August 9, 2012
RE: National Coverage Analysis for Positron Emission Tomography (CAG-00065R2)
Dear Dr. Roche and Mr. Caplan:
Siemens Molecular Imaging Biomarker Research (MIBR) thanks the Centers for Medicare and Medicaid Services (CMS) for opening a comment period on the reconsideration of the National Coverage Determination (NCD) for the use of positron emission tomography (PET) at Section 220.6 of the Medicare National Coverage Determinations Manual.
MIBR, the discovery and development unit of Siemens Molecular Imaging, is actively engaged in the discovery and development of new imaging biomarkers for applications in oncology, cardiology, neurology and other important clinical indications. Siemens Molecular Imaging develops vertically integrated solutions that include innovative imaging biomarkers, preclinical and clinical imaging equipment and software applications, and is a business unit within Siemens Healthcare, the global healthcare business of Siemens AG.
In addition, PETNET Solutions is a manufacturing and distribution unit for Siemens Molecular Imaging, providing a broad portfolio of PET radiopharmaceutical products and services to imaging centers nationwide. Siemens’ PETNET Solutions will be providing complementary comments in a separate letter.
Siemens MIBR appreciates the opportunity to comment on the reconsideration of the current NCD for PET. We believe that enabling a pathway for coverage of recent and future Food and Drug Administration (FDA) approved PET radiopharmaceuticals through the removal of the exclusionary rule would be a positive development for patient care.
Scientists at Siemens MIBR have developed a portfolio of PET imaging tracers in the areas of oncology, neurology and cardiology, six of which are already in human trials. In oncology, our pipeline includes angiogenesis and hypoxia tracers. Clinical trials are ongoing to determine if they can predict patients who will respond to certain therapies versus those who will not respond. Benefits to patients who are non-responders include sparing them of the potential side effects of ineffective treatment and allowing them to switch to more effective treatment sooner, before their tumors grow or metastasize. In neurology, we are developing PET tracers with the potential use in the evaluation of Alzheimer’s disease, and in cardiology, we have developed PET tracers for in the potential evaluation of atherosclerosis.
Below is a list of publications on our PET imaging tracers:
Zhang W et al, A Highly Selective and Specific PET Tracer for Imaging of Tau Pathologies J Alzheimer’s Disease 31 (2012) 1-12
Chen L et al. 18F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with 18F-FMISO Nucl Med Commun 2012 July 24 [Epub ahead of print]
Doss M et al. Biodistribution and radiation dosimetry of the Integrin Market 18F-RGD-K5 Determined from Whole-Body PET/ET in Monkeys and Humans. J Nucl Med 2012; 53:787-795
Dubois LJ et al. Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. PNAS August 30, 2011 vol.108 no. 35 14620-14625
Doss M et al. Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole body PET/CT Nucl Med Commun 2010, Vol 31 No 12 1016-1024
Van Loon J et al. PET Imaging of hypoxia using [18F]HX4: a phase I trial Eur J Nucl Med Mol Imaging. 2010 Aug; 37(9):1663-8
FDA requirement for approval
In CFR Title 21 Part 315 of FDA Rules and Regulations, the FDA defines the requirement for the determination of safety and effectiveness for a diagnostic radiopharmaceutical.
Sec. 315.5 Evaluation of effectiveness
(a) The effectiveness of a diagnostic radiopharmaceutical is assessed by evaluating its ability to provide useful clinical information related to its proposed indications for use. The method of this evaluation varies depending upon the proposed indication(s) and may use one or more of the following criteria:
(1) The claim of structure delineation is established by demonstrating in a defined clinical setting the ability to locate anatomical structures and to characterize their anatomy.
(2) The claim of functional, physiological, or biochemical assessment is established by demonstrating in a defined clinical setting reliable measurement of function(s) or physiological, biochemical, or molecular process(es).
(3) The claim of disease or pathology detection or assessment is established by demonstrating in a defined clinical setting that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology.
(4) The claim of diagnostic or therapeutic patient management is established by demonstrating in a defined clinical setting that the test is useful in diagnostic or therapeutic patient management.
(5) For a claim that does not fall within the indication categories identified in 315.4, the applicant or sponsor should consult FDA on how to establish the effectiveness of the diagnostic radiopharmaceutical for the claim.
