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

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Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, and reduced survival) derived from clinical trials in several cancer and non-cancer populations prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). We reviewed a large volume of scientific literature, including basic science research, to see if these safety signals seen in randomized controlled trials could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. In doing so we proposed conditions of coverage based on expression of erythropoietin receptors. The scientific understanding of this mechanism is a subject of continuing debate among stakeholders, continues to evolve, and can only be resolved through additional studies. We also reviewed a large volume of comments on the use of ESAs in myelodysplastic syndrome (MDS), a pre-malignant syndrome that transforms into acute myeloid leukemia (AML) in many patients. Though we continue to be interested in these specific issues, this final decision does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease, and we have narrowed the scope of this final decision to make no national coverage determination (NCD) at this time on the use of ESAs in MDS. CMS has determined that there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include: any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis; the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers; the anemia of cancer not related to cancer treatment; any anemia associated only with radiotherapy; prophylactic use to prevent chemotherapy-induced anemia; prophylactic use to reduce tumor hypoxia; patients with erythropoietin-type resistance due to neutralizing antibodies; and anemia due to cancer treatment if patients have uncontrolled hypertension. We have also determined that ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is only reasonable and necessary under the following specified conditions: The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is < 10 g/dL (or the hematocrit is < 30%). The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/three times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is < 30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥ 1g/dL (hematocrit ≥ 3%). For patients whose hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains <10 g/dL after the 4 weeks of treatment (or the hematocrit is <30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises <1 g/dl (hematocrit rise <3 %) compared to pretreatment baseline by 8 weeks of treatment. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit > 3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10 g/dL (or the hematocrit is < 30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen. Local Medicare contractors may continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD.

Decision Memo: To: Administrative File: CAG #000383N The Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions From: Steve Phurrough, MD, MPA Director, Coverage and Analysis Group Louis Jacques, MD Director, Division of Items and Devices Maria Ciccanti, RN Lead Analyst Kimberly Long Analyst Elizabeth Koller, MD, FACE Medical Officer Shamiram Feinglass MD, MPH Medical Officer Subject: Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions Date: July 30, 2007 I. Decision Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, and reduced survival) derived from clinical trials in several cancer and non-cancer populations prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). We reviewed a large volume of scientific literature, including basic science research, to see if these safety signals seen in randomized controlled trials could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. In doing so we proposed conditions of coverage based on expression of erythropoietin receptors. The scientific understanding of this mechanism is a subject of continuing debate among stakeholders, continues to evolve, and can only be resolved through additional studies. We also reviewed a large volume of comments on the use of ESAs in myelodysplastic syndrome (MDS), a pre-malignant syndrome that transforms into acute myeloid leukemia (AML) in many patients. Though we continue to be interested in these specific issues, this final decision does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease, and we have narrowed the scope of this final decision to make no national coverage determination (NCD) at this time on the use of ESAs in MDS. CMS has determined that there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include: any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis; the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers; the anemia of cancer not related to cancer treatment; any anemia associated only with radiotherapy; prophylactic use to prevent chemotherapy-induced anemia; prophylactic use to reduce tumor hypoxia; patients with erythropoietin-type resistance due to neutralizing antibodies; and anemia due to cancer treatment if patients have uncontrolled hypertension. We have also determined that ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is only reasonable and necessary under the following specified conditions: The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is < 10 g/dL (or the hematocrit is < 30%). The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/three times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is < 30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥ 1g/dL (hematocrit ≥ 3%). For patients whose hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains <10 g/dL after the 4 weeks of treatment (or the hematocrit is <30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises <1 g/dl (hematocrit rise <3 %) compared to pretreatment baseline by 8 weeks of treatment. