Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis

April 15, 2011

Louis B. Jacques, M.D.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard, Mail Stop S3-02-01
Baltimore, Maryland 21244

Dear Dr. Jacques:

These comments from the Public Citizen Health Research Group are being submitted in response to the Centers for Medicare & Medicaid Services’ (CMS) March 16, 2011 proposed decision memo referenced above:

1. We strongly oppose the proposal that CMS not issue a national coverage determination at this time for ESAs for treatment of anemia regarding ESAs for the treatment of anemia in adults with chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis. Such a proposal (a) is not supported by the current evidence regarding the known risks and benefits of ESAs; (b) fails to align with the black box warning about the dangers of ESAs required by the Food and Drug Administration (FDA) for all ESAs currently marketed in the United States (U.S.); (c) is not consistent with protecting the public health; and (d) contributes to wasteful expenditures of Medicare dollars.

2. We urge CMS to issue instead a national coverage decision that incorporates the following elements:

   1. For patients on dialysis, a coverage decision for ESAs should be issued that promotes maintenance of hemoglobin levels within the target range of 10-12 grams/deciliter (g/dL) recommended by FDA, and preferably within a level of 10-11 g/dL.

   2. For patients with CKD not on dialysis, a coverage decision for ESAs should be issued that limits ESA treatment to patients with hemoglobin levels less than 10 g/dL. The goal of ESA treatment in these patients should be a hemoglobin level of 10 g/dL, but no higher.

Unless CMS implements a national coverage decision for ESAs that aligns with the FDA’s recommendation for the upper limit of target hemoglobin levels, patients with CKD will continue to be needlessly harmed, and tens – if not hundreds – of millions of Medicare dollars will be wasted.

Background

ESAs are a class of drugs which stimulate red cell production. They are similar to the endogenous protein hormone erythropoietin, which is produced primarily in the kidney, but also in small amounts by the liver. Impaired production of erythropoietin, because of kidney disease, is one of several factors that contribute to the development of anemia in patients with CKD.

Since 1989, ESAs have been used to treat anemia in CKD patients. Two ESA products currently are marketed in the U.S. The first, epoetin alfa (marketed under the brand names of Epogen® and Procrit®; Amgen, Inc.), was approved in 1989 for the treatment of anemia associated with chronic renal failure “to elevate or maintain the red blood cell level and to decrease the need for transfusions.”^[1] The current indication is “for the treatment of anemia associated with chronic renal failure, including patients on dialysis or not on dialysis... to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients.”^[2]

Darbepoetin alpha (marketed under the brand name Aranesp®; Amgen, Inc.), a second ESA, was approved for marketing in the U.S. in 2001 for “the treatment of anemia associated with chronic renal failure, including patients on dialysis or not on dialysis.” In 2002, the FDA also approved darbepoetin alpha for treatment of anemia due to chemotherapy in patients with non-myeloid malignancy.^[3]

Benefits of ESAs

From a benefit standpoint, epoetin alfa has been shown to be effective in increasing and maintaining hemoglobin levels and in decreasing the need for transfusions in patients with CKD. In non-inferiority studies comparing the efficacy of darbepoetin alpha to epoetin alfa, darbepoetin alpha was shown to be effective in increasing and maintaining hemoglobin levels in patients with CKD. However, despite these improvements in surrogate markers for anemia, there have been no well-designed, randomized clinical trials that have demonstrated important clinical benefits from ESAs in patients with CKD beyond the demonstrated improvements in hemoglobin level and reductions in transfusion requirements. Indeed, in terms of benefits of ESAs, CMS concluded the following:

Risks of ESAs

In contrast to the paucity of data on the benefits of ESAs, over the past decade there has been a steadily growing body of evidence indicating that ESAs pose significant risks of cardiovascular morbidity and death when attempts are made to give enough of the drug to achieve relatively higher hemoglobin levels and when high ESA doses are used in patients with CKD.

The Normalization of Hematocrit Trial (NHCT)

This study, published in 1998, was a randomized, open-label, multicenter study in 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 subjects were randomized to receive increasing doses of epoetin with a target hematocrit of 42 percent (normal-hematocrit group); the other 615 subjects were randomized to receive epoetin at doses sufficient to maintain a hematocrit of 30 percent (low-hematocrit group). The median duration of study intervention was 14 months. The primary end point was length of time to death or a first nonfatal myocardial infarction. There were more deaths and nonfatal myocardial infarctions in subjects in the normal-hematocrit group (183 and 19, respectively) than in the low-hematocrit group (150 and 14, respectively) (risk ratio 1.3; 95 percent confidence interval; 0.9-1.9). The study was stopped early upon recommendation of an independent data monitoring committee based on concern about safety of subjects assigned to the high-hematocrit group at the third interim analysis. The study investigators concluded that use of epoetin to achieve a hematocrit of 42 percent in hemodialysis patients with congestive heart failure or ischemic heart disease was not recommended.^[5]

Subsequently in 2006, results of two randomized, open-label, multicenter studies were published that assessed the effect of using ESAs to achieve a high hemoglobin target versus a low hemoglobin target in patients with CKD who were not on dialysis. The first was the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, and the second was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial.

The CHOIR Trial

The CHOIR trial was a randomized, open-label, multicenter study in 1432 patients with CKD not on dialysis: 715 subjects were randomly assigned to receive epoetin alfa to achieve a target hemoglobin level of 13.5 g/dL (high-hemoglobin group); 717 subjects were assigned to receive epoetin alfa to achieve a target hemoglobin level of 11.3 g/dL. The median study duration was 16 months. The primary study end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure, and stroke. Mean hemoglobin values were close to the target of 11.3 g/dL in the low-hematocrit group, but were consistently below the target of 13.5 g/dL in the high-hematocrit group. In the high-hemoglobin group, 125 composite events occurred, compared to 97 in the low-hemoglobin group (hazard ratio, 1.34; 95 percent confidence interval 1.03-1.74; p=0.03). There also was no incremental improvement in quality of life measures in the high-hemoglobin group. This study was terminated early based upon the recommendation of a data and safety monitoring board at the time of the second interim analysis. The study investigators concluded that use of a target hemoglobin level of 13.5 g/dL in patients with CKD is associated with an increased risk of serious adverse outcomes in comparison to a target hemoglobin of 11.3 g/dL.^[6]

The CREATE Trial

The CREATE trial also was a randomized, open-label, multicenter clinical trial, which involved 603 patients with CKD not on dialysis who had mild to moderate anemia: 301 subjects were randomized to receive epoetin beta to a target hemoglobin of 13.0-15.0 g/dL (high-hemoglobin group); 302 subjects were randomly assigned to achieve a target hemoglobin of 10.5 to 11.5 g/dL (low-hemoglobin group; in this group epoetin was not given unless the subject’s hemoglobin level decreased to less than 10.5 g/dL). The primary end point was a composite of eight cardiovascular events, including sudden death, myocardial infarction, acute heart failure, stroke, transient ischemic attack, angina pectoris resulting in hospitalization for 24 hours or more or prolongation of hospitalization, complication of peripheral vascular disease, or cardiac arrhythmia resulting in hospitalization for 24 hours or more. There were several secondary end points including death from any cause, death from cardiovascular causes, and change in glomerular filtration rate (GFR). At the end of the study, there were 58 subjects in the high-hemoglobin group reached a primary composite end point, in comparison to 47 in the low-hemoglobin group (hazard ratio 0.78; 95 percent confidence intervals 0.53-1.14; p=0.20). Of note, more subjects progressed to needing hemodialysis in the high hemoglobin group than the low-hemoglobin group (127 versus 111; p=0.03).>[7]

FDA-Required Black Box Warning for ESAs

In December 2007, based on a review of the above-referenced studies (particularly the NHCT and CHOIR trials) the FDA required that the following black box warning be added to the labels for ESA products marketed in the U.S.:

The FDA also required that the warning section of the label for ESA products marketed in the U.S. be modified to include the following:

Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)

The most recent evidence of serious risks associated with the use of ESAs came from the TREAT trial. This study was a randomized, double-blind, placebo-controlled, multicenter study involving 4038 patients with diabetes mellitus, CKD (not on dialysis), and anemia: 2012 subjects were randomly assigned to receive darbepoetin alpha with a target hemoglobin of 13 g/dL (darbepoetin group); 2026 subjects were randomized to receive placebo, with rescue darbepoetin alfa administered whenever the hemoglobin level was 9.0 g/dL (control group). The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. Death or cardiovascular event occurred in 632 subjects in the darbepoetin group and in 602 subjects in the placebo group (hazard ratio 1.05; 95 percent confidence interval 0.94-1.17; p=0.41). Death or end-stage renal disease occurred in 652 subjects in the darbepoetin group and in 618 control subjects (hazard ratio 1.06; 95 percent confidence interval 0.95-1.19; p=0.29). Fatal or nonfatal stroke occurred in 101 subjects in the darbepoetin group and in 53 control subjects (hazard ratio 1.92; 95 percent confidence interval 1.38-2.68; p<0.001). The investigators concluded that use of darbepoetin alfa in patients with diabetes mellitus, CKD, and moderate anemia who are not on dialysis did not reduce the risk of either primary composite end point and was associated with an increased risk of stroke, and “for many persons involved in clinical decision making, this risk will outweigh the potential benefits.”^[10]

FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) Meeting to Discuss the Results of the TREAT Trial

On October 18, 2010, the FDA convened its CRDAC to discuss the results of the TREAT trial. In the FDA briefing document for this meeting, the FDA noted the following:

A review of the transcript of the October 18, 2010 CRDAC meeting reveals the following important comments regarding the risks of ESAs:

Dr. Ann Farrell, Acting Division Director, Division of Hematology Products, Office of Oncology Drug Products (OODP), Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER), FDA, stated the following in opening remarks to the CRDAC:

Dr. Paul Eisenberg, Senior Vice President, Global Regulatory Affairs & Safety, Amgen, Inc.:

…we believe additional risk mitigation is warranted and we have proposed significant revisions to the label including restricting the use to patients with chronic renal failure [not on dialysis] who have, at a minimum, a hemoglobin less than 10 g/dL, who have a high likelihood of frequent transfusion, and who would benefit from ESAs as treatment strategy for their anemia. We have also proposed more conservative dosing designed to achieve a hemoglobin of 10 but not greater and we continue to believe a hemoglobin target of 10 is appropriate based on data we’ll review today that this is the level that has been demonstrated to consistently achieve transfusion avoidance.^[13]

Dr. Robert Kane, Acting Safety Deputy Director, Division of Hematology Products, OODP, OND, CDER, FDA:

Dr. Shona Pendse, Medical Officer, Division of Cardiovascular and Renal Drug Products, OND, CDER, FDA:

Dr. Ajay Singh, a nephrologist at the Brigham Women’s Hospital and the principal investigator for the CHOIR study, speaking during the open public hearing:

Dr. Wolfgang Winkelmayer, a nephrologist speaking on behalf of the American Society of Nephrology during the open public hearing:

CMS Conclusions

Regarding the available data on risks of ESAs, CMS concluded the following:

Medicare Expenditures for ESAs

According to the U.S. Renal Data System’s (USRDS) 2010 Annual Data Report, total Medicare spending for end-stage renal disease care in 2008 rose to $26.6 billion, a 13.2 percent increase over 2007 spending. Of this total, Medicare spent $1.8 billion (6.7 percent) on ESAs for ESRD patients.^[22] The USRDS report notes that Medicare payment policies for ESAs only decrease reimbursement for those patients in whom hemoglobin levels were greater than 13 g/dL for three months. As a result of these current policies, a significant proportion of the $1.8 billion spent on ESAs in 2008 covered ESA use in patients whose hemoglobin levels exceeded the FDA recommended upper limit of 12 g/dL.

