National Alzheimer's Project Act: Public Comments on Advisory Council Meeting, April 2017

• S. DeSanti  |  04-12-2017
• M. Sharp  |  04-12-2017

Hello and thank you for another opportunity to provide input from the perspective of FTD -- one of the "related disorders". In addition to input on the recommendations voted on this morning I would like to reiterate the need for a clear and consistent terminology on dementia and emphasize the potential benefits that could come from a working group on dementia nomenclature as recommended by the research sub-committee.

But first, I would like to follow-up on the topic of the February's council meeting and announce that the FTD Disorders Registry was launched on [Date] and that within [x days] of it going live, [x#] of people registered, which exceeded expectations by far. The creation of the FTD Disorders Registry was a joint effort between The Association for Frontotemporal Degeneration (AFTD) and The Bluefield Project to cure Frontotemporal Dementia. Registry data will be used by advocacy groups, scientists, and clinicians to support research studies and clinical trials. It is both a Contact Registry and a Research Registry and will become a powerful new tool to help develop therapies and treatments for FTD. I urge you all to look up the registry online and please do not hesitate to contact me or AFTD for more information.

As the Program Manager at The Association for Frontotemporal Degeneration I speak to a lot of people coping with one of the various clinical diagnoses that fall under the umbrella of FTD. One of the most common complaints I hear is how frustrating and exhausting it is to repeatedly have to say "no, my spouse is not too young to have dementia" or "no it doesn't affect memory" and "yes FTD is a form of dementia but it's not the same as Alzheimer's". On top of everything else people coping with FTD will often have to educate others about the disease, including the medical professionals and healthcare providers they turn to for help. For them, the need for clearer and more consistent terms is painfully clear and even small improvement could help ease their burden.

We realize there are many reasons why developing a uniform nomenclature is a challenge. Not the least of which is the fact that we still do not fully understand the pathologies underlying the different causes of dementia. The NAPA council has already done a lot to promote a better understanding of different types of dementia. But as discoveries and breakthroughs are made, clear and accurate language will be needed to share the news and make the importance of dementia research clear to all the potential supporters and stakeholders. It would be unrealistic to expect a working group to unravel all the linguistic knots around dementia, but how we talk about it will guide what we do about it. I encourage the council to see the working group on nomenclature as both an opportunity for continued success in increasing awareness and understanding of dementia and necessary to gain the support required to accomplish the goals of the National Plan.

Good afternoon. My name is Dr. Susan De Santi and I am the Vice President of Medical Affairs, North America and Asia Pacific, for Piramal Imaging. I want to thank the council for the opportunity to make comments during this very important meeting.

Piramal Imaging markets Neuraceq™, a diagnostic radiopharmaceutical indicated 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.¹

Today, AD is usually diagnosed after an already symptomatic patient with a cognitive impairment undergoes an extensive clinical diagnostic workup. This workup typically includes family and medical history, physical and neurological examinations, psychiatric screen, laboratory tests (i.e. folate, B12 and thyroid blood tests) and imaging procedures such as computed tomography (CT) or magnetic resonance imaging (MRI) scans.

However, despite having acess to these mainstream diagnostic workups, it is clear that we are still far way from being able to early and accurately asses and characterize the cause of disease. A definitive diagnosis of AD can only be made post-mortum by histopathology which can reveal the presence of beta-amyloid plaques and neurofibrillary tangles. Recent post-mortem studies looking for AD pathology have shown that 10 to 30 percent of diagnoses based on clinical examinations alone are incorrect -- thus missing an opprtunity to better manage and provide care for patients who are suffering with the uncertainty of their cognitive decline.²

Our company is working to improve the diagnostic accuracy of patients by detecting the underlying pathologies causing the cognitive impairment. Combined with current diagnostic tests a PET scan with Neuraceq holds the promise to detect or rule out, with a high degree of sensitvity and specificity, the presence of beta-amyloid plaques in the brains of living patients. Studies have shown that diagnostic accuracy, physician confidence, and changes to patient management are seen when the results of the PET procedure, such as amyloid imaging are included as part of the diagnostic workup.³