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit > 3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10 g/dL (or the hematocrit is < 30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen. Local Medicare contractors may continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD. II. Background In this section in our proposed decision memorandum, we described the technological developments that gave rise to the use of genetically engineered (recombinant) erythropoietin and related ESAs (see appendix A). We then described the anemias for which ESAs are prescribed in oncologic conditions, with an emphasis on solid tumors that constituted the majority of tumors in the studies upon which FDA approval was based. We refer the reader to Appendix A for a detailed discussion of the biochemical background of ESAs and their current usages. We will summarize these points here. Erythropoietin is a glycoprotein produced primarily in the kidney and to a lesser extent in the liver. In the classic hormone pathway, erythropoietin regulates erythrocyte production by stimulating red cell production in the bone marrow. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin has resulted in anemias in several disease processes to include renal disease, cancer treatment, other chronic diseases and use of certain drugs. To combat these anemias, several forms of recombinant human erythropoietin have been developed. The two currently available in the US are epoetin and darbepoetin alpha. Recombinant erythropoietin was initially used as a replacement for missing hormone in select patients with anemia of end-stage renal disease. Use of ESAs has been extended to a variety of anemic conditions including the anemia of chronic renal disease (not yet on dialysis), anemia secondary to chemotherapy of solid tumors, anemia secondary to AZT therapy, anemia in myelodysplastic disorders and prophylactic use during the perioperative period to reduce the need for allogenic blood transfusions. In cancer, anemia occurs with varying degrees of frequency and severity. It is most frequent in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment. Oncologic anemia occurs by a variety of mechanisms. Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B-12) essential for the red cell production. Antibodies in certain tumor types may cause increased erythrocyte destruction through hemolysis. Tumors may cause blood loss via tissue invasion, e.g. gastrointestinal bleeding from colon cancer. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment. In more advanced cases, there may be marrow replacement with tumor or amyloid. Marrow dysfunction can occur, however, even in the absence of frank invasion (Faquin 1992; Mikami 1998). Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization as well as a direct suppression of red cell production. The treatment of cancer may also cause anemia. Radical cancer surgery can result in acute blood loss. Radiotherapy and many cytotoxic chemotherapeutic agents cause marrow suppression to some degree. Damage is due to a variety of mechanisms. For example, alkylating agents cause cumulative DNA damage, anti-metabolites damage DNA indirectly, and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells. Myelodysplastic disorders are a heterogenous group of pre-leukemic diseases characterized by cytopenias due to abnormal hematopoietic differentiation and maturation. The disease may be idiopathic or secondary to chemotherapy or radiation therapy for other disease. The primary defect resides in hematopoietic stem cells. New cases exceed 10,000/year. Transformation to acute non-lymphocytic leukemia occurs in 10 to 40% of patients with idiopathic MDS. Thrombocytopenic bleeding and neutropenic infections contribute to death. Survival at 3 years is approximately 40% for those over 50 (Ma 2007). Transfusion dependence and risk for leukemic transformation appear related to disease severity/diagnostic category. Therapeutic treatment of MDS related anemia requires treatment of the underlying marrow disorder. Treatment in younger patients is allogenic bone marrow transplantation. Treatment with cytotoxic agents has demonstrated limited utility. Supportive care includes transfusions and avoidance/treatment of iron overload. Readers interested in more information may wish to review the discussion of MDS by the National Cancer Institute (NCI) at http://www.cancer.gov/cancertopics . In opening this NCD in March of this year, CMS stated that it would be reviewing the non-ESRD uses of ESAs. In our proposed decision in May of this year, we restricted our proposal to oncologic uses of ESAs. However, as pointed out to us, MDS is not an oncologic condition. Thus, we are making no decision on MDS in this final decision. The level at which anemia requires intervention is not well established. By tradition, patients have been transfused at the hemoglobin level of 7 or 8 g/dl to avoid symptoms and physiologic complications. A transfusion of 2 or more units would result in an increase of at least 2 g/dl of hemoglobin (6 units of hematocrit). Indeed, one of the endpoints for pharmaceutical registration, need for transfusion, employed an 8 g/dl hemoglobin cut-off (FDA Medical Officer Review, Aranesp 2002). Most of these practices, however, are based on empiric observations and not clinical trials. In one of the few studies, Carson et al. found that hip-fracture patients transfused to hemoglobin levels in excess of 10 g/dl did not have more exercise tolerance than non-transfused patients who were transfused after hemoglobin levels dropped to below 8 g/dl or patients became symptomatic (Carson 1998). The British Blood Transfusion Society has delineated the weaknesses in our knowledge base. Their guidelines state that transfusions are indicated in patients with hemoglobin levels less than 7 g/dl and that transfusion should not be undertaken for hemoglobin levels greater than 10 g/dl. They indicate that management of patients with hemoglobin levels between 7 and 10 remains unclear although the hemoglobin threshold for the treatment of patients with co-morbid conditions is probably higher than 7 g/dl. Although they have done so in the past, the College