Obviously, as the target hemoglobin levels in patients with CKD increase to levels greater than the upper limit recommended by the FDA, so too do the doses of ESAs that needs to be administered to achieve these targets. In one study on the cost-effectiveness of maintaining higher hemoglobin targets with epoetin alfa in hemodialysis patients, the average predicted doses of intravenous (IV) and subcutaneous (SQ) doses of epoetin alfa to achieve varying levels of target hemoglobin were as follows:^[23]

Based on these predicted doses, an increase from a target hemoglobin of 9.5-10.5 g/dL to 11.0-12.0 g/dL in hemodialysis patients would require on average a 44 percent increase in the IV or SQ dose of epoetin alfa; an increase in the target hemoglobin to 12.0-12.5 would require a 73 percent increase in dose.

Risk:Benefit and Cost Assessment and Recommended Actions

With regards to benefits, CMS acknowledges that there have been no well-designed, randomized clinical trials that have demonstrated important clinical benefits from ESAs in patients with CKD beyond the demonstrated improvements in hemoglobin level and transfusion requirements. There certainly is no evidence from randomized clinical trials that there is significant clinical benefit from using ESAs (a) in patients on dialysis to achieve a target hemoglobin greater than 12 g/dL or even greater than 11 g/dL, or (b) in patients with CKD who are not on dialysis to achieve a target hemoglobin greater than 10 g/dL.

In contrast, all randomized, controlled trials comparing various high-hemoglobin targets to low-hemoglobin targets have consistently shown a safety signal indicating increased risks of serious adverse cardiovascular outcomes and death in subjects assigned to the high-hemoglobin targets.

Thus, there is compelling evidence that the risk of using ESAs increases at higher hemoglobin targets, and there is no evidence of an off-setting increased benefit at higher hemoglobin levels.

Furthermore, trying to achieve higher target levels of hemoglobin requires significant escalation in both the dose of ESAs and the accompanying Medicare spending for these drugs. Thus, higher hemoglobin targets not only result in more adverse outcomes in CKD patients, including more patient deaths, they waste significant amounts of Medicare resources.

Given this risk: benefit and cost analysis, we are astonished that CMS proposes to not issue a national coverage determination at this time for ESAs for treatment of anemia regarding ESAs for the treatment of anemia in adults with CKD, including patients on dialysis and patients not on dialysis. Such a proposal (a) is not supported by the current evidence regarding the known risks and benefits of ESAs; (b) fails to align with the black box warning about the dangers of ESAs required by the FDA for all ESAs currently marketed in the U.S.; (c) is not consistent with protecting the public health; and (d) contributes to wasteful expenditures of Medicare dollars.

The available evidence provides strong support for a policy under which ESAs are dosed in an individualized manner so as to achieve the lowest possible hemoglobin level necessary to minimize the need for blood transfusions. Therefore, in order to minimize harm to patients and avoid unnecessary spending of tens to hundreds of millions of Medicare dollars, we urge CMS to issue a national coverage decision that incorporates the following elements:

1. For patients on dialysis, a coverage decision for ESAs should be issued that promotes maintenance of hemoglobin levels within a target range of 10-12 g/dL, and preferably within a level of 10-11 g/dL

2. For patients with CKD not on dialysis, a coverage decision for ESAs should be issued that limits ESA treatment to patients with hemoglobin levels less than 10 g/dL. The goal of ESA treatment in these patients should be a hemoglobin level of 10 g/dL, but no higher. This approach is consistent with labeling changes proposed by Amgen, Inc., the manufacturer of ESAs marketed in the U.S, during the October 18, 2010 FDA CRDAC meeting.

Thank you for the opportunity to comment on the proposed national coverage decision memo.

Sincerely,

/s/
Michael A. Carome, M.D.
Deputy Director

/s/
Sidney M. Wolfe, M.D.
Director
Public Citizen Health Research Group

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April 15, 2011

Louis Jacques, MD
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services
S3-02-01
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed Decision Memorandum for Erythropoiesis Stimulating Agents for Treatment of Anemia in Adults with Chronic Kidney Disease Including Patients on Dialysis and Patients Not on Dialysis (CAG-00413N)

Dear Dr. Jacques:

Amgen Inc. (Amgen) welcomes the opportunity to submit comments on the Proposed Decision Memorandum (PDM) regarding erythropoiesis stimulating agents (ESAs) for treatment of anemia in chronic kidney disease (CKD) that the Centers for Medicare and Medicaid Services (CMS) issued on March 16, 2011.

Amgen supports the agency’s decision not to issue a national coverage determination (NCD) for the use of ESAs in CKD. Amgen recommends that CMS issue a final decision memorandum determining that an NCD is not appropriate given the totality of available evidence.

Amgen recognizes CMS’ concerns about the appropriate and safe utilization of ESAs in patients with CKD. ESAs are approved by the U.S. Food and Drug Administration (FDA) for treatment of anemia associated with chronic renal failure (CRF), including dialysis patients and patients not on dialysis.^1,2 As a science-based, patient-care focused company, Amgen is committed to using science and innovation to dramatically improve patients’ lives and is vitally interested in improving access to innovative drugs and biologicals for Medicare beneficiaries.

Patient safety is of utmost importance to Amgen. As such, Amgen has been fully engaged and transparent with all stakeholders during multiple deliberations to provide objective, rigorous, and evidence-based information regarding the appropriate and safe use of ESAs in patients with CKD. This effort has included the following activities:

• participation in two Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meetings;
• participation in two FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meetings;
• submission of extensive comments to the Agency for Healthcare Research and Quality (AHRQ) in response to the draft technology assessment (TA) commissioned by CMS through AHRQ; and
• submission of thousands of pages of documents – many of which are proprietary – including primary data from the registration trials that supported regulatory approval of both products and other relevant information in response to CMS’ request for detailed study reports and data.

Public access to Amgen submissions for the FDA and CMS meetings referenced above are as follows:

• Amgen briefing document for March 24, 2010 MEDCAC. (Available at: http://www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=21312&ReportType=nca and http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/0716ofmancomment.pdf.)
• Amgen briefing document for January 19, 2011 MEDCAC. (Available at: http://www.amgen.com/media/amgen_medcac_esa_meeting-Jan2011.html.)
• Amgen briefing information for October 18, 2010 CRDAC. (Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM229328.pdf.)
• Amgen briefing material and slide presentation for September 11, 2007 CRDAC. (Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4315b1-04-AMGEN.pdf.)

CMS should finalize its proposal for the following reasons (which are supported by more detailed discussion and specific citations included in Amgen’s complete response):

1. Dialysis patients represent an extremely sick patient population, with a range of substantial comorbid conditions and significant clinical heterogeneity. Hemoglobin levels are also highly variable in response to ESAs necessitating highly individualized care. As a part of the shared decision-making process with their patients, physicians require discretion to apply appropriate medical judgment in the management of the causes and symptoms of anemia and to avoid blood transfusions.
2. As CMS heard from many patients at the January 19, 2011 MEDCAC meeting, the life of a dialysis patient is extremely challenging. Nearly all dialysis patients suffer from significant chronic anemia because their failed kidneys no longer produce the protein that stimulates the production of red blood cells and due to ongoing blood loss. This is entirely different from acute anemia that is seen in trauma patients, patients undergoing chemotherapy, or anemia in the surgical or intensive care unit (ICU) settings where patients are immobile and anemia is transient. Anemia in kidney disease is more severe, patients are ambulatory and active, and their severe anemia is chronic literally life-long. The patients who presented testimony at the January 19, 2011 MEDCAC meeting discussed the debilitating effects of anemia, including very low energy and fatigue, dizziness, headaches, and trouble concentrating, making it difficult, if not impossible, to complete the functions of daily life.
3. There are important subgroups within the dialysis population in whom anemia is even more common and more severe. It is widely recognized that minority populations are disproportionately affected by end-stage renal disease (ESRD), and that the impact of race on the treatment of ESRD and its complications has been well documented, with African Americans using a disproportionately higher amount of healthcare resources, requiring higher doses of ESAs to manage their anemia, and requiring longer wait times for a kidney transplant.
4. Before the introduction of ESAs, CKD patients required frequent blood transfusions (on average, four to twelve units annually). The benefits of transfusion are fleeting and carry significant risks, including the development of antibodies that promote rejection and accelerate the failure of transplanted kidneys. Thus blood transfusions can prevent patients from obtaining a kidney transplant or increase the time that a patient waits for a transplant. It is also well known that transfusions can transmit known and unknown infectious diseases, among other complications.
5. There is unequivocal evidence that ESAs effectively reduce the need for blood transfusions to manage the chronic anemia of CKD. ESAs also improve exercise tolerance and physical functioning, and the published literature supports improvements in patient reported symptoms and health-related quality of life. Dialysis and pre-dialysis patients are distinctly different and have a different benefit-risk profile as it relates to the severity of anemia, the risk of transfusion and the impact of transfusion avoidance on their future clinical course. This distinction is well recognized and accepted. The benefit-risk profile of ESAs in the dialysis population is clearly positive. The literature and clinical consensus also support a favorable benefit-risk profile for CKD patients not on dialysis with significant anemia at high risk of transfusion for whom transfusion avoidance is an important clinical outcome.
6. CMS has established the appropriate policies to effectively manage and monitor ESA use in dialysis. The recently enacted Prospective Payment System (PPS), ESRD Quality Incentive Program (QIP), and the current ESA Monitoring Policy (EMP) effectively ensure that clinical and financial incentives are aligned, that patient protections are in place to prevent under-utilization, and that utilization patterns are monitored. These complex new policies, in addition to the existing EMP, require careful implementation and evaluation before a new and untested policy is introduced.

Amgen appreciates the significant effort taken by CMS to evaluate the large body of evidence on ESA use in patients with renal insufficiency. The complexity of the clinical evidence-base is considerable, accumulating over 20 years in a very complicated disease state. Appraising the quality of this evidence base and drawing meaningful conclusions certainly is a complex, technical clinical challenge. While we agree with the conclusion not to issue an NCD, we believe the PDM contains a number of important omissions and statements that run counter to those reached by the FDA and many other authoritative bodies. We provide in our complete response a review of the scientific literature that identifies several references for clarification. As it is currently drafted, the PDM evidence review could be misinterpreted and/or misapplied by clinicians and by decision-makers responsible for payment and coverage at the national, regional and local levels. CMS should strive to assure Medicare beneficiaries that the care they receive is based upon a comprehensive and consistent assessment of the evidence. As such, Amgen welcomes the opportunity to provide a summary of the totality of evidence in Section I and specific comments on the evidence review in Section II of our complete response.

Amgen also requests that CMS revise the PDM evidence review based on the comments it receives from stakeholders and with consideration of the analyses and interpretation of the evidence by other authoritative bodies as part of the final decision memorandum.

Finally, providers, patients, and all other members of the nephrology community need specific proposals to react to when considering potential coverage restrictions. Since CMS has not proposed coverage changes in this PDM, we anticipate that the agency will follow its NCA procedures for initiating a new NCA, should the agency determine there is new clinical, regulatory or other significant evidence that would warrant an NCD.

In sum, Amgen agrees with CMS’ conclusion that an NCD is not appropriate and requests that the agency reaffirm this conclusion in the final decision memorandum. Thank you for your attention to these important matters.

