Anticancer Chemotherapy for Colorectal Cancer

The Alliance of Dedicated Cancer Centers
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
City of Hope National Medical Center
Dana-Farber Cancer Institute
Fox Chase Cancer Center
H. Lee Moffitt Cancer Center and Research Institute
M.D. Anderson Cancer Center
Memorial Sloan-Kettering Cancer Center
Roswell Park Cancer Institute
Seattle Cancer Care Alliance
Sylvester Comprehensive Cancer Center

December 31, 2004

By Electronic Mail

Gay W. Burton
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Room C1-11-14
7500 Security Blvd.
Baltimore, MD 21244-1850
Re: Comments on CMS Draft Decision Memo: Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N)

Dear Ms. Burton:

On behalf of the Alliance of Dedicated Cancer Centers, I am writing to comment on the above-referenced proposed coverage decision on off-label uses of certain chemotherapeutic drugs for the treatment of colorectal cancer that are provided in NCI-sponsored trials (the Draft Decision Memo). The Alliance is an association of ten comprehensive cancer centers, listed individually above, that focus exclusively on the care of cancer patients.

While we generally applaud this initiative, we have a number of concerns about the Draft Decision Memo. As you are aware, drug innovation regarding off-label indications is a dynamic, complex and incremental process. Indications for use rarely develop in a linear and predictable pattern. As a result, the current coverage decision-making process does not provide cancer clinicians and researchers with the flexibility required to explore and tailor treatment options to those with the greatest need. A new process is needed that provides for greater efficiency, effectiveness and timeliness. The Draft Decision Memo is a positive step forward in improving this system with regard to the drugs in question. However, as described below, it does not represent a comprehensive response to existing deficiencies. In this regard, we offer the following recommendations for revising the Draft Decision Memo:

I. Coverage Should Not Be Limited to Drugs Provided in NCI-sponsored Trials

The Alliance supports CMS’s efforts to extend Medicare coverage to certain drugs under investigation in NCI-sponsored clinical trials, and thereby to encourage additional research by increasing clinical trial participation. However, we believe that, as proposed, the Draft Decision Memo has a number of shortcomings that could impede the realization of this goal by failing to recognize the realities of many clinical trial protocols.

First, in the Draft Decision Memo, CMS proposes to cover drugs provided in only nine studies. All of the listed trials are either Phase II or Phase III trials. As we understand it, pharmaceutical manufacturers may often provide drugs for such trials free of charge. If this is the case for drugs provided in the listed trials, it is unlikely that extending Medicare coverage would increase participation in these studies because the proposal would do little more than transfer the cost of these drugs from the private sector to the Medicare Program. Consequently, we are concerned that CMS’s proposal will not materially increase patient or physician participation in these clinical trials.

Further, because the listed trials would cover only a small number of patients at a relatively small number of sites of care, patients living in areas without access to these clinical trial sites will be denied coverage under CMS’s proposal. Given the large number of Medicare beneficiaries afflicted with colorectal cancer who could potentially participate in a study of the effectiveness of drugs used for off- label indications, CMS’s proposal is unlikely to make significant inroads to benefit these patients.

Similarly, the Draft Decision Memo would provide only limited opportunities for research into other types of cancer, since only three of the listed studies target drugs used to treat non-colorectal cancers. As you may be aware, there is compelling clinical evidence demonstrating the value of these drugs in treating other forms of cancer. For example, European studies have shown positive results in the use of oxaliplatin to treat bladder cancer, but because of limited resources, comparable research has not been performed in the United States.¹ Pancreatic cancer also has been demonstrated to respond favorably to treatment with both oxaliplatin and irinotecan², but the Draft Decision Memo proposes to cover drugs used in only one trial targeted at this cancer.

To address these concerns, we propose the following. First, we recommend that CMS revise the Draft Decision Memo to focus on coverage of these drugs in clinical trials where the manufacturer is not providing financial support, such as treatments for rare “orphan” and other diseases that do not affect sufficiently large patient populations to attract industry funding. To truly expand coverage and encourage enrollment, Medicare should offer coverage where none currently exists to help defray patients’ out-of-pocket costs. Otherwise, patient access to these vital medicines could be solely dependent on the business imperatives of drug manufacturers. Second, we recommend that, at a minimum, CMS provide coverage for the listed drugs provided in trials conducted at NCI-designated comprehensive cancer centers, such as members of the Alliance, as well as trials sponsored by other leading cancer organizations. Trials conducted at these centers are often based on emerging clinical understanding and development of new drugs and, therefore, are testing concepts that lead to NCI-sponsored trials such as those listed in the Draft Decision Memo. We are concerned that CMS’s proposed linking of coverage to only the listed trials could potentially decrease accruals to trials at non- NCI sites such as comprehensive cancer centers.

Alternatively, CMS could revise the Draft Decision Memo to provide coverage of the listed drugs in studies that are “deemed” to be covered under the 2000 National Coverage Determination for clinical trials. Currently, that decision covers the routine patient care costs associated with these deemed trials, but does not cover the investigational item or service itself. By expanding the NCD to cover the listed drugs, CMS would be able to develop a much more significant body of knowledge on the efficacy of off-label uses of these treatments. The Alliance recognizes that the issues surrounding coverage of off-label indications of chemotherapeutic agents are complex, and we hope that the recommendations discussed above are helpful to CMS as it reviews the Draft Decision Memo. Our paramount concern is that CMS be as flexible as possible in identifying those clinical trials for which it will cover the listed drugs. Toward this end, we would be pleased to discuss these issues further with CMS and to work cooperatively with the agency in identifying those specific trials for which it would be appropriate to provide coverage.

Finally, CMS should facilitate patient access to the listed trials by working to increase the visibility of these trials to the public. In this regard, we recommend that the agency consider partnering with cancer advocacy groups and other stakeholders that have the necessary resources and expertise to provide patients with appropriate information about cancer clinical trials.

II. CMS Should Further Clarify That It Does Not Intend to Limit Contractor Discretion to Cover Off-label Uses of the Listed Drugs

The Alliance is also concerned that, while ostensibly not limiting the existing ability of Medicare contractors to provide coverage for off-label uses of the drugs in question³, the Draft Decision Memo may be setting the stage for a future cabining of contractor discretion. In particular, we are concerned that, once the results of the listed trials are published, CMS may direct Medicare contractors to restrict coverage of any off-label uses of these drugs that were not supported by the trials. This would severely restrict patient access to necessary therapies because, as described above, the listed trials are not sufficiently comprehensive to identify and evaluate all potential off-label uses of these drugs. Therefore, we request CMS to clarify that, once the results of the listed trials become available, the agency will not bar Medicare contractors from extending coverage to off-label uses of these drugs that are supported by other clinical evidence, including data derived from non-listed trials.

We also request that CMS expressly direct contractors not to withhold coverage for off-label uses for these drugs while the results of the listed trials are pending. The Alliance is concerned that the mere existence of this Draft Decision Memo, if finalized as proposed, could have a chilling effect on local contractors and make them very reluctant to approve off-label indications for these therapies unless coverage is specifically required under the Medicare regulations. Limiting drug approvals for the several years needed to complete these trials will mean denying the drug to many patients who could benefit from them. This approach appears to be neither practical nor ethical. Consequently, we ask CMS to clarify to its contractors that they should not withhold coverage pending the outcomes of the listed trials if there is sufficient clinical evidence demonstrating the appropriateness of the off-label use.

III. CMS Should Establish a Cancer-Specific Compendium

In the Draft Decision Memo, CMS specifically invites comment on improvements to the guidance provided to Medicare contractors regarding coverage of off-label uses of these and other anticancer drugs⁴. In response to this request, we offer the following recommendations.

To facilitate the coverage of off-label uses of anticancer drugs, we urge CMS to establish a cancer-specific compendium that could be used by Medicare contractors, as well as by private payers. Currently, as you are aware, the Medicare Act requires coverage of off-label indications for anticancer therapeutic agents that are supported in one of three enumerated compendia, unless the off-label use is otherwise determined to not be medically appropriate⁵. However, the law also grants CMS the authority to revise the listed compendia as appropriate⁶. Given the complexity and magnitude of drug use in oncology, we recommend that CMS exercise its authority to create the aforementioned cancer-specific compendium. In establishing such a compendium, the agency could build on the existing work of the National Comprehensive Cancer Network, the American Society of Clinical Oncologists, and other stakeholders.

Specifically, we recommend that the new compendium be sponsored by CMS and governed by a panel of cancer experts, including oncologists at Alliance members and other leading institutions, community oncologists, industry representatives, payers, and cancer advocacy representatives. These experts should be charged with implementing a process designed to quickly respond to the rapidly changing landscape of cancer research and treatment. For example, the criteria for approval of off-label indications for inclusion in the compendium should include not only traditional peer- reviewed literature, but also peer-reviewed presentation of data at major meetings that achieve appropriate benchmarks. Such flexible criteria would accelerate coverage of appropriate indications and avoid the sometimes significant delays in coverage associated with the publication process. A cancer-specific compendium should address not only appropriate off-label uses for therapeutic oncology drugs, but also for cancer supportive care and symptom management drugs, thereby constituting a single authoritative source for the complex and unique coverage issues surrounding cancer care.

As an interim measure while a cancer- specific compendium is being developed, we recommend that CMS expand the list of peer- reviewed literature in the Medicare Benefit Policy Manual that Medicare contractors may rely on to extend coverage for off-label indications⁷. In addition to these titles, we recommend the following publications for inclusion on this list: Annals of Oncology, Gynecologic Oncology, Anti-Cancer Drugs, Clinical Cancer Research, Investigational New Drugs, Seminars in Hematology, Seminars in Oncology, the Journal of Neurological Oncology, and Lymphoma. Contractors should also be expressly permitted to examine peer-reviewed journals other than those listed in the Manual in considering off-label coverage issues.

Finally, in conducting their review of the compendia and peer-reviewed journals, it is imperative that contractors significantly reduce the time it takes to issue local coverage decisions. In our experience, an LCD review may frequently last between six months and one year. It is simply unacceptable for patients to wait this long for a coverage determination. CMS should require its contractors to accelerate their coverage deliberations to the fullest extent possible consistent with maintaining the quality of these determinations.

IV. CONCLUSION

Thank you for your willingness to consider our views. We are hopeful that CMS will address the concerns described above and make the necessary adjustments to the Draft Decision Memo. If you have any questions or require additional information, please contact Dr. James B. Dougherty, of the Arcus Group, LLC, at (212) 785-2236.

Sincerely yours,

James S. Quirk
Senior Vice President
Memorial Sloan-Kettering Cancer Center

---

1 See S. Culine, et al., Gemcitabine and Oxaliplatin in Advanced Transitional Cell Carcinoma of the Urothelium: A Pilot Study. 23 Anticancer Research 1903-06 (Mar.-Apr. 2003).
2 See M. Cantore, et al., Combined Irinotecan and Oxaliplatin in Patients With Advanced Pre-treated Pancreatic Cancer, 67 Oncology 93-97 (2004).
3 See Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), Pt. I, VIII.
4 See id
5 See 42 u.s.c. § 1395x(t)(2)(B)(ii)(I).
6 See id. § I395x(t)(2)(B).
7 See Medicare Benefit Policy Manual 100-3, § 50.4.5D.

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The Alliance of Dedicated Cancer Centers
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
City of Hope National Medical Center
Dana-Farber Cancer Institute
Fox Chase Cancer Center
H. Lee Moffitt Cancer Center and Research Institute
M.D. Anderson Cancer Center
Memorial Sloan-Kettering Cancer Center
Roswell Park Cancer Institute
Seattle Cancer Care Alliance
Sylvester Comprehensive Cancer Center

On behalf of the Alliance of Dedicated Cancer Centers, I am writing to comment on the above-referenced proposed coverage decision on off-label uses of certain chemotherapeutic drugs for the treatment of colorectal cancer that are provided in NCI-sponsored trials (the Draft Decision Memo). The Alliance is an association of ten comprehensive cancer centers, listed individually above, that focus exclusively on the care of cancer patients.

While we generally applaud this initiative, we have a number of concerns about the Draft Decision Memo. As you are aware, drug innovation regarding off-label indications is a dynamic, complex and incremental process. Indications for use rarely develop in a linear and predictable pattern. As a result, the current coverage decision-making process does not provide cancer clinicians and researchers with the flexibility required to explore and tailor treatment options to those with the greatest need. A new process is needed that provides for greater efficiency, effectiveness and timeliness. The Draft Decision Memo is a positive step forward in improving this system with regard to the drugs in question. However, as described below, it does not represent a comprehensive response to existing deficiencies. In this regard, we offer the following recommendations for revising the Draft Decision Memo:

I. Coverage Should Not Be Limited to Drugs Provided in NCI-sponsored Trials

The Alliance supports CMS's efforts to extend Medicare coverage to certain drugs under investigation in NCI-sponsored clinical trials, and thereby to encourage additional research by increasing clinical trial participation. However, we believe that, as proposed, the Draft Decision Memo has a number of shortcomings that could impede the realization of this goal by failing to recognize the realities of many clinical trial protocols.

First, in the Draft Decision Memo, CMS proposes to cover drugs provided in only nine studies. All of the listed trials are either Phase II or Phase Ill trials. As we understand it, pharmaceutical manufacturers may often provide drugs for such trials free of charge. If this is the case for drugs provided in the listed trials, it is unlikely that extending Medicare coverage would increase participation in these studies because the proposal would do little more than transfer the cost of these drugs from the private sector to the Medicare Program. Consequently, we are concerned that CMS's proposal will not materially increase patient or physician participation in these clinical trials.

Further, because the listed trials would cover only a small number of patients at a relatively small number of sites of care, patients living in areas without access to these clinical trial sites will be denied coverage under CMS's proposal. Given the large number of Medicare beneficiaries afflicted with colorectal cancer who could potentially participate in a study of the effectiveness of drugs used for off-label indications, CMS's proposal is unlikely to make significant inroads to benefit these patients.

Similarly, the Draft Decision Memo would provide only limited opportunities for research into other types of cancer, since only three of the listed studies target drugs used to treat non-colorectal cancers. As you may be aware, there is compelling clinical evidence demonstrating the value of these drugs in treating other forms of cancer. For example, European studies have shown positive results in the use of oxaliplatin to treat bladder cancer, but because of limited resources, comparable research has not been performed in the United States.¹ Pancreatic cancer also has been demonstrated to respond favorably to treatment with both oxaliplatin and irinotecan ², but the Draft Decision Memo proposes to cover drugs used in only one trial targeted at this cancer.

To address these concerns, we propose the following. First, we recommend that CMS revise the Draft Decision Memo to focus on coverage of these drugs in clinical trials where the manufacturer is not providing financial support, such as treatments for rare "orphan" and other diseases that do not affect sufficiently large patient populations to attract industry funding. To truly expand coverage and encourage enrollment, Medicare should offer coverage where none currently exists to help defray patients' out-of-pocket costs. Otherwise, patient access to these vital medicines could be solely dependent on the business imperatives of drug manufacturers.

Second, we recommend that, at a minimum, CMS provide coverage for the listed drugs provided in trials conducted at NCI-designated comprehensive cancer centers, such as members of the Alliance, as well as trials sponsored by other leading cancer organizations. Trials conducted at these centers are often based on emerging clinical understanding and development of new drugs and, therefore, are testing concepts that lead to NCI-sponsored trials such as those listed in the Draft Decision Memo. We are concerned that CMS 's proposed linking of coverage to only the listed trials could potentially decrease accruals to trials at non-NCI sites such as comprehensive cancer centers.

Alternatively, CMS could revise the Draft Decision Memo to provide coverage of the listed drugs in studies that are "deemed" to be covered under the 2000 National Coverage Determination for clinical trials. Currently, that decision covers the routine patient care costs associated with these deemed trials, but does not cover the investigational item or service itself. By expanding the NCD to cover the listed drugs, CMS would be able to develop a much more significant body of knowledge on the efficacy of off-label uses of these treatments.

The Alliance recognizes that the issues surrounding coverage of off-label indications of chemotherapeutic agents are complex, and we hope that the recommendations discussed above are helpful to OMS as it reviews the Draft Decision Memo. Our paramount concern is that CMS be as flexible as possible in identifying those clinical trials for which it will cover the listed drugs. Toward this end, we would be pleased to discuss these issues further with CMS and to work cooperatively with the agency in identifying those specific trials for which it would be appropriate to provide coverage.

Finally, CMS should facilitate patient access to the listed trials by working to increase the visibility of these trials to the public. In this regard, we recommend that the agency consider partnering with cancer advocacy groups and other stakeholders that have the necessary resources and expertise to provide patients with appropriate information about cancer clinical trials.

II. CMS Should Further Clarify That It Does Not Intend to Limit Contractor Discretion to Cover Off-label Uses of the Listed Drugs

The Alliance is also concerned that, while ostensibly not limiting the existing ability of Medicare contractors to provide coverage for off-label uses of the drugs in question,³ the Draft Decision Memo may be setting the stage for a future cabining of contractor discretion. In particular, we are concerned that, once the results of the listed trials are published, CMS may direct Medicare contractors to restrict coverage of any off-label uses of these drugs that were not supported by the trials. This would severely restrict patient access to necessary therapies because, as described above, the listed trials are not sufficiently comprehensive to identify and evaluate all potential off-label uses of these drugs. Therefore, we request CMS to clarify that, once the results of the listed trials become available, the agency will not bar Medicare contractors from extending coverage to off-label uses of these drugs that are supported by other clinical evidence, including data derived from non-listed trials.

We also request that CMS expressly direct contractors not to withhold coverage for off-label uses for these drugs while the results of the listed trials are pending. The Alliance is concerned that the mere existence of this Draft Decision Memo, if finalized as proposed, could have a chilling effect on local contractors and make them very reluctant to approve off-label indications for these therapies unless coverage is specifically required under the Medicare regulations. Limiting drug approvals for the several years needed to complete these trials will mean denying the drug to many patients who could benefit from them. This approach appears to be neither practical nor ethical. Consequently, we ask CMS to clarify to its contractors that they should not withhold coverage pending the outcomes of the listed trials if there is sufficient clinical evidence demonstrating the appropriateness of the off-label use.

III. CMS Should Establish a Cancer-Specific Compendium

In the Draft Decision Memo, CMS specifically invites comment on improvements to the guidance provided to Medicare contractors regarding coverage of off-label uses of these and other anticancer drugs.⁴ In response to this request, we offer the following recommendations.

To facilitate the coverage of off-label uses of anticancer drugs, we urge CMS to establish a cancer-specific compendium that could be used by Medicare contractors, as well as by private payers. Currently, as you are aware, the Medicare Act requires coverage of off-label indications for anticancer therapeutic agents that are supported in one of three enumerated compendia, unless the off-label use is otherwise determined to not be medically appropriate.⁵ However, the law also grants CMS the authority to revise the listed compendia as appropriate.⁶ Given the complexity and magnitude of drug use in oncology, we recommend that CMS exercise its authority to create the aforementioned cancer-specific compendium. In establishing such a compendium, the agency could build on the existing work of the National Comprehensive Cancer Network, the American Society of Clinical Oncologists, and other stakeholders.

Specifically, we recommend that the new compendium be sponsored by CMS and governed by a panel of cancer experts, including oncologists at Alliance members and other leading institutions, community oncologists, industry representatives, payers, and cancer advocacy representatives. These experts should be charged with implementing a process designed to quickly respond to the rapidly changing landscape of cancer research and treatment. For example, the criteria for approval of off-label indications for inclusion in the compendium should include not only traditional peer-reviewed literature, but also peer-reviewed presentation of data at major meetings that achieve appropriate benchmarks. Such flexible criteria would accelerate coverage of appropriate indications and avoid the sometimes significant delays in coverage associated with the publication process. A cancer-specific compendium should address not only appropriate off-label uses for therapeutic oncology drugs, but also for cancer supportive care and symptom management drugs, thereby constituting a single authoritative source for the complex and unique coverage issues surrounding cancer care.

As an interim measure while a cancer-specific compendium is being developed, we recommend that CMS expand the list of peer-reviewed literature in the Medicare Benefit Policy Manual that Medicare contractors may rely on to extend coverage for off-label indications.⁷ In addition to these titles, we recommend the following publications for inclusion on this list: Annals of Oncology, Gynecologic Oncology, Anti-Cancer Drugs, Clinical Cancer Research, Investigational New Drugs, Seminars in Hematology, Seminars in Oncology, the Journal of Neurological Oncology, and Lymphoma. Contractors should also be expressly permitted to examine peer-reviewed journals other than those listed in the Manual in considering off-label coverage issues.

Finally, in conducting their review of the compendia and peer-reviewed journals, it is imperative that contractors significantly reduce the time it takes to issue local coverage decisions. In our experience, an LCD review may frequently last between six months and one year. It is simply unacceptable for patients to wait this long for a coverage determination. CMS should require its contractors to accelerate their coverage deliberations to the fullest extent possible consistent with maintaining the quality of these determinations.

IV. CONCLUSION

Thank you for your willingness to consider our views. We are hopeful that CMS will address the concerns described above and make the necessary adjustments to the Draft Decision Memo.

---

1 See S. Culine, et al., Gemcitabine and Oxalinlatin in Advanced Transitional Cell Carcinoma of the Urothelium: A Pilot Study, 23 Anticancer Research 1903-06 (Mar.-Apr. 2003).

2 See M. Gantore, et al., Combined Irinotecan and Oxalinlatin in Patients With Advanced Pre-treated Pancreatic Cancer 67 Oncology 93-97 (2004).

3 See Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), Pt. I, VIII.

4 See id.

5 See 42 U.S.C. § 1395x(t)(2)(B)(ii)(I).

6 See id. § 1395x(t)(2XB).

7 See Medicare Benefit Policy Manual 100-3, § 50.4.5D.

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Thank you for the opportunity to comment on the Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N).

I am responding on behalf of the Colorectal Cancer Coalition, an advocacy organization working on behalf of patients with colorectal cancer, to decrease the suffering and death caused by colorectal cancer.

The Draft Decision Memo requests comment on a variety of topics; this response includes a summary of our position on the CMS decision (section 1) followed by more detailed comments (sections 2 and 3).

I hope our comments are helpful. Please do not hesitate to contact me directly for clarification.

1. Summary

The Colorectal Cancer Coalition fully supports all efforts to generate evidence-based treatment of cancer. As the details of the Centers for Medicare and Medicaid Services (CMS) support of clinical trials are developed, we offer the following ‘guiding principles’ with the hope that they will simplify a complex situation:

• Use existing infrastructure and organizations where possible
• Involve all levels of the community in a transparent process
• Provide resources, either directly or indirectly

We provide specific suggestions using these principles in following sections. In addition, we have laid out many questions to which we would appreciate answers. While the National Coverage Determination (NCD) began in February 2003, this Decision Memo has had only a two month comment period. In addition, the Decision Memo proposes specific actions without much detail, and asks broad questions without much guidance. This unusual situation raises as many questions as it answers, leading to comments mixed with questions and suggestions.

In addition, while we support efforts to generate evidence to support off-label use of cancer drugs, we want to be sure that the Decision Memo does not provide a justification to remove off-label use of cancer drugs as a treatment option. CMS has repeatedly stated that the proposed determination will make no change in coverage for any off-label uses of the anti-cancer drugs not provided in the selected clinical trials

However, we have heard much concern in the community about the intent behind this CMS action. In addition, the Decision Memo says:

The highlighted portion of this paragraph is alarming, because off-label use of cancer drugs is recognized as standard therapy in many forms of cancer, and is also recognized in the Medicare statute. The future restriction of off-label reimbursement to clinical trials would remove viable treatment options from many patients, including patients who are ineligible for trials, far from trial sites or unable to tolerate standard therapy.

We believe the language in the above paragraph should be clarified, to ensure that existing protection of off-label use of drugs is not at risk.

We look forward to working with CMS to support patients through the development of evidence-based treatments.

2. Comments requested by CMS

The Decision Memo identifies three topics where public comment is requested. Language from the Decision Memo follows, with topics identified as [Topic One, Two, Three]:

“I. Proposed Decision

[Topic One:] The Centers for Medicare & Medicaid Services (CMS) is seeking public comment on its proposed determination that the use of oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux™), or bevacizumab (Avastin™) is covered in clinical trials sponsored by the National Cancer Institute (NCI). …

[Topic Two:] … CMS is also seeking public comments on potential improvements in the guidance provided to contractors regarding coverage of off-label uses of these and other anti-cancer drugs. …

VII. CMS Analysis

[Topic Three:] … In addition to the NCI trial selection process, we are interested in establishing other processes to identify appropriate trials for which we may provide coverage. We are also interested in identifying additional means of gathering evidence outside of a clinical trial setting for use in decision-making such as registries and analysis of routinely collected electronic data. As a function of the public comment period, we are soliciting ideas and strategies for:

• incorporating input from patient groups, medical professional organizations and other stakeholders into the clinical trial selection process.
• soliciting and facilitating the participation of beneficiaries in selected clinical trials,
• implementing programs that allow both coverage of the off-label use of anti-cancer chemotherapeutic agents and collection of data to advance knowledge in the appropriate use of these agents outside of a clinical trial setting, e.g., drug registration program
• enabling more timely contractor determinations of medically accepted off-label indications on a local level.” ²

These topics concern wide-ranging issues, and comments which address them may fall outside of CMS statutory authority.

2.1. Topic One: CMS coverage of specified trials

We support the stated goal of the Decision Memo, which is focused on developing evidence to inform treatment decisions by patients and their doctors.

The Decision Memo indicates that the designated trials were identified as “high priority” by the National Cancer Institute. We have the following questions about both the trials and the process used to identify them:

• What were the standards and criteria used by NCI and CMS to identify and prioritize possible trials? Were the standards and criteria reviewed by consumers or clinicians prior to trial selection?

• The Decision Memo states that CMS “is seeking public comment on its proposed determination that the use of oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux™), or bevacizumab (Avastin™) is covered in clinical trials sponsored by the National Cancer Institute (NCI).”³

  Does “covered” mean that CMS will now pay for use of these drugs in the designated trials? Industry often provides drugs at reduced- or no-cost for cooperative group trials. If industry is now reimbursed for the cost of the drugs in those trials, will industry have an incentive to provide funding for correlative science instead? Or, if industry would prefer to provide drugs for trials, could CMS consider funding correlative science? Section 2.3.5 has additional comments around correlative science.

  Does “covered” mean that CMS will bring other forms of support and resources to these trials?

• Is a National Coverage Decision (NCD) for colorectal cancer drugs the appropriate mechanism for supporting clinical research in several tumor types? A review of NCDs on the CMS website⁴ shows that many past NCDs are focused on specific narrow issues. We would like to understand why the NCD mechanism was picked, and the implications that its use has for the future.

  • One immediate implication is the exclusion of high-priority research which does not involve these four drugs, such as research which identifies patients who may or may not need adjuvant therapy with drugs other than the four drugs identified in the NCD.

As stated in our Section 1, we oppose implied or actual restrictions to current off-label treatment reimbursement.

2.2. Topic Two: Improvements in guidance provided to contractors regarding off-label uses of these and other anti-cancer drugs

We believe that the system for evaluating reimbursement of off-label use of drugs should be reviewed and possibly updated. We urge CMS to work with FDA, NCI, consumers, clinical researchers and clinicians to make this happen, possibly through an organization which already brings these stakeholders to the table. Successful collaborations are characterized by clear goals, good plans, adequate resources and strong leadership – we assume that any effort put forward by CMS would have all four characteristics.

2.3. Topic 3: Process questions

The Decision Memo says:

CMS identified questions surrounding these goals, which are listed below. Many of our responses to CMS questions suggest consultation with others who may already be engaged in these types of efforts.

2.3.1. How can CMS incorporate input from patient groups, medical professional organizations and other stakeholders into the clinical trial selection process?

We suggest that CMS work within the existing structures in the community to tease out explicit selection criteria which are widely understood and supported.

The oncology research environment is very complex, with multiple layers of goals and strategies which make consistent criteria difficult to develop and apply. At the same time, there are ongoing efforts around research maps and strategies, such as:

• NCI Clinical Trials Working Group (http://integratedtrials.nci.nih.gov/ict/)
• NCI Progress Review Group (PRG) implementations (http://prg.nci.nih.gov/index.html)
• NCI Pancreatic Cancer Research Map (http://www.cancermap.org/pancreatic/index.jsp)
• Coalition of National Cancer Cooperative Groups’ recent work in colorectal cancer.

