this diagnostic workup. The current diagnostic workup does not provide highly sensitive and specific information concerning the diagnosis. Now we finally have a method which is sensitive and specific and CMS is stating that the evidence is insufficient that amyloid imaging “improves health outcomes”. I strongly object to this because CMS is obviously being inconsistent in its approach.

Having an accurate diagnosis of Alzheimer’s disease during life is certainly going to affect outcomes in several ways. First, it is known that Alzheimer’s disease is genetic, and family members will want to know whether or not they have increased risk. Second, it is known that individuals who do have Alzheimer’s disease are more likely to progress rapidly than individuals without Alzheimer’s disease. Thus knowledge of the presence of Alzheimer’s disease has tangible effects on important life-planing decisions including where to live, investments, career planning, and estate planning. Importantly, knowledge of the presence of Alzheimer’s disease might prompt some to seek enrollment in clinical treatment trials. All of these”outcomes” are important to patients and their families, but would take many years to document in prospective clinical trials which CMS suggests must be done. We can't wait! Therefore, I very stongly urge CMS to reconsider its position and approve reimbursement for use of florbetapir and other amyloid-detecting PET ligands.

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July 30, 2013

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01 7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dr. Jacques:

On behalf of Siemens Medical Solutions USA, Inc. and Siemens’ PETNET Solutions, thank you for the opportunity to provide commentary on the Proposed Decision Memo for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N).

Siemens firmly believes beta-amyloid imaging is reasonable and necessary in accordance with §1862(a)(1)(A) of the Social Security Act for certain populations and should therefore be covered by the Centers for Medicare and Medicaid Services (CMS) for those specific groups. More specifically, coverage should be established for the Medicare populations as described in the Amyloid Imaging Task Force’s publication of Appropriate Use Criteria (AUC),¹ to wit:

a) Mild cognitive impaired (MCI) patients whose clinical management would change as a result of greater certainty about the cause of their symptoms,
b) Patients with atypical clinical courses or comorbid conditions which confound interpretation of the clinical signs and symptoms, or
c) Younger Medicare beneficiaries (e.g. disabled patients 50-65 years old) presenting with features of both Alzheimer’s disease and other dementias.

Siemens further supports the points made in the update to the Amyloid Imaging Task Force’s original publication, clarifying the nature of the differential diagnostic dilemmas and the incremental benefit of beta-amyloid imaging for clinical management.² It also clarified the appropriate clinical decision-making process and documentation as well as, the skill set necessary for cognitive experts to make use of the information from beta-amyloid imaging.

The standard of care today still relies on a presumptive diagnosis of Alzheimer’s disease based on subjective assessments, which diagnosis can only be confirmed at autopsy when beta-amyloid plaque is demonstrated on tissue staining. Eli Lilly and Company’s Amyvid™ (Florbetapir F 18 Injection) has been approved by the US Food and Drug Administration (FDA). Ruling out Alzheimer’s disease avoids the unnecessary risk of adverse effects associated with treatments for Alzheimer’s disease, particularly in patient populations already at risk from polypharmacy. Ruling out Alzheimer’s disease with beta-amyloid PET gives medical practitioners confidence that other treatable explanations must be sought for the patient’s symptoms, including, for example, depression and Parkinson’s disease, for some of whom the treatments for Alzheimer’s disease would be contra-indicated. Access to this reasonable and necessary clinical tool for making patient management decisions should be enabled by CMS without delay based on current clinical evidence.

CMS should adopt the recently published Appropriate Use Criteria (AUC) as recommended by the Amyloid Imaging Task Force comprised of the American Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging.¹ This task force was duly constituted of domain knowledge experts in patient care and technology who gave appropriate recognizance to the published clinical evidence. These recommendations were presented during the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)³ meeting, but were not included in the proposed memorandum, which recommends AUC only in allowing coverage within the context of a clinical trial for the development of a therapeutic agent. For appropriate clinical use there is no diversity of views; these recommendations, which specifically exclude use in screening, are not opposed by any of the relevant professional societies. For these reasons Siemens supports the AUC.

The proposed coverage with evidence development (CED) omits the most clinically relevant outcomes. The proposed endpoints (such as autopsy data) are infeasible, while the endpoints which seem to be excluded (such as avoidance of unnecessary treatment) are instead important outcomes more relevant to patient management decisions. Concordance between autopsy and imaging data would be unnecessarily redundant and of no additional benefit to data already reviewed and approved by the FDA in their decision to approve Amyvid. In addition, the proposed design would be onerous for practitioners in the community and therefore the population accruing to the registry would be biased, unrepresentative of CMS’ constituency. Alternatively, a rule-out in early stages of disease as per the AUC can readily be assessed for its utility in directing patient management decisions.

The proposed rule is not aligned with the National Alzheimer's Project Act (NAPA) release by the Health and Human Services recommendations in that it restricts access to a clinical tool crucial for the evaluation of patients exhibiting Alzheimer’s disease symptoms. NAPA’s goals are to optimize care quality, efficiency and drive improvement. In partnership with Alzheimer’s Disease Neuroimaging Initiative (ADNI), PET imaging biomarkers will be included as a valuable diagnostic tool. Per the U.S Department of Health and Human Services’ national plan to address Alzheimer’s disease:

a)Strategy 1.C: Accelerate Efforts to Identify Early and Presymptomatic Stages of Alzheimer’s Disease.⁴
b)Action 1/C.1: Identify imaging and biomarkers to monitor disease progression.⁴

This initiative aims to take immediate action on Alzheimer’s disease without waiting for Congress to act.⁴ Government, industry and health care centers across the US must come together in full efforts to provide the best healthcare technology to manage this devastating disease. Adoption of the coverage proposed in this letter would resolve this apparent conflict between CMS and the NAPA.

Siemens recommends that CMS broaden the scope of the Medicare population eligible for beta-amyloid imaging without requiring CED. The currently available diagnostic radiopharmaceutical, (Amyvid) received FDA approval based on the extensive clinical trial data submitted to the agency. Non-coverage for this innovative neurological imaging procedure would limit access to Medicare beneficiaries and other patients who could benefit from beta-amyloid imaging when used appropriately in accordance with the label and with AUC. It is important that CMS approve a national coverage policy as soon as possible to facilitate access to amyloid imaging by Medicare beneficiaries.

In conclusion, Siemens would like to thank CMS for the proposed memorandum and for continuing to work with the imaging community. Siemens is committed to discovering, developing and delivering molecular imaging solutions that enable physicians to improve outcomes for their patients. Achieving CMS coverage for beta-amyloid positron emission tomography in dementia and neurodegenerative disease is an important milestone in evaluating patients for such diseases.

Sincerely,

Richard Frank, MD, PhD
Chief Medical Officer
Siemens Medical Solutions, USA Inc.
Christoph Zindel, MD
Chief Executive Officer Siemens’ PETNET Solutions

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(1)Johnson, KA, 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. J Nuc Med 54(3);pp1-16 (Mar 2013) (doi:10.2967/jnumed.113.120618).
(2)Johnson, KA, et al; Update on appropriate use criteria foramloid PET imaging: Dementia experts, mild cognitive impairment, and education. Alzheimer’s and Dementia 9 (online exclusive; 2013 e106-e109; http://dx,doi.org/10.1016/j.jalz.2013.06.001).
(3)MEDCAC, Beta Amyloid PET in Dementia and Neurodegenerative Disease, Jan 30, 2013, available at: http://www.cms.gov/medicare-coverage-database/details/medcac-meeting-details.aspx?MEDCACId=66.
(4)U.S. Department of Health and Human Services. National Plan to Address Alzheimer’s Disease. May 15, 2012. http://www.alzheimers.gov/pdf/NationalPlantoAddressAlzheimersDisease.pdf

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July 29, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Piramal Imaging Provides Comments to the Proposed Decision Memo for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

Piramal Imaging thanks the Centers for Medicare and Medicaid Services (CMS) for releasing a proposed decision memo regarding Medicare coverage of beta-amyloid positron emission tomography (PET) imaging.

Piramal Imaging was recently formed when Piramal Enterprises acquired the global rights to a molecular-imaging research and development portfolio from Bayer AG. The portfolio includes the rights to florbetaben F18, a specialized molecule used in PET imaging to detect beta-amyloid in the brain, a widely recognized marker for Alzheimer’s disease. Recently, florbetaben F18 successfully completed Phase III clinical trials and is now under review with the U.S. Food and Drug Administration and the European Medicines Agency. By developing novel PET tracers for molecular imaging, Piramal Imaging is focusing on a key future field of modern medicine that enables early diagnosis, patient stratification and tailored intervention.

In the proposed decision memo, CMS considers beta-amyloid PET imaging valuable in two specific scenarios:

1. To exclude Alzheimer’s disease (AD) in narrowly defined and clinically difficult differential diagnoses; and
2. To enrich clinical trials that seek 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, CMS is proposing to limit Medicare coverage via Coverage with Evidence Development to one beta-amyloid PET scan only for beneficiaries participating in clinical trials which meet certain criteria specified by CMS and have obtained CMS approval. Clinical trials must also address at least one of three research questions included in the proposed decision memo.

Piramal Imaging is concerned that CMS’ draft coverage decision does not appropriately consider the clinical benefits and potential for improved patient health outcomes. It is overly restrictive and, if finalized in its current form, will place an undue burden on physicians, patients, and caregivers by delaying the definitive diagnosis of certain types of dementia and neurodegenerative diseases, including Alzheimer’s.

Our specific concerns and recommendations are outlined below:

1. We agree with CMS that there is a clear benefit to rule out Alzheimer’s disease (AD) in precisely defined patient populations where a differential diagnosis is clinically difficult and to distinguish from other forms of dementia, e.g. frontotemporal dementia. We request Medicare coverage for these patients without requiring enrollment in a clinical trial.

   Clinical presentation of early onset Alzheimer’s disease can be difficult to distinguish from other forms of dementia. AD can present with many atypical features which obfuscate the diagnosis. Certainly there are many other examples where a differential diagnosis may be challenging, e.g., behavioral-variant frontotemporal lobar degeneration (bvFTLD), aphasic frontotemporal dementia (primary progressive aphasia), extrapyramidal form of frontotemporal lobar degeneration (parasupranuclear palsy and/or corticobasal degeneration), complex posterior cortical atrophy syndromes and encephalopathy (Creutzfeldt-Jakob disease).

   The results of beta-amyloid PET imaging thus can help the physician with the differential diagnosis of the patient, leading to identification of other appropriate treatment and tests to administer. It can help the physician select pharmacologic and non-pharmacologic options for the patient’s treatable conditions, avoiding harm that might be caused by use of medications for AD in patients for whom they are contra-indicated or pose higher risks of adverse effects, such as patients with frontotemporal dementia or Parkinson’s disease or patients taking medications for other medical conditions. In addition, it can help the physician determine whether further testing is needed, and it may enable the patient to forgo potentially futile testing and treatment.

   Furthermore, Piramal believes that there is a patient population for which beta-amyloid PET imaging meets the "reasonable and necessary" threshold for the diagnosis of disease: those patients meeting the Appropriate Use Criteria (AUC) developed by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer's Association. The taskforce was comprised of a cross section of experts including radiologists, nuclear medicine specialists and neurologists. In the proposed decision memo, CMS states that the AUC has a "different purpose entirely" from the question currently before CMS. We respectfully disagree. Instead, we feel that the AUC represents the consensus view that beta-amyloid scans have clinical diagnostic value for certain patients, and that those patients' needs are unmet via other currently available diagnostic tools. The AUC provides important guidance to protect against misuse of beta-amyloid PET imaging, including specifying that it should not be used in asymptomatic patients, patients with unconfirmed cognitive complaints, and patients who could be diagnosed without beta-amyloid PET imaging. These guidelines will aid physicians, patients, and caregivers to understand the circumstances in which beta-amyloid PET imaging is and is not appropriate, and they support use of the technology only when it is reasonable and necessary for diagnosis of the patient’s condition.

   We believe that there is adequate clinical evidence to support coverage without CED in which beta-amyloid PET imaging should be considered.

2. CMS should establish a clear standard of the level of evidence required to expand coverage.

   CMS should approve clinical trials that are likely to expeditiously answer three research questions without onerous restrictions: 1) improvement in meaningful outcomes; 2) assessment of specific subpopulations, patient characteristics, or differential diagnoses that are predicative of improved health outcomes; and 3) change in treatment management.

   In the proposed decision memo, CMS places great emphasis on the lack of longitudinal clinical trial data. While those types of trials are certainly important, CMS should not exclude data gathered from trials that follow a different design, but which still include endpoints that address at least one of the three study questions. Piramal Imaging is concerned that CMS’ standard of evidence cannot reasonably be achieved and its questions answered in a timely and cost-effective manner.

   CMS’ current guidance for the public, industry, and CMS staff regarding National Coverage Determinations under Coverage with Evidence Development specifically states that CMS will consider trials other than randomized controlled clinical trials – such as observational trials –acceptable. Therefore, we encourage CMS to approve, in this instance, trial designs other than randomized controlled clinical trials that are designed to help answer all or part of one or more of CMS’ questions.

   CMS should ensure that it approves a sufficient range of clinical trials, allowing for a variety of practical clinical trial designs, providing they address relevant endpoints and help answer all or at least one of CMS' research questions.

3. CMS should state in the final decision memo that once a clinical trial meets endpoints as agreed upon by CMS, CMS will expand Medicare coverage in a corresponding manner without any undue delay.

   Under the “proposed coverage decision” there is no assurance that once a clinical trial meets the agreed-upon endpoint(s), CMS will expand coverage accordingly and in a timely manner. Piramal Imaging understands CMS’ desire to make coverage determinations that are based on sound medical and clinical evidence. We therefore request CMS commit to expanding Medicare beneficiary access to beta-amyloid PET imaging under appropriate circumstances, as stated above, as soon as additional evidence collected by a CMS-approved clinical trial justifies doing so.

   The decision to expand coverage based on the results of a successful clinical trial should not unnecessarily delay the National Coverage Determination process. Medicare beneficiaries should not lose access to diagnostic technologies that would have demonstrated clinical benefits in patient outcomes.

   CMS should commit to expanding Medicare coverage in an expeditious manner if the clinical trials have successfully met the endpoints.

4. CMS should not require a postmortem autopsy as an endpoint for any CMS-approved clinical trial.

   Piramal urges CMS to remove the reference to postmortem autopsy as a potentially required endpoint for a CMS-approved clinical trial from the final decision memo.

   • Several pivotal autopsy studies demonstrate amyloid imaging agents bind to beta-amyloid in the brain; therefore, further biomarker studies are redundant. According to the Agency for Healthcare Research and Quality (AHRQ) Clinical Research Standard no. 3, “the research study does not unjustifiably duplicate existing studies.” Therefore, additional postmortem autopsy studies would not fulfill the above AHRQ standard.
   • Requiring a subject to agree to a postmortem autopsy as a condition of receiving coverage for a diagnostic scan is unnecessary to answer CMS’ three research questions.
   • CMS acknowledges that patients diagnosed with Alzheimer’s disease have a typical life expectancy of eight to ten years after onset of symptoms. Therefore postmortem autopsy as an endpoint will unreasonably lengthen the amount of time it takes to conduct the requested clinical trials without providing any additional data on patient outcomes. Furthermore, patients who are near death are not the likely intended population of amyloid imaging studies.
   • Many Medicare beneficiaries may understandably be very uncomfortable or unwilling to agree to such a requirement to undergo a diagnostic imaging scan. Since CMS’ goal is to collect robust data regarding clinical utility and patient outcome of beta-amyloid PET scans in a reasonable time frame, any such requirement that may strongly discourage beneficiaries from participating should be immediately eliminated.

   Appropriate clinical trials can certainly be designed to answer the research questions identified by CMS without a requirement of an autopsy.

Piramal Imaging appreciates your acknowledgement that there is a clear benefit to ruling out Alzheimer’s disease and to distinguishing it from other forms of dementia. Therefore, we request that Medicare cover beta-amyloid scans for these indications, without requiring Medicare beneficiaries to participate in a clinical trial. We remain committed to working with CMS to ensure the appropriate clinical exploration and future utilization of this promising technology. We are hopeful that CMS will moderate its position when it renders its final decision by finding less restrictive ways to gather the information it seeks regarding health outcomes.

If you have any further questions, please do not hesitate to contact andrew.stephens@piramal.com or steve.sandor@piramal.com.

Sincerely,

Andrew Stephens, MD, Ph.D.
VP, Clinical Research and Development

Steve Sandor
VP, Global HEOR / Market Access

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CMS reviewers:

I support the Appropriate Use Criteria for amyloid PET developed by the Soc for Nuclear Medicine and Molecular Imaging, Alzheimer's Association, and many informed scientists and clinicians working in Alzheimer's disease (AD) research and care.

The availability of a diagnostic-support test for symptomatic patients is critically important. Autopsy and clinical studies show a high rate of misdiagnosis of AD with resulting improper management decisions. Similary, only about half of patients presenting with memory abnormalities have AD as the underlying cause, these patients progress to AD dementia at high rates whereas those without plaques on amyloid imaging may improve, stay stable, or progress to other dementias. Knowing which patients have underlying AD is critical to management.

We use amyloid imaging frequently at the Cleveland Clinic Lou Ruvo Center for Brain Health and we see that it assists in patient diagnosis and management. It should be available to all appropriate patietns regardless of their ability to pay. Amyloid imaging has helped us "undiagnose" AD in complex cases of late-onset frontotemporal dementia and to diagnose AD in complex cases with comorbid disease.

There are nuances to using amyloid imaging especially in persons without symptoms and I am not advocating for its availabilty in such circumstances. Education regarding the appropriate use of amyloid imaging is critically important and I support the development of these educational programs.

Amyloid imaging is helpful in diagnosis and differential diagnosis; it represents an advance in the care of patients with this horrible disease; its wider use is consistent with NAPA and the President's interest in improving care for AD patients; it has been endorsed by many scientists and clinicians knowledgegable about AD; it has been useful for me in my practice. It should be approved by CMS for reimbursement using the guidance of the appropriate use criteria.

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As a behavioral neurologist and dementia clinical researcher, I appreciate this opportunity to encourage the Centers for Medicaid and Medicare Services (CMS) to reconsider their decision regarding coverage for beta-amyloid PET scans. Despite the lack of effective disease modifying therapy for Alzheimer's disease at this time, beta-amyloid PET scans still have significant clinical importance for diagnosis, management (choice of medications), and, perhaps most importantly, for family, estate, and long-term care planning for patients and their families. Thus, in the appropriate clinical setting, I strongly encourage the CMS to cover beta-amyloid PET scans.