Currently, beta-amyloid PET imaging is not covered by the Centers for Medicare and Medicaid Services (CMS) except for a limited number of scans performed under an approved Coverage with Evidence Development (CED) program. Per CMS program requirements, Medicare beneficiaries are eligible for one beta-amyloid PET imaging scan per lifetime, as long as the beneficiary is enrolled in a CMS-approved clinical trial.⁴

Since finalizing the CED decision in September 2013, CMS has approved four clinical trials of which three are actively enrolling with a total estimated beneficiary enrollment of 18,788. The bulk of patient enrollment is expected to occur through the Imaging Dementia -- Evidence for Amyloid Scanning (IDEAS) Study, which anticipates Medicare beneficiary enrollment of 18,488.⁵

Enrollment is expected to end in less than 1 year. Of the 46 million medicare beneficiaries over the age of 65, 15-20% are estimated to suffer from Mild Cognitive Impairment (MCI), a condition that increases the possibility of developing Alzheimer's or other dementias.⁶ However, fewer than 19,000 Medicare beneficiaries have access to beta-amyloid PET imaging as a covered Medicare benefit, due to the lack of clinical trial approvals by CMS. This means that less than 1% of the estimated 8 million to 11 million Medicare beneficiaries with MCI have access to beta-amyloid PET imaging.

This coverage ratio is lower than other Medicare CED programs, such as the National Oncologic PET Registry (NOPR), which enrolled over 100,000 Medicare beneficiaries⁷ and the Transcatheter Aortic Valve Replacement (TAVR) registry, which had registered almost 55,000 procedures by the end of 2015.⁸

While we recognize that CMS has the authority to institute CED decisions, Medicare is an entitlement program. All beneficiaries are supposed to have access to covered services and benefits. CMS is limiting coverage by not approving additional clinical trials under the beta-amyloid PET imaging CED. This is blocking beneficiary access to this important diagnostic tool, a benefit to which the beneficiaries are entitled. Furthermore, we are concerned that CMS has not approved clinical trials that will generate enough evidence to determine whether or not beta-amyloid PET imaging meets Medicare's "reasonable and necessary" standards for coverage.

We request that this Advisory Council ask CMS to explain how the current trials that have been approved under the existing CED will generate the evidence the agency needs to reconsider the PET coverage determination and efforts by the agency to develop or recruit investigators to develop new clinical trials that will generate other evidence necessary to reconsider the coverage determination.

Such an update provided in a public forum will inform stakeholders as to the current status of the CED determination, as well as publicize the types of research that the agency would like to see proposed in the near future.

We appreciate the opportunity to provide these comments, and we look forward to working with the Advisory Council to change the trajectory of Alzheimer's disease and related dementias. Piramal Imaging has also submitted written comments in advance of this meeting. Thank you.

NOTES:

1. Full Neuraceq Prescribing information is available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf.
2. Beach TG, Monsell SE, Phillips LE, Kukull W. J. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. Neuropathol Exp Neurol. 2012 Apr;71(4):266-73.
3. Boccardi M, et al. Jama Neurology, 2016
4. Additional details on CMS' coverage requirements are available online: https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/Amyloid-PET.html.
5. IDEAS Study. ClinicalTrials.gov NCT 02420756: https://clinicaltrials.gov/ct2/show/NCT02420756.
6. Alzheimer's Association. 2017 Alzheimer's Disease Facts and Figures. https://www.alz.org/documents_custom/2017-facts-and-figures.pdf.
7. CMS. https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/NaF-18-PET-for-Bone-Metastasis.html.
8. Grover F et al. 2016 Annual Report of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Jour of Am Coll Cardiology (December 9, 2016). http://www.onlinejacc.org/content/early/2016/12/02/j.jacc.2016.11.033?_ga=1.92519133.1911975317.1484767598.