of American Pathologists (CAP) no longer issues transfusion practice guidelines. Other groups have developed definitions for anemia and have been cited for these definitions, but these definitions cannot be extrapolated into guidelines for oncologic treatment. The World Health Organization (WHO) definitions for anemia were developed for surveillance of anemia due to nutritional deficiency and parasitic infections. The National Cancer Institute (NCI) has information on anemia, but does not issue treatment guidelines (Robin Bason 301-594-9051; NCI anemia information from web). Both the NCI and WHO consider hemoglobin levels less than 6.5 g/dl to be life-threatening. III. History of Medicare Coverage Prior to this National Coverage Analysis, there was no National Coverage Decision (NCD) concerning the use of ESAs for the indications discussed in this Decision Memorandum. Currently, the Medicare benefit for ESAs for end-stage renal disease (ESRD) related anemia is outlined in the Medicare Benefit Policy Manual, Chapter 11, Section 90 and Chapter 15, Section 50.5.2. For other indications, Medicare coverage of ESAs administered incident to a physician service for other indications under Part B is determined by local Medicare contractors. Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage. § 1812 (Scope of Part A); § 1832 (Scope of Part B); § 1861(s) (Definition of Medical and Other Health Services). ESAs fall within the benefit categories specified in 1861(s)(2)(A) & 1861(s)(2)(B) of the Social Security Act. IV. Timeline of Recent Activities Date Action March 14, 2007 CMS opened an internally generated National Coverage Decision (NCD) to evaluate coverage of uses of ESAs in non-renal disease applications. The initial 30-day comment period opened. April 13, 2007 The initial public comment period closed; 69 timely comments were received. May 14, 2007 CMS published the Proposed Decision Memorandum. The 30-day public comment period opened. June 13, 2007 The public comment period on the proposed decision closed. 2641 timely comments were received. V. FDA Status A. Erythropoietin-alpha was the first ESA approved by the FDA for use in renal failure (1989). Subsequently two ESAs were approved for the management of the anemia of cancer treatment (chemotherapy) of non-myeloid neoplastic disease: epoetin (1993) and darbepoetin alpha (2002). B. FDA reviewed results of the Breast Cancer Erythropoietin Trial (BEST) and Henke studies. Concerns regarding an increased rate of tumor progression and increased mortality were incorporated into the Precautions Section of product labeling in 2004. C. FDA convened a meeting of the Oncologic Drugs Advisory Committee 5/4/2004 to discuss safety issue for ESAs. The briefing information and transcript for the meeting is available at www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic. D. In conjunction with the FDA, Amgen issued a “Dear Doctor Letter” regarding the use of ESAs for anemia management in the absence of chemotherapy, which was sent 1/26/2007.(See www.fda.gov/medwatch/safety/2007/safety07.htm#Aranesp) E. Serial FDA ALERTS regarding ESA safety information were issued: 11/16/2006, 2/16/2007, and 3/09/2007. F. FDA strengthened its warning about cardiovascular and thrombotic events in a variety of populations via a BLACK BOX warning. A "black box" warning is the most serious warning placed in the labeling of a prescription medication. FDA included BLACK BOX warnings for tumor progression and decreased survival in cancer patients undergoing cancer treatment. FDA also warned that ESAs are not indicated for anemic cancer patients not undergoing treatment and that mortality is increased when ESAs are used by this population. Specific warnings on the use of ESAs included that they: shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a hemoglobin of greater than 12 g/dL, shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin of greater than 12 g/dL, increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for this population. G. FDA convened a meeting of the Oncologic Drugs Advisory Committee (ODAC) on May 10, 2007 to discuss updated risk information on ESAs for the indication of cancer. The ODAC transcripts were recently posted at http://www.fda.gov/ohrms/dockets/ac/cder07.htm#OncologicDrugs . VI. General Methodologic Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that are used to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, the blinding of readers of the index test and reference test results. Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. VII. Evidence 1. Introduction We are providing a summary of the evidence that we considered during our review. CMS extensively reviewed the body of literature on the use of ESAs in its proposed decision memorandum released on May 14, 2007. ( http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=203 ). We will not review that evidence again in this final decision. We refer the reader to Appendix A for a full discussion. This section presents the agency's evaluation of the evidence considered for the assessment questions: 1. Is the evidence sufficient to conclude that erythropoiesis stimulating agent therapy affects health outcomes when used by Medicare beneficiaries with cancer and related neoplastic conditions? 