Jeffrey Roche MD, MPH
Centers for Medicare & Medicaid Services
7500 Security Boulevard,
Baltimore, MD 21244
Dear Dr. Roche:
We appreciate this opportunity to submit comments to the Centers for Medicare & Medicaid Services (CMS) regarding the National Coverage Analysis for Positron Emission Tomography (CAG-00065R2).1 We support expanded coverage of reasonable and necessary Positron Emission Tomography (PET) services with PET radiopharmaceuticals that have FDA approval. We respectfully request that CMS remove from section 220.6 of the National Coverage Determination (NCD) manual the blanket exclusion of non-coverage for new PET drugs for the reasons outlined below.
Current State of PET
Mayo Clinic has witnessed the astonishing transformation of PET scanning from a research-only modality to a full fledged clinical tool that provides accurate metabolic targeting of disease. More importantly, numerous studies have proven that PET has very significant impact on patient treatment strategies.
The current pathway for CMS approval of PET radiopharmaceuticals has created a stumbling block to delivering the diagnostic benefits of PET to many patients. Currently there are only three PET drugs covered by CMS in addition to fludeoxyglucose F 18 injection (F-18 FDG). However, any new drugs are subject to a pre-emptive national non-coverage policy for new PET radiopharmaceutical agents. Given the increasingly strict FDA (Food and Drug Administration) criteria for approval, this pre-emptive non-coverage approach may no longer be practical.
For example, a recently reported research study demonstrated the effectiveness of F-18 florbetapir (Amyvid) imaging of in-vivo neuritic plaques, found in Alzheimer’s disease (Lancet Neurol 2012; 11: 669–78).2 Concerns were raised during the FDA approval process about whether or not non-expert imagers could be taught to properly interpret these studies in a community (non-academic) setting. The FDA then required the manufacturer to develop a validated reader training program be implemented to ensure proper reader interpretations. This was done, and the data reviewed favorably by the FDA before formal approval. However, despite this intensive and rigorous FDA process, the existing CMS policy currently prohibits coverage of this tracer, which in turn effectively results in non-utilization. In other words, despite the requirement that any physician interpreting florbetapir studies first complete the training course, patients are denied the chance for more accurate diagnosis of their disease.
Although the above is only one example, the same reasoning can be applied to the many other new PET drugs that have been shown to be effective in a variety of diseases. Advances in imaging and CMS’ past experience with PET coverage no longer support a clinical rationale for a pre-emptive national non-coverage policy for new PET radiopharmaceutical agents that have already undergone a rigorous FDA review and approval process as indicated below.
Food and Drug Administration Modernization and Accountability Act of 1997 (FDAMA)
The origin of current federal regulations for PET drugs is the Food and Drug Administration Modernization and Accountability Act of 1997 (FDAMA).3 Section 121(c)(1)(A) of this act directed the FDA to establish appropriate approval procedures and current good manufacturing practice (CGMP) requirements for PET drugs.4 Section 121(c)(2)(A) of the act specified that PET drug manufacturers and compounders would be required to submit applications for approval within 24 months of the establishment of such procedures and requirements. It is worthy to note that U.S. Senate issued a report to provide background information, as well as the reasons for the establishment of the statutes of FDAMA.5 This report clearly depicts why the Senate felt strongly that it was vital to revamp the regulatory framework, as well as to expand reimbursement for PET drugs. The following statements are taken from the Senate Report No. 43, 105th Congress, 1st Session and provide a glimpse into PET situations prior to FDAMA 1997:5
- PET radiopharmaceuticals have been used in patients in the United States for over 30 years. Recent research and advances in imaging technology have enhanced the clinical importance of PET
- At present [July 1, 1997], there are 70 PET centers in the United States, almost all of which are part of academic medical centers. PET technology and its applications were developed in large part with almost $2 billion in federal research funds. Yet, while PET is widely used in Europe, its benefits have not been widely available to American patients,
- Academic medical centers are facing unprecedented cost pressures. …many PET centers are likely to close, and the benefits of PET will be unavailable to the taxpayers who funded their development.
One cause for this dismal situation as stated in this report is the lack of reimbursement (particularly reimbursement from the Medicare program), as well as inappropriate and costly regulations promulgated by FDA.5 Under current FDA regulations, PET centers which compound PET radiopharmaceuticals on an individual dose basis would be required to meet FDA’s CGMP and to file new drug application (NDAs) and abbreviated new drug application (ANDAs) for each type of PET drug and for each indication for which the PET radiopharmaceutical might be used.4 This is the same type of regulation which the FDA applies to large pharmaceutical manufacturers.