These ongoing efforts, which typically engage representation of all stakeholders and are thus relatively transparent, could provide CMS with a means of developing criteria for CMS sponsorship of trials.

We suggest that CMS consult with:

• Paula Kim, a founder of the Pancreatic Cancer Action Network (PanCAN). Ms. Kim has a well-earned reputation for looking at oncology research in an out-of-the-box and productive way. paulakim@cox.net, (310) 704-5260
• Bob Comis, president of the National Coalition of Cancer Cooperative Groups. Dr. Comis organized a recent Coalition planning meeting around colorectal cancer that could – with the inclusion of additional stakeholders such as consumers provide a model for other disease sites. robert.l.comis@drexel.edu, 215.893.6437

2.3.2. How can CMS solicit and facilitate the participation of beneficiaries in selected clinical trials?

Trial participation involves two sides of the fence: patients and health care professionals.

On the patient side, we suggest that CMS utilize the expertise of people who are working on data-driven methods of trial accrual:

• Peggy Devine, Cancer Information and Support Network: Ms. Devine has developed trial support material for cooperative group and SPORE trials, and has presented at the San Antonio Breast Cancer Symposium about the impact of her work. PDevine@pacbell.net, 925-462-4963
• Margo Michaels, Education Network to Advance Cancer Clinical Trials (ENACCT): ENACCT is a new organization which is working to identify and implement evidence-based approaches to effective cancer clinical trials education, outreach and recruitment in order to enhance accrual to these trials. margomichaels@enacct.org, 301-537-5647
• Nancy Fredericks, American College of Radiology Imaging Network (ACRIN): Ms. Fredericks handles accrual planning for ACRIN trials, and is working with ACRIN and its patient advocate committee to develop formal structures for protocol development and “marketing” to patients. nfredericks@phila.acr.org 215-717-2769 x 4769

On the clinician side, we suggest that CMS consider meeting with the Gastrointestinal Intergroup, which brings together GI researchers from all of the cooperative oncology groups, in order to get a clear picture of what doing clinical oncology research looks like on a day-in-day-out basis. The professionals in the trenches – the oncologists, research associates and other research staff are in the best position to identify barriers and actions that will help them overcome the barriers. Joel Tepper and Dan Haller are the co-chairs of the GI Intergroup (joel_tepper@med.unc.edu, dgh@mail.med.upenn.edu).

2.3.3. How can CMS implement programs that allow both coverage of the off-label use of anti-cancer chemotherapeutic agents and collection of data to advance knowledge in the appropriate use of these agents outside of a clinical trial setting, e.g., drug registration program?

We believe that implementation of these programs could greatly benefit patients. And conceptually, this type of program (drug registries) seems simple.

However, there are significant privacy, technological and financial barriers to implementing this seemingly simple suggestion. Our suggestion is that CMS work with NCI and with institutional and community-level oncologists, research associates and biostatisticians through the cooperative groups and SPORES, and see what it would take in the real world to make this possible. Another suggestion would be to find a single institution with a good informatics infrastructure, and implement a pilot program so examine the cost-benefit ratio. David Dilts at Vanderbilt is bringing formal systems theory and application to cancer research; his perspective on such a system might be very valuable. david.dilts@Vanderbilt.Edu, 615-322-2322

NCI’s Cancer Biomedical Informatics Grid (ca-BIG) effort (http://cabig.nci.nih.gov/) could be a tool in this effort; in addition, CMS could consider consulting external experts in large database management (such as people involved with the Multistate Anti-TeRrorism Information EXchange - MATRIX, http://www.matrix-at.org/). Given the privacy issues involved with any kind of data collection, an open development process, tight security and human subject protection are critical.

Development and implementation of these types of systems is resource-intensive; we assume that CMS will identify new resources to support this effort.

2.3.4. How can CMS enable more timely contractor determinations of medically accepted off-label indications on a local level?

We feel that more timely determinations will result from:

• Faster research
• Improvements to the informatics
• Improvements to the off-label guidance

2.3.5. How can CMS encourage industry to invest in studies that will expand knowledge base for patient and doctor discussions?

CMS didn’t raise this as a question; rather, it was framed as goal. However, we have comments on this topic, around the concept of targeted therapies.

A goal of targeted therapies is to identify the patients who will benefit from treatment – and likewise, the patients who will not, thus sparing them the associated toxicities of the treatment. Breast cancer patients quickly learn the importance of ER/PgR assays in selecting patients for hormonal therapy, and HER-2 IHC and FISH tests in selecting patients for trastuzumab (Herceptin®). These tests spare those who will not respond from the toxicities and expense of treatment that will do them no good. These tests are far from perfect, but the tests don't need to be perfect to accomplish their goals. They just need to carve out a significant number of non-responders.

However, targeted therapies are not a reality for most cancer patients. Rather, therapies characterized as “targeted” are approved without a clear understanding of what “targeted” means to patients. For example, gefitinib (Iressa®) was granted accelerated approval based on a response rate of approximately 10% in an unselected population. Between the time that gefitinib was granted accelerated approval and the present, major progress has been made on identifying the particular EGFR mutation that characterizes responders to gefitinib. Recent disappointing research results from an unselected patient population make gefitinib’s future uncertain. However, gefitinib may offer a clear benefit to patients who respond to the drug. Thus, patients would benefit most from a clear answer to the action of gefitinib in a selected patient population – and also from research that shows how long such patients should use gefitinib.

While some biotech companies have begun to tackle these issues, industry as a whole has little incentive to conduct this correlative research and develop such products. At the same time, the correlative science adds expense and complexity to the existing publicly-funded trial system – which many would say is already overly complex and under-funded.

How can the government increase resources – private or public – for this type of research? Will incentives work, or should “requirements” be established? We doubt that simple answers exist, but we believe that there are forums such as NCI’s Clinical Trials Working Group, C-Change and the Landsdowne Meeting where these topics have been discussed. We urge CMS to work within the existing infrastructure of cancer organizations to identify ways to move forward.

In addition, Lee Hartwell of the Fred Hutchinson Cancer Research Center presented interesting remarks on the issue of targeted diagnostics and therapeutics at the 2004 AACR and ASCO annual meetings. We suggest that CMS consider consultation with Dr. Hartwell. lhartwel@fhcrc.org (206) 667-5670

We look forward to the day when a cancer diagnosis includes a biomarker analysis that identifies productive treatment options which maximize benefit and minimize toxicity.

3. Drug-to-Drug Comparisons

We have a comment to add about the issue of drug-to-drug comparisons. There are times when drugs may be roughly equivalent (for example, capecitabine and infusional 5-FU), and research to evaluate the relative risk-benefit of those drugs is important.

However, many cancer therapies have no “equivalent”. On an NCI-CMS-FDA advocate call, Steve Phurrough from CMS talked about the need to see which is best – bevacizumab or cetuximab. This was alarming because most patients with metastatic disease will ultimately use both drugs. For them, the question isn’t “which drug is best?” but rather “what’s the best way to use the drugs we have?”

At the same time, a head-to-head comparison of these drugs in the adjuvant setting would provide valuable data to patients and physicians making treatment decisions.

We urge CMS to seek external comment when considering drug-to-drug comparisons, to ensure that the comparisons are appropriate and beneficial to patients. At the same time, we urge the research community – including NCI, the cooperative groups and the SPORES – to conduct head-to-head comparisons when appropriate and beneficial to patients.

¹ Draft Decision Memo http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=90

² Ibid.

³ Ibid.

⁴ CMS NCD list http://www.cms.hhs.gov/mcd/index_list.asp?list_type=ncd

⁵ Draft Decision Memo http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=90

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Roche Laboratories Inc. ("Roche"), a research- based pharmaceutical company, submits the following comments in response to the draft national coverage decision (NCD) for anticancer chemotherapy for colorectal cancer (CAG-00179N). As the manufacturer of Xeloda (capecitabine), we are interested in the immediate impact of this draft NCD because Xeloda is specifically mentioned in this NCD for the first time and is included in three of the nine trials listed in the draft. We also are interested in the Centers for Medicare and Medicaid Service's (CMS) plans to use the proposal in the draft NCD as a model for coverage policy for off-label uses for anti- cancer and other drugs in the future. Given the unprecedented coverage proposal introduced for the first time in this draft NCD, we particularly appreciate the 30-day extension of the comment deadline.

Our comments are based on the assumption that this NCD does not make any changes to current Medicare policy with respect to coverage of off- label uses of anti-cancer drugs, as expressly set forth in Section 50.4.5 of the Medicare Benefit Policy Manual. Instead, we are interpreting the draft NCD to be a coverage expansion with respect to off-label uses of four drugs: Eloxatin® (oxaliplatin), Camptosar® (irinotecan), Erbitux™ (cetuximab), and Avastin™ (bevacizumab). We presume that if CMS were changing current policy and practice with respect to coverage of anti-cancer therapies in this NCD (beyond requiring coverage of drugs in the listed clinical trials), CMS would make this statement expressly in the NCD and provide opportunity for public comment from the various stakeholders that would be interested in such a change.

As discussed in more detail below, because this NCD is not now and never has been about coverage of Xeloda, we request that CMS remove specific statements about Xeloda from the NCD. We also urge CMS to:

• Make it clear to local Medicare carriers that coverage of Xeloda is not limited to the use of the drug in the clinical trials listed in the NCD and that carriers retain the flexibility to make coverage decisions for Xeloda based on clinical and other relevant factors available in the current process at the local level;

• Clarify the specific criteria guiding the Agency's choice of the nine NCI trials listed in the draft decision;

• Provide more detail on the boundaries of Medicare coverage of these drugs when used in certain clinical trials, and in particular, the financial implications for beneficiary coinsurance obligations;

• Consider the potential, possibly unintended, consequences of providing coverage of these drugs in clinical trials; and

• Remove the proposal set forth in the draft NCD from the NCD process and consider re- issuing it as a notice of proposed rulemaking that provides for broader stakeholder input over a longer period of time.

I. CMS should remove all references to Xeloda in the draft NCD except where Xeloda is listed in particular NCI clinical trial protocols in the NCD. CMS also should make clear to local carriers that coverage is not limited to use of Xeloda in any of the clinical trials listed in the final NCI) and that carriers retain the flexibility to make coverage decisions about Xeloda.

The draft NCD clearly states: "5-FU[fluorouracil] and capecitabine are not subjects of this national coverage determination review." But this clear statement is directly followed by a brief paragraph about Xeloda and its use in the treatment of colorectal cancer. The statements about Xeloda provide a wholly incomplete description of the Medicare coverage potential for Xeloda, and have no place in an NCD that is not about Xeloda. We urge CMS to remove them from this NCD in order to avoid creating confusion about coverage of Xeloda for local carriers and physicians and other practitioners who prescribe anti-cancer treatments.

This NCD, which has been pending for nearly two years, has never focused on Xeloda and it is only in this most recent draft that Xeloda was mentioned.¹ We believe it is inappropriate to include any statements about use of Xeloda in this NCD because the information could mistakenly be taken out of context. We would be eager to meet with CMS if the Agency were interested in having further discussions about Xeloda.

We understand that CMS intends for this NCD to ensure that local carriers provide coverage for the drugs included in the designated clinical trials and is not intended to limit carrier discretion to provide coverage in other contexts. Unfortunately, in its current form, this NCD creates confusion about its scope and purpose and may lead to unintended limitations to Medicare coverage of items or services. To preclude this, CMS should further clarify the scope of the NCD to avoid creating confusion for prescribers and local carriers.

This is particularly important in the case of Xeloda, because the Agency already has provided confusing and potentially misleading guidance about Xeloda in the publicly disseminated draft coverage decision analysis. Accordingly, we believe CMS needs to do more than just remove specific statements about Xeloda from the final NCD. To set the record straight and ensure that beneficiaries and local carriers have accurate and complete information about Xeloda, we request that CMS include language from the Medicare Benefit Policy Manual in the final NCD reinforcing local carrier discretion with respect to coverage of Xeloda. The Medicare Benefit Policy Manual is quite clear on the parameters of coverage for off-label uses of anti-cancer drugs: Local carriers may not deny coverage of an anti- cancer drug based solely on FDA-approved labeling if the particular use:

• is in one of the three compendia,
• is supported by clinical research that appears in one of the listed peer-reviewed medical journals; or
• has been determined by the carrier to be medically accepted generally as safe and effective.²

This language should be reiterated in the NCD to make it clear to prescribers and local caniers that existing Medicare policy with respect to off- label coverage of Xeloda and other anti-cancer drugs remains unchanged, except for requiring coverage of the drugs used in the clinical trials listed in the NCD.

Finally, we note that in the statements about Xeloda included in the draft NCD, CMS makes specific reference to treatment of Xeloda in the 2004 Colon Cancer Clinical Practice Guidelines of the National Comprehensive Cancer Network (NCCN). The cancer treatment landscape is constantly changing, and clinical practice guidelines are often slow to incorporate the latest developments in anti-cancer therapy. In addition, there are a number of cancer treatment guidelines available to clinicians, and no single set of guidelines represents the clinical consensus for how to treat a particular type of cancer. Consequently; we urge CMS to avoid making reference to specific guidelines for specific products in this or any other coverage document concerning cancer treatment.

II. CMS should clarify the specific criteria guiding the Agency's choice of the nine NCI trials listed in the draft decision.

CMS has proposed guaranteeing Medicare coverage for off-label uses of four cancer drugs when they are used in nine clinical trials sponsored by the National Cancer Institute (NCI) that are studying the off-label use of one or more of these drugs in colorectal cancer and other cancer types. Tying coverage to use in clinical trials is itself an unusual step, but the Agency takes the further step of limiting coverage to nine NCI- sponsored trials. CMS has provided no explanation of why it selected these nine trials out of the hundreds of cancer treatment trials sponsored by NCI. We note that some of the trials listed are not for colorectal cancer (although this NCD began as an examination of coverage for off-label uses of drugs for colorectal cancer), and most of the trials are still in development, so we have no information on the protocols. CMS should provide the public with more details on its trial selection criteria before moving forward to implement this proposal.

CMS also has not explained why the Agency limited coverage to trials sponsored by NCI. There are a number of important trials, both industry- sponsored as well as investigator-initiated, that are ongoing or in development across the country exploring critical questions concerning optimal therapies for patients with various stages of cancer. Although Xeloda is included in three of the nine trials listed in the NCD, we cannot endorse this proposal without further clarification from CMS on the criteria CMS is using to select trials for coverage.

This information is particularly important if CMS plans to use this coverage approach for clinical trials of other drugs and disease states. CMS is taking an unparelleled step that could have negative consequences for some beneficiaries, as described in more detail below. The Agency needs to provide beneficiaries and other stakeholders with further details of this proposal and any plans to apply it more broadly in the future before taking any further steps toward implementation.

We also understand that CMS is interested in hearing about additional trials that might be covered as part of this NCD. Because CMS has provided little information in the draft NCD on its criteria for selecting trials for coverage, or what the Agency plans to do with the data generated by the covered trials, we are reluctant to offer specific suggestions in these written comments. But we would like to become more involved as CMS continues to develop this proposal. Roche has an active clinical research program for Xeloda, and we are interested in sharing information with the Agency about important clinical trials that have not yet begun to accrue subjects and that include Xeloda in combination with one or more of the drugs included in this NCD. We request a meeting with you at your earliest convenience where our clinical team can provide you with the details on these trials, and we can discuss the potential for including them in this or a future coverage proposal.

III. CMS should provide more detail on the scope of Medicare coverage of drugs when used in certain clinical trials.

In many clinical trials, manufacturers provide drugs being studied for free or at a significantly reduced rate to clinical trial participants; however, if Medicare provides coverage of drugs used in clinical trials, beneficiaries will be forced to pay a 20% co- payment on the cost of the drugs. The draft NCD is silent on how Medicare coverage of these drugs in certain clinical trials can be reconciled with industry practice of providing these drugs for free to trial participants.

Before going further with this proposal, CMS needs to consider

• Whether establishing a policy of providing coverage for drugs used in clinical trials (even just a subset of certain clinical trials) will in the long term provide a financial disincentive for manufacturers to provide drugs for free in clinical trials (and if so, whether beneficiaries who now have access to free drugs when they enroll in clinical trials will be financially harmed by this policy);

• Whether beneficiaries will be more reluctant to enroll in trials if Medicare coverage were provided, because of the co-payment obligation;

• Whether beneficiaries would be inappropriately steered toward the few trials that offer coverage, potentially resulting in enrollment bias (or will the opposite effect occur - will beneficiaries instead be inappropriately steered away from trials that offer coverage and toward trials that still offer drugs for free, again due to beneficiary co- payment obligations); and

• Whether coverage of the drug should continue until treatment ends for those beneficiaries whose clinical trial participation ends for non-clinical reasons (such as a change in residence or a premature end to the trial that is not related to adverse health outcomes).

We also assume that the cost of a drug provided in a Medicare-covered clinical trial would have to be included in the manufacturer's Average Sales Price (ASP) and Medicaid "best price" calculations for that drug. As a result, manufacturers will not be able to ease the financial burden for beneficiaries participating in Medicare-covered trials by discounting the price of the drug because of the potential impact such a price adjustment would have on those ASP and "best price" calculations.

IV. Consider the potential, possibly unintended, consequences of providing coverage of these drugs in clinical trials.

We also question whether it is appropriate for CMS to guarantee coverage of drugs when used in clinical trials that would deny access for a number of beneficiaries who may be unable to participate in a covered clinical trial. For instance, access would be denied to those beneficiaries who did not meet the protocol specifications (due to multiple co-morbidities or functional limitations), or because they did not live close to one of the clinical trial sites and did not have the resources (or were too infirm) to travel to a clinical trial site. Rural beneficiaries, in particular, would be the least likely to be able to take advantage of this policy because they reside in remote locations and often do not have other nearby resources to assist them with travel to a covered clinical trial site. We recognize that for health care items and services that are under local carrier discretion, there are sometimes disparities in care among beneficiaries due to differences in local carrier determinations. But we believe it would be unwise to promulgate national Medicare program policy that, on its face, treats some beneficiaries better than others, on the basis of factors that are not in the control of the beneficiary.

V. CMS should remove its coverage proposal from the NCD process and reissue it in a more public forum such as a notice of proposed rulemaking.

The national coverage decisionmaking process is CMS' vehicle for making decisions about whether a particular item or service is reasonable and necessary for beneficiaries and thus covered under the Medicare program. NCDs are typically about one or two specific items or services, and the community of individuals with a vested interest in any one particular NCD is relatively narrow. Ideally, the NCD process should be used to respond to medical innovation and to allow Medicare beneficiaries to access the latest developments in clinical care as quickly as possible. In the MMA, Congress enacted provisions to shorten the timeframes for issuing NCDs in order to improve the responsiveness of the coverage decisionmaking process to beneficiary needs.

But what CMS has proposed in this NCD is unprecedented and is likely to have ramifications far beyond Medicare coverage of the four drugs that are the focus of the NCD.

Consequently, we believe it is more appropriate for CMS to launch this proposal in a formal notice of proposed rulemaking (NPRM). In the draft NCD, CMS specifically requests comment on whether this approach should be used for additional drugs or disease states and how to identify appropriate trials for which CMS might provide coverage. We already have identified in our comments above some of the potential unintended consequences of CMS' proposal. If CMS is going to be involving itself more directly into the design of clinical trials, this proposal needs to be discussed in a forum like an NPRM that will allow for more public dialogue, over a longer period of time and including other stakeholders from the scientific community.

The draft NCD does not include a discussion of the costs to the Medicare program of providing coverage for the trials listed in the NCD, nor of the long-term costs if this proposal is adopted more widely by CMS for other drugs and disease states. Similarly, there is no discussion of the financial effect on beneficiaries, both in the short and long-term, or on private payers who, if they are not providing this type of coverage already, would be under pressure to do so once this policy is implemented. CMS would have to include such an impact statement as part of an NPRM, which makes it a more appropriate vehicle for launching a coverage proposal of this potential magnitude and that may impose significant costs on the Medicare program and the private sector. As a final note, we recall that when the Agency proposed providing Medicare coverage for routine costs of clinical trials, the proposal was initially launched as an NPRM, supported by sub-regulatory guidance on some of the technical details. The proposal set forth in this NCD is groundbreaking and deserves similar treatment.

There has been speculation that CMS might consider reissuing this proposal as a demonstration project rather than as part of this NCD. Although we agree with raking the proposal out of this NCD, we cannot comment on whether it would work better as a demonstration project, or whether introducing it as a demonstration project would provide a better forum for broader public consideration, until we see an actual demonstration project proposal. At a minimum, if CMS decides to launch this as a demonstration, we urge the Agency to structure it as a formal demonstration project. The Agency should issue an RFP for the project that sets forth criteria for trials to be included in the demonstration, and the public should have an opportunity to comment on those criteria before the RFP is finalized. Similarly, the clinical trials that are submitted to CMS for inclusion in the project should first be vetted by an expert evaluation panel that includes outside clinical trial experts who are qualified to rank each trial in terms of its scientific validity and clinical importance, as well as how well the trial meets the criteria set forth in the RFP. Such a structure would bring some outside expertise into the process of selecting clinical trials for Medicare coverage and put CMS on much firmer footing in terms of justifying the additional expense to the Medicare program. A more formal structure for selecting clinical trials for Medicare coverage is also likely to lead to better results.

VI. Conclusion

We hope that CMS will consider our comments as it evaluates the proposal set forth in the draft NCD. We look forward to working with CMS further on the issues identified in our comments.

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1/ Xeloda is included in three of the nine NCI- sponsored clinical trials listed in the NCD (NSABP R-04, ECOG E2204, and 6660). But Gezrnar (gemcitabine) and Gleevac (iniatinib) are also included in one or more of the trials, and specific statements about these drugs were not included in the NCD.

2/ Section 50.4.5 - Unlabeled Use for Anti-Cancer Drugs.

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The Coalition of National Cancer Cooperative Groups is a non-profit organization dedicated to increasing awareness and participation in cancer clinical trials. Our membership represents approximately 8,000 physician/researchers who comprise the NCI-sponsored cooperative group system that accounts for more than half of all patients entered onto cancer clinical trials in the United States.

We believe that the Draft Decision #CAG-00179N is an extremely important recognition of the work of the cooperative group system in establishing the standard of care, based on evidence, for Medicare patients in this country. We believe also that it is an important extension of the commitment CMS has made to clinical trials since 2000. CMS embraced the significance of cancer clinical trials in 2000 through the issuance of a National Coverage Decision (NCD) requiring coverage of all routine patient care costs for participants in clinical trials. As CMS considers coverage decisions now and in the future, the 2000 NCD should be the foundation of future decisions. Nothing in CMS's current coverage decisions should challenge the fundamental validity of the 2000 decision.

As we understand the Draft Decision it is important that it does not in any way abrogate, or in any way weaken, the existing policies regarding the off-label usage of anticancer drugs based upon the review of published data or listing in various qualified compendia listings.

It is understood that, in most instances, drugs being used in NCI-sponsored clinical trials are provided under the auspices of NCI held INDs. Generally, in those instances, the drugs such as those cited in the Draft Decision are provided free of charge and directly by the NCI. On the other hand, there are certain instances in which a commercially available drug might be used to support a particular study but would be used off label. The Draft Decision, in its current form, will hopefully establish a precedent that will continue to facilitate accrual onto important clinical trials beyond colorectal cancer for the future. As well, we would hope that some consideration in the future be made to establish a broader based approach which would include studies beyond those performed under the auspices of the Nd. Indeed, we believe that any trial deemed qualified under the 2000 NCD should be supported by the new Draft Decision.

In summary, we applaud this first attempt to encourage participation in clinical trials for Medicare patients, understanding that elderly patients tend to be under-represented in all clinical trials, independent of sponsorship.

We appreciate the opportunity to comment on this Draft Decision.

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The Association of Community Cancer Centers (ACCC) and the 12 undersigned state oncology societies appreciate this opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS) draft coverage decision memorandum for anticancer chemotherapy for colorectal cancer (CAG-00179N).¹ ACCC is a membership organization whose members include hospitals, physicians, nurses, social workers, and oncology team members who care for millions of patients and families fighting cancer. ACCC’s more than 700 member institutions and organizations treat 45% of all U.S. cancer patients. Combined with our physician membership, ACCC represents the facilities and providers responsible for treating over 65% of all U.S. cancer patients. The undersigned state oncology societies represent over 525 additional oncologists.

ACCC and the state societies are committed to ensuring that cancer patients have access to the entire continuum of quality cancer care, including access to the most appropriate cancer therapies, both through participation in clinical trials and outside clinical trials. In the draft decision memorandum, CMS states, “to ensure that beneficiaries have access to the most appropriate cancer treatments, it is imperative that adequate clinical trial data for off-label uses be made available to patients and providers for clinical decision-making and to policymaker[s].” We agree completely with this statement. Indeed, our members depend on valid clinical data to provide the best quality care to their patients.

Cancer care evolves through a cyclical process. The outcomes of clinical research are published in peer-reviewed journals that are reviewed and summarized in compendia that define the current standard of care. As they gain experience with a standard of care, physicians identify potential improvements to existing treatment regimens, leading to more clinical trials, publications, and new standards of care. The process also is driven by continued drug development, leading to more clinical trials. Through this process, we gather the data necessary to use new therapies effectively, including in combination with older drugs. Although this process is used in all areas of medicine, it is particularly important in oncology where finding new therapies can be a matter of life and death and off-label drug use is a critical component of many treatment regimens.

We believe that continued research must be a priority for all stakeholders involved in cancer care, including CMS. We also recognize that some new therapies are quite costly, and that some therapeutic regimens can have significant financial, as well as medical, consequences for patients and providers. We believe that patients always should have a choice of clinically appropriate therapies, but we also understand the need to spend health care funds wisely, and we support clinical trials that will help us learn how to use new therapies most effectively.

However, after careful review of the draft decision memorandum, we have concluded that this proposed national coverage determination (NCD) is not an appropriate means for achieving these goals. As stated, we are concerned that the proposed NCD:

• threatens the Medicare carriers’ current coverage policies, which have succeeded at providing timely access to modern cancer therapies;
• raises myriad unanswered questions about beneficiary access to care inside and outside these trials; and
• is an inappropriate use of the NCD process to create a profoundly different approach to Medicare coverage of advanced drugs and biologicals.

We question CMS’ use of the NCD process to pioneer an untested approach to Medicare coverage of advanced drugs and biologicals. Rather than pursuing this draft NCD, we recommend that CMS focus its limited resources on enhancing processes already in place, including Medicare’s current local coverage rules that facilitate appropriate beneficiary access to innovative therapies. Current rules could benefit from improvement in two areas: Medicare beneficiaries’ participation in clinical trials and publication of authoritative compendia. Our comments seek to initiate a dialogue on these topics, and we are committed to working with CMS to address these crucial elements of the continual improvement of the standards of cancer care.

1. Current Medicare coverage policies ensure coverage keeps pace with changes in the standard of care.

Medicare’s current coverage rules effectively provide beneficiary access to innovative therapies, used in conformity with evolving standards of care. The Medicare statute requires carriers to cover off-label uses of cancer therapies when such uses are supported by citations in certain compendia or by clinical evidence in peer-reviewed literature.² Medicare’s longstanding instructions to carriers also allow coverage when the use is “determined by the carrier to be medically accepted generally as safe and effective for the particular use.”³ These rules establish appropriate constraints on carriers’ discretion and at the same time also allow them the necessary flexibility to adapt to new discoveries in cancer care. In our members’ experience, the carriers have exercised their authority with great care, seeking evidence to justify coverage of new uses, while also respecting physicians’ professional judgment regarding the best course of treatment for their patients.

Medicare’s current national coverage policy for clinical trials also provides beneficiary access to cutting edge therapies. Since September 2000, Medicare has covered the costs of routine care in qualifying clinical trials.⁴ This policy allows Medicare beneficiaries enrolled in trials funded by several federal agencies, including the National Institutes of Health (NIH), to receive Medicare coverage for routine care associated with those trials. Under this policy, Medicare beneficiaries have been encouraged to seek out and enroll in qualifying trials, providing the beneficiaries with improved access to cutting edge therapies and helping to further our understanding of modern cancer technologies. We believe that CMS should continue to encourage beneficiaries to enroll in a wide range of clinical trials and should finalize its criteria for coverage of additional trials.

2. CMS’s goals and intentions are questionable, given the myriad of unanswered questions regarding access to these therapies raised by the proposed NCD.