2. If the answer to Question 1 is affirmative, what characteristics of the patient, the disease, or the treatment regimen reliably predict a favorable or unfavorable health outcome? We will review each of the questions in the context of our proposed individual coverage criteria separately, respond to comments on that recommendation, discuss any new evidence, and provide our response with any proposed changes. Our responses to comments on aspects of the proposed decision other than the proposed coverage criteria are summarized in the Comment Section. Multiple studies have raised significant safety concerns about the potential for ESAs to increase tumor progression and decrease survival in cancer patients. Although some of these were studies of ESAs used during radiotherapy or for anemia of cancerboth off-label usesthe data nonetheless raises concerns about the use of ESAs for all cancer indications to include labeled indications. Because tumor progression has now been seen in some cancer patients, we believe that to demonstrate improved health outcomes, all ESA indications need evidence demonstrating that they do not cause tumor progression and/or decrease survival even if they might decrease transfusions or improve quality of life. In concert with our general methodologic principles (Appendix B), we believe that in most instances, this evidence can only be obtained in randomized controlled trials. Several commenters questioned CMS’ references in the proposed decision to basic science literature rather than solely to clinical trials. We emphasize that the safety signals came from randomized controlled clinical trials. Our review of other literature was to shed light on the possible underlying biological processes that may account for the trial findings. This was not a shift in CMS’ stated preference for methodologically robust clinical evidence in determining whether health outcomes are affected by various technologies. We remain concerned that a number of trials have been terminated, suspended, or otherwise not completedpossibly due to signals of harmand that the existing fund of published evidence may reflect a bias toward ESA use. Transparent public access to clinical trial datasets, as opposed to data summaries, would enhance public confidence in this body of literature. 2. External Technology Assessments Please refer to the Proposed Decision Memorandum for a review of this matter. ( http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=203 ) 3. Internal Technology Assessment Systematic reviews are based on a comprehensive search of published materials to answer a clearly defined and specific set of clinical questions. A well-defined strategy or protocol (established before the results of individual studies are known) is optimal. CMS staff extensively searched Medline (1988 to present) for primary studies evaluating ESA therapy in cancer and related conditions. The emphasis was on studies structured to assess adverse events and mortality. CMS staff likewise searched the Cochrane collection, National Institute for Health and Clinical Excellence (UK) appraisals, and the Agency for Healthcare Research and Quality (AHRQ) library for systematic reviews and technology assessments. Systematic reviews were used to help locate some of the more obscure publications and abstracts. Preference was given to English publications. Because much of the material remains outside the domain of the published medical literature, additional sources were used. CMS examined FDA reviews of the registration trials for epoetin and darbepoetin alpha as well as the FDA safety data for epoetin and darbepoetin alpha. CMS reviewed the transcripts and briefing documents (FDA and pharmaceutical sponsor) from the 2004 FDA Oncologic Drugs Advisory Committee (ODAC) meeting on ESA safety. CMS reviewed the FDA ESA drug safety alerts and label changes. CMS searched the National Institutes of Health (NIH) Clinical Trials.gov database for ongoing/completed trials of ESAs. CMS used internet searches to identify websites with clinical trial results, press releases for clinical trial termination, and U.S. government regulatory action. We catalogued these trials in our proposed decision (Appendix A). Following the release of the proposed NCD on May 14, 2007, we received some additional references, primarily non-Medline publications. We also updated our search and broadened it to be more inclusive for MDS and multiple myeloma. We received over 300 additional citations as comments. Many of these addressed the blood supply, transfusion errors and erythropoietin receptors. We received many articles that duplicated items in our library. We also received numerous non-Medline abstracts. We did not receive any substantive raw data for analysis. The clinical trial tables have been updated to reflect the additional data. Published Trials of ESA Use in Cancer More than 100 papers or abstracts on ESA use in cancer have been published. Most studies have not been structured to assess survival, tumor progression and adverse events. Many studies enrolled patients with a variety of tumors. Others enrolled patients with a single disease, but were not stratified for tumor stage. Many studies included patients on a variety of treatment regimens. Many were not randomized, placebo-controlled trials. Many studies used another ESA as an active control. Most studies did not use fixed ESA doses, instead they titrated doses upward in poor responders without a statistical analysis that took this variability into account. Concomitant iron administration limited to patients in the ESA cohort was sometimes a confounding variable. Study endpoints were hemoglobin thresholds, changes in hemoglobin, transfusion requirements (without a priori definition), or quality of life. Frequently, the hematologic endpoint was a composite based on either a change in transfusion needs or hemoglobin level. Many studies did not declare a primary endpoint. Survival and/or tumor progression, if assessed, were secondary or add on endpoints. No studies presented a priori power calculations for patient number and study duration that would be required to demonstrate clinically significant survival differences for neoplastic diseases. No studies presented a priori methods for the assessment of tumor progression. Stratification of risk by tumor type, tumor stage, treatment modality, ESA dose, or ESA response to dose was not present in any of the studies reviewed. The additional data reviewed following the proposed decision did not change these conclusions (See Tables 2 and 3). 4. Medicare Evidence Development and Coverage Advisory Committee (MedCAC) A MedCAC meeting was not convened for this issue. 