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I thank CMS for the opportunity to comment on this memo decision related to Amyvid clinical coverage. I respectfully disagree with the decision. As pointed out in the memo and AIT report, poor quality of care is achieved from high levels of uncertainty in the clinical diagnosis of AD as is the current practice. The AIT report pointed out also that the survey from Harvard found that more than half of dementia patients have no established diagnosis (quite unacceptable). Amyvid would improve this and be a step in the right direction towards better clinical management of dementias.

The memo acknowledges the fact that PET Amyloid imaging/accumulation can be considered as a risk factor for AD or an early detectable stage of AD. Therefore, it seems like no doubt should exist on the importance of this tool. And as every new clinical test some tweaking may be needed to assess the way to use it but not its utility. No other FDA approved test can currently target a process directly involved in the pathophysiology of AD.
I am requesting full coverage of Amyvid scans as a biomarker for AD diagnosis.

However, in the light of the CED proposal, I would like to additionally point out that the way the CED is currently written is unreasonable and of no clinical or research value. It is impractical to have any trial performed with this strict of a CED and autopsy correlation, although not the only roadblock is not a conceivable outcome to hope for. Can the CED be modified to include ways of intermediate assessments of benefit of the scan that would be more qualitative than oncologic type straightforward targets? The NOPR has shown that FDG PET changed management in more than 25-33% of cancer patients.

• Can an inconclusive FDG brain PET imaging result for the evaluation of AD be used as a tool to determine eligibility for Amyvid scan coverage?
• Can CMS approve the brain scan portion versus the radio tracer component for coverage in an extreme case scenario?
• I thank CMS for their consideration of my comments.

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As a neurologist caring for patients with dementias and as a researcher in the field, I have considerable interest in evolving biomarker tools, including brain amyloid imaging. As a taxpayer and citizen, I have concerns about the financial impact that may come from making new imaging tools broadly available. Amyloid PET ligands are indeed useful, but must be applied thoughtfully and judiciously. A test of comparable or greater diagnostic utility is already available through CSF examination of both amyloid-beta and tau levels, but this is not over-utilized because of the need for invasive lumbar punctures. There will be no such brakes on the use of amyloid imaging using PET ligands. Unrestricted ability to order these studies will lead to widespread, inappropriate, and costly overuse of the modality.

I applaud the thoughtfulness of the current proposal, which allows Medicare to support rational deployment of amyloid PET imaging in an arena where it may do some real good without opening the floodgates to widespread inappropriate and expensive use of the new technology.

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The recent proposed CMS decision to cover Amyloid Plaque brain imaging under CED should be reversed and the coverage for Ab imaging should be similar to the already approved coverage guidelines that exist for FDG. CMS has already approved FDG imaging for the evaluating dementia that mat be caused by AD vs. Frontaltemporal Dementia. Ab imaging is much easier to interpret and will provide better patient care and outcomes for the patients involved. Given the already approved use of FDG in dementia imaging there is no real reason to approve AB imaging under CED. It has been evaluated by the FDA and given approval after rigorous testing. AB imaging should be approved in similar fashion to the already approved use of FDG for imaging in dementia indications.

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Alzheimer’s Disease (AD) is an increasingly important health problem in the US. Prevention and treatment of this disease depends critically on our ability to make an early and specific diagnosis. Because the neurodegeneration that occurs in AD is irreversible, early diagnosis is absolutely critical. Positron Emission Tomography (PET) using imaging agents designed to measure amyloid plaque deposition, an early indicator of AD pathology, has been shown to be an accurate, safe, and effective method for early diagnosis of AD (Clark, J Am Med Assoc. 2011, 305: 275) and has received FDA approval for the indication of AD diagnosis. There is considerable experience in the use of PET amyloid imaging agents, representing years of research (Rowe CC, Med Clin North Am. 2013 97:377) and leading to consensus guidelines on appropriate use (Johnson, J Nucl Med. 2013 54:1011).

Despite scientific and clinical evidence strongly in support of the utility of amyloid PET imaging for the diagnosis of AD, the CMS draft decision “Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease” has concluded that PET amyloid imaging is not considered part of current clinical care and should be covered only under CED, namely CMS-approved research protocols to provide evidence of Amyloid PET’s utility and impact. While I applaud CMS’s desire to support research to refine the use of Amyloid PET imaging, prior research has already established its utility for 3 indications listed in the recent consensus guidelines cited above:

1. Patients with persistent or progressive unexplained mild cognitive impairment (MCI)
2. Patients satisfying core clinical criteria for possible AD, but requiring further clarification of diagnosis because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation
3. Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age)

Based on the available evidence and consensus of experts in this area, I therefore urge CMS to provide coverage for patients meeting the consensus criteria above. CMS could use CED for other possible indications outside of these criteria, but CMS should provide coverage for the established areas of Amyloid PET imaging represented by the consensus indications. Withholding coverage for these established, consensus indications for use will deny Medicare recipients an FDA-approved method for early and specific diagnosis of AD that could significantly impact their lives and medical care.

I thank you for your consideration of this comment.

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I am a behavioral neurologist with over 30 years clinical experience, in both VA Medical Centers and in academic institutions, in evaluating and, when possible, treating patients with a variety of dementia syndromes. Treating patients also means, in most cases, treating their families.

 Most patients over 70 years of age harboring a degenerative dementing disease present symptomatically with the clinical syndrome of "Dementia of the Alzheimer type (DAT)," and a large majority will prove at autopsy (if obtained) to have suffered as will have their families in the care of these persons from pathologic Alzheimer's disease (AD).

However, a substantial minority of these persons, and most of those presenting below age (about) 70, do not present clinically with DAT. For example, initial symptoms such as progressive aphasia or visual impairment or personality change indicate in many cases a likely non-Alzheimer pathology.

The key word is "likely." Many of these persons will prove at autopsy (if obtained) indeed to have had pathologic Alzheimer's and will thus have presented "atypically." They and their families are therefore subjected either to an incorrect diagnosis or to years of diagnostic uncertainty, and I'm often not able to respond accurately about hereditary risk.

Most Americans do not have access to neuropsychologic testing or even to potentially diagnostic (but costly and invasive) spinal fluid studies, results from both of which often overlap with "normals" when cognitive or behavioral symptoms are mild. Most Americans have either no access to or are ineligible for clinical trials.

Results of florbetapir PET scanning indicate with reasonable certainly whether a person with clinically properly ascertained cognitive/behavioral symptoms harbors significant brain amyloid pathology. While abnormal amyloid "burden," or lack thereof, does not prove in every case the presence or absence of pathologic Alzheimer's disease, the sensitivity and specificity of this technology allow correct diagnosis far more often than without it.
An early diagnosis of AD a. allows whatever therapy is available to be prescribed when it's most likely to be beneficial b. allows affected patients to be segregated more clearly in(to) clinical therapeutic trials, thus increasing specificity of results c. at least allows the patient and/or other caregivers the opportunity to execute whatever financial and logistic options (often quite limited) are available for the future care of the affected person d. avoids other, often expensive and sometimes invasive additional testing (for those persons who have access to such testing).

I urge the CMS to reconsider its decision. I urge the CMS to approve Medicare coverage of florbetapir PET testing for persons suspected, by competent clinicians, of having a degenerative dementing disease.

Please note that the above represents my own personal and professional opinion, and not that of the Department of Veterans Affairs.

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As a nurse practitioner providing care to patients at an academic medical center in both research and clinical venues, I appreciate the need for evidence-based practice and the careful evaluation of re-imbursement for new technology. Our center is involved in the evaluation of patients with more atypical dementias, especially FTD and the clinical diagnosis can be challenging. The road to accurate diagnosis is often a long and frustrating one for patients and families, leading them to multiple providers and exhaustive work-ups. In this case, evidence does exist for the use of amyloid PET imaging and this technology can provide experts with additional information in diagnosing these more atypical patients. Since this determination has implications for treatment and management of patients, the distinction between these etiologies is vital and any evidence-based technology that can assist in this diagnosis should be available to use by the experts and reimbursed by their insurer.

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I have and continue to experience the tragedy of Alzheimer's disease as a caregiver, as a physician, and as a laboratory scientist. Given the emotional and economical impact of dementia, the notion that reimbursement of the breakthrough technology of amyloid imaging will be denied is, frankly, stultifying.

The role of the physician as diagnostician is just as important as the role as healer. Amyloid scanning enables diagnostic precision and accuracy heretofore not available to physicians caring for patients with dementia. No longer need these physicians tell families that autopsy will be required to establish whether or not their loved ones suffer from the cerebral amyloidosis of Alzheimer's disease.

Further, denial of this simple, noninvasive and valuable tool is difficult to reconcile with the mandate toward evidence-based medicine, especially outside academic centers. The proposed decision threatens to deny the practicing physician and the general CMS population access to a breakthrough opportunity for state-of-the-art evidence because, apparently, certainty in dementia diagnosis, in and of itself, is not of sufficient value to merit reimbursement.

At best, the denial of reimbursement of amyloid imaging strikes me as arbitrary. At worst, a negative determination provides an institutional and governmental imprimatur to the nihilistic attitude toward dementia that already thwarts the promising science emerging from the academic and industry physicians and scientists who have dedicated their lives toward defeating dementia.

Enhanced certainty of dementia diagnosis will almost certainly accelerate the development of effective drugs that delay or prevent Alzheimer's disease. I would urge CMS not to turn away from such a tantalizing possibility.

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As a behavioral neurologist who cares for patients suffering from dementia, I greatly value the information provided by beta amyloid-PET imaging. I see patients who are diagnostically challenging and need amyloid-PET imaging to determine if their dementia is most likely due to Alzheimer's disease or a non-Alzheimer's dementia. Patients are much more likely to agree to PET imaging than a lumbar puncture. Amyloid-PET imaging results help me to decide on the most appropriate therapy for my patients.

Keith Vossel, MD
Assistant Professor of Neurology
Memory and Aging Center
University of California, San Francisco

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We have had the opportunity to use amyloid imaging in a research setting for the past 5 years. During this time we have had the opportunity to scan more than 100 patients. This experience had led us to the conclusion that amyloid imaging is a very important part of the diagnostic process. amyloid imaging leads not only to more accurate diagnosis, but to earlier diagnosis. Early and accurate diagnosis leads to significantly better management and treatment of patients with Alzheimer's disease. The proposed policy regarding amyloid imaging in dementia will preclude the vast majority of patients from obtaining these scans. It is my impression that this policy will be detrimental to the treatment and management of patients with dementing illnesses and represents a disservice to the patients and their families. I respectfully request that CMS reconsider this policy.

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Alzheimer’s Disease (AD) is an increasingly important health problem in the US. Prevention and treatment of this disease depends critically on our ability to make an early and specific diagnosis. Positron Emission Tomography (PET) using imaging agents designed to measure amyloid placque deposition, an early indicator of AD pathology, has been shown to be an accurate, safe, and effective method for early diagnosis of Alzheimer’s disease (Clark, J Am Med Assoc. 2011, 305: 275) and has received FDA approval for the indication of AD diagnosis. There is considerable experience in the use of PET amyloid imaging agents, representing years of research (Rowe CC, Med Clin North Am. 2013 97:377) and leading to consensus guidelines on appropriate use (Johnson, J Nucl Med. 2013 54:1011).

Despite scientific and clinical evidence strongly in support of the utility of amyloid PET imaging for the diagnosis of AD, the CMS draft decision “Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease” has concluded that PET amyloid imaging is not considered part of current clinical care and should be covered only under CED, namely CMS-approved research protocols to provide evidence of Amyloid PET’s utility and impact. While I applaud CMS’s desire to support research to refine the use of Amyloid PET imaging, prior research has already established its utility for 3 indications listed the recent consensus guidelines cited above:

1. Patients with persistent or progressive unexplained mild cognitive impairment (MCI)
2. Patients satisfying core clinical criteria for possible AD, but requiring further clarification of diagnosis because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation
3. Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age)

Based on the available evidence and consensus of experts in this area, I therefore urge CMS to provide coverage for patients meeting the consensus criteria above. CMS could use CED for other possible indications outside of these criteria, but CMS should provide coverage for the established areas of Amyloid PET imaging represented by the consensus indications. Withholding coverage for these established, consensus indications for use will deny Medicare recipients an FDA-approved method for early and specific diagnosis of AD that could significantly impact their lives and medical care.

I thank you for your consideration of this comment.

Sincerely,
David A. Mankoff, MD, PhD
Professor of Radiology
Chief, Division of Nuclear Medicine and Clinical Molecular Imaging
Perelman School of Medicine
University of Pennsylvania

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I have been a researcher in dementia and Alzheimer's Disease for over 30 years. I've been involved in the development of clinical trials, and neuropathological validation of the first amyloid imaging agent Pittsburgh Compound B (PiB), and have had extensive experience using such compounds in research, in particular for difficult cases. I strongly urge an approval for use of these agents for use by clinicians, with appropriate restrictions to assure appropriate use, but not so strict as to make it nearly impossible to utilize in suitable cases (as has been an issue with the restrictions on FDG-PET). This methodology has high ability to clarify diagnosis and direct therapy.

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I understand that the CMS has issued a negative decision about coverage of amyloid PET imaging. I am a neurologist who has been caring for patients with dementia and studying dementia for over 25 years. While I am sure that the CMS decision was well reasoned, there are a few points I would like to bring to your attention.

1. FDG-PET is now approved by CMS for the differentiation of Alzheimer’s disease and Frontotemporal lobe dementia. However, FDG-PET has no biochemical specificity; indeed its diagnostic utility rests upon a pattern of glucose hypometabolism that reflects brain function and behavior. It seems very unreasonable that CMS would cover FDG-PET, which is biochemicically non-specific, and yet not cover amyloid PET, which defines the molecular pathology of the disease. I don’t think this situation makes sense.

2. I don’t know exactly how CMS came to its decision, but I understand that factors associated with measurable patient outcomes might have been involved. It is indeed early in the case of this technology to prove that a better diagnosis improves outcomes. But is this something that really requires proof? Our duty as physicians is to do our utmost for our patients. Part of that is to explain what is wrong and attempt to help patients and families come to terms with the process. That can only be done through accurate diagnosis, which leads to a variety of behavoirs that ultimately help families cope. The alternative is interminable “doctor shopping”, repeated expert opinions, and failure to manage the problem.

3. The determination for “coverage with evidence development” is not something likely to help the field of dementia research actually develop evidence. In fact, this approach to FDG-PET (in indications other than AD vs FTLD) has largely been a failure, if the anticipated outcome is more evidence (I have seen none as a result of this program). In contrast, it is only with widespread application of this technology to standard clinical practice that we will advance our knowledge about the relationship between disease and biomarkers, but that we will develop evidence that shows how patient care is actually affected.

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I am a physician located at an academic medical center and have had significant experience with interpretation of this study.

The greatest benefit of this study is to provide additional data to support an earlier diagnosis of AD or to exclude the presence of AD. Exclusion of AD is particularly important since it allows the clinician to pursue other avenues of treatment, some of which may result in improved performance. When significant amyloid plaque is found AND the symptoms of the patient suggest AD, then the diagnosis of AD is more likely and the patient family can be more prepared to arrange long term care. Earlier diagnosis leads to earlier family decision making regarding ultimate care and less uncertainty. A finding suggesting AD would likely lead to fewer investigations to confirm a diagnosis that no one wants to hear that a family member has.

Please expand coverage to perform as proposed by the appropriateness criteria defined by the Society of Nuclear Medicine and Molecular Imaging and the Alzheimer's Association. Narrow coverage to established research protocols will decrease access for some individuals to only urban areas with the facilities to conduct such research.

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Beta Amyloid PET should continue to be covered, to aid in the diagnosis of Alzheimer's disease and early-onset dementias. Early detection is key in the patient starting medication to slow the progression of the disease. In my case, my loved one was misdiagnosed with Alzheimer's disease, when his actual problem is frontotemporal dementia. PET imaging would have been helpful in obtaining a proper diagnosis, and in turn, selecting appropriate medication, behavior modifications (e.g. driving privileges) and family issues. It is too late for us but beta amyloid PET imaging can help someone else.

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I urgently support the use of Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative disease. For the last 9 years, I have facilitated and early stage support group for the Alzheimer's Association. The participants strongly advocate for research which will aid in the better detection of a dementing illness to provide for better care and support for those diagnosed. The use of the beta amyloid marker for PET scans with thoughtful consent will advance the care and support for those living with an identified form of dementia. Thank you for your consideration, Peter

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To whom it may concern:

As an Alzheimer's researcher and family member of patients suffering from Alzheimer's disease, I STRONGLY urge you to reconsider your non-coverage decision for florbetapir F18 PET (Amyvid). This biomarker product has the potential to reinvigorate an Alzheimer's community that is distraught after the failures of bapinuzimab, solenuzemab, and other promising drugs last year. It has the potential to stimulate the crippled AD pipeline. It has the potential to motivate research efforts for years to come. If CMS will not cover Amyvid, what is there to motivate drug companies to pursue similar biomarker products, which will be fundamentally necessary if we are ever to "cure" Alzheimer's disease.

Please, for the sake of the future, reconsider this decision.

Thank you,
Nicholas R. Simmons-Stern

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Many professionals in the field of dementia care and dementia research have already provided learned arguments for coverage of this technology as a diagnostic tool. As a caregiver and a volunteer advocate with the Alzheimer's Association, I would like to give you the layman's perspective. Any procedure that adds to the ability of the physician and caregiver to more knowledgeably intervene and participate earlier in the treatment of a loved one's disease will provide incalculable benefit in both treatment and the psychological well being of the sufferer and the caregiver. Knowledge is a most powerful tool in relieving the incredible stress of caregiving and a most powerful tool in enabling a caregiver to cope and to help the person s/he is caring for to cope. The benefits to research have been discussed. The benefits to the very human side of people affected by dementia cannot be overstated. Please recognize the benefits Beta Amyloid PET technology will provide to the people Medicare is supposed to serve.

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July 26, 2013

Louis Jacques, MD
Director, Coverage and Analysis Group
Center for Medicaid and Medicare Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for : CAG-00431N
Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease

Dear Dr. Jacques,

On behalf of the Association for Frontotemporal Degeneration, we are writing in response to the preliminary decision on coverage of Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease released earlier this month. Specifically, our comments will focus on the preliminary conclusion that there is insufficient evidence to conclude that PET Aß imaging results inform the treating physician's management of the beneficiary to improve meaningful health outcomes, as well as insufficient evidence that those outcomes may include reasonably considered beneficial therapeutic management or the avoidance of unnecessary, burdensome interventions. We believe these conclusions to be erroneous and strongly urge CMS to reconsider this opinion.

The Association for Frontotemporal Degeneration (AFTD) is a non-profit organization founded in 2002 to fund research into FTD and to develop resources and advocate for services for patients and their families who must live with these rare disorders. We are governed by a caregiver-led Board of Directors and advised by a Council of medical and scientific experts in the pathologies and clinical disorders which constitute FTD. We represent and are funded by a growing community of families and professionals across the US and around the world.