Although we agree with CMS that more clinical data are needed to guide physicians in the most appropriate use of innovative cancer therapies, we believe the proposed NCD is not the best means to collect this information. The draft decision memorandum raises many significant questions that remain unanswered, even after our meetings with CMS and the National Cancer Institute (NCI). Unless these issues are resolved appropriately, we cannot agree with CMS’ assertion that the NCD will expand access to oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux®), or bevacizumab (Avastin™). We are greatly concerned that the proposed NCD will restrict, not expand, access to these therapies.

In the draft decision memorandum, CMS calls its proposal to cover these four therapies when used in specified NCI-sponsored clinical trials a “coverage expansion.” The draft decision memorandum does not provide enough information for us to evaluate whether it would significantly improve Medicare beneficiaries’ access to these therapies, however. To expand coverage, the selected trials must enroll Medicare beneficiaries who would not otherwise be able to receive these drugs. The trials also must be appealing treatment options, allowing beneficiaries to receive care from their preferred providers in convenient locations, without imposing extra costs on participants. In addition, physicians from all areas of the country must be encouraged to participate and must be provided with the necessary resources to meet the trials’ data collection requirements. In short, we need to know:

• How many Medicare beneficiaries does CMS expect to enroll in the trials?
• Where will the trials take place? Will patients in all areas of the country have access to trials near their homes? Will they be able to receive care from their regular doctors and cancer centers or will they have to change providers?
• What kinds of treatment, medical tests, or procedures will patients receive in these trials? How much will patients have to pay for these services, including the non-routine costs not covered by Medicare?
• How long will the trials last? Will participating beneficiaries who must drop out of a trial prematurely receive Medicare reimbursement for their care?
• Which providers can participate?
• What support will CMS provide to participating physicians to help them fulfill the trials’ data collection requirements?

We cannot fully understand the effects this proposal will have on beneficiary access to care unless we know the answers to these questions for each trial Medicare will cover. We therefore urge CMS to respond to these questions before proceeding with this proposal so ACCC, state oncology societies, and other stakeholders may provide more detailed comments. From our conversations with NCI representatives, we have learned that some of the trials listed in the draft decision memorandum could change, be cancelled, or be replaced with different trials. Given the high level of uncertainty that continues to surround this proposal, we question the urgency for its implementation. If CMS makes any changes to its list of trials considered for coverage, we request that CMS provide updated information to its stakeholders.

The proposal’s effects on access to care also depend on whether it alters coverage of these drugs when used outside the listed clinical trials. Not all patients who currently receive these drugs are eligible to participate in the clinical trials, and some who are eligible might decline to enroll if they would be required to travel, change physicians, or bear additional costs. These patients must continue to have access to appropriate care regardless of whether the NCD is implemented.

The draft decision memorandum states that it “makes no change in coverage for any off-label uses of these drugs not provided in the selected clinical trials,”⁵ but its restatement of the current coverage rules is ambiguous. CMS says, “contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature,”⁶ but fails to mention local carriers’ discretion under current policies to cover uses they determine to be “medically accepted generally as safe and effective for the particular use.”⁷ If CMS intends to leave coverage unchanged for uses not included in the trials, as it asserts is its intent, the agency must also continue to allow carriers to cover off-label uses they find to be appropriate.

The proposed NCD also appears to treat several generally accepted treatment regimens as experimental. Specifically, although the FDA approved Avastin™ (bevacizumab) for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic cancer of the colon or rectum, CMS contends that Avastin™ is indicated with a 5-FU infusion only. Avastin™ is used routinely with FOLFOX (oxaliplatin, 5-FU, leucovorin) in compliance with its label and as recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology™.⁸ Under the proposed NCD, CMS treats the use of Avastin™ with this and other 5-FU-based chemotherapy regimens as experimental in trial C80405, even though they comply with the drug’s labeling. Likewise, many oncologists use Eloxatin® (oxaliplatin) for neoadjuvant treatment of high risk rectal cancer, based on data in collected in studies of colon cancer, yet CMS is treating this use as experimental in trial NSABP R-04. If CMS decides these uses are experimental when provided in the nine selected trials, we are concerned that the agency will deny access to these uses outside the trials. We urge CMS to ensure that its proposed coverage expansion does not curtail beneficiary access to medically accepted therapeutic regimens.

Additionally, we request clarification on how the proposed NCD relates to CMS’ 2000 decision to pay for the costs of routine services in qualifying clinical trials. Under the 2000 clinical trial NCD, all of these identified trials would qualify for coverage because they are sponsored by NCI, an Institute within NIH. All Medicare beneficiaries enrolling in these trials would be entitled to coverage for their routine costs of care under the current policy. Now, CMS proposes to cover their routine costs plus the costs of the experimental drug, if the drug is not provided for free to the beneficiary. We do not know whether any of the drugs in these trials will be provided by their manufacturers, but we note that manufacturers commonly donate their drugs for use in major clinical trials. Therefore, if the drugs used in these trials are donated, this proposed NCD appears to be merely a specific application of the 2000 clinical trial NCD, not a new expansion of coverage. If this is true, then the proposed NCD is not necessary and should be withdrawn.

If, on the other hand, CMS intends to pay under the proposed NCD for items and services not currently covered, we request more information on what it plans to cover and how CMS will reimburse for these items. For example:

• Does CMS intend to pay for non-routine costs of care, including infusion services and additional laboratory and diagnostic tests required by the trials?
• How will CMS reimburse providers for drugs not donated for these trials?
• If these items services are reasonable and necessary in these nine trials, how does CMS explain why they should not be covered in other qualifying trials?

We are particularly concerned that CMS’ reimbursement decisions will affect patients’ and providers’ decisions to participate in trials, as well as manufacturers’ decisions to sponsor trials. Beneficiaries should choose their care based on clinical concerns, not cost. But, if Medicare coverage is available for their chosen therapy only if they enroll in clinical trials, beneficiaries will be swayed to enroll in the trials. Likewise, if providers can receive reimbursement for their services only in the context of a clinical trial, providers may feel pressure to enroll their patients in trials, regardless of whether the trial is the best course of care for the individual patient.

Alternatively, if a beneficiary has a choice between a trial covered by Medicare, with the corresponding coinsurance liability, or one in which all costs are paid by a sponsor, the beneficiary will choose the second trial. CMS must then take care to ensure that its choice to cover care in these nine trials does not perversely discourage beneficiaries from enrolling in them. To determine whether the proposed NCD actually will attract Medicare beneficiaries, we need more information about CMS’ reimbursement plans. We urge CMS to provide answers to these questions should it proceed with this proposal.

CMS also risks upsetting the current support system for clinical trials by replacing industry support with limited Medicare funding. Manufacturers may be dissuaded from sponsoring trials, including paying for non-routine care, if Medicare will reimburse these services. The impact on patient care could be profound if manufacturers ultimately choose not to invest in advancing cancer research. CMS’ proposal could shift the costs of clinical trials from manufacturers to the Medicare program and its beneficiaries. We do not believe CMS intends to discourage industry support of clinical trials, particularly at the expense of Medicare beneficiaries. We urge CMS to consider carefully the potential consequences of its coverage proposal.

By focusing solely on NCI trials, access to these therapies could actually be restricted. Instead of proposing coverage for nine trials, CMS should work to encourage Medicare beneficiaries to enroll in all qualifying trials, including other government-sponsored trials, trials under an investigational new drug application (IND) reviewed by the Food and Drug Administration (FDA), and trials exempt from having an IND under 21 C.F.R. 312.2(b)(1). The agency’s goals of improving trial participation and gathering more clinical data would be better served by promoting beneficiary participation in all trials, not just a select few.

3. The NCD process is not an appropriate forum to address the need for more clinical data.

In the draft decision memorandum, CMS presents important proposals regarding its implementation of this NCD, as well as the agency’s efforts to collect clinical evidence on these and other therapies. CMS attempts to use the comment period on this NCD to seek comments on ideas and strategies for identifying other trials for coverage, developing additional means of gathering clinical evidence while covering off-label uses of chemotherapeutic agents, facilitating beneficiary participation in clinical trials, and reforming carriers’ coverage determination processes. We believe these questions merit serious discussion with CMS’ stakeholders, but the NCD process is not an appropriate forum for this dialogue.

CMS developed the NCD process to evaluate scientific and clinical evidence to determine whether particular items and services qualify for coverage because they are “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”⁹ This longstanding process was codified by section 731 of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, defining the timeframes for drafting proposed NCDs, soliciting public comment, and the agency’s review of those comments.¹⁰ The process is designed to allow CMS to review appropriate evidence, draft a proposal, and inform interested stakeholders of its proposal in a timely and efficient manner. This process is distinct from the more formal procedures used to propose policy changes with broad effect, such as revisions to the coverage process itself. CMS’ custom is to announce policy changes that apply to all Medicare beneficiaries and providers through notices in the Federal Register, not informal announcements on its website.¹¹

In contrast to CMS’ longstanding practice and the statutory requirements for NCDs, this proposed NCD announces a coverage decision based not on available evidence for particular items or services, but on the lack of evidence for a collection of different drugs and biologicals. In addition, CMS appears to have considered the costs of these therapies when it initiated the NCD process instead of confining itself to the available clinical and scientific evidence regarding their use. Furthermore, the draft decision memorandum requests comments on policy questions with broad application to future coverage decisions. These departures from the normal NCD process and content indicate that CMS’ proposals are not appropriately addressed in this forum.

4. CMS should focus its efforts on enhancing current local coverage rules.

As we explained in section I, above, Medicare’s current local coverage rules allow beneficiaries access to essential off-label cancer therapies, used in accordance with evolving standards of care. We support the continued use of these rules, but we believe that they could be used more effectively if carriers and providers had better clinical evidence to support their decisions. Instead of covering a limited selection of clinical trials, as proposed in this NCD, CMS should focus its efforts on improving Medicare beneficiaries’ participation in all clinical trials and on developing additional sources of authoritative information on off-label uses of cancer therapies.

We strongly believe that Medicare beneficiaries should have expanded access to clinical trials. Clinical trials provide participating beneficiaries with new hope in their battles with cancer and are essential to improving care for future patients. CMS was correct to expand coverage for routine care associated with clinical trials in 2000, but CMS can do more to encourage Medicare beneficiaries to participate in trials. First, CMS should finalize its criteria for coverage of additional trials. In the four years since CMS first announced that it would cover qualifying trials, the agency has not defined the criteria for coverage of trials that are not sponsored by government agencies or conducted under an IND. Final criteria would help physicians and beneficiaries determine whether a particular trial is covered, making it easier for them to select among treatment options. Second, CMS should evaluate its payment policies for non-routine care in clinical trials. In particular, CMS should provide reimbursement for infusion costs that are not currently reimbursed by many trial sponsors. Physicians are less likely to participate in trials if they are not reimbursed for their costs of care, limiting their patients’ treatment options. Expanding Medicare beneficiaries’ access to all clinical trials will help us continue to learn about the most effective off-label uses of cancer therapies, particularly in elderly patients.

Gathering more data through increased participation in clinical trials is just the first step to enhancing the current local coverage rules. After trial data are collected, they must be disseminated to providers and carriers. The Medicare statute and rules currently identify three authoritative compendia for off-label indications: the American Hospital Formulary Service-Drug Information, the American Medical Association Drug Evaluations, and the United States Pharmacopoeia-Drug Information.¹² Of these three publications, the American Medical Association Drug Evaluations is no longer in print, and the United States Pharmacopoeia-Drug Information has been sold to another publisher and soon will undergo a name change. Fortunately, the Medicare statute allows the Secretary to recognize additional compendia as appropriate for identifying medical accepted indications for drugs.¹³ We urge CMS to work with its stakeholders to develop new sources of authoritative, up-to-date information on the uses of anti-cancer drugs that both physicians and carriers can use to identify appropriate therapeutic regimens.

We suggest that CMS expand its list of authoritative compendia to include the NCCN Drugs and Biologics Compendium. This recently released publication provides extensive information on off-label uses of cancer therapies, derived from the NCCN Clinical Practice Guidelines in Oncology™, the recognized standard for clinical policy in oncology.¹⁴ The first chapter of the Compendium, covering colon, rectal, and anal cancers, was released in October 2004. We also recommend that CMS consider other reliable sources of information on recent research, such as presentations at American Society of Clinical Oncology (ASCO) clinical conferences. Many physicians learn about off-label uses through these conferences, but coverage often is delayed until the same findings are published in the compendia. Rather than requiring patients to wait on publication schedules for coverage of new therapies that may dramatically extend their lives, we recommend that CMS develop a process for recognizing these presentations when they occur.

In addition to the NCI trial selection process addressed in the draft decision memo, CMS expressed an interest in strategies for incorporating input from patient groups, medical professional organizations and other stakeholders into the clinical trial process. Given the agency’s request along with our objection to CMS implementing this ill-conceived NCD, we suggest CMS work with its stakeholders to develop an approach that would truly foster the clinical trial system. As such, we suggest that CMS work with its stakeholders to create a prospectus to identify off-label uses for which more data are needed. The prospectus would support the general use of clinical trials and drug administration protocols, clarify the reimbursement policies associated with all government-sponsored clinical trials, and make recommendations to fulfill specific clinical information needs. It would help to identify regimens to be tested in clinical trials and would define the threshold of evidence needed to establish the standard of care. The prospectus also would ensure that patient groups, medical professional organizations, and researchers, have a role in guiding NCI’s research priorities and informing CMS of reimbursement policies in need of clarification.

In conclusion, ACCC and the 12 undersigned state oncology societies agree with CMS that more data are needed to support clinical decision making regarding off-label uses of innovative cancer therapies. We disagree with CMS’ proposal to gather these data by covering four colorectal cancer therapies in nine selected trials, however. As CMS itself acknowledges in the draft NCD, the need for more information extends beyond these four drugs. The solution, we argue, also extends beyond the scope of a single NCD.

We urge CMS to withdraw this NCD and engage its stakeholders – beneficiaries, physicians, providers, researchers, and carriers – in discussions on how best to improve the clinical information available regarding off-label cancer therapies. These discussions should focus on both the collection of information through increased Medicare beneficiary participation in clinical trials and on the dissemination of information through authoritative publications. ACCC would be pleased to work with CMS to organize these discussions.

We appreciate the opportunity to offer these comments. We look forward to continuing to work with CMS to address these critical issues in the future.

1 Draft Decision Memorandum for Anticancer Chemotherapy for Colorectal Cancer (CAG-00178N), Nov. 1, 2004, available at http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=90.

2 Social Security Act (SSA) § 1861(t)(2).

3 Medicare Benefit Policy Manual (CMS Pub. 100-02), ch. 15, § 50.4.5.

4 National Coverage Determinations Manual, § 310.1.

5 Draft Decision Memo.

6 Id.

7 Medicare Benefit Policy Manual (CMS Pub. 100-02), ch. 15, § 50.4.5.

8 NCCN Clinical Practice Guidelines in Oncology, available at http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf.

9 See CMS, Medicare Program; Revised Process for Making Medicare National Coverage Determinations, 68 Fed. Reg. 55634, 55635 (Sept. 26, 2003); SSA § 1862(a)(1).

10 See SSA § 1862(l)(3).

11 A list of Federal Register announcements regarding the Medicare coverage process are available at http://www.cms.hhs.gov/coverage/8a.asp.

12 SSA § 1861(t)(2)(B)(ii).

13 Id. (“and other authoritative compendia as identified by the Secretary.”)

14 The Compendium is available online at http://www.nccn.org/professionals/drug_compendium/login/login.aspx.

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Sanofi-Aventis¹ appreciates the opportunity to comment on the draft national coverage decision (NCD) for anticancer chemotherapy for colorectal cancer (CAG-00179N). As the manufacturer of oxaliplatin (Eloxatin®), we have been engaged actively in this NCD since it began in February 2003 with an internally generated request to review Medicare coverage of Eloxatin®. Throughout every stage of review we have found CMS staff to be deeply interested in the science and benefits of Eloxatin® for cancer patients and supportive of Sanofi-Aventis’ efforts in maintaining an active, ongoing clinical research program into the drug.

In November 2004, the original NCD was expanded to encompass the off-label uses of Eloxatin® as well as three additional anticancer agents.² CMS proposed covering these four drugs when used in nine specific clinical trials sponsored by the National Cancer Institute (NCI). This proposal is unprecedented, and we thank CMS for extending the comment deadline by an additional 30 days to allow interested stakeholders to submit comments. We are particularly grateful to Dr. Steve Phurrough, Dr. Louis Jacques, Dr. James Rollins, Gay Burton, and other members of the Coverage and Analysis Group team working on this NCD for taking the time to clarify the agency’s objectives and to explore with us some logistical and other challenges raised by the proposal. Our comments are based on our understanding of these matters to date.

Specifically, we understand that CMS considers this NCD as a potential first step in the agency's ongoing efforts to improve the evidentiary basis underlying coverage of Medicare beneficiaries’ clinical care by increasing their enrollment in clinical trials. Sanofi-Aventis strongly supports this goal. We are well aware of the enormous challenges facing the clinical research enterprise, including ensuring the participation of the elderly in clinical trials. We currently provide support for all NCI-sponsored colorectal cancer clinical trials currently underway in the U.S. in which Eloxatin® is being used, including all the clinical trials utilizing Eloxatin® listed in the draft NCD. Therefore, we are particularly interested in the outcome of this NCD and believe we have some helpful comments to offer as the agency considers ways to accomplish the goal stated above.

As explained in more detail in the body of our comments, we believe that the approach proposed in the NCD is problematic and CMS should consider alternative approaches for the following reasons:

• Providing coverage for off-label uses of these drugs in a restricted program of only nine specific NCI-sponsored trials may discriminate against beneficiaries who are ineligible to participate in these trials or are unable to participate in the program for geographic or for any other reason, thus creating significant coverage disparities in the overall Medicare program. As NCI data shows, less than 10% of adult patients in the U.S with a diagnosis of cancer currently participate in a clinical trial during their course of treatment.

• Using coverage as a vehicle for increasing the number of Medicare beneficiaries participating in clinical trials could have unintended consequences, including introducing enrollment bias and perhaps skewing trial results. For example, an elderly patient with cancer, who would customarily not be considered by their physician to be good a candidate for participation in a clinical trial, might be encouraged to do so predominantly for reimbursement reasons. Reimbursement never should be the primary motivation for participation in a clinical trial.

• The draft NCD is likely to be perceived by providers and local carriers as limiting coverage of the four included drugs.

• Because of Medicare co-insurance obligations, beneficiaries may have increased out-of-pocket costs for participating in clinical trials than they would have if the parameters of clinical trial participation were left to negotiation between sponsors, investigators and manufacturers, as is currently the case.

• CMS has not provided much detail in the draft NCD on its policy and operational criteria for selecting the nine trials listed in the draft NCD. The agency also does not provide a framework by which to select additional trials in the future.

• CMS has not explained how it intends to use the data generated by these trials.

• The NCD is CMS’ primary vehicle for determining whether a particular item or service is reasonable and necessary for Medicare beneficiaries, and thus covered under the Medicare program. We question whether it is the appropriate vehicle for launching a far-reaching program designed to increase the number of seniors participating in U.S. clinical trials.

Given the potential for possibly unintended consequences of the draft proposal, we request that CMS consider the following recommendations. These options are intended to place the agency on the soundest possible footing in meeting its objectives of advancing true evidence-based medicine and increasing the participation of the elderly in clinical trials. Following the summary recommendations, we offer additional information on the concerns raised above, on the challenges of enrolling the elderly in clinical trials, and on our reasoning behind the recommendations.

Recommendations:

We appreciate your consideration of these recommendations. Following are detailed comments on all the points summarized above. As a preface, even though less than 10% of patients with cancer in the U.S. participate in clinical trials as part of their overall treatment,³ the lack of participation in clinical trials by seniors, women, minorities and other population subgroups is well-documented in the scientific literature and is a persistent challenge for clinical research, both in the U.S. and around the world. In a recent article in the Journal of Clinical Oncology entitled “Participation of Patients 65 Years of Age or Older in Cancer Clinical Trials,” the authors explored the factors accounting for the dearth of participation of elderly patients in cancer clinical trials. The authors cited numerous reasons why the elderly are either routinely excluded from clinical trials or choose not to participate. The authors concluded that the incidence of co-morbid conditions in the elderly was the main reason for their routine exclusion. In particular, the authors stated that “protocol exclusion criteria that are based on organ-system abnormalities and functional status limitations are associated with lower rates of elderly participation in cancer trials and almost fully explain the observed under-representation of the elderly in these trials relative to their burden of disease.”⁴ The authors further noted that recent federal policy to expand Medicare coverage for cancer clinical trials was unlikely to increase substantially the level of participation in clinical trials by the elderly.⁵ If CMS’ goal in implementing this proposal is merely to drive increased participation by Medicare beneficiaries in clinical trials, providing coverage for these four drugs in nine specific NCI trials is not likely to accomplish this objective.

In addition, the Institute of Medicine (IOM) did a far-reaching study in 1994 on including women as the subjects of health research. Because women are disproportionately represented among the elderly, the IOM Study Committee also considered the barriers to participation in clinical trials by elderly women. The IOM Study Committee made a number of comprehensive recommendations for rectifying the lack of participation of women in clinical research, including the development of commissions of a wide range of experts, increased training of investigators, tailoring study designs to address conditions that are more common in women, and collecting data from existing clinical trials about participation of women and minorities.⁶ The Committee did not specifically recommend widespread coverage of drugs in clinical trials as a strategy for increasing the number of women participants in trials, suggesting that the Committee believed there were other mechanisms for addressing this challenging research problem.

In fact, CMS already may have the resources to help determine whether providing coverage actually increases beneficiary participation in clinical trials. For example, CMS instituted a policy of covering routine costs in clinical trials in September 2000. As a result, Medicare already provides coverage for much of the costs of participation in clinical trials, except for the costs of the actual item or service being studied. Has CMS done an analysis of whether providing coverage of routine costs has increased the participation of Medicare beneficiaries in clinical trials? Similarly, since 1996 Medicare has provided coverage for some Category B devices being studied under Investigational Device Exemption (IDE) protocols. Has CMS looked at whether providing this coverage has resulted in more Medicare beneficiaries being enrolled in clinical trials of these devices? We encourage CMS to use information it already may have about the impact of coverage on clinical trial participation before embarking on this new course.

We agree with CMS that too few Medicare beneficiaries are enrolled in clinical trials. We believe CMS, as the primary payor of medical care for the elderly in the U.S., has an important role to play in establishing a comprehensive national solution to this problem, and we are committed to working with you to address it. However, we question whether the proposal set forth in this draft NCD is the optimal approach. In particular, we are concerned that the proposal could have a number of unintended consequences for Medicare beneficiaries, as well as for clinical research policy in the U.S., in both the short and long-term. The NCD touches upon coverage and payment policies of sufficient import that it would be best if the Agency lifted these proposals out of the “sub-regulatory” NCD process. We discuss our specific concerns and questions below. As a result of these concerns, however, we urge CMS to withdraw the draft NCD and pursue any proposal to increase clinical trial participation among beneficiaries more deliberatively through another more rigorous and thoughtful process as recommended above.

I. Providing coverage for off-label uses of these drugs in only those trials listed in the NCD may discriminate against beneficiaries who are ineligible to participate for any reason, thereby creating coverage disparities in the overall Medicare program.

Under current Medicare policy, all beneficiaries participating in clinical trials are entitled to have their “routine costs” covered under Medicare. This policy benefits all clinical trial participants and is not limited to specific NCI trials. In contrast, this NCD would provide coverage for the four drugs only when used in specific trials. We are concerned there is an inequity inherent in this proposal.

For example, some Medicare patients could benefit from one or more of the four drugs on an off-label basis, administered in a manner consistent with the protocol for one of the listed trials, but will be precluded from participating in one of the trials due to protocol specifications, the trial location, or some other factor. These beneficiaries will not be guaranteed coverage of their drugs by Medicare, unlike beneficiaries in need of the same drugs who are enrolled in one of the covered clinical trials. Such coverage disparities seem unjustifiable.

It seems inherently unfair to use participation in clinical trials as the deciding factor for which beneficiaries with cancer are guaranteed coverage of their drugs and which are not. Rural beneficiaries, in particular, are disadvantaged by this policy because they are less likely to be located near clinical trial sites or a participating physician or have the capacity or resources to travel to a clinical trial location. Moreover, even beneficiaries who live close to clinical trial sites may be precluded from participating because they are suffering from co-morbid conditions that require them to be excluded from the protocol. They also may be reluctant to change their cancer care from a trusted doctor to a clinical trial site.

According to the same article in the Journal of Clinical Oncology cited above, the key reasons for lack of participation by the elderly in clinical trials include:

• Protocol exclusion criteria based on co-morbid conditions or functional limitations;
  
• Older patients being less likely to seek out clinical trials and to obtain treatment from community physicians rather than at academic medical centers or cancer centers;
  
• Difficulty for elderly patients in getting to and from clinical trial sites (a particular concern for beneficiaries living in more remote rural areas);
  
• Preconceived notions on the part of the elderly and their families about the potential benefits from participating in clinical trials; and
  
• Reluctance on the part of investigators to enroll elderly patients in clinical trails due to preconceived notions about the ability of the elderly to tolerate aggressive therapy.⁷

Providing Medicare coverage for these four drugs when used in a specific clinical trial will not change any of these factors and thus is not likely to significantly increase clinical trial participation.

Given the potential for discrimination, CMS should consider other alternatives of increasing the participation of seniors in clinical trials and enhancing the scientific base of knowledge that informs the care of older cancer patients. Again, Sanofi-Aventis is committed to CMS’ stated goals and wants to be an active partner in finding an appropriate avenue for achieving them.

II. Using coverage as a vehicle for increasing the number of Medicare beneficiaries participating in drug clinical trials could have unintended consequences, including introducing the potential for enrollment bias.

With this proposal, CMS assumes that providing Medicare coverage of one or more of these four drugs in select trials will increase the number of beneficiaries enrolled in these trials and thereby provide an evidentiary basis for coverage of the clinical care received by beneficiaries with cancer in the future. As we discussed above, there are still many unanswered questions about the outcomes of CMS’ prior efforts to increase beneficiary enrollment in clinical trials. Unfortunately, we do not believe that providing coverage and payment for these drugs when used in a clinical trial is likely to have a significant impact on the number of beneficiaries enrolled in these trials.⁸ Instead, the approach may be counter-productive by introducing research bias into the nine clinical trials included in the NCD, as well as other trials for which CMS may consider extending coverage in the future.

As noted above, drug product used for off-label use in clinical trials is routinely provided by the trial sponsor, removing financial consideration from the selection of clinical trial participants. However, the financial considerations that could arise from beneficiary co-payment obligations potentially could skew enrollment in clinical trials in two different directions.

If a beneficiary is a potential participant in two competing clinical trials and one of those trials is covered by Medicare, and drug product is provided by the study sponsor in the other study, the beneficiary is likely to be steered toward the trial where the drug is provided for free in order to minimize the financial burden associated with co-payments. (The beneficiary might still have some co-payment liability for routine costs, if the beneficiary is relying on Medicare coverage for those costs.) But if the beneficiary’s only way to get at least some coverage of drug costs is to access a clinical trial with Medicare coverage, the incentive will be to steer the beneficiary to the trial that offers coverage. In both situations, the guarantee of Medicare coverage has the potential to impact the enrollment of participants in clinical trials and therefore may inappropriately skew the trial results. Moreover, an elderly patient with cancer, who customarily would not be considered by their physician to be good a candidate for participation in a clinical trial, might be encouraged to participate predominantly for reimbursement reasons. This never should be the primary motivation for participation in a clinical trial.

The potential for enrollment to be skewed due to financial considerations is even greater when there are multiple trials being conducted at one clinical site. In that situation, the choice of the most financially advantageous clinical trial or trials will be well known to providers associated with that clinical site, thereby enhancing the chances of enrollment bias. This scenario is complicated further where trials include multiple drugs, some of which may be covered, others of which may be offered for free or available only to beneficiaries with the ability to pay out of pocket. Unfortunately, because we do not know which drugs will be provided free of charge in these nine trials, we cannot predict the likely financial impact of any of these trials for participating beneficiaries or providers.