5. Evidence Based Guidelines There were no additional guidelines provided to CMS during the comment period. We describe guidelines in Appendix A. 6. Professional Society Position Published Statements CMS received many comments from persons affiliated with various organizations. We distinguished bona fide position statements from professional organizations in part by determining if the author was identified as the president, executive vice president, executive director or equivalent of the society and if the comment was stated to be the position of the society rather than of an individual. All of these commenters disagreed with some provision of the proposed decision. In general, all thought that the decision was too restrictive. Some questioned CMS’ legal authority to make this decision. We have summarized their input in Table 4 of the appendices; the full texts of their comments are available on our website ( http://www.cms.hhs.gov/mcd/viewpubliccomments.asp?nca_id=203 ). All of their comments focused on one of the proposed criteria and we respond to those below where we separately review each of our proposed determinations. 7. Industry comments We received comments from both marketers of ESAs in this country. They presented similar recommendations that supported the following noncovered indications in the proposed decision: Indication 1. Any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding or bone marrow fibrosis Indication 3. Anemia of myeloid cancers (specifically AML/CML, not multiple myeloma) Indication 6. Anemia associated with radiotherapy (primary treatment) Indication 7. Prophylactic use to prevent chemotherapy-induced anemia (in patients who have never suffered from CIA) Indication 8. Prophylactic use to reduce tumor hypoxia Indication 9. Patients with erythropoietin-type resistance due to neutralizing antibodies Indication 12. Anemia due to cancer treatment if patients have uncontrolled hypertension They did not agree with the other proposed noncovered indications: Indication 2. Anemia of myelodysplasia Indication 10. Patients with treatment regimens including anti-angiogenic drugs such as bevacizumab Indication 11. Patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor Indication 13. Patients with thrombotic episodes related to malignancy Furthermore, they recommended several changes to the restrictions on the covered indications: The starting hemoglobin level should be 11 g/dL There should be no maximum dose For patients whose hemoglobin does not rise > 1 g/dL in the 4 weeks, two dose escalations should be allowed Patients with a rapid rise in hemoglobin should have a dose reduction ESA use should be discontinued when the hemoglobin level is 12 g/dL We respond to these below where we separately review each of our proposed determinations. 8. Public Comments Initial comment period: 3/14/2007 - 4/13/2007 We received 70 comments during the initial public comment period. Of the public commenters who furnished this information, 37 were from providers, 5 were from caregivers, 1 was from a patient, 13 were from professional organizations, 7 were from patient advocacy groups, 1 was from a national oncology policy consulting group and 2 were from pharmaceutical companies. Two comments regarding the use of ESAs for renal disease and two related to code assignments are included in the 70; both topics are outside the scope of this NCD. The majority of commenters requested CMS to provide coverage of ESAs for all non-renal FDA approved indications. Several commenter included studies and scientific literature with their comments. Comment period on the proposed decision: 5/14/2007 - 6/13/2007 CMS received 2641 comments on the proposed decision. Several individual commenters submitted multiple comments; in some cases the same comment was submitted more than once by the same commenter. It appears in quite a few instances that many clinical and/or administrative support staff members from a single medical practice submitted comments. Some commenters submitted identical comments. Most commenters did not refer to or provide any scientific or medical evidence that had not already been reviewed in the proposed decision memorandum or that could definitively answer the outstanding safety questions surrounding ESAs. However, we received a comment from Michael Henke, MD, Professor of Medicine/Radio Oncology at the University of Freiburg, Germany, the principal investigator from one of the trials that demonstrated the safety concerns. He states, “I am convinced that ESA treatment negatively affects disease control and survival of head and neck cancer patients.” He further states that confirmed findings (RTOG 99 03 and DAHANCA 10) and his own research (Henke 2003) support this view. Dr. Henke indicated that comparable safety concerns can be assumed for other cancer sites as well, for example, Leyland Jones (2005) and Wright (2007) suggest breast and lung cancer. Many commenters described their current clinical practice or current specialty guidelines. Of the physicians who commented, almost all were self-identified as hematologists and/or oncologists. CMS staff also received comments during meetings with representatives of Amgen, Ortho Biotech-Johnson & Johnson, Genentech, ASCO, US Oncology, Marti Nelson Cancer Foundation, Colorectal Cancer Coalition, and other institutions. Each organization used these meetings to emphasize their formal comments which are available online and summarized elsewhere in this document. Almost all commenters disagreed with some provision of the proposed decision. Some commenters expressed agreement with some aspects of the proposed decision while disagreeing with other aspects. Some commenters did not express approval or disapproval. Thus, the count of commenters is a different number than the count of opinions of the commenters. Consequently, we will provide a summary of the different opinions and not the number of commenters supporting any specific opinions. Myelodysplasia was the subject of the largest number of comments about a specific clinical condition. Commenters also