A Medicare advisory panel could not find adequate evidence to conclude that beta amyloid positron emission tomography imaging of brain beta amyloid changes health outcomes in patients who display early symptoms or signs of cognitive dysfunction.

CMS convened the Medicare Evidence Development and Coverage Advisory Committee at its Baltimore headquarters on Jan. 30 to review the available evidence on beta amyloid PET imaging for the management of dementia and neurodegenerative disease, such as Alzheimer’s disease, and consider possibly revising the relevant national Medicare coverage policy.

Certain PET tracers, such as Avid Radiopharmaceuticals Inc.’s FDA-approved Amyvid (florbetapir), allow imaging of beta amyloid plaque in the brain, which some studies suggest could inform the clinical management of patients with cognitive impairment under evaluation for possible Alzheimer’s disease.

The Medicare agency does not currently cover beta amyloid PET imaging. Some applications of PET with radioisotopes are subject to coverage-with-evidence-development policies, while others are nationally noncovered.

“Amyloid PET imaging is arguably the most important recent advance in [Alzheimer’s disease] therapeutic research” – Paul Aisen, University of California School of Medicine, San Diego

CMS asked MedCAC to consider the impact of amyloid PET on patient outcomes, including function and quality of life, and whether or not the published evidence identifies patient characteristics that predict which patients are most likely to benefit from this imaging modality. “The impact of a diagnostic test result is generally derived from the downstream changes in patient management rather than from the mere administration of the test, and that the avoidance of unnecessary or harmful treatment may also produce improved health outcomes,” CMS instructed the panel.

The panel’s assessment relied largely on presentations on the clinical work-up and management of patients with cognitive impairment and possible Alzheimer’s disease, the state of research and the potential impact of beta amyloid PET imaging. According to CMS, Alzheimer’s disease is the number one cause of dementia in Americans age 65 and older. Currently, more than 5 million older Americans suffer from the disease, a figure that is expected to rise to 8.7 million by 2030.

Dementia has traditionally been considered a disease that progressively interferes with daily function. But that view “has changed dramatically over the past few years,” said Paul S. Aisen, a professor in the department of neurosciences at the University of California School of Medicine, San Diego, who was one of the experts invited by CMS to speak at the meeting.

Diagnosis of Alzheimer’s disease has changed, he explained, moving from standard clinical diagnosis of dementia – with evaluation of cognitive and behavioral symptoms, impact on function and a mental status examination – to screening patients with pre-clinical or pre-symptomatic Alzheimer’s disease for the presence of amyloid plaques and neurofibrillary tangles, a cluster of proteins associated with Alzheimer’s disease.

“Amyloid PET imaging is arguably the most important recent advance in [Alzheimer’s disease] therapeutic research,” Aisen said, further explaining that a negative amyloid PET scan “effectively rules out” Alzheimer’s disease, while a positive scan “effectively assures” Alzheimer’s disease diagnosis in individuals with dementia, and it “provides prognosis in individuals with [mild cognitive impairment].”

Research from the trial unit of the Dominantly Inherited Alzheimer Network, a publicly and privately supported international research initiative, has shown that incidence of dementia is delayed by 10-15 years from the prevalence of Alzheimer’s pathology in population pathological studies, and that Alzheimer’s disease biomarkers are abnormal in asymptomatic individuals in an age-dependent fashion.

“Given the long pathobiological progression, observational studies [are] needed over many years, unless we can predict who will have Alzheimer’s disease and when,” said expert speaker Randall J. Bateman, a professor of neurology at the Washington University School of Medicine, St. Louis, and the principal investigator for the DIAN trial unit.

“I think the model you’re proposing is actually good and reasonable but I just can’t connect the dots between … the way the test performs and the outcomes. I don’t think you can create a chain of evidence there that works,” said A. Mark Fendrick, panelist.

Steven Pearson, president of the Institute for Clinical and Economic Review, Boston, discussed the findings of a white paper written by the academic research group. Recognizing that biomarkers play many different roles is important, he said, and they are useful in identifying patients who have amyloid in the brain, as the correspondence between Alzheimer’s disease pathology and symptoms are not always consistent.

The paper is intended to define the standards by which evidence will be evaluated for coverage, both now and after the potential advent of more effective treatments, by providing recommendations for future research and research design. It concludes that randomized controlled trials will be needed to evaluate the net health benefits of diagnostic tests, and that consensus standards should be developed for biomarker test deployment and interpretation.

Another invited guest speaker, Mark Mintun, chief medical officer with Avid Radiopharmaceuticals, presented studies on the potential impact of amyloid PET. In a study of 229 subjects with a history of cognitive decline and uncertain diagnosis, results of an amyloid PET scan caused physicians to change their reported diagnosis in 54.6 percent of the cases. Physicians’ diagnostic confidence increased by an average of 21.6 percent with the inclusion of the Amyloid PET results. In 89.6 percent of all cases, the doctor made at least one change to the patient’s intended management plan following the amyloid PET scan.