FTD comprises a group of clinical neurodegenerative syndromes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), and corticobasal degeneration (CBD). For each of these syndromes there is currently no approved treatment and no cure. It is worth noting that in recent years organizations like AFTD, in partnership with leading clinical teams, have successfully lobbied for these three clinical syndromes to be included in the group of disorders that qualify for Disability under the Social Security Administration’s Compassionate Allowances program. Thus, though the majority of individuals diagnosed with these conditions may be under the age of 65, they nonetheless do fall under the purview of Medicare.

Our strong recommendation in favor of using amyloid scanning stems from the fact that there are many different kinds of dementia. Some are caused by Alzheimer’s disease (AD) and others not. Proper diagnosis is essential for optimal patient care. This is especially true for PPA, bvFTD and CBD, in which accurate clinical diagnosis does not provide reliable insight into the underlying disease pathology: In PPA and CBD, for example, a substantial proportion of patients have AD and the remainder another disease, most often frontotemporal lobar degeneration (FTLD)(Gefen et al. , 2012).

Since PPA, bvFTD and CBD patients with and without underlying AD pathology are clinically indistinguishable, diagnostic accuracy is completely dependent on biomarkers such as cerebrospinal fluid analysis and positron emission tomography (PET).

According to the proposed decision released by CMS on July 3, there is insufficient evidence that Amyloid-PET scanning "improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease." (Page 1, paragraph 1) We believe that this conclusion is inaccurate and harmful when applied to patients with PPA, bvFTD and CBD. As noted above, in each of these syndromes, identical clinical diagnoses can be associated with either AD or FTLD pathology. Conversely, some patients with typical Alzheimer-type memory loss may turn out to have FTLD at post-mortem (Rademakers et al. , 2007). The current clinical criteria for CBD require exclusion of AD, yet there is a substantial proportion of AD in the CBD syndrome thus making amyloid PET scanning a very helpful addition to patient diagnosis (Armstrong et al., 2013). A recent PET Aß study reports that amyloid imaging may be used to distinguish PPA caused by AD from PPA caused by another degenerative disease (Mendez & Sabodash, 2013). We would argue therefore, that biomarkers such as amyloid imaging are critical for resolving these questions of differential diagnosis.

If access to Amyloid-PET is denied, the clinician will not be able to accurately determine which PPA, bvFTD or CBD patient has AD and which has FTLD. It will also be impossible to detect the occasional patient with progressive memory impairment whose dementia is caused by atypical FTLD rather than AD (Zannas et al., 2013). This state of affairs can have two negative consequences. In some cases, FTLD patients are given futile, potentially harmful and expensive AD drugs. In other instances, AD patients are denied FDA-approved drugs that they need.

Current clinical tools are insufficient for the physician to reliably diagnose the underlying pathology that is causing a patient’s clinical disorder. As acknowledged in the CMS preliminary ruling, Amyloid-PET scanning does help to distinguish between FTLD and AD pathology in a live patient, thereby providing these clinicians with the means to make informed treatment decisions that certainly improve health outcomes, for both FTD and AD patients. We urge CMS in the strongest terms to reconsider providing reimbursement for the judicious clinical use of this test, per the appropriate use guidelines published and recently updated (Johnson et al., 2013).

We appreciate the opportunity to provide these comments, and remain available as a resource as you craft a final version of this ruling.

Sincerely,

Susan L-J Dickinson, MS, CGC
Executive Director
The Association for Frontotemporal Degeneration

M.-Marsel Mesulam, MD
Chair, AFTD Medical Advisory Council
Professor of Neurology
Director, Cognitive Neurology and Alzheimer's Disease Center
Northwestern University
Feinberg School of Medicine

Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;8:496-503.
Gefen T, Gasho K, Rademaker A, Lalehzari M, Weintraub S, Rogalski E, Wieneke C, Bigio E, Geula C, Mesulam M-M. Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain. 2012;135:1554-65.
Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, et al. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-T (Arg493X) mutation: an international initiative. Lancet Neurology. 2007;6:857-68.
Johnson K, Minoshima S, Bohnen N, Donohoe K, Foster N, 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 & Dementia. 2013; 9:e1-16 and J Nucl Med. 2013;54:476-90.
Johnson K, Minoshima S, Bohnen N, Donohoe K, Foster N, et al. Update on appropriate use criteria for amyloid PET imaging: Dementia experts, mild cognitive impairment, and education. Alzheimer’s & Dementia. 2013; 9:e106-109 and J Nucl Med. 2013; 54:1011-3.
Mendez MF, Sabodash V. Clinical amyloid imaging in logopenic progressive aphasia. Alzheimer Dis Assoc Disord (in press).
Zannas AS, Doraiswamy PM, Shpanskaya KS, Murphy KR, Petrella JR, et al. Impact of 18F-florbetapir PET imaging of ?-amyloid neuritic plaque density on clinical decision-making. Neurocase: DOI: 10.1080/13554794.2013.791867

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A massive amount of money is wasted on patients who are diagnosed with Alzheimer disease but do not have it. I would suggest that, instead of a blanket refusal to cover, CMS develops criteria for which exams should be covered. For example, an 80 year-old presenting with an amnestic disorder does not need amyloid imaging; the likelihood of positive imaging (which is nonspecific) is absurdly high. However, a 55 year-old presenting with cognitive disturbance and no conclusive diagnosis after MRI, neuropsychological testing, and (perhaps) FDG-PET should be considered a reasonable candidate. I'll even help to review the cases if you like!

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As a clinician at a very busy memory disorders clinic, I strongly support CMS coverage of PET amyloid imaging, particularly in certain clinical circumstances. As it is pointed out in your Decision Summary, there is sufficient evidence that PET amyloid imaging can be very useful in the differential diagnostic process. In line with other comments, patients with young onset dementia, atypical presentations or comorbid conditions such as cerebrovascular disease present difficult diagnostic cases, leading to excessive testing and possibly inappropriate treatments. It is unfair that patients may be subjected to these unnecesary tests or medications when the technology currently exists to assist in correct diagnosis. Thus, I would request CMS reconsider their proposed decision and cover PET amyloid imaging for certain clinical indications.

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Thank you for the opportunity to comment on the recent decision of CMS not to cover Beta Amyloid PET Imaging.

I support the response from the Society of Nuclear Medicine and Molecular Imaging, but I would like to add to their statement.

Given the need to distribute limited financial resources across a group of beneficiaries, it would behoove CMS to review procedures that are approved for reimbursement but may not warrant it in light of new evidence.

To illustrate the point consider CT Angiography for the diagnosis of pulmonary embolus.

The literature shows that the previous standard of care, V/Q imaging, is not inferior to the new modality. Moreover, data from 2010 shows that CT Angiography may over diagnose pulmonary emboli. Indeed there has not be a decreased in the mortality from pulmonary embolus since the advent of CT Angiography.

However, CT Angiogram for pulmonary embolus is reimbursed without the same scrutiny that CMS affords to new technologies.

I agree that it is necessary to evaluate new technologies, but I emphasize that old technologies need to be reevaluated against the actual clinical experience once they are approved. This happens with PET imaging, but not with CT imaging.

1. Anderson, David R., Susan R. Kahn, Marc A. Rodger, Michael J. Kovacs, Tim Morris, Andrew Hirsch, Eddy Lang, et al. “Computed Tomographic Pulmonary Angiography Vs Ventilation-Perfusion Lung Scanning in Patients With Suspected Pulmonary Embolism: A Randomized Controlled Trial.” JAMA 298, no. 23 (December 19, 2007): 2743–2753. doi:10.1001/jama.298.23.2743.

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The decision to drastically limit amyloid imaging is in direct conflict with what President Obama's Administration called its “historic effort to fight Alzheimer’s disease”.

In the preliminary determination, the CMS discussion sadly revolves around a very simplistic and one-sided point - no data exists to support that a positive scan may change a physician’s algorithm of treatment. It may be true that a confirmatory study may not dramatically change the course of treatment, but this theory dismisses the importance of appropriate planning by caregivers and potential entry into any number of studies looking at disease modifiers.

More importantly, though, is the negative scan.

The journal Neurology recently reported a study revealing that in early onset dementia (ages 46-60) 53% of patients identified as Alzheimer's patients were incorrectly diagnosed. Add in the myriad of patients aged 65 and older who have been given a diagnosis of Alzheimer's disease, yet may not have the pathology, and the potential for changing outcomes becomes staggering. Patients with multi-infarct dementia, NPH or other causes of cognitive decline, who have been set adrift toward a dismal fate that may be unnecessary, could benefit from other therapies or procedures that may salvage cognition should the true cause of their condition be revealed.

And what is the cost? With appropriate use criteria already established, the limited scope of physicians permitted to order an amyloid scan would dramatically decrease the number of studies deemed unnecessary. Looking at another study that states 20% of individuals (nearly 2 million) diagnosed with AD will not actually have pathology upon autopsy, CMS could realize billions in savings when these individuals are permitted to discover the true cause of their cognitive decline and eliminate medications used in Alzheimer’s disease. Medications, mind you, which do not reverse the disease.

Yes, it will seem expensive on the surface. But with Medicare costs estimated to exceed $627 billion by 2050 (http://www.alz.org/documents_custom/final_trajectory_report_release-emb_5-11-10.pdf) for Alzheimer's patients, ruling out AD could reduce those costs dramatically. Add in the potential to regain lost revenue for caregivers and the overall savings becomes even more dramatic.

In following this race to find answers for dementia patients, I am amazed at the hurdles thrown at progress. For the first time in history, physicians are now able to “look the enemy in the eye”. Whether a study is positive or negative, the veil of uncertainty will be lifted with these scans and will provide patient and doctor greater insight into the appropriate planning and treatment going forward. To limit coverage will strip that knowledge away from all patients except the very wealthy who can afford this cutting edge opportunity.

I hope that CMS reconsiders this position and allows the appropriate use criteria to determine eligibility for this innovative and groundbreaking test.

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July 26, 2013

By electronic mail

Louis Jacques, MD
Director
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

The Medical Imaging & Technology Alliance (MITA) is pleased to submit comments on the Centers for Medicare and Medicaid Services' (CMS) proposed decision memorandum for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N) (the "Proposed Decision").¹ As the leading trade association representing medical imaging, radiation therapy, and radiopharmaceutical manufacturers, we have in-depth knowledge of the significant benefits to the health of Medicare beneficiaries that medical imaging and radiation therapy provide. MITA appreciates this opportunity to advise CMS about appropriate coverage for use of advanced imaging technologies for diagnosis of dementia and neurodegenerative disease.

Medical imaging encompasses X-ray imaging, computed tomography (CT) scans, radiation therapy, related imaging acquisitions, diagnostic ultrasound, and nuclear imaging (including positron emission tomography (PET)), and magnetic resonance imaging (MRI). Medical imaging is used to diagnose patients with disease, often reducing the need for costly medical services and invasive surgical procedures.² In addition, medical imaging equipment often is used to select, guide, and facilitate effective treatment, for example, by using image guidance for surgical or radiotherapeutic interventions.³ MITA's members also develop and manufacture innovative radiotherapy equipment used in cancer treatment.

CMS proposes that "the evidence is insufficient to conclude that use of PET amyloid-beta (Aβ) imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease, and thus PET Aβ imaging is not reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act (SSA)." CMS concludes that there is sufficient evidence that the use of PET Aβ imaging "could be 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." CMS proposes to cover one PET Aβ scan per patient in these scenarios through coverage with evidence development (CED), under §1862(a)(1)(E) of the Act, in clinical studies that meet specified criteria.

MITA respectfully disagrees with this proposed decision. We believe that the evidence is sufficient to conclude that PET Aβ imaging improves health outcomes by helping physicians manage beneficiaries' medical conditions. We urge CMS to cover PET Aβ imaging, without CED, when used in accordance with the Appropriate Use Criteria (AUC) developed by the Alzheimer's Association (AA) in partnership with the Society of Nuclear Medicine and Molecular Imaging (SNMMI). We also are troubled by CMS's proposed requirements for studies under CED described in the Proposed Decision, which are highly inconsistent with the AUC, and we urge the agency to not move forward with any application of CED using the proposed criteria for studies.

I. The Evidence is Sufficient to Conclude that PET Aβ Imaging Improves Meaningful Health Outcomes.

Under section 1862(a)(1)(A) of the SSA, Medicare may pay for items and services only if they are "reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member." CMS's General Methodological Principles state, "an improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary."⁴ In the Proposed Decision, CMS finds that PET Aβ imaging is not reasonable and necessary because CMS believes it lacks adequate evidence to "conclude that PET Aβ imaging improves meaningful health outcomes in beneficiaries who display signs and symptoms of AD" or to "conclude that PET Aβ imaging results inform the treating physician's management of the beneficiary to improve meaningful health outcomes."⁵

When the evidence on PET Aβ imaging is examined in light of its use for helping with the management of the patient's course of treatment, we believe the benefits of PET Aβ imaging are clear. Appropriate use of PET Aβ imaging, as an adjunct to other types of evaluation and in compliance with the AUC, allows for earlier and more certain diagnosis. As described in the Food and Drug Administration (FDA) approved labeling for Amyvid (florbetapir F-18 injection), a negative result is "inconsistent with a neuropathological diagnosis of AD at the time of image acquisition" and "reduces the likelihood that a patient's cognitive impairment is caused by AD."⁶

With this information, the physician can change the medication management and prescribed diagnostic services for the patient. A negative result informs the physician that he or she should investigate whether the patient's symptoms are caused by other conditions, such as depression or Parkinson's disease. The results of PET Aβ imaging thus can help the physician with the differential diagnosis of the patient, leading to identification of other appropriate tests to administer. It also can help the physician select medications for the patient's treatable conditions, avoiding harm that might be associated with use of medications for AD in patients for whom they are counter-indicated or pose higher risks of adverse effects, such as patients with frontotemporal dementia or Parkinson's disease or patients taking numerous medications. A positive result can help the physician diagnose AD or other forms of dementia in conjunction with other tests. These results also can aid in selection of appropriate medications, particularly at an earlier stage of the disease. In addition, a positive result can help the physician determine whether further testing is needed, and it may enable the patient to forgo potentially futile testing and treatment.

II. PET Aβ Imaging Should be Covered When Used in Accordance with Consensus-Based Appropriate Use Criteria

MITA urges CMS to adopt the rigorous AUC developed by the Amyloid Imaging Taskforce (AIT) formed by the AA and SNMMI. These evidence-based, peer-reviewed, consensus guidelines were developed by expert stakeholders to provide guidance to dementia care practitioners, patients, and caregivers. The criteria state,

Amyloid imaging is appropriate in the situations listed here for individuals with all of the following characteristics: Preamble: (i) a cognitive complaint with objectively confirmed impairment; (ii) AD as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (iii) when knowledge of the presence or absence of Aβ pathology is expected to increase diagnostic certainty and alter management.

1. Patients with persistent or progressive unexplained MCI
2. Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation
3. Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age)

Amyloid imaging is inappropriate in the following situations:

4. Patients with core clinical criteria for probable AD with typical age of onset
5. To determine dementia severity
6. Based solely on a positive family history of dementia or presence of ApoE4
7. Patients with a cognitive complaint that is unconfirmed on clinical examination
8. In lieu of genotyping for suspected autosomal mutation carriers
9. In asymptomatic individuals
10. Nonmedical use (e.g., legal, insurance coverage, or employment screening)⁷

Of note, the AUC provide important guidance to protect against overuse of the PET Aβ imaging, including specifying that it should not be used in asymptomatic patients, patients with unconfirmed cognitive complaints, and patients who could be diagnosed without PET Aβ imaging. These guidelines will help physicians understand the circumstances in which PET Aβ imaging is appropriate, and support use of the technology only when it is reasonable and necessary for diagnosis of the patient's condition.

In an update to the AUC, the AIT provided additional guidance on use of PET Aβ imaging. This published article identified the following information that dementia experts should consider before ordering a PET Aβ imaging, and it recommends that payers consider this information sufficient to demonstrate the medical necessity of PET Aβ imaging.

• Age and date of onset of symptoms;
• Identification of clinical syndrome (mild cognitive impairment, or MCI; dementia);
• Clinical evidence of persistent or progressive cognitive decline;
• Structured objective assessment of mental status such as the Mini-Mental State Examination, Montreal Cognitive Assessment, or a similar measure;
• Known comorbidities;
• List of prescribed medications and rationale for use of psychoactive medications, if any;
• Results of neuropsychologic testing performed;
• Results of structural brain imaging (such as MR imaging or CT) performed;
• Relevant laboratory tests, which should include complete blood count, chemistry profile, B12, and thyroid hormone;
• Reasons that the cause of cognitive impairment remains uncertain after completion of a standard clinical evaluation and treatment of comorbidities; and
• Treatment and care plan based on amyloid PET findings.⁸

The AUC are more than an "impressive first effort," as CMS describes them; they are the most current and clinically sound guidelines available for use of this innovative technology. MITA urges CMS to adopt the AUC as the basis for Medicare coverage of PET Aβ imaging.

III. CMS Should Not Implement Any CED Policies Using the Proposed Criteria.

MITA is troubled by the requirements that CMS proposes to apply to any studies of PET Aβ imaging conducted under CED. First, CMS proposes to require the studies to use postmortem diagnosis as the endpoint, where appropriate. This requirement is unnecessary because the studies the Food and Drug Administration (FDA) considered when it approved Amyvid (florbetapir F-18 injection) confirmed that the test safely and effectively estimates β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive decline. CMS should not require evidence that is duplicative of the FDA's requirements. Confirmation of AD at death, rather than at the time PET Aβ imaging was used for the purpose of early detection, would not be helpful because it would not reveal any information about the benefit of imaging to help determine the course of treatment. Moreover, the requirement for postmortem diagnosis could needlessly prolong completion of studies until the end of the patients' lives.

Second, CMS proposes to cover PET Aβ imaging only when it is used in approved clinical trials that assess whether it leads to improved health outcomes including "avoidance of futile treatment or tests; improving, or slowing the decline of, quality of life; and survival." As MITA has explained in its comments on past coverage determinations, the relevant health outcomes for diagnostic services are intermediate endpoints, such as use of the test's results to determine or change the course of the patient's treatment. Longer term, therapeutic outcomes, including survival and disease progression, are dependent on factors other than the diagnostic test, including the effectiveness of the treatment prescribed and the patient's compliance with the prescribed therapy, and therefore should not be used to evaluate whether a diagnostic service is reasonable and necessary.