Sincerely,

Joshua J. Ofman, MD, MSHS
Vice President, Global Coverage and Reimbursement
and Global Health Economics

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April 11, 2011

Louis B. Jacques, M.D.
Director, Coverage and Analysis Group
Elizabeth Koller, M.D.
Lead Medical Director
Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop S3-02-01
7500 Social Security Boulevard
Baltimore, MD 21244

Dear Drs. Jacques and Koller:

National Patient Advocate Foundation (NPAF) is the voice for millions of patients who have sought care after a diagnosis of a chronic, debilitating or life-threatening illness. The advocacy activities of NPAF are informed and influenced by the experience of patients who receive direct, sustained services from Patient Advocate Foundation (PAF), which provides professional case management assistance to patients with chronic, debilitating or life-threatening conditions. In annual year 2010, PAF resolved 82,963 patient cases and received more than four million additional inquires from patients nationally.

NPAF provided comments as part of the National Coverage Analysis process related to CAG #00413N via a letter dated July 16, 2010. Those comments were informed by input from NPAF’s Scientific Advisory Committee, chaired by Robert Rifkin, M.D. F.A.C.P., Director of Cellular Therapeutics, Rocky Mountain Blood & Marrow Transplant Program, Rocky Mountain Cancer Centers, and Dennis Gastineau, M.D., Director, Human Cell Therapy Laboratory, Divisions of Transfusion Medicine & Hematology, Mayo Clinic, and current President of the NPAF Board. They reflected an assessment based on a thorough review of the clinical literature.

In its comments, NPAF recommended precisely the position you have proposed adopting because our scientific advisors were of the view that the available evidence about the risks and benefits associated with ESA use was insufficient to warrant a narrowing of the discretion to select treatment options in consultation with their physicians that is currently available to patients with all stages of CKD. Our Scientific Advisory Committee re-evaluated the evidence again in the fall of 2010 with a focus on the transfusion issue and again came to the same conclusion.

We are writing to commend CMS’ decision not to issue a National Coverage Decision for ESAs for the treatment of anemia in adults with CKD set forth in the Proposed Decision Memorandum referenced above. We strongly encourage you to reaffirm this conclusion and not add additional coverage restrictions to ESAs in the Final Decision Memorandum to be issued by June 16, 2011.

Sincerely,

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March 31, 2011

Dear Ms. Long and Dr. Koller:

The American Kidney Fund (AKF) appreciates the opportunity to provide comments on the Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis CAG #00413N”. We are committed to ensuring that kidney patients have access to safe and appropriate anemia management care, and our comments support that overriding goal.

The American Kidney Fund is the nation’s leading charitable organization providing treatment-related assistance to kidney patients. Last year, AKF provided over $200 million in financial assistance to just over 100,000 patients on dialysis to help pay for health insurance and dialysis treatment related expenses. Along with providing financial services, AKF works to ensure that kidney patients have access to the quality health care that they need.

AKF applauds the efforts that CMS has put forth to ensure that anemia management practices remain safe and effective. We support the Centers for Medicare and Medicaid Services’ (CMS’) recent decision not to issue a National Coverage Determination (NCD) for ESAs for treatment of anemia in adults with CKD including patients on dialysis and patients not on dialysis. We believe, however, that ESA usage should continue to be evaluated and any change in policy should be based on complete and conclusive clinical evidence.

As CMS moves forward with a final recommendation, it is important that CMS understands that ESRD patients are very fragile, and each patient’s health condition is unique. CMS should ensure that patient access to appropriate anemia care is of the highest priority.

Chronic Kidney Disease Management

Anemia is a serious, life-threatening problem affecting many patients with kidney disease. Prior to the introduction of ESAs, patients suffering from anemia relied heavily on blood transfusions to maintain a healthy red blood cell count. Blood transfusions are necessary for some patients, but carry many risks including disease, infection and iron overload. While helpful with anemia management, blood transfusions in patients with chronic kidney disease have been associated with high panel-reactive antibody (PRA) titers, which can preclude or delay time to kidney transplantation and complicate patient management (Opelz, 2005).

FDA-approved ESAs elevate hemoglobin levels and dramatically decrease transfusion needs for patients with CKD. Lower PRA levels have the ability to allow for a more successful transplantation process. Aside from the transplantation issue, there are significant health benefits associated with ESA use. With the appropriate dosing and administration of ESAs and control of factors that hinder the body’s response to ESA’s, patients require less medical attention and hospitalization, and rarely need blood transfusions.

While there has been controversy over dosage administrative practices, it is important to emphasize that each patient receiving dialysis responds differently to the medications used to treat anemia. It is not possible to determine a single dosing regimen that works for all patients at all times. Because of this, it is important that the physician and patient be permitted to decide on an anemia management care plan that is best suited for that patient from a clinical perspective. CMS should not restrict or place limitations on this process.

Quality of Life Measurements

All dialysis patients have the right to live normal and productive lives. Patients should have access to the best quality of care that allows them to have careers, raise children, and enjoy life.

There have been advances and achievements in anemia management brought about by ESAs. Studies have demonstrated that hemoglobin levels greater than 10 are associated with improved survival and quality of life compared to hemoglobin levels less than 10.

Receiving the proper doses of ESAs has made living a normal life possible for many patients. Additionally, ESAs have reduced the rate of transfusions in the dialysis population. .

ESA’s Should Remain Accessible

The Medicare Benefit has provided great new advances and successes in fighting kidney disease. AKF believes that any change in policy should take into consideration its impact on quality patient care and not be solely focused on reimbursement incentives.

Patients should have access to ESAs when their physicians and their chronic management team determine that there is a need. AKF believes that addressing anemia issues prior to dialysis should result in better outcomes and healthier patients for those who later require dialysis and are kidney transplant candidates.

Consequently, healthier patients at the onset of dialysis are likely to help drive down first year mortality rates among dialysis patients. According to an article “Comparative mortality risk of anemia management practices in incident hemodialysis patients” in the Journal of American Medical Association, greater ESA and iron use among patients with CKD were associated with decreased mortality risk at the onset of dialysis.

Conclusion
In closing, AKF is committed to the goals of safe, appropriate, and high-quality care for kidney patients. We believe that any change in anemia management policy, including coverage rules, should be based on conclusive clinical evidence and considerations of all clinical data available. As CMS develops its final recommendations on a NCD, we encourage it to ensure that doctors retain the ability to prescribe the most appropriate medication, have the flexibility to adjust medications based on patient needs and that patients have access to the medications that provide the best health outcomes for their conditions.

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April 15, 2011

Dear Ms. Long and Dr. Koller:

The National Renal Administrators Association (NRAA) is pleased to provide the Centers for Medicare and Medicaid Services (CMS) comments on the Proposed Decision Memorandum recently issued as part of its National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD including Patients on Dialysis and Patients not on Dialysis.

NRAA is a voluntary organization representing independent, regional and community-based dialysis providers throughout the United States. Our membership is primarily small and medium-sized dialysis organizations, both for-profit and non-profit providers serving patients in urban, rural and suburban areas in both free-standing and hospital-based facilities.

The NRAA agrees with CMS that an NCD should not be issued for ESAs

The NRAA supports the recommendation to the Center for Medicare and Medicaid Services (CMS) to maintain the status quo and not issue a National Coverage Determination (NCD) for ESAs. A change in Medicare payment policy for ESAs would present an additional operational challenge for dialysis facilities, especially at a time when dialysis facilities are in the midst of implementing the new Medicare dialysis payment bundle.

CMS’s decision not to issue an NCD for ESAs allows nephrologists and dialysis facilities to continue to manage patient care in a manner that best suits individual patient needs. Physicians and dialysis patients, in cooperation with their community dialysis facility, are in the best position to make decisions about the appropriateness of treatment. We urge CMS to maintain the recommendation when the agency concludes the final coverage determination.

CMS Should Ensure that its Policies on this Matter are Consistent Across the Board

Any NCD that CMS issues with regard to ESAs has the potential to come into conflict with other CMS programs that also establish policy, particularly CMS’s Quality Improvement Program (QIP) and ESA Monitoring Policy (EMP).

As you are aware, CMS is in the final stages of implementing the QIP for dialysis payments in the Medicare program. The QIP is scheduled to begin on January 1, 2012, with the year 2010 being used as the initial performance year. Dialysis facilities across America are preparing to participate in the QIP, which will be the first value-based purchasing program of its kind in the Medicare program.

In implementing the QIP, CMS has established initial performance measures, which set a standard for ESA use in dialysis patients and is consistent with the ESA Monitoring Policy. The QIP measures require that patient hemoglobin levels at less than 10 g/dl and greater than 12 g/dl be minimized. In order to meet the performance standards, dialysis facilities and physicians will need to work to maintain patient hemoglobin levels between 10 g/dl and 12 g/dl. There is broad support for this standard in the dialysis community. The use of ESAs is crucial to this process and to patient health. An NCD that is inconsistent with the standards established in the QIP would result in a no-win situation for dialysis facilities and the patients they serve. Complying with one set of CMS standards would result in non-compliance with another set, with the likely outcome being a negative impact on patient care and penalties for dialysis facilities.

CMS Should Consider the Challenges for Small and Medium Dialysis Organizations

Adopting an NCD that is inconsistent with the QIP will only exacerbate the challenges of complying with the new QIP. This is a problem for all dialysis providers. However, the burden would be felt particularly by small and medium dialysis organizations (SDOs and MDOs). Meeting the QIP will require SDOs and MDOs to implement new systems for monitoring and managing the impact of the QIP. For instance, there is additional staff time needed to explain the requirements of the QIP to patients, particularly for facilities with a higher number of patients where English is a second language. Contradictory guidance from an NCD would add unnecessary confusion and unwarranted additional burdens for SDOs and MDOS at a time when MedPAC has reported that the Medicare margins for these facilities average only a fraction of one percent. Multiple targets created by inconsistent policies can create confusion for dialysis facilities about which policy to follow. This confusion wastes time and resources and has the potential to cause quality variability in patient care.

Policy Decisions with Regard to Payment for ESAs can Affect Patient Care

ESAs are not only important for the treatment of anemia, but improve the quality of care and the quality of life for the chronic dialysis patients who receive them. Prior to the advent of ESAs, the most common treatment for anemia suffered by ESRD patients was blood transfusion, which exposed patients to blood-borne disease, infection, and other complications. ESAs have provided dialysis patients with a safer, easier, more effective method of treatment and have virtually eliminated the need for blood transfusion in the ESRD population. ESAs increase patient energy and activity level and improve their overall health status, which, in turn, leads to a better quality of life for ESRD patients. Each patient is unique and responds to various therapies in different ways and there are many co-morbid conditions that can affect the required dose of ESAs for each patient. CMS should consider patient health and quality of life when evaluating ESA policies and be careful to avoid unintended consequences that could have a negative impact on patients’ quality of life.

Conclusion

NRAA strongly supports the recommendation of the Proposed Decision Memorandum not to issue an NCD for ESAs for the Treatment of Anemia in Adults with CKS Including Patients on Dialysis and Patients not on Dialysis and encourages CMS to incorporate it in to their final decision. NRAA appreciates CMS’ work in this area. We look forward to continuing to work with CMS to maintain a high standard of care for our dialysis patients.