frequently speculated on the effect of the proposed decision on the need for transfusions and the adequacy of the blood supply to meet higher demands. Subjects outside of the scope of this decision Comment Several commenters discussed the use of ESA therapy in the setting of anemia related to kidney disease or other uses that are beyond the scope of the proposed decision. Response We will not address those comments in this decision memorandum. Personal or family member experience Comment Many commenters noted personal, friend, or family experience with ESA therapy. We heard from many cancer patients attesting to the benefit of ESAs regarding their quality of life. Beneficiaries submitted testimonies describing activities that were no longer difficult or impossible as a result of ESA therapy. Family members of beneficiaries receiving ESA therapy expressed concern over the costs of ESAs should CMS no long provider coverage. They expressed anger at Medicare for burdening them with the costs of ESAs. Beneficiaries and family members commented about their belief regarding the benefit and necessity of ESA therapy, adding that they would be forced to find a means to incur the costs. Response CMS carefully reviewed all the concerns submitted to us. We appreciate the comments received from the beneficiaries we serve and their families. We want our beneficiaries to have access to appropriate and quality care. While personal experiences are important and helpful to the Agency in understanding the impact of its decisions, CMS generally gives greater weight to published scientific evidence. Lack of transparency/access regarding primary ESA data Comment Several commenters noted that it has been difficult if not impossible to obtain access to primary data from ESA clinical trials, and that this has made it problematic to have independent analyses of these data. They voiced support for measures that would increase public access to these data. CMS received a comment from Marcia Angell, MD, Senior Lecturer in Social Medicine, Harvard Medical School, Former Editor in Chief, New England Journal of Medicine (NEJM.) who also expressed concern regarding the lack of transparency and access of primary ESA data. She states, “Medicare should have access to all the clinical trial information that the FDA has. Currently, companies seeking marketing approval must submit to the FDA all trials, not just the positive ones, but the agency generally does not share this information without the permission of the sponsoring company. That puts the proprietary interests of drug companies ahead of the public interest. Medicare should require full disclosure from the FDA as a condition of its support.” Response We agree with the need for greater access to these unpublished datasets. Blood supply and transfusion demand Comment Several commenters asked CMS to consider the effect of ESA use on the blood supply, i.e. blood available for transfusion, if the final decision resulted in more transfusions. Commenters expressed concern that shortages in the blood supply commonly exist and is a particular problem in some minority populations. Response The concern about the adequacy of the nation’s blood supply is not a relevant factor for consideration in this national coverage determination. Our focus is whether the use of ESA is reasonable and necessary to treat a particular illness. Financial considerations Comment Some commenters alleged that the specific provisions of the decision were prompted by CMS financial concerns. Some allege that we are trying to save money. Others suggest that the proposed decision would result in increased Medicare expenditures. Response The specific provisions of the proposed decision were derived from the regimens, including doses and durations of treatment, that were studied in clinical trials. We did not consider financial implications for these issues. Whether the decision ultimately affects Medicare expenditures is not a consideration in conducting national coverage analyses. Quality of life as a research outcome Comment Many professional societies suggested that quality of life (QoL) outcomes should be a sufficient research endpoint. They urged CMS to use QoL outcomes as evidence to make a reasonable and necessary determination for coverage. For example, the American Society of Hematology (ASH) submitted a list of supporting evidence that included literature pertaining to QoL as an outcome measure for patients with cancer receiving ESA therapy. Response Wisloff et al. examined the impact of hemoglobin concentration on QoL scores in 745 patients with multiple myeloma. They had the following conclusion: “When examining the effect of haemoglobin on QoL, it is essential to adjust for disease parameters and response to therapy in order not to overestimate the impact of haemoglobin on QoL. Our findings imply that uncontrolled studies on the effect of erythropoietin (EPO) in cancer patients may be making exaggerated claims for the effect of EPO on QoL” (Wisloff 2005). We believe that there is currently insufficient evidence to postulate a QoL benefit to support ESA use. Such evidence of benefit, if one indeed exists, requires more robust research than we have reviewed to date. However, even if such evidence existed, it would need to be weighed against the new evidence suggesting tumor progression and increased mortality. Pediatric populations Comment Some commenters suggested that the proposed decision would adversely effect pediatric populations. Response Infants and young children with cancer or leukemia are generally not Medicare beneficiaries. Any issues peculiar to the pediatric population are not generalizable to the Medicare population at large. Coding Comment We were asked to provide ICD-9 codes with the policy. Response We do not provide coding instructions in NCDs. We do, however, consider coding in the instructions that are developed to direct our contractors who process claims for items and services billed to Medicare. CMS authority to make the NCD Comment