Although we cannot tell yet whether the NCD would cause too many or too few Medicare beneficiaries to enroll in these trials, we are concerned that CMS’ coverage policy will not produce optimal participation by patients aged 65 or older, consistent with the trials’ designs and purposes. Given the potential for reimbursement to skew enrollment in a trial, we urge CMS to be careful in choosing trials for coverage if it moves forward with this proposal. If the endpoint of the trial is to study the impact on health and survival of elderly patients with a particular form of cancer, it makes sense to enroll a number of Medicare beneficiaries as participants. Nevertheless, if the trial is designed to address another important scientific question, enrollment of a large number of Medicare beneficiaries due to financial incentives could introduce bias in the trial results.

In the long term, decisions made by CMS in this NCD potentially could affect the National Institutes of Health (NIH) and private research funding priorities and decisions in countless ways, potentially impacting decisions by research sponsors as to whether to undertake certain studies, how studies are designed, where they are conducted, which drugs are included, and whether to seek or participate in NIH-funded research. There is no indication that CMS has determined what the broader implications of this NCD approach will be and whether the agency’s decisions could have the effect of driving resources from the highest valued research objectives. We urge CMS to hold public discussions with the federal agencies most concerned about clinical research, including the Food and Drug Administration (FDA), National Institutes of Health (NIH), and Centers for Disease Control and Prevention (CDC), to evaluate the effects of this NCD on medical research in general and on the particular problem of improving clinical data about health care for the elderly.

We are also greatly concerned that studies subject to this NCD approach eventually could be designed and implemented in a manner that restricts access by beneficiaries or serves largely cost-driven objectives. Such impacts, whether intended or unintended, are considered more appropriately in the legislative or rulemaking context with full transparency and stakeholder input.

III. The draft NCD is likely to be perceived by providers and local carriers as limiting coverage of the four included drugs.

Sanofi-Aventis is encouraged at indications that this draft decision is intended to expand coverage of these four drugs and to ensure that local contractors provide coverage of these drugs when they are used in the clinical trials designated in the NCD. However, we are concerned that the current language of the NCD does not go far enough in making it clear to providers and carriers that the NCD expands coverage and should not be interpreted to remove pre-existent coverage of these drugs or limit the authority and discretion of local carriers to expand coverage of these four drugs in the future.

Because this particular NCD began with a question about whether Medicare coverage of Eloxatin® was warranted, the tone of this particular NCD historically has been about potential limitations in coverage. In fact, even NCDs that grant Medicare coverage for a particular item or service typically are accompanied with coverage limitation language such as “all other indications beyond those specified in this NCD are not covered.” We acknowledge that CMS is aware that NCDs typically have a chilling effect on local coverage policy, and we appreciate that CMS has added language to the NCD in an effort to strike a new tone and establish that this redirected NCD is about coverage expansion and not coverage limitation. Should CMS proceed with this proposal, we believe the language needs to be much clearer, to ensure that local carriers and providers know that existing Medicare coverage of these four drugs in the treatment of cancer is unchanged by this NCD.

According to the Medicare statute, contractors are not permitted to deny coverage of an anti-cancer drug based solely on FDA-approved labeling for a particular use, if the use is listed in one of the three compendia (and is not listed as “not indicated” by one of those compendia), or if the use is supported by clinical research that appears in one of the listed peer-reviewed medical journals.⁹ In addition, according to the Benefit Policy Manual, “unlabeled uses may also be considered medically accepted if determined by the carrier to be medically accepted generally as safe and effective for a particular use.”¹⁰ This discretion has allowed seniors access to medically necessary and appropriate drugs even when they cannot enroll in clinical trials for reasons cited above. Carriers have been rigorous in exercising this discretion, asking physicians for documentation to support their off-label use of drugs. We believe this system is appropriate and generally works well. It is our understanding that the only change made by this NCD to existing policy and practice is that when these four drugs are being used in the identified clinical trials, local contractors must provide coverage. The NCD needs to clarify further that the discretion given to local carriers on coverage of off-label uses of these four drugs remains as stated in the Benefit Policy Manual and is not changed in this NCD except to require coverage of these four drugs in the clinical trials listed in the NCD. Medicare beneficiaries with cancer who currently are being treated with drugs reimbursed by Medicare would be devastated if this NCD were to be interpreted to change current policy and practice. We understand that this was not your intent, and we urge you to clarify this for providers and contractors in the final NCD should the agency proceed.

Although we do not recommend that CMS finalize this NCD, in the event the agency chooses to implement this proposal, we propose the following language to clarify that local coverage policies remain unchanged.

We further recommend that the title of the NCD be revised to reflect its actual purpose. As CMS made clear, the NCD does not solely address chemotherapy for colorectal cancer. In fact, several of the trials listed in the draft NCD study the impact of the four drugs on other cancers such as pancreatic cancer, advanced head and neck cancer, and GI/breast/ovarian cancer. This NCD has always been about coverage of specific drugs (beginning with Eloxatin® and adding the other three over time). To avoid potentially confusing beneficiaries, providers and local carriers, the title of the NCD should be changed to “Expanded Coverage of Clinical Trial-Based Uses of oxaliplatin (Eloxatin®), Irinotecan (Camptosar®), Cetuximab (Erbitux®), and Bevacizumab (AvastinTM).” Although changing the title of the NCD alone is not sufficient to ensure that local carriers do not interpret the NCD to limit their authority and discretion to cover these four drugs, a change in the title accompanied by clearer language in the NCD may help ensure that coverage of these four drugs will only expand as a result of this NCD.

IV. Under the approach proposed in this NCD, beneficiaries are likely to have increased financial obligations associated with participating in clinical trials.

In many clinical trials, manufacturers provide the drug or drugs being studied for free to clinical trial participants. Indeed in 2003, 24.9% of all Eloxatin® produced by Sanofi-Synthelabo Inc. for sale in the U.S. was provided for free in clinical trials. In all of the six NCI trials using Eloxatin® and listed in the NCD, the drug has been requested by the sponsor and will be supplied to trial participants by Sanofi-Synthelabo Inc. The draft NCD is silent on how Medicare coverage of these drugs in certain clinical trials can be reconciled with industry practice of providing these drugs for free.

Providing Medicare drug coverage could have long-term financial consequences for the beneficiaries who participate in these trials and for the manufacturers of drugs included in clinical trials. We understand that CMS only intends to provide coverage of these four drugs in these nine clinical trials if beneficiaries otherwise would have to pay for the drugs out of pocket. CMS also will not allow trial sponsors to structure the trial so that Medicare beneficiaries receive coverage under Medicare and all other trial participants receive the drug for free. Although Sanofi-Synthelabo Inc. historically has provided Eloxatin® for clinical trials for which it is not the primary sponsor, e.g. NCI-sponsored studies and has no current plans to change its policies, we are concerned that CMS’ proposal will discourage other manufacturers from providing their drugs for free when the drugs could be covered by Medicare. In the long term manufacturers could elect to stop providing drugs for free for NCI-sponsored clinical trials, thereby making beneficiaries liable for the 20% co-insurance on these drugs. This could be a costly unintended consequence of this proposal and could result in fewer beneficiaries being willing to participate in clinical trials.

Further, we question whether it makes sense to shift the cost of drugs provided in clinical trials from manufacturers to the Medicare program in an era when policymakers are concerned about the rising costs of the entire program. Thus, we believe CMS should give further consideration to the cost-shifting implications of its proposal.

We also are concerned that the draft NCD is silent on the implications of this proposal on the calculation of each drug’s “average sales price” (ASP) for reimbursement under Medicare Part B or on the calculation of Medicaid’s “best price” for rebate purposes. Manufacturers may be hesitant to provide any significant discounts for drugs sold for use in clinical trials because of the impact these sales could have on these important calculations. Thus, not only will beneficiaries be burdened by a 20% co-payment, it may be more costly than anticipated if it is based on the full acquisition cost of the drug instead of a discounted price.

It is unclear whether manufacturers could provide financial assistance to beneficiaries participating in clinical trials to cover these co-payments under federal fraud and abuse laws. In its proposed regulations for the Part D prescription drug program, CMS requested comment on whether it would be possible for manufacturer patient assistance programs to provide financial assistance for beneficiary’s out-of-pocket expenses under the federal fraud and abuse laws. Given that CMS has raised this issue in another similar circumstance, it gives us pause in considering how we can be of assistance to beneficiaries in this context.

In the nine NCI trials listed in the NCD, some uses of some of the drugs are currently on-label or listed in the major compendia, or are already covered under local carrier discretion. If manufacturers chose not to provide drugs free of charge in these circumstances and CMS provides coverage for Medicare recipients, there is significant inequity between patient groups participating in the same trial. Similarly, if manufacturers provide drugs for free to all trial participants, CMS will need to make it clear that these drugs are available for free to all participants in the trial, including Medicare beneficiaries. In particular, CMS needs to clarify that beneficiaries shall not be charged co-payments for drugs provided by manufacturers for free in a clinical trial, even if Medicare already covers the uses of those drugs.

Additionally, CMS should clarify whether it will cover non-routine care provided in these trials. Medicare’s current coverage policy for clinical trials covers only routine care, not the items and services provided solely to satisfy data collection and analysis needs or provided by research sponsors free of charge for any enrollee in the trial.¹¹ It is not clear whether Medicare will pay for these services under this proposed decision. If Medicare begins to pay for these services, the concerns about costs to beneficiaries that we discussed for drug coverage would apply to these non-routine services too. CMS should consider carefully whether these costs should be shifted from manufacturers to beneficiaries.

V. CMS should provide more detail on its criteria for selecting the nine trials listed in the draft NCD.

Because the NCD provides no detail on the selection criteria, we are curious about CMS’ selection of the nine specific NCI trials listed in the NCD. CMS also has not explained in the NCD why the agency limited coverage to these nine trials and not others that are similarly to be sponsored by the NCI. We also again point out that Medicare already covers the routine costs associated with numerous clinical trials that are not primarily sponsored by the NCI.

We understand that CMS asked NCI to suggest trials that were well known to the Institute and that would not start accruing patients until at least 90 days after CMS published the final NCD to ensure Medicare beneficiaries the opportunity to take advantage of the new, expanded coverage. Although we reiterate that we do not believe that CMS should move forward with this draft NCD and that there are other, more appropriate avenues to pursue the agency’s goals, other trials should be included if the agency does indeed finalize this NCD. Specifically, there are other major clinical trials, both sponsored by NCI and by the manufacturers, of off-label uses of one or more of these four drugs that are either in development or are currently underway that CMS should consider adding to the NCD. We would be happy to work with you to identify other trials that may be candidates for consideration. We believe that it is critically important that the trial selection process be as transparent as possible and be determined via predefined selection criteria. We propose a mechanism similar to that proposed a few years ago by the Agency for Healthcare Policy and Research, whereby a “Clinical Trials Advisory Panel” or similar interagency working group be established that would incorporate a structured public process to ensure transparency.

Not only should CMS consider adding to the list of nine trials if this draft NCD is finalized, but CMS also should carefully review the trials selected by NCI to ensure that they meet CMS’ criteria. For example, at least one of the NCI trials, ECOG–E3201, already has begun accruing patients and thus does not meet CMS’ criteria of not accruing patients until 90 days after the final NCD is published. Nevertheless, we agree that this specific trial has high scientific merit and is worthy of inclusion in the program subject to the concerns that we have raised.

VI. CMS has not explained how it intends to use the data generated by these trials.

In the proposed NCD, CMS acknowledges the importance to policymakers, as well as patients and providers, of adequate clinical trial data for clinical decision-making. CMS has said that it plans to use the data gathered from the trials “to learn more about the benefits and risks of . . . these treatments in Medicare beneficiaries,”¹² but has not said whether the data will be used in future coverage decisions. We explained in section II of this letter our concerns about the NCD’s potential to cause disproportionate enrollment of Medicare beneficiaries in these trials that would produce skewed results. These concerns also are relevant to any plans to use the data in future coverage decisions. For example, there may be an insufficient number of Medicare beneficiaries in the trials to draw scientifically valid conclusions about the efficacy of the drugs in Medicare beneficiaries. Nevertheless, if CMS has data from these trials, but no other good scientific data on drug outcomes in the elderly, the agency might use the data to make coverage decisions, despite the potential biases induced by the CMS NCD approach. If CMS intends to use the data from these clinical trials in making future coverage decisions, the agency needs to be clear about that in its final policy. CMS also should specify the safeguards the agency will put in place to ensure that any data taken from the trials are scientifically valid for the intended use.

VII. A NCD is not the appropriate vehicle for launching a new Medicare initiative designed to increase the number of seniors participating in U.S. clinical trials.

This draft decision memorandum proposes a new approach to coverage decisions that would affect not only the four named drugs and biologicals, but also would set a new standard for coverage decisions potentially affecting many more innovative therapies. We understand CMS’ effort to drive research evaluating the effects of new technologies on seniors’ health,¹³ and we are supportive of CMS’ overall goals in this endeavor. Because of the far-reaching impact of what CMS has put forth in this draft NCD, however, we respectfully suggest that the NCD process is not the right vehicle for this proposal. As mentioned previously, we recommend that CMS withdraw the draft NCD and use a different approach with more transparency and opportunity for stakeholder input to address the important yet complicated question of how best to increase Medicare beneficiary participation in clinical trials.

For decades, CMS has made NCDs by reviewing the scientific and clinical evidence supporting the benefits of specific items or services.¹⁴ CMS’ process for making these decisions, codified by Congress in the Medicare, Prescription Drug, Improvement, and Modernization Act of 2003 (MMA),¹⁵ is designed to allow the agency to conduct this review and receive public comment from interested stakeholders in a timely manner. In recognition of the narrow focus of each NCD and the limited population affected by these decisions, the Medicare statute sets appropriately short periods for drafting each decision and permits informal announcements of proposed decisions. This statutory language governing NCDs, and CMS’ long-standing practice in handling NCDs, are quite different from the more open and formal processes used to develop substantial changes in Medicare policy. For example, CMS announced changes to its process for issuing NCDs through notices in the Federal Register, where all stakeholders could see the modifications.¹⁶

Contrary to the Medicare statute and the agency’s historical practice, CMS now is suggesting the use of the NCD process to propose a policy-based coverage decision affecting a wide range of therapies. First, the draft decision memorandum bases coverage of these therapies on the policy goal of collecting data, not on the existing scientific evidence of their medical benefits. Second, instead of applying to a specific item or service, the NCD would apply to at least four unique drugs or biologicals, plus combinations of those drugs with each other and with other therapies. In addition, CMS solicits comments in the draft decision memorandum on how it can apply its policy-based coverage decision to other drugs and biologicals. These departures from the standard basis and scope of coverage decisions indicate that CMS’ proposals far exceed the scope of the NCD process. Such significant proposals are not appropriate to present in a draft decision memorandum and should be discussed in a forum that is addressed to all Medicare stakeholders.

Furthermore, what CMS is proposing could have an important impact on how clinical trials are conducted in the U.S. The entry by CMS into science policy is not unwelcome, but should be done in a forum that allows substantial opportunities and time for public consideration and comment. For example, has CMS sought input on this proposal from the major private research institutions in the U.S.? It is possible that because this decision was announced through the NCD process typically followed only by beneficiary advocates, providers and manufacturers the proposal is proceeding to finalization without meaningful input from a number of interested stakeholders likely to be impacted by it. The NCD process, a narrowly-focused vehicle for CMS to exercise its authority to determine whether a particular item or service is reasonable and necessary for Medicare beneficiaries, seems an inappropriate mechanism for resolving bigger concerns about the strength of the evidentiary basis for provision of coverage for Medicare beneficiaries. Similarly, evaluation of mechanisms to improve the enrollment of the elderly into well-controlled randomized clinical trials should part of the ongoing national healthcare debate and should not be restricted to the oncology drugs currently included in this NCD. We strongly urge CMS to reconsider its use of the NCD process as a vehicle for making far-reaching Medicare and science policy decisions.

VIII. Conclusion

Sanofi-Aventis appreciates this opportunity to share our concerns about the draft NCD, and we look forward to working closely with CMS to increase the participation of beneficiaries in clinical trials and to expanding beneficiaries’ access to innovative, effective drug therapies. Please do not hesitate to contact me or Saira Sultan, Director of Federal Affairs, at 202-898-3197 if you have any questions about our comments or if we can be of further assistance as you consider these important issues.

1 These comments are submitted on behalf of Sanofi-Synthelabo Inc. and Aventis Pharmaceuticals, both part of the Sanofi-Aventis Group.
2 These agents are irinotecan (Camptosar®), cetuximab (Erbitux®), and bevacizumab (AvastinTM).
3 See NCI, Facts and Figures About Cancer Clinical Trials, http://www.cancer.gov/clinicaltrials/facts-and-figures#patients.
4 Joy H. Lewis et. al., "Participation of Patients 65 Years of Age or Older in Cancer Clinical Trials," Journal of Clinical Oncology, Vol. 21, No. 7 (April 1, 2003), pp. 1383-1389 (emphasis added).
5 Id. at 1388.
6 See Women and Health Research, Institute of Medicine (National Academy Press, 1994).
7/ Joy H. Lewis et al., “Participation of Patients 65 Years of Age or Older in Cancer Clinical Trials,” Journal of Clinical Oncology, Vol. 21, No. 7 (April 1, 2003), pp.1383-1389; 1388.
8 See Id. at 13889/SSA § 1861(t)(2), 42 U.S.C. § 1395x(t)(2).
10 Ch. 15, § 50.4.5 – Unlabeled Use for Anti-Cancer Drugs.
11 National Coverage Decision: Medicare Coverage of Clinical Trials, available at http://www.cms.hhs.gov/coverage/8d2.asp.
12 CMS Press Release, Medicare Launches Efforts to Improve Care for Cancer Patients, Nov. 1, 2004, available at www.cms.hhs.gov/media/pressrelease.asp?Counter=1244.
13 See Gina Kolata, Medicare Covers New Treatments With a Catch, New York Times, Nov. 5, 2004 (describing CMS as “creating a whole new role for Medicare”).
14 Social Security Act §§ 1862(l)(6)(A), 1869(f)(1)(B); CMS, Medicare Program; Revised Process for Making National Coverage Determinations, 68 Fed. Reg. 55634, 66535 (Sept. 26, 2003).
15 MMA sec. 731, creating SSA §1862(l).
16/See http://www.cms.hhs.gov/coverage/8a.asp for a list of notices placed in the Federal Register about changes to the national coverage determination process.

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AstraZeneca Pharmaceuticals ("AstraZeneca") appreciates the opportunity to submit comments on the draft national coverage determination (NCD) for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), released on November 1, 2004. AstraZeneca, as one of the world's leading pharmaceutical companies, is engaged in the research and development of new medicines. Through its leadership in the oncology area, AstraZeneca is committed to the discovery of drugs that will allow Medicare beneficiaries to lead longer, healthier and more productive lives. AstraZeneca introduced tamoxifen, the first widely prescribed oral oncology drug, over 25 years ago, and has since developed a series of innovative cancer treatments such as Arimidex®, Casodex®, Faslodex®, Iressa® and Zoladex®. Many of these medicines were first in class discoveries and have become oncologist recognized standards of care. This commitment to cancer care is underscored by key AstraZeneca goals for the Medicare population,

• Ensure access to life-saving, life-extending and innovative therapies, which should not be compromised by cost-sharing commitments

• Promote high quality of care and improvement of overall health status among all healthcare providers

The draft NCD proposes an expansion of coverage of oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux™), or bevacizumab (Avastin™) when used in select clinical trials sponsored by the National Cancer Institute (NCI). The draft NCD states that it "does not propose to modify the existing requirement for coverage of these and other anticancer chemotherapeutic agents for [Food and Drug Administration] FDA-approved indications or for indications listed in an approved compendium."¹ In addition, it notes "this decision makes no change in coverage for any off-label uses of these drugs not provided in the selected clinical trials. Contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature."²

AstraZeneca believes that access to drugs that are part of the current standard of care, as well as future innovations, is key to maximizing health outcomes for the Medicare population. AstraZeneca opposes the draft NCD, sharing many of the concerns expressed by the members of PhRMA and BIO, as there are many unanswered questions on the structure of the analysis. Moreover, the current proposal has potential unintended consequences, some of which include

• Compromised beneficiary access to necessary medications resulting from inappropriate trial design criteria and patient cost-sharing responsibilities
• Confusion around the accepted policy and guidelines for off-label drug use resulting from the unclear guidance given to local contractors

We provide comments on the draft NCD in two broad areas:

I. General comments on process and off-label drug use

1. Process used to develop the draft NCD and the proposed policy

In the draft NCD, CMS notes that public comments were solicited in February 2003, and that the public comment period was extended in May 2003 and again in June 2003. CMS met with industry representatives and other experts, including the manufacturers of the four drugs included in the review, during August and November 2003. Recent changes to the draft NCD, especially CMS' consultation with NCI in September 2004 to include specific NCI-sponsored trials under this determination, have surfaced some points that urge AstraZeneca to now comment on the draft NCD. AstraZeneca supports CMS' having solicited public comments (November 1, 2004) and extending the comment period to allow further comments from interested groups.

AstraZeneca is concerned, however, that discussions between NCI and CMS were not open to the public, and that public input was not solicited in selecting the group of clinical trials that Medicare would cover. CMS and NCI met without holding a public meeting. Furthermore, CMS and NCI did not collect input from the public on criteria for selecting trials, or on additional potential trials that CMS should include. AstraZeneca is also concerned about the implications of collaboration between CMS and NCI on this issue. NCI should do the very best science and the CMS should decide what to reimburse. These two organizations are and can become "best in the world" at their respective tasks. That said, these are two different things, and blending them may result in an NCI that can no longer be "the very best in science". We recommend

• CMS and NCI should, if NCI continues to be involved in selecting trials, host open meetings to the public and gather input from invested third parties such as patient advocacy groups (e.g., National Patient Advocate Foundation, NPAF), professional associations (e.g., American Society of Clinical Oncology, ASCO; Association of Community Cancer Centers, ACCC), and manufacturers.
• CMS and NCI should solicit comments from the public regarding the criteria that should be used to select trials.

We note that AstraZeneca has a long-standing relationship with NCI and that we would be happy to discuss our ongoing work with NCI and CMS officials, or participate in an open forum to provide comments.

2. Supporting appropriate off-label drug use

AstraZeneca supports appropriate off-label drug use that ensures patient access to necessary medications, defers to physician judgment and uses a variety of sources to determine appropriate use (e.g., peer-reviewed medical literature, clinical guidelines (e.g., those developed by ASCO and the National Comprehensive Cancer Network) and listings in drug compendia (e.g., the United States Pharmacopoeia Drug Information (USP-DI), and the American Hospital Formulary Service (AHFS) compendia). Our position on off-label drug use is consistent with current coverage policies for drugs covered under Medicare Part B (i.e., as of October 31, 2004).³ A critical provision of this current off-label policy, the notion of local carrier discretion, was omitted in the draft NCD. This omission is highlighted in BIO's comments on the draft NCD: "Although the draft NCD states that it 'makes no change in coverage for any off-label uses of these drugs not provided in the selected clinical trials,' it also says, 'contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature.'⁴ This statement omits an important element of the current off-label coverage policy, local carriers' discretion to cover uses they determine to be 'medically accepted generally as safe and effective for the particular use.”⁵

As a result, we have concerns with CMS' expansion of coverage of off-label uses of FDA-approved chemotherapeutic and novel anti-cancer agents to Medicare beneficiaries enrolled in certain clinical trials sponsored by NCI, as proposed in the draft NCD. We are concerned about the interpretations of this coverage analysis and potential unintended consequences for Medicare beneficiaries (e.g., compromised access; potential cost-sharing obligations). We highlight similar concerns from BIO in their comments on the draft NCD: "If beneficiaries are liable for 20 percent coinsurance on the drugs and biologicals provided in these trials, but could enroll in other trials where all costs are paid by the manufacturers, beneficiaries will not choose to enroll in CMS' selected trials and access under Medicare will not be expanded. Additionally, patients may not want to enroll in these trials if they would be required to change physicians or travel to receive care. CMS must answer these essential questions about the trials' designs before Medicare's stakeholders can provide meaningful comment on this proposal.”⁶ Accordingly, we encourage CMS to facilitate public dialogue on the process for data collection and analysis. We would require more time to contemplate the potential ramifications.

In addition, we provide one key recommendation for off-label drug use in light of the draft NCD.

• CMS should preserve the authority of physicians to remain the key decision makers, especially when treating patients with cancer, which is in keeping with the current off-label policy. Regardless of the disease being treated, no one is better suited to make a drug selection decision than a patient's physician who has clinical expertise as well as intimate knowledge of the individual patient's medical needs. The "off-label use" of medications is vitally important for cancer patients and is the mainstay of medical practice for successfully managing other complex medical conditions, such as mental illnesses, chronic pain, chronic heart failure, arthritis, Parkinson's, HIV/AIDS and dementia.^{7, 8} The FDA recognizes that "off-label use of drugs by prescribers is often appropriate and may represent the standard of practice.”⁹ Off-label use often facilitates emerging science, provides an opportunity to reveal additional clinical benefits of existing agents,¹⁰ and results in new treatment approaches for both acute and chronic illnesses. ¹¹

II. Specific comments on four areas outlined in draft NCD

1. Identifying appropriate trials for which to extend coverage for off-label coverage of anti-cancer drugs

AstraZeneca urges CMS to adopt a process for selecting appropriate clinical trials that is efficient and does not compromise Medicare beneficiaries' timely access to medications. Therefore the final approach for trial selection should be the product of active collaboration of all interested parties and stakeholders, with public input. We believe that CMS should develop criteria for the selection of appropriate trials in conjunction with key stakeholders such as FDA, NCI, ASCO, ACCC, PhRMA and BIO. Moreover, AstraZeneca urges CMS to provide clarification on the process, criteria and decision-making that supported the chosen trials and agents in the draft NCD. Key open questions for appropriate trial selection include:

• Who are the stakeholders who should be involved in identifying appropriate trials for which to extend coverage for off-label coverage of anti-cancer drugs?
• How should the decision on appropriate trials be made?
• What are the potential criteria that should be taken into consideration when making the decision (e.g., beneficiary cost-sharing considerations)?
• What are the types of trials that would be appropriate targets?

2. Facilitating the participation of beneficiaries in selected clinical trials

Strong participation of Medicare beneficiaries will be important to the success of this analysis in order for results to be meaningful. CMS has been developing patient outreach capabilities and has done so most successfully in recent programs through collaborative efforts with invested third parties (e.g., patient advocacy groups and manufacturers on the MRDD). AstraZeneca provides the following recommendations to facilitate robust participation.

• CMS should select a Medicare staff person to serve as the program coordinator to oversee the enrollment of Medicare beneficiaries into selected trials and to coordinate educational efforts aimed at encouraging enrollment by both beneficiaries and providers. In addition, the newly formed Patient Advocacy Program may serve as a resource and an ideal center to support such activities.
• CMS should involve all appropriate stakeholders and leverage third party expertise in all areas related to this draft NCD before a final decision is agreed upon. AZ has worked closely with CMS on issues related to infrastructure, relationships and education. We are glad to give continued support in these areas as we have done on other CMS demonstrations (e.g., MRDD).

3. Identifying alternative programs that allow both coverage of the off-label use of anticancer drugs and collection of data on their appropriate use (e.g., drug registries)

We reiterate our position on appropriate off-label drug use that ensures patient access to necessary medications, defers to physician judgment and uses a variety of sources to determine appropriate use (e.g., compendia).

In relation, AstraZeneca urges CMS to appropriately weigh the benefits of using registries and analysis of electronic medical records to generate evidence on effectiveness, and de-prioritize these in relation to clinical trials. There is a clear distinction in usefulness of results derived from prospective clinical trials (which are planned and focused on particular end-points) vs. comparative analysis of patient records from clinical registries (which are sometimes useful in selected applications). Retrospective analysis of patient records are often more useful for obtaining information on safety, informing clinical practice guidelines and understanding quality of life indicators, as opposed to being a robust platform for answering questions on efficacy. This is especially true for diseases with low prevalence or for which long-term follow up, in the context of a clinical trial, is difficult (e.g., prostate cancer).12/

4. Facilitating more timely determinations of medically accepted off-label indications by local contractors

CMS should ensure timely access to proven off-label uses of medications by developing mechanisms that enable local medical directors, carrier staff, and local coverage advisory committee members to be continually updated on changes to drug compendia listings. AstraZeneca provides the following suggestions to support timely access to and distribution of medically accepted off-label indications to local contractors.