Sincerely,

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April 15, 2011

Centers for Medicare and Medicaid Services

RE: Administrative File: CAG # 00413N Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis

To whom it may concern:

On behalf of the American Society of Nephrology (ASN), a not-for-profit organization of more than 12,000 physicians and scientists dedicated to promoting excellence in the care of patients with kidney disease, thank you for the opportunity to provide comment regarding the proposed decision memorandum for CAG-00413N, Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis. Foremost among ASN’s concerns is the preservation of access to optimal quality of care for patients with chronic kidney disease (CKD) including patients requiring dialysis as well as future candidates for, or current recipients of, a kidney transplant .

ASN supports the Centers for Medicare and Medicaid Services’ (CMS) commitment to protecting patient safety and access to the most appropriate treatments by conducting the recent National Coverage Analysis (NCA) and Technology Assessment. These efforts precipitated the proposed decision memorandum that CMS not issue a national coverage determination (NCD) at this time for CAG-00413N, Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis. ASN has closely followed this process, providing comment letters and presenting expert testimony at all related CMS and Food and Drug Administration meetings. ASN appreciates the opportunities provided to the kidney care community to offer feedback on this important issue.

ASN read with particular interest that CMS noted on page 94 of the proposed decision memorandum ASN’s previously stated positions that “current ESAs may be dangerous if used for overly aggressive treatment targets compared with practices that are compatible with current treatment guidelines. [ASN] also believes that continued access to ESAs is required to give both dialysis and non-dialysis patients with CKD, a better chance at receiving and maintaining the function of a kidney transplant.” ASN appreciates that CMS incorporated these vitally important points into the proposed decision memorandum and believes the points support the proposal not to issue an NCD.

ASN supports the proposed decision memorandum that CMS not issue an NCD at this time. Insufficient evidence exists to warrant a change in current policies regarding ESAs for the treatment of anemia in adults with CKD, including patients on dialysis and not on dialysis.

Furthermore, not issuing an NCD at this time would best allow for CMS reimbursement policy to remain consistent with existing quality measures and pay-for-performance standards in the Medicare ESRD Program. The ESRD Quality Incentive Program (QIP) Final Rule established in July 2010 that dialysis providers will be penalized with lower payments if a higher than specified fraction of patients’ hemoglobin concentrations fall outside of the 10 to 12 g/dL range. The recently-implemented ESRD Prospective Payment System also creates disincentives to administer any more ESAs than absolutely necessary to maintain patients’ hemoglobin levels within that range. Consistency between CMS quality standards and reimbursement polices is imperative to protect patient access to necessary medications. A final memorandum not to issue an NCD would safeguard patients’ access to ESAs.

ESAs are a cornerstone of care for anemia management in patients with kidney disease and have been proven effective for that purpose. Most importantly, nephrologists can treat kidney patients’ anemia with ESAs instead of with red blood cell transfusions. The latter can lead to exposure to foreign human antigens, causing immune sensitization. Immune sensitization reduces patients’ likelihood of receiving a transplant, and immunosensitized patients who do receive a transplant face higher chances of long-term dysfunction of their kidney. Many patients with CKD will eventually progress to kidney failure, for which transplantation is the best treatment option both from patient quality of life and payor perspectives. Thus, it is of the utmost importance to avoid transfusions in order to not jeopardize these patients’ prospects of receiving and maintaining a kidney graft.

Only with administration of ESAs can patients with CKD or ESRD successfully manage anemia while avoiding the hazards of red blood cell transfusions. Continued access to these medications is required to give patients with kidney disease—both on dialysis and not on dialysis—a fair chance at first receiving and then maintaining the function of a kidney transplant. The proposed decision memorandum not to issue an NCD would ensure preservation of patient access to these vital drugs.

In the future, ASN suggests that comparative effectiveness research be conducted to close the evidence gap regarding the optimal role of ESAs in the treatment of relatively severe anemia, while ensuring that patients remain transfusion-free.

In conclusion, ASN believes that no changes to the current CMS policies regarding ESAs are warranted at this time. Maintaining reasonable latitude for patients and their physicians to make individualized decisions about these medications, within FDA guidelines, is crucial. As such, ASN supports the proposed decision memorandum that CMS not issue an NCD.

Again, thank you for your time and consideration. ASN would be pleased to discuss these comments with the CMS if it would be helpful. To discuss ASN’s comments, please contact ASN Director of Policy and Public Affairs, Paul C. Smedberg, at (202) 416-0640 or at psmedberg@asn-online.org.

Sincerely,

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Renal Support Network
1311 N. Maryland Ave.,
Glendale, CA 91207
April 15, 2011

Kimberly Long
Elizabeth Koller, MD
Centers for Medicare and Medicaid Services
Mail Stop C1-09-01
7500 Security Boulevard
Baltimore MD 21244-1850

Reference: Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis CAG# 00413N (Proposed Decision Memo)

Dear Ms. Long and Dr. Koller,

I am writing on behalf of the thousands of kidney patient advocates of the Renal Support Network (RSN) regarding the above referenced proposed decision, and to thank you for the opportunity to comment. As the President and Founder of RSN, a patient-focused, patient-run organization dedicated to helping improve the quality of life for renal patients by educating and empowering them, I support the decision by CMS not to issue a restrictive National Coverage Determination (NCD) for the use of ESAs in anemia management in people with CKD.

RSN hears from people who have kidney disease across the country every day and this decision is consistent to help these individuals be able to live life to the fullest. I appreciate that this decision reflects the commentary and testimony previously provided by this organization as well as other kidney organizations on the use of erythropoiesis-stimulating agents (ESAs), embodying the patient’s perspective on how anemia affects our lives.

We are grateful that in CMS’s memorandum they have clearly outlined the benefit that ESAs have in managing anemia well by keeping hemoglobin at desired levels. RSN encourages CMS to finalize that determination as drafted. We would further urge CMS to consider and acknowledge that appropriate and individualized treatment of anemia is critically important for us to maintain a good quality of life and health, while minimizing our need for blood transfusions. The latter especially is critical for patients to avoid antibody sensitization and preserve our options for current and future kidney transplantation.

We have been very concerned that any change in the proposed NCD policy in its final form might encourage lower hemoglobin levels or mandate reductions in ESA doses that could result in a downward trend in mean hemoglobin levels and a consequential increase in the number of patients who will need transfusions. We believe that such an occurrence would be disastrous for patients; precluding, delaying, or complicating our options for kidney transplantation, and negatively impacting the quality and duration of our lives. We therefore reiterate our request that in the final analysis, CMS continue to support the use of ESAs to maintain safe and beneficial hemoglobin levels of 10 to 12 g/dL, as outlined in the prescribing information for these agents that is approved by the Food & Drug Administration (FDA), and reiterated as recently as October of 2010 by its Cardiovascular and Renal Drugs Advisory Committee. It is vital that physicians continue to have the discretion to treat anemia in individuals with CKD appropriately—working in partnership with patients to avoid cookie-cutter medicine and encourage individualized therapy based on each patient’s need.

Our reasoning for the inclusion of these very important stipulations of benefit is as follows:

Emphasize That Recommendations Help Patients With CKD Avoid Transfusions:

Prior to the development of ESA’s, patients with CKD who were on dialysis often had extremely low hemoglobin levels and required constant blood transfusions. A wide range of significant and potentially serious side effects accompanies blood transfusions, including iron overload and infection. People seem to forget that when blood transfusions were widely used before the introduction of ESAs iron levels were often so high that clinicians were forced to phlebotomize (bleed) patients to drain off excess iron. Transfusions also cause a tremendous drain on the patient due to factors such as the constant variability (up and down changes) in hemoglobin that occurs between blood transfusions (negatively affecting patient quality of life), the need for extra visits to a doctor’s office or clinic to receive a blood transfusion (negatively affecting patient quality of life and ability to work), and the need to actually suffer through the transfusion process (not a pleasant experience and negatively affecting patient quality of life).

Blood transfusions are like playing Russian roulette with our health. Some patients experience only the less serious side effects from transfusions, such as fever and chills or an allergic reaction, such as hives. However, others have much more serious reactions to transfusions that can have a significant and long lasting impact on their health, and even increase their risk for mortality.

Blood transfusions also can have a significant negative effect on our ability to receive kidney transplants. I would like to share an example from a woman who told me of her experience. This woman had CKD since she was a small child, and received a number of blood transfusions before ESAs were available. The reactive antibodies developed from repeated blood transfusions caused her to have fewer matched kidneys from potential donors. So, even though she had not received blood transfusions in some time, the effect of those transfusions continued to haunt her—decades later she had a panel reactive antibody (PRA) level well over 85. As a result, the number of potential kidney donors that were a compatible match was severely limited. The transplant team at her center was not confident that she would ever find a match within her own region. As a result, they encouraged her to multi-list at other centers to increase the pool of potential donors. However, she did not have the economic resources or the knowledge to “work the system” and give herself a better chance for finding a compatible kidney. Confronting an interminable wait for a matched kidney—and with her health deteriorating—she ended up dying while still waiting for a new kidney.

We believe that any policy that might increases the use of blood transfusions as therapy when hemoglobin levels drop too low will essentially condemn thousands of patients to never having the chance to receive a kidney transplant. Transfusion avoidance is a significant benefit of ESA therapy that cannot be over emphasized—by avoiding transfusions you provide us with a greatly improved opportunity for a transplant and a return to a “normal” life, free from dialysis. In contrast, any policy that lowers the current recommended hemoglobin target level will inevitably lead to many more patients with unacceptably low hemoglobin levels—and many of these patients will require a blood transfusion. Importantly, the people you will be affecting the most are the economically disadvantaged. These individuals among my fellow patients cannot afford to search for a compatible kidney in different regions throughout the country, and an increase in transfusions will inevitably mean that they will be unfairly and disproportionately disadvantaged.

Acknowledge that Hemoglobin Levels Below the Recommended Range of 10 to 12 g/dL Negatively Affect Our Quality of Life:

We would also like you to acknowledge how anemia affects our quality of life. Many people who have CKD—and especially those of us who were affected prior to the introduction of ESAs— can relate painfully personal experiences of how anemia has affected their lives. Symptoms can include chest pain, feeling cold, feeling tired, low energy levels even doing routine activities of daily living, poor appetite, shortness of breath, depression, a poor sense of well-being, and an inability to work, manage a home, or volunteer—in short, loss of a meaningful life.

Contrary to anecdotal information provided at a previous CMS MedCAC hearing, where it was stated by a presenter that the clinical benefits of higher hemoglobin are not discernable to patients, and that we (i.e., the patient) cannot tell the difference when hemoglobin levels rise or fall, we, in fact, are most aware of when this happens. We are not sure what patients this clinician was speaking with or about to come to this conclusion, but his perspective is very different from what our patient advocates tell us on a daily basis. Relative drops in Hgb are most certainly experienced by the patients as a lesser ability to feel well and function; the difference can be staggering. We would wager that this clinician has never experienced the low hemoglobin levels that patients dealt with in the pre-ESA era. He couldn’t possibly understand how terrible we felt when our hemoglobin levels progressively dropped and our quality of life slowly drained away between blood transfusions.

[PHI Redacted]

There are thousands upon thousands of similar stories about the effect of anemia on quality of life in individuals with CKD. I would like to share with you a representative sample of what fellow patients have told me regarding how anemia management impacts quality of life:

We believe that these brief quotes are representative of the hundreds of thousands of patients with CKD who currently enjoy the quality of life benefits provided by higher hemoglobin levels subsequent to ESA therapy. You will find that every advocacy group that represents patient’s voices throughout the country has stated a similar opinion.

