Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications

I am supportive of the concept of an NCD for the use of Erythropoiesis Stimulating Agents (ESA) in cancer and related neoplastic conditions based on medical evidence and clinician experience. The proposed NCD should not be enacted because of the following reasons:

1. The conclusions supporting the proposed NCD are based on studies of patients treated in non- FDA approved indications and then extrapolated to cancer patients overall.

2. Inappropriate restrictions on ESA use that ignore a large body of scientific data and medical experience will have a severe negative impact on the treatment and quality of life (QOL) of cancer patients due to untreated anemia.

3. Blood transfusions are not an appropriate substitute for ESAs in the treatment of anemia in cancer patients. Additionally, the increased need for blood transfusions as a result of restrictions on ESAs would unnecessarily overwhelm the national blood supply, as well as put cancer patients at serious risk for medical complications avoidable with ESAs.

I call on CMS to carefully consider the serious ramifications of the proposed NCD. I urge CMS to substantially revise the proposed NCD so that it is based on sound scienfific data and analysis, and to make it reflective of the important on- label use of ESAs in enhancing the treatment and QOL of cancer patients. Thank you for the opportunity to comment. I am sure you will take steps to change the proposed decision memorandum.

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During my over 30 year oncology practice,the most gratifying and exciting times were the arrival of Tamoxiphen in the early years and the ESAs in the recent times.The latter resulted in much happier patients with clearly better QOL.I am a proud member of ASCO and support Dr.J.Bailes' comments wholeheartedly.The proposed decision for ESAs usage is very cruel and unthinkable. I for one do not understand this.If I have to consciously provide a lower level of care to the Medicare beneficiaries,most of them my friends over the years,I may as well quit practicing before I reach Medicare and get a different line of work that does not involve any logic or coscience!

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I am very disturbed at the proposed policy from CMS. These agents are very effective in patients with anemia due to chronic kidney disease, chemotherapy-induced anemia and myelodysplasia. They have reduced transfusion need, kept patients out of the hospital, and improved their quality of life. Without adequate access to these drugs (by lowering Hgb requirements to < 9), transfusion needs will increase. The blood supply in this country cannot handle this increase. If you eliminate use in patients with diseases like MDS, it will require far more toxic therapies. How is that helping patients deal with their cancer?

In summary, access to ESA's with the proposed 9 gram Hgb level is too low to help this population of patients. Lack of access for MDS patients and lack of access to ESA's beyond 12 weeks per year (almost no chemotherapy program is finished in this short a time period) and capping dose levels below even current "label" doses makes the proposed changes impossible for good patient care.

Michael Hensberry

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The recent media coverage regarding Erythropoiesis Stimulating Agents (ESAs) such as Aranesp, Procrit or Neupogen are extremely concerning. While I worry about the negative health effects supposedly related to overuse of these drugs, I am even more concerned that hasty decisions based on media coverage or studies that might not be applicable to specific conditions might impact patient access to these lifesaving therapies. Further, most people do not realize that before the advent of this modern medicine, the only alternative was risky blood transfusions.

We simply cannot rush to condemn these drugs, or the experienced doctors who prescribe them responsibly and effectively. I feel very strongly that without access to ESA treatment, many people would not have the energy to work and tend to family responsibilites in an efficient and positive manner. And they are not alone. There are many cancer survivors that benefit from this treatment that allows them to maintain a good quality of life and contributes to their state of health as they work toward healing and long term survivorship.

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The Centers for Medicare and Medicaid (CMS), has proposed potentially adverse and highly restrictive changes in reimbursement for erythropoiesis stimulating agents (ESAs), which include Procrit (epoetin alfa) and Aranesp (darbepoetin alfa) in cancer and related conditions. I believes that because the Food and Drug Administration (FDA), which has primary responsibility for determining how these agents should be used to maximize patient benefit, has not yet changed the existing labeling for these products, it is inappropriate for CMS to limit coverage prior to such action by FDA.

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Eliminating coverage of ESAs for management of anemia in the proposed conditions (including myelodysplasia) would be the single greatest mistake in the history of US medical coverage. To deny ESAs to patients who require these agents to maintain quality of life and to offset the need for blood transfusions would be simply absurd. The adverse health consequences, detriment in quality of life, and drainage of the blood blanks would lead to an unparalleled problem in the health care system.

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I am an academic medical oncologist with a specialized clinical and research interest in symptom management including fatigue and anemia. I have participated in a number of ESA clinical trials over the past decade.

The proposal described is nonsensical and appears to be solely driven by cost savings goals. This proposal ignores and, in some ways, misrepresents 10+ years of scientifically rigorous, peer-reviewed, published clinical trials in which the safety and efficacy of these agents in patients with chemotherapy induced anemia has been clearly demonstrated. There is simply no data to support the following proposed guidelines:
1) "Initiating ESA support when hemoglobin drops below 9." - Substantial data supports earlier use of these agents with resulting quality of life and transfusion reduction improvements. A variety of authoritative national guidelines have been published (i.e. ASCO, ASH, NCCN)and it boggles the mind to think that these carefully crafted, peer-reviewed, evidence based guidelines have simply been ignored!
2)"The maximum coverage would be 12 weeks per year." - This is capricious and arbitrary. It once again ignores and contradicts current evidence-based guidelines, clinical trial data and published practice pattern data.
3)"The maximum covered 4 week treatment dose is 126,000 units for erythropoietin and 630 Îg for darbepoietin" - Where in the world does this come from? Once again, 10+ years of clinical trial data and expert, evidence-based guidelines have been IGNORED. These agents have a dose response and level 1 data has been generated to support current dosing strategies which have been FDA approved.
4)"Continued use of the drug is not reasonable and necessary if there is evidence of poor drug response (hemoglobin/hematocrit rise < 1 g/dl/< 3%) after 4 weeks of treatment" - see above! Dose escalation after 4-6 weeks of therapy has been standard practice with published, peer-reviewed, clinical trials and evidence-based guidelines confirming this appropriate and necessary approach to dose modification at this early timepoint.
5)"Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin/hematocrit >1 g/dl/>3% after 2 weeks of treatment" - This is arbitrary and contrary to the same evidence base practice guidelines and clinical trial data described above.
6) "We also propose that ESA treatment is only reasonable and necessary under specified conditions for the treatment of anemia in those types of cancer in which the presence of erythropoietin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature" - This is nonsensical and irrelevant. The presence of Epo receptors on tumors has not conclusively been proven to be relevant to a given patient's response to ESA's or to their risk of harm from ESA's.

In summary, I believe it is dangerous and flawed to disregard a huge body of peer-reviewed data and guidelines which represents decades of effort to establish the safety and appropriate use of ESA's. I urge CMS to consult with the appropriate National Groups - ASCO, ASH, NCCN in the U.S. - in an effort to develop appropriate, evidence-based coverage decision-making which will not preclude appropriate patients from being effectively treated with a class of agents that has been shown to yield improvements in quality of life and decreased transfusion requirements.

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I have been an oncology nurse for several years and I know from experience that ESAs significantly improve quality of life for patients undergoing chemotherapy and those with MDS. I agree that hemoglobin levels should not be driven above 12 due to the increased risk associated with this but I also feel that the current proposed changes are too strict and will negatively impact my patient's quality of life. Also, by decreasing the use of ESAs in chemo patients and discontinuing the use of ESAs for MDS, there will be an increased need for blood transfusions. Blood is already in short supply and transfursions carry the risk of transfusion reactions and iron overload. Both of which can be detrimental to the patient's health but also can be quite costly to treat and manage. I strongly suggest that prior to implementing any of the proposed changes that these factors be taken into strong consideration.

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On behalf of patients with rare bone marrow failure diseases, the Aplastic Anemia & MDS International Foundation (AA&MDSIF) is submitting comments to CMS on its Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N). The AA&MDSIF, a non-profit organization with a volunteer Medical Advisory Board comprised of prominent experts in the field, is extremely concerned that CMS has proposed eliminating coverage of ESAs for the anemia of myelodysplasia or of myelodysplastic syndromes (MDS).

We should first state that the AA&MDSIF has no financial incentives to support or to oppose the CMS recommendations in the proposed decision memo; our only incentives are the interests of patients. We also recognize that ESAs are not appropriate for all patients and not all patients with bone marrow failure respond to ESAs. Still, many patients with bone marrow failure benefit from ESAs. If there were evidence that these growth factors were generally inappropriate for MDS patients, the Foundation would actively and promptly inform our patients of the change in the scientific consensus. However, CMS has not provided the rationale necessary to refute this consensus.

As we noted in our comments dated April 13, 2007 on the CMS National Coverage Analysis (NCA) on the administration of erythropoiesis-stimulating agents for non-renal disease applications, ESAs promote red blood cell growth and are used to treat anemia in MDS patients. The most common signs and symptoms associated with MDS are related to anemia, and this practice is considered "accepted" (as opposed to "acceptance not established" or "unaccepted") in the USP-DI. Four published articles, two of which are surprisingly not listed in the CMS bibliography, support the use of ESAs in MDS. ^1,2 Because of this listing in the USP-DI, Medicare covers this off-label use for MDS.

In addition to the research cited in the USP-DI, several other published studies the use of ESAs for MDS patients. In fact, we submitted in our initial comments four such articles and meeting presentations. The MDS Foundation, another non-profit organization, submitted the three of the four same citations as well as three others for a total of six. We were dismayed to see none of those seven citations included in the bibliography to the proposed decision memo, yet according to the CMS website, 'CMS considers all public comments, and is particularly interested in clinical studies and other scientific information relevant to the technology under (consideration)..' We can only surmise that our comments were disregarded and not properly deliberated and hope that CMS will take a careful look at them at this point in the process. The paragraph with the four citations is repeated below:

In fact, there have been some studies of ESAs in bone marrow failure patients that do not demonstrate a negative impact. Studies assessing the long term use of Epo (with or without granulocyte colony-stimulating factors) in MDS patients compared to either randomized controls ³ or historical controls ^4,5 have shown no negative impact on survival or on evolution to acute myelogenous leukemia (AML) with such treatment. In addition, the 2006 Jadersten et al study indicates improved survival in low-risk MDS patients with low transfusion need who have been treated with these agents. An even more recent article ⁶ provides more evidence for improved survival in low-risk MDS patients. We are unaware of any data that would contraindicate the use of ESAs in responsive BMF individuals. The risk-benefit analysis of ESAs in MDS patients strongly favors their beneficial effect of minimizing blood transfusions in this highly compromised population, as a greater number of blood transfusions and resultant higher iron overload burden correlates with diminished survival in MDS patients.

In addition, we are surprised and disappointed that CMS issued the memo a mere two business days after the hearing of the Oncologic Drugs Advisory Committee (ODAC), part of the Food and Drug Administration (FDA). We believe that CMS should have waited for the panel of hematology and cancer experts (who had hundreds of pages of data plus a day of testimony to review) to weigh in on the matter. Incidentally, the ODAC meeting is not even mentioned in Section V 'FDA Status,,' although other FDA action is listed, including the black box warning which is clearly irrelevant to MDS.

As explained in our April comments, the studies that led to the FDAA's black box warning do not appear to have included any patients with bone marrow failure (such as MDS) but only patients who had end-stage solid cancers and/or renal disease. Moreover, in those studies, the patientss' hemoglobin levels typically were kept above 12 g/dl while bone marrow failure patients rarely reach a hemoglobin level that high even with the addition of growth factors. Thus findings from these studies cannot be said to apply to patients with MDS. In general, MDS patients do not share the same risks as patients who were part of the ESA studies on adverse events and have not experienced the same adverse events. Physicians of course still must monitor hemoglobin levels in bone marrow failure patients receiving ESAs, especially those with renal and/or heart disease, to ascertain that their levels do not rise above 12 g/dl.

We find that, in the proposed decision memo, CMS has made no scientific case for eliminating coverage of ESAs for MDS. In fact, CMS does not include in its proposed decision memo much background about the use of ESAs in MDS. A search of the memo for 'myelodysplastic,,' 'myelodysplasia,,' and 'MDSS' reveals that these terms are only rarely used. The term 'myelodysplasiaa' is used only in listing 'the anemia of myelodysplasiaa' as a condition to be no longer covered. The terms 'myelodysplasticc' and 'MDSS' are used only in one sentence in the entire text of the decision memo: 'There has even been a report of the conversion of myelodysplastic syndrome (MDS) to leukemia attributed to erythropoietinn's angiogenic effects on the bone marrow (Bunworasate 2001, Ribatti 2002)..' (from Section VIII 'CMS Analysiss') Hence there are only two citations noted in the body of the text of the proposed decision memo that relate to MDS, and neither is a study: Bunworasate 2001 is just a case report and Ribatti 2002 is a letter to the editor in response to the case report.

Even if the case report of an MDS patient who progressed to acute monoblastic leukemia (AML) had definitely been caused by an ESA and not a natural progression of the MDS, the AML was reversed and not a cause of death. Moreover, it is only one case report published in 2001 and one letter published in 2002, with no similar publications since. (It is well known among clinicians that the blood counts of all patients on ESAs should be monitored to prevent adverse events.) If this progression were seen more often clinically, there would certainly be more case reports and possibly even studies on the development. Instead, there is a significant body of evidence to support using ESAs for MDS. In one 2007 article alone, the authors found 87 articles of more than 1500 MDS patients treated with ESAs for whom treatment and outcome were known. ⁶ All of the guidelines cited in Section VII.B.5. 'Evidence Based Guidelines/Professional Society Position Published Statementss' support the use of ESAs for MDS or are silent on the matter; none opposes the use.

We are further concerned about the citations that CMS did include in its bibliography: they do not justify removing coverage of ESAs for MDS and in fact support the use of ESAs for MDS. For example, one randomized double-blind placebo-controlled study listed in the bibliography actually showed a significantly higher erythroid response in the ESA arm for refractory anemia patients and for non-transfused patients: 'In conclusion, rHuEpo was effective in the treatment of low-risk MDS. RA subtype, no transfusions prior to rHuEpo therapy, and low basal Epo levels were associated with higher probability of response. Soluble transferrin receptor level at the fourth week was an early predictor of response..' ⁷ Another study on an ESA included in the bibliography found that '(r)esponses to therapy were durable and generally occurred at r-HuEpo doses of 150-200 U/kg t.i.w. There were no reports of thrombosis, seizures or therapy-related hypertension. The data show that patients with MDS, especially those with the RA and RARS subtypes, can benefit from treatment with r-HuEpo..' ⁸ We cannot find in any of the studies listed in the bibliography a conclusion that warrants not covering ESAs for MDS.

With the exception of one sentence, in the proposed decision memo, the text to justify not covering ESAs for MDS does not even pertain to MDS. The diagnosis of MDS does not involve tumors, or vascular disease that can increase onee's risk for blood clots and strokes. MDS, cancer, and kidney disease are very different diseases, as the FDA and its ODAC recognize. In fact, Richard Pazdur, MD, Director of the FDAA's Office of Oncology Drug Products, firmly noted so in the May 10 hearing and promised a committee member that the FDA would work with CMS so that MDS patients did not lose coverage for ESAs because of the black box warning for kidney and cancer patients.

We agree with Dr. Pazdur. ESAs are a crucial part of treatment options for bone marrow failure patients. There are no alternatives to ESAs other than blood transfusions, yet blood transfusions are not a solution for this patient population. In addition to the issue of blood-supply shortages, MDS patients need irradiated platelets. Irradiated platelets can be difficult to obtain, and this need both complicates the process and increases the expense. Further, bone marrow failure patients who get transfusions typically have a chronic need for them (something not seen in cancer and chemotherapy patients). This chronic need for transfusions puts MDS patients at great risk for iron overload which is difficult alone for these patients but is especially problematic with the newly revised FDA warning on Exjade http://www.fda.gov/medwatch/safety/2007/safety07.htm#Exjade, a medication used to treat iron overload. This warning is relevant to MDS patients, so treating physicians will have to be particularly careful in devising a treatment regimen for MDS patients.

The significant expense of treating iron overload should also be calculated in the cost of a transfusion v. the cost of an ESA if CMS is considering cost factors in making its coverage recommendations. (CMS states in Section VIII 'CMS Analysiss' that 'with limited exceptions, the expenses incurred for items or services must be 'reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body memberr' ((Â 1862(a)(1)(A))..') CMS should also bear in mind that treatment options for MDS are limited and that most non-growth-factor medications for MDS work only 20-30% of the time and carry significant side effects. ^6,9 Moreover, patients who take non-growth-factor medications may need ESAs in conjunction with those drugs.

Finally, the AA&MDSIF is concerned about the limitations for patients undergoing treatment for certain named cancers in the proposed decision memo. While MDS is not listed as one of the cancers affected (not surprisingly as MDS does not meet a definition of cancer used by the National Institutes of Health), we would object to two of those limitations being applied to MDS patients: 1.) 'the maximum covered treatment duration is 12 weeks/yearr' and 2.), 'continued use of the drug is not reasonable and necessary if there is evidence of poor drug response (hemoglobin/hematocrit rise <1 g/dl/<3%) after 4 weeks of treatment..' The first limitation is unfair to MDS patients who may need weekly transfusions. The second limitation should be modified to allow for eight weeks of treatment before determining that the patient is not responding.

CMS states in Section I of the proposed decision memo that it is specifically seeking comments on whether or not 'there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions includee'the anemia of myelodysplasiaa'..' CMS clearly has not presented sufficient evidence to show that ESAs are not reasonable and necessary for patients with MDS: one case report on a reversed adverse event and a letter to the editor on the case report do not demonstrate that ESAs have 'a deleterious effectt'on their underlying diseasee' or that MDS 'increases their risk of adverse effects related to ESA use..' Until there is sufficient evidence to show that ESAs harm MDS patients, the AA&MDSIF believes that Medicare coverage policy on ESAs for MDS should remain the same so as to not alter access to this effective treatment for MDS patients.

Thank you very much for taking the time to review our comments. If we can provide any additional information or answer any questions, please do not hesitate to contact us. We would be pleased to help CMS formulate an appropriate, science-based coverage policy.

Sincerely,

Richard Stone, MD
Chairperson, AA&MDSIF Medical Advisory Board
Clinical Director, Adult Leukemia Program
Dana-Farber Cancer Institute
Associate Professor of Medicine, Harvard Medical
School

Mikkael Sekeres, MD, MS
Co-Chairperson, AA&MDSIF Medical Advisory Board
Department of Hematologic Oncology and Blood
Disorders
Cleveland Clinic
Assistant Professor of Medicine, Cleveland Clinic
Lerner College of Medicine of Case Western
Reserve University

1 Depaoli L, Levis A, Isabella N, Ficara F, Priotto C, Lista P, Fooà R, Resegotti L. Serum erythropoietin level and marrow erythroid infiltration predict response to recombinant human erythropoietin in myelodysplastic syndromes. Haematologica. 1993;Mar-Apr;78(2):118-22.

2 Stasi R, Brunetti M, Bussa S, Conforti M, Di Giulio C, Crescenzi A, Terzoli E, Vecchione A, Pagano A. Response to recombinant human erythropoietin in patients with myelodysplastic syndromes. Clin Cancer Res. 1997;May;3(5):733-9.

3 Miller KB, Kim HT, Greenberg P, van der Jagt R, Bennett JM, Tallman MS, Paietta E, Dewald G, Houston JG, Thomas M, Rowe J. Leukemia Committee, Eastern Cooperative Oncology Group, Brookline MA,; Leukemia Committee, Canadian Leukemia Study Group, Ottawa ON. Phase III Prospective Randomized Trial of EPO with or without G-CSF Versus Supportive Therapy Alone in the Treatment of Myelodysplastic Syndromes (MDS): Results of the ECOG- CLSG Trial (E1996), Proc Am Soc Hematology meeting, Blood 104 (11): 24a, 2004.

4 Jadersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellstrom-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood 106(3): 803-11, 2005.

5 Jadersten M, Malcovati L, Dybedal I, Della Porta MG, Invernizzi R, Montgomery SM, Pascutto C, Porwit-MacDonald A, Cazzola M, Hellstrom-Lindberg E. Treatment with Epo and GCSF improves survival in MDS patients with low transfusion need. Proc Am Soc Hematology meeting, Blood 108 (11): 158a, 2006.

6 Golshayan A, Jin T, Maciejewski J, Fu AZ, Bershadsky B, Kattan MW, Kalaycio ME, Sekeres MA. Efficacy of growth factors compared to other therapies for low-risk myelodysplastic syndromes, Br J of Haematology 137: 125-132, 2007.

7 Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol 103:1070-4, 1998.

8 Rose EH, Abels RI, Nelson RA, McCullough DM, Lessin L. The use of r-HuEpo in the treatment of anaemia related to myelodysplasia (MDS). Br J Haematol. 1995 Apr;89(4):831-7.

9 Sekeres MA, Fu AZ, Maciejewski JP, Golshayan A, Kalaycio ME, Kattan MW. A decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes. Cancer. 109(6):1125-1132.

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As medical director of Regional Consultants in Hematology and Oncology I find it deplorable the decision made by CMS,

We would like to express the significant concerns voiced by our MDS patients and their families (mostly Medicare beneficiaries), to the recent proposed decision memorandum regarding coverage of erythropoiesis stimulating agents (ESAs) in non-renal disease indications. We strongly believe that there is no scientific evidence to rescind the coverage of ESAs in anemia of myelodysplasia. The use of these agents in the context of MDS is well established in practice and supported by a long list of scientific data that have established not only their efficacy but as well as their safety for this clonal hematologic disorder. It is also recommended in the joint guidelines of the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO). Based on all the above, we believe that there is no medical evidence to support such restrictions and that such decision is not in the best interest of these patients. We strongly request a review of your proposed decision memorandum.

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Having reviewed this proposed policy, if passed, would be an injustice to patients. This appears to be a step backwards in treating chemotherapy induced anemia and MDS. Many risks are involved with sending patients to the hospital for blood transfusion which will most likely happen if this is passed. Time is valuable and spending time in the hospital is not usually a patients first choice of things to do. The Quality of Life in patients that are now getting the ESAs and doing well will probably decline. Please reconsider this proposal.

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AS a practicing hematologist/oncologist, my experience shows that the use of ESAs clearly improves quality of life in patients undergoing chemotherapy. Initiation of ESAs<11 allows less opportunity for symptomatic moderate to severe anemia to develop and reduces transfusions which have their own attendant risks.This is particularly true in the elderly, the group at risk for cancer. Careful monitoring reduces the risks of ESA use I believe the current CMS proposal is not consistent with current evidence and may cause harm for my patients.

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In my practice I have always adhered to starting ESA's when strictly appropriate and holding dose when appropriate. If these agents are not available for patients, they will clearly suffer from the risks associated with blood transfusions, i.e. transfusion reactions, iron overload, exposure to viral risk. This will also strain the nation's blood supply by giving transfusions when simplier measure would work better. In the long run the cost might be more, certainly the health cost/risk will be more to the patient.

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I have come to realize that CMS does not want cancer patients and patients who have MDS treated. It seems that CMS doesn't have the fortitude to tell the public this. CMS wants the oncologists to tell the public this news. With drug cuts and now ESAs, it is very clear.

If CMS is as tough as it thinks it is , there needs to be an announcement."We, at CMS want the public to know that if you have cancer, or MDS, we want you to go ahead and die. You are taking up too much of the public money. We have healthy people who need drugs, not you. We do not care if it is our mother or sister. We do not care if it is our father or son. We want you dead."

And sign it " your government at work"

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I completely disagree with current recommendations regarding the label change for ESAs. Some patients with MDS are solely treated with supportive care such as ESAs. Patients receive more than 3 months a year of chemo and should not have the amount or duration of ESAs limited. If this does take effect it will result in more transfusions with associated risk, cost, and inconvenience for patients in addition to a poorer and impaired quality of life for our patients. Julie Plantamura RN, MSN, FNPc

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Obviously you have not researched or considered the long term effects of denying people the aranesp/epogen medications that have been helping people cope with anemia. The alternative is to have blood transfusions, which is great since there is no shortage of blood, and the hospitals all have extra time and personnel to handle the increased flow of people. Disregard the fact that many of these people cannot sit or endure the lengthy periods of time it takes to infuse blood or the dangers of giving blood. I hope you noticed I used People and not patients.

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As an oncologist/hematologist I have witnessed patients (dx: MDS, chronic renal disease without dialysis, previous treatment for cancer now in partial remissions, etc.) that have low endogenous erythropoietin levels and who have responded to Procrit (The ESA that I have the most experience with). They no longer needed transfusions in the past several years. Those same individuals, still living, are now requiring transfusions, since the March '07 change in policy by CMS. Some who do not meet transfusion levels, are simply not able to do their enjoyable activities of life, such as playing with grandchildren. The option of maintaining a Hg. level of approximately 12 grams had given these individuals a new quality of life which has subsequently been withdrawn by CMS with the 3/07 ruling. The 12 gm Hg. limit was effective for nearly all individuals in symptom relief and apparently was not associated with the problems of the modified (late 2006) Hg. 13.5 gm. level. For more detailed references please refer to the detailed papers filed by ASCO and ASH. Thank you for the opportunity to submmit this comment.

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to restrict pt's with anemia's from recieving ESA's is insane. medicare already limits and restricts in some cases coverage for b12 injections for pt, that probably wouldn't have an issue with slef injecting if they weren't already ill, and not all family members have the capacity to learn how to do this. this frustrates patients and families, and causes them less likely to ask for help getting to a doctors appt. "for lab work, follow-ups, etc" they feel they are being burdens. so they fall further into the spiraling anemia pit.Then the pts, that require chemotherapy, that will compound the anemia's, combined with the issues with the Vitamin B12 defiencienies, whether from diet, absorption or financial reasons. To further compound their healthcare coverage or limit what is accessible is just putting more nails in their coffin. their labs continue to decline, they have to have blood transfusions which opens a whole host of other complications for pt already in such poor health they have to defense against the possible infections, the possible side effects associated with blood transfusions. And the worst part is this could all be prevented with injection most of the time. Its difficult for me as a 22 year nurse to believe this is cuts that are even being considered. Don't tie the doctors hands more than you already have, they and the patients already have to fight for everything they get now, please don't add insult to injury.

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For nearly 15 years, ESAs have been employed by physicians to reduce the burden of red blood cell transfusions in patients receiving myelosuppressive chemotherapy. ESA treatment has reduces by half the number of transfusions in such patients and extends the time to first transfusion. In addition, ESA treatment helps alleviate the signs and symptoms of anemia, which provoke physicians to transfuse red blood cells, this informatin has been documented in several clinical studies. Without ESA therapy, many MDS patients will have to undergo a greater number of blood transfusions and resultant higher iron overload burdens correlates with diminished survival in MDS patients. Also clinic practice guidelines published by American Society of Clinical Oncology and the National Comprehensive Caner Network also support certain uses of ESA s, especially those with renal and/or heart disease, to ascertain that thier levels do not rise above 12g/dl. We oppose the rigid non covered indications for either agent and believe treatment should be dedtermined by the physician and patient, given the patient's clinical status and regular treatment regimen. Thank you for this opportunity to provide input on this important topic.

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This is a very troubling proposal indeed. The levels of ESA are not sufficient to help cancer patients. Indeed, the lower level proposed means unecessary transfusions (at greater expense to everyone). Clinical trials suggest that the "stopping rule" at 4 weeks is folly if, as the data indicate, a longer period of drug administration is necessary for efficacy. Finally, there should not be a 12 week limit as cancer patients often require more than this.It is wrong to exclude patients receiving VEGT and ERGF inhibitors since no clinical data supports this and this would prevent a large number of patients in need from receiving treatment. The same goes for multiple myeloma patients who would suffer tremendously from the repeated transfusions that this limitation would impose. Any cancer patients, indeed, anyone who will greatly benefit from ESAs should receive them in a dose that coincides with the most recent clinical indications.

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As a practicing medical oncologist/hematologist for 26 years in both academic and community practice, I am deeply concerned about the proposed CMS changes to the coverage of ESAs in non-renal disease indications. I believe that these changes are premature, are not based on the wealth of scientific data and will significantly impact on the quality of life of my patients.Having practiced prior to the era of ESAs, I am well aware of the symptoms associated with the anemia of cancer and cancer chemotherapy, the inadequacy of transfusions and the compromise of the nation's blood supply, if these proposals are enacted.

I am a member of both ASCO and ASH and have read the compelling comments of both organizations, but I would like to emphasize my perspective with the following points.

• The proposed coverage for CIA is not consistent with any scientific evidence for an initiation point of less than 9g/dl. Studies have shown that symptoms develop at hemoglobin levels below 11g and the maximal benefit is seen at a hemoglobin of 12g/dl. There is a black box warning concerning the risk of attaining a Hgb>12g and our practice strictly follows the current guidelines to prevent complications associated with levels in excess of 12g/dl. I am very concerned that if we must wait for a Hgb < 9 to institute ESAs we will be forced to begin transfusions in order to alleviate symptoms which will put an undue burden on our blood supply.
• The proposed treatment of 12 weeks/yr is inadequate, not based on scientific evidence.
• CMS has ignored scientific evidence of the benefit of ESAs in myelodysplasia and multiple myeloma.
• Targeted biologic agents are often used in conjunction with chemotherapy and the proposal would not even allow us to use ESAs if we are treating patients with both chemotherapy and targeted biologic therapy.

I urge CMS to review the recommendations made by ASCO, ASH, US Oncology and COA and allow the FDA to make its recommendations which will be based on a thorough scientific review and will hopefully take into consideration the wealth of experience with ESAs which have done so much to improve the quality of my patients' lives.

Thank you for your consideration.
Steven W. Papish, MD FAC
PMedical Director
Carol G. Simon Cancer Center
Morristown, NJ

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I am a hematologist/oncologist in Fresh Meadows Queens. I have been a hematologist for 40 years. I always follow the guidelines outlined by my societies and the FDA and I am deeply troubled by your proposed distortion of those guidelines. I believe you are an insurance company and should cover treatments deemed appropriate by expert panels, not based on your own conclusions. I agree with some of your proposals but three in particular are troubling. One is the limitation of treatment for people on chemotherapy to 12 doses/year. Since our treatments may be given for many months and cause persistent anemia, the twelve treatment limitation is grossly inadequate. The proposal that treatment not be used until the hgb is under nine is unreasonable. Many of our patients have comorbid conditions and their quality of life is impaired with such low hgbs. A level of 10 should be the absolute minimum and a level of 11 in some patients makes better sense. In our area, Oxford allows the start of erythropoietin injections for hgbs under 10 and then allows continuation to a level of 12. Finally, if a patient has mild myelodysplasia and minimally elevated erythropoietin levels, erythropooietin injections have been well documented to delay or eliminate the need for transfusions with their risks especially of iron overload and also in my experience improve the quality of these patients' lives.

I hope you will reconsider carefully your whole proposal but especially these three items.

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I have practiced hematology and oncology for 30 years,and the growth factors have been one of the breakthroughs in patient care during the last 15 years. The loss of erythropoeitin-type drugs will be a loss for patients with MDS, where it is used as a first line agent and has kept many patients from being exposed to the risks of blood transfusion and transfusion related hemochromatosis, and for many patients who experience long-term anemia due to radiation and chemotherapy long after completing these treatments. These patients are often incapacitated with terrible quality of life with their anemias. You are doing areal disservice to them be preventing this form of treatment. The Amgen 145 study just released has shown no additional incidence of thrombosis when used in lung cancer patients in their series. With proper follow-up and appropriate use and monitoring, these drugs may provide more benefit than risk and their loss or rationing is a terrible loss to the Heme/Onc armamentarium of treatment.

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For nearly 15 years, ESAs have been employed by physicians to reduce the burden of red blood cell transfusions in patients receiving myelosuppressive chemotherapy.

ESA treatment has reduces by half the number of transfusions in such patients and extends the time to first transfusion. In addition, ESA treatment helps alleviate the signs and symptoms of anemia, which provoke physicians to transfuse red blood cells, this information has been documented in several clinical studies. Without ESA therapy, many MDS patients will have to undergo a greater number of blood transfusions and resultant higher iron overload burden correlates with diminished survival in MDS patients.

Also clinical practice guidelines published by American Society of Clinical Oncology and the National Comprehensive Cancer Network also support certain uses of ESAs for treatment of myelodysplasia in select patients. Physicians of course still must monitor hemoglobin levels in bone marrow failure patients receiving ESAs, especially those with renal and/or heart disease, to ascertain that their levels do not rise above 12 g/dl.

We oppose the rigid non covered indications for either agent and believe treatment should be determined by the physician and patient, given the patient's clinical status and regular treatment regimen.

Thank you for this opportunity to provide input on this important topic.

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I am greatly concerned regarding excessive cuts in ESA indications. Many of our patient's quality of life is dependent on continued to these drugs.

Thrombosis risks are seen in other classes of drugs such as estrogens and BCP's. These thrombotic events are idiosyncratic and are contraindicated with a history of DVT, PE, or arterial thrombosis.

Without expanded access to ESA we will be more dependent on blood products and stress the already limited blood supply. Repeated blood transfusion is also full of risk such as infusion reactions, viral exposure, and iron overload. I have patients who have received over 100 tranfused units of blood, because they have not responded to ESA.

Without reliable access to these drugs patients may feel the need to buy these drugs on the black market or go to Mexico, for drugs or treatment.

The ESA codes for myeloma do not allow cite chemotherapy induced anemia. We have given this drug using the unspecified anemia with secondary code for myeloma. This will ned an update if propsosed policy is followed.

We are all expecting reductions in therapeutic goals and starting points for this class of drugs, but elimainating the ESA codes for whole disease syndromes seems to be more a fiscal decision rather than considering the individual patients. A decision from "above" that limits each patient's choices and provider options.

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Coverage for treatment of anemia due to chemotherapy is too restricted in this proposal. Most patients have symptoms by a Hgb of 9, and will remain symptomatic for some time if therapy is delayed until this point.

Under these guidelines, a patient who has received epo for 12 weeks in a year, but remains symptomatically anemic on chemotherapy would have two options: 1) receive transfusion (at significant cost and use of hospital resources and blood products) or 2) discontinue treatment of malignancy until anemia improves.

Epo agents should be covered for treatment of MDS and myeloma, among other "anemia of malignancy" diagnoses. The appropriate use of epo medication helps many patients with these diseases, and epo should not be resticted to those patients who are receiving chemo.

The proposed changes would adversely affect patient care. Please review the memo and make appropriate modifications. Thank you.

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I work in the outpatient chemotherapy setting of a hospital and would like to have someone know that some patients are unable to tolerate multiple transfusions r/t congestive heart failure and other comorbidities and ESAs allow the patient to avoid multiple transfusions and ESAs also avoid treatment delays r/t anemia which ultimately can affect the overall survival of many cancer patients...Please consider this when deciding an option... I know the drugs are expensive, but what's best for the patient SHOULD be our priority.

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To Whom it May Concern: As a senior manager with Rocky Mountain Cancer Centers who treats upwards of 30,000 cancer patients per year, I am strongly oppose to the recent actions taken by CMS regarding Erythropoetin Stimulating Agents (ESAs). Specifically, while supportive of the concept of an NCD, the primary concerns of Rocky Mountain Cancer Center physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States; and,

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Thank you for your attention to this matter and ensuring that cancer patients continue to receive the services they require that are clinically appropriate and evidenced based.

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I write out of concern regarding the proposed NCD restricting the use of ESA's, particularly in the setting of myelodysplastic syndromes. I have several patients in my practice with MDS, who have demonstrated clinical benefit as a result of ESA's. This benefit is most apparent in the ability to avoid or defer blood product transfusions, as well as their associated risks and inconveniences.

As noted in previously published reports, ESA's have been demonstrated to benenfit MDS patients. ESA's are included in the NCCN Clinical Practice Guidelines in the management of MDS.

I believe that the proposed NCD will have the effect of increasing transfusion requirements for many of my patients, therefore increasing the problems and risks associated with transfusions. It will place further burden on blood banks and the already tenuous supply of donor blood.

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Your proposal to limit the use of ESAs is not only out of the realm of your jurisdiction, but is also potentially harmful to patients. The decision as to how best to treat anemia in any patient is best left to the physician and the patient and should never be in the hands of any health insurance agency, and particularly not one which is under the jurisdiction of the federal government. Options for anemia management should include ESAs as well as transfusion, and not be limited simply by what the underlying cause might be.

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I am writing to address the proposed coverage policy for the use of ESA's. I am a clinic manager for a large oncology practice and I believe that the proposed changes in the coverage policy for the use of ESA's is not in the best interests of our patients'. I am convinced that these changes would do more harm than good. From reading the proposed changes I feel that if anything should be done at this time it is more research. Our patients' are waging the greatest battle of their lives which is the fignt to stay alive, and at the same time still trying to be husbands, wives, mothers, fathers, grandmothers, grandfathers, friends, bosses, and employees. If you change these guidelines you will in essesnce rob a great number of people in our country of the ability to continue to fulfill these roles. By limiting access to ESA's our patients' will not be able to sustain blood counts high enough to continue their chemotherapy. As a result they will have to stop treatment or reduce their treatment dose which will greatly affect whether their treatment is successful. Without access to ESA's our patients' will require more blood transfusions putting a greater strain on our nations blood supply and a hospital system that currently does not have enough nurses to meet the demand for hospital beds. However, most importantly is the negative impact this will have on our patients' lives and the quality of the time they have left. There is no price you can put on life and time once it is gone you can never get it back. I hope that you seriously consider all of these issues before you make your decision. Theresa Zarnowski

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Kindly consider the following thoughts on the proposed National Coverage Decision for the use of ESAs.

As an oncologist in practice since 1978, I have witnessed the significant improvement in the quality of life in cancer patients,much of it owing to the availability of erythrocyte and granulocyte growth factors.

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It is entirely appropriate that in general circumstances ESAs use in anemia in due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, not be covered. Patients who can not or will not receive blood such as those with severe alloimmunization or Jehovah WItnesses may be exceptions. Based upon clinical data use in anemia associated with radiotherapy, prophylactic use of ESAs to prevent chemotherapy-induced anemia and to reduce tumor hypoxia is also not appropriate.

However, ESAs in cancer induced anemia should not be restricted to use until patients develop Hgb of 9, nor be limited to 12 weeks/year as this is not in keeping with clinical data. There is also a excellent support for the use in MDS and myeloma. In fact the propsed PQRI monitors the use of ESAs in MDS as a measure of good performance. How can it be therefore that CMS would not cover it?

The FDA should cover ESAs in oncology patient consistent with the guidelines and in the doses noted in the NCCN guidelines and the ASCO guidelines.

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Comments on CMS draft NCD: NCA Tracking Sheet for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N)

Dear CMS:

I am community medical oncologist, practicing with a 20 physician medical oncology group in Marietta, Georgia, as well as the part-time Medical Director of Oncology for a large, 5-County, 5-Hospital Health Care System in the Northwest Atlanta Metropolitan area, each treating more than 2,500 new cancer patients annually. I would like to comment on the above captioned National Coverage Analysis (NCA), and the proposed National Coverage Determination (Draft NCD) for Erythropoiesis Stimulating Agents (ESA's) used to support cancer patients.