In recent national coverage determinations involving diagnostic services, CMS has recognized that diagnostics should be evaluated using different outcomes than therapeutic interventions. In its review of F-18 fluorodeoxyglucose (FDG) PET scans for multiple indications, CMS assessed whether the test improves health outcomes by considering evidence showing that physicians use the test information to manage the course of the patient's treatment.⁹ Although CMS has expressed interest in outcomes such as survival, the agency has recognized that difference in courses of treatment and side effects are important, as well.¹⁰ In addition, CMS has acknowledged that there may be many reasons patients do not respond to treatment after diagnostic testing is performed.¹¹ For these reasons, CMS correctly recognizes that because diagnostic tests do not directly change health outcomes, their value should be measured by looking at how physicians use the tests to manage the course of the patient's treatment.¹²

At two public meetings, CMS has reiterated its understanding that the evidence required to determine if a diagnostic service improves health outcomes is different from the evidence required for therapeutic services. At a 2011 workshop, Dr. Louis Jacques identified the following as CMS's preferred "road to diagnostic coverage":

Provide adequate evidence that the incremental information obtained by the new diagnostic technology, compared with alternatives, changes physician recommendations resulting in changes in therapy that improve clinically meaningful health outcomes in Medicare beneficiaries.¹³

At a 2012 workshop, Dr. Jacques made the following points:

• In and of themselves, diagnostic tests, such as imaging examinations, do not have a direct therapeutic effect. The potential benefits of diagnostic tests relate to their providing information to optimize treatment plans and, thereby, improve clinical care and health outcomes.
• The potential benefits and harms associated with diagnostic tests accrue from the capacity of the test to inform downstream clinical management of the patient.
• The balance of risk and harm, the acuity and severity of the patient's condition, characteristics of the test, and the likelihood of a positive result should inform a caregiver's decision to perform a test.
• Diagnostic tests can help avoid futile treatment; by so doing, they can improve health outcomes.¹⁴

MITA agrees that the health outcomes associated with new diagnostic technologies should be evaluated based on their ability to inform clinical management, and we strongly recommend that CMS use this approach in this national coverage analysis.

In the Proposed Decision, CMS diverges from the approach it has used in other recent decisions and that it discussed at the aforementioned workshops by seeking evidence not only of the effect of PET Aβ imaging on clinical management of the patient, but also on the patient's longer-term outcomes. Within the draft decision, CMS asks if the results of PET Aβ imaging lead to improved health outcomes, which the agency defines as including "avoidance of futile treatment or tests; improving, or slowing the decline of, quality of life; and survival." MITA agrees that avoidance of futile treatment or tests is a relevant outcome for a diagnostic service, but we believe that improvements in quality of life or survival are not appropriate endpoints to use in evaluating whether the test itself is reasonable and necessary. CMS should take the same approach it used in evaluating FDG PET and consider whether PET Aβ imaging improves health outcomes by supporting the physician and patient's treatment decisions without specifically identified and explicitly tied patient health outcomes. As discussed above, we believe the available evidence is sufficient to conclude that PET Aβ imaging improves health outcomes under this standard.

Third, CMS proposes to apply the 13 criteria that were discussed in the November 2012 draft CED Guidance to coverage of PET Aβ imaging under CED. CMS collected comments from the public on that draft but has not issued the final guidance that responds to those comments. Until CMS issues a new draft of the guidance, it is not appropriate for the agency to begin applying these criteria in coverage decisions.

IV. CMS Should Comply with the Spirit of the National Alzheimer's Project Act.

Finally, in addition to covering PET Aβ imaging because it is reasonable and necessary for the diagnosis of illness, MITA urges CMS to comply with the spirit of the National Alzheimer's Project Act (NAPA)¹⁵ and work to protect access to innovative diagnostics and therapies for AD. NAPA and the National Plan to Address Alzheimer's Disease developed pursuant to NAPA call on the Secretary of Health and Human Services to improve the early diagnosis of AD and "ensure that as evidence-based solutions are identified they are quickly translated, put into practice, and brought to scale so that individuals with Alzheimer's disease can benefit from increases in scientific knowledge."¹⁶ Covering PET Aβ imaging for appropriate patients, as identified using the consensus-based AUC, is an important step toward achieving the goals of NAPA, encouraging continued innovating in AD diagnosis, and helping address this growing challenge to Americans' health.

V. Conclusion

MITA appreciates this opportunity to present our comments on the proposed decision memorandum for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease. We urge CMS to cover PET Aβ imaging in accordance with the AUC, without use of CED. We are hopeful that we can continue to work with CMS to ensure that Medicare beneficiaries have access to innovative diagnostic technologies. If you have any questions or would like to discuss these matters further, please contact me at 703-841-3235. Thank you for consideration of these comments.

Respectfully,

/s/
Gail M. Rodriguez, Ph.D.
Executive Director
Medical Imaging & Technology Alliance

1 Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N), July 3, 2013, available at http://www.cms.gov/medicare-coverage-database/details/ncaproposed-decisionmemo.aspx?NCAId=265 (hereinafter "ProposedDecision").
2 See, e.g., Perrier, et al., "Multidetector-Row Computed Tomography in Suspected Pulmonary Embolism," NewEngland Journal of Medicine, 352(2005): 1760-1768.
3 See, e.g., Jelinek, JS et al., "Diagnosis of Primary Bone Tumors with Image-Guided Percutaneous Biopsy: Experience with 110 Tumors." Radiology. 223(2002): 731-37.
4 Proposed Decision, at Section VI.
5 Id., at Section VIII.B.
6 Prescribing Information for Amyvid (florbetapir F-18 injection), http://pi.lilly.com/us/amyvid-uspi.pdf.
7 Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force (AIT), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer Association (AA). Alzheimer's & Dementia. 25 January 2013;1-15.
8 Johnson KA, Minoshima S, Bohnen NI, et al. Update on Appropriate Use Criteria for Amyloid PET Imaging: Dementia Experts, Mild Cognitive Impairment, and Education. J Nucl Med 2013; 54:1011.1013
9 See, e.g., Decision Memo for Positron Emission Tomography (FDG) for Solid Tumors (CAG-00181R4), June 11, 2013; Decision Memo for Positron Emission Tomography for Initial Treatment Strategy in Solid Tumors and Myeloma (CAG-00181R3), Aug. 4, 2010.
10 Id.
11 Id.
12 Id.
13 Hillman BJ, Frank RA, Rodriguez GM. New Pathways to Medicare Coverage for Innovative PET Radiopharmaceuticals: Report of a Medical Imaging & Technology Alliance (MITA) Workshop. J Am Coll Radiol 2012;9: p109.
14 Hillman BJ, Frank RA, Abraham BC. The Medical Imaging and Technology Alliance (MITA) Conference on Research Endpoints Appropriate for Medicare Coverage of New PET Radiopharmaceuticals. J Am Coll Radiol (in press).
15 Pub. L. No. 111-375 (2011).
16 National Plan to Address Alzheimer's Disease (2012), available at http://aspe.hhs.gov/daltcp/napa/NatlPlan.shtml.

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I am a practicing geriatric psychiatrist, medical educator and clinical researcher. The technology of amyloid PET imaging will allow for the identiation of beta amyloid pathology for individuals showing signs of memory decline. This technology is not approriate for widespread clinical use at this time. However, for those individuas meeting The Society of Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association Amyloid Imaging Taskforce's (AIT) recently published appropriate use criteria, the availability of amyloid PET imaging may beneficially impact diagnostic assessment and treatment planning for individuals with dementia and their families. I urge CMS to consider covering amyloid PET imaging for those inviduals meeting the appropriate use criteria below.

"The AIT concluded that amyloid imaging could potentially be helpful in the diagnosis of people with cognitive impairment when considered along with other clinical information, and when performed according to standardized protocols by trained staff. In addition, they emphasized that the decision whether or not to order amyloid imaging should be made only after a comprehensive evaluation by a physician experienced in the assessment and diagnosis of cognitive impairment and dementia, and only if the presence or absence of amyloid would increase certainty in the diagnosis and alter the treatment plan.
According to the AIT, appropriate candidates for amyloid PET imaging include:

Those who complain of persistent or progressive unexplained memory problems or confusion and who demonstrate impairments using standard tests of cognition and memory.
Individuals meeting tests for possible Alzheimer's, but who are unusual in their clinical presentation.
Individuals with progressive dementia and atypically early age of onset (before age 65)."

Thank you for your consideration.

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I am a clinician who has had extensive experience with amyloid PET scan imaging of the brain. Amyloid imaging clearly has a significant impact on differential diagnosis and treatment decisions.

I think this technology is extremely helpful in patients with mild cognitive impairment and clearly affects treatment. Patients with a negative amyloid scan have a very low risk for developing Alzheimer's disease and do not require treatment. Patients with a positive scan have high risk for developing Alzheimer's disease and treatment should be strongly considered.

In the difficult cases of dementia and the early onset dementia patients, amyloid imaging can help determine diagnosis and treatment. In patients with hydrocephalus amyloid imaging is very helpful in evaluating the patient.

I have practiced neurology for many years and I find the most difficult cases are those where the diagnosis is uncertain. We now have an available technology that literally allows us to "look" into the brain and know if amyloid plaque pathology is present. This information helps us with diagnosis and treatment and allows patients and families to plan for the future.

CMS should consider supporting this very powerful technology more aggressively.

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As a board-certified clinical neuropsychologist who specializes in care of the elderly, I urge the panel to reconsider its decision to not provide coverage for diagnostic PET imaging for patients who may have an early-stage neurodegenerative disorder. The Alzheimer’s Association and Society for Nuclear Medicine and Molecular imaging have already provided appropriate use criteria for amyloid imaging that would establish reasonable guidelines for use of this procedure. These include: 1) patients with persistent or progressive unexplained MCI; 2) patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, and 3) patients with progressive dementia and atypically early age of onset.
I thank you very much for your consideration.
William M. Whelihan, Ph.D., ABPP/ABCN

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Having experienced Alzheimer's dementia in unfortunate family members and friends, and having participated in ADNI F-18 florbetapir clinical imaging trials as a Nuclear Medicine physician, I attest that this PET-CT imaging procedure is extremely helpful and relevant in appropriate populations as determined by a referring Neurologist. Although certainly not a screening test, it clearly adds incremental differential clinical information and changes patient management often as documented in the medical literature. Time is saved, some patients can be managed sooner with existing therapy, some can avoid potentially toxic medication for a condition that does not exist, and all can benefit from the agent's use in further evaluations of newer therapies as they affect amyloid burden in the brain, a hallmark of Alzheimer's dementia. Please, make it available, with its users held to sufficient checks and balances for appropriately directed use. Thank you.

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I appreciate the opportunity to comment on the Proposed Decision Memo for Beta Amyloid PET in Dementia and Neurodegenerative Disease. I believe that ample evidence exists to support immediate coverage, which would change patient management, lead to better health outcomes for patients and assist families making care decisions. The following are some items you should consider carefully:

Coverage with evidence development (CED), as proposed, is not appropriate for Aß imaging, which the U.S. Food and Drug Administration (FDA) has already approved, noting its clinical utility.

Earlier this year the Alzheimer’s Association and SNMMI jointly developed appropriate use criteria (AUC). The end result concluded that Aß PET imaging demonstrates more than adequate evidence exists for Medicare to cover Medicare beneficiaries without additional onerous CED.

The AUC determined that for Aß imaging to be considered appropriate, individuals must exhibit several characteristics. These include: (1) a cognitive complaint with objectively confirmed impairment; (2) Alzheimer's disease (AD) as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (3) knowledge of the presence or absence of Aß pathology is expected to increase diagnostic certainty and alter management.

Should all of these criteria be met, Aß PET imaging is appropriate in the following scenarios:

• Patients with persistent or progressive unexplained mild cognitive impairment.
• Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either atypical clinical course or etiologically mixed presentation.
• Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age).

CMS did conclude “there is sufficient evidence that the use of Aß PET imaging could be promising to exclude AD in narrowly defined and clinically difficult differential diagnoses, such as AD versus frontotemporal dementia (FTD).”

What criteria represent a meaningful health outcome for a patient with mental cognitive decline? For a patient, being taken off powerful medications that are not indicated for their condition is most certainly a meaningful health outcome. For a patient who has a diagnosis of AD, and is being treated as having AD, having a test which can rule out AD certainly has a meaningful health outcome. Current standard care for AD and related dementia disorders is not only to attempt fundamental treatments or prevention, but also to provide quality of care and care arrangement. The outcome goes beyond a patient's quality of care and the Medicare beneficiary expenditure of care resources, but also for their family and caregivers. And yet, CMS is proposing that evidence is insufficient to conclude that the use of Aß PET imaging improves health outcomes for Medicare beneficiaries with dementia or neurodegenerative disease and thus is not reasonable and necessary; we disagree.

While CMS decided to cover one scan, it did so under CED which is so onerous, in our opinion and experience, that it is in effect a non-coverage decision. CMS states that the gold standard diagnosis for AD remains postmortem autopsy. Therefore, any CED trial design will need to be tied to autopsy. However, the challenge is the significant time lapse from the initial Aß scan to autopsy of patients who may benefit from Aß PET imaging defined in the AUC. These elderly patients might carry comorbidities that affect their cognitive status and outcome through the course. This is particularly true for early-stage and atypical patients for whom Aß PET imaging is recommended in the AUC. The FDA already set the rigorous standards for the approval of Aß PET imaging. They required that the abnormalities seen on PET closely correlate with neuritic amyloid pathology seen postmortem. The results of imaging vs. postmortem studies with florbetapir met those rigorous standards, leading to FDA approval of Amyvid. Why does the CED need to be tied to autopsy?

CMS states in the proposed decision memo, “Given that the gold standard diagnosis for AD remains postmortem, creating the building blocks of evidence-based appropriate use criteria, and establishing clinical utility on firm ground, will unfortunately take time.” How long should patients wait? Amyvid has already met the rigorous imaging versus postmortem studies, the SNMMI and Alzheimer’s Association Amyloid Imaging Taskforce has firmly established AUC and the FDA established clinical utility with approval. SNMMI is disappointed with the proposed decision memo because we believe Aß PET imaging is a medical advance that meets the major goal of the National Plan to Address Alzheimer’s disease to make major strides in the diagnosis and treatment of AD by 2025.

All Medicare eligible patients, and not just those in limited clinical trials, should have access to a valuable new tool that can assist physicians in better diagnosing patients with cognitive impairment. CMS should reverse its proposed decision memo and cover the three indications of the AUC without inappropriate coverage with evidence development. I disagree with CMS that an Aß scan does not lead to better health outcomes for patients, particularly in the case of a differential diagnosis which can prevent patients from being subjected to inappropriate medications and costs. I believe that additional information provided by the Aß PET study would be helpful assisting physicians to better manage their patients and therefore recommend implementing checks and balances.

Thank you for the opportunity to comment.

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Dear Dr. Hutter:

I have worked in the area of amyloid imaging with PET for the last 10 years, with extensive experience using 11C-PiB and four of the 18F labelled amyloid tracers. The introduction of amyloid imaging was a revolutionary step that allowed not only the non invasive assessment of brain pathology in vivo, but also the assessment of changes in amyloid burden over time.
The approval of Amyvid for clinical use by the FDA was a pivotal step in translating several years of intensive research into clinical practice. Furthermore, the introduction of usage rules for amyloid imaging have clearly delineated how it should be applied in the clinic. Given the increasing public health, societal and economical burden of Alzheimer's disease, it is critical that amyloid imaging should be made widely available to the public, and not restricted to those who can afford to pay for the PET scans.
Therefore I support the revision of the CMS decision in order allow public access to a beneficial technique

Yours sincerely,
Victor L Villemagne, MD

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I am writing as a neurologist and nuclear medicine physician who is very active in clinical management of patients with cognitive decline and in Alzheimer’s disease research.

The decision to severely restrict funding for amyloid PET imaging is of grave concern for many reasons. Firstly, it is based on the assumption that correct diagnosis and prognosis is not important when there is no proven treatment to slow disease progression. Correct diagnosis is the core of good medicine. Correct diagnosis is a fundamental first step in the development and application of treatments. Correct diagnosis allows accurate prognosis and this is of great assistance to patients and their families even in the absence of treatment. This is particularly the case when patients with cognitive decline are still in the workforce or hold other positions of responsibility. The Alzheimer's Association and lay representative groups around the world recognise the need for, and benefits of, earlier and more accurate diagnosis. Accurate diagnosis allows more appropriate use of currently available symptomatic therapies, avoidance of inappropriate therapy, and reduction in further investigation. Accurate diagnosis provides accurate prognosis and this is essential for life planning, including financial and legal considerations.

The diagnosis of Alzheimer's disease is a death sentence. It has immediate and profound impact on the patient and their family and carers. The current diagnostic approach gets it wrong in at least 20% of individuals. This is unacceptable now that amyloid imaging is available, a test proven to have extremely high accuracy for detecting Alzheimer’s disease pathology compared to post mortem examination.

The proposal to fund amyloid PET for screening for therapy trials is a step in the right direction but the restrictions on trial design for this funding make it unlikely that therapy trials will be able to access this support.

Likewise the proposal to fund trials that assess management impact and outcomes for patients with diagnostic uncertainty is useful but the practicalities mean this will severely limit access to amyloid imaging for most patients with suspected Alzheimer’s disease.

The appropriate use criteria developed by the joint Society of Nuclear Medicine and Alzheimer’s Association taskforce represent a very responsible approach to the use of amyloid imaging recognising the cost and limitations of the technology while providing benefit in the areas of greatest need. I strongly urge the CMS to adopt these criteria and not place obstacles in the way of better patient care and progress in the fight against Alzheimer’s disease.

Yours sincerely,

Christopher Rowe MD PhD FRACP
Professorial Fellow
University of Melbourne

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Dr. Hutter and Ms. Barton,

As a clinical researcher, it is clear from the published data that amyloid PET imaging is invaluable as an adjunct to cognitive testing, volumetric MRI, and a comprehensive clinical assessment to further support a diagnosis of MCI due to AD, so called 'prodromal AD'. A positive amyloid scan will greatly strengthen a diagnosis of prodromal AD, whereas a negative scan will encourage deeper consideration of a whole host of other, less common neurodegenerative diseases, as well as encourage working up other medical conditions that can cause MCI.

As a neurologist actively seeing patients in clinic, I have ordered only a handful of such scans in the past year. All have been for patients who met one of the Alzheimer’s Association and Society for Nuclear Medicine and Molecular imaging's 'Appropriate Use Criteria'. And the results have been of immense value to patients and their families. Not because I was able to change the treatment offered, but rather, because I was able to much more definitively answer one critically important question, whose answer is undoubtedly life changing: does my loved one have Alzheimer’s disease or not?

In my opinion, the incorporation of amyloid PET imaging in the evaluation of patients who meet the above stated criteria, allows practicing physicians to approach the commonly faced clinical question of MCI practically, accurately, and comprehensively.