While clinical evidence is certainly useful, please understand that patients visit doctors out of what we sense about ourselves; in other words, “how we feel.” CMS’ own panelist at the 2010 MedCAC hearing on this issue, Dr. Rajiv Agarwal, characterized the very problem of looking merely at the clinical profile of the patient as it exists in the computer, an assortment of diagnostic labs and the like, but failing to remember to ask the patients how they feel, as not taking very good care of patients. It is important that CMS does not do the same at the regulatory level. The goal of medical care is to preserve or regain our quality of life. Quality of life is centered on the foundation of hope and the belief that life is still worth living. To not consider quality of life as a major goal in managing patients with CKD is the same as completely ignoring the needs of patients.

Benefits and Risks:

Since the introduction of ESAs in 1989, hundreds of thousands of people with CKD have been spared the risks associated with of multiple blood transfusions, and their quality of life and general health have improved markedly. Any patient who has lived through the pre-ESA era can provide compelling testimony as to the difference in their life and health.

We are very aware of the fact that ESAs have known serious side effects when used to target hemoglobin levels at or above 13 g/dL, and we take these side effects very seriously. We understand the need for using these agents responsibly in all patients to avoid serious side effects. Further, we support ongoing education to ensure that both patients and clinicians are aware of how anemia should be treated in patients with CKD, and the steps that should be taken to reduce hemoglobin if levels exceed 12 g/dL. The fact that hemoglobin levels are falling in patients with CKD shows that patients and clinicians are already working together to balance benefits and risks. We believe that educational and monitoring efforts should be continued and magnified to ensure that patient safety is always considered.

RSN has been equally concerned that policy makers might evaluate only the potential dangers of ESA therapies, ignoring or minimizing the potential benefits. If this were to occur, it would represent a giant step backward in the quality of care to which we have become accustomed, a dramatic increase in the number of patients with low hemoglobin levels, and a consequential increase in the negative symptoms outlined above. The point is that we do have a safe range for judicious use of a medication that makes a life altering difference for patients. So we will look forward to that use being continued under the decision finalized as drafted.

Most important to mention is the harmonization of various provisions of the care of kidney patients under CMS ESRD program, in every facet. The benefits received by CKD patients under the proposed policy are in concert as already mentioned with the FDA CRDAC recommendations. And it’s critical to note that any change in the Hgb level maintained in kidney patients through ESA use in anemia management, thereby decreasing the quality of a patient’s life, would go against the very point of recent advances in other areas of kidney care such as the CMS Quality Incentive Program. The Medicare Improvements for Patients and Providers Act of 2008 provides for better education for kidney patients with early instruction sessions on their illness and treatments. The Pay for Performance Quality Incentive Measures identifies those markers that measure good quality of dialysis care that will lead to better outcomes for patients. It is so important that in the area of anemia management, we do not take several steps backward with any future restrictive policy on ESA anemia management.

Recognize that Individuals With CKD and Anemia Represent a Unique Patient Population:

We also ask CMS to remember how patients with CKD and anemia differ from patients with cancer who receive ESAs temporarily to treat anemia associated with chemotherapy, although supportive studies included in the proposed memorandum evidence review looked at oncology patients. We sympathize and empathize with the symptoms of anemia that these patients have to endure. However, in the case of chemotherapy, anemia is typically temporary and treated according to an acute care model of medicine. Although anemia can be devastating in these patients, clinicians may feel that patients “can tolerate” hemoglobin levels below 10 g/dL for a short period of time.

In contrast, patients with CKD are permanently affected by anemia. A condition that may be tolerable in the short term is intolerable when you are facing month-after-month and year-after-year of the devastating consequences. Imagine feeling sick and tired and being unable to comfortably perform routine activities of daily life FOREVER! That is the situation that we—the patients— confront when anemia is not treated appropriately. As a result, Renal Support Network respectfully but strongly contests any statement that the long-term benefits of ESA therapy are unclear. To the contrary, as patients who live with CKD, our own personal experiences refute this, and this is supported as well.

Our concern regarding the potential negative effect of anemia management policies on patient outcomes is grounded in firsthand experience. We are the ones who suffer when policies that are not well thought out are implemented wide scale and immediately affect the quality of care provided to over a million patients. To avoid such a scenario, Renal Support Network supports the 2006 CMS Anemia Management Policy, which follows recommendations found in both the prescribing information for ESAs and the guidelines developed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI™). This policy allows physicians to prescribe ESAs to achieve a target hemoglobin between 10 and 12 g/dL. The policy correctly acknowledges that there are considerable differences in how patients respond to ESAs, and contains provisions for appropriate dose adjustments based on hemoglobin and an individual patient’s pattern of response.

The policy is unique in that it has melded current science with reimbursement policies, thereby encouraging clinicians to gradually reduce ESA doses rather than holding or dramatically reducing doses. This approach prevents a patient’s hemoglobin level from plummeting, which has been associated with poorer outcomes and may increase the need for blood transfusions. This approach is also consistent with CMS’s policy of patient-centered care. We agree that the treatment of CKD is not an exact science, and CMS has demonstrated an understanding of the fact that there is a delicate balance between research and clinical practice. We are grateful for this approach, and appreciate that this has been taken into account when making these recommendations.

Conclusions and Recommendations
To conclude, we would like to thank CMS for constantly focusing on the quality and safety of our care and taking patient concerns into consideration. We would like to emphasize that we are not downplaying the safety results from the clinical trials that have been published on ESAs. We feel that a drug’s safety profile must be carefully scrutinized, with available data shared with patients and clinicians. All drugs carry risks, and patients deal with these risks every day in every facet of medicine. We are reminded of these risks every time we see or hear a commercial for a medication on TV, talk with members of our health care team, or see the results from a new clinical study.

There are still a lot of questions about anemia management and the effects of ESA therapy, and more studies need to be conducted to clarify these issues. We also believe that educational and monitoring efforts should be continued and magnified to ensure that patients and clinicians are aware of the risks associated with ESA therapy, and that patient safety is always prioritized. However, patients with CKD are also acutely aware that anemia is one of the most devastating conditions that affect those of us who live on a day-to-day basis with this disease. As a result, we believe that ESAs should be available to provide rational and responsible care to patients who desperately need these therapies, and we support this policy in doing so.

Finally, we hope CMS will adopt as final its proposed policy as drafted, increasing the focus on the importance of quality of life and transplant access benefits in its final form. It is for these very reasons that physicians need to retain the ability to individualize ESA therapy in response to an individual patient’s need. If these therapies are restricted in the future, the patient will be consequentially forced to lead a lower quality of life.

Thank you again for considering the patients’ perspective. Please feel free to contact me at any time if you have any questions or would like assistance in developing your final recommendations from individuals with CKD who have experienced anemia firsthand.

Sincerely,

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April 14, 2011

RE: National Coverage Analysis (NCA) for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N)

Dear Dr. Berwick:

On March 16, 2011, the Centers for Medicare and Medicaid Services (CMS) Coverage and Analysis Group published a Proposed Decision Memorandum (PDM) for CAG # 00413N, advising that CMS not issue a national coverage determination (NCD) at this time. The National Kidney Foundation, representing 50,000 individuals with Chronic Kidney Disease (CKD), and the health service professionals who are part of the kidney care team, urges CMS to finalize the decision not to issue an NCD for Treatment of Anemia in Adults with CKD. We maintain that this is the appropriate course of action considering the deficiencies in the analysis provided to the Medicare Evidence Development Coverage Advisory Committee (MEDCAC), the failure to recognize the benefits of ESA use in the treatment of anemia in adults with CKD during the coverage analysis process, and PDM evidence review (transfusion avoidance, improved quality of life). As important, it is necessary to consider the contraindications for red blood cell transfusions as an alternative to ESA treatment in this patient population.

Benefits of ESA Therapy

The analysis that accompanies the proposed decision memorandum and the information that had been provided to MEDCAC discount the benefits of ESA therapy. Conversely, the work group for the 2007 KDOQI Update of Hemoglobin (Hb) Target (American Journal of Kidney Diseases, Vol 50, No 3, September 2007) recommended that the selection of the Hemoglobin (Hb) target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include consideration of potential benefits (including improvement in quality of life and avoidance of transfusion) and potential harms (including the risk of life-threatening adverse events).

The KDOQI guidelines are evidenced based and apply to both persons with End Stage Renal Disease (ESRD) as well as to individuals with CKD who have anemia but are not treated with dialysis. With regard to the latter, trends documented by the United States Renal Data System (USRDS) are particularly concerning. Hb levels in patients starting dialysis have been falling such that in May 2008 50% of patients had a Hb, indicated on the Medical Evidence Form 2728, less than 10gm/dl (USRDS 2009Annual Report, Volume Two, Chapter 3, figure 3.6.ii, page 245). This makes clinical targets for the correction of anemia in the first months of dialysis more challenging and complicates achievement of the CMS Clinical Performance Measure to minimize the percent of dialysis patients with Hb below target minimum. Without the use of ESA therapy, the mean Hb level for those initiating dialysis would be dramatically lower.

ESA Therapy and Quality of Life in CKD

Health-Related Quality of Life (HRQoL) is an outcome of direct importance to patients. Arguably, given the trials testing Hb target on cardiovascular outcomes, HRQoL should now be one of the most central focuses in the discussion of the treatment of anemia and ESA therapy. Some of the studies that could have been cited in the assessment of the coverage decision and need particular attention follow.

Randomized controlled trials show potential HRQoL benefit at higher compared to lower Hb targets. (See for example, Table 9, at page 498 of the 2007 KDOQI Update of Hemoglobin (Hb) Target.) This summary table highlights findings of improved vitality. Similarly, David E. Leaf and David S. Goldfarb concluded that the HRQOL domains that are most improved with ESAs relate to physical symptoms, vitality, energy and performance, after reviewing 11 studies. (“Interpretation and Review of Health-related Quality of Life Data in CKD Patients Receiving Treatment for Anemia,” Kidney International 75, 15-24 (January (1) 2009). The authors note that commonly used HRQOL instruments, although not validated specifically in CKD patients, have shown a remarkable convergence of results across different disease groups.

A study of 1200 patients with stage 3, 4, or 5 CKD, followed in 7 centers, utilizing the Kidney Disease Quality of Life questionnaire domains demonstrated that increasing Hb levels directly correlated with a statistically significant increase in all four physical domains, the energy/vitality domain and the physical composite score of the Short Form (SF) 36, and the general health score on the kidney disease component of the questionnaire. (Fredric O. Finkelstein, et al. “Health-Related Quality of Life and Hemoglobin Levels in Chronic Kidney Disease Patients,” Clinical Journal of the American Society of Nephrology, 4: 33-38, 2009.)

Patient Reported Outcomes were also analyzed in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT). This study involved 4,038 patients. Among type-2 diabetic CKD patients, enrolled in TREAT, there was a modest but statistically significant improvement in patient-reported fatigue in the ESA arm versus the placebo group. However, there was no difference in the other pre-specified quality of life domains, energy or physical functioning, as assessed by the SF36. (Marc A. Pfeffer, et al. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. New England Journal of Medicine, 2009.)

Finally, a literature review by Shravanthi Gandra and colleagues also disclosed indications from randomized controlled trials and single-arm studies that treatment of anemia with ESAs improved energy and physical function in nondialysis CKD patients. (“Impact of Erythropoiesis-Stimulating Agents on Energy and Physical Function in Nondialysis CKD Patients with Anemia: A Systematic Review,” American Journal of Kidney Diseases, Vol 55, No 3 (March) 2010: pp 519-534.)