• CMS should facilitate continuing education programs for local contractors (e.g., interaction with key opinion leaders).
• CMS should explore new channels for gathering contractors in disparate locations (e.g., Webex meetings).

To develop an informed starting point for current state of knowledge, CMS should conduct an assessment of how local carrier medical directors currently receive clinical updates, the sources of information they reference, and existing needs.

In summary, CMS has a significant stake in understanding the value of off-label drug use for cancer therapy in the Medicare population, as well as the cost of care. There are several ramifications of this draft NCD that should be contemplated before interpretations are made. For example, decisions made from this analysis will likely have significant implications for commercial payors, which often follow the lead of Medicare. Accordingly, CMS should recognize and consult with the group of third-party stakeholders which represents not only significant interest in understanding these issues for off-label drug use, but also valuable expertise to help shape the approach for appropriately studying this issue.

AstraZeneca appreciates this opportunity to comment on the draft decision. AstraZeneca is committed to ensuring that Medicare beneficiaries have affordable access to the life-improving therapies they need. We look forward to working further with CMS on this important issue.

1 Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N)

2 Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N)

3 CMS Carriers Manual, Part III, Chapter II, Section 2049.4

4 Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N)

5 BIO's draft comments on Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG00179N), as at December 14, 2004

6 BIO's draft comments on Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG00179N), as at December 14, 2004

7 Pfeffer, Marc A.. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme, Lancet 2003, 362, 759-766

8 Motsinger. Charles D.. Perron, Gregoiy A., Lacy, Timothy J. Use of atypical antipsychotic drugs in patients with dementia, Am. Earn. Physician 2003, 67, 2335-2340

9 http://www.fda.2ovIcder/present/diamontrealIreeaDpr/sldOO5.htm

10 Pfeffer, Marc A., Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme, Lancet 2003, 362, 759-766

11 Parsonnet J, Harris RA. Hack HM, Owens DK. Modelling cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials, Lancet 1996, 348 (902 l):150-154

12 Cooperberg MR. Park S. Carroll PR. Prostate cancer 2004: insights from national disease registries, Oncology (Huntington) 2004. 18 (10): 1239-47

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Pfizer Inc. respectfully submits these comments on the Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer, dated November 1, 2004 ("Draft Decision").

Pfizer is a research-based, global pharmaceutical company dedicated to the discovery and development of innovative medicines and treatment that improve the quality of life of people around the world. In the United States, Pfizer markets Camptosar® (irinotecan hydrochloride injection), one of the four chemotherapy agents that is the subject of the Draft Decision. Accordingly, we appreciate this opportunity to share our views with respect to a number of important issues raised by the Draft Decision that may affect Medicare beneficiaries' access to Camptosar and to anticancer therapies more generally.

As a preliminary matter, we commend CMS and its Office of Clinical Standards and Quality for supporting the important therapeutic role of off-label uses in the field of oncology through this proposed "expansion of Medicare coverage for off-label use of anticancer chemotherapeutic agents on a national level". Also, we specifically commend CMS for its explicit affirmation of the current scope of local carrier discretion with respect to Medicare coverage for "any [medically accepted] off-label uses of these drugs not provided in the selected clinical trials." We believe the contractor guidances currently in place for determining coverage for off-label indications are sound and consistent with the 1993 amendments to the Medicare statute, which expressly authorized coverage for off-label uses of anticancer agents and recognized the important role of local carrier decision-making, guided by evolving scientific evidence, in the field of cancer care.¹

We submit these comments in an effort to help identify issues that we believe would benefit from further clarification or discussion in the final Decision Memorandum. As set forth in greater detail below, we believe the Decision Memorandum will be enhanced

• By eliminating any ambiguities with respect to the scope of the NCD and making it clear that it represents coverage expansion and is not intended otherwise to change or limit the bases for Medicare coverage for off-label uses of these four agents, or other anticancers agents, generally.
• By describing in greater detail (i) the specific criteria used to select the nine NCI trials and (ii) the items and services that will be covered pursuant to the NCD. With respect to the second item, we believe CMS should address the interaction among the proposed NCD, the existing NCD with respect to clinical trials generally, and the Food and Drug Administration's regulations on clinical trials conducted under investigational new drug applications.
• By clarifying CMS' objectives with respect to Medicare coverage of off-label uses and the role clinical trials.

Pfizer's specific comments, set forth below, are meant to complement, and should be read in conjunction with, the comments to the Draft Decision submitted by the Pharmaceutical Research and Manufacturers of America ("PhRMA") and by the Biotechnology Industry Organization ("BIO"). both of which we broadly endorse.

Detailed Comments

A. Eliminate the Ambiguities with Respect to the Scope of the NCD.

The Draft Decision states at several points that the "decision makes no change in coverage for any off-label uses of these drugs not provided in the selected clinical trials" and that "[c]ontractors would continue to provide coverage for medically accepted uses of off-label indications". However, questions raised by the oncology community regarding the Draft Decision indicate significant confusion about its intended effect. To ensure that the NCD is interpreted unambiguously as an expansion of coverage, the final decision memorandum should incorporate the following three revisions.

1. Add Clear Statement of the Intended Impact of the NCD on Coverage for the 4 Agents. There remains significant confusion about the impact of this Draft Decision on coverage of off-label uses of the four agents that are the subject of the Draft. To mitigate the confusion, we request that CMS make very clear in the final Decision Memo that the intent of the NCD is solely to ensure uniform coverage for the four agents in the identified trials and that the Draft Decision is not intended to address, limit or restrict off-label uses of these agents generally. In that regard, we strongly suggest inclusion of the following clarification in the final decision memorandum

2. Accurately Enumerate all the Bases for Coverage of Off-Label Uses of Anticancer Drugs. In several places, the Draft Decision describes when local carriers may provide coverage for off-label uses of anticancer chemotherapy agents. In each instance, the Draft Decision provides in substance that Medicare contractors may provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature. See Section VII. (CMS Analysis) and Section VIII. (Conclusion). However, this articulation of the local carrier's discretion fails to fully reflect CMS' prior published guidance to its contractors and should be revised in the final decision memorandum to conform to the Medicare Benefits Policy Manual.

The Medicare Benefits Policy Manual identifies specific publications that carriers may use to obtain supportive clinical evidence for medically acceptable off-label uses for anticancer drugs that are not specifically identified in the compendia. However, following the enumeration of approved journals, the Manual expressly advises carriers that

The foregoing, which applies specifically to unlabeled uses for anticancer drugs, is consistent with the Manual's guidance regarding coverage of off-label uses of drugs generally, which states that

Consistent with the Draft Decision's stated intent to expand coverage and to avoid any unnecessary ambiguity, the final decision memorandum should accurately describe all the existing bases for local carriers to make coverage determinations for off label uses.

3. Revise or Eliminate Simplified Treatment of Compendia Listing. We strongly urge the Office of Clinical Standards and Quality to revise the way it summarizes the compendia information on uses, specifically as set forth in the table entitled "Indications Cited in the 2004 Compendia" and the accompanying text of the Draft Decision. The simplified presentation of the detailed discussion in the compendia and the use of the term, "not established" (paired against "indicated"), is inconsistent both with the statutory language in Section 1861(t)(2) and with CMS' prior directives to the local carriers with regard to the function and interpretation of compendial listing. To avoid creating unintended barriers to beneficiary access, we urge CMS either to revise the table to note only whether an off-label use is indicated or explicitly not indicated, or to eliminate the table.

With respect to anticancer chemotherapeutic agents, Section 1861(t)(2) of the Social Security Act expressly defines the term "medically accepted indication" to include (among others) any use approved by the FDA. or another use of the drug if

Consistent with the statutory definition of "medically accepted indication", the Medicare Benefits Policy Manual bars contractors from denying coverage for off-label indications supported by one of the listed compendia. The Manual specifically states that

The text of both the statute and the Manual permit using the compendia to deny coverage only under very limited circumstances (i.e., where there has been an affirmative finding that the use is "not indicated"). In contrast, the statute and the Manual both permit coverage if the compendia discussion supports the off-label use. Further, clinical support does not need to be stated as a definitive finding in the compendia. Indeed, the Manual expressly recognizes that, particularly in the case of the AHFS-DI, "[t]he text must be analyzed to make a determination whether a particular use is supported." MBPM, Chap. 15, §50.4.5.A.

The table in the Draft Decision deviates significantly from these clear standards and may result in unintended coverage restrictions for beneficiaries. First, by opposing the term "indicated" with the term "not established", the table creates the misleading impression that "not established" is equivalent to "not indicated". Accordingly, some carriers may interpret the table as a statement by CMS that coverage must be denied for uses that are not established.

More importantly, the use of "not established" appears to apply a stricter standard than the one embodied in the statute, which permits coverage if the off-label use is supported by the compendia discussion. For example, in the case of irinotecan, the discussion in the AHFS-Dl of its studied uses clearly supports its use as an active agent (either alone or in combination regimens) for the treatment of small cell lung cancer: The AHFS-DI reports objective response rates of 16-47% among patients receiving irinotecan as a single agent for refractory or relapsed small cell lung cancer; and an objective response rate of 84% in a study of patients receiving irinotecan in combination with cisplatin for previously untreated limited-stage or extensive-stage small cell lung cancer. Similarly, the AI-IFS-DI reports positive response rates in studies using irinotecan, both alone and in combination with other agents, for the treatment of cervical cancer. Neither of the authorized compendia list irinotecan as not indicated for small cell lung or cervical cancer. Notwithstanding the foregoing, the table in the Draft Decision lists irinotecan as “not established" for use as mono- or combination therapy for either cancer and would require carriers to turn to clinical sources other than the compendia to support coverage.

If CMS feels there is a compelling need to retain the table format for this information in the final decision memorandum, we strongly urge the agency to limit the presentation to indications that are either indicated or affirmatively "not indicated" in the authorized compendia. In the alternative, we would recommend deleting the table in its entirety, and, consistent with the Manual guidance, directing carriers to continue analyzing the text of the compendia to determine whether any particular use is supported (appropriately taking into consideration such factors as patient type, stage of disease and role of the agent).

B. Provide the Criteria Used to Select the Particular NCI Trials and the Items and Services To Be Covered Under the NCD.

Elsewhere, CMS has described a Decision Memorandum as "the public document that describes the analytical framework for [its] decision on a topic under National Coverage Determination (NCD) review. Its purpose is to inform the public of the decision, the reasons for the decision, the process followed, and to provide a summary of the evidence considered." FAQ, Medicare/Coverage (Answer ID 2655). To fulfill its objectives, the final decision memorandum should, at a minimum, describe in greater detail (i) the criteria used to select these nine NCI trials and (ii) the specific items and services related to the clinical trials that will be covered.

A more robust discussion of the selection criteria for the clinical trials, including the justification for the required nexus with the NCI, will provide much needed insight into why other similar trials were not included, and, more broadly, into CMS' objectives here. Discussion of the criteria could also provide investigators and study sponsors with valuable information on how to design future studies, particularly if the study is likely to significantly impact the growing Medicare population.

CMS also should provide greater detail in the final decision memorandum about the types of items and services that will be covered by Medicare under the proposed NCD, taking into consideration the existing NCD on clinical trials generally and the FDA regulations governing clinical trials conducted under investigational new drug applications. As stated in PhRMA's comments to the Draft Decision, the practical effect of the proposed NCD remains uncertain because it is unclear how the NCD will interact with these other policies regarding payment for costs of clinical trials. CMS should also explain clearly how coverage for the different arms of a randomized trial would be handled. Similarly, the final decision memorandum should explain whether all agents in a combination regimen will be covered.

C. Clarify CMS' Objectives with Respect to Medicare Coverage of Off-Label Uses and the Role Clinical Trials.

As stated in greater detail in PhRMA's comments, the Draft Decision signals two CMS objectives with respect to Medicare coverage and clinical trials that require further elucidation. Any special preference, whether in regard to Medicare coverage or to the generated data, conferred by participation in an NCI sponsored trial, must take into consideration the fact that many Medicare patients are not be able to participate in a clinical trial, whether because of personal circumstances (particularly in the case of rural cancer patients), the limited number of available trials, or because of the specific inclusion criteria for existing trials.

We, like PhRMA, are fully supportive of expanding Medicare's clinical trials coverage policy. It appropriately recognizes the need to provide access to needed off-label anticancer drugs while medical evidence is being collected, rather than barring it until such evidence is collected. However, to ensure that some Medicare beneficiaries are not unfairly prejudiced, we believe CMS must use the final decision memorandum to clarify that the use of anticancer medicines in NCI trials (or clinical trials generally) offers a supplementary, rather than a unique, basis for Medicare coverage. In that regard, we concur with PhRMA's recommendation to remove the word "only" from the portion of the Conclusion that states that while off-label uses of anti-cancer could provide clinical benefits to Medicare beneficiaries, "that those benefits are only likely to be present in the context of a clinical trial."

Similarly, while we believe the data generated in Medicare covered clinical trials has the potential to provide valuable additional evidence for clinicians and patients, the limited number of such covered trials counsels against over-reliance on such data, which are likely to produce too narrow a slice of evidence with respect to any particular clinical issue. Accordingly, if CMS intends to give any preference to the results of these nine NCI trials, the final decision memorandum should provide clear justification for such preferential treatment based on relevant clinical (e.g., outcomes) or data (e.g., phamacoeconomic) objectives of the specific trials.

Reserve Discussion of Other Important Issues for Separate Process

We concur with PhRMA that, to the extent CMS intended to use this NDC review to address broader Medicare policy issues such as identifying federal oncology research priorities or to establish additional means to gather clinical evidence outside the clinical trial setting, those very important objectives should be pursued through a separate process. At least three processes already exist and are available to CMS to obtain much-needed input from all relevant stakeholders: (i) the Town Hall meetings that CMS has used to vet other coverage related issues; (ii) the process outlined in Section 1013 of the Medicare Prescription Drug Improvement and Modernization Act of 2003 for identifying national research priorities on outcomes; and (iii) the regulatory process announced in September to generate general Guidances related to National Coverage Determinations.²

Again, we appreciate the opportunity to comment on the Draft Decision. We hope our suggestions are helpful to CMS in finalizing the decision memorandum and the NCD. Our intent is to ensure appropriate implementation of the proposed NCD consistent with CMS' stated objective of providing Medicare beneficiaries with expanded access to available anticancer therapies. Thank you for giving consideration of our views.

1 See Social Security Act, §1861 (t)(2). codified at 42 U.S.C. § 1395x(t)(2).

2 See "Procedure for Producing Guidance Documents Describing Medicare's Coverage Process," 69 Fed. Reg. 57325 (Sept. 24, 2004).

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December 23, 2004

Mark A. McClellan, M.D., Ph.D.
AdministratorCenters for Medicare & Medicaid Services
Department of Health & Human Services
200 Independence Avenue, S.W.
Room 314-G – HHH Bldg.
Washington, D.C. 20201

Re: Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer [CAG-00179N]

Dear Dr. McClellan:

The undersigned organizations representing cancer patients, providers and research organizations are writing to offer comment on the above-referenced coverage determination. While we support efforts by the Centers for Medicare & Medicaid Services (CMS) to collect more data on the effectiveness of cancer therapies, it is important to do so within the context of existing statutory, regulatory and other frameworks. We would suggest a reconsideration of the proposed coverage determination to take into account current law and practices and to focus more narrowly on the areas of unmet need with respect to coverage, mostly in the arena of relatively rare “orphan” cancers where clinical trials are very difficult to organize, initiate and bring to closure.

Background

Since 1993, the Medicare statute has recognized the importance of so-called “off-label” uses of cancer drugs and has set forth mechanisms to facilitate their coverage by Medicare. This coverage is based on references in recognized medical compendia and on reports of effectiveness in certain peer-reviewed medical journals. In recent years, the system established by Congress in 1993 has not functioned with optimal efficiency, in part because the compendia process has slowed unacceptably and CMS has not updated the list of appropriate peer-reviewed journals. We urge CMS to take all possible steps to remedy these deficiencies so as to return the coverage process to the efficiency that was formerly in place.

In addition, it is important to recognize the role of clinical trials both in the treatment of individual cancer patients and as the engine for progress against cancer in the future. CMS embraced the significance of cancer clinical trials in 2000 through the issuance of a National Coverage Decision (NCD) requiring coverage of all routine patient care costs in clinical trials. As CMS considers coverage decisions now and in the future, the 2000 NCD should be part of the landscape. Nothing in CMS’s current coverage decisions should challenge the fundamental validity of the 2000 decision.

CMS Proposal

The general concept underlying the current proposal is commendable—i.e., that Medicare will cover as-yet-unproven therapies in the context of clinical trials—and there are undoubtedly situations where such an approach is warranted. However, we have grave concerns about limiting the coverage-triggering trials to those sponsored by the National Cancer Institute (NCI). As we understand it, those trials will customarily feature patient access to the investigational drugs free of charge. If this is the case, there would seem to be no purpose to Medicare coverage of the drugs in the context of NCI-sponsored trials.

However, we do believe that there will be other circumstances where quality clinical trials may be underway before the existing statutory and other mechanisms would mandate coverage, and in that setting CMS coverage of the off-label uses would be welcome, but only if the pharmaceutical sponsor is not providing the drug without charge. In other situations, particularly those involving rare “orphan” cancers where there is little commercial incentive to initiate clinical trials, we would endorse the concept of submission of data to a central registry to enable collection of information about effectiveness.

Summary

Our organizations support CMS efforts to collect more data, through clinical trials or data registries, regarding the effectiveness of anticancer drugs. However, CMS must recognize, endorse and enhance existing statutory and other mechanisms for Medicare coverage of cancer drugs for both approved and off-label uses. The cancer community looks forward to working with CMS to optimize the uses of anticancer chemotherapy for the benefit of beneficiaries with cancer.

Sincerely,

Cancer Leadership Council

American Cancer Society
American Society of Clinical Oncology
American Society for Therapeutic Radiology & Oncology, Inc.
Cancer Research and Prevention Foundation
International Myeloma Foundation
Kidney Cancer Association
The Leukemia & Lymphoma Society
Lymphoma Research Foundation
Multiple Myeloma Research Foundation
National Coalition for Cancer Survivorship
North American Brain Tumor Coalition
Ovarian Cancer National Alliance
Pancreatic Cancer Action Network
The Susan G. Komen Breast Cancer Foundation
Us Too International Prostate Cancer Education and Support Network
Y-ME National Breast Cancer Organization

CONTACT: Ellen Stovall
National Coalition for Cancer Survivorship
1010 Wayne Avenue – Suite 770
Silver Spring, MD 20910
Phone: 301/650-9127
Fax: 301/565-9670

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The American Society of Clinical Oncology (ASCO) submits these comments in response to the Centers for Medicare and Medicaid Services (CMS) proposed coverage determination on the use of oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux™), or bevacizumab (Avastin™) in certain National Cancer Institute (NCI) trials. ASCO has an abiding interest in the earliest possible access to these life-extending drugs, as well as in the process by which CMS determines whether to make them available to Medicare beneficiaries. We are pleased that CMS is seeking ways to expand coverage of clinical trials and off-label uses of cancer drugs. We appreciate the opportunity to provide comment upon these important issues.

Background

Over the past decade, there have been a number of steps intended to improve the Medicare coverage process for new anticancer drugs. This special emphasis on drugs for the treatment of cancer is based on the fact that, particularly in cancer therapy, drugs approved for one indication by the Food and Drug Administration (FDA) are frequently and appropriately used for other purposes. Such "off-label" use constitutes the standard of care for many cancers.

Recognizing this reality of cancer treatment and wishing to make Medicare decisions more uniform, Congress enacted legislation in 1993, the Omnibus Budget Reconciliation Act (OBRA), which required coverage of medically accepted off-label uses of cancer drugs. Thus, §1861 (t)(2) of the Social Security Act provides that covered drugs include off-label uses of cancer drugs that are listed in several specified medical compendia. In addition, carriers may cover off-label uses of drugs not listed in compendia if they are supported by reports of clinical studies in certain peer-reviewed medical journals as identified by the Secretary.

ASCO was involved in, and supportive of, the off-label coverage provisions of the 1993 law and provided advice to the Secretary in the development of a list of peer-reviewed journals that could support coverage decisions on off-label uses of cancer drugs. We believe that steps should be taken to refine and improve implementation of the OBRA provisions, particularly focused on creating more uniformity in carrier coverage of drugs based on studies in the peer-reviewed journals. We have also submitted previous comments on the need to update the list of journals and are eager to work with CMS to make this improvement.

A second important Medicare coverage expansion for cancer treatment began in September 2000 with coverage of routine patient care costs associated with participation in clinical trials. According to CMS guidance (§30-1, Coverage Issues Manual), Medicare designates certain trials as "deemed" or automatically qualified for coverage. These include trials funded by NIH, the Centers for Disease Control and Prevention (CDC), the Agency for Healthcare Research and Quality (AHRQ), the Department of Defense (DOD), and the Department of Veterans Affairs (VA); trials supported by centers or cooperative groups of these federal departments and agencies; and trials reviewed by the Food and Drug Administration (FDA) as part of an investigational new drug (IND) application.

The proposal by CMS to cover certain trials for off-label uses of oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbituxml), or bevacizumab (Avastin™) represents another important expansion of Medicare's coverage policy, but the success or failure of the proposal will again depend on the details of implementation. ASCO is pleased to offer its perspective on the determinants of success in this most recent initiative.

CMS Proposal vs. Existing Clinical Trials Coverage

The proposal to provide coverage in the context of certain NCI-sponsored clinical trials is commendable. ASCO's chief concern with the proposal, however, relates to its interaction with the clinical trials coverage established in 2000. Section 30-1 of the Medicare Coverage Issues Manual clearly states that the trials listed above are "deemed to be automatically qualified." Therefore, coverage of these deemed trials should be consistent. In other words, there should be no basis for Medicare carriers to refuse coverage of these deemed trials. The draft decision memo on coverage of colorectal cancer drugs states that it will "offer consistent national coverage for these specific trials." Since these trials already qualify for deemed coverage under the 2000 National Coverage Decision, it is not clear why CMS views its current proposal as a coverage expansion.

The 2000 National Coverage Decision also specifies that Medicare covers all routine patient care costs in clinical trials. This includes items or services 1) typically provided absent a clinical trial; 2) required solely for the provision of the investigational item or service, the clinically appropriate monitoring of the effects of the item or service, or the prevention of complications; and 3) needed for reasonable and necessary care arising from the provision of an investigational item or service — in particular, for the diagnosis or treatment of complications. Pure research costs (such as the investigational item or service; items and services provided solely to satisfy data collection and analysis needs and that are not used in the direct clinical management of the patient; and items and services customarily provided by the research sponsors free of charge for any enrollee in the trial) are not covered by Medicare.

The draft decision memo on coverage of colorectal cancer drugs will extend Medicare coverage to include the 4 colorectal cancer drugs. It is our understanding that many pharmaceutical companies typically provide the investigational drugs free of charge in cooperative group studies. If the same holds true for these studies, the draft proposal amounts to little more than a transfer of the cost of clinical research from the participating companies to the taxpayers through Medicare payments. ASCO is concerned that this will not result in more patients or physicians participating in clinical trials.

While the nine trials mentioned in the draft decision memo are important, ASCO believes that the list of trials is too limited in scope. There are other important NCI-sponsored trials that should be included. In addition, the decision memo does not recognize the significant number of important trials being conducted by industry. Rather than choose specific trials, we believe that Medicare coverage should be extended to include all clinical trials deemed qualified under the terms of the 2000 clinical trials National Coverage Decision. All these were deemed to have sufficient oversight and control to be considered quality trials for purposes of the 2000 National Coverage Decision, and ASCO believes that the same criteria should be applied in decisions regarding coverage of off-label uses of drugs in clinical trials. To the extent that a clinical trial lacks sponsorship, support or review by one of the above-referenced entities, it may still meet the quality threshold if it exhibits characteristics that CMS itself has recognized as critical.

In the wake of the 2000 clinical trials National Coverage Decision, CMS sought assistance from AHRQ and the wider medical community in fashioning what CMS called "specific quality standards of a clinical trial." ASCO submitted testimony to the AHRQ panel that a quality clinical trial must include the following elements: (I) a written protocol, including trial design and scientific justification, criteria for inclusion and exclusion, outcome measures, statistical analysis plan, conflicts and other ethical controls, and publication policy; (2) review and oversight by an Institutional Review Board (IRB) consistent with applicable federal regulations; and (3) scientific review by a group of independent and qualified experts. Any clinical trial involving the four colorectal cancer drugs and satisfying these criteria should be eligible for coverage of the drugs, just as they should be eligible for coverage of routine patient care costs in accord with the 2000 National Coverage Decision.

Off-Label Uses Outside Clinical Trials

Even if the more expansive criteria advocated by ASCO were used by CMS to expand coverage of off-label drug trials, there still would be circumstances in which some cancer patients would not be able to access potentially life-extending off-label uses. Extremely rare, or "orphan," cancers may not have sufficient numbers of patients to justify a clinical trial, yet there may be sound, even if not yet proven, reasons to believe that an off-label use of a drug may provide clinical benefit to beneficiaries with such cancers.

In such circumstances, beneficiaries should be able to obtain coverage of off-label drug uses if they enter a registry that would collect data on patient outcomes. Such registries should meet quality standards, including protections for patient privacy. CMS has proposed such a registry system in the case of positron emission tomography (PET) for certain cancers (Draft Decision Memo for Positron Emission Tomography for Brain, Cervical, Ovarian, Pancreatic, Small Cell Lung, and Testicular Cancers—CAG-00181N). ASCO suggests that the same criteria used to approve PET should be applied to allow for registries for orphan cancers. ASCO could provide the medical oncology expertise to develop the data elements for such a registry. Improving Reliance on Peer-Reviewed Journal Renorts

CMS has requested that commenters address how to achieve "more timely contractor determinations of medically accepted off-label indications on a local level." ASCO submits that local contractor determinations would be facilitated by a more complete list of peer-reviewed medical journals reporting the results of clinical trials. The list has not been updated since implementation of the 1993 OBRA provisions, and ASCO has on several occasions requested that the list be amended to include nine additional journals to ensure adequate coverage of cancer clinical trials.

Aside from updating the list of approved peer-reviewed journals, ASCO strongly recommends that CMS exercise its discretion to compel contractors to cover off-label uses supported by reports in the listed journals. A strong underlying goal of 1993 OBRA was to make contractor decisions more uniform nationwide. The cause of national uniformity and consistent results for beneficiaries with cancer would be served if all contractors were mandated to cover off-label uses supported by reports in the listed peer-reviewed medical journals. ASCO would be pleased to work with CMS to define the characteristics of those published reports that should be considered sufficiently "supportive" to warrant coverage.

CONCLUSION

ASCO has collaborated with CMS for more than a decade to try to achieve fair and comprehensive coverage for Medicare beneficiaries who desperately need access to off-label uses of cancer drugs. We view the current proposal as a further step in the right direction, but one that requires clarification and expansion. CMS's desire to obtain meaningful data can be satisfied by a wide range of quality clinical trials beyond those directly sponsored by NCI. Important information can be obtained even outside the clinical trial setting through well-designed and carefully executed registries. Finally, it is essential that CMS immediately take steps to update the list of peer-reviewed journals that inform coverage decisions on off-label uses of cancer drugs and that CMS seriously consider, in the interest of national uniformity, mandating that all contractors act consistently with the information reported in those journals.

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The Pharmaceutical Research and Manufacturers of America ("PhRMA") is pleased to submit these comments in response to the Draft Coverage Decision Memorandum for Anticancer Chemotherapy for Colorectal Cancer (#CAG-00179N), posted on the Centers for Medicare and Medicaid Services ("CMS") web site on November 1, 2004. We appreciate CMS's extension of the comment period on the draft memorandum.

PhRMA is a voluntary, nonprofit association representing the country's leading research-based pharmaceutical and biotechnology companies. Our members are devoted to inventing and manufacturing medicines that allow patients to lead longer, healthier, and more productive lives. As leaders in the search for innovative new treatments, PhRMA and its members have a unique and important perspective on the appropriate coverage of new medicines and new uses of existing medicines.

PhRMA commends CMS for the role it plays in helping millions of America's seniors and people with disabilities gain access to anticancer medicines and other oncology care. PhRMA supports the development of high quality information about patients' medical treatment options. Empowering patients and physicians with high quality information will help ensure that our health system efficiently delivers the best possible results for all patients.