Michael Rafii, MD, PhD
University of California, San Diego

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I am a neurologist specializing in the diagnosis and treatment of neurodegenerative diseases, and have been following the research related to PIB scans for some years now. I have not had cause to use PIB scans for diagnosis of most patients I see with cognitive impairment, but I think it can be useful in a very limited set of circumstances, most prominently in patients with atypical presentations that make one concerned for frontotemporal dementia versus Alzheimer's disease. Since these two diagnoses carry different ramifications for the family (heritability, for example, as well as prognosis) and physician (choosing whether or not to use agents like donepezil and memantine, which are not helpful in FTD), I think it would be very helpful to have PIB scans available in a clinical setting for this particular circumstance. At our center these scans have been possible through research studies, and I think the literature shows they can be helpful under specific circumstances. I hope the committee will consider approving funding for the scans in these specific situations.

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To all responsible parties:

I write to argue against the recent draft on not reimbursing PET imaging in dementia workup and to urge you to reconsider your decision.

I am a young neurologist who completed residency a month ago and who is currently pursuing a Behavioral Neurology Fellowship at UCSF. Reviewing the several comments already posted by leaders in the field, I am not the most experienced person in the field, but I have a passion for what I do and want to advocate for my patients, so here's my two cents.

Your concerns, direct and implied, of how PET is to be used if reimbursed, are reasonable no doubt. Your decision, however, is extreme by not allowing use of this tool in a practical setting. As you are aware, three prominent scientific and community-driven entities (i.e. the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association) agreed on common criteria for using amyloid PET as they had the same concerns as you have. Their approach though allows for a restrained but practical use of this modality. You may argue these entities have a vested interest in wanting PET imaging reimbursed and you would be correct. I would argue though that the patients and their families are in the mind of these entities and they are the ones to truly benefit in two ways.

First, use of PET under the specific criteria will allow for an accurate diagnosis, and further more avoidance of misdiagnosis. It is proven that misdiagnosing a person with Alzheimer disease increases the cost of care (e.g. presentations even on this year's ICAD conference), a burden we all share as a society. Accurately diagnosing someone allows for early interventions that help the patient, the family members and society (e.g. driving implications in dementia). Consider this, even the most experienced neurologists in some treatment trials included up to a third of patients who had presumed Alzheimer's disease and actually did not when reviewing PET imaging results...

Second, the implication of having this non-invasive information of brain pathology from population cohorts will help research in the future. Being able to go back to our clinic patients and see who had and did not have amyloid pathology and correlate it with information obtained from future research will allow for a faster pace in elucidating dementia pathogenesis and providing for better treatments.

I use a common sense approach to the above, as several other people in the field have already provided all the literature on the matter and a more detailed analysis. I am confident in your good intentions and your parsimonious approach; however, just because you see a nail on the wall you do not have to hammer it all the way in, sometimes it is there to hang a painting.

Thank you for your efforts,
Elissaios Karageorgiou, MD

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In my own practice we have been doing Amyvid studies since they were publicly available. I was in the first group of trainees at the SNMMI in 2012. The study when negative is extremely useful to clinicians. The exam is straightforward in its interpretation. I have never had to give an ambiguous report. The impact of a negative exam on the patient workup is great. Other, perhaps more treatable causes of dementia can be searched for and much patient anxiety can be allayed. This exam has not been abused by clinicians. I have never received an order from anyone than a trained neurologist. I cannot imagine why an NOPR format cannot be used if further evaluation of this agent is needed.

I urge you to reconsider your decision. Putting this agent into a research track yet again will reduce the number of patients being studied to a trickle. It will be years before you will have statistically significant data to reconsider what is obviously a useful agent.

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As a neurologist with more than 25 years of experience in neuroscience research and dementia care, I believe that the Amyloid imaging should not be covered by Medicare. My two main reasons are:

1. The results of the test do not change managment of patients. It may add anxiety and confusion, for patients and their doctors.

2. Up to 30% of elderly have amyloid deposits in their brain and yet they have no symptoms. There is still no convincing evidence that Amyloid is the cause of dementia in the early.

3. Most elderly have a dozen reasons for experiencing cognitive declilne and in fact having amyloid plaques in the brain may be protective.

Please feel free to contact me for any further information. I have attached a couple of my review papers on this topic.

Best;

M Fotuhi

Attachments

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24 July 2013

Coverage and Analysis Group (CAG)
Centers for Medicare & Medicaid Services (CMS)
United States Department of Health and Human Services
7500 Security Boulevard, Baltimore, MD 21244
CAGinquiries@cms.hhs.gov

re: National Coverage Analysis (NCA) for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease” (CAG-00431N)

Please consider the following as responsive to your solicitation of comments to the above NCA.

This morning, a comment was posted by Dr. Rabinovici, who makes an excellent case for the value of disntiguishing between frontotemporal dementia (FTD) and Alzheimer's disease (AD) in cognitively impaired patients. This is a value well-supported by evidence, and which has been already accepted by CMS for nearly a decade… and was, in fact, critical in the decision by CMS in 2004 to extend coverage for FDG-PET in assisting with the differential diagnosis of dementia.

More relevant to the decision presently facing CMS, Dr. Rabinovici's comment also drew a comparison between the abilities of FDG-PET and amyloid imaging to assist with this differential diagnosis. This comparison, was unfortunately misleading in a number of ways. For example, in the article cited by Dr. Rabinovici of which he was first author (Neurology 2011;77(23):2034-2042), the comment states that a “head to head comparison of amyloid and FDG-PET in over 100 patients” was made. In fact, the actual diagnosis of these patients was only known (i.e., histopathologically confirmed) in a grand total of 12 patients for whom amyloid imaging data were presented. Even worse, it was only known for 10 patients for whom FDG-PET data were presented (…and one might wonder exactly what definition of "head to head comparison" is being used given that 12 does not equal 10.) The amyloid imaging in this study, incidentally(?), was not performed with Amyvid, but with PIB (for which no FDA clinical indication has been sought or given).

In any event, to the extent that one wishes take at face value the data generated from the remaining patients, whose actual diagnoses were unconfirmed, what the public comment neglects to mention is that the accuracy of FDG-PET in this paper across the range of thresholds taken into account by ROC analysis was indexed by AUC for FDG as 91.0%, while for PIB, the corresponding AUC was only 88.8%. The slightly higher accuracy of FDG-PET compared with PIB was attributable to the much higher quantitative specificity of FDG (98%, vs. 83% for PIB). This means that for every 100 patient evaluated in these ways by PET, that for every 100 patients who do not have AD, FDG analysis would say that they do not in all but 2 cases, whereas amyloid imaging would say that they have AD in 13 cases - a false positive rate that is more than 6-fold worse for amyloid imaging. In clinical terms, this means that more than 6 times as many patients who actually may not benefit, or even be harmed, by the use of cholinesterase inhibitors would be falsely deemed by amyloid imaging as having a form of dementia for which those drugs would be FDA indicated.

Another issue pertinent to this consideration, is that amyloid imaging was being interpreted here under the (highly artificial) circumstance of there being a guarantee by the nature of the study design that 100% of the patients would be thought to have AD or FTD, and no other primary causes of cognitive impairment would thus need to be entertained in the differential diagnosis. In real life, when the differential diagnosis is in fact much wider, another factor to take under consideration is that if an amyloid imaging scan is interpreted as negative for AD, it still provides no evidence (that the FDA would recognize) that the patient has FTD (or any other diagnostic entity)… in contrast with FDG-PET, which not only has a pariticular signature of hypometabolism for early AD, but another (and different) signature of hypometabolism for early FTD, the differential diagnosis may be informed by both AD-positive and AD-negative scans.

There also seems to be a frequent yet unfortunate tendency not only among some of those providing public comment here, but also in this field more generally to confound evidence demonstrating that A) a diagnostic test may change referring physicians' diagnoses and intended (or even actual) management plans, with evidence of what ultimately matters... that B) those changes will result in improved health outcomes AND that they will lead to more good than harm being done by the use of those tests overall.

Not only does A) not necessarily result in B), but perhaps even more to the point in the particular case of amyloid imaging, there is published evidence to suggest that substantial harm may result from amyloid imaging, as a consequence of the way that physicians use the information that they obtain from such tests.

As a further example, in the highly informative public comment offered by Dr. Michael Grundman on this site, with posting date of 7/23/2013, he accurately points out that the treatment of patients with cholinesterase inhibitors who do not actually have prodromal AD “is harmful in most cases for [at least] two reasons: First, cholinesterase inhibitor treatment in this population is associated with morbidity… Second, studies conducted in young and elderly healthy controls have found that cholinesterase inhibitor treatment was associated with significant worsening on some cognitive tests." Dr. Grundman further re-affirms the position in the CMS decision memo that "Cholinesterase inhibitors have been shown to exacerbate symptoms in some patients with FTD, and use of memantine has correlated with greater functional and cognitive decline.”

In addition, Dr. Grundman cites a recent article of which he is first author (Alzheimer Dis Assoc Disord 2013;27:4-15) on the impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline. As demonstrated in this study for which, incidentally(?), 10 of 16 of its listed authors were employees of Avid (a wholly owned subsidiary of Lilly, the pharmaceutical company that sells the amyloid imaging agent Amyvid), and all of the remaining 6 of its 16 listed authors disclosed that they received financial compensation from Avid and/or Lilly the referring physicians indicated that they intend to frequently either neglect to use the information contained in an amyloid imaging scan in a way that could otherwise benefit their patients, and/or to misuse the information that it contains in a way that may do actual harm to their patients.

For instance, despite much evidence (and widespread agreement among expert bodies) that a negative Amyvid scan makes it unlikely that a patient's cognitive impairment is due to Alzheimer’s disease (AD), Dr. Grundman’s study found that of the grand total of 33 amyloid-negative patients whose referring physicians had given pre-scan diagnosis of “due to AD,” the referring physicians of only 10 of those patients (30.3%) changed their post-scan diagnosis to “not due to AD” and, moreover, the majority of the amyloid-negative patients whose pre-scan management plan included AD medications (30 of 57) still included AD medications after the amyloid scan results were available.

Even more potentially disturbing, however, was the reverse situation: that of all amyloid-positive patients whose cognitive impairment was not considered to be “Due to AD” pre-scan, over 98% of them were diagnosed by their referring physicians post-scan as being “Due to AD” including 100% of those whose referring physicians had indicated pre-scan that their patients’ cognitive impairment was specifically “Not due to AD” - despite repeated warnings by the FDA and in the Amyvid manufacturers’ own literature, that an amyloid-positive scan does not mean that a patient has AD, and that amyloid-positive scans can occur in patients whose cognitive impairment is due to conditions other than AD, and that an amyloid-positive scan has not been established to be predictive of even eventual development of AD. Furthermore, there were nearly as many patients to whose management plans were added AD medications folllowing an amyloid-positive scan, as there were to whose management plans were removed AD meds in the face of an amyloid-negative scan (28 vs. 31, respectively).

Thus, the data from peer-reviewed published studies, which appear to be excellently designed and executed (though, perhaps, incompletely interpreted), clearly demonstrate not only the lack of good that will potentially often ensue following an (actually diagnostically informative) amyloid-negative scan, but also the harm that will potentially often ensue from misuse of a (not so diagnostically informative) amyloid-positive scan (...and, none of the above discussion has yet taken under consideration the negative impact that the Medicare co-pay for a $3000 scan may have on the quality of life of millions of cognitively impaired patients and their families... or the negative impact that the non-co-pay portion may have on hundreds of millions of American taxpayers and their families... but that is the focus for a different kind of analysis.)

Of course, it is important to bear in mind that this does not necessarily mean that much more harm than good will be caused by amyloid imaging to cognitively impaired patients (and American taxpayers) and their families. It does, however, mean that to know that the overall effect will not be more negative than positive, that carefully designed and executed peer-reviewed studies (preferably led and primarily funded by people and organizations who do not have a strong financially vested interest in the direction of the data generated by the studies and their interpretation) which specifically address health (and, perhaps, financial) outcomes will be necessary, to demonstrate that the balance of overall effects of amyloid imaging will not be as damaging as all these considerations suggest may be the case. Needless to say, the willingness of CMS to at least partially support such studies through the Coverage with Evidence Development mechanism is a welcome development in what will be a complex and expensive undertaking on the part of whatever parties are able and willing to undertake it.

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July 24, 2013

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard Baltimore, MD 21244-1850

Dear Dr. Jacques,

I am a neurologist who cares for cognitively impaired patients in an academic dementia center. For the past eight years I have also conducted clinical research evaluating the diagnostic utility of amyloid PET. I am writing to urge CMS to reconsider its draft decision and approve reimbursement of amyloid PET imaging under the narrowly defined guidelines set forth in the Appropriate Use Criteria (AUC) (1).

While it is not feasible or appropriate to apply amyloid PET in the routine evaluation of cognitive impairment, this technology can be extremely helpful for diagnosis and management in a subset of the complex patients referred to dementia experts. The AUC represent an excellent effort by leaders in the field to define specific patient populations whose care would immediately benefit from use of this technology. The guidelines balance the importance of developing rigorous evidence-based guidelines for use of amyloid imaging, with the urgent clinical need to improve the diagnosis and care of patients with dementia.

One subset of patients identified under AUC who would most clearly benefit from the clinical availability of amyloid imaging are patients who represent a diagnostic dilemma between Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The CMS draft decision recognizes this scenario as one of the most promising clinical applications of amyloid imaging, and suggests coverage with evidence development (CED) to further investigate this point. I would argue that the scientific rationale for using amyloid imaging in this circumstance is strong enough to warrant coverage given existing literature.

Distinguishing AD and FTD on clinical grounds can be challenging, and misdiagnosis rates are high even at expert centers (2). An accurate diagnosis has an impact on prognosis (3), the likelihood of heritability (4), and most importantly on therapy, since drugs that are used to treat AD (cholinesterase inhibitors and memantine) worsen outcomes in FTD (5, 6). Amyloid imaging detects neuritic plaques, a core feature of AD pathology that is not part of the FTD pathologic spectrum. The differential of AD versus FTD typically arises in young-onset dementia patients, at an age in which the overall prevalence of amyloid in the normal population is low, making “false positives” less likely (7). CMS reimburses FDG-PET for the differentiation of AD and FTD - however, amyloid PET has the advantage of directly detecting molecular pathology, whereas FDG-PET infers the pathology based on spatial patterns of hypometabolism.

Multiple studies from different centers have demonstrated the utility of amyloid PET in distinguishing AD from FTD (8-12). In a head to head comparison of amyloid and FDG-PET in over 100 patients, amyloid PET had higher overall diagnostic accuracy than FDG in differentiating AD from FTD, and showed higher inter-rater reliability (8). At the recent Alzheimer’s Association International Conference (AAIC), we reported the accuracy of amyloid PET versus post-mortem diagnosis in 25 patients evaluated at our center (more than double the number in our initial published report). Amyloid imaging had 100% sensitivity and 93% specificity versus the pathologic gold standard of NIA-Reagan high-likelihood AD (13). These numbers replicate in a clinical population previous findings from the florbetapir end-of-life study (14). We also reported at AAIC on the clinical impact of amyloid imaging at our Center as demonstrated by observed clinician behavior, focusing on the AD versus FTD scenario (15). Amyloid imaging led to a change in diagnosis in 38% of patients who presented a diagnostic dilemma, and was significantly associated with changes in treatment (initiation of AD symptomatic therapy). In contrast, FDG-PET did not impact diagnosis or treatment when controlling for amyloid PET results. These data are still unpublished (manuscripts currently under review or in preparation), but we would be happy to share them with CMS in greater detail if this would be helpful.

Given the strong rationale and existing data, I would argue there is little uncertainty that amyloid imaging is a useful test in differentiating AD vs. FTD. The CMS policy of reimbursing FDG but not amyloid PET in this diagnostic scenario is not supported by current evidence. The expense and delay in the availability of the amyloid imaging that would result from CED studies are not justified. The CMS draft decision states: “we agree that amyloid imaging for this differential appears promising...more evidence needs to be developed, including when the scan would replace, and when it would complement, other biomarkers..." I believe that this is addressed in part by AUC, which would limit the use to patients in whom there is significant diagnostic uncertainty of a diagnosis of AD vs. FTD after comprehensive clinical and cognitive evaluations and structural neuroimaging. Detailed diagnostic algorithms could be further developed in Phase 4 studies. I strongly urge CMS to reconsider this particular point in their final decision.

As a clinician-scientist using amyloid imaging in research, I can't help but appreciate the irony of the current situation. On the one hand I can apply this technology in research to detect molecular changes in the brain a decade or more before the emergence of the earliest cognitive symptoms of AD. On the other hand, the lack of CMS coverage renders the scan inaccessible to patients with established dementia whose care would directly benefit from its use. CMS still has a chance to partner with the AD research community and help us translate this promising new technology to improve standard of care. Such a decision would go a long way towards addressing the nihilism that is unfortunately pervasive in current clinical practice and perhaps in our society regarding the diagnosis and care of patients with dementia.

Sincerely,

Gil D. Rabinovici, M.D.
Assistant Professor in Neurology
UCSF Memory & Aging Center

References:

1. Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, Karlawish JH, Rowe CC, Carrillo MC, Hartley DM, Hedrick S, Pappas V, Thies WH. 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. Alzheimers Dement 2013.

2. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012;71(4):266-273.

3. Roberson ED, Hesse JH, Rose KD, Slama H, Johnson JK, Yaffe K, Forman MS, Miller CA, Trojanowski JQ, Kramer JH, Miller BL. Frontotemporal dementia progresses to death faster than Alzheimer disease. Neurology 2005;65(5):719-725.

4. Goldman JS. New approaches to genetic counseling and testing for Alzheimer's disease and frontotemporal degeneration. Curr Neurol Neurosci Rep 2012;12(5):502-510.

5. Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry 2007;15(1):84-87.

6. Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf-Radford N, Mendez M, Kerwin D, Lerner A, Wu CK, Koestler M, Shapira J, Sullivan K, Klepac K, Lipowski K, Ullah J, Fields S, Kramer JH, Merrilees J, Neuhaus J, Mesulam MM, Miller BL. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013;12(2):149-156.

7. Villemagne VL, Pike KE, Chetelat G, Ellis KA, Mulligan RS, Bourgeat P, Ackermann U, Jones G, Szoeke C, Salvado O, Martins R, O'Keefe G, Mathis CA, Klunk WE, Ames D, Masters CL, Rowe CC. Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 2011;69(1):181-192.

8. Rabinovici GD, Rosen HJ, Alkalay A, Kornak J, Furst AJ, Agarwal N, Mormino EC, O'Neil JP, Janabi M, Karydas A, Growdon ME, Jang JY, Huang EJ, Dearmond SJ, Trojanowski JQ, Grinberg LT, Gorno-Tempini ML, Seeley WW, Miller BL, Jagust WJ. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology 2011;77(23):2034-2042.

9. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O'Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68(20):1718-1725.

10. Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, O'Keefe G, Ackerman U, Tochon-Danguy H, Chan JG, Reininger CB, Fels L, Putz B, Rohde B, Masters CL, Rowe CC. Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias. J Nucl Med 2011;52(8):1210-1217.

11. Drzezga A, Grimmer T, Henriksen G, Stangier I, Perneczky R, Diehl-Schmid J, Mathis CA, Klunk WE, Price J, DeKosky S, Wester HJ, Schwaiger M, Kurz A. Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer's disease. Neuroimage 2008;39(2):619-633.

12. Engler H, Santillo AF, Wang SX, Lindau M, Savitcheva I, Nordberg A, Lannfelt L, Langstrom B, Kilander L. In vivo amyloid imaging with PET in frontotemporal dementia. Eur J Nucl Med Mol Imaging 2008;35(1):100-106.

13. Lehmann M, Seeley WW, Ghosh PM, Madison C, Miller BL, Grinberg LT, Trojanowski JQ, Mendez MF, Vinters HV, Jagust WJ, Rabinovici GD. Utility of amyloid PET in the differential diagnosis of dementia: an autopsy-confirmed series. In: AAIC; 2013; Boston, MA, 2013.

14. Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 2012;11(8):669-678.

15. Sanchez-Juan P, Ghosh PM, Hagen J, Gesierich B, Henry M, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD. The Practical Utility of Amyloid and FDG PET in an Academic Dementia Center. In: AAIC; 2013; Boston, MA, 2013.

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July 23, 2013

Louis B. Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard, Mail Stop S3-02-01
Baltimore, Maryland 21244

Submitted via email to: CAGinquiries@cms.hhs.gov

RE: Proposed Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

Public Citizen, a consumer advocacy organization with more than 300,000 members and supporters nationwide, strongly supports the Centers for Medicare & Medicaid Services’ (CMS’s) proposed evidence-based decision memo regarding coverage for positron emission tomography (PET) amyloid-beta (Aß) imaging in dementia and neurodegenerative disease. The proposed CMS decision included the following conclusions and narrowly constructed circumstances under which CMS would provide coverage for such imaging:¹

We strongly agree that there is a lack of adequate evidence to establish that PET Aß imaging changes the health outcomes of patients displaying early symptoms or signs of cognitive dysfunction. Moreover, we are unaware of data from any completed, well-designed, controlled clinical trials evaluating whether PET Aß imaging changes the health outcomes of any patient population. Therefore, we agree that PET Aß imaging is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act and that any coverage for such imaging in the Medicare beneficiary population should be strictly limited to well-designed clinical studies that satisfy the above-proposed criteria.

As you are aware, in an editorial in the European Journal of Nuclear Medicine and Molecular Imaging²; and a subsequent critical review in the Journal of Alzheimer’s Disease,³ experts in the field of PET neuroimaging identified fundamental technological and practical problems with PET Aß imaging using radiotracers such as Avid Radiopharmaceuticals’ florbetapir F 18 injection (Amyvid), the only radiotracer approved by the Food and Drug Administration (FDA) for such imaging. These problems include the following:

Furthermore, a study measuring cerebral cortical uptake of florbetapir F 18 revealed substantial overlap in the range of uptake among the following three subject groups: patients with probable AD patients, patients with mild cognitive impairment, and older healthy controls.^4 Such performance characteristics of PET Aß imaging predict that the test will have little clinical utility in evaluating patients with mild cognitive impairment or suspected early AD, the type of patients most likely to be offered such imaging.

Finally, data submitted to the FDA comparing the results of florbetapir-PET scans in a cohort of elderly end-of-life patients to staining results for brain Aß at subsequent autopsies (the gold standard for detecting brain ß-amyloid) revealed significant variability among readers interpreting the PET scans.^5 Five nuclear medicine physicians who were trained with Avid Radiopharmaceuticals’ proposed web-based reader training program — the training methodology to be used for clinical implementation of the drug — were asked to retrospectively read florbetapir-PET scans in 59 subjects who subsequently underwent autopsy and staining for brain ß-amyloid. The readers were instructed to use a binary reading system and classify each scan as either positive or negative. The median sensitivity among the five readers was 82 percent, with a range of 69 to 92 percent, and the median specificity was 95 percent, with a range of 90 to 95 percent.^6 The overall median error rate for the five readers was 14 percent, with a range of 8 to 22 percent.

Undoubtedly, when widely deployed in real-world settings, there will be significantly greater variability in reader training and skill as well as in the characteristics of the patient population for which florbetapir-PET brain imaging presumably is intended. As a result, the performance of the test in clinical practice will be substantially worse than that seen in the carefully controlled setting of a clinical trial.

Most important, even if there existed a perfectly accurate (100% sensitive and 100% specific) imaging for detecting brain Aß deposits — and no such test does exist — such imaging would still lack clinical utility because: (a) brain Aß deposits occur in multiple other pathologic conditions, including dementia with Lewy bodies, cerebral amyloid angiopathy, Parkinson’s disease, Huntington’s disease, and inclusion body myositis, as well as normal aging;^7,^8,^9,^10 and (b) the currently available treatments for AD are ineffective in preventing progression of the disease and offer minimal clinically significant benefits in treating the signs and symptoms of the disease. Therefore, all patients being evaluated for cognitive impairment or early onset dementia should undergo the same thorough evaluation for possible reversible causes of impaired cognition or early dementia regardless of whether they have a negative or positive imaging test for brain Aß.

In summary, we strongly recommend that CMS finalize its decision memo for PET Aß imaging in dementia and neurodegenerative disease (CAG-00431N) as proposed, for the following reasons:

1. There are no data from any completed, well-designed, controlled clinical trials evaluating whether PET imaging of brain Aß changes the health outcomes of patients who display early symptoms or signs of cognitive dysfunction, or in any other patient population.
2. There is a lack of correlation in AD patients between the areas of the brain showing a positive signal on PET Aß scans and those areas of the brain having the highest density of Aß deposits at autopsy.
3. Interpretation of brain Aß PET scans is subject to significant variability among readers.
4. The results of brain Aß PET scans currently have no clinical utility because the results of such imaging should have no impact on the clinical evaluation of patients with cognitive impairment or early onset dementia.

Thank you for considering our comments regarding this important issue.

1 Centers for Medicare & Medicaid Services. Proposed decision memo for beta amyloid positron emission tomography in dementia and neurodegenerative disease (CAG-00431N). http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265. Accessed July 22, 2013.

2 Moghbel MC, Saboury B, Basu S, et al. Amyloid- imaging with PET in Alzheimer’s disease: Is it feasible with current radiotracers and technologies? Eur J Nucl Med Mol Imaging. 2012;39(2):202-208.

3 Kepe V, Moghbel MC, Langstrom B, et al. Amyloid- positron emission tomography imaging probes: A critical review. J Alzheimers Dis. May 6, 2013 [Epub ahead of print]. DOI:10.3233/JAD-130485.

4 Fleisher AS, Chen K, Liu X, et al. 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.

5 Feng Q. Center for Drug Evaluation and Research Clinical Review for NDA 202-008, Amyvid (florbetapir F 18 injection). March 7, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202008Orig1s000MedR.pdf. Accessed July 22, 2013.

6 Eli Lilly and Company. Drug label for Amyvid (florbetapir F 18 injection) for intravenous use. Revised April 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf. Accessed July 22, 2013.

7 Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol. 1985;42(11):1097-1105.

8 The Food and Drug Administration. Summary minutes of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting. October 23, 2008. http://www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4382m1-Final.pdf. Accessed July 22, 2013.

9 Eli Lilly and Company. Drug label for Amyvid (florbetapir F 18 injection) for intravenous use. Revised April 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf. Accessed July 22, 2013.

10 Centers for Medicare & Medicaid Services. Proposed decision memo for beta amyloid positron emission tomography in dementia and neurodegenerative disease (CAG-00431N). http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265. Accessed July 22, 2013.

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July 23, 2013

Louis Jacques, M.D.
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) Tracking Sheet for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dear Dr. Jacques:

I am a neurologist who has been studying Alzheimer’s disease for over 25 years. I am surprised and dismayed by the CMS proposed decision memo for brain amyloid imaging and believe it does a disservice to patients.

I endorse the comments made previously by Drs. Foster, Salloway, Fleisher, and Devous and the experts who developed the Appropriate Use Criteria (1) in conjunction with the Alzheimer’s Association and the Society for Nuclear Medicine and Molecular Imaging.

It should be borne in mind that medicine is an imperfect science and that treatment decisions are typically based on currently available informative studies, even when they are imperfect. I cannot understand the CMS position, essentially requiring the community to wait years or decades for the perfect study to complete, when patients need the most appropriate treatment now.

An example of this requirement for a perfect study to complete before coverage will be provided can be seen in the decision memo discussion on differentiating frontotemporal dementia (FTD) and Alzheimer’s disease; the decision memo states:

1. Regarding AD medications, “harm potentially exists if patients with FTD are mistakenly diagnosed with AD and placed on such medications”.
2. “Cholinesterase inhibitors have been shown to exacerbate symptoms in some patients with FTD, and use of memantine has correlated with greater functional and cognitive decline”.
3. For amyloid imaging “overall classification accuracy (using 2 visual and 1 quantitative techniques) was 97%”.
4. Nevertheless the reviewers conclude that although “a negative scan could avoid inappropriate and possibly toxic use of medications, more evidence needs to be developed”.

CMS notes in their decision memo that “we consider avoidance of harm to be a legitimate health outcome”. The decision memo also indicates with respect to treating dementia patients with cholinesterase inhibitors that “no additional harm appears to result from a misdiagnosis that places patients on such dementia medications”.

In regard to these last points, I’d like to offer some additional data regarding the harm that the CMS decision will likely inflict upon large numbers of patients with Mild Cognitive Impairment (MCI) who do not have Alzheimer’s disease but who may ultimately be treated with cholinesterase inhibitors due to this draft lack-of-coverage decision.

Please consider the following data:

1. It has been shown repeatedly that amyloid PET positive MCI patients have more rapid cognitive and functional decline compared to amyloid negative MCI patients.(2-4) These findings are consistent with the presence of AD pathology in amyloid PET positive MCI subjects, and with the high accuracy observed between amyloid PET and amyloid pathology seen at autopsy. (5)
2. Off label treatment of MCI patients with cholinesterase inhibitors is widespread and is as high as 35%-44% in some studies.(6-8)
3. The treatment of MCI patients with cholinesterase inhibitors who have underlying AD pathology based on amyloid PET may be justified on the basis that these drugs are approved for patients with mild Alzheimer’s disease and that amyloid PET positive MCI subjects show the phenotypic pattern of decline of AD patients.
4. The treatment of MCI patients with cholinesterase inhibitors who do not have underlying AD pathology and who are unlikely to decline is harmful in most cases for two reasons: First, cholinesterase inhibitor treatment in this population is associated with morbidity. In prior MCI trials (9-12) the incidence of adverse events for approved cholinesterase inhibitors ranged between 8.4%-49.3% for nausea; 15%-23.2% for diarrhea; and 8.2%-12.3% for insomnia. In the majority of these studies these event rates were twofold or greater compared with placebo. In some of these studies additional side effects included muscle cramps (13.3%-16.3%),(10,13) vomiting (6.0%-32.5%),(12,13) and dizziness (14%-24.8%).(11,12) Second, studies conducted in young and elderly healthy controls have found that cholinesterase inhibitor treatment was associated with significant worsening on some cognitive tests.(14,15) The study authors note that the negative findings observed on cognition may be “particularly relevant for clinicians who must distinguish between MCI with impending conversion to AD and the normal memory decline that occurs with aging”.(15)
5. In patients with MCI, amyloid PET can help clinicians determine which patients have underlying AD pathology and which patients do not; moreover, current data suggest that this information is likely to change physician behavior and lead to more appropriate treatment decisions.(16)
6. MCI prevalence in older individuals ranges between 11% and 20% with a prevalence of 16% in Rochester, Minnesota.13 The 2010 census bureau report estimates that in the US there are approximately 40 million people over age 65; given these figures, there may be 6 million or more people in the US with MCI. The prevalence of amyloid negative MCI ranges between 31% and 63% depending on the study,(2-4) so possibly one-third to two-thirds of potentially millions of patients treated for MCI with cholinesterase inhibitors are treated unnecessarily and subjected to unnecessary side effects.
7. By declining amyloid PET coverage in MCI patients CMS is subjecting large numbers of MCI patients who do not have underlying AD to a trial and error treatment approach by their physicians that likely harms them without offering any benefit. If CMS seriously considers “avoidance of harm to be a legitimate health outcome”, CMS should consider allowing coverage of amyloid PET in patients with MCI based on these data so that physicians can make more informed treatment decisions. The scale of unnecessary treatments and potential side effects that CMS may impose on the elderly of this country by denying coverage in MCI patients should be recognized.

The FDA product insert for Amyvid asserts that a negative Amyvid scan “reduces the likelihood that a patient’s cognitive impairment is due to AD”. By differentiating MCI patients who have AD from those who don’t, better treatment decisions can be made that avoid the needless and potentially harmful treatment of amyloid negative MCI patients with cholinesterase inhibitors. The CMS requirement for new health outcome studies prior to coverage will be associated with at least a several year delay of coverage for MCI patients while the community waits for these studies to finish. In the meantime MCI patients will continue to be exposed to potential harm that could have been avoided by coverage of amyloid PET in patients with MCI.

Thank you for considering these comments.

References:

1. Johnson KA, Minoshima S, Bohnen NI, 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. Alzheimers Dement 2013;9:e-1-16.

2. Villemagne VL, Pike KE, Chetelat G, et al. Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 2011;69:181-92.

3. Okello A, Koivunen J, Edison P, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 2009;73:754-60.

4. Doraiswamy PM, Sperling RA, Coleman RE, et al. Amyloid-beta assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology 2012;79:1636-44.

5. Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 2012;11:669-78.

6. Schneider LS, Insel PS, Weiner MW. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol 2011;68:58-66.

7. Epstein NU, Saykin AJ, Risacher SL, Gao S, Farlow MR. Differences in medication use in the Alzheimer's disease neuroimaging initiative: analysis of baseline characteristics. Drugs Aging 2010;27:677-86.

8. McClendon MJ, Hernandez S, Smyth KA, Lerner AJ. Memantine and acetylcholinesterase inhibitor treatment in cases of CDR 0.5 or questionable impairment. J Alzheimers Dis 2009;16:577-83.

9. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-88.

10. Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology 2009;72:1555-61.

11. Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008;70:2024-35.

12. Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 2007;6:501-12.

13. Petersen RC, Roberts RO, Knopman DS, et al. Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging. Neurology 2010;75:889-97.

14. Beglinger LJ, Gaydos BL, Kareken DA, Tangphao-Daniels O, Siemers ER, Mohs RC. Neuropsychological test performance in healthy volunteers before and after donepezil administration. J Psychopharmacol 2004;18:102-8.

15. Beglinger LJ, Tangphao-Daniels O, Kareken DA, Zhang L, Mohs R, Siemers ER. Neuropsychological test performance in healthy elderly volunteers before and after donepezil administration: a randomized, controlled study. J Clin Psychopharmacol 2005;25:159-65.

16. Grundman M, Pontecorvo MJ, Salloway SP, et al. Potential impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline. Alzheimer Dis Assoc Disord 2013;27:4-15.

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With regards to the prognosis argument…

…many proponents for broadening the decision for CMS coverage of amyloid imaging are arguing for CMS to cover for indications that follow the guidelines suggested by SNMMI-AA “appropriate use” criteria and the FDA-approved language for amyloid imaging; some amyloid imaging proponents are concomitantly arguing that CMS should provide coverage for use in establishing “prognosis of MCI.”

So what are the guidelines laid out by the SNMMI-AA joint taskforce and the FDA, with respect to prognosis?

The SNMMI-AA taskforce has asserted that, with regard to “Prognosis in healthy individuals and in patients with MCI,” that “someday, as longitudinal research studies accumulate data, amyloid imaging may become useful to predict future clinical conditions, such as the risk of developing cognitive decline or of transitioning into clinical states such as MCI or dementia. However, these studies need further replication,” while the FDA-approved language for Amyvid (currently the only approved amyloid imaging agent in the United States) indicates, “Safety and effectiveness of Amyvid have not been established for predicting development of dementia.”

Thus, with respect to prognosis of MCI, the CMS proposed coverage decision in its current draft form is in line with not only MEDCAC recommendations, but also with the consensus opinions of the SNMMI-AA joint taskforce on the evidentiary basis for appropriate (and inappropriate) use of amyloid imaging, as well as with its FDA-approved indication language.

Dan Silverman, MD, PhD
Head, Neuronuclear Imaging Section
Ahmanson Translational Imaging Division
Professor, Department of Molecular and Medical Pharmacology
David Geffen School of Medicine, University of California, Los Angeles

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I performed an Amyvid scan recently on one of my 81yo male patients with Parkinson's Disease and cognitive impairment ( possible early Alzheimer's disease). Family and I are concerned about this patient since his wife is dying of hepatocellular carcinoma ( life expectancy 6-12months). Pt and wife living alone, in remote location, and in a large home. Entire family concerned about patient's increasing disability, especially if Parkinson's combined with Alzheimer's dementia in the near future. The Amvyid scan was negative ( no evidence of Beta amyloid plaque in cerebral cortical areas) . Thus, family relieved that Alzheimer's dementia will not be a major concern in near future. This has changed attitude of family toward patient, and pt has a much better mental outlook for himself. The scan had a significant impact on future care, especially for the next 3-5 years. Amyvid scan has been a significant tool in this patient's medical management. 2 other scans planned for similar type patient scenarios.

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I write primarily as a clinician but I am also an active investigator and teacher in the field and I was a non-voting member of the CMS panel that evaluated the utility of this new technology. I am also director of the Johns Hopkins Memory and Alzheimer's Treatment Center and Associate DIrector of the Johns Hopkins Alzheimer's Disease Research Center.

My main point is that the DRAFT proposal to limit payment for this test to the research setting is too limited and must be revised. I would like to argue that CMS should pay for the use of the test in the differential diagnosis and prognosis of patients with late life cognitive disorders such as Mild Cognitive Impairments that are NOT dementia. I argue further that initially this use should be limited to authorized Memory Centers affiliated with NIH-funded Alzheimer's Centers.

I am a clinician who has evaluated thousands of patients with dementia over the years. In my experiences, the two major questions that patients and families with cognitive disorders have are: 1) what will become of me (the patient) and 2) what can you do to help? Nowadays there is a lot of evidence supporting the 'package' of dementia care (see Giltin, Kales, Lyketsos in JAMA 2012;308(19):2020-2029) as the answer to #2. The word is out about this such that memory centers are inundated with patients. More and more they come at early stages to receive care, for example with the clinical disorders we call MCI or its cousins. The VAST majority are CMS beneficiaries.