Transfusion Avoidance and Access to Kidney Transplantation

Transfusion risks include life threatening transfusion reactions as well as the induction of HLA antibodies that may limit access to kidney transplantation, which is the modality of choice for many individuals with ESRD. Data from the USRDS (figure 46, page 322, 2010 USRDS Annual Data Report, Vol Two) show the dramatic reduction in pre-transplant transfusion status of kidney transplant patients since ESAs were introduced. While MEDAC explored the relationship between red blood cell transfusions, Panel Reactive Antibody (PRA) status, and kidney transplant graft survival, the technology assessment prepared for the January 19, 2011 meeting did not consider the health outcomes of candidates on the transplant wait list who were not able to receive a kidney transplant because they had been sensitized as a result of red blood cell transfusions, nor the health outcomes of individuals with End Stage Renal Disease (ESRD) who were never offered the option of kidney transplantation or failed to consider that option because of sensitization due to red blood cell transfusions. Transfusion avoidance is necessary to preserve patient options for the spectrum of ESRD treatment modalities. This is even more pronounced among African Americans who have a higher likelihood of being sensitized and a lower probability of finding a suitable matching organ. From an economic perspective, the Medicare ESRD program benefits from facilitating successful kidney transplantation because that modality is the most cost-effective ESRD therapy option. Unlike the suggestion at the January 19, 2011 MEDCAC meeting, Donor Specific Transfusion strategies are not a routine way to preserve access to transplantation for kidney transplant candidates who have been sensitized because of blood transfusions. There are no contemporary data culled in the present era of transplantation that identify populations of transplant candidates who would benefit from such an approach. Even if they were effective, such transfusions are not universally available, and thus such a strategy potentially accentuates disparities and access to transplantation.

Red Blood Cell Transfusions and Safety of Kidney Patients

Unlike the suggestion at the January 19, 2011 MEDCAC meeting, red blood cell transfusions are not an acceptable alternative to ESA treatment for the treatment of anemia of CKD. In contrast to oncology patients and patients in the acute care setting, individuals on dialysis experience long term blood loss because of trapped blood in the dialyzer and tubing, and are at increased risk for bleeding due to the use of anticoagulants. Replacing these losses via transfusion carries risks that are specific to kidney patients, such as hyperkalemia, in addition to the possible exposure to blood borne pathogens that transfusions present. Transfusion may lead to congestive heart failure, particularly in the elderly CKD patient. The administration of many red blood cell transfusions over a prolonged period can eventually lead to iron overload in patients with reduced kidney function.

With the above considerations in mind, the National Kidney Foundation urges CMS to reaffirm the Proposed Decision Memorandum for Treatment of Anemia in Adults with CKD.

Lynda A Szczech, MD
President
National Kidney Foundation, Inc.

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April 15, 2011

From:
Robert Bazemore, Jr.
President, Centocor Ortho Biotech Inc
800 Ridgeview Drive
Horsham, PA 19044

To:
Louis B. Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services (CMS)
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with Chronic Kidney Disease (CKD) Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N)

Dr. Jacques:

On behalf of Centocor Ortho Biotech Products, L.P., I am pleased to submit comments on the proposed decision by CMS to not issue a National Coverage Determination for ESAs for treatment of Anemia in Adults with CKD including patients on dialysis and not on dialysis. Centocor Ortho Biotech Products, L.P. concurs with CMS’s decision to not issue a national coverage determination based on the currently available evidence.

Centocor Ortho Biotech Products, L.P. markets PROCRIT® (epoetin alfa) for treatment of anemia in patients with CKD not on dialysis. Epoetin alfa is a manufactured form of a naturally occurring hormone (erythropoietin) administered by intravenous or subcutaneous injection to stimulate bone marrow production of red blood cells. Clinical studies and approximately 20 years of clinical experience have demonstrated that when used according to the approved label, epoetin alfa, one of two ESAs currently approved by the United States Food and Drug Administration (US FDA), effectively treats anemia associated with chronic renal failure.

Preservation of coverage for ESAs across the continuum of CKD is consistent with the core concept of person-centered treatment. ESAs provide an important treatment option for patients with anemia associated with CKD when transfusion avoidance is a clinically important goal.

The attached clinical white paper summarizes key elements of Centocor Ortho Biotech’s position and provides comments on the proposed decision memorandum for ESAs in anemia of CKD. It supplements our previous white papers, which were submitted for the Medicare Evidence Development Coverage Advisory Committee meeting on January 19, 2011 and the National Coverage Analysis (NCA) opened on June 16, 2010. The previously submitted white papers are also attached for reference. The attached white papers summarize the evidence supporting the importance of ESAs as a treatment option in patients with anemia associated with CKD.

Centocor Ortho Biotech, LP supports the following key points (details are provided in the attached clinical white paper):

1. The continuum of chronic kidney disease, which includes patients on dialysis and those not yet on dialysis, is frequently complicated by anemia and potential blood transfusion requirements.
2. The decision to administer ESA treatment should only occur after the physician and patient have carefully evaluated the patient’s unique clinical situation. Treatment should only be considered when the patient’s hemoglobin is less than 10 g/dL, when the anemia is chronic and clinically relevant, and when transfusion avoidance is a clinically important goal. Individualized care needs in anemia management are highlighted by pre-transfusion hemoglobin level which ranged from 5.0-11.9 g/dL in CKD randomized clinical trials.
3. Continued CMS coverage for ESA use in patients with CKD is consistent with the recent decisions of expert panels in different regulatory settings that are supportive of the current ESA label for patients with anemia associated with CKD who are not on dialysis.
4. Preservation of ESA coverage is consistent with recent HHS/CMS policy directives (eg, Shared Decision Making, Elimination of Disparities of Care, and Quality Incentive Program). Furthermore, anemia associated with CKD is a significant unmet medical need with a limited range of treatment options, particularly among African-Americans and women. Consequently, restrictions on ESA use for the treatment of CKD-associated anemia may have a disproportionate impact on these groups.

I hope you find the attached clinical white paper helpful. Please do not hesitate to contact me if you need more information.

Sincerely,

CC:
James Rollins, MD, PhD
Division Director

Elizabeth Koller, MD
Lead Medical Officer

Kimberly Long,
Lead Analyst

Attachments:

Clinical White Paper Developed for Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N) April 2011

Clinical White Paper Developed for MEDCAC regarding Erythropoiesis Stimulating Agents for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis: The Impact of ESA Use on Renal Transplant Graft Survival (CAG 00413N) December 2010

Clinical White Paper Developed for National Coverage Analysis for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N) July 2010

PROCRIT® full prescribing information

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Re: AAKP’s Comments on Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG # 00413N)

Dear Dr. Jacques and other members of the Coverage and Analysis Group:

AAKP applauds you for your proposed decision to not issue a national coverage determination for erythropoiesis stimulating agents (ESAs) for the treatment of anemia in adults at all stages of chronic kidney disease.

We appreciate the opportunity to provide comments to support a final decision memorandum that no coverage determination is appropriate.

Anemia in Renal Disease-Etiology

The proposed decision memorandum correctly highlights that there are multiple causes of anemia in patients with renal disease.¹ In addition to erythropoietin deficiency, the memorandum highlights an extensive variety of other factors, among which is the effect of uremia on erythropoiesis, gastrointestinal blood loss, iron deficiency and resistance to erythropoietin. Essentially, inflammation and chronic co morbid conditions create a number of events that downgrade hematopoietic precursors availability and ability to respond to stimulation.²

It is strongly postulated that this latter series of conditions explains the observation that in chronic kidney disease, patients on the largest doses of ESAs had worse outcomes. This was noted in the CHOIR study published in 2006, an intent to treat trial that randomized chronic kidney disease patients into two arms, 715 subjects in one arm, with a target hemoglobin of 11.3 g/dL vs. 717 in the other, with a target hemoglobin of 13.5 g/dL. Approximately 50% of the patients were diabetic. In the patients who achieved their target goals the weekly epoietin-alpha dosage was 6276 units and 10,694 units. ESA dosage was actually higher if the target hemoglobin was not reached, (11,098 and 12,884 units).³ A secondary analysis of the CHOIR trial demonstrated that there was not an increased risk associated with the higher hemoglobin, and that patients who did not achieve their targets had worse outcomes.⁴ It is often impossible to tease out a direct ESA adverse event from the underlying clinical conditions creating resistance. Also, it is well known that a high hemoglobin level per se does not impact outcomes in dialysis patients who are not receiving ESAs, or carefully selected patients whose response to low dose ESA is strong.⁵

Thus, the existing clinical evidence can only suggest that ESA dosing is predictive of a poorer prognosis because it is a function of the concurrent morbid events that interfere with erythropoiesis, not erythropoiesis itself.⁶ Without new direct proof that ESAs are toxic in renal patients who have hemoglobin levels in the range from 10 – 12 grams,⁷ proof that contradicts the registration papers used by the FDA to approve erythropoietin-alpha use in 1989, darbepoetin in 2001, and more recently, recommendations made by an FDA advisory committee October 18, 2010, there is not a basis for issuing a national coverage determination.

Blood products vs. ESAs

It is not justifiable to compare blood products triggers across disease spectrums, nor between patients treated on an inpatient, outpatient, or critical care setting.⁸ Too many unique characteristics of these individual populations of patients confound the ability to make any logical inferences. This discussion will therefore be limited to the CKD population.

Many clinicians recall the early days of dialysis therapy, when fatigue and weakness contributed to the poor levels of functioning for dialysis patients. Dialysis in those days was often supplemented by blood transfusions, and in the 1970s and 1980s, for instance, it was a common site to see dialysis patients receiving blood in the dialysis facility. In addition, many patients required multiple blood transfusions because of chronic arteriovenous malformations or other gastrointestinal problems.⁹ Dialysis patients chronically lose blood,¹⁰ and not repleting it either through blood infusion or blood cell stimulation leads to fatigue, weakness and poor function. Yet, as is correctly pointed out in this memorandum, there is a paucity of well-defined clinical trials that look at hard outcomes related to blood transfusions.¹¹ It is noteworthy that there are no validated hemoglobin thresholds for initiating transfusion. The issue of precisely when to give blood products to a dialysis patient does not satisfy the criteria of clinical equipoise. Many expert physicians felt that prior to the availability of ESAs, it was just too unethical to randomize patients to a profoundly anemic arm (hemoglobin below 7, as suggested in some reviews) that would derive the defined benefit of a blood transfusion, and a placebo group that would not. The emergence of ESAs represented a significant advance in therapy, and likewise, randomizing patients to a blood transfusion vs. erythropoietin-alpha for profound anemia would not satisfy clinical equipoise, either, given the potential adverse effects of blood transfusions.^12-14 Thus, there is a lack of ideal, evidence-based studies.

The issue of when to transfuse blood products to a chronic dialysis patient presents a conundrum, and at this point, it is unlikely there will be a randomized, double blind, well-powered study that looks at blood transfusion vs. a sustained low hemoglobin. It seems logical that no patient with ESRD is willing to be part of the study arm that has the critically low hemoglobin. It is unlikely that this will change in the foreseeable future, and thus you are to be applauded for not issuing an NCD. We strongly endorse this position in the final memorandum.

