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

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1 1300 North 17 th Street Suite 1752 Arlington, Virginia Tel: Fax: July 26, 2013 By electronic mail Louis Jacques, MD Director Coverage and Analysis Group Centers for Medicare and Medicaid Services Mail Stop S Security Blvd. Baltimore, MD 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 N) (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.

2 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

3 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

4 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.

5 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.

6 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.

7 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 Thank you for consideration of these comments. Respectfully, 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 Dementia+and+Neurodegenerative+Disease&bc=ACAAAAAACAAAAA%3d%3d& (hereinafter Proposed Decision ). 2 See, e.g., Perrier, et al., Multidetector-Row Computed Tomography in Suspected Pulmonary Embolism, New England Journal of Medicine, 352(2005): See, e.g., Jelinek, JS et al., Diagnosis of Primary Bone Tumors with Image-Guided Percutaneous Biopsy: Experience with 110 Tumors. Radiology. 223(2002): Proposed Decision, at Section VI. 5 Id., at Section VIII.B. 6 Prescribing Information for Amyvid (florbetapir F-18 injection), 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; 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: 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, 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: p 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 (2011). 16 National Plan to Address Alzheimer s Disease (2012), available at