(b) The accuracy and usefulness of the diagnostic information is determined by comparison with a reliable assessment of actual clinical status. A reliable assessment of actual clinical status may be provided by a diagnostic standard or standards of demonstrated accuracy. In the absence of such diagnostic standard(s), the actual clinical status must be established in another manner, e.g., patient follow up.
These requirements ensure that new radiopharmaceuticals coming on the market will already have significant data on effectiveness for the label indication.
Current policy deters innovation of new products and national non-coverage language should be removed accordingly
For any drug developers of therapeutic or diagnostic compounds, the risk of drug development is enormous. The first risk is the FDA approval process, which can be lengthy and costly with a high level of uncertainty.
In 1964, the FDA withdrew the “new drug“ requirement for radiopharmaceuticals. This decision greatly reduced the cost of bringing a new imaging agent to the clinic, which is especially critical for a diagnostic agent that has a smaller market than a therapeutic agent. In 1977, FDA withdrew this exemption and required manufacturers to obtain an approved new drug application for new and existing radiopharmaceuticals, implementing essentially the same requirements as therapeutic drugs. The deterent to innovation is evident in the fact that “there are only 23 radiopharmaceuticals in clinical use today and the average age of these agents is 25 years.“
Even with FDA approval, the second uncertainty a manufacturer has to overcome is coverage by CMS. Both uncertainities give any drug development program a highly unpredictable return on investment (ROI). As in any business, ROI calculation plays a critical role in the decision of whether to move a compound forward in its development program. As such, many potentially beneficial compounds may never be developed despite potential value to patients due to the extreme uncertainty of CMS coverage. Alternatively, compounds with larger market potential are more likely to be considered whereas compounds addressing the needs of smaller patient populations have a smaller chance of development.
At Siemens, we are facing this uncertainty on the ROI of a PET tracer with the potential to assist in the evaluation of Alzheimer’s disease. If this tracer proves to have unique uptake in the brain of patients with pre-symptomatic Alzheimer’s, there is a potential to intervene with the proper patient population that may benefit from therapeutic agents that are currently in phase III development.
The cost of bringing a therapeutic compound from research stage to market has been quoted as over $1 billion and more than seven years. While diagnostic agents may take somewhat lower investment, without CMS coverage, the ROI on a new tracer is highly uncertain, given the time and cost of clinical development. As a business with responsibilities towards our shareholders, Siemens is at a crucial point of deciding the path forward for a number of our compounds, including the PET tracer with the potential to assist in the evaluation of Alzheimer’s disease. Removing the national non-coverage language from section 220.6 of the National Coverage Determinations Manual on PET scans when PET is furnished with new FDA-approved radioisotopes, would help encourage manufacturers to bring new tracers to market, ultimately benefiting patients. Accordingly, we encourage CMS to adopt this modification, as recommended by the Medical Imaging Technology Alliance (MITA), the American College of Radiology (ACR), the Society of Nuclear Medicine (SNM), the Council on Radionuclides and Radiopharmaceuticals (CORAR), and the World Molecular Imaging Society (WMIS).
Siemens Molecular Imaging Biomarker Research is actively engaged in the discovery and development of new imaging biomarkers for applications in oncology, neurology and cardiology. These novel imaging biomarkers, when approved for clinical use and covered by CMS will increase imaging-based disease characterization, improve therapy management and ultimately, enable personalized medicine for Medicare patients.
However, the current non-coverage language contained in section 220.6 of the National Coverage Determinations Manual on PET scans is limiting the clinical trial program for our broad portfolio of PET imaging biomarkers due to the uncertainty of Medicare coverage despite receiving FDA approval. We ask CMS to remove this pre-emptive national non-coverage language for new PET radiopharmaceutical agents in light of the fact that the imaging technology to enable personalized medicine has been evolving quickly. Doing so will help ensure that innovative, emerging PET tracers are brought from the research stage to the market where they will benefit patients.
Hartmuth Kolb, PhD
Vice President, Molecular Imaging Biomarker Research
Siemens Molecular Imaging
1 Miller, JC et al “Radiopharmaceutical Development at the Massachusetts General Hospital”
2 Outlook 2010 by Tufts Center for the Study of Drug Development.