A commenter contested CMS’ authority to limit reimbursement for ESA therapy, claiming that toxicity is not relevant to decisions about medical reasonableness. Other commenters suggest that, under Section 1861(t)(2) of the Social Security Act, Medicare cannot establish coverage conditions for ESA use in the context of anticancer treatment. Response We disagree with these comments. CMS’ authority to develop and implement NCDs is clearly and unequivocally established in statute. In determining if a particular drug is reasonable and necessary, one of several considerations is whether the drug improves health outcomes. In this context, toxicity is relevant in determining if health outcomes are improved. Section 1861(t)(1) of the Social Security Act defines the terms “drugs” and “biologicals.” The statute at § 1861(t)(2) defines a subset of “drugs,” those used in an anticancer chemotherapeutic regime for a medically accepted indication. ESAs may fall under either definition, depending on the use. The definitions of drugs and biologics at § 1861(t)(1) & (t)(2) include listings in compendia. The United States Pharmacopoeia-Drug Information (USP-DI) is a compendium that lists accepted and unaccepted uses of drugs. Both epoetin and darbepoetin alpha are included in USP-DI and have listings that were changed after the FDA released its black box warning. Prior to the changes made in March of 2007 in the USP-DI, both darbepoetin alpha and epoetin had accepted indications for the treatment of anemia in cancer patients when the anemia was due to chemotherapy. Epoetin had an off-label indication for treatment of chronic anemia associated with neoplastic diseases. Darbepoetin alpha had an unaccepted indication for treatment of anemia of cancer not due to chemotherapy. Following the FDA black box warning, the darbepoetin alpha unaccepted indication was strengthened with additional data. The epoetin section also had additional language added that stated that epoetin improves anemia due to cancer in patients not receiving chemotherapy, but may compromise survival. Additional language in the cancer treatment section stated that epoetin has not demonstrated improvements in cancer outcomes and may compromise survival. In sum, the current US-PDI compendium listings provide unfavorable evaluations for these drugs. Finally, we emphasize that Medicare NCDs instruct our contractors on the coverage of items or services for which claims are made. NCDs do not direct physicians regarding the provision of any particular item or service. ESA overuse and revision of treatment guidelines Comment A commenter said in part that ESAs are overused and suggested that revised guidelines and a lower upper threshold could allow continued use of these agents in those patients who would benefit. Response We agree. Preserving appropriate access Comment Y-ME National Breast Cancer Organization stated that breast cancer patients should have access to medications, including ESAs if appropriate, and noted that a significant portion of breast cancer patients are Medicare beneficiaries. Response We did not propose to eliminate coverage to ESA therapy for beneficiaries with breast cancer, though we did propose limitations on the dosing that would be covered by Medicare. We believe that our final decision preserves appropriate access with due attention to the serious concerns that are reflected in the FDA black box warnings, the discussions of the ODAC, and the evidence we reviewed. ESAs are equivalent Comment Several commenters stated that ESAs have the same effects and should be treated similarly in this decision. Response We agree. Need for more clinical trials Comment Several commenters pointed out that more clinical trials are needed to answer important outstanding questions. Response We agree. ESAs as anti-tumor therapy Comment Commenters stated that current data do not support ESA use solely to potentiate the effectiveness of anti-tumor therapy. Response We agree. CMS and FDA Comment A commenter said that FDA approved labeling indicates when treatment is “necessary.” Other commenters made various comments about FDA processes. Response The labeled indication for the treatment of anemia related to chemotherapy is to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy. The FDA approved label does not identify a hemoglobin (or hematocrit) level at which ESA therapy may be indicated or necessary to treat anemia in patients who have cancer that is related to receiving chemotherapy. However, the FDA label does identify hemoglobin (or hematocrit) levels at which ESA therapy may be indicated, or necessary for the treatment anemia related to chronic renal failure, and for anemic patients scheduled to undergo elective, non-cardiac, nonvascular surgery. Some commenters were confused and believed that the FDA label did, in fact, identify a specific hemoglobin/hematocrit level at which ESA therapy may be indicated or necessary to treat anemia related to chemotherapy. CMS is not changing the FDA indication for ESA therapy for cancer patients who have anemia related to chemotherapy. CMS’ coverage provision is the FDA label indication and ensures that cancer beneficiaries who have anemia related to chemotherapy can avoid transfusions by receiving ESA therapy “that will gradually increase the hemoglobin (or hematocrit)concentration to the lowest level sufficient to avoid the need for transfusion”, as stated in the FDA labeled Black Box Warning. CMS and FDA are separate agencies with different statutory missions, and operate under distinct legal authorities. CMS cannot address these comments about FDA’s processes. They should be addressed to FDA directly. FDA and ODAC Comment Several commenters requested that CMS delay rendering a proposed decision until after the FDA ODAC meeting scheduled for May 11, 2007. Other commenters suggested that we defer any final decision until the FDA has responded to the ODAC recommendations. Commenters suggested that CMS review the literature and data distributed at the