Regulatory Status for PET Drugs
The regulatory status for PET drugs dates back to 1997 where the FDA conducted several public meetings to discuss FDA proposals for PET drug approval procedures and CGMP requirements. In March 2000, the FDA presented its findings of safety and effectiveness for F-18 FDG, ammonia N 13 injection, and sodium fluoride F 18 injection, as well as described the types of applications that can be submitted for these three PET drugs.6,7 Guidance for the applications (i.e., NDAs and ANDAs) for these three PET drugs was initially issued by the FDA in March 2000, and a final version of this guidance was released by the FDA in August 2011.7,8
FDA recognized that, due to the following unique aspects of PET drugs, application of certain provisions of the CGMP regulations for conventional drugs to the manufacturer of PET drugs might result in unsafe handling or be otherwise inappropriate:
- Short physical half-lives of PET radioisotopes – prolonged manufacturing (including quality control) time significantly erodes the useful life of PET drugs.
- The quantities of radioactive ingredients vary from nanogram to milligram amounts – reported instance of any adverse reaction to PET drugs is almost non-exist or very rare.
- PET drugs usually do not enter a general drug distribution chain – distribution may occur to other PET centers when the geographic proximity will allow for distribution and use within the drug product’s half-life parameters.
In April 2002, FDA issued a preliminary draft proposed CGMP regulation for PET drugs, and draft guidance on CGMP requirements for public comments; a proposed rule and revised draft guidance were issued in September 2005, to solicit additional public input. In December 2009, FDA published a final CGMP for PET drugs – this release triggered the two-year clock for applications (NDAs and/or ANDAs) to be submitted for any PET drug used clinically.
FDA was supposed to enforce the requirement that all producers of PET drugs submit applications after December 12, 2011.12 However, this deadline was extended to June 12, 2012 possibly due to some PET centers unable to meet the deadline.13 If PET drug producers submit the required application(s), FDA will not object if clinical use of the PET drug(s) continues during the application review period, provided that the facility complies with all other FDA requirements, including CGMP.13 Nevertheless, all PET drug producers must be operating under an approved NDA or ANDA, or effective IND, by December 12, 2015.13
Recommendations to CMS
Since the establishment of this act (i.e., 1997 FDAMA),3 the FDA has worked closely and diligently with professional associations, manufacturers, and other interested persons (e.g., patient advocacy groups and physicians and scientists licensed to make or use PET drugs, etc.) to develop PET drug approval procedures (i.e., NDA and ANDA), as well as CGMP regulations specifically for PET drugs. FDA’s early recognition of the unique natures of PET drugs, and its open-minded approaches contributed a great deal in offering a significant regulatory relief to the PET community for meeting the requirements on NDA/ANDA approvals and CGMP.
The objective of Section 121 was to establish a regulatory framework for PET drugs that will enable PET centers to continue to make this valuable technology available to patients at reasonable cost and assure that the public health will be protected.4,5 To achieve this objective we sincerely hope that CMS will expand coverage to new FDA-approved PET drugs. The scientific evidence of efficacy and safety of each approved PET drug have been thoroughly reviewed and accessed by the FDA. Thus, it is not necessary to waste any precious resources to reevaluate these aspects. As pointed out in the Senate Report, we need to ensure that the valuable PET drugs are available to our patients at reasonable cost since this technology was originally developed in our country with research funding from our taxpayers.5 We should not prevent the general public (in particular Medicare/Medicaid patients) from accessing useful PET drugs because of the lack of reimbursement.
Mayo Clinic praises CMS for its decision to open the PET NCA (National Coverage Analysis).1 Allowing coverage of new FDA approved drugs will provide beneficiaries greater access to clinically-proven PET imaging drugs in procedures that provide clinically meaningful information to their physicians. Should you have any questions, please free to reach us at the telephone numbers or e-mail addresses provided below.
Michael C. Roarke, M.D.
Consultant, Diagnostic Radiology
Section Head, Nuclear Medicine
Assistant Professor of Radiology, College of Medicine
Mark A. Nathan, M.D.
Consultant, Department of Radiology
Chair, Division of Nuclear Medicine
Joseph C. Hung, Ph.D., BCNP
Consultant, Department of Radiology
Director, Mayo Clinic PET Radiochemistry Facility
1. Available at http://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx?NCAId=261
2. Lancet Neurol 2012; 11: 669–678.
3. Available at http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct
4. Available at http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct
5. See pages 52-53 on the Internet at http://www.gpo.gov/fdsys/pkg/CRPT-105srpt43/pdf/CRPT-105srpt43.pdf
6. Available at http://www.fda.gov/ohrms/dockets/98fr/031000a.txt
7. Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm181434.htm
8. Available at
9. Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM182664.pdf
10. Available at http://www.gpo.gov/fdsys/pkg/FR-2005-09-20/pdf/05-18510.pdf
11. Available at http://www.gpo.gov/fdsys/pkg/FR-2009-12-10/pdf/E9-29286.pdf
12. Available at http://www.gpo.gov/fdsys/pkg/FR-2009-12-10/pdf/E9-29285.pdf
13. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291573.pdf