Piramal Imaging is pleased to provide the following comments to the National Advisory Council on Alzheimer's Research, Care, and Services. Piramal Imaging markets Neuraceq™, a diagnostic radiopharmaceutical indicated 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.¹

Today, AD is usually diagnosed after an already symptomatic patient with a cognitive impairment undergoes an extensive clinical diagnostic workup. Thisn workup typically includes family and medical history, physical and neurological examinations, psychiatric screen, laboratory tests (i.e. folate, B12, and thyroid blood tests) and imaging procedures such as computed tomography (CT) or magnetic resonance imaging (MRI) scans.

However, despite having access to these mainstream diagnostic workups, it is clear we are still far awar from being able to early and accurately asses and characterize the cause of disease. A definitive diagnosis of AD can only be made post-mortem by histopathology which can reveal the presence of beta-amyloid plaques and neurofibrillary tangles. Recent post-mortem studies looking for AD pathology have shown that 10 to 30 percent of diagnoses based on clinical examinations alone are incorrect.²

This misses an opportunity to better manage and provide care for patients who are suffering from the uncertainty of their cognitive decline. Our company is working to improve the diagnostic accuracy of patients by detecting the underlying pathologies causing the cohnitive impairment. Combined with current diagnostic tests, a PET scan with Neuraceq holds the promise to detect or rule out, with a high degree of sensitivity and specificity, the presence of beta-amyloid plaques in the brains of living patients. Studies have shown that diagnostic accuarcy, physician confidence, and changes to patient management are seen when the results of the PET procedure are included as part of the diagnostic workup.³

Neuraceq may be used to assist in the differential diagnosis of Alzheimer's disease or other dementia types. In a pivotal phase 3 clinical trial, Neuraceq was shown to have a high affinity to beta-amyloid plaques in the brain, a hallmark of Alzheimer's disease.⁴ A negative Neuraceq 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 Neuraceq 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. Neuraceq is an adjunct to other diagnostic evaluations.⁵

In clinical practice, a patient suffering from cognitive impairment would undergo a clinical assessment by his or her clinician. If after the clinical assessment there is still some uncertainty regarding the cause of cognitive impairment, the clinician will then refer the patient to an imaging center for a beta-amyloid PET scan, using Neuraceq as the diagnostic agent. A radiologist/nuclear medicine specialist reads and interprets the scan and sends a report back to the patient's referring physician. The report includes the reader's findings about the presence of beta-amyloid plaques in the patient's brain. The referring physician can use the clinical findings with the results of the Neuraceq PET scan, including the presence or absence of beta-amyloid plaques, in their differential diagnosis of the patient. Both clinical and Neuraceq findings are important to consider when constructing the patient's treatment plan. Studies have shown that physician confidence in diagnosis is increased when results from beta-amyloid scans are used.⁶

Currently, beta-amyloid PET imaging is covered under Medicare's Coverage with Evidence Development (CED) program. Per CMS program requirements, Medicare beneficiaries are eligible for one beta-amyloid PET imaging scan per lifetime, as long as the beneficiary is enrolled in a CMS-approved clinical trial.⁷ Since finalizing the CED decision in September 2013, CMS has approved four clinical trials -- of which three are actively enrolling - with a total estimated beneficiary enrollment of 18,788. The bulk of patient enrollment is expected to occur through the Imaging Dementia -- Evidence for Amyloid Scanning (IDEAS) Study, which anticipates Medicare beneficiary enrollment of 18,488.⁸ Enrollment is expected to end in less than one year.

To our knowledge, CMS has not provided a public update on this CED program at an advisory council meeting. We urge the advisory council to request regular updates from CMS outlining the agency's progress on reviewing and approving new trials under the beta-amyloid PET imaging CED at the Council's public meetings.