We appreciate the steps CMS has taken in the draft coverage decision memorandum to maintain existing beneficiary access to these four anticancer medicines prescribed for off-label use while simultaneously taking steps to expand Medicare's clinical trials policy to cover the identified National Cancer Institute clinical trials. As you know, physician prescribing of medicines for off-label uses plays an important role in chemotherapeutic cancer care. Due to this, the Medicare law has established a special framework for covering off-label uses of anticancer chemotherapeutic drugs.

CMS should continue to adhere to this statutory framework, which recognizes the importance of local coverage decision-making guided by evolving scientific evidence. As discussed in more detail in the attachment, the agency should clearly restate current policy on which off-label uses of oncology medicines are eligible for Medicare coverage: those that are 1) listed in recognized compendia, 2) supported by peer-reviewed literature, or 3) medically accepted as being safe and effective for that particular use.

Cancer exacts a heavy burden on Americans. In 2000, there were 553,091 cancer deaths in this country. For 2004, the American Cancer Society estimates that this number will increase to approximately 563,700, due to an aging and growing population.¹ As CMS notes in its draft coverage decision memorandum, colorectal cancer is the second leading cause of cancer death in the United States, with 146,940 new cases diagnosed and 56,730 deaths projected to occur this year.

At the same time, the U.S. is making progress in the fight against cancer. A survey released by PhRMA in October, for example, showed that 154 biotechnology medicines are currently in development for cancer alone. Though prescription medicines represent a small percentage of spending on cancer care (3.6% in 2001) ² , they provide a large proportion of the mortality gains achieved over the past 30 years. Research indicates that new medicines have provided 50-60% of the gains achieved over this time period.³ These gains yield large value in both human and economic terms. Murphy and Topel have estimated that a 10 percent reduction in deaths from cancer would generate roughly $4.4 trillion in economic value.⁴

Off-label prescription of anticancer medicines is a significant and essential aspect of effectively treating and caring for cancer patients.⁵ As noted by the American Society of Clinical Oncology, "[t]he off-label uses of approved drugs have been an important tool for advancing the treatment of cancer."⁶ A 1991 report by the General Accounting Office found that more than half the cancer patients studied were treated with at least one medicine prescribed for an off-label indication.⁷

We share CMS's goals of expanding patient access and making use of the best available evidence on what works and what does not work In all areas of medical care, including cancer treatment. Indeed, earlier this year PhRMA adopted principles for government-supported health outcomes research. (These PhRMA principles are attached.) However, we believe that the draft coverage decision memorandum also raises some matters that deserve fuller explanation and dialogue with stakeholders. A number of these matters relate to broad policy issues, and we believe they should be addressed in a forum apart from individual national coverage determinations.

For example, the identification of national clinical research priorities to be supported with Medicare funds, as well as the coverage and payment strategies CMS might use to further this priority research, should be addressed separately from individual national coverage determinations. Based on the language of the draft national coverage memorandum, it is difficult to understand fully and respond to CMS's goals in regard to identifying and conducting priority research in oncology. To the extent that the draft memorandum does identify support for this initiative as an underlying policy goal, we believe that the national coverage decision-making process is poorly suited to achieve the appropriate degree of stakeholder involvement.

As stated above, we fully support CMS' goals of expanding beneficiary access to appropriate care and supporting patient and physician decision-making based on the best available evidence. However, for the reasons discussed below, we believe that individual NCDs on specific medicines are not the appropriate mechanism to pursue these goals.

As CMS seeks steps to expand beneficiary access to oncology care, we believe the agency should consider expanding the list of independent compendia that can be relied on as a basis for Medicare coverage. As noted in the draft memorandum, one of the recognized compendia is out of print, and the length of time to obtain compendia listing can be lengthy. Thus, availability of additional independent compendia would help ensure timely beneficiary access to medically appropriate cancer therapy. As stated in the draft memorandum, current statute authorizes the Department of Health and Human Services to revise the list of recognized drug compendia "as is appropriate for identifying medically accepted indications for drugs." PhRMA would be pleased to meet with CMS to discuss this issue further.

Two goals that CMS identifies explicitly in the draft national coverage memorandum relate to: (1) expanding Medicare's coverage policy to include off-label uses in specified clinical trials of the four anticancer medicines under review; and (2) obtaining additional data on the uses of these four medicines.

1) Expanding Medicare Clinical Trial Coverage Policy

We are fully supportive of this first goal, expanding Medicare's clinical trials coverage policy to include off-label uses of medicines in clinical trials. However, we also believe that many trials beyond those selected by CMS should qualify for coverage based on criteria such as those alluded to in the draft coverage memorandum. Indeed, CMS, in the draft memorandum, says it is "interested in establishing other processes to identify appropriate trials for which we may provide coverage.”

Medicare coverage of clinical trials represents an important policy issue, and one that we think warrants a broader discussion than is possible within the context of a single national coverage decision for a specific item or service. Thus, we recommend that CMS make use of a broader forum for public discussion of this important issue. For example, CMS has often used Town Hall Meetings to address special issues of Medicare coverage. For the novel issues raised in the draft national coverage memorandum on anticancer chemotherapy, a Town Hall would be well suited to addressing the overall policy, as well as such questions as:

• What will be the practical impact of this coverage decision in light of FDA regulations concerning charging for investigational products in IND trials?
• What standards must a clinical trial meet in order for the interventions studied in the trial to qualify for this expanded coverage?⁸
• What process should be used to identify trials with interventions that qualify for expanded coverage?
• How will CMS determine what to cover and pay for within the qualifying trials? Will local contractors be involved in this effort?
• How will CMS' make use of the results of covered clinical trials'?
• Are there other policy changes CMS should consider to expand patient access to medically-accepted off-label uses of anticancer medicines?

PhRMA would be pleased to work with CMS in support of this type of event. In addition, we believe several specific sections of the draft memorandum should be revised to ensure that it does not result in unintended restrictions in beneficiary access. These suggested revisions are discussed in more detail in the attached appendix.

2) Generating evidence on oncology interventions

The second goal evident in this draft national coverage memorandum relates to CMS efforts to generate additional data or evidence bearing on the off label uses of oncology therapies. PhRMA fully supports development of information and evidence to support high-quality, efficient health care.

However, we believe the connection between the identification and pursuit of national research priorities for off-label uses of medicines by CMS and the statutory basis for coverage decisions that is, determining whether an item or service is “reasonable and necessary" is unclear. In addition, there is the potential that CMS' involvement in setting research priorities could affect its role as a payer such that improvements in the quality and efficiency of care are not maximized.

Thus, while we support development of additional evidence in the area of oncology, we would recommend that identification and pursuit of national research priorities be vetted and carried out through a separate process.

Private sector researchers currently are generating a large quantity of new research in the field of oncology, as are researchers in NCI and other institutions. To the extent that the Department of Health and Human Services would like to develop new, government- supported approaches to outcomes research in oncology, we believe it should identify mechanisms that allow broader consideration than is possible within the narrow, case-by-case confines of a national coverage decision on specific medicines.

Indeed, PhRMA would welcome a broader discussion of national priorities for oncology outcomes research. The prioritization of oncology outcomes research should be lead by an independent non-governmental coalition or task force. A discussion of priorities could include oncology academicians from basic science, clinical science and health services research, professional societies, patient advocacy groups, and biopharmaceutical research companies. The discussion should focus on what research questions are the most important for the advancement of patient care. Results from this effort can then be presented to the appropriate government agencies.

This type of approach could help ensure that evidence collection for oncology therapies is framed with appropriate breadth, and ensure that alternative views such as the patient and treating physician's perspective are adequately and publicly considered. It could also avoid over-reliance on a limited number of trials that may produce too narrow a slice of evidence to be meaningful for cancer patients as a whole.

To the extent that HHS views the current CMS/NCI collaboration as the principal mechanism for addressing cancer research priorities, appropriate steps should be taken to ensure that the process is open and that stakeholder participation is encouraged. We suggest that the starting point for this prioritization should be a "broad and ongoing consultation with relevant stakeholders" such as that contemplated for identifying national research priorities on outcomes for certain health care items and services.⁹ The process for setting these priorities is outlined in Sec. 1013 of the Medicare law enacted last year, and key transparency and participation features of this process might be imported to the CMS/NCI collaboration on cancer research.

Finally, though not explicitly articulated, a potential third CMS policy goal seems implicit in the draft national coverage memorandum a desire to change Medicare's coverage policy framework for addressing off-label uses of medicines in general. Whatever the merits of such a goal, we again believe it is a policy far broader than can reasonably be addressed in an individual coverage decision. We strongly recommend that CMS use other policy-making procedures to pursue changes such as these.

We note that, during the recent Open Door Forum on implementation of good guidance practices under Sec. 731 of the Medicare Modernization Act, panelists stressed to the agency the importance of delineating when formal rulemaking, rather than a guidance document, should be pursued. Participants also made the point that when guidance is developed, good guidance practices should be followed.

We believe that, if CMS determines there is a need for formal guidance in this area, it would be important to develop guidance documents on the coverage process itself prior to adoption of any policy (or policies) on coverage of off-label uses of medicines. PhRMA supports this process and would be happy to work with the agency to continue implementing good guidance practices and guidance on the coverage process.¹⁰

In summary, PhRMA supports broadening Medicare's coverage and payment policies with respect to clinical trials of off label uses of oncology medicines, and development of evidence on these uses. These appear to be two of CMS' goals in the draft memo. CMS also appears interested in addressing broader issues related to coverage of off-label uses of cancer medicines under Part B of the Medicare program. However, we believe individual national coverage decisions are not the appropriate mechanism for achieving these goals. Given the importance of these issues, we have enclosed a more detailed analysis of the draft coverage memorandum, based on our understanding of Medicare policy that might assist you as you consider changes to the draft memorandum on Anticancer Chemotherapy for Colorectal Cancer (#CAG-00179N).

Conclusion

PhRMA appreciates this opportunity to provide comments on the draft decision memorandum. We support expanding beneficiary access and making use of sound evidence by patients and physicians in making health-care decisions, and believe the agency can accomplish its stated objectives more appropriately and effectively through other mechanisms. We look forward to continuing to work with CMS on this matter.

1 American Cancer Society, Cancer Facts & Figures 2004, accessed at www.cancer.org/downloads/STT/CAFF finalPWSecured.pdf, Nov. 14, 2004.

2 PhRMA analysis based on Agency for Healthcare Research and Quality, 2001 Medical Expenditure Panel Survey (Rockville, MD: AHRQ),http://www.meps.ahrq.gov.

3 FR. Lichtenberg. "The Expanding Pharmaceutical Arsenal in the War on Cancer." National Bureau of Economic Research Working Paper No. 10328 (Cambridge, MA: NBER, February 2004).

4 Kevin Murphy and Robert Topel, Measuring tile Gains from Medical Research: An Economic Approach. 2003, University of Chicago Press, p. 42

5 Thakkar S, "Oncologists judge themselves the best judges of cancer treatments." J Nat! Cancer Inst.1997; 89:1188-1189.

6 American Society of Clinical Oncology, "Off-Label Drug Indications," accessed at www.asco.orglac/1.1003. 12-002217,00.asp, Nov. 14, 2004.

7 See GAO, "Off-Label Drugs: Reimbursement Policies Constrain Physicians in Their Choice of Cancer Therapies" (Sept. 1991) (GAO/PEMD-91-14) (report to the Chairman, Sen. Comm. on Labor and Human Resources) ("GAO Report"), at 4.

8 By "expanded coverage," we mean trials in which interventions are being studied that would qualify for Medicare coverage, such as the anticancer medicines subject to the draft memorandum.

9 See § 1013(a)(2)(C)(i) of the Medicare Prescription Drug. Improvement, and Modernization Act of 2003 (P.L. 108-173).

10 We note CMS' publication of a notice in the Sept. 24, 2004 Federal Register regarding establishment of a process for issuing guidance under Sec. 731 of the Medicare Modemization Act that is consistent with FDA good guidance practices. We look forward to working with CMS to further develop its good guidance practices and develop guidance specific to the national coverage process.

APPENDIX I

Detailed Comments on Draft Coverage Memorandum for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N)

If CMS seeks to finalize the draft memo, it should ensure that the final decision memorandum (and resulting national coverage determination) is consistent with the current legal and policy framework for addressing off-label uses of anticancer medicines. To accomplish this, we recommend the following:

• Clearly describe the relationship of the proposed national decision to decision-making by local contractors to ensure that patients will continue to have access to off-label medicines outside the identified clinical trials.
• Clarify how coverage of these medicines is being expanded, and how Medicare payment will be made for these therapies.
• Explain more clearly CMS 's rationale for the decision.
• Delete references to broader coverage policy issues that are raised in the draft memorandum, which should only be addressed through other mechanisms.

Medicare Has a Sound Statutory and Policy Framework for Addressing Off-Label Uses

Because of the far-reaching implications Medicare policy holds for patient access to off-label uses of anticancer medicines, the Medicare statute has for over 10 years contained provisions tailored to this important patient-access objective. Specifically, the statute provides that any off-label use of an FDA-approved drug or biological employed in an anticancer chemotherapeutic regimen is eligible for Medicare coverage if such a use is included in a recognized compendium or if the local Medicare contractor determines it to be medically accepted based on clinical evidence from peer-reviewed literature recognized by the Secretary.¹

Medicare has implemented this provision through a set of manual instructions that bar contractors from denying coverage of off-label uses of chemotherapeutic anticancer drugs based solely on the absence of FDA-approved labeling if the unlabeled use is supported in one of a designated set of drug compendia; is supported by clinical research in certain peer-reviewed medical literature; or is medically accepted generally as safe and effective for the particular use.²

CMS Should More Precisely Delineate the Relationship of the Proposed National Decision to Existing Coverage Policy

1. CMS Should Clarify How the Draft Memorandum Will Expand Patient Access to Off-Label Cancer Therapies

CMS describes the draft decision memorandum as an "expansion of Medicare coverage for off-label use of anti-cancer chemotherapeutic agents,” but it is unclear as to what extent and how coverage will be expanded. The agency, in explaining this expansion, says simply that it will extend national coverage to the use of the four drugs in the nine designated NCI trials.

As addressed below, the draft memorandum's actual effects are uncertain, because it is not clear how the memorandum interacts with current FDA and Medicare policies regarding payment for costs of clinical trials.

• Current FDA IND Policy

  FDA regulations generally prohibit sponsors of clinical trials conducted under an investigational new drug application ("IND") from charging patients or their insurers for the investigational drug.⁶ In these situations, under current policy, the costs of the drugs cannot be billed to Medicare. Thus, where the manufacturer of the drug is actively participating in the study or otherwise providing a trial drug supply for free, there would be no drug "cost" and thus no claim for Medicare reimbursement.

  The practical impact of the draft memorandum is unclear and, at best, seems dependent on the particular facts and circumstances of each NCI trial.

• Current Medicare Policy on Coverage of Clinical Trials

  It is unclear how the draft memorandum relates to Medicare's current policy on reimbursement for certain costs of clinical trials.⁷ Under this policy, Medicare can cover the routine care costs of Medicare beneficiaries participating in clinical trials. Presumably, the identified NCI trials would be eligible for coverage of routine costs of care under this policy. In addition, it is possible that at least some of the medicines would be provided free of charge.

  Thus, it is possible that the draft memorandum may produce little, if any, actual expansion in coverage. We ask that CMS clarify exactly how the draft memorandum would interact with the FDA and Medicare policies noted above and how much, if at all, coverage for uses of the four drugs would actually be expanded.

2. CMS Should Clarify Its Rationale for the Proposed Coverage Decision

PhRMA also asks CMS to clarify its rationale for the proposed national coverage decision in the draft memorandum. Certainly, PhRMA supports CMS' stated interest in covering off-label uses within NCI trials: to encourage increased understanding of emerging approaches for treating cancer and to ensure that beneficiaries have access to the most appropriate cancer treatments. At the same time, the role of a new intervention often evolves considerably after it is introduced, particularly in areas such as oncology, where new life-saving testing and treatment options are needed. It is important to take this natural evolution into account when considering research to better understand emerging treatment options.

Moreover, PhRMA also concurs in the proposed decisions premise of providing access to needed off-label anticancer drug uses while medical evidence is being collected, rather than barring such access until such evidence is collected. That said, it is difficult to discern the precise connection between this evidence-collection effort and the basis for Medicare coverage (that specific items and services are "reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”⁸).

In addition, the draft memorandum does not clearly describe how CMS plans to use the results of the selected trials. The proposal simply states: "To ensure that beneficiaries have access to the most appropriate cancer treatments, it is imperative that adequate clinical trial data for off-label uses be made available to patients and providers for clinical decision-making and to policymaker[s]."

While access to medically accepted therapies and adequate data on treatment options both are crucial goals, CMS should clarify how it intends use of the results of the identified NCI trials to further these goals.

3. Additional Policy Issues Raised in the Draft Memorandum are Better Handled Through Other Mechanisms

CMS' draft decision memorandum seeks to address not only proposed coverage determinations for identified anticancer drugs, but several broader coverage policy issues as well. PhRMA believes these additional issues are more appropriately addressed outside the narrow context of a specific national coverage review.

• Scope of Decision Memoranda and NCDs

  CMS has elsewhere noted that a decision memorandum "is the public document that lays out and describes the analytic framework for our decision on a topic" that is under review for a national coverage determination (NCD).⁹ In turn, an NCD is defined in the Medicare statute as
  "[A] determination by the Secretary [of Health and Human Sc't-vices] with respect to whether or not a particular item or service is covered nationally under this title, but does not include a determination of what code, if any, is assigned to a particular item or service covered under this title or a determination with respect to the amount of payment made for a particular item or service so covered."¹⁰

  The plain language of the statute, which CMS has essentially reproduced in regulations,'¹¹ states that an NCD, and thus the final decision memorandum that precedes it, concerns only "particular" items or services that are candidates for national coverage. In contrast, the sweep of some elements of the draft decision memorandum is far broader than the off-label uses of the "particular" medicines under review:

  • Guidance to Local Contractors

    The draft decision memorandum states that

    "CMS is seeking public comments on potential improvements in the guidance provided to contractors regarding coverage of off-label uses of these and other anticancer drugs."

    We understand this to mean that CMS is providing an opportunity to comment on the existing manual instructions to contractors on off-label uses of anticancer chemotherapeutic drugs. PhRMA appreciates this comment opportunity. However, to the extent this invitation extends to "other" anticancer drugs, it is not sufficiently related to the "particular" drug uses under review to be within the appropriate scope of this national coverage determination. Instead, we recommend that CMS identify an alternative mechanism for securing the input it seeks.

  • Additional Means" for Gathering Evidence

    CMS states in the draft decision memorandum that it is

    [I]nterested in identifying additional means of gathering evidence outside of a clinical trial setting for use in decision-making such as registries and analysis of routinely collected electronic data.

    The agency also solicits ideas and strategies for

    implementing programs that allow both coverage of the off-label use of anti-cancer chemotherapeutic agents and collection of data to advance knowledge in the appropriate use of these agents outside of a clinical trial setting, e.g., drug registration program.

    These are important suggestions deserving of careful attention. However, we question whether a decision memorandum applicable to four particular drugs is the appropriate vehicle for addressing topics so broadly couched. Again, we suggest that CMS identify an alternative mechanism for eliciting stakeholder feedback perhaps in connection with a broader focus on oncology research, as suggested above.

1 SeeSocial Security Act § 1861(t) (42 U.S.C. § 1395x(t)).

2 § 50.4.5. Medicare Benefit Policy Manual, Chap. 15 (CMS Pub. 100-02).

3 § 50.4.5. Medicare Benefit Policy Manual, Chap. 15 (CMS Pub. 100-02) (emphasis added).

4 Emphasis supplied.

5 Emphasis supplied.

6 21 C.F.R. 312.7(d).

7 See § 310.1. Medicare National Coverage Determinations Manual (CMS Pub. 100-03).

8 42 U.S.C. § 1395y(a)(1)(A).

9 Notice, "Medicare Program; Revised Process for Making Medicare National Coverage Determinations,'~ Centers for Medicare & Medicaid Services," 68 Fed. Reg. 55634, at 55635 (Sept. 26, 2003).

10 Social Security Act § 1869(fXl)(B) (42 U.S.C. ]395ff(f)(I)(B)) (emphasis supplied).

11 See 42 CFR § 400.202.

Health Outcomes Principles

PhRMA supports the development of high quality information about patients' medical treatment options. Empowering patients and physicians with high quality information will help ensure that our health system efficiently delivers the best possible results for all patients. Research from a range of sources in the public and private sectors provides valuable information for patients and health care professionals in making treatment decisions.

The following principles establish a framework to help ensure government-supported health outcomes research, including research on comparative effectiveness, meets patients' needs and supports continued improvement in medical care. Research that meets these principles can improve health care decision-making, while research inconsistent with these principles in how it is designed or used will make it more difficult for patients to obtain the best and most efficient medical care.

SCOPE:

1. Conduct research in the context of health care quality improvement: Government support of health outcomes research should occur as part of a broad agenda to improve health care quality and patient outcomes across the health care system. Efforts focused on cost-containment alone often shift cost from one medical service to another without improving patient outcomes. A research program geared toward improving quality and patient outcomes across the health care system is consistent with good research practice and answers the key question of how to most efficiently achieve better results for patients.

2. Prioritize to meet societal needs: Government priorities for health outcomes research should address diseases and conditions that are recognized as imposing a high clinical and economic burden on patients and society, rather than being limited to high cost interventions.
3. Consider the full range of treatment options: Health outcomes research should consider the full range of health care interventions and evaluate total health care costs or savings, not just cost of specific treatments.
4. Support appropriate use of health care interventions: Failure to use interventions appropriately carries costs to patients and society. Research should encourage more appropriate use of health interventions, examining the widespread failure to use medical technologies appropriately as well as the overuse and misuse of technologies.

DESIGN:

5. Consider the broad effects of health interventions: Health care interventions can have a wide range of costs and benefits. In evaluating outcomes of particular interventions, government-supported research should include direct benefits and broader and indirect benefits hat are important to patients and society, such as quality of life, patient functionality and economic productivity.
6. Keep research standards Up to date: Health outcomes research is a growing and changing area of inquiry. Government-supported research in this area should stay at the forefront of knowledge in the field.
7. Design and conduct qualitv research: Government-supported health outcomes research should use well-established standards for high-quality research, including making studies sufficiently powered (e.g., large enough patient groups) to provide sound results. Studies should report the strengths and limitations of the data and results, and conclusions should be consistent with these strengths and limitations

APPLICATION:

8. Support physician and patient decision-making: Patients have unique medical needs that are not reflected by population-level research, requiring that patients and their health care professionals have the central role in making medical treatment decisions. Communication and use of research findings should explicitly recognize that health outcomes research is just one of many tools to help inform patients' and doctors' treatment choices.
9. Recognize the benefits of multiple treatment options: Access to multiple therapies is needed to ensure that individual patients are optimally treated. Government-sponsored research also should acknowledge the potential economic benefits of having multiple treatment options. the ways that innovation can alter cost inputs such as prices over time, and the fact that medical progress often is achieved through a series of incremental improvements that cumulatively represent significant advances over time.
10. Support patient access to new health technologies: Health outcomes research findings should be used to help make more informed treatment decisions, not as a barrier that restricts or delays access to treatment choices. Health outcomes research is best applied to health care technologies after they have been used in a variety of clinical settings in the real world over an adequate period of time. Requiring health outcomes data before making a new technology available to patients would create significant delays in access and discourage innovation.
11. Examine patient subgroups to meet individual patient needs and optimize value: Health outcomes research should consider and reflect the needs of patient subpopulations, who often respond differently to medicines based on factors such as age, genetic variation, and comorbidities. Because patient sub-populations can differ in their response to therapy, a variety of treatment options may be required to optimize treatment and provide the most clinical benefit and the greatest value
12. Seek public input from stakeholders: Government decisions related to the funding and conduct of health outcomes research should be made through open, transparent procedures that ensure appropriate and timely involvement of stakeholders such as patients, health care professionals and medical researchers on issues such as proposed research goals, study designs and communication of study results.
13. Facilitate communication of findings: The government should help ensure that consumers, patients, physicians and other health care professionals have access to the range of peer-reviewed results on all treatment options in a fair and balanced manner that is understandable to each group.

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The Biotechnology Industry Organization (BIO) appreciates this opportunity to comment on the Centers for Medicare and Medicaid Services' (CMS) draft coverage decision memorandum for anticancer chemotherapy for colorectal cancer (CAG-00179N). BIO is the largest trade organization to serve and represent the biotechnology industry in the United States and around the globe. BIO represents more than 1,000 biotechnology companies, academic institutions, state biotechnology centers, and related organizations in the United States. BLO members are involved in the research and development of health-care, agricultural, industrial and environmental biotechnology products.

Representing an industry that is devoted to discovering new cures and ensuring patient access to them, BIO supports expanded Medicare coverage for drug and biological therapies. We commend Medicare's current local coverage rules for helping to ensure that Medicare coverage keeps pace with advances in standards of care, and we applaud CMS' desire to encourage seniors to participate in clinical trials by expanding Medicare coverage for certain drugs and biologicals. We note, however, that the draft decision memorandum raises numerous legal, practical, and policy questions that must be answered before we can frilly support the effects of the proposed coverage decision. BIO is committed to working with CMS to resolve these issues in a manner that will best protect patient access to innovative therapies.

BIO supports Medicare's current coverage rules¹ and procedures for off-label uses of drugs and biologicals, and we urge CMS to clarify that these policies are not altered and should be applied as they are today.

Medicare's current coverage policies for off-label uses of drugs and biologicals work well to ensure beneficiary access to critical therapies. The practice of medicine, especially oncology, constantly evolves (approximately every six months) through the incorporation of clinical evidence into improved standards of care. Current Medicare coverage policies support this evolution by allowing carriers to respond quickly to advances in care and new research thereby reducing beneficiaries' wait for access to innovative therapies. Under these policies, carriers enjoy the flexibility to cover off-label uses of therapies that are listed in selected compendia, supported by clinical research that appears in peer-reviewed medical literature, or are "determined by the carrier to be medically accepted generally as safe and effective for the particular use."² The current off-label policies also allow physicians to exercise their professional judgment in choosing the best treatment options for their patients. We urge CMS to continue to apply these policies and leave the current local coverage process intact.

In the draft decision memorandum, CMS respects the importance of Medicare's current local coverage policies, but further clarification that the proposed national coverage determination (NCD) would not upset these policies would help ensure beneficiary access to the current standards of care. However CMS decides to proceed, the agency should clarify that it does not intend to effect coverage for off-label uses of these four therapies outside the nine selected trials. Specifically, we urge CMS to reiterate that local carriers are permitted to cover these therapies outside the context of the NCD. Although the draft NCD states that it "makes no change in coverage for any off-label uses of these drugs not provided in the selected clinical trials," it also says, "contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature."³ This statement omits an important element of the current off-label coverage policy, local carriers' discretion to cover uses they determine to be "medically accepted generally as safe and effective for the particular use." BIO urges CMS to include this statement in any final NCD to ensure that local carriers continue to provide access to innovative therapies.

To prevent confusion among carriers and the public about the NCD's scope, we also recommend that CMS change the NCD's title to accurately reflect its contents. The title, "Anticancer Chemotherapy for Colorectal Cancer," suggests that the NCD applies only to colorectal cancer, when the trials to be covered would study six kinds of cancer. Renaming the NCD with a more appropriate title, such as "Expanded Coverage of Clinical Trial-Based Uses of Oxalipatin (Eloxatin®). Irinotecan (Camptosar®), Cetuximab (Erbitux™), and Bevacizumab (Avastin™)," would help beneficiaries, providers, and contractors to better understand its purpose.

CMS proposes significant policy changes in the draft that are inappropriate for a NCD.

CMS is using this draft decision memorandum to request comments on a significant new policy that reaches far beyond coverage for four anticancer chemotherapeutic drugs and biologicals. As CMS recently acknowledged, the agency is developing a new role for Medicare by using its coverage decisions to expand clinical research of drugs and biologicals.⁴ CMS has chosen to use this draft decision memorandum to seek comments on how to fulfill this role for all therapies, not just the four chemotherapeutic agents named on the NCD tracking sheet. BLO understands the importance of valid clinical data in making patient care decisions, and we appreciate CMS' desire to rely on clinical evidence to support coverage decisions. We also believe CMS' plans to collect, analyze, and use data for coverage decisions merit serious discussion with all of Medicare's stakeholders in an appropriate forum. However, the NCD process is not the appropriate forum for a policy discussion of this scope and significance.