Regarding coverage of ESA's, a NCD is welcome as an alternative to the patchwork quilt of Local Coverage Determinations (LCD's) currently in existence. The development of an appropriate NCD will allow Medicare beneficiaries consistent access to appropriate therapy for treatment of anemia treated with these agents. An appropriate NCD should provide comprehensive coverage guidelines for the use of these agents. Unfortunately, the current Draft NCD fails to provide appropriate guidance due to several major flaws in its development. I have outlined these flaws below:

1. Inappropriate Evidence Base: A National Coverage Decision should be based on published, peer-reviewed, relevant clinical literature. The draft NCD goes well beyond established clinical literature, and introduces speculative basic research which would be considered hypothesis-generating for clinical trials. As an example, the proposed restrictions applied to patients with tumors expressing Erythropoiten Receptors has no established clinical evidence base. To include restrictions/ exclusions based upon untested hypotheses would undermine the entire NCD and LCD process, which relies upon established clinical literature. Indeed, it is such speculative use of therapies, based upon pre-clinical hypotheses, that a NCD seeks to control. Throughout the draft document, un-published, anecdotal, and lay press sources of information and in-vitro test reports are cited, which may, or may not be, relevant to the clinical use of ESA's. Examples of restrictions based upon inadequate or inappropriate evidence base include:

2. Miss-application of Evidence Base: Where clinical literature does exist, the NCD has miss-applied the findings to create an unusually restrictive interpretation of the data. Clinical literature, based upon carefully designed clinical trials, simply cannot cover every clinical situation where the intervention may be appropriate. Some trials, however, may provide 'proof-of-principle', providing data that can be generalized within the sphere of that principle. Additional trials may refine the principle or refute the principle, but lack of data do not refute the principle. In the Draft NCD, the limitations proposed on covered use of ESA's in certain cancer patients are unduly restrictive in their interpretation based on available product labeling, Compendia, and relevant clinical literature. Examples of miss-application include:

3. Substitution of Policy for Medical Decision Making: The Draft NCD goes far beyond the usual limits of defining acceptable use of therapies for an established medical diagnosis or condition. The limits proposed for ESA therapy initiation, choice of dose and interval, monitoring, dose change, length of therapy, and discontinuation go far beyond product labeling, medical literature, and published evidence-based guidelines. Completely ignored is true guideline-based medical decision making where the total of laboratory values, patient clinical parameters, and underlying risk factors are analyzed by the clinician to make appropriate therapy decisions. A NCD should encourage appropriate medical decision making, not simply provide cookie-cutter restrictions that may be appropriate in some circumstances, and not in others. The proposed restrictions would allow ESA use in some circumstances where appropriate medical decision making would utilize another approach (such as further observation), yet deny coverage in other circumstances where the beneficiary would truly benefit from therapy.

4. Failure to Consider Unintended Consequences: The Draft NCD completely ignores the potential unintended consequences of the NCD. In the years since ESA's have been introduced to the treatment of CIA, the delivery system for cancer treatment has been radically altered. Many more patients receive myelosuppressive chemotherapy than a decade ago, and the use of transfusion has been reduced in these patients. The current medical delivery system may be unable rapidly adjust to an increased demand for transfusion services, which may result in Medicare beneficiaries suffering from severe anemia related symptoms, or worse, be denied access to effective anti-cancer care due to the inability to effectively support the adverse effects on red blood cell production. WellStar Health System is already having difficulty in providing timely outpatient transfusion services for Medicare beneficiaries, and is currently not prepared to provide transfusion services to additional bemeficiaries as a result of the Draft NCD. Although the concerns regarding the safety of ESA's merit further investigation, any proposed policy should consider the safety and effectiveness implications of alternative therapy that may result from an unduly restrictive NCD.

5. Lack of comprehensiveness: ESA's are billed as 'J' Codes in the HCPCS coding system. Any NCD addressing the coverage of a particular 'J' code should comprehensively address all covered uses of the product billed under the specific 'J' code. CMS has specifically omitted uses in patients with renal insufficiency as well as uses in a vague group of cancer patients not covered by the Draft NCD. Medicare beneficiaries and providers are thus subject to a bewildering array of local and national coverage guidelines. Potential discrepancies may lead to inconsistent coverage for beneficiaries for the same product/ treatment from state-to-state, resulting in patient liability for payment due to re-location or travel. Providers are also likely to be held accountable for a confusing array of national and local coverage determinations, inconsistent with accepted national guidelines.

6. Comment regarding restriction of coverage to selected clinical trials: While additional clinical trials should be encouraged, even supported, by CMS, coverage of an FDA-approved drug should not be dependent upon clinical trials participation, especially when administered in a manner consistent with product labeling. Requiring clinical trials participation as a determinant of coverage for an approved product would be in direct conflict with the ethical underpinnings of the conduct of clinical trials: Voluntary informed consent. The financial implications of patients not participating in such trials would be an unethical inducement to participate in the trials simply to obtain coverage. Hence, participation would not be voluntary.

In summary, the proposed NCD does not follow accepted procedure or evidence base for coverage decisions: Federal Drug Administration approved product labeling, Compendium listing, and peer-reviewed clinical literature. The proposal is inappropriately restrictive, and does not consider the unintended consequences which may be suffered by Medicare Beneficiaries. The agency should completely re-evaluate the development of the proposed NCD to reflect established medical literature and guidelines, such as those of the American Society of Clinical Oncology, American Society of Hematology, and the National Comprehensive Cancer Network. Emerging safety concerns regarding the use of these agents will undoubtedly influence product labeling and guidelines in the future, and medical care will reflect these changes.

Respectfully Submitted,
Robert C. Hermann, MD
Northwest Georgia Oncology Centers, PC
Medical Director, Oncology Services, WellStar
Health System

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I WOULD LIKE TO MAKE A COMMENT REGARDING THE PROPOSED CHANGES REGARDING ESAs. I HAVE BEEN AN ONCOLOGY NURSE FOR 15YEARS, SERVING THE LAST 4 AS A NURSE MANAGER AT A HEM/ONC. PRACTICE. I HAVE SEEN THE IMRPOVEMENT IN THE QUALITY OF LIFE WHICH ESAs PROVIDE OUR PATIENTS. A LARGE PERCENTAGE OF OUR PATIENTS HAVE BEEN ABLE TO CONTINUE TO WORK WHILE ON CHEMOTHERAPY DUE TO THE ESAs. IN MY EXPERIENCE, MOST OF OUR PATIENTS BECOME SYMPTOMATIC WITH A HGB. 11 OR LESS. WITH THE NEW GUIDELINES, THERE ARE TIMES WHEN THE HGB MAY BE LESS THAN 11 BUT THE HCT. MAY BE SLIGHTLY MORE THE 36. THEREFORE, THESE PATIENTS MUST RETURN TYPICALLY A WK. LATER TO BE RECHECKED AND AT THAT TIME, SOME ARE VERY SYMPTOMATIC. THIS IS A BIG INCONVENIENCE FOR OUR ELDERLY PATIENTS, MOST OF WHICH MUST HAVE SOMEONE TO BRING THEM IN TO THE OFFICE. LIVING IN A RURAL AREA, SOME OF OUR PATIENTS LIVE UP TO A 2 HOUR DRIVE FROM OUR FACILITY. ALSO, THE CHANGES BEING PROPOSED FOR MDS PTS. WE HAVE A LARGE POPULATION OF THIS GROUP. TO MAKE THEM INELIGIBLE FOR THIS DRUG, WOULD CAUSE A HUGE BURDEN ON THE ACUTE CARE FACILITIES FOR MULTIPLE BLOOD TRANSFUSIONS FOR THIS PATIENT POPULATION AND IN THE LONG-RUN, WOULD BE MUCH MORE EXPENSIVE FOR CMS. I THINK THE DECISIONS REGARDING THE USE OF THIS DRUG NEEDS TO BE THOROUGHLY REVIEWED PRIOR TO MAKING SUCH DRASTIC CHANGES.

THANK YOU FOR YOUR TIME,

KIMBERLY HOOKS, RN,OCN
BLOOD AND CANCER CENTER OF EAST TX.
825 MEDICAL DRIVE
TYLER, TX. 75701

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Medicare's proposed changes to limit the use of ESAs will unfortunate affect many patients' quality of life. Patients undergoing chemotherapy will be more fatique and will likely require more hospitalizations for blood transfusions which in turn would expose them to the risk of HIV and hepatitis. For patient with MDS, this will increase their transfusion requirement and lead to more iron overload and necessitate treatments for iron chelation. CMS proposed changes are unfortunately not based on evidence based practice of medicine. If ESAs are used correctly (without trying to increase the hgb to greater than 12), they are in general effective and safe. Obviously all medications have potential risks and benefits. The benefits of ESAs outweigh the risks for most patients undergoing chemotherapy.

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It isn't right to withhold this treatment from people who need it, see my specific comments below.
1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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Dear CMS,

I am disappointed in the proposed changes in ESA for non-renal disease indications. As a pharmacist, I am a proponent for efficacy and safety, but also providing the best care for our rural oncology patients in Colorado. I was unaware that CMS can dictate how physicians practice medicine - this is the role of the FDA. As a pharmacist who tries to practice and encourage evidence based medicine, the proposed guidelines fall short of this approach. There is very supportive data in the medical literature to support the use of ESAs in myelodysplasia. It is so important to improve the quality of life in our cancer patients and receiving PRBCs in a clinic does not improve quality of life. Also, the weekly limit on erythropoietin does not make clinic sense due to the formulations of this product. What about the higher dose of 80,000 units weekly that eleviates anemia in MDS patients? How do we ready the medical community for the increased need of red blood cells and how do we acquire more donors? Is the Red Cross preparing for the need of more blood transfusions?

Living at elevation in Colorado, we are able to push the Hct levels to 39.5 currently, but cannot start ESAs until Hct is 32.5 and now the proposal cuts this starting level to 27%. Will there be stipulation for high elevation patients that they can be started at an earlier Hct? Our patients are symptomatic typically at 30 with shortness of breath and increased fatigue.

The maximum covered treatment of 12 weeks a year is disturbing for those metastatic patients who are chronically on and off therapy to preserve disease control. Why continue treatment in the metastatic setting if you cannot enjoy the time you have left?

And lastly, discontinuing after 4 weeks of poor response is noted does not allow for dose titration or the addition of IV iron replacement. If it takes 28 days to generate new red blood cells, then is it really adequate to only give 4 weeks of treatment? I am all for a window of treatment where doses are escalated and iron stores replaced, and if this fails, discontinue the medication. I do find that the medical community has a hard time discontinuing drugs if a response is not achieved, but 4 weeks is not adequate to achieve desired response.

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The proposed legislation will cause a significant impact on oncology patients . Many patients have a significant drop in hemoglobin and hematocrit levels from chemotherapy . These drops cause poor performance levels ,due to fatigue, weakness and difficultly concentrating .The work force is impacted ,this also places cancer patients at risk for job loss due to poor attendance. The proposed legislation will also cause an increase rise in the number of blood transfusions that will be needed potentially causing a greater shortage of blood supplies.

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I find the proposed coverage to be huge disservice to cancer patients. I am not even sure where to start! Patients will suffer, experience more fatigue, and end up requiring transfusions. Transfusions, though safe, still have risks involved,especially when needed repeatedly. I would imagine transfusions are quite costly, too. To only cover treatment with ESAs for 3 months out of the year is ludicrous. Patients require multiple rounds of chemo, and to deny them the use ESAs partway through their treatment is awful. As is waiting to initiate treatment with ESAs until Hgb anemias and certain cancer diagnoses.

I strongly urge you to reconsider these guidelines to help the patients that we all care for.

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I am writing on behalf of my many patients who are affected by the recent Medicare decision regarding the use of Erythropoietin Stimulating Agents (ESAs). This decision has resulted in a great inconvenience for many patients, and also less than ideal medical care. I feel that Medicare has over-interpreted and overstepped the boundaries of good science in Medicare's interpretation of what this data means. In short, Medicare has assumed that any cancerous process treated with ESAs that such patients are in danger of severe complications. There is a wealth of data in the use of ESAs in anemia of chronic renal insufficiency/failure, myelodysplasia, chemotherapy-induced anemia and other areas that demonstrate when the hematocrit goal is in the low-normal range patients are well served with improvement in symptoms of anemia without untoward increase in complications such as heart disease or hypertension. Medicare has unfairly grouped diseases such as myelodysplasia into that of the cancer. This is incorrect. Myelodysplasia is a unique hematologic disorder for which there is ample data indicating the safety and utility of ESAs. It is my opinion that Medicare is using this as an opportunity to reinvent guidelines that have already been well established by years of clinical research. I urge Medicare to strongly reverse its position on ESAs and to resume its previous approved indications for their use as long as the goal is to maintain the hematocrit in the low-normal range.

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When I was a chemo nurse in the 1980s, numerous patients' chemotherapy was held due to low Hemoglobin/Hematocrit counts. It has been shown that delaying chemotherapy for any reason results in decreased disease response. Many of those patients either later recurred or their disease progressed while on treatment. With the development of ESAs, treatment delays have become much more rare. Patients stay on their regimens, and the results are more effective. I see serious harm coming from the proposal you have put forward. I also do not believe this will save money for Medicare. Medicare will have to pay for more transfusions, and will be paying for further treatment for patients who progress or recur do to previous treatment delays from low blood counts. This is a huge step backward that will not only negatively impact patients, but will also INCREASE Medicare costs.

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In response to CMS request for comments, I would like to take this opportunity to comment on the proposed changes to current use of ESA's. First let me say that I have significant concerns when an agency such as CMS makes a proposal that is either unsupported by clinical evidence, or uses clinical evidence incorrectly, and that proposal has the potential to affect the well being of cancer patients in my practice.

We support a National Coverage Decision but are concerned that the proposed NCD does not rely on current scientific data, nor does it comply with accepted standards of care for cancer patients in this country. We are concerned that the outcome of such restrictions will have a negative impact on the health and welfare of our patients, their families, and potentially the nation's blood supply and to the already overburdened facilities where it is provided.

The following comments express either support or concerns with the proposed regulations as outlined below:

I agree that there should be restrictions on treatment with ESA's in the following areas:

1. Anemia in cancer or cancer treatment in patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis.
2. Anemia of myeloid cancers, specifically acute myeloid Leukemia (AML) and chronic myeloid leukemia (CML)
3. Anemia associated with the treatment of myeloid cancers or erythroid cancers
4. Anemia associated with primary treatment with radiotherapy
5. Prophylactic use ot prevent chemotherapy-9induced anemia in patients who have never suffered from CIA
6. Prophylactic use to reduce tumor hypoxia in non-anemic patients
7. Patients with erythropoietin-type resistance due to neutralizing antibodies
8. Anemia due to cancer treatments if patients have uncontrolled hypertension

However, we disagree with other portions of the propose rules and have outlined those as follows:

1. Use with anti-angiogenic and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies: There is no basis in clinical evidence that ESAs stimulate angiogenesis.
2. Anemia of cancer: Evidence of detriment to survival is questionable in that such evidence is based on studies of much higher hemoglobin levels than targeted in common practice, with such studies looking for new indications for the use of ESAs, and a further study in which the patient population was often end stage or hospice. There is however, a significant body of published evidence identifying benefit through controlled clinical trials and supporting current recommended doses and hemoglobin levels.
3. MDS Myelodysplastic Syndrome: There is significant pool of studies involving epoetin alpha and darbepoetin alfa, all of which includes safety and efficacy data of ESAs in treatment of MDS related anemia. Restriction of usage is not reasonable because data is not available to support such a restriction.
4. Effects of Frequent Transfusion: There is concern that restrictions proposed may increase the need for transfusion in many patients. Frequent transfusion shows documented toxities which may require additional treatment such as toxicity from iron overload which may affect all body systems/organ function. Additionally, delays in therapy may occur in order that patients may be scheduled for transfusion, further overburdening our facilities and blood supply.
5. Initiation and limitations based on hemoglobin targets: Evidence suggests initiation of ESA's when hemoglobin falls below 11 g/dL has the greatest opportunity to prevent transfusion. A target of 9 g/dL will almost certainly create a need in some patients for transfusion. We believe that the physician should have flexibility in managing patients to maintain an optimal hemoglobin level by dose reduction rather than withholding at hemoglobin greater than 12 g/dL if, in their judgement, the patient will benefit more from dose reduction to maintain adequate hemoglobins. A 4 week trial is not sufficient to evaluate response in patients undergoing chemotherapy. The natural rebound after cytotoxic therapy often takes longer as therapy progresses.
6. Limits on patients with weight gain and fluid retention: Not all patients who experience weight gain and fluid retention experience hypertension. Some therapies require high volumes of hydration and/or by their nature cause fluid retention and weight gain. Using weight gain and fluid retention as an independent determinant for withholding ESA therapy is not an appropriate measure to prohibit the use of ESA therapy.
7. Duration of therapy: Patients frequently receive more than 12 weeks therapy, and often receive more than one regimen due to recurrence. Therapy should be tailored to the needs of the individual patient. Limiting the number of weeks annually they may receive ESA therapy is not reasonable because of the wide range of variables involved. As an example, a sarcoma patient is often in treatment for 12 months, not 12 weeks.
8. Limits on dosing/dose adjustments: Clinical trials determine safe and efficacious dosing of drugs. The FDA label specifies clearly use of the lowest necessary dose to be managed in concert with the hemoglobin levels. There is no scientific evidence to support management of the hemoglobin level separate from recommended dosing levels, and neither are the suggested limitations on dose adjustments supported by data.

I urge you to review recommendations made by ASCO, ASH, ACCC, COA, USO and the many other clinical and scientific organizations that have studied and provided you with detailed clinical support for continued ESA therapy under appropriate guidelines. The proposal set forth by CMS is clearly unacceptable and has the potential to negatively impact cancer patients.

Warden L. Woodard, III, MD

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June 13, 2007

To whom it may concern:

We are sending this in response to the recent publication of the 'Proposed Decision for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications'. We feel that instituting these rules would severely hinder the health of cancer patients under our care. The use of ESAs has been shown to decrease the number of transfusions and improve quality of life in cancer patients.^1,2

Some of the proposed rules do not correspond with current NCCN and ASCO/ASH guidelines for the treatment of anemia in cancer patients or with current prescribing information for Procrit® or Aransep®. We wish to specifically address some of these discrepancies as outlined below:

1) Non-coverage for anemia of myelodysplasia

Current guidelines for the treatment of myelodysplasia include the use of Procrit® for management of anemia.^5,6 Aransep® has also proven to benefit these patients.^7,8,9

The use of ESAs has been shown to decrease the number of transfusions required by patients with MDS, thereby increasing quality of life and potentially decreasing the need for expensive drugs (Desferral®, Exjade®) for treatment of iron overload.

2)'the hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be < 9 g/dl/27% in patients without known cardiovascular disease and < 10 g/dl/30% in patients with documented symptomatic ischemic disease that cannot be treated with blood transfusion.'

This does not correspond with the current guidelines for the treatment of Anemia in Cancer Patients.^1,2 These guidelines recommend initiating ESAs when hemoglobin is < 10 g/dl regardless of any history of cardiac disease. In addition, the prescribing information for Procrit® specifically recommends targeting a hemoglobin of 10-12 g/dl.⁴

3) The maximum covered treatment duration is 12 weeks/year AND4) Continued use of the drug is not reasonable and necessary if there is evidence of poor drug response (hemoglobin/hematocrit rise < 1 g/dl/<3%) after 4 weeks of treatment.

Chemotherapy administration frequently exceeds 12 weeks per year. The need for these drugs will continue for the duration of chemotherapy.

In addition, it may take 8-12 weeks for patients to fully respond to these drugs. Current guidelines and prescribing information recommend dose increases in non-responders after a 4 week trial period for Procrit®^1,2,4 or a 6 week trial of Aransep®³.

The 12 week limit of treatment per year may just barely allow patients to achieve an initial benefit from ESAs before they must be discontinued. The discontinuation of the drugs after an inadequate response at 4 weeks is contrary to current guidelines and prescribing information.

5) The maximum covered 4 week treatment dose is 126,000 units for erythropoietin and 630 mcg for darbepoietin. Dosing of Procrit® per current guidelines includes a standard dose of 40,000 units weekly.^1,2,4 This equates to 160,000 units every 4 weeks. In addition, dose escalation to 60,000 units every week (240,000 units every 4 weeks) is recommended for non-responders^2,4.

Dosing of Aransep® per guidelines¹ as well as the prescribing information³, includes a dosing schedule of 500 mcg every 3 weeks. This calculates out to an average dose of 666 units every 6 weeks.

We hope that additional consideration will be given to these proposed rules before they are instituted based on the information provided in this letter.

Sincerely,

Patrick Gomez, MD
J. Wendall Goodwin MD
Thomas Froehlich, MD
Janet Kreifels, Pharm.D, BCOP
The Cancer Hematology Center
2115 S. Fremont, Suite 1000
Springfield, MO 65804

References:

1) Rizzo JD, Lichten AE, Woolf SH, Seidenfeld J et al: Use of Epoetin in Patients With Cancer: Evidence-Based Clinical Practice Guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20(19):4083-4107, 2002.

2) NCNN Clinical Practice Guidelines in Oncology: Cancer and Treatment-Related Anemia, 2007.

3) Prescribing information: Aranesp for injection, Amgen.

4) Prescribing information: Procrit for injection, Ortho Biotech.

5) NCNN Clinical Practice Guidelines in Oncology: Multiple Myeloma, 2007.

6) Guidelines for the Diagnosis and Therapy of Adult Myelodysplastic Syndromes. British Journal of Haematology 120:187-200, 2003.

7) Musto P, Lanza F, Balleari E, Grossi A et al: Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. British Journal of Haematology 128(2):204-9, 2005.

8) Mannone L, Ardin C, Quarre MC, Bernard JF et al: High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. British Journal of Haematology 133(5):513-9, 2006.

9) Stasi R, Abruzzeese E, Lanzetta G, Terzoli E et al: Darbepoetin alfa for the treatment of anemic patients with low and initermediate 1 risk myelodysplastic syndromes. Annals of Oncology 16(12):1921-7, 2005.

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Non-coverage of ESAs for use in any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis. Non-coverage on anemia associated with radiotherapy. Non-coverage of prophylactic use of ESAs to prevent chemotherapy-induced anemia and to reduce tumor hypoxia. However, the physicians of the US Oncology network have grave concerns about a number of other CMS proposals discussed in detail in the comment letter. They are as follows:

1. CMS appears to have based many of its proposals on an unsubstantiated theory that the alleged presence of erythropoietin ('Epo') receptors on cancer cells invitro causes tumor progression and mitigates the tumorigenic effects of certain anti-cancer agents when used clinically.

2. The draft NCD appears to ignore virtually all the clinical evidence and clinical experience substantiating the safety of ESAs when they are used according to their FDA labeled indications.

3. The proposed coverage for chemotherapy induced anemia ('CIA') is not consistent with the evidence and the initiation point of less than 9g/dl is too low to avoid most transfusions. Moreover, the policy does not address the black box warning concerning the risks of attaining a Hgb level that exceeds 12g/dl.

4. The proposed treatment duration limit of 12 weeks/yr is grossly inadequate and the proposal to not cover any dose escalation is not consistent with the medical evidence.

5. CMS has ignored the clinical evidence showing that ESAs are safe and effective when used to treat Myelodysplasia ('MDS') and Multiple Myeloma ('MM').

6. CMS appears to have misinterpreted the safety signals under FDA review; the signals are limited to off-label uses of ESAs such as prevention of anemia and obtaining hemoglobin levels above 12g/dl but CMS assumes that those safety signals also exist when ESAs are used according to their labeled indications.

7. CMS appears to have not taken into account the effect of its proposal on the US blood supply nor on the number of patients who will catch transmissible illnesses through receipt of blood transfusions that were medically unnecessary but required by its ESA coverage policy.

8. CMS seems not to have considered the effect on patients who for religious or other reasons do not wish to have blood transfusions (e.g., Jehovah's Witnesses).

9. The proposed CMS policy inappropriately interferes with the patient/physician relationship because it substitutes CMS' judgment about the benefits and risks of ESAs for the judgments patients and physicians need to make in order to optimize care.

10. The US Oncology network believes that CMS is bound by law and its longstanding policy to cover all FDA labeled indications for ESAs irrespective of whether the label carries a block box warning.

The US Oncology network recommends that CMS establish the following coverage policies in its final NCD in lieu of its proposed policies:

1. Cover ESA use consistent with the US Oncology network clinical pathway for ESA use in chemotherapy-induced anemia (See Exhibit A.).

a. Cover ESA use for chemotherapy-induced anemia with an initiation Hgb level of 11g/dl for all patients.

b. Non-cover any ESA use when the patients Hgb level is 12g/dl or greater.

c. Cover a single 50% ESA dose escalation for patients where the Hgb level has not increased by 1g/dl within 6 weeks of initiation of ESA therapy.

2. Cover ESA use during any course of chemotherapy and for up to 12 weeks after the last dose of chemotherapy is administered.

3. Cover ESA use in conjunction with all anti-cancer drugs and biologics.

4. Cover ESA use for patients with MDS consistent with the US Oncology network pathway for ESA use in MDS (Pathway attached as Exhibit B.).

5. Cover ESA use for patients with MM who are anemic irrespective of whether they are on chemotherapy.

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June 13, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244

RE: National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

Dear Dr. Phurrough,

After reviewing the proposed NCD for Erythropoiesis Stimulating Agents, I have several concerns with the proposed indication changes. These changes would negatively impact patient care.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.

Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

Thanks for your consideration of these points!

Sincerely Yours,

Elquis M. Castillo. MD
President, Hematology & Oncology Associates of
Alabama, LLC

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PLEASE allow Oncology Spec. to decide appropriate care for ESA usage!PLEASE eliminate 12 wk. per yr. max. Treatment! It will underserve patients w/proloned chemo trt!PLEASE do not change criteria and delay start of ESA therapy!PLEASE allow use for patients and MDS, non-coverage goes againstg accepted Nat'l clinical guidelines! PLEASE allow cancer patients to maintain quality life!PLEASE allow trtment of cancer to advance, do not push it back to the days when bl. transfusions were the only alternative!Thank you for making my comments count..it may one day be your family memeber....

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TO: Steve Phurrough, MD, MPA
Elizabeth Koller, MD, FACE
Maria Ciccanti, RN

I am writing to offer a few comments on the NCA for Erythropoiesis Stimulating Agents for non- renal disease. I agree with CMS that there is a need for an NCD for these agents given their huge costs and given the potential for significant toxicities when they are used inappropriately. However, I do have several concerns about certain specific proposals in the NCA as put forward. I would like to comment briefly upon these.

1) Erythropoietin receptors: With regard to the possible significance of the putative epo receptors on tumor cells, there is no clear clinical data to show any harmful effect of ESA's. There is no in vivo evidence of tumor growth promoting effect of ESA's, nor is there evidence of any adverse cancer treatment outcome in the tumors types named in the CMS proposal when ESA's are used according to accepted dosing and administration standards. I do not agree with the proposal to use in vitro evidence of possible erythropoietin receptors on cells to restrict clinical use of these agents.

2) Myelodysplastic disorders: There is abundant evidence that ESA's are of substantial value in the therapeutic management of myelodysplastic syndromes. A major clinical problem with these diseases is the huge impact of anemia on quality of life and survival, and in the past episodic transfusion was the only tool for treatment. With the use of ESA's, the need for transfusion of MDS patients has been greatly reduced, quality of life improved, and the many risks associated with chronic repetitive transfusion virtually eliminated. There is no evidence of a risk of disease progression in MDS with ESA's. The CMS document cites the development of acute myeloid leukemia as an adverse effect of ESA use - in fact, AML is a specific risk of MDS itself, reflecting the biology and natural history of the disease. The evidence does not support a conclusion that ESA's can cause AML or accelerate the development of AML in MDS patients.

3) Multiple Myeloma: For similar reasons to those stated above, I am concerned that the proposed NCD will eliminate access of patients with multiple myeloma to ESA's without any clinical or experimental evidence to support that recommendation. Like MDS, multiple myeloma causes disabling chronic anemia, resulting in crippling effects on quality of life in this typically older patient population. The same caveats apply as to the need for repeated transfusions with their attendant risks and costs in myeloma patients who are denied access to ESA's. As with MDS, there is no evidence that ESA's when dosed and administered appropriately have an adverse effect on patients with multiple myeloma. I suspect that multiple myeloma was inadvertently included with "myeloid malignancies" in the CMS proposal.

4) Quality of Life: Along these same lines, I do not feel that the CMS proposal gives proper heed to the issue of quality of life. Symptomatic anemia in cancer patients, patients undergoing chemotherapy, and patients with MDS or multiple myeloma experience fatigue, shortness of breath, restriction on physical activity, and frequently more dangerous effects (e.g., cardiovascular impairment, CHF, even risk of death). The management of QOL loss with periodic transfusion is clearly NOT equivalent to ESA's - transfusion is initiated once patients are already experiencing symptoms, provide temporary relief, and do not provide a stable continuing control of symptoms. Furthermore, they require hospitalization, time away from family and work, periods of non- productivity, not to mention substantial cost (both in financial and societal). In addition, while the risk of individual transfusions "episodes" is small, the need for repeated transfusion greatly increases the risk of alloimmunization (and attendant risk of reactions or inability to find compatible blood), infection, risk of fluid overload, and so on.

5) ESA Use Parameters: I entirely agree that ESA dosing should follow scientifically sound, clinically proven, safe dosing schedules. However, I do not agree with the dosing recommendations in the CMS proposal. There is abundant controlled clinical trial data that initiation of ESA treatment at Hgb will not be as effective as initiation at a Hgb of 11 gm/dl in avoiding need for transfusion. The inevitability of further drop in Hgb before a response is seen will also result in additional compromise of quality of life and additional risk. The clinical trial data clearly support a target Hgb between 11 gm/dl and 12 gm/dl as optimal for QOL, and for safety. Studies in which adverse outcomes have been seen have used inappropriately high Hgb targets (> 12 gm/dl). Additionally, the restriction to 12 weeks of therapy with ESA's per year is arbitrary and has no basis in science or in clinical experience. Finally, the restriction of duration of therapeutic trial to 4 weeks and the preclusion of dose escalation are not consistent with the results of peer-reviewed clinical trials.

6) Concerns About Transfusion as an Alternative to ESA Use: As noted earlier, repeated transfusion therapy for patients who would otherwise be candidates for ESA use are not clinically equivalent. QOL is much less well managed with transfusion, and the potential risks and adverse consequences of transfusion will become a major clinical issue in the care of our patients. It is also not true that transfusion will be an effective cost control measure compared to ESA use - transfusion requires at least brief hospital stays, diverts hospital resources away from other uses, take patients away for productive contributions to family/work/society, and result in the consumption of an already very limited resource. Many others have commented upon the very real risk to the nation's blood supply, already tenuous and clearly at grave risk when the NCD results in a huge increase in number of transfusions administered. The true cost of transfusions is enormous, and it would be short- sighted to fail to take these issues into account in considering these proposals.

7) EGFR and VEGFR Inhibitors and ESA's: As with the issue of Epo receptors which may (or may not) exist on tumor cells, but for which there is no evidence of adverse effects with ESA's, there is no clinical evidence that ESA administration to patients receiving these biologic agents as part of their chemotherapy regimens are adversely affected. There is no data showing increased risk of thromboembolic or cardiovascular adverse events in these patients, and it is my conclusion that the CMS recommendation is based upon theoretical considerations and not upon clinical trial data. Therefore I do not feel there is a valid reason at this time for the proposed restriction.

I would like to conclude with a brief personal note. [PHI Redacted] with a myelodysplastic syndrome (CMML) has been on ESA support for some time, and has experienced a dramatic improvement in her quality of life. She has not needed any transfusions since ESA's were started. If she needs to discontinue ESA therapy and begin transfusion again, her life will become very difficult indeed. She is very frail, has extremely limited mobility due to arthritis, and getting to and from the hospital is very difficult and painful for her.

I respectfully submit these comments for your consideration. I know that a great deal of work has gone into the CMS proposal, and I appreciate all of you efforts. I hope that you will give my comments and those of other interested commentators serious consideration.

Michael A. Savin, M.D.

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1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb < 9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the < 9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (< 11g has been shown to be superior to < 10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.

Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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To CMS Advisory committee:

I am writting on behalf of my group of hematologist/oncologist located in Orlando, FL. We have been using ESA products under the guidelines published by both the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO)in the year 2002.

We find the proposed initiation levels of hemoglobin/hematocrit at which patients receiving chemotherapy need to reach before treatment with an ESA, extremely low. The proposed guidelines do not take into consideration the baseline hemoglobin nor it takes into consideration the level of fatigue that these patients have as their hemoglobin decreases. For example, 60 year old man with a baseline hemoglobin of 15 is receiving chemotherapy for lung cancer and after 2 months his hemoglobin is 10.8. He may have significant fatigue and under the proposed rule he would need to wait until his hemoglobin is less than 9 before receiving an ESA.

Also the proposed CMS guidelines excludes patients with Myelodysplasia (MDS) from getting ESAs when we have publish data to support the use of these agents in this population of patients. We do agree that after a trial period of 6-8 weeks, it would be appropriate to discontinue the ESA.

We expect a dramatic increase in blood transfusions for the treatment of anemia secondary to chemotherapy. One of the reviewers from ODAC stated that the risk associated with blood transfusion was minimal. We respectfully disagree with those comments since blood transfusions not only are associated with blood bourne viral pathogens, but also can be associated with allergic/incompatibility reactions, alloimmunization, iron overload, and it could provoke decompensated heart failure and even transfussion related acute lung injury (TRALI). In addition to this, the need for blood transfusions might provoke further weakning of our blood bank inventory, and consequently creating a shortage of blood.

In summary, the quality of life of hundreds of thousands could potentially be affected if the proposed CMS guidelines pass without been significantly revised.

Thank you for the opportunity to communicate our wories and on behalf of my colleagues and patients, we hope that these comments can help in your decision.

Respectfully

Carlos Alemany, MD
Hematologist/Oncologist

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Genentech, Inc.
Government Affairs
1399 New York Ave, NW, Suite 300
Washington, DC 20005
Phone: (202) 296-7272
Fax: (202) 296-7290

June 13, 2007

Steve Phurrough, MD, MPA
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Mailstop: C1-12-28
7500 Security Boulevard
Baltimore, MD 21244

[Complete Comments with Tables Referenced below Submitted Directly via E-mail to CMS]

Re: Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions (CAG-000383N)

Dear Dr. Phurrough:

Genentech, Inc. ('Genentech') appreciates the opportunity to submit the following comments in response to The Centers for Medicare & Medicaid Services ('CMS') proposed national coverage decision memorandum for the use of erythropoiesis stimulating agents ('ESAs') in cancer and related neoplastic conditions ('Proposed NCD').

As you are aware, Genentech is a leading biotechnology company focused on discovering, developing, manufacturing, and commercializing biotherapeutics that address serious unmet medical needs. Genentech has discovered and introduced over a dozen significant therapies for serious and life-threatening diseases affecting the lives of Medicare patients, including cancer, heart disease, pulmonary disease, rheumatoid arthritis, and age-related macular degeneration. Medicare policy relating to both coverage and reimbursement of products like ESAs directly impacts patient access to the life-saving therapies we develop and is, therefore, of significant interest to Genentech.

While Genentech supports CMS' ongoing efforts to promote the collection of evidence for use by physicians in making treatment decisions, we are concerned that the draft policy, as currently written, does not accomplish this goal. In fact, the Proposed NCD may inappropriately limit Medicare beneficiary access to and physician choice of proven and medically appropriate therapies used to treat life-threatening conditions like cancer. We are particularly concerned that the Proposed NCD wrongly prohibits Medicare coverage for ESAs used in patients with treatment regimens including anti-angiogenic drugs like bevacizumab (Avastin®), as this proposal is neither grounded in nor supported by scientific or clinical evidence.

The following comments provide evidence, based on existing data, that ESAs do not have a deleterious effect on cancer by causing tumor growth and counteracting the clinical effect of an anti-angiogenesis drug like Avastin. We also provide data from Phase III clinical trials that illustrate ESA use does not increase the risk of adverse events like arterial or venous thromboembolic events and hypertension when using anti-angiogenesis drugs like Avastin. Genentech is concerned that the Proposed NCD, if finalized in its current form, could seriously harm Medicare beneficiaries and limit the treatment options available to beneficiaries with cancer. As written, the Proposed NCD could improperly cause physicians not to prescribe Avastin, a product with proven survival benefits, either because physicians incorrectly infer that there is a safety risk associated with ESAs when used with Avastin, or because physicians may be forced to choose between prescribing a therapy like Avastin or prescribing ESAs that they determine are necessary to treat a patient's anemia. Based on these concerns, we request CMS to remove any restrictions of ESA use with Avastin in its final coverage policy.

I. Overall Policy Comments on Proposed NCD

Below, we provide overall comments on the policy implications of the Proposed NCD.

Inappropriate Restriction of Anti-Cancer Chemotherapeutic Regimen

As part of statutory authority to cover only products and services for which it deems 'reasonable and necessaryy' for Medicare beneficiaries,¹ CMS also is required to cover drugs or biologicals used in an anti-cancer chemotherapeutic regimen for a medically accepted indication that has been approved by the FDA, is supported by one of the recognized compendia, or is determined by a Medicare contractor to be supported in the peer-reviewed medical literature.² Although the Proposed NCD does not place any direct coverage restrictions on anti-angiogenesis products like Avastin, we are concerned that restricting use of ESAs when used with Avastin is, by default, inappropriately restricting coverage of an anti-cancer regimen.

While CMS has a legitimate role in determining whether products are 'reasonable and necessaryy' and therefore a covered benefit for Medicare beneficiaries, we are concerned that the Proposed NCD, while intended to limit coverage of ESAs due to safety concerns, also will unintentionally limit patient access to other, proven anti-cancer therapies. Although Genentech also appreciates the need for CMS to be a judicious steward of Medicare funds, we do not believe that significantly restricting use of ESAs with proven safe and efficacious anti-cancer treatments is an appropriate and effective use of CMS' authority, nor is in the best interest of Medicare beneficiaries.

Proposed NCD Not Evidence-Based

In concert with the multitude of other provider, patient, and industry stakeholders who have provided comments to CMS on the Proposed NCD, Genentech also believes that CMS inappropriately restricts use of ESAs and other named anti-cancer therapies because the Proposed NCD relies on pre-clinical, theoretical data that are in conflict with the standard of care for cancer patients currently practiced in the United States. CMS' reliance on data from off-label, experimental, and investigational uses to determine a non-coverage decision for life-saving therapies like Avastin sends a conflicting message to the stakeholder community regarding the robustness of evidence-based medicine for which CMS claims to base its coverage decisions. CMS' explicit demand for use of proven evidence, not theoretical assumptions, to make coverage decisions appears to be ignored in the Proposed NCD.

Instead of relying on scientifically rigorous data to base its decision, CMS specifically cites the lack of data as the basis for its Proposed NCD. Although restricting coverage of FDA-approved indications for a Medicare Part B drug due solely to the absence of clinical data has not been previously imposed by CMS, the current adoption of such a policy is unrealistic and unsustainable, particularly with respect to Medicare beneficiaries with cancer. It seems extreme for CMS to expect all products administered to Medicare beneficiaries be tested against endless combinations of other products in order to rule out the possibility of a potential adverse event or deleterious effect. Although CMS may consider it within its realm of authority to make such coverage decisions, denying beneficiaries' access to therapies proven safe and efficacious by the FDA for their labeled indication because of a theoretical safety concern is clearly not in the best interest of Medicare beneficiaries.

CMS Inappropriately Assuming Role of FDA

Genentech also is concerned that CMS is circumventing the role of the FDA in the Proposed NCD. Specifically, it is not CMS' role to make scientific judgments about the appropriate use of products prior to FDA decisions on the same issue, even if under the guise of CMS' 'reasonable and necessaryy' authority. Congress has vested the FDA with the responsibility of evaluating the safety and efficacy of drugs and biologics, not CMS. As such, CMS should wait to make decisions regarding Medicare coverage for a product until the FDA has completed its safety review of the product in question. By CMS making decisions regarding the safety and efficacy of various products already approved by the FDA, it is prematurely limiting the ability for patients to access products already approved by the regulatory agency responsible for making such decisions, and is, in essence, dictating the treatment decisions of physicians.