Health Outcomes Vs. Diagnostic Outcomes

However, panelists expressed concern throughout the meeting that there is not enough evidence related to patient health outcomes.

“I take exception to the notion that the outcome can be just change and change in the past behavior,” said panelist A. Mark Fendrick, a professor in the department of internal medicine at the University of Michigan School of Public Health, Ann Arbor. “I think the model you’re proposing is actually good and reasonable but I just can’t connect the dots between …the way the test performs and the outcomes. I don’t think you can create a chain of evidence there that works,” he added.

He voted for a score of two, indicating he has between low confidence and intermediate confidence that there is adequate evidence to determine whether or not PET imaging of brain beta amyloid changes health outcomes in patients who display early symptoms or signs of cognitive dysfunction.

Susan Levine, VP of Hayes Inc., a health research and consulting firm, and editor-in-chief of Technology Assessment, voted for a score of one – low confidence. She said she agreed with “what’s been said about the inadequate evidence base both related to the change in patient outcome or the patient management or patient-centered outcomes.”

She echoed the call of several other panelists for more studies.

Panelist Robert Zeman, professor and chairman of radiology at George Washington University School of Medicine in Washington, D.C., said he had hoped the scores would have been “a little higher to have discussion around coverage with evidence development” and to “get into diagnostic category action,” although he conceded that “there were still a lot of questions I really couldn’t answer.” Zeman voted for three – intermediate confidence.

Amy Sanders, assistant professor in the department of neurology at the Albert Einstein College of Medicine in the Bronx, N.Y., voted for four – between intermediate and high confidence – because she was “primarily persuaded by the patient-centered outcomes idea and the expressions of the various panel members about how physician behavior would change in the overall gestalt.”

Stakeholders Protest Meeting Outcome

“The Medical Imaging & Technology Alliance today encouraged [CMS] to consider diagnostic endpoints as the basis for its coverage of beta amyloid positron emission tomography imaging despite [MedCAC]’s determination that there is not adequate evidence that the technology improves health outcomes,” MITA wrote in a Jan. 31 press release. MITA also expressed support for broader access to amyloid PET imaging among Medicare patients in comments submitted after CMS opened the national coverage analysis Oct. 9. (See Also see "CMS Urged To Cover Beta Amyloid PET Scans For Alzheimer's, But Cautiously" - Medtech Insight, 12 November, 2012..)

“The data and evidence presented to MedCAC clearly demonstrates the clinical benefit of beta amyloid PET imaging for patients with signs of cognitive dysfunction. MITA urges CMS to consider diagnostic endpoints – not therapeutic ones – when reviewing the evidence and making its coverage decision,” said Gail Rodriguez, executive director of MITA, in the release.

A Jan. 30 statement from the Alzheimer’s Association also expressed disappointment with the panel’s vote and urged CMS “to review the evidence and make a positive determination about coverage.” William Theis, chief medical and scientific officer for the Alzheimer’s Association, also presented at the meeting.

The association also stated its support for the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging consensus criteria that describe appropriate use of brain amyloid imaging. The criteria were published online Jan. 28 as an article in press in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association and Journal of Nuclear Medicine.

Eli Lilly & Co., which owns Amyvid-manufacturer Avid Radiopharmaceuticals, also issued a statement on Jan. 30 in which Wei-Li Shao, senior director of Lilly’s Alzheimer’s business division said, “The overwhelmingly positive testimony presented by the medical experts around the clinical utility of beta-amyloid imaging agents reinforces that these tools should be a Medicare-covered benefit for patients with cognitive impairment being evaluated for Alzheimer’s disease and other causes of cognitive decline.”

The panel also discussed whether there are any evidence gaps and the types of clinical studies that would be needed to confidently close those gaps.

Panelist Zeman suggested a coverage-with-evidence-development approach, while panel chair, Rita Redberg, professor of medicine at the University of California School of Medicine, San Franciso, emphasized the need to consider the quality of life of the family and other caregivers in randomized controlled studies.

Another panelist, Theresa Miskimen, vice president of medical services at the University of Medicine and Dentistry of New Jersey in Newark, N.J., said she would like to see more research on mild cognitive impairment regressions with or without amyloid. “I think that that would definitely take it that next step.”

Sanders opined that it would be interesting to see “to what extent [this will create] a new class of health disparity,” depending on whether CMS covers this technology and the socioeconomic implications of noncoverage.

CMS plans to issue a coverage proposal on this issue topic by July 9, 2013, and a final determination by Oct. 7, 2013.

Medicare Panel Finds Little Support For Amyloid PET Imaging Changes

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