In this context, over the years the field has been keen to have methods that assist in differential diagnosis and, especially, PROGNOSIS. After the onset of the syndrome of dementia, we are pretty good at making prognosis using available methods. We hope that emerging biomarkers will improve prognosis after onset of dementia.

We are faced with a serious challenge in prognosis when patients present with milder cognitive disorders, such as MCI. These patients may also have a range of symptoms, both cognitive and neuropsychiatric (e.g., affective symptoms, agitation, apathy) and many have atypical presentations.

Beta amyloid imaging has SOLID data that support its use in this setting: 1) Amyloid positive MCI has a bad prognosis and amyloid negative MCI has a good prognosis; 2) Amyloid imaging in MCI and related cognitive disorders (e.g., late life depression) also provides direction as to treatment that should be applied. For example, a patient with late life onset of atypical depression who is amyloid negative will be treated very differently than an amyloid positive such patient. The same is true for a patient who has apparent "Vascular Cognitive Impairment' but turns out to be amyloid positive (as opposed to amyloid negative).

I am recommending that this decision be modified to allow the use of Beta Amyloid Imaging in the differential diagnosis or prognosis of MCI and related late life cognitive disorders. As a first step this could be limited to Memory Disorder Centers that are already established and associated with the 29 currently NIH-funded Alzheimer's Disease Centers. These should be thought of as the equivalent of Comprehensive Cancer Centers. The field can then quickly develop ways of credentialing new Centers that would be authorized to conduct this testing in this context.

This staged approach will make the test available right away to CMS beneficiaries who will benefit right away. It will also lay a roadmap for further expansion of limited use of this very important diagnostic and prognostic test. CMS can also work with the 'authorized centers' to collect data that will aid in further defining, and possibly expand, the evidence-based clinical utility of beta-amyloid brain imaging.

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To whom it may concern:

I applaud the exhaustive and comprehensive review conducted by the Panel that resulted in the current decision to limit coverage to a single beta amyloid PET in select clinical research studies. Although I am in agreement with much of the panel's interpretation of the existing literature,I strongly disagree with the interpretation of the existing data on the current impact beta amyloid PET (specifically florbetapir)tests have on clinical practice and diagnosis (e.g., Grundman et al., 2012). For the reasons summarized below, I urge CMS to change its recommendation and provide coverage for the appropriate clinical use of beta amyloid PET in the diagnosis of Alzheimer's disease (AD).

We are at a critical juncture in the field of AD clinical care and research. The majority of patients with dementia from AD are neither diagnosed nor treated by primary care physicians (PCPs). This is due, in part, to the current view of PCPs that: (1) there is no way of accurately diagnosing AD prior to postmortem neuropathological evaluation and, therefore, they do not diagnose their patients with AD, nor have the ability to make an appropriate differential diagnosis between AD and other causes of cognitive/behavioral decline and dementia; and (2) if a patient has cognitive impairment and functional decline, the patient may have "dementia," but they do not feel comfortable using the diagnosis of AD; this results in patients and their loved ones feeling that they are "fortunate" that they "only" have "dementia," but do not have "Alzheimer's." Without PCPs (and specialists) having the ability to improve their diagnostic accuracy and/or feel that it is appropriate to diagnose patients with AD, we are doing an injustice to the millions of Americans who likely go undiagnosed or misdiagnosed. And, although the current FDA approved medications do not provide a tremendous benefit, they do provide some symptomatic improvement in some patients. Moreover, there are tremendously important non-pharmacological approaches and additional low-cost supportive and educational tasks that can improve quality of life, reduce risk of medication mismanagement or poor compliance, keep patients out of the hospital, and, most importantly, provide the patient and loved ones with invaluable answers.

Although I do applaud the decision to support beta amyloid PET for much needed clinical research (especially at this most hopeful time of the potential efficacy of early treatment with disease-modifying compounds), I strongly disagree with the decision to not provide coverage for clinical use of these tests. I fervently urge CMS to provide coverage for appropriate clinical use of beta amyloid PET.

Sincerely,

Dr. Robert Stern
Professor of Neurology and Neurosurgery
Director, Clinical Core, BU Alzheimer's Disease Center
Boston University School of Medicine

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July 18, 2013

Louis B. Jacques, MD
Director, Coverage & Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memorandum on National Coverage Analysis (NCA) for Beta-Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N)

Dr. Jacques:

On behalf of Lilly USA, LLC (Lilly), we are providing our first set of comments on the Centers for Medicare & Medicaid Services (CMS) Proposed Decision Memorandum on Beta-amyloid Positron Emission Tomography (PET) in Dementia and Neurodegenerative Disease (CAG-00431N), published on July 3rd.^*1 We will follow up with a more detailed set of comments towards the end of the month, which will expand on the numerous medical/scientific/policy related challenges we have with the proposed decision.

Lilly strongly disagrees with the CMS draft decision failing to propose coverage for beta amyloid imaging for indications outlined in the Appropriate Use Criteria (AUC)^*2, except in the quite limited and wholly inadequate context of Coverage with Evidence Development (CED). Lilly maintains that in these populations, both the scientific evidence and the statutory standards for Medicare coverage support a determination that beta amyloid imaging agents, such as Amyvid™ (Florbetapir F-18 Injection), are reasonable and necessary in the diagnosis of patients with suspected Alzheimer’s Disease or other forms of cognitive impairment. We outline three key reasons for our opposition to the decision as proposed:

1. The lack of consistency between CMS’ proposal and the expert consensus recommendations, as published in the Appropriate Use Criteria (AUC).
2. The inaccurate characterization of the current care and treatment landscape for patients with Alzheimer’s Disease and other forms of cognitive impairment.
3. The clear conflict with the Administration’s initiative to prioritize and conquer Alzheimer’s disease, as articulated in the National Alzheimer’s Project Act^*3

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1. National Coverage Consistent with the Expert Consensus Appropriate Use Criteria (AUC) Is Both Warranted and Required.

Following the FDA approval of Amyvid, clinical thought leaders, patient advocates, and physician specialty societies developed a rigorous and evidence-based set of appropriate use recommendations for the use of beta amyloid imaging. This group, representing many prominent U.S. experts in the clinical evaluation and treatment of cognitive disorders, were convened by the Alzheimer’s Association in partnership with the Society of Nuclear Medicine and Molecular Imaging. As CMS is aware, these expert stakeholders are widely accepted as leaders in developing and identifying best practices for patients with cognitive impairment and Alzheimer’s Disease. Lilly strongly endorses the AUC and we believe these criteria provide CMS with a viable framework for coverage. Further, dismissing these standards as nothing more than a good start – as is stated within this draft decision – unfairly and incorrectly attempts to marginalize the expertise and medical leadership that went into their creation, as well as the patient needs for which they were developed.

The AUC emphasize that the use of beta amyloid imaging should be carefully targeted, and only utilized in patients who present with “(i) a cognitive complaint with objectively confirmed impairment; (ii) AD as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and (iii) when knowledge of the presence or absence of amyloid pathology is expected to increase diagnostic certainty and alter management.”^*4 Moreover, the new criteria take the additional—and important—step of identifying a number of circumstances in which the use of beta amyloid PET is inappropriate, providing practitioners with clear and appropriate limitations on utilization. The AUC make abundantly clear that beta amyloid imaging is not to be used for screening in asymptomatic patients, with patients that have no documentation of cognitive decline, or for patients that present with symptoms and clinical profiles that facilitate a clear and confident without the scan in the judgment of the treating physician.

The AUC population should be covered without CED. This ensures that amyloid imaging is immediately available, without further unnecessary delay, to patients with a reasonable and necessary need for this innovative technology. To do otherwise deprives Medicare beneficiaries of their statutory right to diagnostic coverage. We believe that the proposed decision, if not modified before its finalization, will violate the plain language of the Medicare Act.

Like many other stakeholders representing patient groups and providers in disparate disease states, Lilly is concerned that CMS is applying an inappropriate standard for coverage in their evaluation. It is important to recognize that the standards to assess the “reasonable and necessary” nature of diagnostic and treatment agents are different. Significantly, the statute’s plain language refers to items and services that are “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” 42 U.S.C. §1395y(a)(1)(A). If “improvement in health outcomes” is used as a coverage requirement for this or any other diagnostic tool, then CMS will have, in essence, required the statute to require both diagnosis and treatment. Such a decision would be contrary to the plain language of the statute and, as such, both arbitrary and capricious. More to the point, however, it would represent a fundamental retreat in Medicare coverage that would threaten access to diagnostic and other services far beyond the one class of products at issue here.

2. The Inaccurate and Inconsistent Characterization of the Current Care and Treatment Landscape Undermines the Integrity of the Proposed Decision Memorandum.

In the proposed decision, CMS challenges the value of beta amyloid imaging, attempting to support that position through statements suggesting an ineffective and ambiguous treatment landscape. Indeed, there are several medications approved specifically and exclusively for the treatment of Alzheimer's Disease that underscore the importance of a more accurate and informed diagnosis. Many of these medications (and some cases services/procedures) are currently being reimbursed by CMS, establishing them as reasonable and necessary as defined within their FDA-approved labels. As such, it is inappropriate for the agency to suggest that there is no value in further informing the diagnostic process in order to ensure their appropriate use.

Of course, there is still an opportunity to correct the draft decision prior to final decision and we would welcome this correction. The medical and scientific community that has advocated for beta amyloid imaging has done so on the basis that, in appropriate circumstances, it provides information that is useful to the diagnostic process. This adjunctive diagnostic tool, in these circumstances, also may impact the way providers ultimately manage their patients. We found the remarks in the draft decision inappropriately dismissive of these efforts and internally inconsistent.

Moreover, the recent NCD for FDG PET for Solid Tumors (CAG-00181R4)^*5 provides additional support for non-CED based coverage of beta amyloid imaging. In that decision, CMS endorsed intermediate outcomes of intended changes to patient management as the standard for the coverage of PET diagnostics, without citing specific examples of additional research that explicitly linked those changes to observed health outcomes. Lilly believes that the evidence supporting the value of amyloid imaging clearly meets this same threshold and hence should be covered in line with the established precedent.

Finally, it is important to revisit this draft decision with the understanding that the currently approved beta amyloid imaging agent – (Amyvid™ (Florbetapir F-18 Injection) – is indicated as an adjunct to other diagnostic evaluations. Despite this, the draft decision continually posits questions and statements that are inconsistent with this FDA-approved use, and hence are inappropriately included in an unsuccessful attempt to undermine the clear value of the innovative tool. When discussing the “Competing views on the role of amyloid” (Section II, Background), for example, the three paragraphs offered by CMS on the topic question and evaluate amyloid deposition in the brain as if it can only be covered by the program if it were an independent predictor of Alzheimer’s disease – questioning the “threshold level of amyloid” for a diagnosis and noting that “Aß accumulation is necessary but not sufficient to produce the clinical manifestations of AD.” Given that Medicare covers the clinical evaluations of patients that are inadequate to arrive at a diagnosis of Alzheimer’s without determining that plaque is present, Medicare’s coverage positions are internally inconsistent. Indeed, although it is true that amyloid deposition is only understood in combination with a substantial and well-defined clinical work-up, the reverse is also the case in many circumstances. CMS, however, does not dispute or challenge the necessity of the clinical work-up and its coverage.

The AUC provide all of the necessary clinical context and offer the definition of how value should be assessed and assigned within this clinical space when amyloid testing is undertaken. Evaluating beta amyloid imaging without this medically nuanced and clinically-meaningful perspective is not appropriate. Beta amyloid imaging offers one of several critical components of the diagnostic process for appropriate patients suffering from Alzheimer’s Disease and other forms of cognitive impairment. To dismiss this value and importance on the basis of an erroneous evaluation would be a mistake and would disregard the incredible work being undertaken each day by the entire community working to identify and treat these diseases.

3. Providing Coverage for the AUC Population (without CED) Is Necessary to Support a Key Component of the National Alzheimer’s Project Act (NAPA).

In response to the mounting national health threat posed by Alzheimer’s Disease, a unanimous and bipartisan Congress passed NAPA in 2010. NAPA has brought about renewed urgency and focus on the new advances in the diagnosis, support, and treatment of patients suffering from Alzheimer’s Disease. NAPA specifically charges the Secretary of Health and Human Services with the responsibility to pursue efforts to “improve the early diagnosis of Alzheimer’s Disease” and to “accelerate the development of treatments that would prevent, halt, or reverse the course of Alzheimer’s.” The plan also states that “far too many people with Alzheimer’s Disease are not diagnosed until their symptoms have become severe” and “timely diagnosis gives people with the condition and their family’s time to plan and prepare for the future, leading to more positive outcomes for both.” The National Plan specifically declares that HHS will “ensure that as evidence-based solutions are identified they are quickly translated, put into practice, and brought to scale so that individuals with Alzheimer’s Disease can benefit from increases in scientific knowledge.” ^*6

CMS coverage for beta amyloid imaging in the AUC population—the first (and only) product approved by FDA after CMS last updated Section 220.6 in 2009— would constitute a crucial step forward in bringing to reality the achievements required by NAPA. A rejection of coverage as suggested in this draft would be fundamentally inconsistent with the Secretary’s statement regarding the value of timely diagnosis, as well as the Administration’s commitment to innovation in Alzheimer’s Disease. We urge CMS to reconsider their approach and act in a fashion that is consistent with and furthers the goals, objectives, and values codified within the National Plan.

Conclusion

The proposed memorandum’s failure to provide any non-CED coverage for beta amyloid imaging is in conflict with expert consensus and the Administration's National Alzheimer’s Project Act. If made final, the proposed coverage decision for CED will represent a significant delay, potentially by years, in appropriate patient access to this innovative tool. There is a recognized need to improve the accuracy and timeliness of diagnosis, and there is sufficient, existing clinical evidence of the benefits of this innovative technology to beneficiaries. When combined with the rigorous framework of the AUC, national Medicare coverage for this new class of PET tracers for beta amyloid identification in this population without CED is feasible, reasonable, and necessary.

Lilly is committed to developing innovative technologies that improve the lives of patients. We look forward to continuing to work with CMS and Alzheimer’s disease stakeholders to ensure that Medicare beneficiaries have timely and appropriate access to this important technology.

Sincerely,

Derek Asay
Sr. Director, Government Strategy, Federal Accounts and Quality

Sean Donohue
Sr. Director, Federal Affairs

REFERENCES

*1 Centers for Medicare & Medicaid Services. Proposed decision memo for beta amyloid positron emission tomography in dementia and neurodegenerative disease (CAG-00431N). http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=265. Published July 3, 2013. Accessed July 3, 2013.

*2 KA Johnson, S Minoshima, 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 & Dementia (2013) 1-15. Available at http://www.alz.org/research/downloads/appropriate_use_criteria_for_amyloid_pet_alz_and_dem_january_2013.pdf.

*3 National Alzheimer’s Project Act, Pub. L. 111-375 (Jan. 4, 2011), available at http://www.gpo.gov/fdsys/pkg/PLAW-111publ375/html/PLAW-111publ375.htm.

*4 KA Johnson, S Minoshima, 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 & Dementia (2013) 1-15. Available at http://www.alz.org/research/downloads/appropriate_use_criteria_for_amyloid_pet_alz_and_dem_january_2013.pdf.

*5 National Coverage Analysis (NCA) for Positron Emission Tomography (FDG) for Solid Tumors (CAG-00181R4): http://www.cms.gov/medicare-coverage-database/details/nca-details.aspx?NCAId=263&NcaName=Positron+Emission+Tomography+(FDG)+for+Solid+Tumors+(4th+Recon)&bc=ACAAAAAAAAAAAA%3d%3d&

*6 National Alzheimer’s Project Act, Pub. L. 111-375 (Jan. 4, 2011), available at http://www.gpo.gov/fdsys/pkg/PLAW-111publ375/html/PLAW-111publ375.htm.

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As CMS is recommending that coverage be in the context of evidence development, the requirement that the compound tested be FDA approved should extend to compounds for which the investigator could obtain an IND. For instance, it would be foolish not to cover PIB, the amyloid compound that provides the best quality images and for which there is the most experience. There are already in the pipeline compounds likely as good as PIB, but for which there is still very little experience. Covering the use of PIB would render the proposed evidence development meaningful for compounds better than florbetapir, likely to be available when the CED studies are completed. This approach would additionally serve to validate the intent of CMS, making it less likely that it be perceived as a decision aimed at avoiding the deluge of florbetapir scans likely to occur if any clinical scan were covered.

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Full text of the comment is also available at: http://www.mybraintest.org/2013/07/should-medicare-cover-the-cost-of-brain-imaging-tests-for-alzheimers-diagnosis/

Positron Emission Tomography (PET) imaging tests can identify amyloid beta deposits in the brain by using imaging agents that are introduced into the brain through the bloodstream. These imaging agents bind to amyloid beta plaques in the brain, allowing for a sensitive and generally accurate measure of amyloid beta “load” or “burden” in the patient’s brain – the higher the amyloid burden, the higher the probability of an Alzheimer’s diagnosis, in combination with other measures like neurocognitive testing that confirms memory impairment.

The technology and science behind PET imaging is very solid, confirmed through countless research studies and clinical trials.

That’s the good news. Now for the bad news: PET imaging tests are an expensive diagnostic option, with an average cost of $3,000 per brain scan.

On an individual level, it’s clear that many concerned older adults and family members would want the (probable) certainty provided by a positive PET imaging test result. Knowing with certainty that a family member has Alzheimer’s allows for proactive choices on care planning, medication management, patient safety, and many other positive benefits.

On a national level, one of the elephants in the room is the potentially enormous cost of PET brain imaging tests, if used on a large scale. Currently, the Centers for Medicare & Medicaid Service (CMS), which acts as a gatekeeper for what Medicare will and will not pay for, does not cover amyloid PET scans for the purpose of Alzheimer’s clinical diagnosis.

Estimating Medicare Costs for PET Imaging Tests if used for Alzheimer’s Diagnosis

When CMS makes a decision to cover any new diagnostic test, the implications are important. Consider these Medicare numbers: according to the Kaiser Family Foundation, there are over 49 Million people on Medicare rolls as of 2012. Factoring out people under age 65 (SSI disability, etc), there are about 40 Million people age 65+ on Medicare.

So, how many of these 40 Million Medicare enrollees might ask (through their physician) for an Alzheimer’s diagnostic brain scan in the future? That’s hard to say, but we can use a couple of guideposts to start: Medicare’s Annual Wellness Visit benefit (which includes a loosely worded “detection of any cognitive impairment”) posted a utilization rate of 9% in 2012, up from about 6% in 2011. Secondly, the CDC reports in a recent study that 1 in 8 people over age 65 report memory problems, or about 12.5% of all people over age 65.

