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

CMS NCA document | source_status=Closed | review_type=New | public_comment_open=False | document_id=CAG-00413N

Given the totality of the currently available evidence, CMS will not issue a national coverage determination at this time for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N).

Decision Memo: To: 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 From: Louis B. Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group James Rollins, MD, PhD Division Director Kimberly Long Lead Analyst Elizabeth Koller, MD Lead Medical Officer Subject: Final Decision Memorandum for CAG # 00413N Erythropoiesis Stimulating Agents (ESA) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis Date: June 16, 2011 I. Final Decision Given the totality of the currently available evidence, CMS will not issue a national coverage determination at this time for Erythropoiesis Stimulating Agents (ESAs) for Treatment of Anemia in Adults with CKD Including Patients on Dialysis and Patients not on Dialysis (CAG-00413N). II. Background In this section, we describe the technological developments that gave rise to recombinant erythropoietin and related erythrocyte stimulating agents (ESAs). We then describe the physiologic role of the kidneys, pathology of renal disease, and the demographics of renal disease. This is followed by a description of the types of anemia found in renal disease. Finally, we describe how anemia management has changed over time. For purposes of this discussion, therapy for a medical condition includes treatment for the signs and symptoms of the underlying condition. Though we have tried to simplify the discussion for the lay reader, the topic is scientifically complex and we believe that an overly simplistic treatment would ultimately be detrimental to the understanding of our review. We caution the reader that the term “inulin” refers to a polysaccharide used to measure kidney function and should not be misread as the term “insulin.” ERYTHROPOIETIN IN RENAL DISEASE A. Biochemical Background Erythropoietin is a 34-kDa glycoprotein hormone produced primarily, but not exclusively, in the kidney and to a lesser extent in the liver. (Miyake 1977) The native protein is a 193 amino acid peptide sequence from which a 27 amino acid peptide leader sequence is removed from the N-terminus. An arginyl residue at the carboxyl terminus also appears to be cleaved during post-translation processing. The mature protein consists of a 165 amino acid backbone with 2 disulfide bonds, three N-linked carbohydrate chains, and one O-linked carbohydrate chain. The major side chains, sialated tetra-antennary saccharides, contribute to in vivo stability (Faults 1989). As indicated above, production of this hormone is controlled via a feedback loop. (Bauer 1898, Erslev 1980)) Anemia and/or hypoxia result in decreased oxygen tension at the tissue level. Via intermediate signaling, perhaps with hydrogen peroxide (H 2 O 2 ) and hypoxia inducible factors (HIF), cells increase transcription of the erythropoietin gene and subsequent production of the processed protein hormone. Basal physiologic levels range from approximately 6 to 32 U/L.(Van Dyke 1961) Serum levels of the hormone may transiently increase by a thousand-fold. Erythropoietin has multiple actions. (Bahlmann 2004, Chong 2002, Rossert 2005) Its classic actions are well understood. Erythropoietin regulates erythrocyte production by stimulating progenitor cell proliferation and differentiation in the bone marrow. (Chong 2002, Ingley 2004) It also decreases erythrocyte apoptosis (cell death).(Chong 2002, Polenakovic 1996, Ratajczak 2001, Schwartz 1992) Less well understood are the roles erythropoietin may play either directly or indirectly in angiogenesis (blood vessel formation), e.g., wounds and the female productive tract (Chong 2002, Haroon 2003, Yasuda 1998, Zwezdaryk 2007) and the increase in thrombogenic properties of vascular endothelium.(Fruste 2002) Even less well understood are the proliferative effects it has on other tissues such as the bone marrow (stroma parenchyma) and tumors.(Lai 2005, Shiozawa 2010) Erythropoietin activity is mediated through the classic erythropoietin receptor and perhaps non-classic receptor(s).(Rossert 2005, Sawada 1987, Szenajch 2010) Binding of the erythropoietin receptor by erythropoietin results in phosphorylation of Jak2 (janus kinase 2), which in turn activates other intracellular pathways STAT (signal transducer and activator of transcription), PI 3 K–Akt (phosphatidylinositol-3/Akt), and Ras/MAP (mitogen-activated protein) kinase.