Interfering with Doctor/Patient Relationship

By prohibiting/restricting coverage for ESAs in the Proposed NCD, CMS is improperly inserting itself into physicians' clinical decision-making and interfering with the physician/patient relationship by substituting its judgment for that of the practicing physician. The Proposed NCD appears to be based largely on an incorrect assumption that physician decisions currently are not evidence-based and thus, require intervention by CMS. Such proscriptive medicine ignores patient-specific needs and differences, like co-morbidities and quality of life factors, present at the time a treatment decision is made.

In order to ensure the highest quality of care is provided to Medicare beneficiaries, physicians must be allowed to determine the most medically appropriate course of treatment for each patient, based on their review of the evidence available, each patient's unique characteristics, and patient preferences. Broad practice guidelines developed at the national level by CMS cannot and will not be sufficiently nuanced to reflect important patient differences. In situations for which CMS feels it necessary to created national coverage policies that dictate physician behavior, it should ensure such policies are made on the basis of proven scientific evidence, not theoretical assumptions. Rather than focus on ways to control physician decision-making, particularly for oncology patients, Genentech encourages CMS to focus on ways to ensure physicians have access to the most recent and evidence-based information available in order to inform their decision-making.

Lack of Clarity Regarding Proposed Non-Coverage for Anti-Angiogenesis Drugs

Genentech is concerned that by denying coverage of ESAs with Avastin, the Proposed NCD could have the unintended effect of also denying or restricting the use of Avastin, a therapy proven to increase survival of Medicare beneficiaries with first or second-line metastatic colon cancer and first-line metastatic non-squamous non-small cell lung cancer (NSCLC) in combination with intravenous chemotherapy regimens.³ Avastin itself is not known to cause anemia; however, it is administered in combination with chemotherapeutic regimens that frequently are associated with myelosuppression and anemia, the latter often treated with an ESA.

While we recommend that CMS remove its proposed restriction relating to coverage of ESAs when used with anti-angiogenic agents altogether, we further object to CMS' singling out bevacizumab (Avastin) as the only anti-angiogenic drug listed in the Proposed NCD. We note that a multitude of products claim anti-angiogenic properties, yet the Proposed NCD mentions only Avastin. By doing so, some physicians have unfortunately interpreted this to mean that CMS has specific evidence suggesting a safety problem related to Avastin, which does not exist, and that the Proposed NCD may restrict coverage for Avastin, which also is not the case. Given the treatment benefit Avastin provides to Medicare beneficiaries with colorectal and non-small cell lung cancer, any confusion over its use or coverage could have the unintended and negative effect of denying Medicare beneficiary access to this important therapeutic.

The FDA approved Avastin (bevacizumab) in February 2004 in combination with intravenous 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic carcinoma of the colon or rectum. In 2006, the FDA approved Avastin for second-line treatment of metastatic colorectal cancer, and later that same year, for use in combination with carboplatin and paclitaxel for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. Per its FDA-approved package insert (PI), the recommended dose of Avastin for metastatic colorectal cancer is 5mg/kg every 14 days when used in combination with bolus-irinotecan, 5-fluorouracil bolus and leucovorin (IFL) and 10mg/kg every 14 days when used in combination with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX4). The recommended dose of Avastin for NSCLC is 15mg/kg, as an IV infusion, once every 3 weeks with carboplatin and paclitaxel⁴. After the first six cycles of treatment with chemotherapy for NSCLC, Avastin is typically given alone.

In the Proposed NCD, CMS proposes to non-cover ESA treatment in patients with 'treatment regimens including anti-angiogenic drugs such as bevacizumab;;' however, it is unclear from the proposed NCD what is meant by a 'treatment regimen;;' specifically, when a treatment regimen for an individual patient starts and stops with respect to coverage under the Proposed NCD. This lack of clarity likely will confuse providers and patients when attempting to abide by the parameters of the policy. For example, if a patient diagnosed with first-line metastatic colon cancer is prescribed a chemotherapeutic regimen of 5-FU at the time of diagnosis and after one week of chemotherapy becomes anemic and receives an ESA, then receives Avastin three weeks later, would the patient's first three weeks of chemotherapy treatment be non-covered since Avastin was added to the patient's treatment regimen at a later date? Requiring long-term treatment decisions for oncology patients to be made pre-maturely without regard to assessing a patient's tolerance for each treatment could have significant negative and unintended effects on the quality of care provided to Medicare beneficiaries.

II. Comments on Clinical Aspects of Proposed NCD

In addition to the general policy concerns cited above, we also are troubled by CMS' statements in the Proposed NCD that conclude ESA use is not reasonable and necessary for patients undergoing treatment in an oncology setting with regimens including anti-angiogenic drugs such as bevacizumab⁵. As the company that discovered, developed, and now markets Avastin (bevacizumab) in the United States, we strongly disagree with CMS' review of the literature cited in the Proposed NCD and provide data below to illustrate ESA treatment in patients with anti-angiogenic treatments regimens, specifically Avastin, should continue to be considered reasonable and necessary for Medicare beneficiaries.

Minimal Role of Erythropoietin in Tumor Biology

Of the many laboratories around the world that have been studying normal and abnormal (cancer-associated) angiogenesis over the past 30 years, few have recognized erythropoietin (EPO) and erythropoietin receptors (EPO-R) as biologically and clinically relevant factors in the regulation of angiogenesis. Although non-hematopoietic roles of EPO and EPO-R exist, none of these roles are essential for cell development. Conversely, numerous reviews of other important biologic regulators of angiogenesis, particularly vascular endothelial growth factor (VEGF), have been published in the peer-reviewed literature⁶. Additionally, no scientific basis exists to suggest that ESAs negate the therapeutic utility of anti-angiogenic agents.⁷

Even as a theoretical construct, the papers cited in the Proposed NCD do not indicate a clinical relevant relationship between EPO/EPO-R and angiogenesis, including a deleterious effect like tumor growth as the result of an ESA. In fact, the work by Hardee et al⁸ provides evidence, based on human tumor models, that the EPO/EPO-R pathway has no direct effect on angiogenesis. Moreover, the papers by Ribatti and colleagues are merely descriptive reports that involve an extremely small numbers of patients (20 patients with neuroblastoma and 50 patients with liver cancer) ⁹. Descriptive reports of pre-clinical data that purport an association between EPO/EPO-R expression and microvessel density (a surrogate for angiogenesis) and higher histologic grade and clinical stage are not sufficient, on their own, to claim a scientific or clinical relationship between EPO/EPO-R and angiogenesis.

If one sought to study the potential for an independent contribution of EPO/EPO-R to angiogenesis, it would need to be explored by conducting a multivariate analysis with other, well documented and proven mediators of angiogenesis [such as VEGF and basic fibroblast growth factor (bFGF)]. If such an analysis did in fact confirm an independent association of EPO/EPO-R and microvessel density, scientific rigor would next require more direct evidence of a relationship EPO/EPO-R and angiogenesis. As mentioned above, Hardee and colleagues provide the evidence that directly contradicts the hypothesis set forth by Ribatti et al. Hence, for CMS to base a decision to non-cover ESAs in all Medicare beneficiaries with anti-angiogenesis treatments on the unconvincing level of evidence proposed by Ribatti et al is not defensible.

Analysis of Existing Clinical Data on Avastin and ESAs

Genentech and our collaborators at Roche and the National Cancer Institute (NCI) have reported the results of 10 large randomized and controlled clinical trials of Avastin in the oncology setting including colon, lung, breast, renal, and pancreatic cancers. Several of these trials formed the basis of FDA approval for our marketing applications for Avastin and all of these trials were conducted during a time that ESAs were approved by the FDA for both chemotherapy-associated anemia and for the anemia of cancer¹⁰. Nine of these 10 trials studied Avastin in combination with chemotherapy and one studied Avastin in combination with interferon. In addition, all 10 clinical trials were conducted under protocols which specified that hematopoeitc growth factors'both ESAs and myeloid growth factors'could be used at the investigators' discretion under generally accepted clinical guidelines, including guidelines published by the American Society of Clinical Oncology (ASCO) and The National Comprehensive Cancer Network (NCCN)¹¹.

The use of ESAs was captured in 6 of these 10 trials as outlined in Table One below. Three of the trials (AVF2107, AVF2192, and AVF2119) were conducted primarily in the United States (US) and three (NO16966, AVAIL, and AVOREN) were conducted primarily or exclusively outside the US. Specifically, these 6 trials, involving more than 4,400 patients, routinely captured ESA use on Case Report Forms (CRFs) under a category entitled 'Concomitant Medications,,' for which the use of all pharmacologic agents (other that the specified treatment outlined in the protocol) is captured for each patient¹².

Table One: Avastin Clinical Trials for Which Data Are Available on Use of ESAs

In the analysis, 'ESA users' were identified by a concomitant medications database query for the following terms: epoetin alfa, epoetin beta, epoetin not otherwise specified (NOS), and darbepoetin alfa. Any use of any of these agents for any duration was considered sufficient to place a patient in the 'ESA userr' group. Conversely, 'ESA non-users' are defined as those patients who have no recorded use of these epoetin-related agents. The results of our analyses are described below.

Concurrent Use of ESAs in Avastin Clinical Trials

The ESA use in both the control and Avastin groups of these six trials varies by trial, likely due to differences in the underlying chemotherapy regimens. In this analysis, there was a statistically lower rate of ESA use in patients treated with Avastin compared to the control group. This observation occurred despite the significantly longer time on Avastin treatment, including chemotherapy, noted in five of the six trials. (Table Two below).

Table Two: Concurrent Use of ESAs in Avastin Clinical Trials

*p=0.04

As expected, ESA use was not a random event in these trials. We explored the rate of ESA use in three important prognostic subgroups that were uniformly available in these trials:

Table Four displays the relative treatment effect of Avastin in five of these six clinical trials. (Given the very low rate of ESA use in AVOREN, data from this trial was not included in our outcome analyses.) Four of these five trials were 'positive,,' meaning they achieved their pre- specified primary efficacy endpoint of progression-free survival (PFS) or overall survival (OS). The sole exception was trial AVF2119, which did not achieve its primary endpoint; however, the potential of an efficacy interaction was also investigated in this trial.

The treatment affect achieved with the addition of Avastin to chemotherapy in these trials was similar, looking at either PFS or OS endpoints. The point estimates of effect were similar in ESA users versus non-ESA users, with broadly overlapping confidence intervals around those estimates. The data suggest no indication of a lessened treatment effect with Avastin when used in combination with ESAs.

Table Four: Hazard Ratios for Progression-Free Survival (PFS) and Overall Survival Patients in Avastin Clinical Trials Based on ESA Use Versus Non-ESA Use

Table Five displays the absolute treatment effect of patients in the control group compared to the Avastin group (i.e., those who received chemotherapy alone versus the vastin group who received chemotherapy with Avastin). The data suggest that ESA use may be associated with an inferior outcome, regardless of Avastin use; however because ESA use is associated with other negative prognostic features (as shown in Table 3), we cannot conclude, without further multivariate analyses, whether this inferior outcome is a direct result of ESA use or whether ESA use is simply a surrogate for a patient group with inferior outcomes due largely to other prognostic reasons. In the absence of data to indicate a direct correlation, CMS should refrain from implementing a policy that could unintentionally and negatively limit Medicare beneficiary access to Avastin, particularly when the overall positive treatment effect of Avastin in these patients is clear.

Table Five: Median Number of Months of PFS and OS for Patients in Avastin Clinical Trials Based on ESA Use versus Non-ESA Use

Safety of Avastin with ESA Use

Tables Six through Eight display the rates of three targeted safety signals: arterial thromboembolic events (ATEs), venous thromboembolic events (VTEs), and hypertension.

Table Six: Arterial Thromboembolic Events (ATEs) for Patients in Avastin Clinical Trials Based on ESA Use versus Non-ESA Use

Table Seven: Venous Thromboembolic Events (VTEs) for Patients in Avastin Clinical Trials Based on ESA Use versus Non-ESA Use

Table Eight: Hypertension* Observed in Patients in Avastin Clinical Trials Based on ESA Use versus Non-ESA Use

Based on these data, no additive or synergistic effect appears to occur in the three targeted adverse events outlined above for patients receiving ESAs and Avastin. Although the rate of VTEs appears to be higher in the ESA user group, this increase is independent of Avastin use.

Clarification Needed on Scientific Terminology

Genentech is concerned that CMS has not thoroughly defined some of the scientific terminology used in the Proposed NCD, which likely will cause inconsistent interpretations and confusion about how to implement the policy once finalized. In particular, it is not clear how CMS is defining anti-angiogenic drugs for purposes of the Proposed NCD. Besides Avastin, other FDA-approved anti-cancer therapies have mechanisms of action that include an anti-angiogenic effect, including small molecule oral VEGFR kinase inhibitors. Many classes of classical cytotoxic chemotherapy agents also have demonstrated anti-angiogenic effects in pre-clinical models.

Moreover, it is Genentech's understanding that when CMS refers to 'patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor,,'¹⁴ it means only antibodies directed against the human epidermal growth factor receptor (HER1)/EGF receptor. Although HER2, HER3, and HER4 also are members of the family of EGF receptors, we do not think CMS intended for products targeted against these receptors to be within the scope of the Proposed NCD. As a result, we have not addressed the impact of such products in our comments.

If our interpretation of the above language is not in agreement with CMS' intent, we request CMS provide more clarity and time for public comment before finalizing the policy specific to EGF receptors other than HER1.

III. Comments on Additional Data Collection Efforts

In the Proposed NCD, CMS solicits public comment on whether Medicare coverage for ESAs should 'only occur within appropriately designed clinical research studies where informed consent and safety monitoring can be assured..'¹⁵ Presumably, CMS is requesting comments on whether applying the principle of Coverage with Evidence Development (CED) is appropriate to gain an even better understanding of the clinical interaction between ESAs and anti-angiogenesis therapies like Avastin.

While Genentech continues to support CMS' efforts to collect data that would further inform treatment decisions for patients, including information on the use of ESAs in Medicare beneficiaries, we are confident such data collection efforts can be accomplished through existing patient registries that already are collecting related data. As such, we are opposed to CMS compelling manufacturers to conduct more costly large-scale data collection efforts to study CMS' perceived theoretical assumptions about ESAs and anti-angiogenesis. Such efforts are not a productive use of resources that otherwise would be used to develop therapies for unmet medical need.

IV. Conclusion

In summary, the data analyses Genentech performed in response to the Proposed NCD illustrate that in randomized, controlled clinical trials over 4,400 patients'600 of whom were treated with ESAs in addition to Avastinn'do not suggest a negative interaction between ESA and Avastin use, either with respect to safety or efficacy. We therefore believe that these data are sufficient to remove the restriction included in the Proposed NCD for coverage of ESAs when used in combination with Avastin.

In making its final determination, we urge CMS to reconsider the restrictions outlined in the Proposed NCD, and the negative impact these restrictions are expected to have on the care provided to Medicare beneficiaries. We also request that CMS fulfill its commitment to implement policy changes that are evidence-based and not based merely on theoretical assumptions.

Thank you for the opportunity to provide comments on the draft policy. Please contact Dr. Robert Mass at (650) 225-7223 or via e-mail at mass.robert@gene.com for any clinical questions regarding the above data analyses. Please contact Heidi Wagner at (202) 296-7272 or wagner.heidi@gene.com should you have any general follow-up questions regarding our comments.

Sincerely,
Walter Moore
Vice President, Government Affairs

References:
1 Social Security Act (SSA) 1862(a)(1)(A).
2 SSA 1861(t)(
3 Complete prescribing and safety information for Avastin is available at www.avastin.com.
4 Ibid
5 Proposed NCD
6 Gerber HP, Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med. 1003 Jan;81(1:20-31. Epub 2002, Dec 14. Kowanetz M, Ferrara N. VEGF signaling pathways: therapeutic perspective. Clin Cancer Res. 2006 Sep 1;12(17):5018-22. Ferrara N. VEGF as a therapeutic target in cancer. Oncology. 2005;69 Suppl 3:11-6. Epub 2005 Nov 21. Willett CG, Kozin SV, Duda DG, di Tomaso E, Kozak KR, Boucher Y, Jain RK. Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol. 2006 Oct;33(5 Suppl 10): S35-40. Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science. 2006 May 26; 312(5777):1171-5.
7 Tam BY, Wei K, Rudge JS, Hoffman J, Holash J, Park SK, Yuan J, Hefner C, Chartier C, Lee JS, Jiang S, Niyak NR, Kuypers FA, Ma L, Sundram U, Wu G, Garcia JA, Schrier SL, Maher JJ, Johnson RS, Yancopoulos GD, Mulligan RC, Kuo CJ. Title. Nature Medicine. 2006; Jul;12(7):793-800. Epub 2006 Jun 25. Kuo, CJ. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Proceedings of the National Academy of Sciences. 1998;4605.
8 Hardee M, Kirkpatrick J, Shan S, Snyder S, Vujaskovic Z, Rabanni Z, Dewhirst M, Blackwell K. Human recombinant erythropoietin (rEpo) has no effect on tumor growth or angiogenesis. Br J Cancer. 2005;93:1350-5.
9 Ribatti D. A potential role of erythropoietin in angiogenesis associated with myelodysplastic syndromes. Leukemia. 2002;16:1890. Ribatti D, Marzullo A, Nico B, Crivellato E, Ria R, Vacca A. Erythropoietin as an angiogenic factor in gastric carcinoma. Histopathology. 2003;42:2466'50. Ribatti D, Poliani P, Longo V, Mangieri D, Nico B, Vacca A. Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma. Histopathology. 2007;50:636-41. Ribatti D, Marzullo A, Gentilli A, Longo V, Nico B, Vacca A, Dammacco F. Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma. Histopathology. 2007;50:591-6.
10 Avastin Package Insert. Available at www.avastin.com.
11 Additional information on the 10 trials referenced is available on www.clinicaltrials.gov. 12 The remaining four trials were conducted under an Investigational New Drug (IND) application held by the NCI, which does not routinely utilize CRFs for concomitant medications and therefore ESA use in these four trials was not collected.
13 ECOG performance status levels are available at http://www.ecog.org/general/perf_stat.html
14 Proposed NCD
15 Ibid

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I am a practicing hematologist and oncologist. Your proposed coverage for hematopetic growth factors are detrimental to patients, hospitals, and medicare.

Patients will feel worse with all of the limitations, especially the utilization of a hemoglobin of nine, the limit to twelve weeks, and stopping if no response in 4 weeks. Additionally all of thie recomendations are contrary to clinical trial results and cliinical practice.

Hospitals will be overwhelmed by patients coming in for transfusions. Patients are treated more frequently and aggressively than in prior decades and require more supportive care. The increased transfusions will be at least as costly, are less safe for patients and will limit the availability of blood for other patients in the US and possibly overseas.

While i agree that further research is necessary to determine the effects of ESA's on tumors, there is no clinical data that receptors, if present, matter. Further there is no clinicla assay available to even evaluate this on a routine basis. To limit an excellent therapy in diseases like myeloma, and MDS and is truly ridiculous.

In summary, I feel that these capricious and arbitrary coverage recommendations designed solely based on a perceived financial benefit should be completely discarded. Reasonable modification of coverage should be based on FDA indications, sound data, and clinically expert opinion. Further i believe the CMS' financial outlook may deteriorate if these are instituted based on the increased use of blood transfusion, not to mention lost productivity days by patients under therapy.

Thank you for yor attention

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To Whom It May Concern,

I am a Nurse Practitioner at Pacific Oncology in Portland, Oregon. I acknowledge the need for an evidence-based response to the recent FDA warnings regarding the use of ESA's in cancer and related conditions. I agree that both clinical experience and recent data do indicate potential risks when ESA's are given for the following reasons:

-Hemoglobin levels greater than 12g/dl.
-The anemia of cancer, not related to cancer treatment.
-Anemia's related to vitamin or iron deficiencies.

However, I also believe that there is a strong lack of evidence to support the proposed National Coverage Determination (NCD) of ESA's as currently written. I am specifically concerned about the denial of ESA's in patients with anemia related to chemotherapy and coverage limitation to 12 weeks per year.

There is a substantial amount of evidence regarding improved quality of life for patients with chemo-induced anemia as well as large meta-analyses which demonstrate the safety of EPA's in this population (J Natl Cancer Inst 85: 801-806, 1993; J. Clin. Oncol. May 20, 2006; 24(15): 2290-2297).

The current proposal ignores this preponderance of evidence and claims that ESA's may be related to tumor growth. Currently, there is no clinical data which supports this notion.

The coverage limitation will deprive access to therapy for patients receiving prolonged or multiple treatments.

To date there is not adequate data to suggest that more than 12 weeks of ESA is dangerous or that less than 12 weeks of therapy is safer.

Furthermore, cessation of treatment should ultimately be determined by a patient's provider and the FDA.

I therefore urge CMS to review the current NCD of ESA's as it is far too restrictive, not evidenced based and potentially detrimental to the care and quality of life of patients with cancer and cancer related disorders. I urge CMS to consider the current FDA indications and guidelines as well as guidelines from the National Comprehensive Cancer Network, the American Society of Hematology and the American Society of Clinical Oncology.

Thank you for your consideration of this important matter.

Sincerely,

Joanne T. Eddington, MN, FNP, AOCN
Nurse Practitioner / Advanced Practice Manager

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I would like to express my feelings on the clinical aspects of this decision Noridian has made a regarding the coverage of Erythropoiesis stimulating agents for Medicare beneficiaries.The goal of treatment with ESAs is to increase the number of red blood cells in order to avoid blood transfusions, and thereby alleviate strain on the nations blood supply. We should also consider the fluid overload and iron overload in the individual patient from transfusions.The removal of darboepoetin (Aranesp) coverage for myelodysplastic syndrome (MDS) by Noridian is without clinical rationale. MDS is not commonly classified as a malignancy, but rather a comprehensive term for a heterogeneous collection of hematologic stem cell disorders affecting primarily older adults. At diagnosis, anemia is the most common abnormality with over 80% of patients presenting with hb concentrations < 10g/dlMDS is technically not a malignancy, and should be in it's own category.There is evidence to support the use of ESAs in patients with anemia associated with low-risk myelodysplasia. World health organization classifies low-risk myelodysplasia with less than 5% blasts to include the following forms of myelodysplasia: refractory anemia (ra)Refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia refractory cytopenia with multilineage dysplasia with ringed sideroblasts myelodysplastic syndrome, unclassified MDS associated with isolated del(5q)Refractory anemia can be defined as erythropoietic insufficiencies that cannot be assigned to a specific vitamin or mineral deficiency. Experts in hematology have used ESAs to treat anemic patients with multiple myeloma, non-Hodgkins lymphoma and chronic lymphocytic leuekmia (cll) in the absence of chemotherapy where the esas have proven effective, and without the toxicity of many more commonly used therapies. Although we do acknowledge there are no randomized clinical trials to support the use of ESAs in these hematological malignancies, we do strongly recommend this to be an area for further studies and evaluation.

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Dear CMS, Please allow the oncology specialist to decide appropriate care within the evidence-based guidelines for ESA usage;Eliminate the 12 week per year maximum treatment as it will underserve patients receiving prolonged chemotherapy;Do not change the criteria and delay the start of ESA therapy as this could force patients to the hospitals for transfusions;Allow use for patients with MDS as non-coverage goes against all accepted national clinical guidelines;Allow cancer patients to maintain their quality of life;Allow the treatment of cancer to advance — do not push it back to the days when blood transfusions were the patient's only alternative.Thank you for allowing these public comments before making your final decision.

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I am a practicing hematologist/oncologist and care for many patients undergoing chemotherapy. I am writing because I am extremely concerned about the proposed NCD regarding Erythropoeisis Stimulating Agents (ESAs). Here are my concerns:

1. Use of Hgb < 9g/dl as a treatment initiation point is inadequate.

Current data show that many of the patients who receive ESAs after Hgb drops to the < 9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (< 11g has been shown to be superior to < 10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.

Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

Thank you very much for your attention to this matter.

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June 6, 2007

Centers For Medicare & Medicaid Services
Attention: Public Comment on Draft CAG-00383N
7500 Security Blvd
Baltimore, Maryland 21244

To Whom It May Concern:

Recently, the Centers for Medicare & Medicaid Services released a proposed national coverage policy that would govern Medicare coverage of Erythropoiesis Stimulating Agents (ESAs) for non-renal applications. These proposals would have provisions including that the use of ESAs in conjunction with anemia of myelodysplasia and anemia of myeloid cancers would not be covered. In addition, the maximum cover duration for ESAs would be 12 weeks per year; and that the hemoglobin and hematocrit level prior to initiation of dosing for the month should be less than 9 grams/or less than 27% in patients without known cardiovascular disease and less than 10 grams/or 30% in patients with documented symptomatic ischemic disease that cannot be treated with blood transfusions.

I believe that a number of these proposals are in direct conflict with published scientific evidence and would be in conflict also with expert opinion delivered at the recent Oncology Drug Advisory Committee meetings. Implementation of these provisions would have the potential to introduce serious harm to the many cancer patients who rely on Erythropoiesis Stimulating Agents in the course of receiving treatment for their disease. As well it would seem premature for the Centers for Medicare & Medicaid Services to be making scientific judgments about the appropriate use of the Erythropoiesis Stimulating Agents prior to FDA decisions on the same issue.

Finally, I would be concerned that these proposals would set a dangerous precedent in which evidence based standards of high quality care are ignored in setting national policy. I would encourage the Centers for Medicare & Medicaid Services to reverse their decision to release these proposals,

Sincerely yours,

Anthony Phillips
KJB

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I would like to express my feelings on the clinical aspects of this decision Noridian has made a regarding the coverage of Erythropoiesis stimulating agents for Medicare beneficiaries.The goal of treatment with ESAs is to increase the number of red blood cells in order to avoid blood transfusions, and thereby alleviate strain on the nations blood supply. We should also consider the fluid overload and iron overload in the individual patient from transfusions.The removal of darboepoetin (Aranesp) coverage for myelodysplastic syndrome (MDS) by Noridian is without clinical rationale. MDS is not commonly classified as a malignancy, but rather a comprehensive term for a heterogeneous collection of hematologic stem cell disorders affecting primarily older adults. At diagnosis, anemia is the most common abnormality with over 80% of patients presenting with hb concentrations < 10g/dlMDS is technically not a malignancy, and should be in it's own category.There is evidence to support the use of ESAs in patients with anemia associated with low-risk myelodysplasia. World health organization classifies low-risk myelodysplasia with less than 5% blasts to include the following forms of myelodysplasia: refractory anemia (ra)Refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia refractory cytopenia with multilineage dysplasia with ringed sideroblasts myelodysplastic syndrome, unclassified MDS associated with isolated del(5q)Refractory anemia can be defined as erythropoietic insufficiencies that cannot be assigned to a specific vitamin or mineral deficiency. Experts in hematology have used ESAs to treat anemic patients with multiple myeloma, non-Hodgkins lymphoma and chronic lymphocytic leuekmia (cll) in the absence of chemotherapy where the esas have proven effective, and without the toxicity of many more commonly used therapies. Although we do acknowledge there are no randomized clinical trials to support the use of ESAs in these hematological malignancies, we do strongly recommend this to be an area for further studies and evaluation.

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It has always been a good practice to reevaluate clinical guidelines and make appropriate changes. Therefore, I commend CMS for reviewing ESA utilization. However, I don't believe that these were done for the best interest of the patient. It is evident that their position is a response to a political pressure to reduce the rising medical expenses by responding to inadequate clinical studies. The recent CMS proposed decision for ESAs seems to use a single study that did not show statistically significant results to stop coverage for many previously proven uses.It has been very clear that the use of ESA had a positive impact on patient life. Current ASCO guidelines seems to be very appropriate. CMS should reassess their position toward blood transfusion and the risk that they expose the patient to by receiving the blood transfusion. Also, CMS should take in consideration the availability of blood or lack of.

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June 13, 2007

Via electronic mail and U.S. mail
Barry M. Straube, M.D.
Director and Chief Medical Officer
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
Mail Stop S3-01-02
7500 Security Boulevard
Baltimore, MD 21244-1850

Steve E. Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop: C1-12-28
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for Non- Renal Disease Indications (CAG-00383N)

The Pharmaceutical Research and Manufacturers of America (PhRMA) appreciates this opportunity to submit comments to the Centers for Medicare and Medicaid Services (CMS) on its Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG- 00383N) (Proposed ESA Decision Memo).

PhRMA is a voluntary, nonprofit organization representing the country's leading research- based pharmaceutical and biotechnology companies. Our members are devoted to discovering and developing medicines that allow patients to lead longer, healthier, and more productive lives. PhRMA is committed to the application of the best available evidence in Medicare coverage policy as the basis for timely patient access to safe, effective therapies. Based on this commitment, we offer these comments on the Proposed ESA Decision Memo. Our comments are intended to address policy issues broadly applicable to Part B that are raised by the Proposed Decision Memo, rather than to address the application of proposed CMS policies to any specific products.

PhRMA appreciates the efforts that the agency is making to ensure appropriate Medicare coverage policy in a clinically dynamic, complex environment. However, PhRMA is concerned that the Proposed ESA Decision Memo by rendering judgments on product safety and effectiveness in advance of possible product labeling changes intrudes into the Food and Drug Administrationn's primary responsibility for judgments about clinically appropriate uses of regulated products based on evidence of safety and effectiveness. CMS long has recognized FDA's lead role on these issues, including in statements in the Medicare Benefit Policy Manual. However, we are concerned that, instead of deferring to FDA, CMS issued the policy prematurely, prior to FDA completing its evaluation of the same issues that CMS is addressing in the Proposed ESA Decision Memo. PhRMA also is concerned that CMS is imposing coverage restrictions, including restrictions on indications and uses included in FDA-approved labeling, that in some cases are not supported by clinical and scientific evidence.

As a result, the proposed CMS policy, if finalized in its current form, could create significant barriers to patient access to needed care. CMS should maintain the current coverage of ESAs in cancer and related neoplastic conditions until FDA has had time to evaluate and fully analyze the input it has recently received from its Oncology Drug Advisory Committee (ODAC). In the event that CMS adopts a change in coverage policy at this time, we strongly encourage CMS to ensure that any changes are better aligned with FDA-approved labeling and maintain physicians' ability to prescribe optimal care to individual patients based on this labeling.

I. CMS' Proposed Decision Memo Intrudes on FDA's Jurisdiction Over Determinations of Safety and Efficacy of Pharmaceuticals

In the proposed ESA Decision Memo, CMS proposes a number of restrictions on current coverage of ESA for cancer and related indications, including non-coverage for 13 indications and six additional limitations on use. We are concerned that, as a result of both the timing and nature of these restrictions, CMS is intruding into FDA's primary jurisdiction over matters related to the safety, effectiveness, and appropriate clinical use of regulated products.

Assurance of patient safety is of paramount importance in federal health policy. To this end, policy decisions must appropriately balance the inherent benefits and risks of medical interventions. Responsibility for assuring the safety and effectiveness of medical products is core to FDA's public health mission and expertise. The coverage restrictions proposed by CMS intrude into this central FDA responsibility. FDA is the Nationn's Premier Consumer Protection and Health Agency, whose decisions affect products whose safety and effectiveness is our responsibility... FDA has the primary responsibility, and a unique scientific capability, to determine the safety and effectiveness of drugs and biologicals and other regulated products.

CMS' proposed ESA Decision Memo runs counter to the agency's long-standing policy of deferring to FDA on safety and effectiveness of drugs and biologicals for labeled indications. In fact, the Medicare Benefit Policy Manual states as a condition of coverage that the '[u]se of the drug or biological must be safe and effective and otherwise reasonable and necessary,' and that '[d]rugs or biologicals approved for marketing by the Food and Drug Administration (FDA) are considered safe and effective for purposes of this requirement when used for indications specified on the labeling...' CMS also has stated: 'Whereas the FDA must determine that a product is safe and effective as a condition of approval, CMS must determine that the product is reasonable and necessary as a condition of coverage . . . CMS adopts FDA determinations of safety and effectiveness, and CMS evaluates whether or not the product is reasonable and necessary for the Medicare population...' In this instance, however, CMS is proposing restrictions on labeled indications, which would be contrary to the established policy of relying on FDA for safety and effectiveness determinations for FDA-approved indications.

II. CMS' Proposed Decision Memo is Premature Relative to FDA's Decision Processes

In recognition of FDA's lead role and expertise for decisions regarding the safety and effectiveness of regulated products, CMS should ensure that, if and when it does adopt changes in coverage policy related to product safety or effectiveness, those changes reflect FDA determinations. By issuing the Proposed ESA Decision Memo on Monday, May 14, CMS did not give FDA time to fully evaluate the information and expert advice it received at the ODAC meeting on Thursday, May 10. FDA's Center for Drug Evaluation and Research convened the advisory committee meeting to discuss updated information about particular uses of ESAs.

If CMS acts to make changes in Medicare coverage policy for ESAs, it should do so on the basis of FDA's evaluation (which could be either to maintain current FDA regulatory policy regarding ESAs or to implement labeling or other changes), especially considering the wide range, complexity and clinical heterogeneity of the issues being evaluated.

CMS cites 'emerging safety concerns' as the basis for its coverage proposal, which includes draft policy that would non-cover ESAs for some uses that are approved for use by FDA and impose significant new restrictions on other FDA- approved indications. While these emerging concerns are important to consider, their emergent nature is strong reason for CMS to give FDA time to fully evaluate them and consider potential action based on that evaluation. In order to benefit fully from FDA's expertise and establish policy aligned with FDA regulatory decisions, CMS should refrain from developing new coverage policy until FDA has had sufficient opportunity to consider properly all of the information and expert advice presented at the recent ODAC meeting. This will ensure that CMS coverage policy does not conflict with FDA regulation.

III. Medicare National Coverage Decisions Should be Based On the Available Scientific Evidence

PhRMA also is concerned that the Proposed ESA Decision Memo proposes coverage limitations that inappropriately extend well beyond conclusions grounded in the available scientific evidence, and could therefore negatively affect clinical decision making. Our purpose here is not to engage in the discussion about the relative strength or weakness of the scientific basis for all elements of the Proposed ESA Decision Memo. Rather, we highlight that the decision memo includes some provisions that are put forward without supporting clinical and scientific evidence.

For example, organizations representing oncologists and hematologists, such as the American Society of Clinical Oncology and the American Society of Hematology, have raised concerns about the scientific and clinical basis for several aspects of it. These and other organizations have raised concerns in areas such as CMS' proposals for:

• Non-coverage of ESAs in conjunction with anemia of myelodysplasia and anemia of myeloid cancers;
• Maximum covered treatment duration of 12 weeks/year; and
• Hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be < 9 g/dl/27% in patients without known cardiovascular disease and < 10 g/dl/30% in patients with documented symptomatic ischemic disease that cannot be treated with blood transfusion.

Similar concerns also have been raised for other proposed restrictions, including restriction on use of ESA with anti-angiogenic and anti- epidermal growth factor receptor (EGFR) monoclonal antibody therapies, and limitation on use of ESAs under specific conditions for the treatment of anemia in those types of cancers in which the presence of erythropoietin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature.

We urge CMS to carefully reexamine these proposals, and the entirety of its recommendations, to ensure that the final NCD is firmly grounded in scientific evidence and sound principles of evidence-based medicine.

IV. CMS' Proposed Decision Memo Should Not Restrict Access Only to Clinical Trials

CMS states that it is interested in public comment on 'whether coverage for ESA therapy for Medicare beneficiaries with cancer should occur only within appropriately designed clinical research studies where informed consent and safety monitoring can be assured...' It is premature for CMS to suggest this type of severe patient access restriction. We recommend that the agency not implement a policy based on this suggestion in the final NCD.

While PhRMA supports evidence-based medicine and clinical research, we believe that limiting the coverage of ESA therapy for cancer patients to only clinical trials would be overly broad, unwarranted, and inconsistent with CMS policy. CMS has stated that: 'When the evidence is inadequate to determine that the item or service is reasonable and necessary under section 1862(a)(1)(A), Medicare coverage may be extended to patients enrolled in a clinical research study...' CMS has acknowledged that ESAs are reasonable and necessary for patients with certain cancers, and therefore it should not require these patients to enter a trial in order to receive treatment. Restricting beneficiary access to a clinical research protocol would contravene one of the principles governing the CMS policy in this area, which is spelled out in the agency's guidance on Coverage with Evidence Development. In the guidance, CMS states that it 'will not duplicate or replace the FDA's authority in assuring the safety, efficacy, or security of drugs, biological products, and devices...' Restricting coverage of ESAs only to clinical trials could impose significant barriers to access to many Medicare beneficiaries (for example, those who did not live near a clinical research site), and we urge CMS not to impose this coverage restriction.

V. Conclusion

PhRMA appreciates this opportunity to provide input on the Proposed ESA Decision Memo. We urge the agency to proceed judiciously and with a proper understanding of the FDA's role, and thus to refrain from making any changes in national coverage policy until FDA has evaluated the input it received from ODAC at the May 10, 2007 meeting. The final NCD should preserve the current coverage criteria for ESAs for non-renal disease indications while providing CMS the opportunity to revisit the issue after FDA has evaluated ODAC advice. We also suggest that CMS revise the proposed decision so that it is consistent with FDA labeling for ESAs such that ESAs are covered for all FDA-approved indications and uses as well as uses consistent with compendia listings. We look forward to working with CMS in the future on this important initiative.

Sincerely,

Richard I. Smith

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The decision of CMS re: ESA is absolutely absurd! I have been using ESAs since its availability and have helped lots of patients who have EPO deficient anemia.

It is important for physicians who use ESAs to follow and adhere to certain rules. Viz, checking H & H weekly or bi-weekly depending on the product used. Also, B12 and folate studies q 12 weeks to make sure the stores are not depleted. Otherwise, the patient will not respond. If these guidelines are followed strictly, the benefits of these drugs are phenomenal, such as:1) Avoidance of transfusion, thus decreasing risk of transfusion-related complications which include: reactions, delayed transfusion-related hemolysis, auto sensitition with multiple transfusions, infectious complications, fluid overload, etc. Besides, transfused blood does not last long anyway. Once frequency of transfusion is increased then the transfused cells last only 10-12 days necessitating additional transfusion. Then comes the iron load and then the need for iron chelation which is exorbitantly expensive. The cost of transfusion is another issue. Wish the need of transfusion to keep Hct even above 30, the patient will have to transfuse every 10-15 days, increasing the cost of care to much more than the cost of ESAs.

The need for timely chemotherapy is absolutely essential to keep malignancy under control and anemia is definitely going to delay chemotherapy.

The majority of CMS patients have associated co-morbidity and most often it is cardiac or pulmonary. The drop in Hct below 30 will make these patients fatigued, totally exhausted and you add chemotherapy to that, then their response is going to be poor and they will refuse chemotherapy. Thus, changing the current parameters of when to start ESA and stop it is going to have a major impact on the quality of life of these patients. The elderly retired patients should not be denied the best available low risk therapy which is going to improve their quality of life. The Government, CMS, or physicians are not a 'Super Power' who should be dictating to patients with cancer what their choices are. It should strictly be a decision of the patient who should have personal freedom to make informed decisions about their own care. That is what makes this a great country, and why others outside of this great country envy us. I, as a physician who has been practicing for the past 30 years in this country, urge you to make a rational decision based on individual rights and not the cost of a medication. If you uphold your current decision, you will be facing a major calamity, not just a shortage of blood supplies, but refusal on the part of patients to take frequent transfusions. Recurrence and spread of cancer and what we have achieved in the past 25 years of decreasing death due to cancer is going to be going in the other direction!

So I urge you do not listen to politicians, businessmen, or even physicians who are administrators, but listen to the physicians who are in the trenches who have face to face contact with the patients with their social and physical problems and are resolving them to the best of their abilities. Do not make these physicians weaponless.

