The recent FDA approval of a β amyloid imaging agent has cracked open the door for its clinical use in the U.S., but that door will swing wide only if insurance decides to cover amyloid scans. In making these decisions, most private insurance companies follow the lead of the Centers for Medicare & Medicaid Services (CMS), Baltimore, Maryland, a government agency that administers the Medicare and Medicaid programs and decides which medical services are covered for participants. However, CMS explicitly excludes coverage of all new positron emission tomography (PET) radiotracers. By contrast, tracers for magnetic resonance imaging or computed tomography are eligible for coverage as soon as they are FDA approved. Developers of novel PET tracers can appeal to CMS to lift the ban for their particular product, but the process can be lengthy and costly. With numerous β amyloid and other PET radiopharmaceuticals currently in the pipeline, the Medical Imaging and Technology Alliance (MITA), a Washington, DC-based industry association, last July petitioned CMS to remove the blanket exclusion for this class of drug. In response, CMS opened a National Coverage Analysis of the issue, with a decision due in January 2013. Public comments from physicians, imaging associations, and advocacy groups mostly champion the proposed change, although some caution that the technology could be misused. To date, data on how amyloid scans affect the treatment or clinical care of patients are only beginning to be gathered.

The ability to view amyloid deposits in living brains has been developed in the past decade, initially at research facilities that can synthesize the short-lived, 11C-tagged radiotracer Pittsburgh Compound B. Now, a wave of 18F-based PET radiotracers with a longer half-life promises to make the technology widely available. In April this year, Eli Lilly and Company’s florbetapir (trade name Amyvid) gained FDA approval and is now gearing up for commercial use (see ARF related news story and ARF news story). Other tracers, such as GE Healthcare’s flutemetamol and Piramal Healthcare’s florbetaben, are in Phase 3 trials and expected to apply for FDA approval in the near future (see ARF related news story).

Even if these tracers clear FDA standards, however, they then face the second hurdle of obtaining CMS approval. CMS acts as a bellwether for the insurance industry. If CMS does not agree to reimburse for a drug, most private insurance companies follow suit. Without such coverage, amyloid imaging would largely remain an out-of-pocket test, limiting its use (a PET scan in the U.S. typically costs several thousand dollars). Since the year 2000, CMS’s national coverage manual allows reimbursement for only four PET radiotracers, and only for certain indications, most of them in oncology. All other radiotracers and uses are specifically excluded from coverage, meaning that local Medicare contractors have no say in the matter.

MITA contends that, with advances in PET tracers and a more rigorous FDA approval process, this policy is no longer appropriate. MITA represents the interests of more than 60 companies that manufacture medical imaging equipment and radiopharmaceuticals, including GE Healthcare and Eli Lilly. These companies together control some 90 percent of the worldwide market for medical imaging, according to MITA’s website. In July 2011, MITA convened a workshop for leaders from imaging companies and professional associations, as well as CMS representatives, to discuss ways to broaden coverage for PET tracers (see Hillman et al., 2012). These discussions led to MITA’s submission of the Formal Request for Reconsideration. The letter asks CMS to remove the nationwide exclusion for all new PET tracers and instead allow decisions to be made by local Medicare contractors. Executive officers from the American College of Radiology, the Council on Radionuclides and Radiopharmaceuticals, the Society of Nuclear Medicine and Molecular Imaging, and the World Molecular Imaging Society cosigned the letter. Essentially, the effort constitutes a way to side-step CMS’s national authority on the issue.

PET Peeve: Making a Case for Coverage
MITA lays out several reasons for its petition. For one thing, removing the exclusion for PET radiotracers would level the playing field, making this class of pharmaceuticals equivalent to other radiotracers and drugs, said Brian Abraham, senior policy director at MITA. “Practically every other product out there is subject to local contractor discretion, which basically means it is provisionally covered once it is approved by the FDA,” Abraham told Alzforum.

Why are PET radiotracers treated differently? At the time the exclusionary policy was written, the main PET tracer was 18F fluorodeoxyglucose (FDG), which had not been through stringent clinical trials and did not have specific FDA labeling, noted Gail Rodriguez, MITA’s executive director, in the reconsideration request. CMS therefore limited coverage to a handful of oncologic uses for which there was good evidence of benefit to patients. In 2005, CMS developed a “coverage with evidence development” pathway for other oncologic uses of FDG. As part of it, the agency helped establish the National Oncologic PET Registry (NOPR). Under this program, scans for other types of cancer were reimbursed for Medicare patients as long as their physicians submitted data to the registry. Three years of data on more than 100,000 patients showed that scans changed physicians’ treatment decisions about one-third of the time (see Hillner et al., 2008; Tunis and Whicher, 2009), and led to expanded CMS coverage for many cancer indications. NOPR continues to gather data for rarer types of cancer.