ODAC meeting prior to rendering the proposed decision. Others asked if we have consulted with FDA or suggested that we consult with FDA. Response As stated above, CMS and FDA are separate agencies with different statutory missions, and operate under distinct legal authorities. CMS independently reviewed the evidence prior to the ODAC meeting, which was attended by CMS staff. The concerns raised and the evidence discussed at the ODAC are consistent with the body of evidence that we had already reviewed. We are encouraged that the separate and independent analyses of the FDA and CMS have raised similar serious concerns about the use of ESA treatment in patients with cancer and related neoplastic conditions. CMS' proposed decision was published after the ODAC meeting. FDA deliberations are not public and their timeline for making changes (if any are made) in the labeling for ESAs is unknown. We believe the safety concerns that we have identified in this document required CMS to act quickly to protect beneficiaries. Acceptable risk Comment A number of commenters acknowledged risks associated with ESA use but said that among individual patients there will be different judgments made by patients about what risk is acceptable in light of their personal values, religious beliefs, disease severity, and other factors. They propose that patients and physicians should be allowed to make those decisions without CMS influence. Response We agree that treatment decisions regarding the use of ESAs shall be made by physicians and patients, making sound judgments about the risks associated with ESA therapy. In making national coverage determinations, we review the applicable evidence and may, as appropriate, make determinations wherein Medicare coverage for certain items and services is not reasonable and necessary. Thus, in this instance, CMS is making a determination as to those circumstances under which ESA use in patients with cancer and related neoplastic conditions is or is not reasonable and necessary. 9. Expert Opinion CMS received numerous responses from individuals and organizations that could be classified as “expert.” Due to the large number of these comments, we will not separately include those here. We will limit discussion under this heading to a summary of the FDA Oncologic Drugs Advisory committee (ODAC). FDA convened the ODAC on 5/10/07 to consider ESA use in cancer. Background materials are available at: fda.gov/OHRMS/DOCKETS/ac/07/briefing/2007-4301b2-02-FDA.pdf ( accessed 05/25/07) . The ODAC transcripts are available at fda.gov/ohrms/dockets/ac/cder07.htm#OncologicDrugs (accessed 07/03/07). Included among the recommendations made by the ODAC to FDA are: further marketing authorization be contingent upon additional restriction in product labeling; further marketing authorization be contingent upon additional trials; labeling should specifically state that ESAs are not indicated for use in specific tumor types that may include breast cancer, head and neck cancer, and non small-cell lung cancer (NSCLC); the current evidence is insufficient to determine a lower limit different from the current level of 10 g/dl; the current evidence is insufficient to determine an upper limit different from the current level of 12 g/dl; and product labeling should recommend discontinuation of the ESA following completion of a chemotherapy regimen and re-evaluation of the degree of anemia with subsequent chemotherapy regimen. VIII. CMS Analysis National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act, § 1869(f)(1)(B). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, with limited exceptions, the expenses incurred for items or services must be “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member” (§ 1862(a)(1)(A)). This section presents the agency's evaluation of the evidence considered and conclusions reached for the assessment questions: 1. Is the evidence sufficient to conclude that erythropoiesis stimulating agent therapy affects health outcomes when used by Medicare beneficiaries with cancer and related neoplastic conditions? 2. If the answer to Question 1 is affirmative, what characteristics of the patient, the disease, or the treatment regimen reliably predicts a favorable or unfavorable health outcome? As discussed above, CMS considers improved health outcomes in its reasonable and necessary determinations. Because multiple studies have demonstrated increased tumor progression and decreased survival in certain cancer patients, there may be the potential that the ESA stimulated tumor progression and increased mortality seen in these few cancers may be seen in other cancers. Thus, we believe that in order to demonstrate improved health outcomes, we need to review evidence that demonstrates that ESAs do not cause tumor progression and/or decrease survival in these other cancers even if they might decrease transfusions or improve quality of life. Thus, in order to assess the evidence for questions 1 and 2, we consider whether the evidence is robust and demonstrates that the use of ESAs in any cancer patient decreases transfusion requirements and/or improves survival and, if so, does the evidence demonstrate that the use of ESAs does not increase tumor progression or decrease survival? For the convenience of the reader we have organized our analysis by the coverage criteria in our proposed decision. Following a general discussion, we will in each case: review public comments; discuss any additional evidence presented during the comment period; annotate the FDA labeling for that criteria; annotate the recommendation in the United States Pharmacopoeia-Drug Information (USP-DI), a compendium that lists accepted and unaccepted uses of drugs; evaluate the assessment questions above (see Section VII.1); respond to the comments and evidence; and summarize our decision. General Discussion In a typical setting, physiologic replacement of a missing hormone should result in normalization caused by that deficit. Indeed many, albeit not all, patien