Suresh B Katakkar, MD

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Anemia is a common problem confronted by most hematologists/ oncologists in community practice. Prior to the availability of erythropoietin stimulating agents (ESA) treatment of anemia was largely limited to transfusions, with associated inconvenience; cost; and risk of sensitization, transfusion reactions, volume overload, and infection.

The use of ESA has dramatically and substantially improved the management of many patients with anemia. My personal experience and many clinical studies have validated an improvement in quality of life (QOL) that corresponds with a rise in hemoglobin from ESA use.(1,2,3) Furthermore, many trials have suggested that the greatest net improvement in QOL scores occurs with a hemoglobin rise between 11 gm/dl and 12 gm/dl (4). In addition, both retrospective and prospective trials have provided evidence that early intervention with ESA, prevents a decline in hemoglobin and ultimately proves cost-effective, as less drug is required to achieve a desired hemoglobin.

I am concerned that a reduction in the availability of ESA in cancer patients and patients with blood disorders will severely and adversely affect patients quality of life, productivity, motivation and ability to endure the demands of cancer treatment.

Recent data has raised concerns about the safety of ESAs in certain patient populations. I caution CMS to exercise caution in interrpreting these findings. Many of these studies targeted a hemoglobin higher than those allowed or recommended in clinical practice. In addition in several of these studies the end point of concern (eg excess mortality) was not the intended endpoint of the study.

Enough of a concern has been raised to (1)justify a "black box" warning; (2) stimulate physician and patient discussion regarding the appropriateness of commencing or continuing ESA therapy in potentially high risk situations (eg. would a patient with advanced terminal cancer, not receiving chemotherapy, be willing to accept a potentially small increased risk of mortality if it meant improvement in QOL during remaining life?); and (3)to mandate additional specific clinical trials to further explore the potential harful effect as it applies to specific patient subsets.

It is however, essential that CMS not seize this opportunity to mandate sweeping, unjustified changes in the use of ESA as a cloaked maneuver to contain costs.

ESA have been used in the management of anemia in patients with myelodysplasia and some hematologic malignancies, based on established, peer-reviewed published guidelines. The use of these drugs has dramatically reduced the need for transfusions for many patients. Compared to a little over a decade ago, it is now considerably less common that a patient with myelodysplasia (or other bone marrow failure state) will be inconvenienced by the burdon of frequent (sometimes weekly) transfusions. Many of these patients in the pre-ESA era would die from complications of frequent transfusions long before they would die of their underlying disease.

In addition, anemia may be the only manifestation of disease for certain patients with myeloma and othe hematologic malignancies. These patients may go for months or years with their anemia effectively managed with ESA alone, avoiding the need for cytotoxic chemotherapy or other treatments.

Finally, I raise concern about imposed mandatory dose reduction of ESA if a certain targeted hemoglobin threshold is exceded (currently 12 gm/dl in the state of NJ). I believe a more desirable approach is to decrease the frequency of injections, while maintaing dose. This approach achieves the same goals of attenuating hemoglobin rise and reducing the use of ESA, while allowing patients less frequent visits for injections (not trivial for many elderly patients who travel long distances to receive ESA). In addition, decreasing the frequency of injections (as opposed to mandatory dose reduction) allows one to work with existing stock of ESA and greatly simplifies nursing time and aggravation in determining appropriate ESA dose.

1 Littlewood TJ et. al. JCO 19:2865,2001

2Straus et. al. Seminars in Hematology 39 (sup 3) 25-31, 2002

3Patrick DL, et. al. Eur Journal of Cancer 39:335, 2003

4Crawford J et. al.Cancer 95: 888, 2002

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The 7 physicians in our pracrtice have reviewed and commment as follows:
1. 12 week duration of treatment per year: If ESAs maintain a hemoglobin level and then are discontinued with subsequent redevelopment of symptomatic anemia, under the 12 week rule, we would have to discontinue use for a year even if there is a subsequent decrease iln hemoglobin to pre ESA levels

2. 126,000 units / week: Patients are treated in the community for non-renal disease with 160000 to 200000 units per 4 weeks.

3. Quality of life: Symptomatilc anemia whlich is present can add to reduced quality of life in patients with terminal disease, even without chemotherapy treatment.

4. Risks of blood products: The use of blood products have a multitude of side effects. To presume they are safer than ESAs is unscientific and simplisdtic.

5. Knowledgeable patients are complaining that CMS, whose goal should be quality and cost containment, is worrying more about the latter than being concerned about quality.

6. We heartily agree with the observations and recommendations of ACCC and ASH.

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As a health care worker I find the scope of the proposed limitations on the use of Aranesp and Procrit alarming. I do agree that the use of these products should be only when they have been proven to be safe and efficacious. However, to limit their use to HGb levels of 9 and below is not in the best interest of patients. To suggest that blood transfusions are an acceptable alternative is not true in my opinion. Even if our hospitals had available beds the risks involved with transfusions is unacceptable. Additionally the decrease in the quality of life in these patients would significantly suffer.

I suggest limiting their use to HGb levels of less than 10 to 11, with their discontinuation above a value of 12. The literature supports this range.

Thank you for this opportunity.

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June 13, 2007
Via Electronic Submission and Mail

Steve Phurrough, MD, MPA, CPE
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mail Stop: C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244

Re: Comments Regarding Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

Dear Dr. Phurrough:

1. The PDM Fails to Follow Decision-Making Guidelines for National Coverage Determinations.

CMS has stated that its determinations regarding whether services are reasonable and necessary are to be based on 'the best scientific and clinical evidence available . . . and the highest attainable level of expertise to evaluate such evidence' CMS has explained that principles of evidence-based medicine should be used to derive coverage positions. In the PDM, however, CMS has chosen to ignore evidence that should be given at least equal weight based on the opinions of experts who have carefully considered the use of ESA for anemia in cancer treatment.

For example, the PDM relies heavily on an unproven erythropoietin receptor theory to limit coverage of ESAs for use in cancer treatment, despite the absence of definitive evidence (1) that erythropoietin receptors on cancer cells exist, (2) that cancer cells respond to erythropoietin signals, or (3) that there exists any link between erythropoietin receptors and tumor progression. The erythropoietin receptor theory, however, has been questioned by experts in the field and CMS has not explained why it has chosen to ignore clinical findings in favor of a theory that is unsupported by significant empirical research.

The proposed Medicare coverage policy would also impose coverage restrictions well beyond what is warranted by available 'scientific or clinical evidence' on safety and effectiveness. We believe that CMS should consider all of the available evidence, including the experience of treating physicians with experience in the management of anemia in cancer treatment situations.

2. The PDM Excludes Myelodysplastic Syndrome (MDS) Without Supporting Evidence.

Numerous reported studies demonstrate the benefit of ESAs in treating MDS patients, including the reduction in the need for transfusions, and avoiding transfusion dependence and the related risks of transfusion, and while the use of ESAs has been incorporated into evidence-based guidelines, CMS proposes to deny coverage in MDS cases in the absence of evidence of adverse survival outcomes for these patients. CMS should remove MDS from the conditions excluded from ESA coverage in the final NCD.

3. The PDM would Impose Limits on the Initiation and Duration of ESA Therapy that are Inconsistent with Principles of Evidence-Based Medicine and Sound Medical Science.

The imposition of mandated, rigid initiation and treatment suspension thresholds by the PDM is not supported by clinical experience or empirical evidence because, for different patients, different hemoglobin levels may be acceptable and different durations of therapy may be required avoid transfusion risk and to achieve other established clinical benefits of anemia treatment. Medicare coverage policy should allow treating physicians to treat their patients, not just their hemoglobin levels. We discuss each of these proposed limits below.

A. Proposed Initiation Threshold

The PDM proposes delaying the initiation of ESA treatment (indeed, perhaps any treatment) of anemia induced by chemotherapy until the patient's hemoglobin level reaches 9 g/dL. CMS does not cite scientific or clinical evidence to support its proposal, which appears to be based on a critical care model that does not reflect current evidence-based treatment practices. In fact, while the current FDA-approved labeling warns against administering ESAs after a patent achieves a hemoglobin level of 12 g/dL, it does not recommend any particular initiation threshold. The FDA-approved labeling recognizes that treating physicians need to exercise medical judgment regarding when to initiate ESA treatment for each particular patient. The PDM, however, fails to permit such flexibility even though patients frequently experience significant symptoms of anemia at hemoglobin levels above 9 g/dL. Treating physicians must retain flexibility to begin ESA treatment sooner to address these symptoms, such as: fatigue, lethargy, ashen grey pallor, shortness of breath, and potentially including myocardial infarction as well as the effects of comorbidities associated with low tolerance for anemia (e.g., coronary artery disease, chronic pulmonary disease and major organ dysfunctions such as liver and kidney abnormalities), severity of presenting anemia symptoms, the effects of the particular chemotherapy regimen, the timing of the anemia presentation and hemoglobin measurement in relation to the ordered chemotherapy administration, the particular ESA treatment that is being employed, and the treating physician's real time assessment of the individual patient's clinical situation. We believe that requiring a physician to wait for anemia to become severe enough to require transfusion in some patients before starting ESA therapy is misguided; the principal indication for ESA therapy in the FDA-approved labeling is avoiding the need for RBC transfusion, but the proposed policy would unnecessarily expose Medicare cancer patients to risks associated with receiving transfusions when ESA therapy is intended to avoid that risk.

Furthermore, the proposed initiation threshold is inconsistent with most reported randomized clinical trials, which initiated therapy when hemoglobin fell below 11 g/dL and with evidence-based practice guidelines issued by the American Society of Hematology and American Society of Clinical Oncology, and the National Comprehensive Cancer Networks have recommended initiation of ESA treatment in cancer patients as soon as a patient's hemoglobin falls below 11 g/dL. Although further research on the question is required, limiting coverage to the use of ESAs in patients with hemoglobins not exceeding 12 g/dL may be warranted, but there is no basis in the literature cited in the PDM for imposing an initiation threshold lower than 11 g/dL.

The proposed initiation threshold should not be included in the final NCD.

B. Proposed Duration Limitation

Chemotherapy regimens frequently provide treatment lasting beyond 12 weeks, and many patients require multiple shorter courses of chemotherapy exceeding 12 weeks in aggregate during a year, based on their individual clinical situations. In fact, patients undergoing cancer treatment develop anemia not only during actual chemotherapy administration, but also following the completion of a course of chemotherapy, across periods that vary based on the type of cancer being treated and the specific chemotherapeutic agents used. Despite these facts, the PDM proposes to limit coverage of ESAs for cancer patients to a maximum of 12 weeks per year. This limitation is simply unfounded. We do not believe that data exist to support the imposition of any duration limitation, and that the inclusion of such a limitation would be arbitrary and capricious.

The proposed limitation should not be included in the final NCD.

4. CMS Should Not Limit Coverage to Clinical Research Settings.

CMS requested comments regarding whether coverage of ESAs for anemia in cancer treatment situations should be limited to clinical research settings. In this regard we note that the FDA retains primary responsibility for assuring safety and has determined that ESAs are considered safe and effective when used according to approved labeling, which now includes the new 'black box' warning. Accordingly, there is no reason that the Medicare program should limit coverage to clinical trials based on safety concerns. The Medicare program might properly limit coverage based on safety concerns to the letter of the FDA-approved labeling, but it should not impose any narrower coverage requirements on that basis. The final NCD should cover ESAs for cancer treatment indications when used in accordance with FDA-approved labeling without additional limitations or requirements.

If CMS limits Medicare coverage of ESAs for FDA-labeled indications to clinical research studies, the effect will be to deny coverage to numerous beneficiaries who cannot participate in such trials (e.g., because of lack of trials in their locality, or participant qualifying criteria under specific clinical trial protocols). In addition to the unfairness of effectively limiting FDA- approved treatment options based on geography or other irrelevant factors, the fact remains that most community oncologists are not investigators and that such a limitation could result in inappropriate interference with patient-physician relationships. Furthermore, such coverage limitations for ESAs would effectively force many Medicare cancer patients into dependence on red blood cell transfusions for anemia management.

5. Encouraging Substitution of Transfusions for ESA Treatment is Unsafe.

The proposed coverage policy is inconsistent with patient safety since it would encourage providers to use blood transfusions instead of ESA therapy. The proposed coverage policy would encourage the substitution of transfusions for ESA treatments by requiring hemoglobin levels at which transfusions may be necessary before covering ESA treatment and by forcing beneficiaries to choose between paying out of pocket for ESA treatments based on Advance Beneficiary Notices (ABNs) from providers or a covered transfusion. We believe that this policy is inappropriate since transfusions present significant clinical risks, including viral and bacterial infections; transfusion-related acute lung injury; febrile reactions; hemolytic reactions; administration of wrong blood due to clerical errors; and iron overload in patients, such as MDS patients, who must receive repeated and prolonged transfusions. The PDM also fails to consider the impact of the proposal on the nation's already-challenged blood supply and the prospect that transfusions-which could have been avoided by timely ESA therapy-may be unavailable when needed by Medicare patients. We believe that the proposed Medicare coverage policy would further, and unnecessarily, strain the existing blood supply.

* * *

We appreciate the opportunity to comment on the PDM. Thank you for considering these comments in preparing the final NCD regarding ESAs for Non-Renal Disease Indications.Sincerely,

Timothy P. Blanchard

Please also see endnotes transmitted in emailed version of these comments.

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June 13, 2007

Leslie V. Norwalk, Esq.
Acting administrator
Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
Room 445-^
Hubert H. Humphrey Building
200 Independence Avenue, SW
Washington, DC 20201

RE: CAG#000383N, The Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions

Dear Acting Administrator Norwalk:

On behalf of the National Black Nurses Association, which represents 150,000 African American nurses in the United States; with 77 chapters in 34 states, I would like to thank the agency for this opportunity to submit comments regarding the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions. As part of its mission, NBNA works tirelessly to eliminate health care disparities among the unserved and the underserved communities of color.

NBNA is concerned about the use of and payment for ESAs to treat anemia in people with cancer. NBNA has long-standing positions that health professionals and patients should make appropriate decisions about their health care. ESAs are vital to this care for cancer patients. For example, shortening of the time that ESAs are available will place in jeopardy cancer patient's health. According to oncology nurse experts, patients do not want to go through unnecessary blood transfusion when ESAs will help them manage anemia and other side effects relating to cancer and cancer treatment.

NBNA hopes that the Medicare reimbursement for ESAs will reflect the full scope of services related to treatment for cancer patients, and specifically related to anemia. NBNA believes that it is important for CMS to take into consideration treatment regimen that adhere to national practice guidelines through scientific consensus.

Sincerely,

Millicent Gorham, MBA
Executive Director

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The CMS proposed Guidelines are not supported by clinical evidence but more likely the thought of saving money, which in the outcome is actually more costly. Our Gynecologic Oncology Practice uses ESAs according to the current guidelines and only while our patients are being treated with chemotherapy and or radiation therapy. To deny our patients ESAs would necessitate blood transfusions as our only alternative.We ask that your final NCD be based upon the available scientific evidence and allow us to continue to follow our evidence-based national treatment guidelines.There is literature showing the risk of requiring a transfusion goes up the lower the initiation hemoglobin, with an initiation level of 11 appearing to be optimal. Similarly, there are no data to support an arbitrary 12-week limit to therapy. Review of the relevant publications showing a safety signal does not reveal a relationship between length of exposure to ESA and safety. I am unable to find a scientific explanation for these recommendations. ESA therapy has been recognized as a standard of care for a number of myelodysplastic syndrome (MDS), supported by national guidelines (ASCO, ASH, and NCCN) for years. I am unable to identify any safety concerns in any of the relevant medical literature to support the proposed changes. In fact the justification for the proposed changes remains very unclear.Tina Q. Harris, NP-C

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To Whom It May Concern,

I am a Nurse Practitioner at Pacific Oncology in Portland, Oregon. I acknowledge the need for an evidence-based response to the recent FDA warnings regarding the use of ESA's in cancer and related conditions. I agree that both clinical experience and recent data do indicate potential risks when ESA's are given for the following reasons:

Please delay changes until after the FDA has issued it's final report and changed it's existing labeling for ESAs. Medicare and Medicaid patients with the cancers most effected by this decision deserve continued care based on current standards. It is too much to ask a MDS patient to go from Procrit to increased transfusions, just to save Medicare dollars. Please keep the patients best interest in mind when deciding to pull coverage for a treatment that is working for many of them. They deserve every small consideration that can be give to them. Thank you for your consideration, Brenda Chaloupka

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On behalf of the 16 physicians and providers of The Center for Cancer and Blood Disorders I am submitting the following comments in response to the proposed changes in ESA coverage in non-renal disease indications (CAG-00383N). Our clinicians strongly believe this proposal lacks scientific support and should be withdrawn pending future determinations, if any, by the Food and Drug Administration (FDA).

Our clinicians consider ESA therapy a vital component of the cancer care provided to our patients. For many years ESAs have given cancer patients a significant improvement in their quality of life; greatly reduced risky transfusions and minimized dangerous delays in treatment regimens. The CMS proposed changes will place the practice of oncology back 15 years to a time where costly hospitalizations were numerous; many patients received risky transfusions and outcomes were detrimentally impacted by chemotherapy regimen delays.

As is the case with many oncology practices The Center for Cancer and Blood Disorders has a natural utilization policy. This policy prohibits anyone in the practice or any outside representative from discussing drug pricing or costs with our clinicians. As a result, I am not able to assess the financial basis for the CMS proposal. However I will outline below the scientific/clinical concerns I have with the major points of the proposed decision memorandum:

As a Practice Administrator and Oncology Nurse I was quite shocked to see the draft proposal for ESA for non-renal disease indications. After the advancements that have been made in oncology over the past few decades, it seems as if this will be a giant step backwards. Patient's quality of life have improved dramatically with the use of supportive drugs such as the ESAs and now we are going to jeopardize the quality of life that we have given the patients. As the draft proposal has been presented, there are many indicated diagnosis that have been approved by the FDA for the use of ESAs that will not be a covered diagnois in the NCD. I am not sure how CMS can state that the treatment is not reasonable and necessary for the beneficiaries with these clinical conditions. I see the benefit of these supportive drugs in our patients everyday. When you tell a patient that they don't need a blood transfusion and you see the smiles and tears of joy, then you will see the benefit of these patients. I think that CMS is jeopardizing the advancement in care that we have given these patients and ultimately the cost of healthcare will rise because the patients will require tranfusions on a consistent basis, which puts each patient at risk for developing infections, hospilizations, and transfusion related reactions. Other issues that need to be addressed are the hemoglobin level initiation - a patient will already be at a level where a transfusion would be required upon initiation of the ESAs. The maximum duration and amount are unreasonable. Many times it takes approximately four weeks to get at least a 1g/dL rise and if we don't see that rise, then we would increase the dose for the patients. This is the package insert that was approved by the FDA and now CMS is stating patients can't receive the ESAs for the indication and utilization that the FDA had approved the ESA. Also the increase in weight in a two week period of (5kg). Many of the patients may have a weight gain, because their quality of life has improved and they feel like eating. Sometimes the chemotherapy treatments help the disease process and patients gain weight. I am not sure that we can look at a 5kg weight gain as an indication to stop ESAs treatment. Of course, all nurses would assess for fluid retention and this would be addressed and orders received from the physician. I hope that CMS will take the comments that have been made and revise the proposed decision for ESAs.

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It is with great disappointment that I read about the proposed changes in the Medicare coverage of the erythropoietins. Supportive care in oncology has permitted greatly improved quality of life. Patients have more energy, tolerate chemotherapy much better and are able to live longer and safer as a result of these agents. As an oncologist I've seen the real benefit of these for my patients. I have not made the rules regarding their use or reimbursement but have adhered to evidence-based medicine. Although the reason for the proposed changes is in part justified as a safety issue there is no question that economics is the driving force. It insults the intelligence of the treating physicians to say that EPO is unsafe or has its benefits outweighed by risks. I wish that if the real reason for markedly restricting the use of EPO is $$ CMS would be honest and state that. To say that erythropoietin is unsafe is genuinely ridiculous. This is a class of agents that has lead to significant reductions in transfusions and transfusion-related reactions, time in the hospital, potential for transmission of infectious agents etc. Clearly restricting or eliminating their use in some of the proposed settings is akin to throwing out the patient with the bathwater. Please don't let our cancer patients suffer under the guise of safety concerns.

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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

June 13, 2007

By Electronic Delivery

Steve Phurrough, MD, MPA
Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (CAG-00383N)

Dear Dr. Phurrough:

On behalf of the Alliance of Dedicated Cancer Centers (ADCC), an alliance of ten nationally recognized institutions focusing exclusively on the care of cancer patients, I am writing to comment on the above-referenced proposed national coverage decision on erythropoiesis stimulating agents (ESAs) for non-renal disease conditions (CAG-00383N), as published on CMS's website on May 14, 2007. The Cancer Centers, individually listed above, appreciate the opportunity to submit these comments.

The ADCC wishes to comment on several specific aspects of the proposed decision memorandum. These comments represent a clinical consensus achieved after extensive discussion among a number of leading experts at the ADCC Centers. Our comments are summarized below:

Clinical condition restrictions:

June 13, 2007
Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244

RE: National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

As a practicing community based hematology and oncology practice we have observed the changing landscape of cancer treatment in the US over the past 16 years. Today we have more to offer our patients in converting a diagnosis of cancer to a cure or a chronic disease instead of just a terminal one. While many of the newer targeted drugs have allowed for this gain, Erythropoiesis Stimulating Agents (ESAs) have been a major part of this change. We view the ESAs as a remarkable supportive drug and also in many of the diseases we treat we consider it part of the treatment.

A scripted drugs' use is evaluated and decided upon by recommendation of the practicing physician in collaboration with the patient, taking into account the risk-benefit ratio. It is assumed that if a drug has to be controlled by script that there are issues of safety and efficacy We allow the marketing and sale of products like peanut oil and peanut products and seafood, fully aware of the injury and death that faces an at risk population with various serious food allergies.

While we are in the age of entering outcome-based medicine it would be hypocritical to base patient access to top efficient care based on fuzzy science. I recently attended the FDA ODAC meeting. Many issues were addressed with more agendas than speakers. I was amazed that a scientific body was using an algorithm similar to some healthcare insurance companies' formula for quality healthcare (the lower the cost the better the provider - no reference to the outcome of the patient!)

I will be commenting on the points of the NCA and citing references whenever possible.

The American Society of Clinical Oncology (ASCO) in their June 8, 2007 response pointed out a major legal issue of these proposed changes:
- Legal Considerations
The Medicare statute was amended in 1993 to restrict the ability of CMS and its contractors to deny reimbursement for drugs and biologics used in cancer chemotherapy. Section 1861(t)(2) of the Social Security Act (42 U.S.C. Â1395x(t)(2) defines covered drugs as including -any drugs or biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication. A 'medically accepted indication' includes 'any use which has been approved by the Food and Drug Administration,' as well as uses supported by references in medical compendia that have not been specifically determined by the Secretary to be medically inappropriate. Therefore, CMS lacks authority to make coverage decisions that are narrower than the FDA-approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. The proposed decision memorandum is completely inconsistent with these Medicare provisions and must accordingly be withdrawn. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings unless they are found to be medically inappropriate.

Section I.

We appreciate that the FDA was given several safety signals from multiple studies that were performed completely outside of the labeled indications or compendia listings for the ESAs, many of which were run outside of the US and not according to all our standards. The oncology community self-governs our treatments by peer reviewed journals and scientific authorities such as the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH) and the National Comprehensive Cancer Network (NCCN).

I.2. Anemia of myelodysplasia
Use of ESAs in Myelodysplastic Syndromes is an accepted use in the USP Compendia. We view the use of ESAs for MDS as therapeutic and not supportive. The use is supported by ASCO and ASH. Many of our patients are elderly with comorbidities that make alternative treatments contraindicated because of their greater risk. These patients if not treated with ESAs will rapidly require chronic transfusions. Transfusion dependence in this population will impact their overall survival and lead to clinically significant iron overload.If this change is implemented it will put an undue burden on the blood banks and hospitals. It will further cause various complications of chronic transfusions including infections, transfusion reactions, allo-immunization, and complications of iron overload

I.3. Multiple Myeloma

We feel that it is inappropriate to eliminate coverage for Multiple Myeloma. ESAs have been effective with this population and are considered a standard of care. The following excerpt of a 2007 guideline follows:

GUIDELINE TITLE
Guidelines on the diagnosis and management of multiple myeloma 2005.BIBLIOGRAPHIC SOURCE(S)Smith A, Wisloff F, Samson D, UK Myeloma Forum, Nordic Myeloma Study Group,British Committee for Standards in Haematology. Guidelines on the diagnosis andmanagement of multiple myeloma 2005. Br J Haematol 2006 Feb;132(4):410-51.[292 references] PubMedThis NGC summary was completed by ECRI on September 25, 2006. Theinformation was verified by the guideline developer on October 25, 2006. This19 of 20 summary was updated by ECRI on January 29, 2007, following the U.S. Food and Drug Administration advisory on erythropoiesis stimulating agents.

Management of Anemia

While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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To: Steve Phurrough, MD, MPA
Director
Coverage and Analysis group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (CAG-00383N)

Dear Dr. Phurrough,

I am writing on behalf of Roswell Park Cancer Institute to provide comments regarding the above proposed Decision Memorandum for the Use of ESAs in Cancer and Related Neoplastic Conditions. Roswell Park has contributed comments as part of a letter from The Alliance of Dedicated Cancer Centers but we also are providing this supporting letter as an individual National Cancer Institute (NCI) Designated Comprehensive Cancer Center.

The RPCI Clinical Care Staff is concerned about proposed restrictions on the use of ESAs. Patients who receive extended treatment with chemotherapy are at risk for the development of anemia. Restricting the yearly treatment to only 12 weeks could jeopardize the ability to maintain a patient with a safe hemoglobin without resorting to chronic red cell transfusion therapy with the attendant complications and risks. Further, dosing of ESAs is variable and capping a weekly dose could result in impaired responses in patients who require higher ESA dosing. Finally, a hemoglobin of 9 mg/dl may be safe in a patient without cardiac disease however cardiac disease patients may require hemoglobins of 10 mg/dl or higher to prevent cardiac destabilization.

There are certain disease indications that may benefit from ESA use. These include:

1. myelodysplasia/myelodysplastic syndromes (including refractory anemia, refractory anemia with excess blasts, Chronic myelomonocytic leukemia and myelofibrosis),
2. other hematologic disorders such as large granular lymphocyte leukemia, pure red cell aplasia,
3. patients chronically receiving epidermal growth factor inhibitors,
4. patients with renal insufficiency but not renal failure,
5. patients with a hematologic disease who do not wish to receive red cell tranfusions for religious reasons (Jehovah's Witnesses)
6. and patients receiving marrow suppressive therapy. The latter category includes patients who are post-Hematopoietic Stem Cell Transplant.

We appreciate the opportunity to make comments regarding ESA use and look forward to finalization of guidelines that optimize patient care and safety.

Sincerely,

Philip L. McCarthy, MD
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263

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To Whom It May Concern,

Pacific Oncology P.C. acknowledges the need for an evidence-based response to the recent FDA warnings regarding the use of ESA's in cancer and related conditions. We agree and that both clinical experience and recent data do indicate potential risks when ESA's are given for the following reasons:

While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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There is a disconnect between this policy and your PQRI 2007 quality measures. This policy excludes payment for myelodysplastic syndrome, yet your quality reporting measure #68 indicates that there is value in give erythropoietin to MDS patients (provided you check iron stores prior to initiating). It seems that quality and payment policies should be consistent.

There is also significant concern among our physicians that removing MDS as a covered indication will result in increased blood transfusions putting blood supply in further jeopardy; detrimental effects on ability to care for patients in infusion areas as transfusions take several hours per patient, rather than a few minutes for injections and capacity to care for patients is at great risk; limited capacity in infusion areas would likely necessitate an increase in hospital admissions for transfusions.

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In regards to the CMS decision regarding ESA's, I find the policies proposed to be quite disingenuous. The policies are contrary to published medical series regarding the best use of ESA's. For example, the starting level of hemoglobin, the duration of treatment, the total yearly use of ESA's are all contrary to published medical data. I have patients with cancer not actively receiving chemotherapy who have maintained performance status with ESA's and now are already close to requiring transfusion. I think that this policy was based only on financial concerns and represents a significant departure from the criteria of best patient care. If CMS cannot base its policies on the best data, and act upon it, then it should admit this publically and not try to base it on small, incorrectly cited studies and questionable preclinical rationales.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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While supportive of the concept of an NCD, the primary concerns of our state medical oncology society are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

We disagree with the following:

1.Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7.One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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It is under great concern that I eamil you regarding the proposed changes to ESA use in the oncology setting. Much research has proven that use of these agents effectively decreases the number of blood transfusions and sharply decreases fatigue in patients with chemotherapy induced anemia. In a time when healthcare costs are rising, we are at war and have a blood shortage, I feel the use of agents that improve QOL and reduce the number of transfusions is imperative. Thank you for your consideration in this sensitive matter.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level ( superior to randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.

Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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It is interesting to note that CMS even has a measure (#68) in the 2007 Physician Quality Reporting Initiative (PQRI) that specifically addresses MDS patients receiving erythropoietin therapy. According to CMS the rationale states, "To be effective erythropoietin requires that adequate iron stores be present..." CMS even acknowledges the effectiveness of ESA therapy for MDS patients. What would we measure if these patients no longer even have access to this "effective" therapy? I hope that CMS reconsiders this policy. The current draft discriminates against patients by denying access to effective thearpies.

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While supportive of the concept of an NCD, the primary concerns of US Oncology Pharmacy & Therapeutics Committee physicians are:

1. The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States.

2. Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved by appropriate ESA therapy.

Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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I would like to express my feelings on the clinical aspects of this decision Noridian has made a regarding the coverage of Erythropoiesis stimulating agents for Medicare beneficiaries.The goal of treatment with ESAs is to increase the number of red blood cells in order to avoid blood transfusions, and thereby alleviate strain on the nations blood supply. We should also consider the fluid overload and iron overload in the individual patient from transfusions.The removal of darboepoetin (Aranesp) coverage for myelodysplastic syndrome (MDS) by Noridian is without clinical rationale. MDS is not commonly classified as a malignancy, but rather a comprehensive term for a heterogeneous collection of hematologic stem cell disorders affecting primarily older adults. At diagnosis, anemia is the most common abnormality with over 80% of patients presenting with hb concentrations MDS is technically not a malignancy, and should be in itt?s own category.There is evidence to support the use of ESAs in patients with anemia associated with low-risk myelodysplasia. World health organization classifies low-risk myelodysplasia with less than 5% blasts to include the following forms of myelodysplasia: refractory anemia (ra)Refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia refractory cytopenia with multilineage dysplasia with ringed sideroblasts myelodysplastic syndrome, unclassified MDS associated with isolated del(5q)Refractory anemia can be defined as erythropoietic insufficiencies that cannot be assigned to a specific vitamin or mineral deficiency. Experts in hematology have used ESAs to treat anemic patients with multiple myeloma, non-Hodgkins lymphoma and chronic lymphocytic leuekmia (cll) in the absence of chemotherapy where the esas have proven effective, and without the toxicity of many more commonly used therapies. Although we do acknowledge there are no randomized clinical trials to support the use of ESAs in these hematological malignancies, we do strongly recommend this to be an area for further studies and evaluation.

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Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244

RE: National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

Dear Dr. Phurrough:

I am writing on behalf of The Leukemia & Lymphoma Society (LLS) to express objections to the Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) issued by the Centers for Medicare & Medicaid Services (CMS). LLS is the largest organization dedicated to research on blood cancers and the nation's second largest voluntary health agency focused on cancer.

We urge CMS to withhold action on coverage of ESAs until completion of the Food and Drug Administration (FDA) review of the oncology-related uses of these products. The Oncologic Drugs Advisory Committee (ODAC) has evaluated the data on ESAs and made recommendations that are currently under review by the agency. It is possible that FDA will make changes in the product labeling, and CMS action should not proceed until the FDA process is complete.

This course of action would be consistent with Medicare law, which requires coverage of drugs used in an anticancer chemotherapeutic regimen if the use is approved by FDA or if the use is supported by the medical compendia and is not found by the Secretary to be medically inappropriate. These provisions of Medicare law, sought by cancer patient advocates, researchers, and physicians in 1993 to ensure access to quality cancer care, deny CMS the discretion to restrict coverage in a manner that is inconsistent with FDA labeling and restrict agency discretion regarding off-label uses listed in the compendia.

We recommend that CMS discontinue this coverage effort pending the recommendation from FDA regarding appropriate uses of these products.

Sincerely,

George Dahlman
Senior Vice President, Public Policy
The Leukemia & Lymphoma Society
202-543-7033
george.dahlman@lls.org

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June 12, 2007

Steve Phurrough, M.D., MPH
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mailstop: C1-13-18
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal indications (CAG-00383N)

Dear Dr. Phurrough:

The Hematology-Oncology Division of Dayton Physicians LLC appreciates this opportunity to comment on the Centers for Medicare and Medicaid Services' (CMS) proposed decision regarding Medicare National Coverage Determination for Erythropoiesis Stimulating Agents (ESAs). Dayton Physicians LLC is a multispeciality group practice which cares for a significant number of patients with cancer and blood disorders in the Greater Dayton, and southwestern Ohio area. We strive to provide care for our patients using the latest information from the medical literature and professional guidelines, including those from the National Comprehensive Cancer Network, the American Society of Hematology, and the American Society of Clinical Oncology.

We believe that these recommendations are based on a thorough review of the medical literature, with appropriate analysis by national experts for these conditions. Most of the physicians in our group also remember how difficult it was to deal with anemia due to chemotherapy or myelodysplasia, prior to the development and use of ESAs. The impact that significant anemia had on symptoms, and an individual's ability to remain in the workforce, or live independently in their home, was a major problem for individuals receiving chemotherapy, or with significant chronic anemia associated with myelodysplastic syndrome.

We believe that the recent CMS decision to enforce severe limitations in the use of these agents is not supported by the full medical literature, and is in clear conflict with the practice guidelines from the National Comprehensive Cancer Network, the American Society of Hematology, and the American Society of Clinical Oncology. We also believe that our own personal experience, seeing the benefits of these agents, supports those practice guidelines.

There are clearly some minor safety issues regarding the use of ESAs. In our practice we discontinue ESA use when the hemoglobin is just below the normal range to avoid these rare complications. Certainly as we review the literature, we believe that appropriate use of these agents is far safer than frequent blood transfusion.

Finally we believe these changes will not result in a significant cost savings to the health care system. We believe these changes will result in severe problems with the local blood supply. There will also be an increased need for iron chelation therapy as patients previously treated successfully with ESAs will no longer qualify for this therapy, and will need to rely on transfusion support. Many patients with severe fatigue secondary to their anemia, who had been successfully treated with ESAs, will now suffer the loss of their independence, and require placement in assisted living or extended care facilities, or will be unable to remain productive members in the workforce.

We believe that the best course of action is for CMS to cover all indications outlined by the FDA, and the guidelines from the American Society of Hematology, the American Society of Oncology and the National Comprehensive Cancer Network.

Dayton Physicians appreciates the opportunity to comment on the proposed changes by CMS, and we would be pleased to answer any questions regarding these comments.

Sincerely,
James H. Sabiers MD, Chairman
Clinical Practice Committee
Dayton Physicians, LLC
9000 North Main Street
Suite G36
Dayton, Ohio 45415
Phone: (937)832-1093
Fax: (937)832-5344

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June 12, 2007

Re: New Medicare Proposal on Erythropoiesis Stimulating Agents.

On behalf of the physicians of Central Indiana Cancer Centers, I would like to express our concerns related to the current proposal by CMS regarding the use of Erythropoiesis Stimulating Agents (ESA's) in cancer and other related neoplastic conditions.

The proposed restriction of ESA's is a major concern to all of us specializing in the field of Hematology and Oncology. This innovative drug therapy has helped thousands and thousands of patients with symptoms related to chemotherapy. In addition, patients who experience cardiac and cerebrovascular decompensation suffer from disease related fatigability; a condition that responds well to ESA's. The American Society of Hematology (ASH) guidelines scientifically reflect the fact that patients have shown a significant benefit from the use of these drugs. The Policy and Practice News published by ASH on 05/18/2007 can be reviewed for further information on their findings.

With the decreased use of ESA's physicians can expect to treat more complications stemming from blood transfusion therapy including infectious processes, immune dysfunction, transfusion-induced hemosiderosis as well as alloimunization. Currently, central blood centers are already experiencing bouts of blood shortages, making the procurement of blood and blood products even more difficult. This shortage can only be expected to increase as we are forced to prescribe more transfusions for our patients. Not only do we anticipate excessive usage of blood products but we expect higher healthcare costs and more frequent hospitalizations. All of these factors must be considered when deliberating the appropriate use of ESA's. We encourage you to work with the American Society of Hematology and the American Society of Clinical Oncology in an effort to reformat your guidelines. As physicians we are dedicated to making sure our patients can continue to receive this wonderful new molecule that has helped to significantly decrease the number of blood transfusions while improving quality of life.

Sincerely yours,

Magaral S. Murali, M.D.

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Relative to the CMS proposed limitations of coverage of ESA use for hemoglobin levels immediately prior to initiation of dosing for the month for patients undergoing treatment for certain listed cancers being without known cardiovascular disease and in patients with documented symptomatic ischemic disease that cannot be treated with blood transfusion, I would like to respectfully bring to your attention that both NCCN and ASCO recommend initiating treatment when the hemoglobin level falls to level of accepted national guideling.

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I have serious concerns regarding the elimination of erythropoietin and darbepoetin for use of anemia of myelodysplasia. My experiences are by the patient's receiving erythropoietin we are saving the patient the need to have continuous blood transfusions. The patients health improves significantly which allows most patients to be more self sufficient. It definitely decreases the need for health care services as well as the need for family member's assistance. If the patients receive the proper dosage there is minimal risk to the patient. I have had a great percentage of patients respond to this treatment. I hope we are considering what's best for the patients.

I also have concerns regarding the proposal to hold erythropoietin until hemoglobin is below 9.One concern is once the hemoglobin is that lowthe patient may take longer to respond to the treatment. This may result in the need for moreblood transfusions. The patient will feel more fatigue and not as mobile, possible difficultywalking. I feel again this is not in the best interest of my patients.

I feel erythropoietin and darbepoetin should be given according to the current label.

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As an oncology certified nurse, I appreciate the opportunity to comment on the proposed decision regarding the use of ESAs in the cancer treatment setting. Cancer treatment has advanced considerably in the twenty years I have been in practice, and one of the greatest improvements in patient care has been the growth of effective symptom management.

Anemia is one of the many consequences of cancer treatment which contribute to a decrease in quality of life. The judicious use of ESAs during cancer treatment has both quality of life and financial advantages. In my experience, patients experience a significant increase in fatigue, with its accompanying symptoms of dizziness and exertional dyspnea, when the hemoglobin falls below 11.0. If unrelieved, these symptoms also contribute to the ongoing burden of treatment, resulting in such problems as lost work time, less participation in healthful activity such as exercise and socialization, more insomnia and depression.

If the proposed decision is approved, it will require patients to wait for initiation of ESA therapy until the hemoglobin is less than 9.0. This will undoubtedly result in much poorer quality of life during cancer treatment for the reasons listed above. In addition, it will likely result in more frequent need for blood transfusions, which will add cost and possibly delay the patient's cancer treatment. Treatment delays can adversely affect the effectiveness of the cancer treatment itself.

The restriction on ESA treatment to only twelve weeks per year does not take into account the fact that many cancer treatment regimens last six months or longer. This will end the ESA treatment of anemia in the middle of a treatment regimen, leaving the patient more vulnerable to the cumulative effects of treatment on red blood cell production. The restriction on total dosage in a month will necessitate a dose reduction for many patients whose anemias currently are safely and well controlled on 40,000 to 60,000 units per week.