CMS' longstanding practice is to use the NCD process to determine whether specific items or services are "reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member."⁵ Historically, CMS has used this process to evaluate scientific and clinical evidence to address narrow coverage issues for "a particular item or service "⁶ not to develop expansive new Medicare policies as presented here. The NCD development process, reiterated in section 731 of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, was designed to enable timely review of the scientific evidence measuring the medical benefits of a particular item or service and to allow public notice and comment on coverage decisions.⁷ The process's short drafting period and informal means of announcing proposed decisions are appropriate because each NCD is intended to affect only a limited portion of the Medicare benefit. This process would not be sufficient, however, for a proposal to fundamentally change CMS' coverage decision-making process or the requirements for coverage.

This draft decision memorandum departs from CMS' well-established practice and the statutory requirements for NCDs. In this memorandum CMS uses a different approach to making coverage decisions. Instead of being based on available evidence measuring the medical benefits of a therapy, their new approach would base a coverage decision on the need to collect more data. Additionally, CMS proposes to apply this policy not to a specific item or service, but to four distinctly different drugs and biologicals, used in combination with each other and with five other therapies. This departure from CMS' standard coverage decision process does not belong in a NCD draft decision memorandum.

CMS' additional requests for input in the draft decision memorandum further demonstrate the agency's misguided use of the NCD process to announce major changes in coverage requirements. CMS attempts to use the NCD comment period to solicit ideas and strategies on wide-ranging policy matters that affect far more than the four therapies named in the NCD, including:

• incorporating input from patient groups, medical professional organizations and other stakeholders into the clinical trial selection process;
• soliciting and facilitating the participation of beneficiaries in selected clinical trials;
• implementing programs that allow both coverage of the off-label use of anti-cancer chemotherapeutic agents and collection of data to advance knowledge in the appropriate use of these agents outside of a clinical trial setting, e.g., drug registration programs;
• enabling more timely contractor determinations of medically accepted off-label indications on a local level; and,
• potential improvements in the guidance provided to contractors regarding coverage of off-label uses of these and other anti-cancer drugs.⁸

These questions are directed toward CMS' efforts to establish a new role for itself in evaluating innovative technology. The questions do not serve the purpose of a draft decision memorandum for a specific national coverage analysis, which is to "lay out and describe the analytic framework for [a] decision under NCD review."⁹ These topics do not belong in a draft decision memorandum, but rather are addressed appropriately in a forum that allows for broader notice to the public and fuller opportunity to comment. If the agency wishes to establish new rules and procedures for all Medicare coverage decisions, it should reissue these questions in a more appropriate forum.

BIO supports coverage expansions, but the draft decision memorandum leaves too many questions unanswered for us to fully endorse it.

CMS described this draft NCD as a "coverage expansion,"¹⁰ providing Medicare payment for oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux™), and bevacizumab (Avastin™) when used in selected clinical trials. At this point, however, we are unable to assess whether this NCD would actually improve beneficiary access to these therapies or other innovative drugs and biologicals. The effects of the coverage proposal cannot be determined until its many unanswered questions are addressed.

Our primary concern is to provide beneficiaries access to these innovative drugs and biologicals in the nine selected trials as well as access to other cuffing-edge therapies in the future. We have not been able, through repeated attempts, to answer many of the basic questions that CMS and the National Cancer Institute (NCI) recommend patients ask before participating in clinical trials. These questions include:

• Who is eligible to enroll in the study?
• What is the purpose of the study?
• How do the possible risks and benefits of the trial compare with those of other options?
• What kinds of treatment, medical tests, or procedures will the participants have during the study? How much will patients have to pay for these services?
• Where will participants receive their medical care? Will participants be able to see their own doctor?
• How long will participants need to stay in the study? Will beneficiaries who must drop out of a trial prematurely still receive Medicare reimbursement for their course of therapy?
• How will the results be shared?¹¹

The answers to these questions will determine what effect, if any, the NCD would have on beneficiary access to advanced cancer therapies through these trials. For example, the trials' entry criteria are critical for estimating the number of Medicare beneficiaries who could participate in these trials. The cost to beneficiaries of participating in these trials also will affect access. If beneficiaries are liable for 20 percent coinsurance on the drugs and biologicals provided in these trials, but could enroll in other trials where all costs are paid by the manufacturers, beneficiaries will not choose to enroll in CMS' selected trials and access under Medicare will not be expanded. Additionally, patients may not want to enroll in these trials if they would be required to change physicians or travel to receive care. CMS must answer these essential questions about the trials' designs before Medicare's stakeholders can provide meaningful comment on this proposal.

Expanding beneficiary access also requires giving patients a choice of therapies and sites of care. This NCD could have consequences for beneficiary access to care in other trials or in non-clinical-trial settings. As we discussed above, the draft decision memorandum appears to protect carriers' ability to make local coverage decisions, although some clarification is still needed. Unless CMS takes care to ensure beneficiary access to these therapies outside these nine clinical trials, the agency's proposal could fail to expand coverage significantly. This is why we believe it is critical for CMS to clarify that local coverage policies remain unchanged. We also ask that the agency respond to the following questions, carefully considering this NCD's potential effects on patient access to care:

• How and why were these trials selected? How will other trials be added, and what criteria will be applied? Will non-NCI trials be eligible?
• Will beneficiaries in all areas of the country have access to these clinical trials? If not, can they still obtain Medicare coverage for these treatments if their use is consistent with an approved trial protocol?
• Will beneficiaries who do not meet the requirements of the protocols and thus are unable to enroll because of comorbidities, use of other drugs, or other circumstances still be able to obtain Medicare coverage for these treatments?

Second, we are concerned about CMS' payment for the drugs, biologicals, and other services provided in these trials. Since September 2000, CMS has paid for the routine costs of care in certain clinical trials, including NCI-sponsored trials. We would appreciate clarification as to how the proposed NCD is an expansion of coverage, not merely an application of the current NCD to the nine listed clinical trials. We also request more information on CMS' plans to pay for the non-routine costs of these trials, such as infusion services and additional laboratory and diagnostic tests. We recognize that NCDs do not address payment issues, but this NCD raises significant payment questions that must be answered before we can fully understand its effects on access to care, providers' willingness to participate, and manufacturers' support of clinical trials. BIO looks forward to talking with CMS to discuss these concerns. We pose the following questions to encourage these discussions:

• Will manufacturers still be requested to donate drugs and biologicals or non-routine items and services for these clinical trials?
• How are donated or substantially discounted sales for these selected clinical trials reflected in a manufacturer's Medicaid best price? Is this treatment consistent with CMS' objectives?
• We ask for confirmation that donated drugs or drugs sold at a nominal cost are not counted under Average Sales Price methodology.
• How will these rules interface with the Food and Drug Administration's (FDA's) IND process?
• How will the logistics of reimbursement work to ensure that the trials continue to be blinded?
• How will CMS and NCI ensure that reimbursement does not create selection bias, especially when multiple trials are being conducted at the same site and not all trials will be reimbursed by Medicare?

Third, we request more information about CMS' plans to collect, use, and disseminate the information gathered during these trials. The long-term effects of the trials will depend on what data are collected and how the data are gathered and analyzed. We urge CMS to facilitate stakeholder involvement in the coverage process by sharing its plans for the data and by providing timely public access to the trials' findings. BIO looks forward to working with CMS to establish the appropriate data standards in order to accurately make clinical decisions. Before CMS finalizes any coverage decision, we ask CMS to address these concerns with stakeholder input, including the following questions:

• Are these trials intended to collect data CMS will use to make future coverage decisions?
• Will the trials enroll enough Medicare beneficiaries to reach valid conclusions about these therapies' benefits for this population?
• Who will own the data gathered in these trials?
• Who will analyze it?
• When and how will the data be shared with the public?
• Will this coverage remain in effect until all of the studies are completed and analyzed?

We look forward to working with CMS and the NCI in order to resolve the many issues raised by this policy initiative. However, in the meantime, we urge CMS to reconsider the specifics of this NCD in light of the many yet unanswered questions.

In conclusion, BIO is committed to ensuring beneficiary access to innovative drug and biological therapies. Until CMS answers the myriad of legal, policy, and practical questions regarding this proposed NCD, however, we are unable to fully assess whether this NCD truly would improve beneficiary access to these four therapies as well as set an important precedent for ensuring access to other breakthroughs in the future.

Furthermore, we believe that the important, general coverage policy questions CMS asks in this draft decision memorandum would be addressed more appropriately outside the NCD process. The NCD process is not intended or designed to resolve broad questions regarding Medicare coverage and CMS' role in evaluating innovative technologies. We encourage CMS to seek input from a full array of beneficiaries, providers, manufacturers, and other stakeholders on these issues by presenting its questions in a more appropriate forum.

In any event, we believe it is critical for Medicare's current coverage policies for off-label drugs and biologicals to remain intact. Continuing to apply these policies as they are today will help ensure Medicare beneficiaries have access to the drugs and biologicals they need in their battle against cancer.

BIO appreciates this opportunity to comment on our concerns about the draft decision memorandum. We look forward to working with CMS to protect Medicare beneficiaries' access to life-improving drug therapies.

1 As described in depth below, we support CM5' current policy regarding off-label use of anti-cancer drugs as expressed in the Medicare Benefit Policy Manual (CMS Pub. 100-02), ch. 15, § 50.4.5 and applied by contractors today.

2 Medicare Benefit Policy Manual (CMS Pub. 100-02), ch. 15, § 50.4.5.

3 Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), Nov. 1, 2004, available at http://www.cms.hhs.gov/mcdlviewdraftdecisiomnemo.asp?id=90.

4 Gina Kolata, Medicare Covers New Treatments With a Catch, New York Times, Nov. 5, 2004 (quoting Dr. Sean Tunis on a "whole new role for Medicare").

5 Social Security Act (SSA) § 1862(a)(1).

6 The Medicare statute defines an NCD as "a determination by the Secretary with respect to whether or not a particular item or service is covered nationally" by Medicare. SSA §§ 1862(1)(6)(A), 1869(f)(l)(B). CMS has interpreted this to mean "a national policy statement granting, limiting, or excluding Medicare coverage for a specific medical item or service." CMS, Medicare Program; Revised Process for Making Medicare National Coverage Determinations, 68 Fed. Reg. 55634. 55635 (Sept. 26, 2003)

7 See SSA § 1862(l)(3).

8 Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), Nov. 1, 2004, available at http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=90.

9 68 Fed. Reg. at 55635.

10 CMS Press Release, Medicare Launches Efforts to Improve Patient Care for Cancer Patients, Nov. 1, 2004, available at http://www.cms.hhs.gov/media/press/release.asp?Counter- 1244.

11 See NCI Clinical Trials: Questions and Answers, Cancer Facts 2.11, available at http://cis.nci.nih.gov/fact/2_11 .htm; CMS, Medicare and Clinical Trials, available at http://www.medicare.gov/Publications/Pubs/pdf/ct.pdf

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Genentech is pleased to respond to the Centers for Medicare & Medicaid Services’ (CMS) request for comments on the draft decision memorandum for Anticancer Chemotherapy for Colorectal Cancer. Genentech is among the world’s leading biotechnology companies with products available for serious and life-threatening medical conditions, including cancer, asthma, and stroke. We are particularly interested in this decision given that on September 1, 2004, CMS expanded the scope of the original National Coverage Analysis (NCA) to include our product, bevacizumab (Avastin™). Avastin is an anti-Vascular Endothelial Growth Factor (Anti-VEGF) antibody that provides Medicare beneficiaries a clinically effective treatment for first-line metastatic colorectal cancer.

Genentech thanks CMS for the opportunity to offer comments and recommendations on the draft decision memorandum. Our remarks focus on four key areas: 1) CMS’ process for developing the draft decision memorandum; 2) areas in which we request CMS provide greater clarity to the public on the draft policy; 3) specific concerns with the National Cancer Institute (NCI) trials identified in the draft policy; and 4) initial recommendations in response to CMS’ specific requests as part of the draft decision memorandum.

Although the draft decision memorandum provides coverage of off-label uses of oxaliplatin (Eloxatin®), irinotecan (Camptosar®), cetuximab (Erbitux™), and bevacizumab (Avastin™) in clinical trials sponsored by NCI, Genentech believes that this decision memorandum should not serve as a model for potential future National Coverage Determinations (NCDs), or as a vehicle for additional coverage decisions in clinical trials for anticancer drugs because it was developed with little public input. As our comments and recommendations indicate, we urge CMS to engage more directly and frequently with interested stakeholders, including manufacturers, during the national coverage process.

Genentech also would like to emphasize that, as per CMS’ instructions in the draft decision memorandum, existing coverage of anticancer chemotherapeutic agents for Food and Drug Administration (FDA)-approved indications, or for indications listed in an approved compendium, are not affected by the draft decision. Genentech strongly supports CMS’ interest in providing instructions to local contractors to cover the off-label uses being studied for the products identified in the draft decision memorandum; however, we encourage CMS to emphasize to contractors that they continue to have discretion to cover other uses of these products, outside of the clinical trials specified, in cases with appropriate documentation.

Comments on CMS’ Process for Developing Draft Decision Memorandum

Based on our experience with the draft decision memorandum under discussion, there are specific areas in which CMS could develop a more transparent coverage process and work more closely with stakeholders who are widely-impacted by draft decisions. As indicated above, CMS expanded the original scope of the NCA for anticancer chemotherapy for colorectal cancer on September 1, 2004 to include our product, Avastin, but did not offer us, or the public, an opportunity to provide comments to this inclusion. Moreover, the original scope of the NCA was broadened through the draft decision memorandum to include other clinical trials and tumor types in addition to colorectal cancer. CMS gave no indication that the original scope of the NCA would be expanded to include other cancers, and in verbal conversations with CMS staff about the NCA, we were told that the draft decision would be limited only to colorectal cancer. In addition, CMS and NCI did not offer the public, or even the manufacturers of the specific anticancer products that are the focus of the draft decision memorandum, the opportunity to be participants in or observers at a meeting the two agencies held on September 15, 2004 to discuss the contents of the draft policy. We recommend that CMS and NCI provide further transparency around their objectives to give greater clarification to the outcomes sought by the draft decision memorandum.

Genentech believes CMS could have been more forthright in its development of the draft decision memo and encourages CMS to communicate more directly with manufacturers and other interested parties during all stages of the coverage development process. Per CMS’ request, Genentech is submitting detailed comments and recommendations on how to improve the national coverage determination process; specifically, the need for more openness and transparency in the development of draft decisions.

Areas in which CMS Should Provide Greater Clarity on the Draft Decision Memorandum

Upon review of the draft decision memorandum, Genentech has identified key issue areas in which CMS should provide greater clarity prior to the release of a final decision. In particular, Genentech believes additional information is needed to notify stakeholders of the reasoning behind some of CMS’ decisions in the draft decision memorandum and assist stakeholders in ensuring smooth implementation of the final decision.

CMS should be more explicit about potential future collaborations between NCI and CMS related to this decision. Specifically, CMS should describe the intent of discussions between the two agencies and if CMS and NCI will continue to identify relevant trials under this decision. As described in greater detail below, CMS also should explain to stakeholders how the specific trials mentioned in the draft decision memorandum were selected, the criteria used to select them, and how other trials may be identified and added in the future. We encourage CMS to indicate why the trials highlighted in the draft decision were limited to those sponsored by NCI and why specific trials were selected rather than general criteria developed to describe the type(s) of trial(s) that would be considered. Genentech urges CMS to develop criteria that may include both NCI-sponsored and non-NCI-sponsored studies to ensure well-rounded research results are obtained. Most importantly, CMS should openly clarify its plans to analyze the results of these trials and the process by which the public will be notified when results from the trials are compiled and publicly available.

Concerns with NCI Trials Identified in Draft Decision Memorandum

Genentech is committed to the health of Medicare beneficiaries with cancer, which is reflected in our long-standing involvement in the development of trials to evaluate treatments for colorectal cancer. We have specific concerns; however, with selection of the NCI trials indicated in the draft decision memorandum since, as mentioned previously, there was little opportunity for stakeholders to comment on the selection of these trials or to provide suggestions to both NCI and CMS on the proposed trial designs. Although we support CMS’ desire to identify clinical studies whose results may lead to advancements in cancer therapy, it is imperative that the study designs of the selected trials offer the most clinical potential and are the most appropriate in assisting the public and CMS in understanding the off-label use of anticancer chemotherapy for colorectal cancer.

Based on our review of the limited publicly available information for these trials, we have identified several issues that warrant further clarification from CMS. CMS does not specifically state its intention for selecting the nine trials highlighted in the draft decision memorandum and does not appropriately define the clinical questions and issues for which CMS believes the identified trials may be a source of evidence. Our analysis of the trials also raises concerns regarding inconsistencies among the trials selected. For example, if CMS is interested in the use of Avastin as an adjunctive therapy, a second major adjuvant trial, NSABP C-08, should be included in addition to the E5202 trial. Moreover, CMS has chosen to analyze both Phase II and Phase III clinical trials, which have different study objectives and results, and therefore may not be appropriate comparisons. As such, Genentech recommends that CMS and NCI further clarify the clinical issues they anticipate the selected trials will address and how such results may be used.

We also would like to raise concern that the lack of public information on these trials makes it impossible to assess whether these trials will result in clinically appropriate conclusions about a product’s effectiveness or have the statistical power to adequately detect differences in health outcomes between study arms. In addition, CMS and NCI have not indicated the number of Medicare beneficiaries required to enroll in these trials in order to draw rigorous conclusions on whether the trial results can be generalized to a Medicare population. Therefore, we suggest CMS and NCI release additional information on these trials, including the actual study protocols, for the public to analyze. CMS and NCI also should involve interested stakeholders in the discussion and development of all study protocols relevant to this draft decision memorandum. Comments in Response to CMS’ Requests in Draft Decision Memorandum

In the draft decision memorandum, CMS explicitly requested input on the following coverage and clinical trial issues. As stated above, we do not believe that this draft decision memorandum should serve as a model for future coverage decisions; however, we offer the following suggestions to ensure Medicare beneficiaries have continued access to needed anticancer therapies.

Identifying appropriate trials for which to extend coverage for off-label uses of anticancer drugs

Genentech believes CMS should involve stakeholders more closely in the process for identifying appropriate trials to extend coverage for off-label uses of anticancer drugs. We suggest CMS work with NCI to assemble a taskforce consisting of representatives from various stakeholder groups including providers, researchers, policy makers, manufacturers, and beneficiaries. The taskforce would be responsible for developing a process to identify appropriate clinical trials and criteria for how these clinical trials will be selected. The recommendations of the taskforce could provide the framework for a draft coverage guidance document, for public comment, that outlines the requirements needed to receive Medicare coverage for these products. As a supplement to creating a stakeholder taskforce, CMS and NCI should host a public Town Hall Meeting to obtain feedback on the draft criteria developed by the taskforce and revise accordingly.Soliciting and facilitating the participation of beneficiaries in selected clinical trials Encouraging beneficiary participation in clinical trials offers an excellent opportunity for CMS to work with stakeholders including manufacturers, physicians, and patient groups, to develop outreach or incentive programs to encourage beneficiary and provider participation in select clinical trials. CMS recently has announced the creation of a Patient Advocacy Program within the agency that will serve as a venue for patient advocates to contribute to Medicare policy issues. Genentech recommends that one of the program’s roles should include encouraging Medicare beneficiaries to participate in clinical trials and provide assistance in developing national coverage determinations. CMS, though the Patient Advocacy Program, also should explore ways to work with manufacturers and other stakeholders to develop education materials for Medicare beneficiaries and providers to encourage participation in clinical trials.Identifying alternative programs that allow both coverage of the off-label use of anticancer chemotherapeutic agents and encourage the collection of data to advance knowledge in the appropriate use of these agents outside of a clinical trial setting We recommend that CMS assemble a taskforce with representatives from interested provider groups such as the American Society of Clinical Oncologists, patient groups, NCI, and manufacturers to develop alternative data collection methods. At minimum, meetings that occur between CMS and other government agencies or organizations, such as the Institute of Medicine or academic centers, should be open to the public and include stakeholder input. Enabling more timely contractor determinations of medically accepted off-label indications by local contractorsGenentech emphasizes its ongoing support for local Medicare contractors to make coverage decisions based on the beneficiaries and clinical practices in their area. We therefore encourage CMS to re-enforce in this decision its instructions to local contractors that the existing policies for off-label use of FDA-approved drugs and biologicals used in anticancer chemotherapeutic regimens for medically accepted indications are considered reasonable and necessary. We further recommend that CMS develop a more formal process to disseminate information to contractors, providers, and patients on recent additions or changes in compendia listings. CMS also should work collaboratively with manufacturers to notify providers and contractors about changes in product labeling and recently published peer-reviewed journal articles for anticancer therapies through program transmittals and other formal correspondence.

Conclusion

Genentech appreciates the opportunity to submit comments to the draft decision memo on Anticancer Chemotherapy for Colorectal Cancer but emphasizes that this decision memorandum should not serve as a model for additional coverage expansions in clinical trials for anticancer drugs. In developing future coverage decisions, it is imperative that CMS collaborate with interested stakeholders during all stages of the development process. We remain interested in partnering with CMS on its future collaborations with NCI and its interpretation of the trial results, and we look forward to participating in the coverage process moving forward.

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National Patient Advocate Foundation (NPAF) is a patient organization whose mission is to seek improved access to and reimbursement for health care services through both policy and legislative reform at the state and federal levels. Our mission is shaped by the experience of the patients we serve through our companion organization, the Patient Advocate Foundation (PAF).

PAF has responded to requests for information and/or direct case management assistance from 3.4 million Americans last fiscal year as they confronted denial of access to treatment for a chronic, debilitating and life-threatening illness with twenty-six percent of that population of patients enrolled in Medicare. In the process of serving these patients and documenting their experiences in our database, we have a very clear and current insight into the scope and complexity of issues Medicare beneficiaries are confronting. Sixteen percent of the Medicare patients we served last year confronted the reality of no pharmaceutical coverage; thirteen percent faced the inability to meet tiered co-payments required in their prescription coverage, and five percent confronted inadequate formulary choices to provide access to the drugs or biologics prescribed through their plan.

NPAF appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services' (CMS) Draft Decision Memo for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N). We would welcome the opportunity to discuss any of our recommendations on the Draft Decision as you move toward the implementation of this coverage policy.

Compendia Recommendations

As provided in the CMS Analysis section of the Draft Decision, current law supports the inclusion of "medically accepted indications" for drugs that have been approved by the Food and Drug Administration (FDA) and include another use of the drug, if they are listed in one of three compendia provided for in Section 186l(t)(2)(B)(ii)(I) of the Social Security Act: "Such use is supported by one or more citations which are included (or approved for inclusion) in one or more of the following compendia: the American Hospital (AMA) Formulary Service-Drug Information, the American Medical Association (AMA) Drug Evaluations, the United States Pharmacopoeia (USP) Drug Information, and other authoritative compendia as identified by the Secretary, unless the Secretary has determined that the use is not medically appropriate or the use is identified as not indicated in one or more such compendia."

The AHA and AMA compendia have faced challenges toward ensuring that new and evolving drugs and therapies are reflected in a timely way to allow for access to necessary treatment, thus limiting access to newly approved drugs for critically ill patients. Off-label coverage for drugs listed in recognized authoritative compendia require timely updates to ensure that patients with serious illnesses have access to the drugs they need, when they need them.

Based on statute, NPAF is urging the inclusion of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, which is widely recognized and applied as the standard for clinical policy in oncology in the United States. Insurers, both public and private, are using the NCCN guidelines as a basis to establish coverage policies for drugs, biologics, devices, and procedures. The NCCN Drugs and Biologics Compendium enjoys a user-friendly format that lists appropriate uses for drugs and biologics in the treatment of cancer patients. The recommendations for use in the Compendium are derived directly from the NCCN Guidelines and represent the conclusions of cancer-specific panels of multidisciplinary thought leaders (18-22 per panel). Thus, these recommendations are based upon an evaluation of scientific evidence integrated with expert clinical judgment. The Guidelines and the Compendium represent the most comprehensive and up-to-date recommendations available in all of cancer care. NCCN Guidelines are updated on a continual basis based upon FDA approvals, new scientific findings and other important circumstances (e.g., halting of letrozole trial). The NCCN publishes patient versions of these guidelines in collaboration with the American Cancer Society in both paper and electronic formats.

The NCCN presently is developing the Compendium for release on a chapter-by-chapter basis. Chapters on colon, rectal, and anal cancers have been released. Chapters on Acute Myeloid Leukemia and chronic myelogenous leukemia are in press. Chapters on kidney cancer, testicular cancer, lung cancer, Non-Hodgkin's Lyrnphoma and breast cancer will follow shortly. It is planned that the full set of NCCN Guidelines will be available as recommendations for drugs and biologics use by the end of 2005. Chapters are being published in both paper and electronic formats. In addition to our recommendation regarding NCCN, we would urge the Association of Community Cancer Centers' (ACCC) Compendia-Based Drug Bulletin to be considered as well.

Local Carrier Recommendations

We appreciate the acknowledgement that CMS is aware of the need for contractors to "review the medical literature and determine the conditions under which off-label indications of FDA-approved drugs and biologicals used in anticancer chemotherapeutic regiments for medically accepted indications are reasonable and necessary." NPAF believes it is essential to have in place a systematic process for local carriers to embrace the compendia in a timely way. If they do not, many beneficiaries with life-threatening diseases could have their coverage delayed. NPAF is aware of anecdotal reports that some carriers do not routinely pay for drugs within six months of being added to a formulary.

We also understand that certain carriers are basing coverage decisions solely on statutory language as it relates to the compendia without consideration of Medicare Carrier Manual policies. NPAF strongly encourages CMS to include Medicare Carrier Manual decisions in its guidance documents, especially when considering off-label uses for drugs that are medically and generally effective. Medicare Benefit Policy Manual Section 50.4.5 states, "Unlabeled uses may also be considered medically accepted if determined by the carrier to be medically accepted generally as safe and effective for the particular use." The Medicare Carrier Manual also provides that drugs can be "reasonable and necessary for the diagnosis and treatment of the illness or injury for which they are administered according to accepted standards of medical practice." (Section 2049)

In addition, the Carrier Manual (Section 2049.4) provides for supportive agents currently available for use in various cancers. NPAF recommends that CMS adopt a broad view of supportive therapies because there is great variability of responses to different drugs from patient to patient.

Clinical Trials

Cancer is the second leading cause of death in the United States. Access to a broad range of chemotherapy products both sole source and combination therapies is critical to assure that patients who may fail on one product or protocol have the opportunity to engage other treatment options with reimbursement. Cancer disease management is often complicated by underlying comorbid conditions in the patient, toxic complications to the therapy and the advance of disease progression. Each of these factors underwrites our support for flexibility in allowing cancer patients access to off-label indications.

NPAF is supportive of the Agency's decision to provide Medicare coverage for National Cancer Institute (NCI)-sponsored trials for colorectal cancer. We are very interested whether there are industry trials that parallel NCI trials in this area of study, and as part of the protocols defined for this national colorectal cancer clinical trial project, could be included as part of this project.

The notice CMS posted November 1, 2004, indicated that information about the NCI-sponsored studies would be available as part of this notice (specifically under Appendix A) as well as on the NCI website. We have been unable to locate any specific information about where the nine trials will be located and how they will be conducted. Without this information, NPAF and its scientific board have found it difficult to provide adequate comment on many issues regarding access to, and scope of the trials.

NPAF believes that more, rather than fewer clinical trial sites, will improve access for beneficiaries in need of new therapeutic treatments. The optimal trial would allow Medicare beneficiaries from all-NCI-designated cancer centers access to these trials. We are concerned that a limit on the number of sites could impede the trials' accrual rate and thus limit the ultimate substantive report of outcomes.

NPAF is also concerned that the clinical trials be fully covered as a benefit under the Medicare Advantage program. We are unsure from our reading of the draft decision memo whether beneficiaries, including those enrolled in managed care plans, would have access to the trials. We would like to be clear all Medicare beneficiaries, including those in Medicare Advantage plans, would receive coverage for all administered drugs as well as accompanying services.

The CMS draft decision memo seems to indicate that drugs are covered under the trials and that Medicare will be reimbursing for those drugs. Upon our review, it is unclear whether trials will include oral drugs as part of protocols within this project. It is also unclear as to whether beneficiaries will be responsible for co-payments associated with the Medicare Part B benefit. We strongly believe that since NCI-sponsored trials typically provide test drugs to participants for free, this demonstration should not require Medicare beneficiaries to pay co-payments normally associated with their benefit.