Beta-amyloid PET imaging is intended to be used according to Appropriate Use Criteria developed by the Amyloid Imaging Task Force, Society of Nuclear Medicine and Molecular Imaging and the Alzheimer's Association, as an adjunct to other diagnostic evaluations in the following instances:

1. A cognitive complaint with objectively confirmed impairment;
2. Alzheimer's disease as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and
3. When knowledge of the presence or absence of beta-amyloid plaque density is expected to increase diagnostic certainty and alter management.⁹

    

Of the 46 million medicare beneficiaries over the age of 65, 15-20% are estimated to suffer from Mild Cognitive Impairment (MCI), a condition that increases the possibility of developing Alzheimer's or other dementias.¹⁰ However, fewer than 19,000 Medicare beneficiaries have access to beta-amyloid PET imaging as a covered Medicare benefit, due to the lack of clinical trial approvals by CMS. This means that less than 1% of the estimated 8 million to 11 million Medicare beneficiaries with MCI have access to beta-amyloid PET imaging. This coverage ratio is lower than other Medicare CED programs, such as the National Oncologic PET Registry (NOPR), which enrolled over 100,000 Medicare beneficiaries¹¹ and the Transcatheter Aortic Valve Replacement (TAVR) registry, which had registered almost 55,000 procedures by the end of 2015.¹²

While we recognize that CMS has the authority to institute CED decisions, Medicare is an entitlement program. All beneficiaries are supposed to have access to covered services and benefits. CMS is arbitrarily limiting coverage by refusing to approve additional clinical trials under the beta-amyloid PET imaging CED. This is blocking beneficiary access to this important diagnostic tool, a benefit to which the beneficiaries are entitled.

Furthermore, we are concerned that CMS has not approved clinical trials that will generate the evidence that the agency itself claims is required in order to determine whether or not beta-amyloid PET imaging meets Medicare's "reasonable and necessary" standards for coverage. In the CED decision memo, the agency stated that approved studies must address one of more aspects of the following questions:

For Medicare beneficiaries with cognitive impairment suspicious for AD, who may be at risk for developing AD:

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 PET Aß imaging?
3. Does using PET Aß imaging in guiding patient management, to enrich clinical trials seeking better treatments or prevention strategies for AD, by selecting patients on the basis of biological as well as clinical and epidemiological factors, lead to improved health outcomes?¹³

    

We request that this Advisory Council ask CMS to explain how the current trials that have been approved under the existing CED will generate the evidence the agency needs to reconsider the PET coverage determination and efforts by the agency to develop or recruit investigators to develop new clinical trials that will generate the evidence necessary to reconsider the coverage determination. Such an update provided in a public forum will inform stakeholders as to the current status of the CED determination, as well as publicize the types of research that the agency would like to see proposed in the near future.

We appreciate the opportunity to provide these comments, and we look forward to working with the Advisory Council to change the trajectory of Alzheimer's disease and related dementias. If you have any additional questions, please do not hesitate to contact me.

NOTES:

1. Full Neuraceq Prescribing information is available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf.
2. Beach TG, Monsell SE, Phillips LE, Kukull W. J. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. Neuropathol Exp Neurol. 2012 Apr;71(4):266-73.
3. Boccardi M, et al. Jama Neurology, 2016.
4. AAN abstract 2012 Marwan Sabbagh (no published manuscript reference).
5. Full Neuraceq Prescribing information is available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf.
6. Schipke CG, Peters O, Heuser I, et al. Impact of beta-amyloid specific florbetaben PET imaging on confidence in early diagnosis of Alzheimer's Disease. Dementia and Geriatric Cognitive Disorders. 2012; 33:416-422.
7. Additional details on CMS' coverage requirements are available online: https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/Amyloid-PET.html.
8. IDEAS Study. ClinicalTrials.gov NCT 02420756: https://clinicaltrials.gov/ct2/show/NCT02420756.
9. Full appropriate use criteria are available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733252/.
10. Alzheimer's Association. 2017 Alzheimer's Disease Facts and Figures. https://www.alz.org/documents_custom/2017-facts-and-figures.pdf.
11. CMS. https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/NaF-18-PET-for-Bone-Metastasis.html.
12. Grover F et al. 2016 Annual Report of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Jour of Am Coll Cardiology (December 9, 2016). http://www.onlinejacc.org/content/early/2016/12/02/j.jacc.2016.11.033?_ga=1.92519133.1911975317.1484767598.
13. CMS. https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/Amyloid-PET.html.