I understand the risks of ESA treatment and the financial burdens on patients and the healthcare system. From clinical experience, however, I believe that ESAs can be used safely in the cancer patient population and that the benefits far outweigh the risks for the majority of patients. In fact, the burdens of restricting ESA use more than advised in the current FDA guidelines may prove more costly in both dollars and patient quality of life. Please do not approve a decision that would reverse the positive direction of cancer care symptom management!

Thank you very much for your consideration of public and professional opinion in your decision.

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Disagreement with the Proposed NCD

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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As a Hematology/Oncology practice with six oncologists and six mid-level providers in five locations in Western North Carolina, we would like to respond to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. We would like to address two concerns regarding the proposed NCD.

First, we would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, we would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, we find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. Our fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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1. Start limit of Hgb 9 gm/dL too strict, since it takes 4-8 weeks to see reversal, during which time patients are symptomatic and could need transfusion. Early intervention shown superior in clinical trials.
2. 12 week maximum is very restrictive; patients with metastatic cancer are often on chemo for 6 months to a whole year and need continued EPO support. This would affect the most needy patients!
3. 126,000 unit epogen limit and 4 week time to response is inconsistent with clinical trials that show 40,000 u/week x 4 weeks fails to respond and need higher dose (60,000/wk).
4. No data to actually support clinically relevant deleterious effect of epo in certain cancers and with EGFR/VEGF inhibitors. This restriction is premature.
5. All these restriction will lead to greater need fro transfusions and cost more money, not to mention the risks to patients of blood transfusions and the stress on an already limited blood supply.

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In response to CMS request for comments, I would like to take this opportunity to comment on the proposed changes to current use of ESA's. First let me say that I have significant concerns when an agency such as CMS makes a proposal that has the potential to affect the well being of cancer patients in my practice.

We support a National Coverage Decision but are concerned that the proposed NCD does not rely on all scientific data, nor does it comply with accepted standards of care for cancer patients in this country. We are concerned that the outcome of such restrictions will have a negative impact on the health and welfare of our patients, their families, and potentially the nation's blood supply and to the already overburdened facilities where it is provided.

The following comments express either support or concerns with the proposed regulations as outlined below:

I agree that there should be restrictions on treatment with ESA's in the following areas:

1. Anemia in cancer or cancer treatment in patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis.
2. Anemia of myeloid cancers, specifically acute myeloid Leukemia (AML) and chronic myeloid leukemia (CML)
3. Anemia associated with the treatment of myeloid cancers or erythroid cancers
4. Anemia associated with primary treatment with radiotherapy
5. Prophylactic use to prevent chemotherapy-induced anemia in patients who have never suffered from CIA
6. Prophylactic use to reduce tumor hypoxia in non-anemic patients
7. Patients with erythropoietin-type resistance due to neutralizing antibodies
8. Anemia due to cancer treatments if patients have uncontrolled hypertension

However, we disagree with other portions of the propose rules and have outlined those as follows:

1. Use with anti-angiogenic and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies: There is no basis in clinical evidence that ESAs stimulate angiogenesis.
2. Anemia of cancer: Evidence of detriment to survival is questionable in that such evidence is based on studies of much higher hemoglobin levels than targeted in common practice, with such studies looking for new indications for the use of ESAs, and a further study in which the patient population was often end stage or hospice. There is however, a significant body of published evidence identifying benefit through controlled clinical trials and supporting current recommended doses and hemoglobin levels.
3. MDS 'Myelodysplastic Syndrome: There is significant pool of studies involving epoetin alpha and darbepoetin alfa, all of which includes safety and efficacy data of ESAs in treatment of MDS related anemia. Restriction of usage is not reasonable because data is not available to support such a restriction.
4. Effects of Frequent Transfusion: There is concern that restrictions proposed may increase the need for transfusion in many patients. Frequent transfusion shows documented toxities which may require additional treatment such as toxicity from iron overload which may affect all body systems/organ function. Additionally, delays in therapy may occur in order that patients may be scheduled for transfusion, further overburdening our facilities and blood supply.
5. Initiation and limitations based on hemoglobin targets: Evidence suggests initiation of ESA's when hemoglobin falls below 11 g/dL has the greatest opportunity to prevent transfusion. A target of 9 g/dL will almost certainly create a need in some patients for transfusion. We believe that the physician should have flexibility in managing patients to maintain an optimal hemoglobin level by dose reduction rather than withholding at hemoglobin greater than 12 g/dL if, in their judgement, the patient will benefit more from dose reduction to maintain adequate hemoglobins. A 4 week trial is not sufficient to evaluate response in patients undergoing chemotherapy. The natural rebound after cytotoxic therapy often takes longer as therapy progresses.
6. Limits on patients with weight gain and fluid retention: Not all patients who experience weight gain and fluid retention experience hypertension. Some therapies require high volumes of hydration and/or by their nature cause fluid retention and weight gain. Using weight gain and fluid retention as an independent determinant for withholding ESA therapy is not an appropriate measure to prohibit the use of ESA therapy.
7. Duration of therapy: Patients frequently receive more than 12 weeks therapy, and often receive more than one regimen due to recurrence. Therapy should be tailored to the needs of the individual patient. Limiting the number of weeks annually they may receive ESA therapy is not reasonable because of the wide range of variables involved. As an example, a sarcoma patient is often in treatment for 12 months, not 12 weeks.
8. Limits on dosing/dose adjustments: Clinical trials determine safe and efficacious dosing of drugs. The FDA label specifies clearly use of the lowest necessary dose to be managed in concert with the hemoglobin levels. There is no scientific evidence to support management of the hemoglobin level separate from recommended dosing levels, and neither are the suggested limitations on dose adjustments supported by data.

I urge you to review recommendations made by ASCO, ASH, ACCC, COA, USO and the many other clinical and scientific organizations that have studied and provided you with detailed clinical support for continued ESA therapy under appropriate guidelines. The proposal set forth by CMS is clearly unacceptable and has the potential to negatively impact cancer patients.

Sincerely, Sridhar E. Pal, MD

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As a legislative chair for North Carolina Oncology Management Society, representing ninety-one members who are a mixture of Oncology administrators, managers, physicians, and nurses, we are writing as a collective voice in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. Our members are comprised of practices and hospitals in rural as well as urban areas of North Carolina. Our members range from the one-physician practice to twelve-physician groups, as well as hospitals, located in the very rural mountains of North Carolina to the well-populated areas of the larger cities, such as Charlotte. As different as the composite of our members may be, the conclusion of all our members is the same. The proposed restrictions for Erythropoietin are without clinical basis and also seem to be without legal standing.

First, we would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, we would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The supply of blood product is not only limited at this time, but patients are concerned regarding the safety of the available product. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, we find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. Our fear is that this is only the beginning of attacks on drugs based on cost-cutting issues rather than the accepted standard of care.

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As a cancer/hematology care worker for the past 9 years, I am truly frightened by the proposed changes to the use of ESA's. Do the decision makers look at anything but the bottom line? What about providing the best treatment possible for patients?

The proposed changes are NOT in the best interest of patients needing ESA's and transfusions are a poor excuse for a replacement therapy. Transfusions are costly, dangerous to the patient and blood supplies are constantly running at critically low levels. Transfusions should be used as a last resort for emergencies...not for chronically ill people.

ESA's changed the course of treatment for our patients and these proposed changes would turn back the clock to a time when less than ideal solutions were available. It's truly sad that we live in a country where the very best in health care treatment is available, but people will no longer be able to access it.

Shame on our government for even considering these proposed changes.

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To Whom it may Concern:

I have two comments in reference to CMS issuing regulations for the use and payment of ESA's.

1. CMS should not be practicing medicine. CMS is neither qualified nor given a mandate to practice medicine. The FDA, and all the trained and licensed physicians who use these (or any other medicines) are charged with medical decision making. I do not think I need to discuss the role of the FDA, and the scope of medical practice, which are very complicated issues.

This is a very important comcern.

2. Experts in the field do not believe that there are data to support the suggestions of CMS on this very complicated topic. When such data exist, the FDA will interpret them, and determine if the FDA needs to do more than it already has. The FDA will also determine whether it has already mistakenly included patients with myelodysplasia, and other groups of patients with malignancy who are not on cytotoxic chemotherapy, in the group for whom the FDA has determined that ESA's are potentially not beneficial/harm may excees risk.

Thank you.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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June 13, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Dr. Phurrough,

Thank you for the opportunity to comment on the upcoming Centers for Medicare and Medicaid Services (CMS) national coverage decision on Erythropoiesis Stimulating Agents (ESAs) for Non-renal Disease Indications. America's Health Insurance Plans (AHIP) is the national trade association representing the private sector in health care. AHIP's member companies provide health benefits to more than 200 million Americans. We are pleased to submit these comments on behalf of our members. AHIP and our member organizations have concerns about CMS's proposed decision regarding erythropoiesis stimulating agent (ESA) treatment for beneficiaries with certain clinical conditions or with certain clinical endpoints.

The Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions

We support CMS's efforts to ensure that all patients receive the most effective and appropriate treatments. AHIP believes CMS must closely follow safety and effectiveness data for treatments, procedures, and biologics and revise coverage and reimbursement policies to reflect the latest evidence.

AHIP encourages CMS to carefully consider broad stakeholder input on both the limitations on dosage linked to hemoglobin levels (hematocrit) and the list of proposed indications to be removed from coverage as stated in its new draft policy. While there is evidence to suggest that ESAs are often overused, AHIP members have consulted with physicians and other experts and have highlighted several areas where they believe that CMS should reconsider this draft policy:

1) The list of excluded indications. The list of excluded indications includes several for which there does not appear to be an evidence base to justify the exclusion and the removal of coverage would likely have an adverse impact on care. For example, patients with myelodysplasia and myeloid cancers frequently require multiple blood transfusions due to the severity of their anemia; removing coverage for these populations could greatly increase their need for transfusions. Multiple and frequent transfusions can adversely affect quality of life, are dependent on the availability of blood supplies, and are costly. Requiring hematocrit levels on claim forms may be an appropriate and feasible way to track ESA use among these patients, and some of AHIP's members have had success in reducing ESA overuse by simply requiring reporting of the hematocrit level on the claim form with no additional guidelines.

As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As an exercise physiologist who works with recovering cancer patients, or patients who have had cancer in the past, I truly believe that they should continue to receive their shots. The other option would be blood transfusions and we are already having a short blood supply. Imagine every single person who has gone through chemotherapy needing blood every month. That will deplete our blood supply and end up costing more money. Please consider continuing your service of covering for these vital shots.
Thank you.
Katie Butterfield

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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I have been an oncology nurse for 15 years and have seen many patients benefit from the use of ESA's. This helps improve quality of life for many patients receiving chemotherapy. I feel to deny them this drug would be a step backwards in cancer care. Patients who suffer from MDS also benefit greatly from ESAs by having fewer blood transfusions. These transfusions take quality time away from patients forcing them to take many days of their life sitting in the transfusion bed, not to mention the side effects from multiple transfusions ie development of antiboties, iron overload, hepatitis etc. Working before we had access to ESA and using them today I feel patients have improved quality of life as they deal with cancer and cancer treatment today.

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1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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I would like to comment on the ESA proposed decision.The proposed NCD has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the USA.Transfusions as an alternative therapy are not the equivalent of hemoglobin maintenance achieved with appropraite ESA therapy.The use of a Hgb br>point is inadequate. Current data shows many of the patients who receive ESA's after Hgb drops to the br>are otherwise avoidable.Stopping at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.One significant, inintended and unanalyzed effect of the draft ESA policy would be to place the nationalblood supply at significant risk due to the millions of avoidable transfusions.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a medical oncologist/hematologist, and on a daily basis treating patients with anemia associated with non-renal disease, quality of life has greatly improved in the majority of patients engaging in ESA therapy. From a practical standpoint where large portion of our work is to alleviate suffering , improve life quality and minimize in-hospital care, this treatment is crucial to a majority of patients independent of their renal function. As an advocate to my patients , who are the primary reason of my work, I feel a great and deep concern for the legislative process in which it is crippling our practices to do the best job we can to take care of our patients.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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June 13, 2007

Re: Proposed Decision Memorandum for the Use of Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

To Whom It May Concern:

On behalf of Little Rock Hematology Oncology Associates, I am submitting comments on the Proposed Decision Memorandum for the Use of Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N), that was issued by the Centers for Medicare and Medicaid Services (CMS) on May 14, 2007.

The proposed ESA policy is not based on scientific data and conflicts with the ESA standards of care in the United States. Clinical trials supporting the proposed ESA policy were performed with aggressive hemoglobin repletion that exceed the standard of care hemoglobin target range for patients with cancer. Also, clinical trials were performed to prevent anemia in patients who were not yet anemic, not to treat anemia. Both are non-FDA approved indications. Results from these trials cannot be extrapolated to cancer patients receiving ESAs under FDA approved guidelines.

The benefits of ESAs in cancer patients have been well established in clinical trials over the last 20 years. ESAs have demonstrated a decrease in transfusions and improvement in quality of life when administered according to FDA approved guidelines.

In closing, the proposed ESA policy is not based on any scientific data. Hemoglobin initiation of < 9 g/dl is completely arbitrary. Adoption of this proposal will significantly compromise medical care in patients with anemia due to a wide variety of conditions, including symptomatic cancer patients. Please see points to condider below.

Sincerely,

Lawrence Mendelsohn, M.D.

POINTS TO CONSIDER:

ESA initiation with hemoglobin < 9 g/dl, is arbitrary, unsupported in scientific data, and will lead to compromise of medical care in patients with anemia.

Clinical trials show patients are more likely to receive a transfusion with ESA therapy if started at lower hemoglobin levels.

The proposed NCD has significant coverage limitations that are not based on scientific data and conflict with the current standard of care in the United States.

Limiting ESA coverage to 12 weeks per year will significantly impact patients receiving prolonged chemotherapy treatments. Patients with metastatic disease often receive multiple courses of chemotherapy that last for many months.

Discontinuing ESA therapy if a 1g/dl increase in hemoglobin is not achieved within 4 weeks is inconsistent with clinical trials. Clinical trials demonstrate that 6-8 weeks may be required to achieve a 1g/dl increase in hemoglobin.

ESAs have changed cancer care and allowed oncologists to provide quality standards of care through evidence based medicine.

Clinical trials have demonstrated ESA benefits outweigh their risks when dosed and administered according to the FDA approved label.

ESAs have significantly decreased transfusions among patients treated with chemotherapy. Adverse effects of chronic transfusions, such as iron overload, allo-immunization, hepatitis, CMV, and infusion-related reactions, should be considered and weighed against the safety risks of ESAs. In addition to adverse effects, the cost to CMS for multiple transfusions, iron overload therapies, and potential hospitalizations must be considered. Also, a significant amount of patient and caregiver time is lost when receiving transfusions. The national blood supply will be at significant risk under the proposed NCD due to millions of unnecessary transfusions.

Clinical trials reporting ESA safety issues do not reflect ESA standards of care. All have elevated target hemoglobin levels (>12 g/dl). FDA approved dosing with lower target hemoglobin levels (12g/dl and dose reduce when >11g/dl) allow safe administration of ESAs in cancer patients.

Many new oral chemotherapy and biologic agents have been shown to exacerbate anemia in patients with cancer. ESA coverage should be allowed when patients are receiving these agents. Many patients receive oral chemotherapy and biologic agents in addition to traditional chemotherapy agents.

Symptomatic anemia secondary to chemotherapy should be covered during chemotherapy treatment and for at least 3 months after chemotherapy completion. This will allow patients to receive ESA therapy until their bone marrow recovers.

In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence they are functional. Restricting ESA use in patients with such cancers is not evidence based.

The majority of multiple myeloma and MDS patients will require multiple transfusions during the course of their disease. Complications that commonly occur from chronic transfusions include iron overload, febrile reactions, antibody formation to red cells, and transfusion refractoriness.

Multiple clinical trials have demonstrated both safety and efficacy of ESAs in MDS and multiple myeloma. ESAs reduce transfusion requirements, improve quality of life, and potentially impact overall survival in these patients.

CMS is taking the medical decision making out of the hands of physicians and assuming this role with a policy not based on scientific data.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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RE: Comments on Proposed National Coverage Determination for Erythropoietin Stimulating Agents (ESAs) CAG-00383N

Dear Coverage Analysis Group:

As a practicing medical oncologist and hematologist, I would like to comment on several points addressed in the proposed decision memorandum for erythropoietin stimulating agents (ESAs).

As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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RE: Comments on Proposed National Coverage Determination for Erythropoietin Stimulating Agents (ESAs) CAG-00383N

Dear Coverage Analysis Group:

As a practicing medical oncologist, I would like to comment on several points addressed in the proposed decision memorandum for erythropoietin stimulating agents (ESAs). In addition to the points addressed below, I am concerned about the blood supply. We already have a shortage of blood products that affects the treatment of my patients in the state of Mississippi. Restricting the use of ESA therapy for our MDS patients and waiting to start ESA therapy until the patient has a Hg below 9 will cause my patient population to need significantly more tranfusions. With the blood supply already at a critical level, I am concerned that this policy will have an adverse affect on the blood supply and endanger my other patients who already rely on this short supply.

As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb < 9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as < 11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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As a nurse practitioner, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

Less

As a nurse practitioner, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

Less

As a nurse practitioner, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse practitioner, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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Coverage for use of ESA's should definitely include all aspects of oncology (including Radiation. The last 15 yrs has seen many Clinical Studies that support their use. Evidence based practice should be the gold standard especially since the # of transfusions are reduced by 50% and time to 1st tranfusion is extended when ESA's are used. I have been an Oncology Nurse since 1982 and can say that ESA's have dramatically improved pt outcomes especially in reguards to keeping chemo regimens on time and alleviating s/s of anemia. There was a time that we were doing so many transfusions that we didn't have enough treatment chairs to accommedate our chemo infusions. Again, this is supported by many studies. The physicians need to be free to order these supportive medications for our pt's to facillitate the best outcome of treatment. The FDA excells in their evaluation of the safe use of these drugs and CMS should model their coverage guidelines from the current evidence and the FDA.

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The fact that Physicians buy and bill for ESA's as well as chemotherapy is part of the problem. Once again, if these agents had been utilized through pharmacy services, such abuse would not have taken place. I had written an article several years ago, promoting the use of the pharmacist, and the true function of pharmacy.

If you look at prescribing patterns of physicians that buy and bill, including the ESA, they are prescribing the medications, with the intention of being reimbursed. I can argue this because many will treat a patient with Aranesp when the Hgb is < 12gm/dl. If you look at the true indication, it is not just based off of a lab value, but rather "prevention or reduction of transfusion requirements". Many Physicians will utilize the medication at this number, and you and I both know that this is not....for a prevention or reduction of trasfusion requirements, since, many including NCCN guidelines, as well as ASCO guideline will not transfuse a patient until the Hgb <8gm/dl.

So, if you looked at even the dosing guidelines, of such products as Aranesp 200mcg every 14 days, the patient may receive the injection on day 1, with a Hgb <12 (11.5) and had chemotherapy the week before, the patient does not return for a lab draw, for 2 weeks, (of which, 7 days later the Hgb may be >12gm/dl). Then when they come in, for a lab draw, it is now <12 gm/dl (11.7), and the prescriber, says, or it didn't work, let's increase it to 300mcg (when in fact it did).Also, since medicare guidelines allow for once a month lab draws this is where abuse of the system can occur as well. Since the labs and the injections can be done where the lab value will always be less and therefore the injection can be given.

If these products were reimbursed through pharmacy services (NOT CAP programs), but for any willing provider of Medicare D services, then the abuse for these medications would stop. I can tell you that if the physician could not get reimbursed for buy and bill of ESA's, then they would have to write a prescription for it, of which then they may just tell the patient...."your labs look fine, I don't think you need the injections right now..."

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As a nurse practitioner, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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As a nurse practitioner, practicing in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

From a nursing standpoint, we are going to have to allow more time for teaching patients how to manage their fatigue. The impact on the quality of life for our patients will be enormous. Those patients, who not only have been able to function fairly well, will, in some circumstances, be unable to do so. Unfortunately, the impact, on our patients who have tried to work during their illness, will be incredible. Removing this piece of normalcy from their lives has a yet-to-be-recognized effect on the outcomes of their disease. Removing an FDA-approved drug without clinical data to support the decision will have an intensely negative effect on the very patients we are trying to help.

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ATTN:
Steve Phurrough, MD, MPA
Elizabeth Koller, MD, FACE
Maria Ciccanti, RN
Coverage Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
Mail Stop C1-12-28
7500 Baltimore, Maryland 21244-1849

Key Points of Policy Disagreement with the Proposed NCD
1. Use of Hgb point is inadequate. Current data shows many of the patients who receive ESAs after Hgb drops to the br>will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.
2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (br>superior to br>randomized studies).
3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data. The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.
Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.
4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.
5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.
6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.
7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.
8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD. I urge you to reconsider these guidelines that are clearly not in the best interests of patient care.

Sincerely,
Bruce Zietz, MD

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As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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1. Use of Hgb<9g/dl as a treatment initiation point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.

Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

Less

As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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June 13, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Mail Stop C1-09-06
Baltimore, Maryland 21244

RE: National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs)For Non-Renal Disease Indications (CAG-00383N)

Dear Dr. Phurrough:

The undersigned organizations represent cancer patients, providers and researchers in connection with responsible coverage policies for cancer therapies, among other issues. We are writing to express concern about the proposed decision memo for the use of erythropoiesis stimulating agents (ESAs) in cancer and related neoplastic conditions. We take no position as to whether Medicare officials have identified appropriate limits on the use of these products because we believe that determination should not be made prior to a determination on that issue by the Food and Drug Administration (FDA). Absent action by FDA, Medicare's proposal is premature and should be withdrawn.

The ESA controversy is under active review by FDA, which has primary responsibility for determining the limits that are set forth in the proposed decision memo. As Medicare officials are no doubt aware, the FDA's Oncologic Drugs Advisory Committee (ODAC) intensively reviewed the available data in a meeting on May 10. Even prior to the ODAC meeting, FDA had taken action to require 'black box' warnings for the products. FDA is currently considering the recommendations from ODAC, but the agency is not compelled to follow them. Until FDA has made a decision to change the existing labeling of ESAs, Medicare should follow the labeling as it is currently configured, certainly taking into account the warnings required by FDA.

This result is necessary, not just as a matter of medical evidence and bureaucratic prudence but also because it is compelled by the laws that govern Medicare coverage policies. In 1993 Congress enacted legislation that was intended to resolve questions about the discretion of Medicare officials and contractors to limit coverage of medically appropriate cancer therapies. Accordingly, in Â1861(t)(2) of the Social Security Act (42 U.S.C. Â1395x(t)(2), the term 'drugs' is specifically defined to include 'any drugs or biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication,' which is further defined to include 'any use which has been approved by the Food and Drug Administration' as well as any compendia-supported use that has not been found by the Secretary to be medically inappropriate.

In light of these legal requirements, Medicare does not have discretion to restrict coverage to be inconsistent with the FDA-approved labeling. In addition, if off-label coverage is to be restricted in a manner that conflicts with compendia references, there must be a specific determination by the Secretary that the restricted uses are medically inappropriate.

The proposed decision memo should be withdrawn to await the decision by FDA as to the medically appropriate uses of ESAs, and any future coverage determination by Medicare should be made in strict conformity with the terms of Â1861(t)(2) of the Act.

Sincerely,

Cancer Leadership Council

American Cancer Society
American Psychosocial Oncology Society
American Society of Clinical Oncology
Bladder Cancer Advocacy Network
C3: Colorectal Cancer Coalition
Cancer Care
Cancer Research and Prevention Foundation
The Children's Cause for Cancer Advocacy
Coalition of Cancer Cooperative Groups
International Myeloma Foundation
Kidney Cancer Association
Lance Armstrong Foundation
The Leukemia & Lymphoma Society
The Lung Cancer Alliance
Lymphoma Research Foundation
Multiple Myeloma Research Foundation
National Coalition for Cancer Survivorship
National Patient Advocate Foundation
National Prostate Cancer Coalition
North American Brain Tumor Coalition
Ovarian Cancer National Alliance
Pancreatic Cancer Action Network
Susan G. Komen for the Cure
Us TOO International Prostate Cancer Education and Support Network
The Wellness Community
Y-ME National Breast Cancer Organization

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The proposed CMS regulations are not in thre best interest of our patients for the following reasons:

1). there is no evidence to support the initiation of ESA therapy at Hgb level less than 9.0gr%; doing so would evoke a greater degree of cardio-respiratory compromise among our patients, increasing the chances of using blood components to alleviate symptoms of anemia quickly rather than waiting for ESA to become effective (delay up to 28 days before ESA to promote increase Hgb level). Blood components (aka PRBC) are also associated with more adverse events such as heart failure,infectious disease transmission (HIV, HCV, etc.), etc. Prior studies have documented a greater chance of having to give PRBC when ESA are delayed for lower Hgb levels (44% if Hgb less than 10gr%, and 95% if Hgb level less then 8gr%)

2). Limiting ESA therapy to 12 weeks per year per patient is totally ludicrous as chemo regimens commonly extend up to 6 months or longer, esp for the more common malignancies of breast, lung, colorectal, lymphoma, etc. The vast majority of patients requiring prolonged therapies are elderly in whom the majority are anemic prior to initiating chemotherapy; they also often have pre-existing and competing comorbid illnesses (heart, lung, renal , liver disease) that are further compromised when Hgb levels fall below 10gr%.

3). myelodysplastic (aka MDS) patients may require copious amounts of blood component support over several years with attendant complications (acquired autoantibodies preventing and/or complicating future PRBC therapy, iron overload, CHF, etc.). In this situation, ESA can avoid, prevent and/or delay these complications. Currently, FDA approved oral meds for MDS are appropriate and/or beneficial for only a minority of pts with MDS, leaving the vast majority able to recieve PRBC vs. ESA to maintaing Hgb levels.

4). Current standards of care demand the use of ESA (in lieu of PRBC) for symptomatic anemia due to the myelosuppressive effects of chemotherapy. The use of ESA have revolutionized our patient's therapy in that their quality of life is superior when anemia is controlled and/or improved through the use of ESA compared to repeated hospital admissions for blood components.

5). CMS has no concept of the emotional and/or psychological effects of chemotherapy upon our patients; not to mention the financial, social and interpersonal strains these cancers place upon our patients. The availability of ESA has been proven on numerous studies to be more efficacious and convient for our patients and is a universally accepted and proven method to maintain their dignity and quality of life. To impair and/or limit our ability to provide this small measure of comfort to patients is wrong, especially when the majority of whom are fighting a life and death struggle with an uncompromising beast that all too often is victorious despite our best efforts.

RK Gamble, MD

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As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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These comments are submitted on behalf of C3: Colorectal Cancer Coalition (C3), a non-profit, nonpartisan advocacy organization that is committed to the fight against colon and rectal cancer. We appreciate the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) National Coverage Analysis (NCA) on the administration of Erythropoiesis Stimulating Agents (ESAs) for non-renal disease applications.

C3 pushes for research to improve screening, diagnosis, and treatment of colorectal cancer; for policy decisions that make the most effective colorectal cancer prevention and treatment available to all; and for increased awareness that colorectal cancer is preventable, treatable, and beatable.

C3 believes in fully disclosing sources of financial support, per our disclosure policy which can be viewed at www.FightColorectalCancer.org/funding.htm. In 2006, C3 received funding from a company that manufacturers an ESA drug in the form of a charitable donation. Neither this company nor any of our other corporate supporters have influenced our comments on this issue.

While CMS is an autonomous agency, it is clear that it must work in conjunction with FDA when establishing reimbursement policy. C3 encourages CMS to rely on the extensive body of clinical data that is analyzed by FDA during the drug approval process and post-marketing monitoring of drugs when establishing this policy. Broadly speaking, we believe CMS should not restrict reimbursement for drugs when they are used in accordance with their FDA approved labels. FDA is currently analyzing data concerning ESA use. We request that CMS allow FDA time to complete their analysis, and that CMS consider their findings before finalizing policy on this issue.

In addition to the aforementioned policy issue, we are concerned about many specific aspects of the proposal issued by your agency on May 14, 2007. The aspects in question concern both conditions in which CMS believes there to be no reasonable or necessary benefit of ESA use, and in the limitations of ESA use in cancers purported to express the erythropoietin receptor. In particular, we disagree with the statement that ESAs have no reasonable or necessary benefit for patients with the following conditions:

• Condition #6: Any anemia associated with radiotherapy;
• Condition #10: Patients with treatment regimens including anti-angiogenic drugs such as bevacizumab; and
• Condition #11: Patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor.

Regarding condition #6, the use of radiotherapy in oncology is often coupled with concomitant use of chemotherapeutic agents (chemoradiation). Rectal cancer patients that are treated with chemoradiation often become anemic, and since they are receiving myelosuppressive chemotherapeutic agents, these drugs must be contributing to their anemia. Therefore by definition they are suffering from chemotherapeutic induced anemia, and as such they should be eligible for ESA treatment. We request that this condition be modified to distinguish between patients that are being treated with radiation only or radiation and chemotherapy.

Regarding conditions #10 and #11 we disagree with CMS that there is sufficient evidence to conclude that ESA treatment is not reasonable and necessary in patients undergoing chemotherapeutic regimens that include anti-angiogenic drugs or epidermal growth factor receptor (EGFR) specific monoclonal antibodies.

The provisions set forth in the CMS National Coverage Analysis will limit ESA use for chemo-related anemia in the greater than 50,000 Americans who turn to bevacizumab and/or cetuximab to fight their metastatic colorectal cancer each year. In the absence of new controlled clinical data supporting the conclusion that ESAs when used as labeled in conjunction with anti-angiogenic drugs and antibodies that inhibit the EGFR causes harm to cancer patients, we urge you to reconsider your proposed ruling.

We are also concerned that CMS is relying on in-vitro data when concluding that putative erythropoietin receptor expression on cancer cells should be used to limit ESA use. While it is possible that cancer cells expressing the erythropoeitin receptor may be stimulated to grow in response to recombinant ESA, we have not found any clinical data which adequately tests this hypothesis. However, if CMS has additional clinical data supporting this hypothesis, we still have questions regarding how this relates to the following limitations that were listed in the Proposed Decision Memo:

Regarding limitation #1, does CMS have clinical data that demonstrates initiation of ESA treatment at hemoglobin levels of reduce the need for red blood cell transfusions in cancer patients receiving chemotherapy? If so, why is this level only appropriate for patients with cancers that express the erythropoeitin receptor?

Regarding limitation #2, the FDA approved use of ESAs is to reduce or eliminate the need for red blood cell transfusions. Therefore patients should be treated with ESAs until they are no longer at risk of needing transfusions. In some cancer patients this period may exceed the 12 week maximum treatment duration proposed by CMS. Does CMS have data that would support their contention that ESA treatment beyond 12 weeks while a patient is being treated with chemotherapy is harmful to the patient? If so, are these data specific to patients with cancers that express the erythropoeitin receptor?

Regarding limitation #3, depending on the dosing regimen, the proper dose of both erythropoietin alpha and darbepoietin may be determined based on the weight of the individual; we are concerned that the four week maximum dose limits may be inadequate for some cancer patients. Further, does CMS have clinical data supporting the contention that ESA use at greater than 126,000 units for erythropoietin alpha and 630 ug for darbepoietin in a four week period (given appropriate hemoglobin levels are maintained as directed by the product labels) is harmful to cancer patients? If so, are these data specific to patients with cancers that express the erythropoeitin receptor?

Regarding limitation #6, does CMS know of clinical data indicating that the guidelines for dose reduction and withholding of drug in the case of a rapid hemoglobin rise as they are written in the existing labels for erythropoietin alpha and darbepoietin are inadequate and harmful to cancer patients receiving chemotherapy? If so, are these data specific to patients with cancers that express the erythropoeitin receptor?

We agree with CMS that ESA utilization should be based on evidence of safety rather than on the absence of harm. Consistent with this point of view, we believe that the existing clinical data demonstrates that ESAs are safe and effective when used in accordance with their FDA-approved labels to treat chemotherapy induced anemia. Based on these safety data, and the benefits resulting from increased control of a chemotherapy patient's hemoglobin, we strongly encourage CMS to reconsider the provisions of CAG-00383N that would restrict the reimbursement for ESA use in the FDA approved indication of chemotherapy induced anemia either with or without the concomitant use of anti-angiogenic drugs, monoclonal antibodies that inhibit the EGF-receptor or radiation therapy.

In order to establish the safety and efficacy of ESA use in indications that are not currently approved by FDA, we request that CMS consult with FDA and the biotechnology/pharmaceutical industry to help prioritize areas of off-label ESA use that will benefit from further clinical investigation.

C3 thanks you for your willingness to hear from patients who would be impacted by this ruling.

Sincerely,

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As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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I feel CMS should: Allow the oncology specialist to decide appropriate care withing the evidence based guidlines for ESA usage; Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy; Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions; Allow use of patients with MDS, non-coverage goes against all accepted national clinical guidelines; Allow cancer patients to maintain their quality of life; Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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I think the more appropriate approach to dealing with the evidence/issues stated for these changes would be to change the standard of practice. Oncology is a fast-paced arena for research. Studies and guidelines should be developed with input from frontline physicians and researchers to determine the most appropriate use of these agents. First of all, dosing to a target of 12 mg/dl with these agents is rarely done in my practice setting. We are happy if we can get patietns to 10 or 11 mg/dl and maintain that level..

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Walt A Kagan, MD, PhD
Commonwealth Hematology-Oncology, PC
10 Willard St
Quincy, MA 02169
617-479-1452

June 13, 2007

Steve Phurrough, MD, MPA
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mailstop: C1-09-06
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions (CAG-00383N)

Dear Dr. Phurrough:

My name is Walt A. Kagan, MD, PhD and I am a hematologist/medical oncologist. I am the President of Commonwealth Hematology Oncology (CHO), practicing in eastern and central Massachusetts. We have 23 hematologists/medical oncologists, one radiation oncologist, 12 nurse practitioners and 35 oncology certified nurses. We currently see approximately 7000 new patients with cancer and blood disorders each year. Many of these patients are currently treated with Erythropoiesis Stimulating Agents (ESAs). I have been in practice for 27 years and have personally seen the benefits of these agents for my patients with certain anemias related to chemotherapy or myelodysplastic syndromes. ESAs increase my ability to administer adequate doses of chemotherapy for patients on curative regimens, to reduce the need for transfusions and to improve the quality of life of my patients with anemias for which ESAs have been used in compliance with published guidelines.

As a practice, CHO has been committed to the use of all drugs in an evidence based manner and as such, we instituted our own practice guidelines based on FDA approval and ASCO/ASH guidelines over three years ago. It has been the standard of care for Commonwealth Hematology Oncology clinicians to monitor patients' hemoglobins very closely and to treat only as necessary for symptomatic relief of anemia, tailored to each patient's specific disease and comorbidities. We are well aware of new clinical data raising a concern that treating patients with ESAs to hemoglobins over 12 g/dl or hematocrits over 36% may increase the risk of certain cardiovascular complications but there is no evidence that treatment with ESAs to hemoglobins less than 12 is hazardous. I believe the proposed National Coverage Determination included in the above Memorandum goes far beyond the bounds of good patient care, available science or the legal regulations regarding cancer care as listed in Medicare statute.

The Medicare Statute as amended in 1993 by the so called Rockefeller Levin Bill, section1861(t)(2) of the Social Security Act (42 U.S.C. $1395x(t) (2) states that CMS must cover anti-neoplastic drugs including supportive medications for which an indication is approved by the FDA, listed as acceptable by approved compendia, or supported by peer reviewed medical literature. The restrictions for coverage included in the proposals of the above Memorandum far exceed any of indications required by statute.

Treatment of anemia due to myelodysplasia with ESAs is standard clinical practice. It is supported by ASCO/ASH guidelines which are strictly evidence based. Additionally, MDS is listed as an 'accepted' indication in the USPDI Drug Compendium. MDS should not be an exclusion for coverage by CMS. Because of the close monitoring of patients across our practice, we have seen safe and effective use of ESA's with a great reduction in the requirement for transfusion and symptoms.

The proposal that treatment with ESAs should not be used in patients with anemia and erythropoietin resistance due to neutralizing antibodies is completely unrealistic as this assay is not clinically available. This proposal should also be rejected.

The proposal that patients being treated with EGFR or VEGF antibodies are not appropriate candidates for ESA therapy is likewise unsupported by evidence based prospective medical literature. This proposal is also inconsistent with FDA labeling and compendia citations and should be rejected.

The proposal that ESA treatment is only reasonable and necessary under specified conditions for the treatment of anemias in those types of cancers in which the presence of erythropoietin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature is completely unsupported by evidence based medical literature.

The proposal that ESA therapy should not be initiated unless the hemoglobin/hematocrit is < 9 g/dl or 27% or < 10g/dl or 30% in those individuals with cardiovascular disease is also contrary to clinical practice and appropriate clinical trials. Further the implication that transfusion of PRBCs is a safer alternative than ESA therapy in this and other clinical situations is clinically nappropriate and an untested hypothesis.

The proposal to limit coverage to 12 weeks per year is completely inconsistent with good clinical practice. Many of my patients are on chemotherapy that lasts well beyond 12 weeks. There is clear evidence that these patients require fewer transfusions and have a better quality of life as a result of ESA therapy. Further there is no evidence that ESA use in compliance with ASCO/ASH guidelines for more than 12 weeks presents a safety risk.

Further, the proposal to limit the total four week dose of erythropoietin to 126,000U is contrary to FDA labeling as well as ASCO/ASH guidelines. Additionally this proposal does not allow for appropriate dose escalations as recommended in the above cited references.

The statement that continued use of the drug (ESAs) is not reasonable and necessary if there is evidence of poor drug response (hemoglobin/hematocrit rise < 1 g/dl/ 3%) after four weeks of treatment is again contrary to good clinical practice or evidence based studies. In clinical practice we treat individuals with anemia due to chemotherapy to levels that will avoid the need for transfusion of PRBCs or prevent cardio-respiratory decompensation. Setting artificial standards of an increase in hemoglobin or hematocrit is contrary to proper patient management. Additionally the product labels specifically allow for dose escalations in hypo-responders.

Lastly the proposal that ESAs should only be covered if dispensed in the context of a clinical trial is completely unreasonable and would deny appropriate treatment to the 95% of American cancer patients who decline participation in or do not have access to clinical trials. Erythropoietin and darbepoietin are FDA approved drugs and when prescribed in the support of anti- neoplastic therapy or for the treatment of MDS must be covered by CMS according to statute.

In summary, if the current CMS proposal is approved without alteration, I will be forced to treat my patients with an increased number of blood transfusions. This change in my practice will be costly to the patients and to the Medicare and Medicaid systems. It will expose patients to the well documented and life threatening side-effects of transfusion including iron overload, transfusion reactions, fluid overload, HIV, Hepatitis and other infections. This change in practice will stress an already tenuous national blood supply. Having to travel to get blood transfusions will create a great hardship for patients already burdened with the rigors of chemotherapy. And lastly, there is no evidence that supporting patients with transfusion therapy is better medical care than the current standard of care using ESAs.