We appreciate the opportunity to comment on the draft coverage decision memo CAG-00179N. If we can be of further assistance to CMS during this process, please do not hesitate to contact me.

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I am writing to comment on the November 1, 2004 draft National Coverage Decision (NCD) on off label indications for certain colorectal anti-cancer therapies (CAG # 00179N). Cell Therapeutics, Inc. (CTI) is a biotechnology company located in Seattle, WA dedicated to identifying new, less toxic and more effective ways to treat cancer. In the draft NCD CMS specifically requests public comment on "enabling more timely contractor determinations of medically accepted off-label indications on a local level." CTI submits the following comment based on recent experience with carrier review of off label indications for our anti-cancer therapy arsenic trioxide (Trisenox). We respectfully request that CMS provide guidance to carriers for a uniform review of the criteria for off label coverage that appear in approved peer review journals.

Coverage of Anti-Cancer Medically Accepted Indications

The coverage of off label indications for FDA approved anti-cancer therapies is set by statute. The statutory provision has been implemented by regulations in the Medicare Carriers Manual. Congress included a specific provision in the Omnibus Budget Reconciliation Act in 1993 on coverage of unlabeled use of anti-cancer drugs. Section 1861 (t)(2) provides that use of FDA approved anti-cancer drugs for clinical indications not approved by the FDA are covered when the specific indication appears in one of the major compendia cited in the statute or based on a carrier determination based on published peer reviewed literature. The statute states in relevant part with respect for coverage an unlabeled indication:

(2)(A) For purposes of paragraph (1), the term "drugs" also includes any drugs or biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication (as described in subparagraph (B)).

(B) In subparagraph (A), the term "medically accepted indication," with respect to the use of a drug, includes any use which has been approved by the Food and Drug Administration for the drug, and includes another use of the drug if

(i) the drug has been approved by the Food and Drug Administration; and(ii)(I) such use is supported by one or more citations which are included (or approved for inclusion) in one or more of the following compendia: the American Hospital Fonnulary Service-Drug Information, the American Medical Association Drug Evaluations, the United States Pharmacopoeia-Drug Information, and other authoritative compendia as identified by the Secretary, unless the Secretary has determined that the use is not medically appropriate or the use is identified ~s not indicated in one or more such compendia,

(II) the carrier involved determines, based upon guidance provided by the Secretary to carriers for determining accepted uses of drugs, that such use is medically accepted based on supportive clinical evidence in peer reviewed medical literature appearing in publications which have been identified for purposes of this subclause by the Secretary.

42 U.S.C. § 1395x(t)(2).

The Medicare Carriers Manual states that contractors must evaluate the quality of the evidence in published peer reviewed medical literature to determine whether there is supportive clinical evidence for a particular off label use of a drug. The following publications are listed in the Medicare Carriers Manual:

American Journal of Medicine, Annals of Internal Medicine, The Journal of the AmericanMedical Association, Journal of Clinical Oncology, Blood, Journal of the NationalCancer Institute, The New England Journal of Medicine, British Journal of Cancer,British Journal of Hematology, British Medical Journal, Cancer, Drugs, EuropeanJournal of Cancer, Lancet, and Leukemia.

Medicare Carriers Manual, § 2049.4(C). The Carriers Manual cites several factors for reviewing journals. When evaluating this literature, contractors should consider the following:

The prevalence and life history of the disease when evaluating the adequacy of the number of subjects and the response rate.

The effect on the patient's well-being and other responses to therapy that indicate effectiveness, e.g., a significant increase in survival rate or life expectancy or an objective and significant decrease in the size of the tumor or a reduction in symptoms related to the tumor.

The appropriateness of the study design.

In addition to the above cited journals, contractor should review other published literature and consult with clinical specialists to determine the safety and effectiveness of off label uses. Itis important to note that Medicare Carriers Manual gives contractors broad authority to make determinations on medically accepted indications beyond those reviewed in the above journals.The Manual further states "Unlabeled uses may also be considered medically accepted if determined by you to be medically accepted generally as safe and effective for the particular use." Medicare Carriers Manual, § 2049.4(C).

TrailBlazer Coverage of Trisenox

Trisenox was approved by the U.S. Food and Drug Administration (FDA) on September 25, 2000 by a New Drug Application (NDA) with Orphan Drug Status. Trisenox currently has Orphan Product Designation and Approvals for multiple myeloma, myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and hepatocellular carcinoma (HCC). Trisenox is a "true" orphan drug because it is used solely to treat rare diseases. Trisenox is one of the products to be categorized by CMS as an "orphan drug" for payment in the hospital outpatient setting.

CTI is concerned that the Medicare contractors are not consistently applying these regulations which has led to a Medicare beneficiary access problem for off label indications that meet the above statutory requirements. Trisenox has been covered by TrailBlazer since 2002 for several forms of cancer including, APL, MDS, multiple myeloma and CML. TrailBlazer issued Local Medical Review Policy (LMRP) #L14256 that took effect for services performed on or after January 14, 2004. The LMRP establishes limited coverage for the drugs included in List A in the HCPCS section of this policy. This policy limits drugs based on a specific list of ICD-9 codes. Under this new coverage policy Trisenox reimbursement is limited to only APL andCML.

CTI has been working for the past year with Trailblazer on off label coverage of arsenic trioxide. As the below letter sets out, CTI has provided Trailblazer with numerous peer review publications which demonstrate the clinical benefits of Trisenox in patients with MDS and multiple myeloma. Based on the statutory provisions and CMS Medicare Manual policy contractors should provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature. The draft NCD states:

This decision makes no change in coverage for any off-label uses of these drugs not provided in the selected clinical trials. Contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature. CMS is also seeking public comments on potential improvements in the guidance provided to contractors regarding coverage of off-label uses of these and other anti-cancer drugs.

On November 15, 2004, Dr. Charles Haley sent a letter to CTI stating that "we also carefully reviewed the pertinent clinical publications submitted and concluded that there are insufficient data to support the off-label use of arsenic tri oxide for either multiple myeloma or myelodysplastic syndrome at this time." Dr. Haley did not provide any further elaboration on why the published literature is insufficient. As set forth below, the published literature clearly demonstrates the benefits of Trisenox in patients with MDS and multiple myeloma.

Literature Supports Coverage of TRISENOX® for Multiple Myeloma and MDS

The use of Trisenox in patients with MDS and multiple myeloma is well supported by both clinical practice and publications in leading peer reviewed oncology journals. Both MDS and multiple myeloma have at least one peer-reviewed journal article in one of the above cited journals, and articles in many other leading peer reviewed hematology and oncology journals demonstrating improved net health outcomes associated with use of Trisenox. Additionally, no studies appear in peer-review publications demonstrating substantial toxicity associated with the drug. This published evidence supports restoring coverage for Trisenox for patients with MDS and multiple myeloma.

The use of MDS and multiple myeloma over the past two years is supported by clinical practice and publications. In particular, an article was published by Dr. Allen List on MDS in Leukemia in 2003 and an article by Dr. Nikhil Munshi at Dana-Farber Cancer Institute on multiple myeloma in Leukemia in 2002. Six articles on the clinical use of MDS and multiple myeloma with Trisenox have been submitted to peer reviewed journals for publication this year.

A new article appeared in the May 2004 edition of the British Journal of Hematology by Dr. Mohamed Hussein of the Cleveland Clinic on Trisenox in multiple myeloma. Dr. Hussein states in the article:

Traditionally, refractory patients are difficult to manage because they are unlikely to respond to further therapeutic manipulations (Pandit & Vesole, 2001). Arsenic trioxide single-agent therapy resulted in a clinical benefit in this poor-prognosis group. Objective responses were obtained in 33% of patients, and an additional 2S% attained stable disease, contributing to an overall benefit in 58% of patients on an intent-to-treat basis.

An additional new peer reviewed article on Trisenox in MDS will be published in the August volume of Leukemia Research by Dr. Azra Raza, Director of the MDS Center at Rush Cancer Center. In the article Dr. Raza states that:

Responses were noted in both low and high risk MDS patients, but were particularly striking for the RAEB and RAEB-t patients. In summary, two patients had a trilineage response, two had a major erythroid response (100% transfusion independence and increase in hemoglobin by 2g/dl), two had a minor erythroid response with 50% reduction in PRBC transfusions and one patient improved his ANC while the blast count decreased enough to change the FAB from RAEB-t toRAEB.

As noted above, the draft NCD specifically states "Contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature." CMS should publish guidance on how carriers should cover off label uses that are in peer reviewed literature. Without clear guidance to the contractors, there will be increased claims, denials and beneficiary appeals.

Conclusion

CTI requests that in the Final NCD CMS provide guidance to Medicare contractors on coverage of off label uses of anti-cancer therapies that are listed in peer reviewed compendia. When peer reviewed compendia shows that an off label use improves health outcome it should be covered and available to Medicare beneficiaries based on the statute and Medicare Carriers manual.

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I am a Nuclear Medicine Physician and Radiologist and I have been practicing for approximately thirty years. I have found PET imaging oncology to be the most helpful and definitive modality when combined with CT fusion for evaluation of various types of cancer, with response to treatment and recurrence included.

It would be most helpful if the restraints on ordering PET studies would be relaxed since I think that this deters physicians from ordering the studies and in the long-run, costs more in the diagnostic and treatment of patients. The treatment of cancer is certainly not inexpensive and in many instances, different types of treatment or changes in treatment before lengthy trials would be influenced by PET with CT fusion.

It also would be of benefit to relax some of the requirements for evaluation of nervous system disorders, specifically Alzheimer’s disease and dementias. There is evidence that with appropriate behavioral therapy and training of the person that would use the plasticity of the brain to avoid the rapid deterioration that occurs, would be beneficial to patients and cost effective at the same time.

It also would be beneficial to include PET scanning using fluorine-18 drug for bone imaging perhaps with moderately specific indications as this would also be beneficial for evaluation of metastatic disease that is not otherwise apparent on routine bone scanning.

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As you know, the National Patient Advocate Foundation (NPAF) is a non-profit healthcare organization dedicated to the mission of creating avenues of patient access to insurance coverage for evolving therapies, therapeutic agents, and devices through policy reform. Each day our companion organization, Patient Advocate Foundation (PAF), is contacted by patients with chronic debilitating or life-threatening diseases who are having difficulty accessing care.

I am writing regarding the Centers for Medicare and Medicaid Service (CMS) draft decision memo for anticancer chemotherapy for colorectal cancer (CAG-O0179N). At the beginning of November, CMS outlined its plans to allow for the use of certain off-label drugs in nine clinical trials to treat colorectal cancer and other cancer types.

NPAF applauds CMS' willingness to pursue coverage opportunities for off-label uses for drugs under clinical trial. We have, however, been unable to find more information on the CMS or National Cancer Institute website cited in the draft decision memorandum about the size and nature of the colorectal cancer trials to be covered and the specific sites where beneficiaries will be able to enroll in the covered trials. Because this information does not appear to be publicly available yet, the thirty-day comment period ending December 1, 2004 does not provide adequate time to allow the cancer community to comment. For organizations such as NPAF that do have a scientific advisory board, additional time to consult with them would be particularly helpful. We realize that we are fast-approaching the Thanksgiving holiday and hope it might be possible to receive feedback from you prior to the holiday, both directly and in the form of a public announcement available to all interested stakeholders, about extending the decision memorandum comment period.

We would very much like the opportunity to review whatever information is available about the proposed clinical trials and site selection, if additional information can be provided at this time. As always, we appreciate your assistance.

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The Association of Community Cancer Centers (ACCC) respectfully urges you to extend the comment period on the Centers for Medicare and Medicaid Services' (CMS) proposed coverage decision memorandum for anticancer chemotherapy for colorectal cancer. ACCC is a membership organization whose members include hospitals, physicians, nurses, social workers, and oncology team members who care for millions of patients and families fighting cancer. ACCC's more than 700 member institutions and organizations treat 45 percent of all U.S. cancer patients. Combined with our physician membership, ACCC represents the facilities and providers responsible for treating over 60 percent of all U.S. cancer patients.

This draft coverage decision could greatly affect our members' ability to provide their patients with life-saving advanced therapies. ACCC plans to comment on the proposal, but we believe the current 30-day comment period will not allow us ample time to analyze fully and comment on all the complex issues raised in the draft decision memorandum. Given the direct and potentially adverse impact that this decision will have on patients and the oncologists who treat them, it is critical that time be provided to solicit input from our physician membership across the county. Indeed, as noted below, the NCD request comments on incorporating input from stakeholders into the clinical selection process. We also note that we are meeting with Dr. Sean Tunis on November 30, 2004 to discuss our questions regarding the proposal, and we hope to be able to incorporate this information into our comments. We therefore request a 60-day extension to the comment period. This draft national coverage determination (NCD) requests comments on a range of issues related to CMS' new self-appointed role in evaluating medical technology.¹ In addition to the coverage of four leading-edge cancer therapies, the proposed NCD requests comments on:
1) drafting guidance to contractors regarding off-label uses of cancer therapies,
2) incorporating input from stakeholders into the clinical trial selection process,
3) facilitating beneficiary participation in selected clinical trials,
4) implementing programs to cover and collect data on off-label uses of drugs in non-clinical trial settings, and
5) using registries as a means to gathering evidence for use in CMS's decision-making. The 30-day comment period is not enough time to conduct the serious evaluation these complex issues deserve.

The 30-day comment period is especially inadequate in light of the recent changes to the NCD's scope. Most of the topics for which CMS requests comment were not part of the NCD's original focus in February 2003 and have not been subject to comment before now, as shown by the draft decision memorandum's first round of initial comments. We particularly are concerned that CMS has changed the NCD's scope significantly in just the past two months. Specifically, CMS added bevacizumab and cetuximab to the review on September 1, 2004, and the announcement of CMS' meeting with the National Cancer Institute on September 15, 2004 barely hints at the many clinical trial issues raised by the proposed NCD.² We will need more time to analyze thoroughly these major changes in the NCD's scope.

We therefore request that CMS use its authority to extend the comment period by 60 days. Although the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) revised the NCD process, CMS has indicated that the MMA's timeline is "effective for NCDs undertaken on or after January 1, 2004."³ The agency initiated this NCD on February 12, 2003, well before the new deadlines would be applicable. Thus CMS can extend the comment period by 60 days and postpone the NCD's effective date, if necessary, without concern of violating the Medicare statute. We also note that CMS previously has extended its comment periods on significant policy proposals. During the development of this NCD, CMS extended its periods for review and comment several times.⁴ The agency also has offered more time to comment on proposed rules, most recently in January 2004.⁵ We would greatly appreciate if CMS gave us the same consideration by extending the comment period on this proposed NCD by 60 days.

We sincerely appreciate your thoughtful consideration of this request.

1 See Gina Kolata, Medicare Covers New Treatments With a Catch New York Times, Nov. 5, 2004 (noting thatMedicare has assumed a "whole new role").
2 NCA Tracking Sheet for Anticancer Chemotherapy for Colorectal Cancer (CAG-00 1 79N), available at http://www.cms.hhs.gov/mcdlvieWtrackiflgsheet.a5P?id9O
3 CMS Changes to the National Coverage Determination Process, available at http://www.cms.hhs.gov/coverage/8a4.asp.
4 NCA Tracking Sheet for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), available athttp://www.cms.hhs.gov/mcdIviewtracking5heet.a5P?id~9O.
5 69 Fed. Reg. 4464 (Jan. 30, 2004).

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I am pleased to submit the following comments on behalf of the oncology business unit of Novartis Pharmaceuticals Corporation ("Novartis"), an affiliate of Novartis Corporation, regarding the above referenced draft coverage decision memorandum for anticancer chemotherapy for colorectal cancer. Novartis is a leading pharmaceutical manufacturer with a strong commitment to the care of the oncology patient, and we look forward to working with CMS to improve access and quality of care for Medicare beneficiaries requiring cancer treatment.

Novartis would like to commend CMS for its thoughtful review of the off-label uses of oxaliplatin, irinotecan, cetuximb, and bevacizumab in the treatment of colorectal cancer. Novartis strongly supports CMS's draft decision to cover certain off-label uses of these four drugs when administered as part of specified National Cancer Institute (NCI) clinical trials. We are also pleased to read of CMS's reminder to Medicare Carriers of the statutory mandate for coverage of certain off-label anticancer treatments as described in §1861(t)(2)(B) of the Social Security Act.

Cancer treatments have advanced significantly in recent years. The development of therapies such as targeted molecular treatments, monoclonal antibodies, biologic response modifiers, and endothelial growth factor inhibitors have revolutionalized the treatment of various oncologic disorders. Unlike other disease states, cancer is very heterogeneous and its biology and response to treatment can vary even within the same type of cancer. This often results in different treatment approaches for patients with the same cancer-type; as such, a great deal of cancer treatment takes place off-label. Novartis realizes the need, both for clinicians and for policy makers, to better understand the response of therapies when used beyond the FDA label or compendia listing, and we agree with CMS that coverage for certain anticancer treatments should be provided within the context of certain clinical trials. In this draft decision memorandum, CMS states that it is seeking public comment on establishing processes to identify other appropriate trials for which CMS would provide coverage beyond these specified NCI trials and beyond these four listed anti-cancer agents. CMS notes, in Appendix B of this draft decision memorandum, issues that are critical when making national coverage determinations: basic principles of strong study methodology and the need for the evidence to be generalizable to the Medicare population. Novartis agrees with CMS that any expansion of the type of clinical trials that receive drug coverage under this decision memorandum should require the trials to be of both strong internal and external validity. To this end, we suggest that CMS consider extending coverage for anti-cancer drugs used for off-label purposes that do not meet the statutory criteria listed in SSA §1861(t)(2)(B) beyond the nine specified NCI trials to include the following four trial types:

1) industry-sponsored randomized controlled trials that meet the methodological principles noted by CMS in Appendix B of this draft decision memorandum;
2) industry-sponsored open-label trials when investigating a drug's use in orphan or rare diseases (e.g. chronic myeloid leukemia or gastro-intestinal stromal tumor) where the ability to conduct randomization or blinded-controls is restricted due to the small number of affected patients or due to ethical concerns of withholding treatment;
3) NCI recognized Cooperative Group trials (e.g., Southwest Oncology Group (SWOG), Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B cooperative group (CALGB), etc.); and,
4) academic center or community cancer care center trials (not industry sponsored or part of an NCI Cooperative Group) when the trial design meets the general methodological principles noted by CMS in Appendix B of this draft decision memorandum.

Cancer treatment is advanced as oncologists gain experience with drugs and drugregimens and the systematic collection of such data should be encouraged. The reality, however, is that to continue collecting such data, anticancer agents must be reimbursed or patients will find difficulty in accessing them. CMS's commitment to maintaining access to novel and effective cancer treatments for its beneficiaries is to be commended. By expanding the list of covered trials, while at the same time insisting that the trials covered be of solid methodology and applicability to the Medicare population, CMS will be providing leadership and support that will aid countless Medicare recipients in their battle against cancer.

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The Biotechnology Industry Organization (BIO) respectfully requests an extension of the comment period on the Centers for Medicare and Medicaid Services' (CMS) draft coverage decision memorandum for anticancer chemotherapy for colorectal cancer (CAG-00179N).

Currently, the comment period for this proposed coverage decision is only 30 days. Given the impact this decision would have on patient access to our member companies' products, as well as on the development of future therapies, we request an extension of 60 days so that we may assess this complex proposal thoroughly before providing detailed comments.

As CMS recently acknowledged, the agency has developed a new role for Medicare by using its coverage decisions to expand clinical research of drugs and biologicals.¹ This proposed national coverage determination (NCD) is a significant component of this new interpretation of Medicare's responsibilities. BIO is the largest trade organization to serve and represent the biotechnology industry in the United States and around the globe, and we are committed to ensuring that patients have access to our therapies. Although we appreciate that the NCD appears to expand coverage for the therapies it addresses, we are concerned about its longer term implications as well as resolving the numerous questions raised by this draft.

Specifically, the proposed NCD offers us only 30 days to comment not only on the coverage of the four colorectal cancer therapies, but also on several other complex issues that relate to patient access to other innovative therapies. These issues include guidance to contractors regarding off-label uses of these and other therapies, methods of incorporating public input in the trial selection process, beneficiary participation in selected clinical trials, programs to cover and collect data on off-label uses of drugs and biologicals in non-clinical trial settings, and improving the timeliness of local coverage determinations regarding off-label uses. We believe that the 30-day comment period is insufficient for us, or other interested parties, to provide thoughtful comments on all of the significant issues raised by this draft NCD.

In addition to the significant number of complex topics to address in our comments, BIO believes that the late addition of these issues to the NCD's scope warrants an extension to the comment period. Although CMS initiated the review process for this NCD20 months ago, the salient issues of the draft decision memorandum were not introduced into the review process until very recently. CMS added bevacizuniab (Avastin™) and cetuximab (Erbitux™) to the review only two months ago, and none of the clinical trial matters in the draft NCD were subject to public comment previously in the review process. In fact, CMS' summary of the comments filed in 2003 reveals that few, if any, of the topics raised by the draft NCD were part of the review's original scope. To fully consider all of the recent, substantial changes in the NCD's focus, we need more than 30 days.

CMS can extend the comment period for this proposed NCD without concern about violating the statutory timeframe. CMS has indicated that the Medicare Modernization Act's amendments to the NCD development process are "effective for NCDs undertaken on or after January 1, 2004."² Because CMS initiated this NCD on February 12, 2003, it does not appear to be subject to the statutory deadlines. CMS therefore can choose to extend the comment period for an additional 60 days, and postpone the NCD's effective date if necessary.

Alternatively, if CMS determines that the statutory deadlines apply to this NCD, it could extend the comment period and still conclude the NCD review process on time. Social Security Act section 1862(1) requires CMS to issue a draft NCD within 6 months of a request for an NCD, followed by a 30-day comment period and a 60-day decision period. The statute demonstrates Congress' understanding of the importance of public input into CMS' coverage decisions, while also requiring CMS to act promptly on requests for NCDs. Ordinarily, the statute's timeline would allow interested parties up to 7 months to study and evaluate the issues involved in the proposed NCD. This might be enough time for meaningful comments when an NCD request is externally generated and the public has been involved in the process from the beginning. However, CMS initiated this NCD process through an internal request, and the agency should take particular care to ensure that all affected parties have adequate time to assess the draft NCD. Here, CMS set the final scope of the NCD review only two months ago, and the agency raised several issues for comment for the first time in this draft NCD. In the interests of allowing meaningful public comment, we respectfully request that CMS extend the comment period for an additional 60 days. The additional time would provide CMS with more substantial comments, while also giving the agency time to fully consider and respond to those comments.

Historically, CMS has extended its comment periods to allow for additional public comment on significant policy proposals. For example, in January 2004, CMS extended the comment period for its proposed rule regarding prospective payment systems for inpatient psychiatric facilities for an additional 30 days. CMS explained that it granted the extension "due to the scope and complexity of [the] proposed rule" and because commenters requested additional time "so that they may provide meaningful comments on its provisions."³ CMS also extended the comment periods in the development of this NCD twice.⁴ We ask CMS to call upon previous precedent to extend this courtesy once again. We believe that an additional 60 days would help us and other interested parties to respond thoughtfully with comments that will help CMS' implementation of this NCD and other coverage decisions.

1 Gina Kolara, Medicare Covers New Treatments With a Catch, New York Times, Nov. 5, 2004 (quoting Dr. Sean Tunis on a “whole new role for Medicare”)
2 CMS, Changes to the National Coverage Determination Process, available at http://www.cms.hhs.gov/coverage/8a4.asp
3 69 Fed Reg 4464 (Jan. 30, 2004).
4 NCA Tracking Sheet for Anticancer Chemotherapy for Colorectal Cancer (CAG-00179N), available at http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?id=90.

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The purpose of this letter is to request an extension of the public comment period on a proposed CMS decision memorandum concerning Medicare national coverage of anticancer chemotherapy for colorectal cancer (CAG-00179N).

The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country's leading pharmaceutical research and biotechnology companies, which are devoted to inventing medicines that allow patients to live longer, healthier and more productive lives. As such, PhRMA is very interested in how patient health might potentially be affected by Medicare's national coverage policies.

We appreciate the approach you have taken in this proposed decision to maintain continued beneficiary access to off-label uses of these medicines while additional trials are conducted. At the same time, the proposal presents a number of significant and complex issues. On September 1, CMS significantly expanded the scope of the review to include certain off-label uses of bevacizumab and cetuximab. Moreover, the posting the agency made on November 1 sought comments not only on the proposed coverage determination itself, but also on several related and potentially far-reaching issues that require additional time to consider and provide responses to, such as:

The identification of a set of nine National Cancer Institute trials recommended for coverage. Although the draft decision memo provides brief descriptions of these trials, little additional information has been made publicly available. Please provide additional details of these studies, and the additional time needed to evaluate them and provide input;

The request for public comments on potential improvements in guidance provided to Medicare contractors on coverage of off-label uses of anti-cancer medicines more generally. Additional time is needed for stakeholders to consider this issue, which plays on important role in Medicare beneficiary access to anticancer therapies;

The interest in establishing new processes for identifying appropriate trials for which CMS "may provide coverage";

The request for ideas for other approaches to obtaining additional data on new cancer interventions outside of the clinical trial setting.

We believe a number of these broader issues are more appropriately addressed outside the narrow context of specific coverage decisions. However, to the extent that they are addressed in this decision, a complete consideration is possible only if CMS extends the comment period from 30 days to 90 days.

Over the course of this particular coverage review CMS has on several occasions extended the public comment period. The Medicare statute now requires that the comment period for certain draft national coverage decisions be 30 days. However, we understand the agency has interpreted this 30-day requirement as applicable only to coverage reviews undertaken on or after January 1, 2004 (see www.cms.hhs.gov/coverage//8a4.asp). Because this particular review was undertaken in early 2003, we believe a comment-period extension is well within the agency's discretion.

CMS has extended deadlines for comments in earlier stages of this national coverage analysis, and we appreciate the agency's commitment to an open, deliberative process. In light of the administrative discretion CMS has in this area, and the significant new issues raised in the November 1 draft decision memo, we ask the agency provide a 90-day comment period.

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Dear CMS,

On behalf of Action to Cure Kidney Cancer (ACKC), I am writing in support of the CMS proposed policy to cover the costs, in clinical trials, of off-label uses for cancer drugs that are already approved for colorectal cancer treatment. But, in addition to supporting this policy, I strongly encourage CMS to expand its coverage to include off-label, investigator initiated trials using currently approved cancer drugs to combat kidney cancer.

Not only is kidney cancer the 10th leading cancer, it is also the third leading cancer in terms of increasing incidence. The only FDA-approved drug for kidney cancer, Proleukin, was approved over 12 years ago, and it has only a 5% complete response rate! Therefore, unlike many other cancers, kidney cancer has an increasing death rate as well.

All four drugs that you are approving have been tried in kidney cancer trials, with varying results. The most promising has been bevacizumab (Avastin), which was used in a trial at the NIH by James Yang, who reported that “bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer”. But bevacizumab is prohibitively expensive at over $100,000 per treatment making it unaffordable unless donated by Genentech or used in NIH-sponsored trials. In addition, although bevacizumab slows tumor growth, it could possibly have a greater impact when combined with other drugs.

Therefore, clinicians need to combine bevacizumab with other treatments into a “cocktail”, similar to the development of effective AIDS drugs, to be able to develop a significant life-extending response in metastatic kidney patients. The pharmaceutical companies are reluctant to compare their drugs against other company’s products and are even less inclined to use their treatments in conjunction with those of other companies. Therefore, CMS has to step in and support such studies if we are to see any progress in the treatment of metastatic kidney cancer and give hope to people stricken by the disease.

Finally, given the highly vascular nature of kidney cancer and its relation to the body’s immune system, the development of successful treatments for kidney cancer can have wider implications in the treatment of other cancers. In other words, if it works for kidney cancer it will have the potential to cure other cancers.

Therefore, if CMS wants to “develop better evidence to support the best possible treatment decisions” for cancer patients, as CMS Administrator Mark McClellan has stated, we urge you to support the expansion of this program to the treatment of metastatic kidney cancer.

Respectfully,

Jay Bitkower, President ACKC

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