KDQOL

In keeping with the objectives of the Institute of Medicine to provide patient centered medical care, it is essential to assess quality of life. However, this assessment is admittedly difficult, and there have been conflicting reports in many large clinical trials. For instance while the CREATE study demonstrated a difference in KDQOL between two targeted hemoglobin ranges,¹⁵ the CHOIR study did not.¹⁶ The reason why it is so difficult to equate quality of life with anemia is that anemia is only one of many factors that affects quality of life in patients with advanced CKD or who are on dialysis. We do know that patients presenting with CKD have a lower QOL compared with the general population,¹⁷ and this varies with the timeliness of the referral, the socioeconomic status and the level of education in addition to the hemoglobin concentration.¹⁸ Many of the patients who present to dialysis have underlying cardiac disease. Diabetes is present in 44.5 percent of incident dialysis patients,¹⁹ and generally kidney disease nears end stages only after diabetes has become advanced. Furthermore, chronic kidney disease patients have increased levels of inflammatory markers.^20,21 Cytokines are factors that respond to an inflammatory stimulus, be it a chronic disease,²² heart failure,²³ insulin resistance,^24,25 malnutrition²⁶ or a smoldering infection.²⁷ These cytokines interfere with the erythropoietin response at several levels.²⁸ In addition, the presence of underlying co-morbid disease states and the attendant inflammation also interfere with well being, as is reflected on quality of life surveys. That it is not possible to clearly tease out the varied causes for an abnormal quality of life survey is reflected in the variability between studies.

AAKP feels that while the quality of life is a critical factor that should be considered when determining drug-dosing targets, evidence-based studies fail to confirm the role of ESAs because of multiple confounding factors. We know that patients with higher hemoglobin levels score better on the physical domains of the QOL questionnaire,²⁹ and there is evidence that anemia management improves fatigue.^30,31 But, there is also evidence that the inflammatory status modulates the QOL responses independent of hemoglobin status. Thus, decisions regarding the use of ESA in CKD that take into account the need to preserve the patient’s quality of life will vary on a case by case basis. The patient and family must participate with their physician in the shared decision making process.

Thus, it is not possible to provide sufficient evidence to issue a NCD that can fully cover the quality of life needs of an individual patient, and again AAKP strongly endorses that no final determination be made.

Respectfully,

Carolyn G. Price, AAKP President

Paul Conway, Vice President, Board of Directors, Chairman of Public Policy Committee

Stephen Z. Fadem, MD, FACP, FASN
Medical Advisory Board Co-chair

Amy Friedman, MD, FACS
Medical Advisory Board Co-chair

REFERENCES

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April 13, 2011

Louis Jacques, MD
Director, Coverage Analysis Group
Office of Clinical Standards and Quality,
Centers for Medicare and Medicaid Services
Mailstop S3-02-0
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N)

Dear Dr. Jacques,

The Renal Physicians Association (RPA) is the professional organization of nephrologists whose goals are to ensure optimal care under the highest standards of medical practice for patients with renal disease and related disorders. RPA acts as the national representative for physicians engaged in the study and management of patients with renal disease.

We are writing to offer comments on the Proposed Decision Memo (PDM) on ESA use in chronic kidney disease (CKD) patients referenced above. RPA supports CMS’ decision to not issue a national coverage determination (NCD) in this area. We believe this is a reasonable and prudent policy decision that reflects current clinical evidence and appropriately balances our mutually shared patient safety concerns with the imperative to provide the most effective patient care possible. Our comments will first discuss the evidence cited in the PDM via the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) process and how we believe it offers an incomplete portrayal of the current impact of ESA use in kidney patient care. We will also outline why we believe that the Agency’s proposal to not issue an NCD is the right decision.

Evidence Cited in PDM and MEDCAC

While RPA commends CMS for reaching what we believe is the correct conclusion in not issuing an NCD, we continue to be concerned that the evidence and literature outlined in the PDM maintains its focus on the narrowly defined segment of data that emanated from MEDCAC Technical Assessment (TA). Without completely restating our comments on the TA, in short, we noted that: (1) the parameters for the TA were structured such that dated literature of seemingly little relevance could be included, while more recent and relevant evidence pertaining to CKD care was excluded; (2) the negative impact of transfusions on potential candidates for transplantation was undervalued if not dismissed; and (3) the MEDCAC process in general did not allow for participation by key relevant knowledge centers such as the United Network for Organ Sharing (UNOS) and the United States Renal Data System (USRDS). As stated in many communications RPA has submitted to CMS and predecessor agencies over the last 30 years, we are extremely sympathetic to the competing priorities that must be balanced in Medicare coverage policy development; however, in this instance, it is our belief that the process was less than optimal.

RPA Support of CMS Proposal

RPA believes that CMS’ proposal to not issue an NCD is appropriate, based on our view that the present policy status quo represents the correct policy for the current point in time. Over the past 15 years there have been a number of policy revisions and advances in clinical literature and understanding that have shaped and informed where the kidney care community is today. These include but are not limited to; (1) the Hematocrit Measurement Audit (HMA) of 1997; (2) the EPO Monitoring Policy (EMP) of 2004; (3) the CHOIR and CREATE studies of 2007-2009 that shed light on cardiac-related safety concerns for patients at high hemoglobin levels (targeting Hb at 13 Gm/dL and achieving Hb over 12 by use of ESAs for both dialysis and pre-dialysis CKD patients); and (4) the implementation of the ESRD Prospective Payment System (PPS) in 2011. The cumulative impact of these events has been or is expected to be reduced use of ESA therapy, particularly in patients near the higher end of the 10-12 Hb range. These circumstances form the basis of our opinion that the current policy strikes the right balance between addressing patient safety concerns and preserving access for CKD patients to the substantial benefits of ESA therapy. It is also RPA’s belief that alignment of ESA coverage policy with the recent decision of the Food and Drug Administration’s Cardiovascular and Renal Drug Advisory Committee (CRDAC) to not recommend a label change would avoid unnecessary confusion for practitioners, local carriers, and other stakeholders.

Finally, RPA urges CMS to continue to preserve the ability of doctors and patients to consider together the risks and benefits of ESAs, and to make individualized patient care decisions about ESAs or other therapies one at a time at the bedside. Appropriate interactions of this nature would incorporate not only the physician’s clinical expertise but also the patient’s preferences, perceptions, and resulting quality of life. An effective process for determining appropriate administration of ESAs to kidney patients must include a discussion of the risks and benefits of ESA therapy.

As always, we welcome the opportunity to work collaboratively with CMS in its efforts to improve the quality of care provided to the nation’s kidney patients, and we stand ready as a resource to CMS in its future endeavors. Any questions or comments regarding this correspondence should be directed to RPA’s Director of Public Policy, Rob Blaser, at 301-468-3515, or by email at rblaser@renalmd.org.

Sincerely,

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I am very concerned about any change to the current recommendations for a change in the Hb range of management. For years I have argued that the range has been made to narrow (was 11-12 per NKF and then 10-12 g/dL per FDA guidelines) and that there is absolutely no data that states that patients with Hb < 13 g/dL using low ESA doses of epoetin alfa, darbepoetin, or any other erythropoietic stimulating agent are harmed by such treatment. The TREAT study did not define for me how to treat my anemia patients whether pre-dialysis or after they need renal replacement therapy. On the other hand, use of large doses of ESA to achieve a Hb > 10 g/dL in a hyporesponsive patient is probably harmful, in part because the physician forgets to look for the explanation of the hyporesponse.

I have argued for the past 20 years that one treats a patient and his symptoms and not some number. Many of my patients with CKD not on dialysis have complained that they feel less vigorous when their HB is maintained at 10-12 than it was when I could maintain it higher.

Going to a lower Hb range of 9-11 g/dL is going to make more of my patients symptomatic, particularly if they lead an active life style or are still working. It will also increase transfusion rates which will have a negative effect on our patients in terms of transplantation.

I have been active in this area for years and believe that the “safety” issue has been overblown. Absolutely we should not target Hb levels > 13 g/dL in any CKD/ESRD patient unless the patient does so spontaneously (SMALL PERCENTAGE OF PATIENTS). We do not phlebotomize such patients unless they have polycythemia vera.

Listed below are some papers I have published. throughout my career I have focused on balancing iron and ESA, being cost-effective, and being pro patient. Any lowering of the current HB range to lower values will have a negative impact on the quality of our patients' lives.

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Dear Members of the Committee:

I laud the Committee’s proposed decision not to render a national coverage determination (NCD) for the use of erythropoiesis stimulating agents (ESAs) for treatment of anemia in adults with CKD. As medical director of a small, hospital based unit, I recognize the importance of ESAs in the ongoing management of hemodialysis patients.

I respectfully disagree with the Committee’s commentary on the status of the evidence regarding the effects of ESAs on dialysis patients’ health related quality of life (HRQoL). Although admittedly, the rigor of studies performed in the late 1980’s may not conform to contemporary research standards, I do believe that the data demonstrate a convincing effect. Moreover, in the context of my clinical practice, I observe daily the impact of ESA therapy on vitality, productivity and overall well being, particularly among high functioning patients.

In that light, I and many of my colleagues recognize the need to individualize anemia therapy to patient circumstances. The proposed withholding of a national coverage determination would enable us to continue such practice without the constraints of a one-size-fits all approach to anemia. I fear that a more restrictive NCD would confront our small facility, and others like it, with the undesirable choice between provision of sub-optimal patient care and financial non-viability.

Whereas I agree with the Committee that clinical trials of ESAs were not designed to study transfusion avoidance as an endpoint, I believe the secular trend data those demonstrating a dramatic reduction in use of transfusion beginning concurrently with ESA market availability in this regard are incontrovertible. Judicious use of ESAs is therefore essential to promote patient well being without incurring the unintended consequences of transfusion vis-à-vis blood borne infections, iron overload syndromes and allo-sensitization.

I therefore urge the Committee to follow through with its decision to withhold a national coverage determination for the use of erythropoiesis stimulating agents for treatment of anemia in adults with CKD.

Sincerely,

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Dialysis Patient Citizens (DPC) would like to thank the Centers for Medicare and Medicaid Services (CMS) for its recent decision not to issue a National Coverage Determination (NCD) for the use of erythropoiesis stimulating agents (ESAs) to manage anemia in patients who have chronic kidney disease (CKD). We believe this is a positive move for kidney patients because it places no extra barriers for patients and physicians to make decisions about the treatment of anemia. With over 22,000 members, DPC is America’s largest dialysis patient organization. On a wide variety of issues we seek to ensure the patients’ point of view is heard by decision makers.

Quality care requires a patient-centered approach, which the Institute of Medicine defines as “respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.” While we agree that science and clinical research should be used to promote and guide best practices that protect patients’ health and safety, we also believe that physicians in consultation with their patients should have the autonomy to determine the most appropriate course of treatment. DPC believes that financial factors should not influence physicians’ decisions to recommend the most optimal course of therapy. Physicians should discuss with their patients all the benefits and risk factors associated with using ESAs to treat anemia in kidney patients, as well as the risks of forgoing ESA therapy, so patients can make well-informed decisions. The decision to not issue an NCD falls very much in-line with our goal to ensure flexibility in the physician and patient decision making relationship.

While we agree with the decision by CMS to not issue an NCD at this time, we do have serious concerns with some of the assertions discussed in the proposed decision memo.

**Quality of Life**
When considering whether to regulate the use of ESAs for patients with CKD, it is important to take into consideration patients’ self-reported quality of life. While we understand how patients feel or the quality of life they experience at different hemoglobin levels is difficult, if not impossible, to measure, this does not give reason to dismiss it. Avoidance of a blood transfusion, while important, is not the only issue patients experience with lower hemoglobin levels. Patients have attested to “feeling” changes in their hemoglobin, and when their hemoglobin is lowered, they experience greater fatigue, weakness and inability to think clearly, among other symptoms. Patients have reported this experience with even the slightest lowering of their hemoglobin. Any future decisions reached by CMS should fully consider patients’ self-reported experiences.