Sincerely,

Walt A. Kagan, MD, PhD
President
Commonwealth Hematology Oncology

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Botton line, our practice never uses an ESA unless we believe that the therapy with which we were treating the patient's cancer is causing his anemia, thereby diminishing or limiting our window of opportunity to aggressively manage his disease. We frequently use Avastin or Cetuximab WITH cytotoxic chemotherapy so to argue that we could not manage the resultant anemia is unreasonable. And, as our practice includes many patients with metastatic disease, the 12 week per year limit is utterly lunatic. We treat patients as long as they tolerate and desire therapy and potentially beneficial agents are, thank God, still available. For our patients this often, and thankfully, goes on for years. As they continue through treatment their bone marrow's ability to recover diminishes and the ESAs become more important, but I promise you they are used with good clinical judgement and ongoing critical evaluation of utilization and response. If you want to impinge upon or regulate a practice, please don't do so at the point of care! The pharma marketing practices for these agents could definitely do with some firm scrutiny and oversight, but not MY patients! Everyone needs to take a step back, calm down, let the current recommendations take hold, and then re-evaluate. In your rush to limit the use of these products you run the very REAL risk of creating the need for even MORE costly solutions and interventions, including hospitalizations, transfusions, and progression of disease due to subtherapeutic dosing. The incidence of cancer related deaths has decreased the past few years, indicating that we are gaining ground, and working, at least in my lifetime, to take something that was terminal and make it something chronic. The ESAs have had impact in that they allow us to continue to treat sick people with life giving drugs. Let's not throw the baby out with the bathwater! Please, please reconsider.

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June 6, 2007

Stephen Phurrough, MD, MPA
Elizabeth Koller, M.D., FACE
Maria Ciccanti, R.N.
Coverage and Analysis Group/Office of Clinical
Standards.
Quality Centers for Medicare & Medicaid Services
Mail Stop: C1-12-28 7500
Baltimore, MD 21244-1849

RE: ESA guidelines

Dear committee members:

I am writing regarding my concern about the change in proposed ESA regulations.

The use of ESA has been a tremendous help to my patients. I have been able to minimize the use of blood transfusions and avoiding all of its possible reactions and complications. It also improves the patient's quality of life while they are on treatment. I have always the followed the guidelines appropriately in order to maximize benefit and yet not overuse the ESAs.

The proposed change in ESA guidelines usage will decrease the threshold for initiating the use of ESAs. I believe this will significantly harm the patient in terms of increasing the requirement for blood transfusions. It will also impact on their quality of life. I believe there is currently enough clinical and safety data regarding the use of ESA in the appropriate setting in patients with cancer and hematologic disorder.

I request that the committee look at the rationale for the proposed drastic change in the guidelines for ESA usage. I believe the proposed guidelines will have a betterment of impact on the patient's quality of life and also quite significantly increase the requirement for blood transfusions. Although, a slight adjustment in the use of ESA may be needed. I think the proposed threshold for initiation of ESA is quite too low.

Respectively yours,

Valiant D. Tan, M.D.

VDT/Pradot/ksp

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I strongly urge you to continue to support the current CMS guidelines,for the usage of erythropoiesis stimulating agents (ESAs). ESA is vital to the successful treatment of gynecologic malignancies. Hgb > 12 gm is associated with improved outcomes in all patients receiving cytotoxic chemotherapy by allowing full strength, on time chemotherapy.

The proposed NCD appears to be an arbitrary decision without literature to support limiting initiation of ESA to hemoglobin of 9. I have observed in the patients I have treated, that once allowed to reach a nadir of 9 grams, it is very difficult to to raise hemoglobin levels above 10 grams.

I haven't been able to find any scientific evidence supporting an arbitrary 12-week limit to therapy. I am also unable to identify any safety concerns in any of the relevant medical literature to support the proposed changes. I t has not been stated on what basis any of these guidelines were established. As an oncology nurse administering chemotherapy, I have seen the value of initiating ESA's early in treatment to improve or maintain a patients quality of life. These agents make a significant impact on our patients' lives, and limiting our patients' access to these life-improving agents would be tragic. I am asking that your final NCD be based upon the available scientific evidence and that you allow cancer care providers to continue to follow the evidence-based national treatment guidelines.
Thank you for your attentiion. Barbara Perchalski, RN, ONS: Chattanooga Gyn-Oncology

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VIA CMS Website and e-Mail (caginquiries@cms.hhs.gov)

June 13, 2007

Steve Phurrough, MD, MPA
Director Coverage Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
Mail Stop C1-12-28
7500 Security Boulevard
Baltimore, Maryland 21244

RE:Comments on Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Non- Renal Disease Indications (CAG-00383N)

Dear Dr. Phurrough:
The following comments are submitted to you on behalf of the members of the Georgia Society of Clinical Oncology (GASCOO). GASCO is a statewide organization representing over 250 hematology, medical oncology and radiation oncology professionals. Our members provide a very diverse clinical and demographic mix of cancer patients in rural, urban and suburban areas of Georgia who receive their care in both institutional and community-based cancer centers. The comments below are in response to the Proposed Decision Memorandum (PDMM) for Erythropoiesis Stimulating Agents (ESAss) released by the Center for Medicare and Medicaid Services (CMSS) on May 14, 2007.

GASCO has had a strong and collaborative relationship with our State Part B Carrier, CAHABA. Our Clinical Practice Committee and representatives to the CAHABA Carrier Advisory Committee (CACC) have been active in drafting a large number of Local Carrier Determinations (LCDss) for hematology, medical oncology and radiation oncology that reflect the latest, accepted science and clinical practice. We believe this is vital to ensure that there is no disparity between care for publicly funded healthcare programs and the commercially insured or private pay patients.

We also accept and endorse the concept that LCDs and NCDs are necessary to prevent patients from receiving care that is not peer reviewed and evidence based from those clinicians operating outside the guidelines of safety and efficacy. Therefore, we are not opposed to the principal of creating a National Coverage Determination (NCD) that provides consistent guidance for appropriate use of ESAs.

GASCO members are concerned that the given the language in the PDM, CMS is abandoning its long- stated goal of only reimbursing care that is scientifically sound, clinically appropriate and supportive of the patientts ability to have the highest quality of life (QOL) and functionality during treatment. In addition, a win-win situation exists when such care can be given in a manner that is generally cost-effective and does not over stress the patient or the care delivery system.

Our specific comments are:
1. The proposed PDM has significant coverage limitations that are not based on current scientific data; additionally several limitations conflict with the current standard of care in the United States. ESAs have been used in the supportive care of cancer patients for over a decade. Multiple studies have shown decreases in transfusion requirements, improvements in QOL, and improvements in functional status for patients prescribed ESAs for treatment of chemotherapy-related anemia.

2. Transfusions as an alternative to ESAs do not produce the equivalent hemoglobin maintenance achieved by appropriate ESA therapy. Furthermore, there are additional costs related to the increased frequency of transfusions, access to appropriate facilities, patient inconvenience and stress on the resources of facilities and blood banks required to provide transfusion services to patients previously managed with ESAs.

3. Use of Hgb < 9g/dL or a hematocrit less < than 27% as a treatment initiation point is inadequate. Current data show many patients who receive ESAs after Hgb drops to < 9g/dL will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated. No clinical trials to support this restriction have been published and, as a result, it is not clear if ESAs used in this manner will be effective in either improving QOL or decreasing blood transfusions. The National Comprehensive Cancer Network (NCCN) expert consensus panel cites multiple randomized studies supporting the initiation of ESAs when hemoglobin levels are less than 11 g/dL.

4. Evidence suggests that transfusion avoidance is better accomplished by early intervention at higher Hgb levels (i.e., Hbg < 11g have been proven superior to Hgb levels <10 as an ignition point by every measure in 6 different randomized studies).

5. A "stopping rule" at 4 weeks if a 1g/dL rise in Hgb is not achieved is not consistent with published clinical trial data. The clinical trials assessing both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dL rise in Hgb levels.

6. Dose escalation has been a critical component of most of the ESA clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

7. A maximum treatment duration of 12 weeks per year is inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

8. CMS is also seeking public comment on its proposed determination that there is sufficient evidence to conclude that ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, including anemia of myelodysplasia (MDS). The diagnosis of MDS is an accepted use and has been a covered indication for Medicare beneficiaries for many years. ESAs have been safely used for years to lower the transfusion requirement for patients with MDS. In fact, the NCCN recommends ESAs in patients with anemia due to certain types of MDS as first- line therapy. Denying coverage for this indication would be a definite step backwards in scientifically supported patient care. Studies dating back to 1991 have shown ESAAs to be safe, despite very high doses given to MDS patients.

9. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients receiving chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

10. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence showing that these receptors actually exist and are functional. No evidence exists to correlated ESA use in patients receiving chemotherapy for such tumors with tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic, not evidence-based policy and, therefore, should be reconsidered.

11. Patients with cancer and anemia usually complain of fatigue, shortness of breath, decreased stamina, and dizziness. The impact of anemia on QOL can be quantified using several established tools. ESAs have been shown to improve QOL and functional status in multiple randomized studies.

12. Packed red blood cell transfusions are not without risk, including transfusion reactions, fevers, rash, and hypotension. Although the risk of infection has decreased with better donor screening, the incidence of transfusion-related infectious diseases is not insignificant.

Summary

GASCO believes the PDM is based on data from clinical trials assessing criteria that differs significantly from the selection criteria used in current clinical practice, supratherapeutic doses of ESAs and ESAs for non-approved indications. The results were then extrapolated to cancer patients, in general, leading to the proposal of arbitrary restrictions not based on clinical experience in this population. Guidelines for the appropriate use of ESAs have been in place for some time. The NCCN and other national panels have published evidence-based utilization guidelines for ESAs. The NCCN guidelines are written by experts in the field of supportive care of cancer patients and are based on reviews of randomized clinical trials, when available, and consensus opinion when they are not.

We appreciate the opportunity to provide these comments and urge CMS to continue in its stated goal of creating coverage policies based on accepted science and the best interest of the patient. Please call either of us at the telephone numbers below if you have any questions concerning GASCOOs comments.

Sincerely

Harvey Lebos, M.D.
President
(912) 354-6187

Fred M. Schnell, M.D
Chairman, Clinical Practice Committee
(478) 743-7068

cc: GASCO Board of Directors
GASCO Clinical Practice Committee

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As a practitioner in a mountain community medical oncology practice, I am writing in response to the proposed National Coverage Determination for Erythropoietin Stimulating Agents. I would like to address two concerns regarding the proposed NCD.

First, I would like to address the legal side of this issue. CMS lacks authority to make coverage decisions that are narrower than the FDA approved indications. Moreover, additional uses unapproved by FDA but referenced in the statutorily identified medical compendia must be covered by Medicare absent a specific decision by the Secretary that such uses are medically appropriate. CMS should await the decision by FDA, if any, to further revise or restrict the labeling for ESAs. No CMS coverage proposal should be issued that is inconsistent with the FDA-approved labeling or with the compendia listings, unless they are found to be medically inappropriate.

Second, I would like to address the clinical aspect of this issue. The coverage limitations in the proposed NCD are in stark contrast with current scientific data and the standard of care in the United States. The exclusion of patients receiving VEGF or EGRF inhibitors is not based on any clinical evidence. These patients should not be excluded unless other risks are present.

Hemoglobin maintenance achieved via early interventional ESA therapy is not equivalent to the use of transfusions as an alternative. Patients experience a continued decline in Hgb for several weeks after initiation of ESA treatment. The proposed NCD allows initiation of treatment only after Hgb<9g/dl is reached, leading to the inevitable requirement for transfusions. Initiating ESA treatment at a higher Hgb level (such as <11) would greatly reduce the demand on our national blood supply.

In reviewing the blood transfusion procedures, the question also has to be addressed as to how effectively hospitals are going to be able to process transfusions on patients who are already immune-compromised. The amount of time, effort, and money that are involved are substantial but, more importantly, there is a quality of life issue for patients who may not even have close access to hospital facilities.

Clinical trials have proven the need for six to eight weeks of treatment to achieve a 1 g/dl rise in Hgb. Clinical trial proof that patients initially unresponsive to ESA use will respond with a dose 50% higher than the initial dose, has made dose escalation the standard of care. The NCD proposal. to stop treatment at four weeks if that rise is not achieved, is contradictory to the current standard.

In order to adequately treat metastatic disease, a patient may be required to undergo multiple courses of chemotherapy, extending over many months. Limiting treatment duration to twelve weeks per year is grossly below the standard of care for these patients, and severely impacts their quality of life.

The exclusion of coverage for MDS and multiple myeloma patients will serve only to needlessly expose our elderly patient population to the complications of chronic transfusions and toxic chemotherapy.

In conclusion, I find it very frustrating to have to defend the use of an FDA-approved drug that, when used appropriately, supports quality of life for so many of our patients. The most frustrating part of this whole situation is that the recommendations of the proposed NCD are not scientifically based nor even legal under CMS's own statutes. My fear is that this is only the beginning of attacks on drugs based on reimbursement issues rather than the accepted standard of care.

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June 6, 2007

Stephen Phurrough, MD, MPA
Elizabeth Koller, MD, F.A.C.E.
Marsha Ciccanti, RN
Coverage Analysis Group/Office of Clinical Standards
Quality Center for Medicare and Medicaid Services
Mail Stop C1-12-28 7500
Baltimore, Maryland 21244-1849

Re: ESA Guidelines

Dear Committee:

I am writing to express my concerns regarding the proposed Erythropoietin Stimulating Agent (ESA) regulations.

I am very much concerned about these proposals and feel that our group, Virginia Oncology Associates, and I have done an excellent job in being consistent with clinical data and clinical guidelines regarding the use of ESA's. In fact, I believe our practice specifically has been careful and even conservative in the use of ESA's. Virginia Oncology Associates has tried to follow appropriate guidelines such as those outlined by the National Comprehensive Cancer Network (NCCN) (Cancer and Treatment-Related Anemia) American Society of Clinical Oncology (ASCO) and through our affiliation with U.S. Oncology clinical pathways in the use of these agents. We have followed the guidelines for initiation of ESA's and also the discontinuation of ESA's.

Generally, ESA's have been a blessing to cancer and hematological disordered patients and are allowing oncologists to minimize transfusions and their inherent complications such as transfusion reactions and iron overload issues. I strongly believe and am concerned that if the thresholds for starting ESA's is lowered significantly, more patients will be put in harms way from the standpoint of needing transfusions and the difficulties of same and will experience clinical symptoms that cancer patients or hematologic disorder patients do not need to experience. I believe there is ample medical evidence to support the continued use of ESA's.

Some minor adjustments to the guidelines for the continued appropriate use of any drug needs to be assessed periodically. However, the current proposed regulations will take away from the quality of life for the cancer or blood disordered patient as well as significantly stress the finite quantity of blood products available for transfusion of our patients.

I respectfully request that your group continue to look at the rationale for use of these agents and not significantly adjust the current guidelines or recommendations. but continue to evaluate clinical data as it becomes available in peer review journals such as Journal of Clinical Oncology and organizations such as ASCO and NCCN.

Respectfully submitted,

Mark T. Fleming, M.D.

MTF/lsh

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Dear Dr. Phurrogh:

I write to you as Chief of the Division of Medical Oncology at Duke University Medical Center, Associate Director for Research at Duke Comprehensive Cancer Center, Vice Chair of the Respiratory Committee of CALGB, an active member of ASCO, NCCN and MASCC, who dedicate themselves to the development of practice guidelines based on evidence based medicine. I also write to you as an expert in the field of hematopoietic growth factors and as one of the presenters to ODAC on May 10th regarding the clinical evidence in support of the current use of ESAs for patients with chemotherapy induced anemia. However, most of all, I write to you as a clinician deeply concerned about the potential impact the proposed CMS restrictions will have in the care of my patients and other patients with cancer and hematologic malignancies, including myelodysplasia. The purpose of the ODAC meeting was to review the safety concerns regarding ESAs in an evidence based manner by all the participants, including the sponsors, the FDA and the members of the ODAC panel. While the deliberations from these meetings are still ongoing at the FDA, I was convinced that the safety signals involving ESAs remain restricted to studies that are 'off-label'and outside the current evidence based guidelines for clinical practice.

While these discussions are still continuing, the proposed CMS restrictions on ESA use seem to be unwarranted and have been instituted without the full input of the FDA, as well as other professional organizations involved in this area, many of whom have already made public comment. In particular, I would fully endorse response of ASCO, asking that the proposed CMS decision memorandum be withdrawn, pending the FDA's final revisions, if there are any, to the product labeling. Moving forward with any of the CMS recommendations at this point would be irresponsible and have a negative impact in providing the best possible care for our patients, a common goal for both the medical community and CMS upon which I am certain we agree.

Thank you for your attention to this matter.

Sincerely,

Jeffrey Crawford, MD
George Barth Geller Professor for Research in Cancer
Chief of Medical Oncology
Department of Medicine
Duke University Medical Center
Associate Director, Clinical Research
Duke Comprehensive Cancer Center

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The use of ESAs are important for cancer patients' quality of life after chemo or radiation treatments. The proposed limitation of a 12 week maximum could be a great hinderance for the recovery of cancer patients. The use of these drugs and the duration of treatment with these should be determined by the individual's physician and not by some national policy that cannot consider each person's individual needs. Afterall, we trust these doctors with our lives. They should not be limited in what treatments they can provide for our quality of life.

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The proposed changes in guidelines for EPO have multiple major flaws and could compromise individual patient outcomes. Apart from the impact on patient care, I wonder if anyone has considered the impact that these changes will have on our national blood supply? Based on my clinical experience, these changes will force clinicians to resort to transfusion much for frequently than we do at present. The drain on the Red Cross supply may exceed available resources and have consequences that reach far beyond the realm of MDS, Chemo, and ESRD patients.

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Dear Sir/Madame

We believe that a lrge component of these guidelines are definitely warranted a serious look. However as a practising hematologist and oncologist I do feel that some aspects of these comments may actually be deviating away from evidence based medicine.
1) Maximum coverage for 12 weeks for chemo induced anemia: I have not come across any literature supporting this guideline
2) Patients with MDS: Restricting use for MDS patients will take away an established practical way of improving QOL for many patients with MDS who otherwise would be forced to retrieve back to transfusion
3)Restricting use of ESA in patients recieveing anti EGFR and anti VGEF would again deprive a large number of patients with lung and colon as well as breast cancer, an access to ESA that would help them maintain their QOL for last few months of their life.

I do feel that upper limit of hemoglobin of 12 is definitely warranted as their does not seem to be any advantage to go beyond that limit. Nevertheless starting ESA at 9 gms once again would compromise with the QOL in these terminally ill patients.

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June 13, 2006

To: Centers for Medicare and Medicaid Services

I am the president of Atlanta Cancer Care, a large hematology/oncology practice located in Atlanta, Georgia. Annually, our providers treat 5,500 newly diagnosed patients and a total of 15,000 patients under on-going care.

I appreciate the opportunity to comment on the proposed National Coverage Determination (NCD) for the ESAs. Our practice is in support of a NCD for the ESAs to assure the safe and effective use of these drugs in patients with cancer.

I will address my comments first on the areas that CMS has identified as not reasonable and necessary conditions for patients to receive an ESA. I recommend the coverage of the ESAs in the areas listed below.

My greatest concern is that all patients that truly need EPO/Aranesp treatments will be denied treatment because of the guidelines. Unfortunately other insurance providers will soon follow suit based on CMS's ruling. It is understandable to take corrective action if a drug is being misused and causing harm, however epo and aranesp are creating good response in many patients and providing a quality of life that would not be available otherwise.Waiting until a patient has a hgb of 9 before initiating treatment is much too late. Ordering transfusions in lieu of treatment will overlaod the already taxed American Red Cross for blood products, not to mention local clinics that administer the blood. Once a patient's hgb goes so low, it takes so much longer for their levels to rise to normal. In some cases this never happens.The ESA's require at least 6-8 weeks for their effect to be realized. A stopping rule at 4 weeks does not allow for adequate time to see an appropriate therapeutic effect for these agents.Failure to treat therapeutically or with additional millions of transfusions does not seem to be an appropriate or efficient answer to treating anemia in cancer patients.

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I'm an oncology nurse and clinical consultant in a career spanning 30 years. In that time, there have been many breakthroughs and changes that have impacted the outcome of those diagnosed with cancer, as well as the quality of life for those living with the disease.

I am deeply troubled by the proposed changes for coverage of ESA's.

1. The hemoglobin/hematocrit level suggest for initiating treatment are too low. At that level there are significant clinical symptoms of anemia.Fatigue, exercise intolerance and the ability to maintain quality of life is diminished. A mother trying to care for children and maintain some semblence of "household normalcy", the ability to continue working, or climbing the bleachers to watch a soccer game. While fatigue is a word that doesn't sound too bad, the reality is devestating. One of my patients describes it as walking through quicksand. A neighbor undergoing treatment had to crawl on all fours to get up the stairs...prior to the initiation of ESA's.

2. Limiting the maximum number of covered treatments to 12 weeks. Chemotherapy treatment doesn't fit into a 12 week time frame.

3. Anemia of cancer Not covering for diseases like MDS, multiple myeloma. Again over the years I've seen the impact of ESA's on the quality of life for this group of patients. I recently had a 52 year old working women with MDS, hanging onto my hands crying and saying "what am I going to do.." ESA's have kept her working, able to enjoy life and prolonging the interval to transfusion to 2 months (had been every 2 weeks).

My patients are desperate to live the life path they've been given. The side effects of anemia and increased transfusions will keep them walking through quicksand. It's all the time they've got...please allow us to help them.

Sue Ellen Loebach RN,MN, OCN

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June 13, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Mail stop C1-09-06
Centers for Medicare and Medicaid Services (CMS)
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions (CAG-00383N)

Dear Dr. Phurrough:

On behalf of Ortho Biotech Products, L.P., I am pleased to submit comments on the Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (CAG- 00383N). Ortho Biotech Products, L.P. markets PROCRITTÃ (Epoetin alfa), a manufactured form of a naturally occurring hormone (erythropoietin) administered by subcutaneous injection to stimulate the bone marrow's production of red blood cells. Clinical studies and approximately 20 years of clinical experience have demonstrated Epoetin alfa effectively treats chemotherapy- induced anemia by increasing hemoglobin, reducing red blood cell transfusion utilization, and reducing anemia-related symptoms, particularly fatigue.

We strongly support CMS's goal of ensuring that its coverage policies encourage appropriate and safe use of ESAs, and discourage uses that are known to be inappropriate. However, we are concerned that the proposed National Coverage Determination (NCD) would restrict coverage of ESAs for certain conditions that are medically reasonable and necessary, and would impose dosing and administration requirements that are incompatible with recently revised product labeling. In particular, the full use described in the labeling for ESAs and other prescription drugs should be covered whenever those uses are the subject of a NCD. The U.S. Food and Drug Administration (FDA) approves the product labeling for prescription drugs only after careful consideration of all available evidence, and a thoughtful determination that the uses described therein are safe and effective as supported by substantial evidence. Uses that have been determined by the Secretary of Health and Human Services (HHS) to be safe and effective on the basis of substantial evidence should not be declared by CMS to lack necessity or reasonableness.

Section 1861(t)(2) of the Social Security Act defines the drugs covered by Medicare Part B as including all drugs and biologics that are: 'used in an anticancer chemotherapeutic regimen for a medically accepted indication.' That provision further defines a medically accepted indication as including: 'any use which has been approved by the Food and Drug Administration for the drug. . . ', as well as uses listed in certain compendia, unless the Secretary of HHS has determined that 'the use is not medically appropriate or the use is identified as not indicated in one or more such compendia."

The standard for FDA's approval of an oncology drug product includes a finding by the Secretary of HHS that the drug is safe and effective for its labeled use, based upon substantial evidence consisting of adequate and well-controlled clinical trials. This standard is clearly higher than, and includes the determination of 'medically appropriate', the Secretary makes in determining coverage of a drug product.

With respect to the compendia indications for PROCRIT, such as myelodysplastic syndrome there are robust clinical data, as evidenced in our accompanying Clinical White Paper, by which the Secretary could determine that the compendia listed uses are medically appropriate. Equally, these data refute any determination that the compendia listed uses of PROCRIT are not medically appropriate. As such, those uses should not be the subject of a National Coverage Determination, but should be left to case-by-case assessments of medical necessity or Local Coverage Determinations (LCD).

Summary of Ortho Biotech's Recommendations on the Proposed NCD

• The results of clinical studies, outlined in the attached Clinical White Paper, demonstrate that PROCRIT is safe and effective when used for FDA-approved indications, and for other medically- accepted uses listed in the DrugPointssà Compendium (which, in July, 2007, will succeed USP DIIÃ). The final NCD should allow for the appropriate use of ESAs for these indications.

• We do not object, in principle, to a determination that ESAs are not reasonable and necessary for the following nine conditions:
  - any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
  - anemia of myeloid cancers;
  - anemia associated with the treatment of myeloid cancers or erythroid cancers;
  - anemia of cancer not related to cancer treatment;
  - any anemia associated with radiotherapy;
  - prophylactic use to prevent chemotherapy-induced anemia;
  - prophylactic use to reduce tumor hypoxia;
  - patients with erythropoietin-type resistance due to neutralizing antibodies; and,
  - anemia due to cancer treatment if patients have uncontrolled hypertension.

  However, the final determination should clarify that 'myeloid cancers' refers to acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) but not to myelodysplasia or multiple myeloma. Additionally, coverage for the use of ESAs in several of these conditions may be reasonable and necessary when such use is part of an evidence development program.

• CMS should specifically allow coverage of ESA use for these conditions:
  - anemia of myelodysplasia or myelodysplastic syndrome (MDS);
  - anemia in patients with treatment regimens including anti-angiogenic drugs;
  - anemia in patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor; and,
  - patients with thrombotic episodes related to malignancy.

• The presence of functional EPO receptors on tumors and tumor proliferation in response to exogenous EPO has not been demonstrated, and thus should not form a basis for determining medical necessity or appropriateness for the described tumor types. Coverage determinations should not be premised on highly theoretical models. In particular, we believe Medicare should not ignore proven clinical benefits of ESA treatment while giving greater weight to theoretical risks.

• The final coverage determination should cover ESA use in patients with chemotherapy-induced anemia if they have a hemoglobin concentration below 11 g/dL, and suspend coverage in patients who reach a Hb concentration over 12 g/dL during a course of treatment, which is consistent with ESA prescribing information.

• ESAs may be necessary for a duration longer than 12 weeks annually, particularly for patients who receive more than one course of chemotherapy in a year. The final coverage determination should restrict the duration of coverage for ESAs to periods of ongoing chemotherapy, and for up to a 3 month period following chemotherapy completion. In most individual cases, ESA treatment duration will be shortened if the final determination prevents coverage for patients with a hemoglobin concentration above 12 g/dL, but ESA coverage should be permitted for a full course of chemotherapy where medically appropriate and necessary.

• Coverage for ESAs should not be subject to an arbitrary dosing cap during a treatment period. The efficacy and safety of ESAs, as demonstrated in controlled clinical trials, are incumbent upon the dose titration described in approved product labeling. The final coverage determination should support the use of ESAs starting with the lowest dose needed to avoid a transfusion, as described in approved labeling, and increasing the dose as needed and as described in the labeling information, to obtain a therapeutic effect. The arbitrary dose limits described in the draft NCD interfere with physicians' ability to appropriately individualize patient care. In practice, if CMS limits ESA use with a Hb limit (i.e., suspending coverage for Hb > 12 g/dL), an appropriate patient-specific dose limit will in fact be in place. Moreover, any arbitrary dose limit will create unintended reimbursement incentives.

• The proposed determination to discontinue coverage if there is evidence of poor drug response after 4 weeks is inconsistent with FDA approved labeling, clinical trial evidence, and anemia treatment guidelines. A determination to discontinue coverage if there is evidence of poor drug response (i.e. hemoglobin/hematocrit rise <1 g/dl/< 3%) at week 8 of treatment (after appropriate dose titration) would be more consistent with clinical trial evidence and established anemia treatment guidelines.

• The final determination should eliminate the following proposals due to lack of supporting scientific evidence:
  - Non-coverage of continued administration if there is an increase in fluid retention or weight (5 kg) after 2 weeks of treatment; and,
  - Non-coverage if there is a rapid rise in hemoglobin/hematocrit >1 g/dL >3% after 2 weeks of treatment.

• Ortho Biotech (OBI) is interested in discussing further Coverage with Evidence Development (CED) approaches for patients with anemia of cancer not related to chemotherapy treatment. We do not believe CED is an appropriate coverage approach for patients with chemotherapy-induced anemia, given the body of evidence demonstrating that ESAs are reasonable and necessary for the treatment of these patients.

• In recognition of our shared interest in developing additional evidence on ESA use, OBI recommends that CMS consider a Pharmacovigilance and Evidence Development Program for ESAs that will include periodic reports from manufacturers, consideration of the pharmacovigilance plans developed with the FDA, and other important elements described in our detailed comments below.

Detailed Comments

Our comments are organized into four sections as outlined below:

1. Safety record and benefits of PROCRIT when used for labeled indications and for indications listed in the DrugPoints Compendium (formerly USP DI).
   
2. Safety signals that have emerged from recent ESA clinical trials, particularly those targeting Hb levels > 12 g/dL
   
3. Potential risks to the country's blood supply associated with decreased ESA use
   

1. Clinical conditions for which proposed non-coverage is appropriate
   
2. Clinical conditions for which proposed non- coverage is not appropriate
   
3. Coverage restrictions based on the presence of EPO receptors
   
4. Hemoglobin/hematocrit levels for initiation of ESA treatment
   
5. Maximum covered treatment duration of 12 weeks per year
   
6. Maximum covered 4 week treatment dose of 126,000 units for erythropoietin and 630 Îg for darbepoetin
   
7. Non-coverage for poor drug response (hemoglobin/hematocrit rise <1 g/dl after 4 weeks of treatment
   
8. Non-coverage for increase in fluid retention
9. Non-coverage for rapid rise in hemoglob
   in/hematocrit >1g/dl/& of treatment
10. Coverage with Evidence Development (CED)

As noted throughout this comment letter, additional details and documentation to support our position are included in the attached Clinical White Paper.

A. Background

1. Safety Record and Benefits of ESAs

Medicare has provided coverage for patients receiving Epoetin alfa since 1989, when it was first approved to avoid transfusions in end-stage renal disease patients treated with dialysis. Epoetin alfa was subsequently approved by FDA for use in chronic renal failure patients (pre- dialysis) and zidovudine-treated HIV-infected patients (1990), as well as for cancer patients receiving chemotherapy (1993), and for patients scheduled for elective, noncardiac, nonvascular surgery (1996) who are not able or willing to donate autologous blood despite significant anticipated blood loss. Since 1989, the DrugPoints Compendium (formerly USP DI) has reviewed evidence in the peer-reviewed literature and, in addition to the FDA-approved indications, currently lists PROCRIT as beneficial for use in anemia related to treatment of hepatitis C, critical illness, MDS, chronic/ neoplastic disease, and blood unit collection for autotransfusion.

ESAs are an important beneficial therapeutic option for anemia treatment in patients who might otherwise require transfusions. Multiple randomized and non-randomized clinical trials involving approximately 15,000 patients treated with ESAs for chemotherapy-induced anemia have been performed over the past 20 years. ESAs have been demonstrated to reduce transfusion risks by approximately 50% and have an acceptable safety profile when used according to label.

It is estimated that over four million patients worldwide have been treated with epoetin alfa. While transfusions are certainly necessary and beneficial in acute situations, many risks associated with transfusion have been well documented, including allergic reactions, transmission of infectious agents, and immunomodulation effects such as TRALI (transfusion-related acute lung injury), especially in patients who are already compromised. Despite high safety standards for the blood supply, many patients still view transfusions with distress and anxiety and clearly want to avoid them.

We share CMSSâ? concerns for safety, but urge CMS to give appropriate consideration to the benefits of ESAs, particularly the widely studied benefits of patient-reported outcomes. According to the General Methodological Principles that are described in numerous national coverage decision memos:

In the case of ESAs, patients have benefited from the reduction in fatigue that is associated with anemia treatment, in addition to transfusion avoidance. While the FDA has not accepted patient-reported outcomes as labeling claims for ESAs in the United States, its thinking on such claims has been, and is constantly, evolving. The FDA issued draft guidance on patient reported outcomes (PROs) for purposes of labeling claims in March 2006, but has since stated publicly its intent to make significant revisions to the guidance when finalized (http://www.fda.gov/cder/present/DIA2006/Burke_Rock.pdf). Other regulatory bodies have a higher level of acceptance of the outcomes data generated from randomized controlled trials. The EMEA and Health Canada have included symptom- based, patient reported outcomes data in the product labeling for ESAs. CMS should carefully consider the large body of evidence of improved PROs that have been reported with ESA use in patients with chemotherapy-related anemia when finalizing its coverage determination. This type of anemia is a common complication of myelosuppressive chemotherapy, with the frequency of occurrence dependent on the underlying malignancy and the regimen and intensity of chemotherapy utilized.

The causes of fatigue are multifactorial and the relationship between hemoglobin concentration and intensity of fatigue is not well understood. However, since patient-reported levels of fatigue in patients who had cancer have been shown to correlate directly with the degree of anemia, anemia is often treated for palliation of symptoms as per guidelines established by the National Comprehensive Cancer Network (NCCN).

2. Safety Signals from Investigational Studies

Recent safety signals, including an increased risk of thromboembolic events (TVE), reduced survival, and possible tumor growth, have emerged from investigational cancer studies, particularly when ESAs were used beyond the correction of anemia (target Hb > 12g/dL.

The risks of ESAs in cancer patients are described in product labeling. An increased incidence of thrombotic events has been observed when ESAs are used for the correction of chemotherapy-induced anemia. Adverse effects on survival and tumor progression are observed when ESAs are used off-label. With the exception of the Amgen Anemia of Cancer Trial (Glaspy 2007), all the studies below evaluated patients with higher Hb initiation levels (> 12 g/dL) and/or targeted higher Hb levels (> 12 g/dL) than currently recommended. The Amgen Anemia of Cancer Trial evaluated a patient population that is currently excluded in the FDA approved ESA labeling information.

The extensive evidence base indicates that ESAs, when used according to product labeling (the treatment of anemia caused by concurrent chemotherapy, with a target hemoglobin concentration not to exceed 12g/dL), have no negative effect on survival or tumor growth. While there is an increased risk for TVEs, this risk is well described in product labeling, and is understood by health care providers.

As proposed, the NCD relies upon safety signals from the investigational studies to unduly limit uses of ESAs that have been shown to be reasonable and necessary. The final determination should cover all uses of ESAs described in approved product labeling, for which there necessarily exists substantial evidence of the safety and effectiveness of those uses, and any other use for which safety signals have not been observed and there is a body of evidence supporting the use, such as there is for MDS. Any other approach threatens patient access and health outcomes.

3. Potential Risks to the Nation's Blood Supply Associated with Decreased ESA Use

The nation's blood supply is a limited resource that could be further strained by the increased demand for transfusions that would likely result from an overly restrictive coverage policy on the use of ESAs. From 1987 to 1997, the collection of allogeneic blood declined from a high of 13.6 million to 11.9 million units. Although supply of blood has increased since then, so has demand, and the current margin between supply and demand has shrunk.

Additionally, processes used for qualifying fully screened units further exacerbate this situation. In 2004, 240,000 units were rejected after screening, leaving a margin of only 648,000 units or 4.5% of the available supply. Based on the 2005 Nationwide Blood Collection and Utilization Survey Report, 8.5% of surveyed hospitals reported postponement of elective surgeries on 1 or more days in 2004 because of blood inventory shortages (range: 1 to 39 days a year). Sixteen percent of hospitals reported they were not able to meet their non-surgical blood needs on at least one day. Although demand is fairly constant, the blood supply is actually highly variable throughout the year. This has led to transient shortages during holiday periods typically associated with low donation.

Ortho Biotech performed a modeling simulation to estimate the impact that limiting the use of ESAs in chemotherapy-induced anemia would have on the U.S. blood supply (data on file). The excess number of units that would be required if patients were not treated with ESAs, was contrasted with the 2004 marginal blood supply data (most recent data available). Model inputs were drawn from the published literature or expert opinion where literature was lacking. Estimates were developed for a range of scenarios and incorporated into appropriate sensitivity analyses.

The model predicts that up to a third of the marginal U.S. blood supply would be required to cover the incremental demand for blood that would arise from a 25% decrease in the use of ESAs (see attached model). Nearly two-thirds of the marginal blood supply could be compromised with a 50% reduction of ESA use in patients with chemotherapy-induced anemia. Recently, Wall Street analysts reported their estimates that implementation of the draft NCD may decrease ESA utilization from 25% to 70% (Porges 2007, Werber 2007, Ende 2007, Hopkins 2007). Such changes in ESA utilization would be associated with an incremental demand of 118,000-237,000 units of blood. This added pressure on the blood supply could be even larger due to regional variations in the number of available units, and the variable frequency of donation.

We urge CMS to consider the potential negative consequences on the nation's blood supply by restricting the use of ESAs.

B. Response to CMS Proposed Decision Memo

1. Clinical Conditions for which Proposed Non-Coverage Is Appropriate

CMS proposes thirteen clinical conditions for which ESA treatment would not be reasonable and necessary.

We agree, in principle, and do not object to a determination that ESAs are not reasonable and necessary for the following nine uses:

1. the treatment of any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
2. the treatment of anemia of myeloid cancers;
3. the treatment of anemia associated with the treatment of myeloid cancers or erythroid cancers;
4. the treatment of anemia of cancer not related to cancer treatment;
5. the treatment any anemia associated with radiotherapy;
6. prophylactic use to prevent chemotherapy-induced anemia;
7. prophylactic use to reduce tumor hypoxia;
8. use in patients with erythropoietin-type resistance due to neutralizing antibodies; and,
9. treatment of anemia due to cancer treatment if patients have uncontrolled hypertension.

2. Clinical Conditions for which ESAs are reasonable and necessary

CMS should allow coverage for the following four conditions based on the body of evidence demonstrating ESAs are reasonable and necessary:

• The anemia of myelodysplasia or myelodysplastic syndrome (MDS)

  MDS is not considered a myeloid cancer but rather a disorder of ineffective hematopoesis. Anemia is the most frequent complication of this irreversible chronic bone marrow disorder that requires long-term transfusions, and is commonly treated with ESAs. Transfusion dependency has been associated with reduced survival and morbidity, including iron overload. ESA benefits include reduced dependency on transfusions, especially in MDS patients presenting with serum erythropoietin levels < 500 mUnits/mL. In addition, studies of EPO use in low risk MDS patients have suggested that survival is improved compared to historical controls. The natural history of MDS is associated with a proportion of patients transforming to acute leukemia, although there is no evidence that use of EPO accelerates this transformation.

  No safety signal has emerged regarding ESAs use in anemia of MDS. Currently, the anemia of MDS is covered by virtually every carrier under LCDs that were recently revised to withdraw coverage for the anemia of cancer. Carriers should continue to exercise discretion when covering the use of ESAs to treat the anemia of MDS based on the existing body of clinical trial evidence, and the fact that no safety signal has emerged. Treatment guidelines, e.g., ASH/ASCO, NCCN, British and Italian national guidelines, and major compendia (DrugPoints (formerly USP DI) and AHFS), have endorsed the use of EPO for MDS. Additionally, CMS appears to have recognized the value of ESA treatment by incorporating evaluation of iron stores for MDS patients undergoing ESA treatment as a physician quality measure under the Physician Voluntary Reporting Program (PVRP).

• Anemia in patients with treatment regimens including anti-angiogenic drugs such as bevacizumab and monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor e.g., cetuximab (ErbituxxÃ) and panitumumab (VectibixxÃ)

  The proposal to restrict coverage for patients whose chemotherapy regimens include an anti- angiogenic or anti-epidermal growth factor receptor agent lacks a sufficient scientific foundation. No safety signals have been identified with the concomitant use of ESAs in the clinical settings where these approved regimens are widely utilized, e.g., colorectal and lung cancer. Furthermore, ESAs for the treatment of anemia are allowed in the ongoing clinical trials evaluating potential new indications for these agents in combination with chemotherapy. This policy would adversely affect many patients for whom anti-angiogenic agents are administered in combination with myelosuppressive chemotherapy regimens that commonly cause anemia.

