This proposed amendment has the potential for significant expansion of PET without a definite corresponding level of increased patient benefits. Coverage based purely on FDA approval would be a remarkable departure from the previously successful CMS model of using a precise and well defined evidentiary framework for making coverage decisions for imaging technologies.
CMS previously defined this approach to evaluating the clinical utility of diagnostic tests as follows:
• Review; when available, high-quality studies that provide direct evidence that test results improve health outcomes.
• If there is no high-quality direct evidence, determine the extent to which there are changes in patient management, particularly when the management strategy is effective in patients with the disease and does not benefit or harm those without the disease
The National Oncologic PET Registry (NOPR) was designed to determine if the results of PET scans influence physicians' intended plans of patient management. In August 2008, Medicare's Evidence Development and Coverage Advisory Committee (MedCAC) reviewed the NOPR results as well as a technology assessment on FDG-PET scanning for 6 cancers which included 112 research studies.
The committee members were asked to rate their confidence in the evidence that FDG-PET scanning improves physician decision making and patient outcomes, as well as their confidence that the results can be generalized to the Medicare population. CMS then requested additional public input on its proposal to expand coverage for FDG-PET scanning in oncology, inviting experts and stakeholders to offer feedback. In January 2009, CMS issued a proposed decision memorandum outlining its intended coverage determination of FDG-PET scanning on the basis of the results of the NOPR, the technology assessment described above, and other published literature. The NOPR process - a consistent approach to nationwide coverage of new indications for PET, with evidence development - has been judged to be a dramatic success1
The MITA Proposal/appeal does not ensure adequate evaluation of the clinical utility of PET in the setting of new PET radiopharmaceuticals approved by the FDA
Case in Point: Amyvid
In the MITA appeal, they point out that the FDA now requires PET radiopharmaceuticals to demonstrate clinical utility, using the recent FDA advisory meetings on new PET radiopharmaceuticals for amyloid imaging in diagnosing Alzheimer's Disease (AD) to demonstrate this recent and increased focus on clinical usefulness. They state that, “This requirement of the FDA for demonstrating clinical usefulness creates confidence that new PET radiopharmaceuticals will not only be accurate and reliable, but also will have defined benefits for the patients in whom they are used as specified in the FDA-approved label.” However, the recent FDA approval of Amyvid (florbetapir F-18 injection) exemplifies the flaws in this reasoning.
The April 10, 2012 FDA press release regarding its approval of Amyvid (florbetapir F-18 injection) contains several disclaimers. These include a surprising lack of specificity noting that, “A positive Amyvid scan indicates moderate to frequent plaques. However, a positive Amyvid scan does not establish a diagnosis of AD because, although patients with AD always have an increased brain content of plaque, the test also may be positive in patients with other types of neurologic conditions, as well as in older people with normal cognition.” There was also a remarkable limitation in its indications and usefulness with statements such as, “Amyvid is not a test for predicting the development of AD-associated dementia and is not for monitoring patient responses to AD therapy. Amyvid does not replace other diagnostic tests used in the evaluation of cognitive impairment. This is a new type of nuclear medicine test and images should be interpreted only by healthcare professionals who successfully complete a special training program developed by the manufacturer.”2
The Siemens press release has similar disclaimers as well as the warnings that, “Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation”; and the more unusual, “Image interpretation should be performed independently of the patient’s clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors.”3
This troubling issue of interpretation errors with florbetapir-PET scans has been discussed in other forums. For example, the substantial inter-reader variability among independent, extensively trained readers of the Florbetapir-PET scans is a significant problem. It has been addressed in a 2011 JAMA article, which noted that Florbetapir-PET imaging fails to provide an accurate and reliable assessment of amyloid burden. In fact the authors stated, “If widely deployed in the real-world setting, with more variability in reader training and skill and in the patient population for whom florbetapir-PET presumably is intended, the performance of the test will most likely be worse. For these reasons, in our opinion the FDA should not approve florbetapir for diagnosis of Alzheimer’s disease.”4
In fact, the FDA Peripheral and Central Nervous System Drugs Advisory Committee unanimously agreed (16-0) that it could only approve florbetapir after the development of a reader training program. Eli Lilly complied with this stipulation and included a warning of possible scan misinterpretation in its prescribing information.5
The Alzheimer's Association supports FDA approval of florbetapir, but acknowledges that it is a “double-edged sword”. While the approval will expand the clinical and research opportunities, the potential uses of florbetapir are not clearly defined. The association is concerned that it may have some undesirable consequences such as “less than scrupulous operators offering imaging services and making unrealistic promises about the value of florbetapir imaging to sometimes vulnerable and worried individuals.” They feel that additional research is needed to clarify the role of florbetapir-PET imaging in Alzheimer's and have convened a task force with the Society of Nuclear Medicine to develop recommendations for the use of amyloid imaging.6
The procedure will probably have very limited practical indications. Dr. Neill Graff-Radford, professor of neurology at Mayo Clinic in Jacksonville, FL, feels that florbetapir may useful in differentiating frontotemporal dementia (FTD) from AD. He noted that physicians currently use PET scans in these types of cases. For the present, Dr. Neill Graff-Radford described the florbetapir test as “boutique.”7 Interestingly, the MedSolutions Guidelines currently acknowledge that the established role of PET in dementia is limited to differentiating AD from FTD.
The example discussed above demonstrates that FDA approval alone does not ensure that a test will be accurate, reliable and clinically useful to the same degree as those which were previously evaluated using CMS’s successful NOPR/MedCAC model. As to the MITA’s desire to have these coverage decisions be left to the discretion of the local Medicare Administrative Contractors (MAC), after initial FDA approval, it is unlikely that the local MACs will have the resources to replicate the CMS national model. Developing these infrastructures in each region would be inefficient and probably less effective. Continuing with the national model will also promote uniformity in coverage, preventing confusion among providers and especially patients who may move from one region to another. In MedSolutions’ view, the process described in the MITA letter would represent the abandonment of a proven deliberative process without any clear clinical advantages being associated with the proposed replacement.
1 Tunis S, Whicher D. The National Oncologic PET Registry: Lessons Learned for Coverage With Evidence Development. Journal of the American College of Radiology Volume 6, Issue 5, Pages 360-365, May 2009.
2 FDA approves imaging drug Amyvid. www.fda.gov. April 10, 2012.
3 Siemens Announces First Integrated Amyloid Imaging Solution in the U.S. Market for Use in Evaluation of Alzheimer’s Disease and Other Causes of Cognitive Decline. www.siemens.com/healthcare.
4 Carome M, Wolfe S. Florbetapir-PET Imaging and Postmortem ß-Amyloid Pathology. JAMA. 2011;305(18):1857-1858. doi:10.1001/jama.2011.579.
5 Rukovets O. FDA Approves Florbetapir for Imaging Amyloid Beta for Alzheimer Disease. Neurology Today 17 May 2012; Volume 12(10); pp 18,20
6 Alzheimer's Association statement on FDA approval of florbetapir (Amyvid). Alzheimer's News 4/6/2012. www.alz.org.
7 Rukovets O. FDA Approves Florbetapir for Imaging Amyloid Beta for Alzheimer Disease. Neurology Today 17 May 2012; Volume 12(10); pp 18,20.