Can this registry do the same thing in Alzheimer’s? No, the industry lobby argues. “Using the NOPR registry would not necessarily help these novel tracers that are emerging now,” Rodriguez told Alzforum, noting that the registry is specific for cancer applications. This leaves amyloid tracers without a clear path for obtaining coverage. In addition, the NOPR process is burdensome for providers, patients, and CMS, and creates a delay in the adoption of new medical imaging advances, Rodriguez claims. The process takes years, as data must be gathered on a large number of patients and then published. “This national non-coverage decision has been a real hindrance to innovation,” she told Alzforum, noting that Amyvid is the first new PET tracer to gain FDA approval in many years. Rodriguez maintained that the evidence development process is no longer necessary. “The medical landscape has changed markedly…. New radiopharmaceuticals now face a far more rigorous regulatory environment,” she wrote in the MITA letter. They must demonstrate reliability and clinical usefulness for specific applications to earn FDA approval, something that was not true of early PET tracers.

The Community Weighs In
CMS representatives, meanwhile, are keeping mum. They declined to speak with Alzforum, citing internal regulations against discussing open analyses. The imaging and Alzheimer’s research communities have been more forthcoming. As part of CMS’s analysis, the agency invited public comments on the proposal through 10 August. Of the 25 published comments, 20 favor the change. Not surprisingly, supporters include developers of radiopharmaceuticals such as Eli Lilly, GE Healthcare, and Piramal Healthcare, who stand to profit from expanding the use of PET tracers in AD, and representatives from various professional imaging associations. Several nuclear medicine physicians also came down on the side of streamlining the approval process for PET imaging agents.

For example, Mark Nathan, chair of the Division of Nuclear Medicine at the Mayo Clinic, Rochester, Minnesota, wrote: “The current pathway for CMS approval of PET radiopharmaceuticals has created a stumbling block to delivering the diagnostic benefits of PET to many patients.” Likewise, David Djang, a physician at Seattle Nuclear Medicine, Washington, commented, “The approval mechanism for PET tracers is far too slow. Patients and clinicians sometimes call me, frustrated, that there is a very promising tracer for their disease, often studied and published in the literature for five years or more, that is still not available clinically.”

Not everyone agrees. Gregg Allen, chief medical officer at MedSolutions, Inc., Franklin, Tennessee, wrote: “The NOPR process—a consistent approach to nationwide coverage of new indications for PET, with evidence development—has been judged to be a dramatic success. The MITA proposal/appeal does not ensure adequate evaluation of the clinical utility of PET.” MedSolutions is a radiology benefits management company employed by insurance companies to screen imaging requests from healthcare providers. Two other insurance and managed care companies, the benefits management company CareCore National and the industry association America’s Health Insurance Plans, also spoke out against the change, questioning whether amyloid scans will translate into actual changes in patient care.

George Vradenburg, chairman of the advocacy group USAgainstAlzheimer’s, attempted to carve out common ground in his comment. He encouraged CMS to remove the national non-coverage policy for new FDA-approved PET tracers, noting that it “effectively prevents any Medicare patient presenting signs of cognitive impairment from having access to this diagnostic tool.” However, Vradenburg added that any national or local coverage decisions should guard against “inappropriate and unnecessary testing.”

What Is Appropriate Use?
The proper use of amyloid scanning technology remains a vexing question. A positive amyloid scan does not equate to a diagnosis of AD, as up to a third of cognitively healthy elderly have amyloid in their brains. Experts agree that amyloid imaging should be used only in conjunction with other diagnostic tools, and only in the cognitively impaired, and some suggest that its most useful application will be to rule out a diagnosis of AD in ambiguous cases. To help develop appropriate use guidelines for β amyloid tracers, the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging established the Amyloid Imaging Task Force (see ARF related news story). Co-chair Satoshi Minoshima, a PET expert at the University of Washington, Seattle, told Alzforum that the task force is conducting a stringent evidence review, but has found very limited data to date on the clinical benefit of using amyloid tracers. Only a few studies have addressed this question.

For example, researchers led by Gunhild Waldemar at Copenhagen University, Denmark, looked at whether amyloid imaging with Pittsburgh Compound B improved diagnostic accuracy in 57 memory clinic patients with uncertain diagnoses. As an exercise, a panel of three clinicians reviewed case reports from each patient and reached a consensus diagnosis, then looked at amyloid imaging scans and re-evaluated the diagnosis. First author Kristian Frederiksen, who presented the data at the 2012 Alzheimer’s Association International Conference in Vancouver, Canada, noted that the addition of amyloid imaging changed diagnosis in about one-quarter of the cases, and also improved the clinicians’ confidence in the diagnosis for about half of the cases. Most commonly, amyloid imaging was helpful in distinguishing between AD and frontotemporal dementia, Frederiksen told Alzforum. These disorders present similar clinical symptoms, especially in the early stages. A negative amyloid scan also helped determine that a patient with amnestic mild cognitive impairment was not likely to progress to AD, Frederiksen noted. In another case, a patient with an initial diagnosis of depression was moved to probable AD based on a positive PIB scan.