  The final coverage determination should be based upon scientific evidence and not on theoretical concerns of overlapping toxicity, which, based on the data from the large registration trials and pharmacovigilance program, remain unsubstantiated. Because there is no basis to conclude that the use of ESAs is not reasonable and necessary in every patient receiving anti- angiogenic drugs, the final national coverage determination should rely on local carrier discretion to determine coverage. We believe CMS would set a new precedent in its coverage of treatments by ignoring the proven benefits of anemia treatment in these patients while giving greater weight to theoretical risks. We recommend that this proposal be withdrawn.
• Patients with thrombotic episodes related to malignancy

  While ESAs are known to increase the risk of thromboembolic events, the determination of the acceptability of such risk should be made in the ordinary course of the practice of medicine, after discussion between healthcare practitioners, patients, and families about the known risks and benefits. Such informed decision- making should not be usurped through a national coverage determination.

There is inadequate scientific evidence upon which to base ESA coverage restrictions concerning selected tumor types that may express EPO-R on the surface of their cells. While we recognize the theoretical concerns raised by the presence of such EPO-R on tumor cells, there is no evidence that these receptors are functional at pharmacologic ESA doses, nor have they been demonstrated to cause tumor growth in the presence of EPO in any in vivo model. We discuss the serious scientific limitations of this theoretical rationale underlying the proposed coverage restrictions in the attached Clinical White Paper.

Briefly stated, the scientific data supporting the presence of functional EPO-R on the surface of tumor cells has significant limitations and are thus unreliable as a basis for selecting specific tumor types for coverage restrictions. The biologic relevance of detecting EPO-R in tumor cells is uncertain, given the lack of antibody specificity for cell surface expression of the EPO-R on tumor cells. The antibody utilized in cited assays recognizes multiple proteins and is unable to differentiate between cytoplasmic and cell surface EPO-R expression. Furthermore even when such receptors are "present" in the tumor cells, there is no evidence of signaling from these receptors even in the presence of exogenous EPO at concentrations that are nearly 2 logs greater than the maximal concentration achieved after labeled doses of EPO are administered. This, coupled with the fact that no studies have been able to derive a binding coefficient (Kd) for the affinity of EPO to the receptors on tumor cells, suggests that, even if such receptors are present, they are irrelevant to the biology of the tumor. In fact, no studies, including those in the CMS proposed decision memorandum, have shown that exogenous EPO leads to increased tumor growth in vivo. Investigators reported less favorable tumor outcomes in EPO-treated head and neck cancer patients whose tumors "express" the EPO-R, have acknowledged such uncertainties.

- if we assume that SC695 (commercially available EPO-R antibody) lacks specificity & sensitivity, as claimed by a recent publication, interpretation of our data would become a real challengee?¦ Henke (2006)

EPO effects on tumor oxygenation and microvasculature have been hypothesized as an alternative mechanism for explaining tumor progression in those studies designed to treat patients to high target Hb levels to potentiate a radiotherapy effect [e.g. 14-15 g/dL, Henke (2003), DAHANCA (Overgaard 2007)]. Specifically, maximal tumor oxygenation in squamous cell carcinoma of the head and neck has been observed at normal gender-specific Hb values. Above this optimal Hb range, studies have demonstrated that tumor oxygenation begins to worsen, potentially counteracting the anti-tumor effectiveness of localized radiotherapy delivered to the tumor (Vaulpel 2006).

FDA scientists have also reviewed this area and described the following:

CHARLESH.SRODES,M.D.,F.A.C.P.
MELISSA M. THIMONS, D.O.
SIGURDUR R. PETURSSON, M.D., F.A.C.P.
JOSE SILVA, M.D.
CYNTHIA K. EVANS, M.D.
JASON THOMAS, M.D.
KATHY J. SELVAGGI, M.D., F.A.C.P.
BEAULA KODURI, M.D.
G. SCOTT LONG, M.D., PhD.
DIANE BUCHBARKER, M.D.
MOSES S. RAJ, M.D.
HEATHER M. MISKE, D.O.
MOHAMMED F. ISLAM, M.D. M.S.
ARUN BHANDARI, M.D.
GENE G. FINLEY, M.D.
ARUNKUMAR SANJEEVI, M.D.
ALEX BARSOUK, M.D.
AMJAD JALIL, M.D.
HELEN ANALO, M.D.
JOHN A. LECH, D.O.

June 12, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

Dear Sir or Madam:

We are writing to comment upon the proposed decision coverage memorandum regarding the use of erythropoiesis stimulating agents (ESAs) for cancer and related diseases. After review of the proposal, review of our prescribing practices, and discussion with physicians in our large group practice we have, as a group, concluded that the scope of the proposal is far too broad and the limits placed on ESA usage will have a profound negative impact on our patients with cancer and hematologic disease. We will address some of the most egregious aspects of the memorandum herein.

1. The conclusion that ESA use is not necessary and reasonable for patients with myelodysplasia (MDS) or myeloid cancer.
Although use of ESAs in this setting is considered off label by the FDA, we and many other practicing hematologists and oncologists have used these agents for more than a decade to great advantage in these diseases, resulting in fewer transfusions and improved quality of life. MDS patients often require multiple transfusions over a period of years resulting in iron overload, a clinical situation that can be delayed or avoided entirely through judicious use of ESAs. We have not seen patterns of excessive thrombosis, nor have we observed progression to myeloid leukemia in this setting. Many of our patients appreciate the convenience of a single weekly injection as opposed to several hours in a chair or hospital bed receiving a blood transfusion. We cannot find within the CMS memorandum any specific justification for this proposed change.

2. The conclusion that ESA use is not necessary and reasonable for patients with anemia receiving radiotherapy.
The basis of this appears to be the Danish Head and Neck Cancer Group Study in which patients received darbepoetin alfa in order to achieve extremely high hemoglobin levels, improve oxygen delivery to the cancer and thereby reduce tumor hypoxia. Unfortunately, there appeared to be an adverse effect of the darbepoetin alfa on outcome with an increase in cancer-specific deaths in the treated group. No one in our practice and no oncologist known to our group would initiate therapy at the hemoglobin level specified in the trial, nor would any of us attempt to achieve such a high hemoglobin level. We have not experienced the kind of rapid progression in our patients noted in this Danish trial.

3. The conclusion that ESA use is not necessary and reasonable for patients receiving monoclonal antibodies such as bevacizumab or anti-EGFR antibodies.
Most of these biologics are given in conjunction with chemotherapy, and the chemotherapy-induced anemia is treated with ESAs to great advantage in our and many other oncology practices. For example, Bevacizumab is often administered in conjunction with and enhances the efficacy of chemotherapy in a wide variety of human tumors. It is common for patients to become anemic when receiving such combination therapies, and ESAs are often used in this setting. Although one publication found adverse outcomes with panitumumab when administered in conjunction with darbepoetin alfa in advanced colorectal cancer patients, this hardly justifies painting all of these biologics with a broad brush and limiting access to ESAs for a large subgroup of our patients who benefit from these agents.

4. The conclusion that ESA use is not necessary and reasonable for patients with thrombotic episodes related to malignancy.
Cancer is a thrombogenic state, as all of us are aware. Many patients may develop thrombotic episodes either from their underlying malignancy or from chemotherapy. Standard anticoagulant strategies are employed and usually prevent recurrent episodes. Once patients are adequately anticoagulated, it is hard for us to understand why ESAs should be withheld in this population.

Next, the CMS memorandum recommends specific limitations on ESA use. Many of these are unreasonable and are not supported by the available data. Specifically:

1. Initiation at a hemoglobin of less than 9 grams or less than 10 grams for patients with known symptomatic cardiovascular disease that cannot be treated with blood transfusion.
We find this recommendation ill conceived. Many cancer patients have fatigue, shortness of breath and other adverse symptoms affecting their day-to-day lives with hemoglobin values higher than those levels. Early therapy with ESAs has been demonstrated to significantly improve quality of life for chemotherapy patients suffering chemotherapy-induced anemia. Our current practice, based upon the recent FDA recommendations, calls for initiation of therapy at a hemoglobin of less than 11 grams targeting a hemoglobin not to exceed 12 grams. It appears to us that this is a reasonable practice guideline and provides a good balance among patient convenience, quality of life and patient safety.

2. A maximum duration of therapy of 12 weeks per year.
Therapy for many individuals lasts much longer than 12 weeks and their chemotherapy induced anemia does not promptly resolve with cessation of chemotherapy. A reasonable percentage of patients, especially older patients, take longer for their bone marrow to recover from the effects of chemotherapy. Limiting ESA use to 12 weeks per year is unreasonable based upon available evidence and will result in reduced quality of life for our patients.

3. The maximum covered treatment dose is 126,000 units in a four-week period
The standard dosage of epoetin alfa is 40,000 units weekly or 160,000 units in a four-week period. The darbepoetin alfa dosage recommended in the CMS memorandum approximates our clinical practice but does not account for patients who are larger than 70 kg who may be under dosed at those levels.

4. Cessation of therapy if there is poor drug response after 4 weeks of treatment.
The median time to response is 4 weeks but many patients require longer administration to see results. Moreover, poor response as measured by hemoglobin rise is not a reasonable endpoint in MDS patients. Many of these patients are treated with the goal of hemoglobin maintenance and reduction in transfusion requirement.

Conclusion:
The proposed CMS decision memorandum will place an undue burden on our cancer patients, and is in direct opposition to our practice of putting the patient's interest first. The current CMS proposal has serious deficiencies that will severely hinder our ability to provide the best care possible while minimizing the negative aspects of treatment. Increased transfusion and related risks (disease transmission, allergic reactions, etc.) will be the result with a concomitant decrement in quality of life for this most vulnerable patient population. The increase in blood product usage will strain an already taxed blood banking system and result in unnecessary hospital admissions for blood transfusion.

CMS should carefully consider the adverse effects of this proposal before implementing such sweeping changes. We remind CMS that the Food and Drug Administration (FDA) is the agency responsible for pharmaceutical approval and monitoring of drug safety and we urge CMS to be guided by FDA recommendations.

Respectfully submitted by the physicians of the West Penn Allegheny Oncology Network, Pittsburgh, Pennsylvania.

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June 13, 2007

Steve E. Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Blvd.
Baltimore, MD 21244

RE: Proposed National Coverage Policy on use of Erythropoiesis Stimulating Agents (ESAs) in Cancer Patients (CAG-00383N)

Dear Dr. Phurrough,

On behalf of our colleagues at Fox Chase Cancer Center, we would like to submit the following comments in response to the recent proposals put forward by CMS regarding coverage of ESAs for cancer and related conditions. Fox Chase Cancer Center is a free-standing NCI-designated Comprehensive Cancer Center whose mission is to reduce the burden of human cancer. Our center treats thousands of cancer patients each year, and has extensive experience with use of ESAs in the management of cancer patients. We believe that CMS's proposed coverage limits are far too restrictive, are not supported by scientific or clinical evidence, and would have serious negative consequences for the care of our patients.

With regard to use of ESAs in patients with the myelodysplastic syndromes (MDS), we believe that the weight of evidence supports the efficacy and safety of ESAs in anemic patients with low-risk MDS. A phase III, randomized, prospective trial conducted by ECOG of erythropoietin +/- G-CSF vs. supportive therapy alone has demonstrated significant hematologic improvement with Epo, with no signal to suggest a negative impact on survival or evolution to AML (Miller KB, et al, Blood 2004; 104 (no 11): 24a). Other cohort and single institution studies have confirmed these findings. We have many patients with low-risk MDS treated at our center with ESAs whose care would be seriously compromised if the proposal for non-coverage were to be implemented.

With regard to use of ESAs in anemic cancer patients receiving treatment regimens containing bevacizumab or antibodies directed against EGFRs, there is no scientific evidence that we are aware of to suggest that ESAs are harmful when used in conjunction with these regimens. Because these antibodies will likely be used with increasing frequency in combination with myelosuppressive therapies that induce anemia, we strongly oppose the CMS proposal to restrict the use of ESAs in these circumstances. Again, we believe that the care of myriad patients who are benefitting from treatment regimens incorporating these novel antibodies would be compromised if access to ESAs were restricted.

We completely oppose efforts by CMS to link coverage decisions for ESAs to certain tumor types based upon expression of erythropoietin receptors as reported in the literature. In our view, the methodology for determining Epo receptor expression on tumor cells is poorly standardized, and the biologic significance of receptor expression is highly controversial, even among scientific experts in this field. In addition, these receptor assays are not yet commercially available.

With regard to the CMS proposal for using a hemoglobin < 9 gm/dL as a trigger for initiating ESAs in anemic cancer patients receiving myelosuppressive chemotherapy, we believe that this threshold is far too low, and is not based on any scientific evidence. The majority of trials substantiating the benefits of ESAs in anemic cancer patients have included patients with higher baseline hemoglobin levels. There is ample evidence from published trials to suggest that use of a higher threshold hemoglobin results in need for significantly fewer red cell transfusions, and that many patients may avoid transfusions completely with more proactive use of ESAs. This has also been borne out by our collective experience at our center.

We completely disagree with CMS's proposal to limit coverage to 12 weeks per year, as this is not based on any scientific or clinical evidence, and would have serious consequences for the care of our patients. In our experience, it often takes 6-8 weeks just to achieve a hematologic response and to establish the appropriate ESA dose in an individual patient. Many of our patients receive myelosuppressive chemotherapy treatments well in excess of 12 weeks per year (some up to 52 weeks), and thus, an arbitrary limit of 12 weeks of ESA coverage per year would essentially doom many of our patients to receiving blood transfusions which they might otherwise avoid. The ramifications of a significant increase in blood transfusions in terms of time and space constraints at our center could be enormous and could literally jeopardize our mission. In addition, this obligation would put a serious strain on the local blood supply, which is already perennially threatened.

Finally, we also disagree with the proposal to discontinue coverage if the hemoglobin response at 4 weeks is suboptimal. A strategy of ESA dose titration depending upon the hemoglobin response at 4 weeks has been validated in several clinical trials, and has been incorporated into various clinical guidelines (eg- NCCN). In our collective experience, many anemic cancer patients receiving chemotherapy will manifest a hemoglobin response between weeks 4 and 8 with a strategy of appropriate ESA dose titration. We therefore would also take issue with the proposal to limit coverage for erythropoietin to 126,000 units/4 week period, and darbepoetin to 630 ug/4 week period for the same reason.

In summary, we would urge that CMS's proposed coverage limits on ESAs either be withdrawn or significantly modified for the reasons stated above. We believe that when used appropriately, and in keeping with the recently revised FDA label, these agents have proven safe and effective, and have had a positive impact on the care of our patients.

Respectfully submitted,

Michael M. Millenson, MD, FACP
Director, Hematology Service
Fox Chase Cancer Center

Corey J. Langer, MD, FACP
Director, Thoracic and Head and Neck Medical
Oncology
Fox Chase Cancer Center

Dwight Kloth, Pharm D, FCCP, BCOP
Co-Chairman, Pharmacy & Therapeutics Committee
and Director of Pharmacy
Fox Chase Cancer Center

Michael Levy, MD, PhD
Vice Chairman, Department of Medical Oncology
Fox Chase Cancer Center

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As a board certified hematologist and medical oncologist, I am very disturbed by some of the proposals to greatly limit the use of erythropoiesis stimulating agents for non-renal indications. Many patients have received ESAs with great clinical benefit and no adverse effects for some of the indications for which it is planned to stop reimbursement. Anemia due to myelodysplastic syndrome has been successfully treated in my practice and that of my colleagues with ESAs. Many of these patients are elderly and do not tolerate anemia well. I have had patients who either had angina or CHF which resolved when their anemia was corrected with Procrit or Aranesp. The option of regular transfusion does not give them a stable, constant steady state hemoglobin, but rather hills and valleys. These drugs have also been extremely clinically useful in certain myeloid malignancies, such as CML in remission but with anemia due to Gleevec, and anemia due to drugs such as thalidomide and Tarceva. Limiting the treatment to 12 weeks a year makes as much sense as it would to limit dialysis to 12 weeks a year, or anti-hypertensive therapy to 12 weeks a year. I would agree with the requirement that the hemoglobin increase by 1 gram, but it could take more than 4 weeks for that response. It should be extended to at least 6 weeks... In short, the proposed regulations, if enacted, will take away an extremely effective therapy which is very well tolerated by most patients. The alternative option of chronic transfusions for these patients will re-introduce the problems of transfusion reactions, blood shortages, iron overload and volume overload. The expense of treating these problems will probably negate the savings from the cost of the ESAs, and will certainly make the lives of the patients affected much worse. (Incidentally, in my hospital-based practice I have not made a profit from providing these drugs to patients) PLEASE RECONSIDER THESE PROPOSED CHANGES.

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June 13, 2007

Steve Phurrough, MD, MPA, CPE
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
Department of Health and Human Services
Mail Stop: C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244

Dear Dr. Phurrough:

Several months ago a group of expert physicians, academic researchers, and advocates developed an independent report on the future of drug safety. The principles asserted in the resulting document 'Drug Safety and Drug Efficacy: Two Sides of the Same Coin' (www.focr.org/drugsafetyreport.htm) are very relevant to current concerns surrounding erythropoietin stimulating agents (ESAs).

At the level of medical practice, safety and efficacy are always considered together by the treatment professional in the context of a patient's specific circumstances and preferences. The regulatory process should reflect this essential balance that is fundamental to all medical decision-making.

Just as this committee concluded that drug safety decisions must be driven by scientific and clinical evidence, so too should coverage decisions made by the Centers for Medicare and Medicaid Services (CMS). While we agree that caution must be taken with the use of ESAs, we are concerned with the lack of clinical evidence to support several conditions of the CMS Proposed Decision Memorandum for ESAs (CAG-00383N). Areas of particular concern include:

• The use of ESAs in conjunction with anemia of myelodysplasia would be non-covered
• Maximum covered treatment duration would be 12 weeks/year
• Hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be <9 g/dl/27% in patients without known cardiovascular disease and <10 g/dl/30% in patients with documented symptomatic ischemic disease that cannot be treated with blood transfusion
• The hypothesis that ESA interaction with erythropoietin receptors drives tumor growth
• The use of ESAs with certain treatment programs that include chemotherapy and biological agents would be non-covered

In all treatment decisions medical professionals and patients must weigh both the benefits and risks associated with a particular treatment. Clinical evidence supports the use of ESAs in the treatment of anemia of MDS. Numerous clinical studies have been conducted demonstrating the benefit of ESA treatment for MDS patients in reducing blood transfusions.¹ Furthermore, a long-term study of MDS patients treated with ESAs and granulocyte-colony stimulating factor revealed no difference in overall survival or risk of AML development in ESA-treated patients compared to data from untreated patients.² In addition, the evidence for continued coverage of ESAs in MDS patients was supported at a May 10, 2007 FDA Oncology Drugs Advisory Committee meeting when OODP Director, Dr. Richard Pazdur, stated, 'Those are two different things. I do not want them [MDS patients] to get swept away with this. We will discuss this with our colleagues at CMS to make sure that does not occur.'³

Due to the fact that the duration of chemotherapy treatment often exceeds 12 weeks, the clinical rationale for this proposed coverage decision is not clear. Medical societies have recognized this in stating that the duration of ESA therapy may need to be up to 90 days post-chemotherapy with potentially longer durations based on individual circumstance.⁴

While ESA should not be used to achieve high hemoglobin levels, the proposal to restrict coverage to patients with levels less than 9.0 g/dL (in patients without known cardiovascular disease) is not clearly supported by clinical evidence. The goal of treatment with ESAs is to prevent the need for blood transfusions in anemic patients. Not only is the proposed coverage restriction not consistent with the approved FDA label and guidelines from major professional societies,⁵ but it could negate the treatment goal giving many patients no other options than to receive higher risk transfusions for treatment of chemotherapy associated anemia.

It appears that some of the proposed CMS coverage decision relies heavily on the hypothesis that erythropoietin receptor (EPO-R) activation by ESAs drives tumor growth. There is little scientific and clinical evidence for this hypothesis. Further examination of the role of EPO-R in malignant human cells is warranted at this point, but the role of EPO-R in human tumor growth remains speculative at this time.⁶

There is no medical evidence that supports restricting the use of ESAs in combination with certain chemotherapy regimens. Epidermal growth factor receptor (EGFR) inhibitors and anti-angiogenic agents are often used in combination with myelosuppressive therapy, which is well known to result in anemia. Studies that specifically demonstrate ESA interference with EGFR signaling are not available. In addition, preclinical and clinical data regarding the direct contribution of exogenous erythropoietin to angiogenesis is purely speculative.⁷

We appreciate the opportunity to share our concerns with you. As a group of physicians and advocates, we have focused our attention on the need for a rigorous, scientific foundation on which to base benefit-risk decisions. We ask that CMS do the same and wait to consider the FDA final decisions before completing the National Coverage Decision for the use of ESAs.

Sincerely,

Robert C. Young, M.D. (Drug Safety Committee Chair) President, Fox Chase Cancer Center,
Philadelphia, PA

Edward J. Benz, Jr., M.D. President, Dana-Farber Cancer Institute, Boston, MA

William P. Bro, President and Chief Executive Officer, Kidney Cancer Association, Evanston, IL

Michael A. Caligiuri, M.D. Director, Comprehensive Cancer Center The Ohio State University James Cancer Hospital & Solove Research Institute, Columbus, OH

Bruce A. Chabner, M.D. Clinical Director, Massachusetts General Hospital Cancer Center, Boston, MA

William S. Dalton, Ph.D., M.D., President, Chief Executive Officer and Center Director, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

G. Denman Hammond, M.D. Founder & Trustee, National Childhood Cancer Foundation, Arcadia, CA

Paul J. Limburg, M.D., M.P.H. Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN

H. Kim Lyerly, M.D. Director, Duke Comprehensive Cancer Center, Durham, NC

Richard L. Schilsky, M.D. Associate Dean for Clinical Research, University of Chicago Pritzker School of Medicine, Chicago, IL

Ellen V. Sigal, Ph.D. Chairperson and Founder, Friends of Cancer Research, Washington, DC

Jerome W. Yates, M.D., M.P.H. National Vice President for Research, American Cancer Society, Atlanta, GA

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The current proposed policy change for ESAa is irresonsible, both clinically and fiscally. As usual CMS doesn't, number one, consider the patient's well-being, nor look beyond the immediate cost effect to see the reality of the situation. First, the current policy is in no way based on clinical data. The strict criteria that are recommended would lead to an increase in blood transfusions, as well as higher incidence of iron overload, which will require expensive treatment in itself. Likewise, specifically for patients with Myelodysplastic syndrome, if we can't reat the anemia in an effective way, we will be forced to prescribe other drugs such as Revlimid or Vidaza or Dacogen, whose costs dwarf that of ESA's. That is short-sighted indeed. While I agree that certain criteria are needed, waiting until a hemoglobin gets below 9 is cruel, and likewise makes it harder to get these drugs to work quickly.

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June 8, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum CAG-00383N for the Use of ErythropoiesisStimulating Agents (ESAs) for Non-Renal Disease Indications

Dear Dr. Phurrough:

I am writing you on behalf of the oncology community in South East Idaho. I have read through the above propose and am chagrined with the apparent lack of forethought to many of the recommendations in the policy. Although I applaud the efforts to standardize the use of ESAs across the nation, I feel that many items in the proposal are "throwing the baby out with the bathwater" and are going to severely impact quality cancer care as well as put a severe strain on both regional blood blanks, overtaxed nursing and hospital units, and likely increased untoward events in non-cancer patients because of the strain on the above issues. The following are the items that are unacceptable in the policy:

1. Use of Hgb < 9g/dl as a treatment initiation point is inadequate. Current data shows many of the patients who receive ESAs after Hgb drops to the < 9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated. In addition " our patients live at an average altitude of around 5000 ft. Hgb levels on these patients are baseline between 13-14. Our experience is that patients become severe symptomatic when the Hgb drops to 10 and by 9 they most are non-functioning. By severely restricting the starting point of use of ESA the quality of life impact on patients is going to be profound.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level ( < 11g has been shown to be superior to < 10 by every measure in 6 different randomized studies).In addition, given the altitude issues of Southeast Idaho and the delay in response of the drugs, if drug administration is delayed to lower Hgb levels it will be unlikely that we will be able to avoid transfusions in these patients, even if the drugs do work. They will likely need 1-2 transfusions before the drug kicks in and as of such; this will add more cost and severe diminution of QOL during this time.

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data. The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care. Because of the strict requirement it is likely that providers will skip lower doses in order to show response. We know from the published trials Hgb rises quicker than 1 g/dl in a 4 week time period is associated with a much greater risk of stroke. As of such it is too onerous to require such a strict endpoint in a short period of time.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.In addition, it is not uncommon to see up to 3 months for counts to recover after chemo and with most treatment courses lasting 6 months, only three month coverage will leave patients uncovered for more than half of their treatments. This will lead to QOL issues and blood bank strain.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD. It is impossible to estimate the profound impact of having millions of patients receiving transfusions that could have been avoided. Likely sequellae include problems such as not having blood available to trauma patients, post-surgery, GI-bleeders, cardiac patients, etc. The impact would be profound. It is likely that any increased mortality from the ESAs in cancer patients (even if significant) would not replace the severe problems in non-cancer patients from not having blood available. Nursing shortages are common in most places in the nation, including our area. Already the ability to dramatically increase nursing care for transfusion patients is limited. Increasing transfusion requirements would place a strain on already strained nursing staffs.

9. Logistics of blood transfusions verses ESAs. By limiting the ESA use, the number of transfusions will go up. Many of our patients live geographically distant (several hours) from any hospital with transfusion abilities. Many of these patients need blood that has been irradiated or have existing antibodies " which requires up to 24 hours to obtain appropriate blood. If the transfusion number goes up with limiting ESAs, it will add cost and time and cause a significant loss of QOL to our patients in as much as they will need to come back to the hospital the next day for the transfusion. This is taking a one day of travel and treatment and doubling it. This puts a severe burden on patients. Many patients have said that they would preferred to have their life expectancy shortened than to have the time that they are around spent more in a hospital settingIn short, I feel that the proposed policy has several glaring deficiencies. I hope that wisdom and cool heads prevail and that the entire policy be looked at in detail. To implement such a short sided policy would severely curtain our ability to take care of patients and would add increased burden on the already taxed health care system.

Sincerely,Dane J. Dickson MD

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We are writing in response to Medicaree's proposed decision memo for ESAs for non-renal disease indications.

We are a group of three practitioners all board certified in internal medicine, hematology, and oncology working in the Rockland (NY) community. Our group sees on average 80 patients per day. We treat a diverse array of disease processes including benign and malignant hematologic processes and solid tumors. This letter is representing the sentiment of the entire group including the nurses and ancillary staff that deal with patients and see their clinical courses on a daily basis.

Unfortunately your decision memo is extraordinarily biased, basing its recommendations on inherently flawed studies. The recent studies that have bolstered the deleterious effects (thrombosis, hypertension, cardiac event, reduced survival, tumor progression) of these agent have a common denominator; they all aim to raise the hemoglobin to high-end normal levels or begin therapy with ESAs prior to an anemic state resulting once again in hemoglobin values that are on the high-end of normal. It is well known amongst practitioners using these drugs scrupulously and judiciously that these agents should be withheld when the hemoglobin rises above 12g/dL because of the untoward effects aforementioned. Therefore it is no surprise that in the myriad of recent clinical studies that essentially ignored the basic tenets of ESA usage that the outcomes were negative and/or harmful.

ESAs have spared many patients with many different disease processes (anemia of chronic inflammation, myelodysplastic syndrome, myeloproliferative disorders, and anemia related to chemotherapy and radiation) red blood cell transfusions and RBC transfusion support on a continued basis. RBC transfusions have an associated risk of transfusion reactions, infectious complications (Hepatitis B, C, HIV, HTLV I/II) and iron overload that can inflict both morbidity and mortality. The cost to the patientt's quality of life and society financially when this occurs is burdensome and avoidable. There is also a cost to society associated with administering red blood cell transfusions that will rise exponentially if ESA usage is restricted. One must not only account for the hospital costs but the man-hours lost when ESAs are withheld and RBC transfusion offered as an alternative.

We implore the committee to re-examine this matter with a broader vision as to the potentially life threatening and costly practice of red blood cell transfusion and your concerns about ESAs based on flawed studies. These issues need to be readdressed by your committee before we restrict the use of a drug that is clearly beneficial when used correctly. Thank you for your time and consideration.

Sincerely,

Robert Goldberg, MD FACP
Anna Mathew, MD FAACP
Seth Benkel, MD FAACP

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I am an Oncology Nurse and have been for 15 years. I have used ESAs for many years. I have concerns with restricting reimbursement as drastically as is bing proposed. For instance I feel that ESAs being used in patients with Myelodysplastic Syndrome over the years has dramatically decreased the use of blood transfusions and increase the Quality of life for these people.I feel that limitations in how high the hemoglobin/ hematocrit is allowed to go when using ESAs could be a indicator of reimburesment, for instance if the H/H is above 11/34 that ESA should not be given and that therefore not eligible for payment. I do not think that we should be taking this predomintantly beneficial treatment away from this population of people. There will most definitely be an increase in transfusions of Red Blood Cells, which in the long run will not be a cost savings for insurance companies.I believe that the proposed changes be reworked after public comment is received and taken into consideration.

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Recommendations were made to the FDA at the May 10th Oncology Drug Advisory Committee (ODAC) meeting. FDA has not made any determinations on these recommendations as yet. There are four items in the NDC that are not scientifically accurate and/or do not follow the current FDA approved indications. Further FDA review is required on the following provisions of the CMS proposed NDC:

1. Anemia of myelodyslasia would not be covered.
2. Hgb/Hct levels at initiation of dosing should be <9g/dl/27% in patients without known cardiovascular disease and <10 g/dl/30% in patients with documented symptomatic ischemic disease that cannot be treated with transfusion.
3. 12 week maximum of coverage per year.
4. Limits of total dose of 126,000 erythropoietin and 630 darbepoietin.

Enforcement of this CMS proposed policy could very well cause further health risks to cancer patients who depend on the support of ESAA?s during chemotherapy treatment. When treating high risk patients, letting the hemoglobin drop below 9 g/l is putting them at increased risk for cardiovascular complications and other problems necessitating transfusions and hospital admissions.

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June 13, 2007

Steve E. Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244

RE: National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Non-Renal Disease Indications (CAG-00383N)

Dear Dr. Phurrough:

The American Society of Hematology (ASH) represents over 11,000 hematologists in the United States who are committed to the treatment of blood and blood-related diseases. ASH members include hematologists and hematologist/oncologists who regularly render services to Medicare beneficiaries. The Society appreciates this opportunity to comment on the Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N).

Of paramount importance to ASH is to ensure that all coverage decisions are guided by the best available scientific evidence to ensure the highest degree of patient safety and to protect against not only the overuse of ESAs, but their underuse and misuse as well. Consequently, the Society is deeply concerned that CMS's proposed decision memo inappropriately restricts use of ESAs because a number of its proposals are not supported by scientific data, rely on poor quality data, or are in conflict with expert scientific analysis.

In addition, ASH is concerned that CMS's proposed decision memo does not take into consideration the discussion during FDA's May 10, 2007 Oncology Drug Advisory Committee meeting, particularly a conclusion that the anemia of myelodysplasia (MDS) should not be included in decisions for restricted use. As FDA is the agency responsible for evaluating drugs for safety and efficacy, ASH believes CMS should not issue its proposal prior to the FDA's scientific review and final decisions on this issue.

Further, ASH notes that the proposed CMS restriction on MDS conflicts with a CMS-approved quality measure for the Physician Quality Reporting Initiative (PQRI). The quality measure involves the use of ESAs in MDS patients (see http://www.cms.hhs.gov/PQRI/Downloads/PQRIMeasuresList.pdf)

68. Myelodysplastic Syndrome(MDS): Documentation of Iron Stores in Patients Receiving Erythropoietin Therapy: Percentage of patients aged 18 years and older with a diagnosis of MDS who are receiving erythropoietin therapy with documentation of iron stores prior to initiating erythropoietin therapy.

ASH developed this evidence-based quality measure with consultation by CMS because of the recognized value of using ESAs to treat these patients. The measure was vetted through the Society and the AMA Physician Consortium for Performance Improvement, endorsed by the AQA, and then approved by CMS as part of the PQRI program. The proposal to restrict coverage in patients with MDS is contrary to the PQRI where CMS recognizes MDS as a condition for which ESA treatment can be considered a standard of practice. Consequently, CMS's proposed restriction for MDS contradicts the national consensus about appropriate quality care and demonstrates a lack of internal consistency within the agency.

ASH's comments on the proposed NCD follow. We note that because all ESAs have the same mechanism of action, ASH believes that the NCD should apply to all ESAs (marketed as Procrit, Epogen, and Aranesp). While some local carriers have separate coverage policies for darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit), ASH believes there should be a single national coverage policy because the products are basically interchangeable and use of one is essentially equal to the use of the other.

Coverage of ESAs for Patients with Conditions Other than End-Stage Renal Disease

Anemia of Myelodysplasia -

In its proposed decision memo, CMS proposes broad coverage restrictions to the FDA-approved indication for ESAs in chemotherapy-induced anemia and broad restrictions for off-label uses. ASH strongly disagrees with CMS's conclusion that there is sufficient evidence to restrict coverage of ESAs for treatment of the anemia of myelodysplasia (MDS). To the contrary, there is evidence to support the use of ESAs in patients with anemia associated with MDS with less than five percent blasts.

Definition of Myelodysplasia: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplastic and ineffective hematopoiesis and a variable risk of transformation to acute leukemia. MDS with less than five percent blasts can include the following (World Health Organization classification) forms of MDS:

Within the framework of the FDA-approved package insert, including the black box warning, there is no clinical reason for CMS to restrict reimbursement. Coverage should be no more restrictive than the FDA-approved label, as required by Medicare law. To apply coverage restrictions (e.g., the presence of erythropoietin receptors or a 12-week/year limit) without any supporting evidence is inappropriate and potentially harmful to patients.

Michele Woods, PharmD, BCOP
Oncology Pharmacy Clinical Specialist
Oncology Hematology Associates of Central Illinois

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Non-coverage of these drugs for MDS and multiple myeloma patients would expose elderly patients to the known complications of continual blood transfusions and toxic chemotherapy. Multiple ranomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals.

While supportive of the concept of a National Coverage Decision, our primary concerns are 1) the current NCD proposals (Hgb levels to onset drug and the stopping rules) have significant limitations that are not based on current scientific data and current US established standards of care, and 2)transfusions as an alternative therapy are not the equivalent of hemoglobin matienance as that is achieved by appropriate ESA therapy.

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As an Oncology Nurse for the last 25 years I disagree with your proposals ¹ Waiting to initiate ESA until the Hgb level is necessitate both transfusion as well as growth factors to maintain their Hgb level,² there is continuously a blood shortage for those undergoing surgery or have had a trauma, now to add those who are receiving chemotherapy will be problematic for hospital resourses, as well as insurance reimbursement,³ because of QOL pt's with cancer are maintaining their work committments however attempting to work either part time or full time, with a Hgb level probably be impossible therefore causing increase in people on disability or overuse of sick time,⁴ we live in a world where cancer patients are told to maintain a normal lifestyle-how are they expected to do that with when they are synpomatic from anemia,⁵ depending on response to therapy pts may require several changes in their treatment some are more myelosuppressive than others therefore maximizing their use of ESA to 12 weeks per calendar year may have a profound effect on their therapy I do agree that there needs to be a change on the indications for ESA -but I would think that initiating therapy once a Hgb level is iron levels are identified and corrected with iron supplements, monitoring CBC values every 2-4 weeks and stopping therapu once the Hgb level is 12. Thank you for considering my opinions.
Elaine Cuomo RN

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I am very concerned about this for several reasons. In order for cancer patients to get the best care, all things should be considered, especially when the outcome would mean more blood transfusions. Even with screening of the units of blood, there is still a risk of hepatitis and HIV infection from receiving blood. Also if patients are weak and tired, and the quality of life would be improved with a shot as opposed to a lengthy blood transfusion, then my vote would be for the ESA. Please consider the following facts:

1. Use of Hgb point is inadequate. Current data shows many of the patients who receive ESAs after Hgb drops to the will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level ( superior to randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise.

Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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The proposed NCD for ESA would certainly be a step back in how far we have come in improving and prolonging lives of cancer patients. These changes would not only affect the blood supply and put a high demand on blood banks due to the overwhelming increase in need for blood transfusions, but waiting until a hgb is less than 9 is going to increase patient hospital admissions and overall decrease a cancer patient's quality of life. I strongly urge you to listen to the experience of our highly educated physicians and nurses in the oncology field and reconsider this proposal based on the medical information you have been provided. Thank you.

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May 30, 2007

Centers for Medicare and Medicaid Services
Mail Stop C1-12-28 7500
Baltimore, Maryland 21244-1849

It is my understand that Medicare is about to reduce the allowed number of treatments using erythropoietic stimulating factors by substantial degree, as well as becoming more stringent on the requirements for their use. From my understanding, the reductions are going to be excessive, as usual. Once again the bureaucracy and the government is about to cut back drastically on an important adjunct to the treatment of cancer patients that will effect not only Medicare patients but also non-Medicare patients.

If you reduce the number of allowable doses of erythropoietic stimulating factors so that we are unable to use it for at least six months out of a year, there will be most definitely increase in usage of transfusions of packed red cells. There are already frequent blood shortages in this country and if cancer specialist begin transfusing blood again, this will be a greater expense since it will have to be done in hospitals and it will also jeopardize the lives of people who might otherwise need that blood in the case of emergencies and accidents.

Why is Medicare so intent on depriving cancer patients of erythropoietic stimulating factors and yet continuing to make them available in an unlimited manner to patients on hemodialysis? The point is that both sets of patients need these materials. There is ample evidence also that indicates that by raising the red blood cell count in cancer patients on chemotherapy that these patients not only have a better quality of life but also respond better to chemotherapy.

Please talk with physicians in private practice more before you make these cuts.

Yours truly,

John C. Halbrook, M.D.

JCH/vck

CC: Dr. Jim Strong
Senator Thad Cochran
Senator Trent Lott
Congressman Chip Pickering

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To whom it may concern: I am writting as a healthcare professional in an hematology / oncology practice. I ask that you reconsider your proposed coverage for Procrit and Aranesp. I feel that this proposal is unethical. I see these patients everyday and the changes you are proposing to make will negativaly impact the quality of life for our patients. For example, patients with MDS, the only other treatment for these patients is to have a blood transfustion. In our area, to have a blood transfustion you have to be admitted to the hospital as an (Inpatient). So the cost of that alone is more than the cost of one injection. Now the treatments with blood transfusions causes additional complications. For one example, Iron overload. Also what about the lack of hospital staff and beds in the area hospitals? You know that there is such a demand for nursing staff. What about the lack of people that do not donate blood? What will happen when we are on a blood shortage (example, natural disaster)? How will our patients be treated?I really think you need to reconsider this proposal. Not only are you affecting this huge patient population quality of life, you would be spending more money in the alterative treatment than giving these patients an injection that works.Thank you for you consideration. Michelle Bonds

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Key Points of Policy Disagreement with the Proposed NCD

1. Use of Hgb point is inadequate.

Current data shows many of the patients who receive ESAs after Hgb drops to the will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level ( superior to randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data.