Using a 10% Medicare utilization rate as a pivot, this can give us a cost range for amyloid PET scans:

These are big numbers for potential Medicare funded amyloid PET scans. At the same time, several studies confirm that Medicare patients with Alzheimer’s or other types of dementia consume health care services at triple the rate of cognitively intact patients. The total cost of Medicare & Medicaid benefits to Alzheimer’s and dementia patients was over $140 Billion last year, and is expected to skyrocket over the next few decades.

Looking at the Economic Benefits of Diagnostic Brain Scans for Alzheimer’s Disease

It would be interesting for the Alzheimer’s Association and other stakeholders to clearly lay out the economic benefit (mainly from reduced health care expenditures) of amyloid PET scans for Alzheimer’s diagnosis, along with other methods such as annual cognitive screening for memory impairment.

According to the criteria suggested by the Alzheimer's Association, appropriate candidates for amyloid PET imaging include:

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I am a physician who frequently evaluates patients with cognitive impairment. I have reviewed the CMS draft decision on amyloid PET in detail. I concur with the broad agreement within the community knowledgeable about Alzheimer’s disease and related dementias that amyloid PET is a valuable clinical tool that are patients need today. I support the published Appropriate Use Criteria for amyloid PET.

I strongly disagree with the proposed draft decision. It should be reconsidered. The overall effect of the decision will not improve the quality of care for patients. Instead it will discourage the best medical care and inhibit advances in knowledge that would benefit patients. It fails to recognize the clinical urgency for patients to the most accurate diagnosis and thus the most appropriate management. It fails to utilize Appropriate Use Criteria to define the intended population for amyloid PET and those for which amyloid PET is clearly inappropriate and potentially would be misused. Failing to cover any clinical use of amyloid PET is likely to increase its misuse by desperate patients and families. The decision fails to outline a clear path to coverage approval and instead proposes impractical and unprecedented requirements for coverage with evidence development.

In the following paragraphs I will provide details about the reasons the current draft requires substantial modification.

Many parts of the draft decision are medically incorrect. It seems to dismiss the fundamental principle of Western medicine that medical management should be based upon the cause of the patient’s illness. It is universally recognized that misdiagnoses is harmful, yet the decision opines that misdiagnoses are not harmful. The decision states without published evidence that “no additional harm results from their use, (i.e. AD drug treatments), because of misdiagnosis”. There also is universal recognition that knowing the underlying pathology in a patient is medically valuable. This is the basis for the entire medical field of pathology. Yet the decision assumes the opposite, without evidence - that knowing pathologic findings have no value to the care of patients with dementia. These statements are central to the draft decision and stand medical science on its head in order to justify denial of coverage.

The decision makes numerous factual errors that should be corrected in the final decision. This misinformation is not trivial, but appears to be central to the decision outcome. In several places the decision states there are “no effective treatments for AD”. However, randomized clinical trials have shown repeatedly that several drugs benefit patients with Alzheimer’s disease; this is the basis for their FDA approval and use in clinical practice. The draft decision states that “memantine and cholinesterase inhibitors are not AD medications”, yet this is their primary approved indication. There are no modern drugs that have FDA approval for otherwise undefined dementia. The decision reflects a misunderstanding of how amyloid PET imaging is intended to be used. It is not intended to be a diagnostic test for Alzheimer’s disease or for excluding the diagnosis of Alzheimer’s disease. FDA approval is not based upon this indication. Instead it is intended to be a diagnostic test for an essential component of Alzheimer’s disease pathology, namely fibrillar amyloid. Repeatedly the decision fails to recognize this distinction. Thus, the results of amyloid PET imaging do not provide a clinical diagnosis. Instead a skilled clinician must integrate these test results with other information to arrive at a clinical diagnosis.

The decision has numerous internal inconsistencies that need to be resolved in the final decision. On the one hand, it recognizes the value of amyloid PET in more accurately identifying patients with and without Alzheimer’s disease pathology in clinical drug trials, yet at the same time denies any value in more accurately identifying patients with and without Alzheimer’s disease in clinical practice. It claims there are no treatments for Alzheimer’s disease, yet later discusses approved drug treatments for Alzheimer’s disease. It denies the clinical benefit of an accurate diagnosis, yet also states that an extensive evaluation is necessary. It recognizes the important role of family support, patient education and counseling and non-drug management as important patient outcomes, but also considers irrelevant to the coverage decision the “need to know” an accurate diagnosis on the part of physicians and families. An accurate diagnosis is necessary to assure that these kinds of interventions, recognized as important patient-oriented outcomes, are appropriate.

Parts of the draft decision are misleading and need revision. There is an extensive discussion about the uncertainty of the role of amyloid in disease causation. This gives leaves the misleading impression that there is uncertainty about whether identifying amyloid is relevant to diagnosis. There is no such disagreement. It is universally recognized that the presence of fibrillar amyloid is a hallmark of Alzheimer’s disease pathology. The discussion about disease causation is irrelevant to the coverage decision and should be deleted or a strong and clear statement about its irrelevance to coverage should be added.

There are unnecessary ambiguities in the decision that need clarification. Will CMS provide coverage with evidence development in a single trial or in multiple trials? This is especially relevant for how such trials would be designed. Precedent suggests only a single trial would be approved. If CMS will not provide financial support for the conduct or analysis of approved trials under this decision this should be explicitly stated. There also should be a statement about how CMS will determine whether outcomes are clinically meaningful and thus lead to a decision for coverage. Examples of diagnostic tests that have been approved for coverage with the proposed standards would help in the appropriate design of feasible trial or trials approved for coverage. If there are no previous examples this should be stated to not misrepresent the situation.

These problems and others not mentioned indicate that the draft decision is flawed and needs reconsideration and revision.

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Speaking as a clinician, I would strongly encourage CMS to consider covering amyloid imaging under two important conditions.

The first is early onset dementia (age < 60). The clinical presentation of Alzheimer's disease can be quite difficult to distinguish from Frontal Temporal Dementia at that age and both are nearly identical in their prevalence. I have considerable experience with the use of FDG PET (which is currently a reimbursable procedure) in this population and I find it extremely useful, but there are times when the images are difficult to interpret. Amyloid imaging is much more specific to AD pathology and therefore would substantially enhance my ability to diagnose and treat these individuals. Such a distinction is important for a number of reasons. FTD is much more likely to have autosomal dominant inheritance. In addition, FTD patients may have untoward responses to cholinesterace inhibitor treatment. As a consequence the management of FTD patients is substantially different than those with AD.

I believe cerebrovascular cognitive impairment to be a second indication for amyloid injury. I see a great deal of patients with cognitive decline after stroke and find myself confounded by the lack of definitive measures for determining AD pathology. Again, the treatment and prognosis for cognitive impairment due to cerebrovascular disease is substantially different than AD pathology.

I strongly encourage CMS to consider approving the use of amyloid imaging for clinical application under these two conditions.

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With respect to the relationship between decisions made by the U.S. Food and Drug Administration (FDA) and CMS...

...it may be "clear" (at least to some) that approval of a "diagnostic tool" by the FDA for a given indication should be regarded as equivalent to an obligation on the part of CMS to pay for the use of that tool for that indication, at least for those Medicare beneficiaries in whom that use would be "appropriate" (i.e., whose health would benefit from doing so) rather than (as current federal policy actually holds) as a minimal condition (except under special circumstances to be considered case by case) for CMS to evaluate whether it is reasonable and necessary for the American taxpayer to incur that financial obligation.

What is less clear, is whether there exist any Medicare beneficiaries whose health would actually benefit by being able "to estimate beta-amyloid neuritic plaque density" which remains the (only) FDA-approved indication for Amyvid.

What is more clear, according to not only the stated positions of the MEDCAC convened by CMS, but also of the joint taskforce of dementia experts convened by SNMMI and the Alzheimer's Association (AA), is that there exists no compelling evidence that such benefit would ensue for Medicare beneficiaries, and that more overall clinical good than harm would come from the use of Amyvid… even for those Medicare beneficiaries for whom its use is deemed to be "appropriate" by the SNMMI-AA taskforce.

Dan Silverman, MD, PhD
Head, Neuronuclear Imaging Section
Ahmanson Translational Imaging Division
Professor, Department of Molecular and Medical Pharmacology
David Geffen School of Medicine, University of California, Los Angeles

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It is clear that the CMS decision to Cover with Evidence Development will relegate this important diagnostic tool to only those that can afford it in this country, given current FDA approval of Amyvid PET. It is in direct contradiction to this administrations current efforts through the affordable care act and NAPA. This decision points to the lack of direct expertise in dementia care of the voting CMS panel and conflicts with a basic tenant in medicine regarding making the proper diagnosis before appropriate informed management decisions can be made. There are useful medical treatments for Alzheimer's disease. If misdiagnosed this result in unnecessary costs and risks to patients, in addition to leading to other unnecessary testing, or missing opportunities to treat the true cause of their impairment. There is clear value in knowing the correct diagnosis for psychological and life planning purposes that are critically important to patients and their families. This decision by CMS is a clear step backwards for the field and a hindrance to the momentum of the scientific community towards finding a cure.

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Since it has been suggested, among comments made here and in other forums, that the "consensus of expert opinion" reported by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer’s Association (AA) joint taskforce (J. Nucl. Med., 2013; 54:476-490) are in support of CMS coverage for amyloid imaging scans, unencumbered by the need to collect additional data via the opportunity provided by CMS through Coverage with Evidence Development (CED), it is worthwhile to look at precisely what this SNMMI-AA joint taskforce actually reported, and the context in which they defined their “appropriate use criteria” (AUC).

From the outset, that Taskforce stated that "empirical evidence of impact on clinical outcomes is not yet available," then amplified this statement saying, "direct evidence linking amyloid PET to health outcomes is currently lacking," and further iterated that "the data supporting specific outcomes for amyloid PET are not yet available." The experts of the SNMMI-AA Taskforce are thus in complete agreement with the consensus conclusion of the CMS MEDCAC that there is inadequate evidence to determine whether amyloid imaging changes health outcomes.

The experts convened by SNMMI and AA also stated that "experience with clinical amyloid PET imaging is limited. Most published studies to date have been designed to validate this technology and understand disease mechanisms rather than to evaluate applications in clinical practice. As a result, published data are available primarily from highly selected populations with prototypical findings rather than from patients with comorbidities, complex histories, and atypical features often seen in clinical practice." The Taskforce experts thus clarified that even those data that are available concerning amyloid imaging cannot be assumed to be generalizable to the scans that would be obtained for the kinds of patients that CMS is being asked to cover. In addition, the experts on this Taskforce acknowledged that they "did not consider other proposed diagnostic biomarkers for AD," including MRI and FDG-PET, and recommended that "the effective use of these diagnostic tests in relation to amyloid PET should be investigated further in the context of patient outcome, benefit, and resource use." In the absence of any clear data to guide such decisions, as well as the absence of this Taskforce, or any other expert group, even addressing the issue, it seems difficult to know whether (and, if ever, when) it might be appropriate for CMS to expend approximately $3000 of taxpayers' money for amyloid imaging, instead of (or in addition to) $1100 for FDG-PET, and/or $800 for brain MRI studies (approx.. Medicare reimbursement rate with and without contrast). In fact, it might be argued that the proposal CMS has made to cover such scans, even in the context of CED, is (overly?) generous – in the face of a penury of published papers providing preliminary evidence concerning when, if ever, it is reasonable or necessary to do so.

Dan Silverman, MD, PhD
Head, Neuronuclear Imaging Section
Ahmanson Translational Imaging Division
Professor, Department of Molecular and Medical Pharmacology
David Geffen School of Medicine, University of California, Los Angeles

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I am disappointed by the Centers for Medicare & Medicaid Services (CMS) draft coverage decision on brain amyloid imaging, particularly given the clear, scientific consensus recommendations provided to CMS by the Alzheimer’s Association and the Society for Nuclear Medicine and Molecular Imaging (SNMMI) regarding appropriate, limited coverage, only in specific populations.

As a nuclear medicine physician familiar with and currently providing beta-amyloid brain PET imaging, with Amyvid, for the diagnosis of Alzheimer’s Disease, I believe that sufficient evidence exists to support immediate coverage, which would change patient management, leading to better health outcomes for patients and assisting families making care decisions.

I understand that the CMS decision is currently in draft format. I recommend that CMS institute a policy similar to the National Oncologic PET Registry (NOPR) that was used to help evaluate 18-FDG PET in oncology. This would allow CMS to easily gather enough information to help make a final decision on beta-amyloid brain PET imaging coverage. A registry program similar to the NOPR program would be an easy way for physicians to enroll their patients in the program. This would allow more patients to be evaluated than if CMS coverage is limited to only those patients who can find an institution offering a CMS approved clinical trial.

Geoffrey R. Bodeau, MD
Medical Director of Nuclear Medicine and PET Imaging
Consulting Radiologists, Ltd.
Minneapolis, Minnesota

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This proposed decision follows the recommendation of the January 2013 MEDCAC, whose members ultimately addressed the question posed by the Chair, "How confident are you that there is adequate evidence to determine whether or not PET imaging of brain beta amyloid changes health outcomes [for either better or worse] in patients who display early symptoms or signs of cognitive dysfunction? One is low confidence and five is high confidence, you can vote anywhere from one to five." Result: none of the twelve voting members of the Committee voted that they had high confidence (a "5"), only one voted that she had moderately high confidence ("4"), the average score of voting members was 2.17, and the mode and median scores were both 2.00.

Of the non-officially voting industry and guest members of the Committee who were balloted, none had high confidence in the adequacy of the evidence; one voted "4." This latter non-officially voting Committee member, Dr. Peter Herscovitch, as President-Elect of the Society of Nuclear Medicine and Molecular Imaging had indicated that it was "a priority to focus on the development of new radiopharmaceuticals, particularly for brain amyloid imaging" nevertheless, Dr. Herscovitch qualified his vote during the MEDCAC meeting in two ways A) first, by explaining, "I would have voted a three [based on the evidence actually available for amyloid imaging], and perhaps this wasn't quite right, but... I did nudge it up to a four [based on "a lot of analogies" with the FDG-PET Medicare experience], and B) second, by following a comment on the need for more research with the statement, "I would concur with that, Coverage with Evidence Development (CED) would help fill in a lot of very substantial questions." Thus, there was nearly unanimous consensus that the evidence is inadequate to support a change [let alone an improvement] in health outcomes resulting from amyloid imaging.

The inadequacy of this evidence is virtually uncontested in the wider medical imaging and business communities as well. Thus, Wei-Li Shao, senior director of the Alzheimer’s business division at Eli Lilly and Company, which has marketed the first FDA-approved amyloid imaging agent, Amyvid, was reported in Molecular Imaging as having made the argument during a Lilly/Avid-sponsored media-attended conference call on 16 May 2013, not that any good evidence exists for improved health outcomes associated with use of Amyvid, but rather that "having to prove better health outcomes is not the business of diagnostic technologies."

The chief question that remains, then, is should good evidence of improved health outcomes exist, before CMS issues a national decision in favor of covering a new diagnostic procedure, outside the context of the CED mechanism? The Director of the CMS Coverage and Analysis Group Dr. Louis Jacques, has made it clear for several years that it is the position of his Group that such evidence should exist, which was well-reflected in how the primary voting question of the January 2013 MEDCAC meeting was framed. Though this may represent a different standard than diagnostic modalities have been held to in the past, that is not a particularly pertinent issue for making the decisions that affect our future... the more relevant question now is, what should the standard be, going forward?

The answer to this question, it seems, depends entirely upon the position and perspective of the person to whom it is posed. If you are the director of a business division of a company trying to market a new diagnostic technology, the (unsurprising) answer is that this is too high a standard. If, on the other hand, you are the director of coverage and analysis for CMS, the (again unsurprising) answer is that this is at the very least, the minimum standard to which a new diagnostic or therapeutic modality should be held, before American taxpayers are compelled to pay for it.

Like most of us, I myself have multiple positions and perspectives from which to consider this question. As a Nuclear Medicine physician whose livelihood might be enhanced by doing more amyloid imaging with our facility's PET scanners, through the increased income that would generate (i.e., through the increased money that would flow from the American taxpayer, to the UCLA Medical Group, to me), it might be considered natural for me to display some sympathy for Wei-Li Shao's position... thereby sharing the professional viewpoint of somebody else whose educational/training background is not as a Nuclear Medicine physician (or radiologist, or geriatrician, psychiatrist, or neurologist), or as a practicing M.D., or as a Ph.D. in molecular pharmacology (or neuroscience or medical imaging), but as an M.B.A. in Marketing. Clincal cash flow makes for strange bed-position fellows. On the other hand, as a potential future patient, and the adult child of a father who is already a Medicare beneficiary, it might be reasonable for me to want to know what the evidence-based odds are that the procedure would do some good for the status of our health and/or our quality of life, if it were to become indicated for either of us, when deciding whether to fork over the (not inconsiderable, in the face of the estimated $3000 approximate procedure cost) Medicare co-pay... not to mention to endure the time, discomfort, and inconvenience of undergoing the procedure.

Moreover, the Medicare-earmarked bite that is chewed out of my monthly paycheck is already Tysonesque (as I would suppose it also is for most of the readers of this comment), and as an American taxpayer, before I newly assume the financial obligation for a large number of other people's amyloid imaging scans, I might be forgiven for wanting, at the very least, to know whether there is convincing evidence that those diagnostic procedures I'm paying for would do some good, and overall do more good for, than harm to, our country's senior citizenry (the principal Medicare beneficiaries whom CMS would be covering to undergo this procedure).

Finally, as a scientist with experience doing PET-based research for over two decades, much of it focused upon neuroimaging performed in the evaluation of Alzheimer's and other neurodegenerative diseases, I think it is fair to consider the overwhelming consensus of the MEDCAC members, that for amyloid imaging no such convincing evidence currently exists, as well-reasoned and well-informed... and that such evidence will not exist, before availability of the kind of data generated from a multi-centered, randomized controlled trial, designed to objectively test the real-world impact of amyloid imaging upon health outcomes that are clinically meaningful, and sufficiently long-term (i.e., not merely upon short-term changes in diagnosis and management plans, without knowing whether such changes ultimately lead to more good than harm) a kind of data whose acquisition the CMS-proposed CED mechanism would help to facilitate.

During the present 30-day public comment period that is now following the release of their proposed decision, the decision-makers at CMS will have the opportunity to weigh the impact of their impending decision on all of these (and other) constituent groups and stakeholders, and then do the right thing... whatever that is ultimately deemed to be… and as a Nuclear Medicine physician/potential-future-patient/present-adult-child-of-a-geriatric-patient/American-taxpayer/biomedical scientist, I would forgive them if they decided to stick to their guns.

Dan Silverman, MD, PhD
Head, Neuronuclear Imaging Section
Ahmanson Translational Imaging Division
Professor, Department of Molecular and Medical Pharmacology
David Geffen School of Medicine, University of California, Los Angeles

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