However, the panel’s diagnosis was not shared with the patients’ physicians, so the study could not determine whether treatment changed as a result of amyloid scanning. “Obviously the implications of a different diagnosis would be that treatment may be different,” Frederiksen said. “Also, since clinicians have increased confidence in the diagnosis following PIB-PET, they may pursue certain treatments more aggressively.” Other case studies have shown that amyloid imaging can help refine diagnosis (see e.g., Cohen et al., 2012; Laforce and Rabinovici, 2011). “Amyloid imaging will help certain patients,” Minoshima said, pointing out that more accurate diagnoses will allow physicians to guide patients to the best care for their condition.

William Klunk at the University of Pittsburgh, Pennsylvania, who co-discovered PIB and is also on the task force, noted that amyloid imaging will achieve its greatest importance when there are effective early interventions for AD. “Amyloid imaging and anti-amyloid therapies have a linked destiny,” he said, with each technology dependent on the success of the other. Klunk said the task force’s job is to interpret the FDA approval for Amyvid and reduce it to everyday practice for clinicians. For example, they are considering such thorny issues as how people should be informed of their brain amyloid status. Studies are underway to see whether learning this information causes distress in patients, but no data are available yet (see ARF related news story and ARF news story).

While the task force deliberates, the Alzheimer’s Association is staying neutral on the MITA proposal. In his comment, Robert Egge, vice president of public policy, expressed his appreciation for CMS’s “thoughtful reconsideration” of PET radiotracer status, but also noted, “These amyloid imaging agents … can be clinically useful, but their appropriate use within a clinical examination has not been fully determined.” In an interview with Alzforum, William Thies, chief medical and scientific officer, declined to offer an opinion on the MITA letter. He said, “We are committed to working with CMS to try to get them the best expert advice about what policies are supported by the best science.”

Amyvid and Beyond
Even if the MITA proposal is adopted for all new FDA-approved PET radiotracers, that may not be enough for the makers of Amyvid, which is already on the market. In June 2012, Eli Lilly filed a separate reconsideration request with CMS, asking the agency to specifically address the status of β amyloid-identifying PET agents for use in patients with cognitive impairment. In a comment on the MITA proposal, Lilly representative Derek Asay affirmed his support for the proposal, but added: “We strongly urge the agency to move forward in parallel with opening Lilly’s reconsideration request specific to the β amyloid imaging class.”

For MITA’s constituent companies, β amyloid tracers are only one of many products under development. The letter notes that a new generation of highly accurate and specific diagnostic radiopharmaceuticals is currently in clinical trials and under review at the FDA. In contrast to the older, broad-use tracers such as FDG, the new tracers label particular targets or processes, such as tumor cells, programmed cell death, and angiogenesis. “These radiopharmaceuticals will be new innovations with unique clinical utility,” Rodriguez wrote in the MITA letter. About a dozen such tracers are now in clinical trials or under review by the FDA. Rodriguez predicted that if CMS coverage policy does not change, “Within a few years, half or more of [CMS’s] National Coverage Analyses could be devoted exclusively to new PET radiopharmaceuticals.”

One public comment supporting MITA’s proposal comes from George Kovach, president of the Association of Community Cancer Centers. This organization represents 17,000 cancer care professionals at 900 hospitals and 1,200 private practices nationwide, according to Kovach. “This revision will allow new and improved tracers to reach patients battling cancer much sooner…. Our patients cannot afford to wait so long for technologies that, under the FDA’s rigorous approval process, already have demonstrated meaningful clinical benefit,” he wrote.—Madolyn Bowman Rogers.

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References

News Citations

  1. FDA Approves Amyvid for Clinical Use
  2. Coming to a City Near You: Tracer to Picture Brain Amyloid
  3. Me, Too: Florbetaben, Flutemetamol Look Good in Trial
  4. Amyloid Imaging Task Force to Work Out Technology's Use
  5. Miami: Scan and Tell? Amyloid Imaging Confronts Disclosure Dilemma
  6. To Reveal or Not to Reveal? New Data on the Question

Paper Citations

  1. . New pathways to medicare coverage for innovative PET radiopharmaceuticals: report of a Medical Imaging & Technology Alliance (MITA) workshop. J Am Coll Radiol. 2012 Feb;9(2):108-14. PubMed.
  2. . Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: initial results from the National Oncologic PET Registry. J Clin Oncol. 2008 May 1;26(13):2155-61. PubMed.
  3. . The National Oncologic PET Registry: lessons learned for coverage with evidence development. J Am Coll Radiol. 2009 May;6(5):360-5. PubMed.
  4. . Using Pittsburgh Compound B for in vivo PET imaging of fibrillar amyloid-beta. Adv Pharmacol. 2012;64:27-81. PubMed.
  5. . Amyloid imaging in the differential diagnosis of dementia: review and potential clinical applications. Alzheimers Res Ther. 2011;3(6):31. PubMed.

External Citations

  1. Centers for Medicare & Medicaid Services
  2. Medical Imaging and Technology Alliance
  3. National Coverage Analysis
  4. Formal Request for Reconsideration
  5. American College of Radiology
  6. Council on Radionuclides and Radiopharmaceuticals
  7. Society of Nuclear Medicine and Molecular Imaging
  8. World Molecular Imaging Society
  9. National Oncologic PET Registry
  10. public comments
  11. Association of Community Cancer Centers

Further Reading