The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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Ovarian Cancer National Alliance Statement On Centers for Medicare and Medicaid Services proposed changes To Erythropoiesis-Stimulating Agent Reimbursement Policies

Introduction

The Ovarian Cancer National Alliance is an umbrella organization with 50 state and local groups representing grassroots activists, women's health advocates and health care professionals. According to the American Cancer Society, in 2007, 22,430 American women will be diagnosed with ovarian cancer, and 15,280 will lose their lives to this terrible disease. Ovarian cancer is the deadliest gynecologic cancer and the fifth leading cause of cancer death among women in America. Currently, more than half of the women diagnosed with ovarian cancer will die within five years. The Ovarian Cancer National Alliance submits this testimony as a patient advocacy group with the aim of conquering ovarian cancer.

Proposed Regulation

On May 13, 2007 the Centers for Medicare and Medicaid Services (CMS) released a proposed decision memo regarding reimbursement for Erythropoiesis-Stimulating Agents (ESAs). In it, CMS proposed to restrict reimbursement for ESAs based on the new studies regarding the potential safety and health risks to patients taking ESAs. CMS proposes that treatment with ESAs is not reasonable or necessary, and therefore not covered, in the following situations:
1. any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis
2. the anemia of myelodysplasia
3. the anemia of myeloid cancers
4. the anemia associated with the treatment of myeloid cancers or erythroid cancers
5. the anemia of cancer not related to cancer treatment
6. any anemia associated with radiotherapy
7. prophylactic use to prevent chemotherapy-induced anemia
8. prophylactic use to reduce tumor hypoxia
9. patients with erythropoietin-type resistance due to neutralizing antibodies
10. patients with treatment regimens including anti-angiogenic drugs such as bevacizumab
11. patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor
12. anemia due to cancer treatment if patients have uncontrolled hypertension
13. patients with thrombotic episodes related to malignancy Under the proposed decision memo, ovarian cancer continues to be a reasonable and necessary condition for which chemotherapy-induced anemia can be treated with ESAs.

The CMS proposes that ESAs be administered to patients when hemoglobin levels fall below 9g/dL, rather than the FDA-recommended 12g/dL, and that ESAs may only be given to patients up to 12 weeks per year.

Impact on Ovarian Cancer Patients

Anemia occurs most frequently in gynecological cancers; however, under this regulation, treatment of cancer-induced anemia will not be reimbursed, only the treatment of chemotherapy-induced anemia.

Because 70 percent to 90 percent of ovarian cancer patients have a recurrence, the specific impact of these CMS policies on ovarian cancer patients may be somewhat unique. Should an ovarian cancer patient recur within one year, choose to undergo a second round of chemotherapy, and experience anemia, her anemia treatment with an ESA will no longer be covered.

Access to care is a continual issue for ovarian cancer patients - their need for prompt treatment by gynecological specialists is already an issue that affects health outcomes for many women. Necessitating transfusions for women with ovarian cancer may present significant obstacles. Women who live in rural areas without access to specialists may also face issues regarding access to certain blood types. Additionally, transfusions pose their own health problems and may not be an option for women for religious or personal reasons.

More importantly, CMS is making a decision that is not based on FDA guidelines, which is counter to controlling statutes. The FDA label and compendia recommendation are to be reimbursed under federal law.

Recommendations of the Ovarian Cancer National Alliance

The Alliance recommends that CMS wait until the FDA has concluded its scientific and medical review before it makes a decision regarding cancer patients' access to this class of drugs. Off-label use may be warranted in certain cases, and under federal law must be reimbursed. Our concern is with the potential impact on ovarian cancer patients, and we await the FDA's determination of the safest course of treatment with ESAs.

Patient safety is of the utmost importance, and any FDA or CMS regulations must reflect scientifically-based evidence in furtherance of patient safety. Quality of life is also a very real concern for patients, and should be protected to the extent it is safe and feasible.

Additionally, the Alliance has signed the Cancer Leadership Council letter to CMS. This letter reminds CMS that its statutory requirements include adhering to the prescription guidelines on the FDA label.

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1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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As a community based Hematologist-Oncologist for the last 30 years, i feel that ESAs have improved the quality of life in innumerable patients with anemia associated with cancer, chemotherapy, Myelodysplasia and certain non-malignant chronic disease states. The new guidlines are too stringent and cumbersome and will eventuate in more patients receiving RBC transfusions. Some private insurers have refused to reimburse for the anemia asociated with Myelodysplasia which is unreasonable. i hope that a "new" balance can be reached so that patients'needs and financial impact be achieved.

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Physicians appreciate the nedd for review of the ESA utilization. However, an extreme reaction to the usage of these medications will negatively impact on the quality of life of our patients. We all support the crucial need for safety reviews and protection against over usage of these drugs. Increased need for transfusions will lead to other significant health risks and will impactly immensely on our nation's blood supply. Risk/benefit analyses of ALL PREVIOUS studies regarding ESA must be carefully performed by individuals who can review, interpret and conclude appropriate treatment measures for our patients.

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As a physician who cares for patients with cancer on a daily basis, I am vehemently opposed to the new CMS proposed guidelines on ESA's. Prior to the arrival of ESA's, we were very limited in cancer management because of chemotherapy's effect on the bone marrow. As a result, myelosuppressive regimens could not be used because of the bone marrow side effects and the associated risks of infection, fatigue/need for transfusions, and bleeding. The arrival of ESA's has given us the opportunity to administer these regimens and reducing the need for transfusions, while improving symptoms such as fatigue. The new guidelines would severely limit the number of patients who would qualify for ESA's thereby increasing the fatigue of patients on chemotherapy, increasing the number of blood transfusions for symptomatic anemia, and cause delays in treatment. In diseases (such as breast cancer, testicular cancer, Hodgkin's Lymphoma) where the goals and intentions of treatment are curative, delays comprimise survival. ESA's as well as leukocyte colony stimulating factors clearly allow us to stay on schedule.

The last decade has heralded tremendous scientific advances in the management of many cancers. Unfortunately anemia is a common side effect of virtually every treatment. The proposed CMS guidelines will be a large step backwards in the progress in cancer treatments and will likely compromise survival in many curative situations.

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I respectfully request that you reconsider the proposed restrictions to the ESA use. These agents have been proven in clinical trials to reduce blood transfusions. Clinically, this reduction is seen most often if the agents are intitiated when the Hgb is 10. If we wait to initiate at a Hgb of 9, the patients often need transfusion first, followed by ESA's. THis is a time consuming process that results in tremendous resource utilization for the hospitals. There is often a blood shortage in our area, and arranging transfusions is difficult.

Second, patients with metastatic cancer on chronic chemotherapy often require the use of these agents for longer periods of times. 12 week limitation in one year is unlikely to be sufficient.

Please reconsider: Target Hgb to be 10-12. No time limitation for use if target Hgb' met.

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Little Rock Cancer Clinic is a 3-doctor office based hematology/oncology practice in Little Rock, Arkansas. We are very concerned on several levels with the proposed changes to coverage of ESA use by CMS based on this NCA. These recommendations are both arbitrary and draconian. They are not based on solid scientific evidence and will result in the use of other, more toxic modalities of care, with increased resultant morbidity and mortality. The end result to our patients will be lowered quality of life and increased long-term costs (in both money and time as they require several hours worth of blood transfusions at a hospital versus a few minutes of ESA injection in our office), and ultimately, increased long-term healthcare costs to CMS.

First, as we understand it, CMS is committed to its beneficiaries receiving the highest quality healthcare while at the same time maintaining (or lowering) costs to provide this quality care. CMS is in the process of instituting Pay For Performance to achieve this goal, and we agree wholeheartedly with this goal (great medicine at the lowest fair cost). In the current model, the cornerstones of CMS clinical coverage, and financial allowable decisions are:
1- FDA approved indications.
2- Approved Compendia listings.
3- ASCO treatment guidelines (for our specialty).
4- NCCN guidelines (for our specialty).The entire 'high quality low-cost' model of healthcare that CMS is trying to achieve is built upon the scientific findings of these 4 separate institutions. We are in agreement with this because it is our experience that these 4 separate institutions give credence to the entire weight of scientific evidence available, and, that our own clinical experiences (68 years combined in hematology/oncology) are very similar to the outcomes expressed by their resulting clinical guidelines.

Second, the question 'Why?' arises. What is motivating these proposed changes? They are a blatant disregard for the entire weight of scientific evidence and as such are in opposition to the recommendations of the FDA, Compendia, ASCO and NCCN. If it isn't good science and good healthcare, then it must be money. Remember, the model is high quality healthcare at the lowest fair cost-high quality comes before low cost, both in this sentence and in the order of importance!

Third, as of this writing hundreds of our current patients will be negatively affected by these proposed changes, and this will cause a ripple effect throughout the entire healthcare system. Many of our patients will move from the office setting for treatment with ESAs to the hospital setting for blood transfusions. The hospitals have neither the physical space nor the trained staff on hand to handle the large influx that will result. As of this writing the Blood Bank is in critical need of blood donations. One of the largest populations of donors, military personnel, are now unable to donate blood due to their having served overseas. The influx of patients needing blood transfusions here in Arkansas and nationally will further reduce the standing supply of blood. This reduction in blood supply will negatively affect every other person who is in need of a blood transfusion in every segment of the healthcare system.

Also, the cost of transfusions in the hospital setting, along with the added costs to the healthcare system for the patients who will contract other diseases, such as hepatitis, as a result of the transfusions, the added hours of treatment to a very ill patients day not to mention the added cost to our clinic (not reimbursed of course) for writing orders and setting appointments for patients in the hospital setting will all combine to make for lower quality healthcare at increased fair costs.

We suggest that instead of CMS proposing changes in treatment modalities based upon their own investigation, they submit their findings to the FDA, the Compendia organizations, ASCO and NCCN. Let these entities determine the veracity of the scientific studies that CMS has accumulated regarding the safety and efficacy of ESA use, and synthesize all the data to determine what represents the best treatment modality. CMS must work within the established framework of the healthcare system, and not go out on its own when determining what does or does not constitute high quality healthcare.

Thank you,

Fernando Padilla, MD, FACP

Stella M. Kamanda, MD, PhD

James F. Beck, MDCC: Representative Vic Snyder, Senator Mark Pryor, and Senator Blanch Lincoln

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I respectfully disagree with the proposals for limiting ESA's in cancer patients. I have two areas of concern: First, patients with metastatic disease are often on chronic chemotherapy throughout the year. Limiting the duration to 12 weeks per year will be insufficient to cover these patients.

Second, initiating therapy at a Hgb of 9 mg/dL is very low. These patients will need transfusions plus ESA's. I beleive the issue that should be limited is restricting the target HgB to be less than 12. A target of 10-12 is sufficient to reduce transfusion and combat fatigue. The higher mortality is restricted to patients with high hemoglobin levels.

Please consider these comments. Thank you.

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Please reconsider the proposed National Coverage Decision (NCD) on Erythropoiesis Stimulating Agents (ESAs).

There is significant concern that the NCD will impact the nation's blood supply and hospital resources. As a result of the proposal by CMS, more patients with myelodysplastic syndrome and chemotherapy-induced anemia will require blood transfusions, which will put a serious strain on the nation's blood supply and add an additional strain on hospital resources.

Additional concerns include:

• CMS is putting clinical limits and duration limits on ESA usage.
• CMS is setting limits in an area that is typically overseen by the Food and Drug Administration.
• CMS should not include anemia of myelodysplastic syndrome in the non-covered category.

Many of our oncology patients rely on ESA's as a quality of life measure. These NCD's will severely limit the access of ESA's to patients who desperately need this treatment.

Thank you for the opportunity to voice my concern over this NCD. Kristi Somes

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Please, reconsider the proposal for ESAs, due to the following discrepancies in the coverage being considered and the data that is available and standards of care that have been established due to this published data.

1. Use of Hgb<9g/dl as a treatment initiation point is inadequate. Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated.

2. Evidence suggests that transfusion avoidance is better accomplished by early intervention at a higher Hgb level (<11g has been shown to be superior to <10 by every measure in 6 different randomized studies).

3. A "stopping rule" at 4 weeks if a 1g/dl rise in Hgb is not achieved is not consistent with the clinical trial data. The clinical trials with both ESA agents demonstrate that 6-8 weeks may be required to achieve a 1 g/dl rise. Dose escalation has been a critical element of most of the clinical trials. A significant number of patients who failed to respond to initial ESA use will respond after administering a single dose 50% higher than the initial dose. Therefore, dose escalation has become part of the standard of care.

4. Maximum treatment duration of 12 weeks per year is grossly inadequate for many patients. Patients with metastatic disease may receive multiple courses of chemotherapy that last for many months.

5. Exclusion of patients receiving VEGF and EGRF inhibitors is not based on any clinical evidence and would preclude treatment with ESAs for dyspneic lung cancer patients on chemotherapy, adjuvant breast cancer patients receiving dose dense therapy, and other critical patient subgroups. For example, no patient on Avastin would be eligible for ESAs, regardless of the other chemotherapy being administered concurrently.

6. Non-coverage of MDS and multiple myeloma patients is not based on clinical data. Multiple randomized trials have shown evidence of efficacy of ESAs in both diseases without any adverse safety signals. Non-coverage would expose elderly patients to the avoidable complications of chronic transfusions and toxic chemotherapy.

7. In spite of in vitro evidence suggesting that certain cancer cell types express erythropoietin receptors, there is no clinical evidence that if those receptors actually exist they are functional. ESA use in patients receiving chemotherapy for such tumors has no clinical experience of tumor progression, or reduced efficacy of treatment. Restricting ESA use in patients with such cancers is theoretic and not evidence-based policy and therefore should be reconsidered.

8. One significant, unintended and unanalyzed effect of the draft ESA policy would be to place the national blood supply at significant risk due to the millions of avoidable transfusions that would be required under the proposed NCD.

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Comments:
1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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As a medical oncologist and hematologist I have used ESAs in patients with symptomatic anemia (HCT < 33) which is caused by chemotherapy, myelodysplastic syndrome, multiple myeloma and other malignancies. These patients had excellent response to their symptoms with improvement in hematocrit when treated with ESAs as based on scientific evidence. Uusally it took 4-6 weeks to see the response and then hemoglobin levels remained within acceptable range with continuation of ESAs. The CMS proposals, among other provisions, are expected in the near future to start ESAs when hemoglobin < 9/dl/27% in patients without known cardiovascular disease and < 10/dl/30% in patients with documented cardiovascular symptomatic disease that cannot be treated with blood transfusions; and covered treatment duration is only 12 weeks/year are against scientific evidence. It would not only affect the standard of high quality care, but also cause a great deal of frustration and disappointment to my patients and myself. If CMS continues to disregard the scientific evidence towards cancer patient's care it does not seem unlikely that their next step will be to deny palliative treatment for stage IV cancer patients that cannot be cured and near death anyway. Therefore, I strongly urge CMS not to make any judgement about the use of ESAs prior to FDA decision on the same issue.

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Comments:
1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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Comments:
1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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I am a practicing medical oncologist and am writing to express my concern with several aspects of the proposed regulations regarding the use of ESAs in oncologic and hematologic settings.

1. I cannot understand why patients with myelodysplasia and multiple myeloma have been included in the "anemia of malignancy" category. The rationale for restricting ESA use in patients with solid tumors does not apply to these groups of patients. In particular, many patients with myelodysplasia have low risk for progression to more aggressive forms of the disease, and yet are transfusion dependent. Furthermore, large clinical trials have been performed in these patient groups and have demonstrated the efficacy and safety of ESA use.

2. The starting and stopping points seem to be at odds with clinical data. Since it may take greater than 1 month to see improvement with ESAs, starting at Hgb of less than 9 will increase the risk for transfusion. If ESAs are to be used, initiating therapy at an earlier point has been shown to be superior in clinical trials.

3. I strongly disagree with the precept that transfusion and improvement of Hgb with ESAs are equivalent. Quality of life is far superior if anemia is treated so that Hgb is maintained as opposed to allowing them to become symptomatically anemic and then exposing them to the risk of blood transfusion. In addition, adding numerous avoidable transfusions will further tax our nation's blood supply.

4. Arbitrarily restricting ESA use to 12 weeks per year will force many patients to be inadequately treated. Approximately 1/2 of my patients have metastatic cancer and many of those require ongoing chemotherapy. If a patient is going to receive chemotherapy for several months, allowing ESA use for only 12 weeks makes no sense to me. The current guidelines (ie - stopping at a Hct of 36 or higher) already prevent excessive use of ESAs. Adding this regulation will only force some patients who need ESAs to forgo that therapy.

I have other specific concerns but the above issues illustrate my basic concern, which is that the proposed restrictions on ESA use are more restrictive than the data supports. I fully support avoiding use of ESAs in situations where their use may be deleterious (such as anemia of malignancy in patients with solid tumors). However, the proposed regulations go far beyond what the clinical data supports. Some of them are based on as-yet undocumented theoretic concerns (that EPO receptors are functional and lead to worse outcomes if stimulated) and some are contrary to published data (safety and efficacy of ESA use in myelodysplasia and multiple myeloma). Thank you for the opportunity to share my concerns with you.

Yours truly,

Ralph Weinstein, MD

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To whom it may concern:
I am writing to express my concern regarding the NCD for the use of ESAs for patients with Cancer and other non-renal diseases for the following reasonsThe proposed NCD has significant coverage limitations and are not based on current scientific data and conflict with the current standard of care in the U.S.Transfusions are not the equivilent of hemaglobin maintenance achieved by the ESA therapy. Also consider the blood supply shortage that exists in this country.The use of Hgb below 9g/dl as a treatment point is inadequate andmany patients are symptomatic with a hemaglobin that low.Current data also shows that patients who receive ESAs after the hgb drops to below 9 level will require transfusions that are otherwise avoidable because their Hgb will fall for several weeks after ESA use has begun.A stopping rule of 4 weeks if a 1g/dl rise in HGB is not achieved is not consisitent with clinical trial data.Please re-consider the data and experience of Medical Oncologists giving ESAs with success in the office setting.Thanks you for your consideration of this important matter to patients with Cancer and other hematologic issues.
Linda Anderson, RN
Executive Director

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Dear Dr. Phurrough:

The Northern New England Clinical Oncology Society (NNECOS) represents more than 220 health care professionals in Maine, Vermont and NewHampshire who care for patients with cancer and related diseases. Our mission is to provide access to high quality cancer care for the citizens of our regions. We believe that the Proposed Coverage Decision, as stated in the above captioned Memorandum, will seriously impair the high quality of care for our patients. The following outlines our specific concerns about the deleterious effects of implementation of the PCD CAG-00383N.

NNECOS is well aware of new clinical data suggesting that treating patients with ESAs to hemoglobins over 12 g/dl or hematocrits over 36% may be deleterious to our patients' health. The Proposed National Coverage Determination included in the above Memorandum of May 14, 2007 is farbeyond the bounds of good patient care, available science or the legal restrictions on cancer care, as listed in the Medicare statute (see below).

The Medicare Statute, as amended in 1993 by the so called Rockefeller Levin Bill, section1861(t)(2) of the Social Security Act (42 U.S.C. $1395x(t)(2) states that CMS must cover anti-neoplastic drugs including supportive medications for which an indication is approved by the FDA, listed asacceptable by approved compendia, or supported by peer reviewed medical literature. The restrictions for coverage included in the proposals of the above Memorandum far exceed any indications required by statute.

Treatment of anemia due to myelodysplasia with ESAs is standard clinical practice. It is supported by strict evidence-based ASCO/ASH guidelines. Additionally, MDS is listed as an 'accepted' indication in the USPDI Drug Compendium. MDS should not be an exclusion for coverage by CMS.

The proposal that treatment with ESAs should not be used in patients with anemia and erythropoietin-type resistance due to neutralizing antibodies is unrealistic since this assay is not clinically available and serves as a research tool.

The proposal that patients being treated with EGFR or VEGF antibodies are not appropriate candidates for ESA therapy is also not supported by evidence based medical literature. This proposal is also inconsistent with FDA labeling and compendia citations and should be rejected.

The proposal that 'ESA treatment is only reasonable and necessary under specified conditions for the treatment of anemias in those types of cancers which the presence of erythropoietin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature' is not supported by evidence based medical literature.

The proposal that ESA therapy should not be initiated unless the hemoglobin/hematocrit is < 9 g/dl or 27% or < 10g/dl or 30% in thoseindividuals with cardiovascular disease is also contrary to clinical practice and appropriate clinical trials. Current data shows many of the patients who receive ESAs after Hgb drops to the <9g/dl level will require transfusions that are otherwise avoidable because their Hgb will continue to fall for several weeks after ESA use is initiated. The implication that transfusion of PRBCs is a safer alternative than ESA therapy in this and other clinical situations is an untested hypothesis.

The proposal to limit coverage to 12 weeks per year is inconsistent with good clinical practice. Many patients receive chemotherapy well beyond 12weeks. There is clear evidence that these patients require fewer transfusions and demonstrate an improved quality of life as a result of ESA therapy.

Furthermore, there is no evidence that ESA use beyond 12 weeks presents a safety risk.Further the proposal to limit the total four week dose of erythropoietin to 126,000U or darbepoietin to 630 mcG is contrary to FDA labeling, as well as ASCO/ASH guidelines. Additionally, this proposal does not allow for appropriate dose escalations, as recommended in the above cited references. The statement that 'continued use of the drug (ESAs) is not reasonable and necessary if there is evidence of poor drug response (hemoglobin/hematocrit rise < 1 g/dl/<3%) after four weeks of treatment' is again contrary to good clinical practice or evidence based studies. In clinicalpractice, individuals with anemia due to chemotherapy are treated to levels that will avoid the need for transfusion of PRBCs or prevent cardiorespiratory decompensation. Setting artificial standards of an increase in hemoglobin or hematocrit is contrary to proper patient management.

Additionally the product labels specifically allow for dose escalations in patients who are slow to respond.

Lastly, the proposal that ESAs should only be covered if dispensed in the context of a clinical trial is inappropriate. Erythropoietin and darbepoietin are FDA approved drugs and when prescribed in the support of anti-neoplastic therapy or for the treatment of MDS must be covered by CMS according to statute.

In summary, if the current CMS proposal is approved without alteration, there will be a significant deterioration in the quality of cancer care in our region, as well as throughout the United States. Oncologists will be forced to support their patients with an increase number of blood transfusions. This change in practice will be result in a rapid and steady rise in costs to the patients and to the Medicare and Medicaid systems. It will expose patients to the potential side effects of transfusions, including iron overload, transfusion reactions, fluid overload and infections. This change in practice will stress an already tenuous national blood supply. In our rural part of the country, patients will have to travel significant distances to receive blood transfusions. Travel time and time spent receiving transfusions will create great hardships for patients already burdened with the rigors of chemotherapy and serious diseases. Lastly, there is no conclusive evidence that supporting patients with transfusion therapy is better medical care than the current standard of care using ESAs.

References in medical literature for all of the aforementioned points can be found on pages 10 and 11 of our parent organization, the American Society of Clinical Oncology's response to CMS.

Thank you for your attention to our concerns.

Sincerely,
Johannes C. Nunnink, MD
President, Board of Directors

NNECOS Board of Directors
Johannes C. Nunnink MD
President
Vermont Ctr for Cancer Medicine
792 College Pkwy Ste. 207
Colchester VT 05446-3040

Daniel M. Hayes MD
Immediate Past President
Maine Ctr. for Cancer Medicine
100 Campus Drive
Scarborough ME 04074

Kenneth Meehan MD
President-Elect
Dartmouth Hitchcock Med. Ctr.
One Med. Ctr. Dr.
Lebanon NH 03756

Denis Hammond, MD
Secretary/Treasurer
NH Oncology-Hematology, PA
200 Technology Drive
Hooksett, NH 03106

Fred Briccetti, MD
NH Oncology-Hematology, PA
200 Technology Drive
Hooksett, NH 03106

Philip L. Brooks, MD
Cancercare of Maine
417 State St. Ste 20
Bangor, ME 04401

Steven Grunberg, MD
Fletcher Allen Health Care
UHC Campus, St. Joseph 3
1 So. Prospect St
Burlington, VT 05401

Andrew Hertler MD
Maine General Health Assoc.
MGHC Thayer Unit
149 North St.
Waterville ME 04901

Steven Larmon, MD
Dartmouth-Hitchcock Keene
201 Chesterfield Road
Keene, NH 03431-2157

L. Herbert Maurer MD
SVHC Oncology Associates
140 Hospital Dr., Ste. 116
Bennington, VT 05201

Kenneth Meehan MD
Dartmouth Hitchcock Med. Ctr.
One Med. Ctr. Dr.
Lebanon NH 03756

Anne Ireland RN, MSN, AOCN
Fletcher Allen Health Care
UHC Campus/Patrick 305
1 So. Prospect St
Burlington, VT 05401

Linda Patchett, RN, MBA
DHMC Hematology/Oncology
One Med. Ctr. Dr.
Lebanon, NH 03756

Troy Roy
Maine General Medical Center
149 North St
Waterville, ME 04901
Ph: 207.872.1769
Fax: 207.872.1079

Elaine Towle
351 Fremont Road
Chester, NH 03036

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I think the proposed restrictions on ESA will harm patient care, particularly for those patients with myeloma and myelodysplasia who clearly benefit from the independence from transfusion support these agents produce. I support the position points which have been presented by ASCO and ASH regarding use of these agents.

At my clinic, we have taken a conservative approach to ESA use for years, targeting a Hgb of 10.5-11.5 grams and avoiding Hgb > 12 grams. In our facility, this approach has not been associated with adverse events.

I am also concerned that the proposed elimination of use of these agents will stress an already stressed blood supply. Substituting transfusion support will waste a precious resource and lead to the expensive use of iron chelation therapy which is avoidable with judicious use of ESAs.

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There is clear documentations of the efficacy of ESAs in patients with myelodysplasia. The best data comes from the Nordik study group based on the patients erythropoietin level and transfusion requirement. Up to 74% in the favorable group responded, and 34% patients overall (Br J Haematol.2003:120:1037.) NCCN guidelines recommend ESAs as trial in supportive care. In addition to quality of life concerns in patients not being transfusion dependent, many of these patients with low IPSS scores live many years and will ultimately require treatment for iron overload directly related to transfusions. One cost consideration is that deferasirox that is now commercially available orally for iron overload is extremely expensive and many more stable patients with myelodysplasia will require this medication if ESAs are deleted from their management.

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The Hubert H Humphrey Cancer Center is responding to the proposed changes in the CMS policy that would govern the use of erythropoiesis stimulating agents. We are in agreement with the statements made by ASCO(American Society of Clinical Oncologists) and by ASH(American Society of Hematology). We are very concerned with the negitive impact the policy changes will have on our patients. The following are of significant concern:

Use of ESA's in conjuction with anemia of myelodysplasia and anemia of myeloid cancers would be non-covered

Maximum covered treatment duration of 12 weeks/year; and

Hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be cardiovascular disease and with documented symptomatic ischemic disease that cannot be treated with a blood transfusion.

The above issues are very concerning to our practice and the ongoing quality of care we can provide to our patients.

Sincerely

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I am writing to express my concerns in regards to the proposed change by the Centers for Medicare and Medicaid Services (CMS) for ESAs(Aranesp/Procrit) in the use for treatment of MDS.

I am the Billing Manager for an oncology practice in a rural setting where our patients drive many many miles to get to our facility. Our patients do not mind coming to our office for an injection they know will take minutes -vs- the 2-4 hours a transfusion can take at the hospital. We have many patients with MDS who benefit greatly from the ESAs.

Without the Aranesp/Procrit drugs, our patients may not be able to get their scheduled chemotherapy treatments on time due to their low blood counts, which could hurt their progress. I have seen what these drugs do for our patients and this is not fair to the them. These ESAs give our patients a better quality of life and if I was a cancer patient, that is the care that I would want for myself.

This change will affect many people, especially our patients and their families. Please reconsider!!!!

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1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative.

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Dear CMS,

The proposed reimbursement proposal is neither in the best interest of patients or general medical care. ESAs have made a major difference in ability of patients to tolerate chemotherapy and improve quality of life, as opposed to the prior system of transfusing packed red blood cells (PRBCs) every month to two months depending on the nature of the chemotherapy. The need for frequent transfusion required a great deal of time, effort and cost and patients' hemoglobin levels were constantly up and down, rather than reaching a comfortable steady state.

The current proposal is problematic in that:
1) the levels for starting and stopping are too stringent
2) there is little room for dose escalation, which is necessary for about 1/3 of patients in my experience
3) there is no justification for a 12 week reimbursement limit - many of my patients with GI cancer (specifically colon cancer) require ESA or blood product support throughout the year (not for a 4 month period only).
4) Questions have been raised about reimbursement exclusion for those patients receiving targeted agents in combination with chemotherapy - this should certainly be allowed
5) there will not be enough blood for transfusions available if ESAs are not available and we will return to the much greater costs of re-staffing blood banks, giving blood transfusions, treating infusion reactions and have a lack of critical supply for emergencies

I urge the committee to re-examine this proposal in light of these issues.

Thank you.

Howard S. Hochster, MD
Professor of Medicine
NYU Cancer Institute

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The Pennsylvania Society of Oncology and Hematology (PSOH) represents over 400 practitioners in the field of medical oncology and hematology in Pennsylvania. We are opposed to the current proposed CMS restrictions on coverage of erythropoiesis stimulating agents (ESA's). Our comments are as follows:

1. We oppose the concept of restricting the delivery of these agents to patients with 'anemia of myelodysplasia' and myeloma. Several placebo-controlled trials have demonstrated efficacy without adverse effects. There can be little rationale for the replacement of efficacious therapy with the well-recognized risk related to undergoing a blood transfusion.

2. CMS has incorporated coverage limits relative to patients with tumors having 'erythropoieis receptors'. There are no data to support this in any way. This has never been shown to be a factor and has never risen above the hypothetical level of reasoning. Incorporating this kind of rationale into a national coverage policy is not only impractical but also irresponsible.

3. Placing thresholds on beginning ESA's only when hemoglobin's are less than 9 gm/dl cannot be justified clinically. Invariably transfusions are not far away or ongoing by that level. Most every clinical experience with ESA's have predictably begun ESA at a higher hemoglobin concentration to avoid exactly that.

4. Limiting the duration of therapy to 12 week has little practical basis. Many regimens of therapy carry far beyond that time. There should never be a time constraint placed on a necessary biologic. Events in biology have never followed a calendar.

These are just a few of the issues that demonstrate flaws in the CMS proposal. What seems to be lost in the mission to limit ESA's is the realization that blood transfusions (which will then replace ESA's) have a well-recognized and frequently far-reaching adverse reaction potential. Bacterial transmission (1 in 1,000 units), hepatitis B (1 in 137,000 units), hepatitis C and HIV (1 in 1,000,000 units), graft vs. host (particularly in our patient population) .15%, and potentially fatal anaphylactoid reactions (1 in 20,000 units) only begin to define the risk associated with a blood transfusion.

In summary, we would request that CMS reconsider its stance on their proposed ESA restrictions.

Ed Balaban, D.O.
President-Elect
Pennsylvania Society of Oncology and Hematology

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1. Allow the oncology specialist to decide appropriate care within the evidence based guidelines for ESA usage;
2. Eliminate the 12 week per year maximum treatment, it will under serve patients receiving prolonged chemotherapy;
3. Do not change the criteria and delay the start of ESA therapy, it may force patients to the hospital for transfusions;
4. Allow the use for patients with MDS, non-coverage goes against all accepted national clinical guidelines;
5. Allow cancer patients to maintain their quality of life;
6. Allow the treatment of cancer to advance, do not push it back to the days when blood transfusions were the only alternative

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Has CMS considered the increased cost of blood transfusions, nursing time and chair time that these changes will precipitate? Also, are the blood banks even equipped to keep up with an increased demand for blood products?

In addition, fatigue is the #1 complaint among cancer patients. The inability to support our patients' anemia with the best treatments available will seriously compromise patient care. MDS patients in particular have very few treatment options and erythroid stimulating agents are a critical part of their care and well- being.

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These proposed rule changes are far too restrictive of the use of ESAs, in my opinion as a practicing medical oncologist. Medicine cannot be well practiced by applying rules- it must be tailored to the patient. Cardiorespiratory status, cancer status, anticipated treatment, and anticipated drops in hemoglobin all need to be considered. It is not feasible to require individual approval for each patient when a rule or guideline fails to give the patient the best possible treatment. Educate me, inform me of ASCO and other guidelines, but please avoid mandates. I feel quite sure that we use ESAs appropriately in our practice currently. Encourage more research regarding epo receptors in/on tumor cells and their biologic meaning, but don't prohibit use of ESAs for patients with a Hb of 10.9 who are beginning chemo, or a cancer patient with fatigue and a Hb of 10 who is not going to receive chemo. Yes, help us be alert to risks of thrombosis (already high from the cancer and already ever present in our minds) but please don't try to rule by fiat. Your job is to provide insurance for our patients, not to practice medicine. Thanks for your consideration.

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The proposed restrictions are based on limited clinical data - vastly less data than that published regarding benefits of ESA use. It is clear that if experienced oncologists and hematologists use ESAs correctly, in accordance with published, peer reviewed data and published expert national consensus guidelines, patients are far more likely to benefit than to be adversely affected. Like in everything else, risk and benefit have to be weighed. The use of ESAs in certain types of myelodysplastic syndromes is well established and part of all treatment guidelines. Individualizing doses of ESAs and treating beyond 4 weeks at higher doses in non-responding patients will lead to more patients responding and avoiding transfusions. There is no question that ESAs are effective and safe in anemia associated with some myeloid malignancies, especially CML. The proposed, across the board changes are more based on financial considerations than medical, scientific or ethical considerations. Certainly, the welfare of patients appears to not play a major role here. CMS appears to have a greater financial incentive here than clinicians who are for the most part more commited to helping their patients by raising their hemoglobin (maintaining Hgb between 11 and 12 is optimal in most instances; Hgb greater than 12 should be avoided), improving their quality of life and reducing what will be a marked increase in transfusions - an outcome that will lead to an outcry from the affected patient population that is certain to raise eyebrows in Washington.

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June 11, 2007

Steve E. Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Blvd.
Baltimore, MD 21244

RE: Proposed National Coverage Policy on use of Erythropoiesis Stimulating Agents (ESAs) in Cancer Patients (CAG-00383N)

On behalf of our colleagues at Fox Chase Cancer Center, we would like to submit the following comments in response to the recent proposals put forward by CMS regarding coverage of ESAs for cancer and related conditions. Fox Chase Cancer Center is a free-standing NCI-designated Comprehensive Cancer Center whose mission is to reduce the burden of human cancer. Our center treats thousands of cancer patients each year, and has extensive experience with use of ESAs in the management of cancer patients. We believe that CMS's proposed coverage limits are far too restrictive, are not supported by scientific or clinical evidence, and would have serious negative consequences for the care of our patients.

With regard to use of ESAs in patients with the myelodysplastic syndromes (MDS), we believe that the weight of evidence supports the efficacy and safety of ESAs in anemic patients with low-risk MDS. A phase III, randomized, prospective trial conducted by ECOG of erythropoietin +/- G-CSF vs. supportive therapy alone has demonstrated significant hematologic improvement with Epo, with no signal to suggest a negative impact on survival or evolution to AML (Miller KB, et al, Blood 2004; 104 (no 11): 24a). Other cohort and single institution studies have confirmed these findings. We have many patients with low-risk MDS treated at our center with ESAs whose care would be seriously compromised if the proposal for non-coverage were to be implemented.

With regard to use of ESAs in anemic cancer patients receiving treatment regimens containing bevacizumab or antibodies directed against EGFRs, there is no scientific evidence that we are aware of to suggest that ESAs are harmful when used in conjunction with these regimens. Because these antibodies will likely be used with increasing frequency in combination with myelosuppressive therapies that induce anemia, we strongly oppose the CMS proposal to restrict the use of ESAs in these circumstances. Again, we believe that the care of myriad patients who are benefitting from treatment regimens incorporating these novel antibodies would be compromised if access to ESAs were restricted.

We completely oppose efforts by CMS to link coverage decisions for ESAs to certain tumor types based upon expression of erythropoietin receptors as reported in the literature. In our view, the methodology for determining Epo receptor expression on tumor cells is poorly standardized, and the biologic significance of receptor expression is highly controversial, even among scientific experts in this field. In addition, these receptor assays are not yet commercially available.

With regard to the CMS proposal for using a hemoglobin < 9 gm/dL as a trigger for initiating ESAs in anemic cancer patients receiving myelosuppressive chemotherapy, we believe that this threshold is far too low, and is not based on any scientific evidence. The majority of trials substantiating the benefits of ESAs in anemic cancer patients have included patients with higher baseline hemoglobin levels. There is ample evidence from published trials to suggest that use of a higher threshold hemoglobin results in need for significantly fewer red cell transfusions, and that many patients may avoid transfusions completely with more proactive use of ESAs. This has also been borne out by our collective experience at our center.

We completely disagree with CMS's proposal to limit coverage to 12 weeks per year, as this is not based on any scientific or clinical evidence, and would have serious consequences for the care of our patients. In our experience, it often takes 6-8 weeks just to achieve a hematologic response and to establish the appropriate ESA dose in an individual patient. Many of our patients receive myelosuppressive chemotherapy treatments well in excess of 12 weeks per year (some up to 52 weeks), and thus, an arbitrary limit of 12 weeks of ESA coverage per year would essential doom many of our patients to receiving blood transfusions which they might otherwise avoid. The ramifications of a significant increase in blood transfusions in terms of time and space constraints at our center could be enormous and could literally jeopardize our mission. In addition, this obligation would put a serious strain on the local blood supply, which is already perennially threatened.

Finally, we also disagree with the proposal to discontinue coverage if the hemoglobin response at 4 weeks is suboptimal. A strategy of ESA dose titration depending upon the hemoglobin response at 4 weeks has been validated in several clinical trials, and has been incorporated into various clinical guidelines (eg- NCCN). In our collective experience, many anemic cancer patients receiving chemotherapy will manifest a hemoglobin response between weeks 4 and 8 with a strategy of appropriate ESA dose titration. We therefore would also take issue with the proposal to limit coverage for erythropoietin to 126,000 units/4 week period, and darbepoetin to 630 ug/4 week period for the same reason.

In summary, we would urge that CMS's proposed coverage limits on ESAs either be withdrawn or significantly modified for the reasons stated above. We believe that when used appropriately, and in keeping with the recently revised FDA label, these agents have proven safe and effective, and have had a positive impact on the care of our patients.

Respectfully submitted,

Michael M. Millenson, MD, FACP
Director, Hematology Service
Fox Chase Cancer Center

Corey J. Langer, MD, FACP
Director, Thoracic and Head and Neck Medical Oncology
Fox Chase Cancer Center

Dwight Kloth, Pharm D, FCCP, BCOP
Co-Chairman, Pharmacy & Therapeutics Committee and Director of Pharmacy
Fox Chase Cancer Center

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As a nurse for over 20 years, I have seen how much the growth factors have helped our patients. I can not imagine what would happen to our patients and their quality of life if these proposed rules went into effect. Procrit and Aranesp not only help our patients to avoid transfusion, but they also allow them to get their full course of therapy therefore allowing for better outcomes. If we have to wait until a hemoglobin of 9g/dL to intervene or we can only utilize the drug for 12 weeks per year, our patients will definitely miss chemo cycles due to low hemoglobin levels. This translates to poorer outcomes for our patients. Oncology has come such a long way in the last ten years. To take a step back like CMS is proposing would be a disservice to our patients and caregivers.

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I would like to echo the concerns and comments brought forth by both ASCO and ACCC. The implementation of the current proposed policy would have a severe negative impact on the cancer community, the cancer patient and overall healthcare and acces to blood supply on a national level. It is the responsibility of the FDA to make these clinical determinations based on clinical and scientific evidence. I am hopeful that CMS thoroughly evaluates all comments submitted and refrains from putting their proposed coverage determination into action, as the current proposal will only result in a national healthcare crisis which will ultimately result in increased healthcare costs and decreased access to necessary care.

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