**Consistency among Coverage Decisions and Quality Programs**
While we fully support the decision not to issue an NCD at this time, we urge CMS to ensure consistency throughout local coverage determinations (LCD) related to ESAs to make sure regional disparities are not made worse. Additionally, for dialysis patients the measurement of hemoglobin levels has been included in the end-stage renal disease (ESRD) Quality Incentive Program (QIP). In order for the QIP program to be effective LCDs will need to be in alignment.

**Transfusions and Transplantation**
Transplant centers have different requirements patients must meet in order to be considered for the kidney transplant waiting list; however, anemia management and the avoidance of transfusions is widely looked at as a determining factor. Patients know from experience that antibody levels in those who have received blood transfusions are scrutinized prior to a decision being made on whether or not the patient is a good match for a particular kidney transplant. Any changes to coverage and reimbursement of ESAs could impact a patient’s anemia, their ability to get on the kidney transplant list and the length of time a patient lingers on the list.

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The American Society for Histocompatibility and Immunogenetics (ASHI) supports the Proposed Decision Memorandum issued by CMS in regard to the use of Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N). ASHI agrees that a national coverage determination should not be made at this time. We would like to reiterate our position that blood transfusions can sensitize patients with CKD to HLA antigens and stimulate the production of HLA specific antibodies. Sensitization is a substantial barrier to renal transplantation, which is the preferred treatment for patients with end stage renal disease. Sensitization has been shown to increase the waiting time for a compatible organ transplant and decrease allograft survival. Increased waiting time leads to increased time on dialysis with associated costs and mortality. Decreased allograft survival leads to a further increase in sensitization and additional costs for re-transplantation. There is little current data on the incidence of sensitization induced by transfusion because, since their introduction, ESAs have been widely used to treat anemia in CKD patients and thereby avoid or minimize the risk of sensitization from transfusions. However, the historical data that prompted the widespread use of ESAs in ESRD patients clearly showed an association between transfusions and sensitization. Given the increased morbidity and mortality that ESRD patients might incur through transfusion-induced sensitization, the members of ASHI believe that the benefits of ESAs in patients with CKD far outweigh any potential health risks.

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April 7, 2011

Kimberly Long
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244-1850

Elizabeth A. Koller, M.D.
Centers for Medicare and Medicaid Services
Mail Stop C1-09-01
7500 Security Boulevard
Baltimore, MD 21244-1850

Dear Ms. Long and Dr. Koller:

On behalf of Kidney Care Partners, I would like to thank you for the opportunity to comment on the “Proposed Decision Memorandum for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis CAG #00413N” (Proposed Decision Memo). KCP is an alliance of members of the kidney care community that includes patient advocates, dialysis care professionals, providers and facilities, and manufacturers dedicated to improving the quality of care for individuals with both Chronic Kidney Disease (CKD) and irreversible kidney failure, known as End-Stage Renal Disease (ESRD).

KCP supports the Centers for Medicare and Medicaid Services’ (CMS’) decision not to issue a National Coverage Determination (NCD) at this time for ESAs for treatment of anemia in adults with CKD including patients on dialysis and patients not on dialysis. KCP is committed to the goals of safe, appropriate, and high-quality care for ESRD patients. Any anemia management policy, including coverage rules, should be well balanced, well grounded, and well considered. KCP appreciates the Agency’s review of the complex issues surrounding anemia management and important questions that have arisen about the optimal use of ESAs in patients with CKD. While we urge CMS to finalize its decision not to issue an NCD, we are concerned that the Proposed Decision Memo makes assertions about the evidence that could be misinterpreted and does not recognize the evidence related to the impact of ESAs on patient quality of life or access to transplantation. Accordingly, we urge the Agency to acknowledge that Local Coverage Determinations (LCDs) in dialysis use would not be appropriate.

KCP is pleased that CMS did not rush to develop an NCD given the current state of the data. Our members support this approach because it will allow the Food and Drug Administration (FDA) to continue its efforts to evaluate ESAs. Most importantly, it maintains consistency among the various policies that relate to the administration of ESAs. Even though we urge the Agency to maintain the conclusion outlined in the Proposed Decision Memo, we are concerned that the evidence review as described in the Proposed Decision Memo could be read to encourage Medicare contractors to revise their current LCDs for ESA use in pre-dialysis or even initiate restrictions in dialysis use, which could lead to inconsistent treatment standards for patients and have a negative impact on their care.

KCP supports the proposal not to issue an NCD because it maintains consistency among coverage policy, the Quality Incentives Program (QIP), and the ESA Monitoring Policy (EMP), as well as the current FDA-approved label. The anemia management measures adopted as part of the QIP are based upon the current FDA label, as is the current EMP. Any NCD that would deviate from current policies would lead to inconsistencies in these policies and make compliance with them extremely difficult. Inconsistent policies could create confusion among beneficiaries that could negatively impact their treatment.

Even though we applaud the Agency’s proposal not to issue an NCD at this time, KCP is concerned that the Proposed Decision Memo could lead local contractors to initiate restrictive LCDs in dialysis use. A patchwork of LCDs would threaten the quality of care beneficiaries receive and create serious compliance issues for dialysis facilities and providers. The Agency’s finding that there is not sufficient data to support an NCD also argues against changing current coverage policies at the local level as well.

Physicians and their patients are in the best position to make decisions about the appropriate treatment protocols based on the emerging scientific data and the individual patient’s characteristics and needs. Physicians respond to changes in clinical evidence without unnecessary regulatory intervention. If there were divergent local policies regarding ESA coverage, a beneficiary’s access to appropriate anemia management would be based upon coverage policies rather than the physician’s best judgment about his/her patient’s medical needs. In addition, beneficiaries who travel could find that they would not be able to follow the treatment protocols agreed to with their physicians if they travel to a facility governed by an LCD with different coverage parameters than those in their hometown. Therefore, KCP strongly urges CMS in its final decision memorandum to discourage the adoption of LCDs in dialysis that differ from the FDA-approved label and that would be inconsistent with other CMS policies.

KCP remains committed to patient safety and agrees that CMS should evaluate new evidence that may raise questions about any treatment protocol. When considering such evidence, however, it is critically important that the Agency examine all relevant data as a whole and not focus on only narrow aspects of research. We are troubled that the Proposed Decision Memo does not recognize the important role ESAs play in improving beneficiaries’ quality of life and also does not acknowledge the unanswered questions related to the impact of ESAs on beneficiaries’ ability to qualify for transplants. We strongly encourage CMS to recognize in the final memorandum that if the Agency sought to issue an NCD in the future it would need to review all available data on the impact of ESAs on beneficiary quality of life and the ability to qualify for transplant.

Policies regarding ESAs should focus on patients and recognize quality of life outcomes as an important consideration. Any statements from CMS regarding the impact of ESAs on patient quality of life should be firmly rooted in beneficiary experiences. Individuals with kidney failure often have severe anemia and experience lower energy in their daily life. In 1991, 84 percent of individuals with kidney failure and on dialysis had a hemoglobin level of 11 g/dL or less; that number fell to 20 percent with the broader prescribing of ESAs by physicians. See U.S. Renal Disease System, USRDS 2008 Annual Data Report 93 (2008). Researchers have found a correlation between ESA use and higher energy or less fatigue and with better physical function in both the predialysis and dialysis CKD population. See, e,g., S.R. Gandra, et. al, “Impact of erythropoiesis stimulating agents on energy and physical function in nondialysis CKD patients with anemia: a systematic review,” 55 Am. J. Kid. Dis. 519-34 (2009); K.L. Johansen, et. al, “Systematic review and meta-analysis of exercise tolerance and physical functioning in dialysis patients treated with erythropoiesis-stimulating agents,” 55 Am. J. Kid. Dis. 535-48 (2010).

Additionally, ESAs have reduced the rate of blood transfusions in the dialysis population. USRDS at 90. Blood transfusions may limit the ability of beneficiaries to qualify for transplant – the only cure for kidney failure. Blood transfusions can sensitize individuals and make it more difficult for them to obtain a transplant. This sensitization may result in longer wait-list times or even disqualification for being considered for a transplant. Although the issue of blood transfusions was discussed during the most recent Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting, the panel did not elicit information about the impact of blood transfusions on the ability of patients to quality for kidney transplant. Additionally, we are concerned that the Proposed Decision Memo does not include the available peer-reviewed literature or available data from national registries that describe the significant risks associated with blood transfusions, most notably, the risk of sensitization.

We urge CMS to clarify in any final memorandum the need for further review and evaluation of these two important areas.

KCP strongly supports the Agency’s decision not to issue an NCD for ESAs for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis. KCP is committed to the goals of safe, appropriate, and high-quality care for ESRD patients. We recognize that clinical practice has and will continue to evolve. The use of any treatment protocol should promote patient safety and be based upon the best available science. In addition, coverage policies should strive to evaluate all available data and answer all relevant questions that impact the treatment of beneficiaries. The Agency should also strive to ensure that such policies are consistent with quality, payment, and FDA-approval policies as well so that beneficiaries are assured that the care they receive is based upon thoughtful and consistent evaluations and decision-making.

We appreciate your review of these comments and would welcome the opportunity to discuss our concerns in more detail with you and your staff. Please do not hesitate to contact Kathy Lester at 202-457-6562 if you have any questions.

Sincerely,

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April 6, 2011

Dennis Wagner
Acting Director
Office of Clinical Standards and Quality
Centers for Medicare & Medicaid Services (CMS)
7500 Security Boulevard
Baltimore, MD 2 1244

RE: Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N)

Dear Mr. Wagner:

The CMS National Coverage Determination (NCO) process serves both as the gate-keeper for beneficiary access to appropriate healthcare services and as the guardian of the Medicare Trust Fund. These critical fiduciary duties, carried out through the NCO process, by their nature, have far-reaching life and death consequences. This is a daunting and sacrosanct task and, therefore, maintaining the integrity of how NCO dec isions are made is paramount.

Generally, CMS applies the standard of "reasonable and necessary" by determining whether the benefits outweigh the risks. It is dismaying and disconcerting that nowhere in the proposed decision memo is there evidence or mention that benefits outweigh the risks of epoetin. Incongruously, in terms of benefits, CMS found no clinical benefits "other than increasing hemoglobin," which they recognize is merely "a putative intermediate clinical surrogate." The intermediate surrogate endpoint of raised hematocrit has not been correlated with hard clinical endpoints such as improved survival or improved quality of life and, therefore, has not been shown to be of clinical benefit. Equally alarming, in terms of risks, CMS ignores FDA findings regarding the safety of epoetin which was based on results of failed randomized controlled trials. FDA has concluded that ESAs pose a danger to patients if hematocrits are elevated above 36%. Their findings led them to restrict epoetin use by issuing an urgent Black Box warning and important patient safety education materials.¹ I fear CMS'non-decision, almost certainly, will undermine the impact of FDA's epoetin safety warning.

How can CMS continue to ignore the risks that FDA has already recognized and deemed sufficient to take action? How can CMS continue to cover an expensive treatment with no apparent clinical benefit?

As the person who requested the NCO many months ago, I am perplexed and baffled by the CMS' rationale supporting a non-decision decision. It makes no sense.

Sincerely,

CC: Paul McGann, M.D., Acting CMS Chief Medical Officer
James Roll ins, MD, PhD Division Director
Louis B. Jacques, MD Director, Coverage and Analysis Group

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