(Arcasoy 2005, Chong 2002, Kirschner 2000, Liang 2010, Pfeffer 2008, Ratajczak 2001, Solar 2008b, Yamazaki 2004) The expression of erythropoietin receptors on erythroid progenitor cells is well known. (D’Andrea 1989, Jones 1990, Winkelman 1990) Less well appreciated is the presence of erythropoietin-binding receptors on other tissues including cardiac myocytes, macrophages, neurons, vascular endothelial cells (Anagnostou 1994, Digicaylioglu 1995, Haroon 2003, Masuda 1993, Wright 2004), and cancers/cancer cell lines (bone sarcoma, breast, cervical, colon, gastric, head-neck [squamous cell], hepatoblastoma, melanoma, ovarian, pediatric, renal, retinal, and uterine (Acs 2001, 2002, 2003, Arcasoy 2003, 2005, Batra 2003, Liang 2010, Ribatti 2003, Selzer 2000, Solar 2008a, Szenajch 2010, Westenfelder 2000, Yasuda 2001). Several forms of recombinant human erythropoietin have been developed (Table 1). (Jelkmann 2010, NKF Position Paper 1989, OTA 1990, Schellekens 2009) They differ in their carbohydrate structure. The most common species are erythropoietin-alpha and beta. The pharmacokinetic half-life of these products is six to eight hours after IV injection (Halstenson 1991). Because the pharmacodynamic response on the bone marrow is prolonged, dosing regimens vary from three times weekly to once weekly. Dosing via the intravenous route may require ~ 10-25% more drug for the same hematologic effect compared to subcutaneous administration. (Besarab 1992, Kaufman 1998, Paganini 1995) The erythropoietin molecule has been modified by the addition of 2 N-linked carbohydrate chains to form darbepoietin. The additional sialic acid residues decrease pharmacokinetic clearance by the body and permit weekly and semi-weekly dosing. (Egrie 2001, MacDougall 1999) More recently, the erythropoietin molecule has been modified by the addition of a methoxy-poly-ethylene glycol polymer chain (pegylation) via a succinimidyl butanoic acid linker (MacDougall 2005). These changes further decrease pharmacokinetic clearance by the body and permit weekly and even monthly dosing. (MacDougall 2005) Although the molecular modifications decrease the affinity of the compound for the erythropoietin receptor in vitro , the increased residence time results in increased exposure of the compound to the erythropoietin receptor and increased erythropoietin-type activity in vivo. (Agoram 2008, El-Komy 2011, MacDougall 2003-abstract, 2005) Molecules that activate the erythropoietin receptor or downstream pathways are under development. (Bugelski 2008 A and B, Johnson 1998, MacDougall 2008, Perez-Ruixo 2009, Sathyanarayana 2009, Sytkowski 1998, 1999, Wrighton 1996, 1997; Patents including #5,767,078, #5,773,569, #5,830,851, and #5,986,047 and patent applications including #20100249032.) These may be fusion proteins, erythropoietin dimers, truncated erythropoietin molecules, mimetic antibodies, or other small molecular entities. Others, such as GATA, may activate the receptor itself along with other hemoglobin synthesis genes. (Chiba 1991, Gregory 1999) Still others may activate/inactivate related pathways involving hypoxia-inducible transcription factor or hematopoietic cell phosphatase. (Bernhardt 2007, Del Vecchio 2010, Liu 2007) Phase III studies (Emerald 1 and 2, Pearl 1 and 2) have been conducted with peginesatide (formerly hematide), a pegylated peptidic erythropoiesis stimulating agent. (Affymax Analyst Day Handout 12/12/2010, Macdougall 2008, 2009, Stead 2006, Woodburn 2010) Table 1: Erythrocyte Stimulating Agents Recommended starting doses of erythropoietin (50 U/kg) results in serum erythropoietin levels that are supraphysiologic for many hours to days (Figure 1). (Brockmoller 1992) The supraphysiologic exposure (area-under-the-curve above) is greater in patients dosed via the intravenous route than via the subcutaneous route (Figure 1). (Brockmoller 1992) The supraphysiologic exposure is greater with higher dosing (Figure 2). (McMahon 1989) There are similar findings with the starting dose of darbepoetin (0.45 mcg/kg) and pegylated erythropoietin (0.6 mcg/kg) although the residence time is longer and the peak serum levels occur later with subcutaneous dosing. (Allon 2002, FDA darbepoietin review-pharmacokinetic section, FDA pegylated erythropoietin review-pharmacokinetic section, Locatelli 2007) Figure 1: Serum levels of erythropoietin after a single dose 50 U/kg by route of administration (Brockmoller 1992) Panel A Intravenous Dose Panel B Subcutaneous Dose Figure 2: Serum levels of erythropoietin after a 300 U/kg intravenous dose on days 1 and 10 (McMahon 1989) Basal physiologic levels of erythropoietin range from approximately 6 to 32 U/L. B. Disease Summary The kidneys are responsible for multiple aspects of physiologic homeostasis. They do this by maintaining acid-base balance, maintaining electrolyte balance, regulating whole body water content, filtering water soluble toxins, retaining/preventing the loss of re-usable biochemical entities, e.g., glucose and proteins including albumin, activating vitamin D to facilitate calcium absorption, and mitigating hypoxia. Renal disease may impair these functions. Kidney damage may manifest itself with urinary protein loss, abnormal urinary sediment with casts and/or blood cell elements (erythrocyte or leukocytes), or structural changes present on medical imaging (scarring, size reduction, and/or cystic changes) even before decreased glomerular filtration is detected. (Levey 2009) In Stage 1 disease, the glomerular filtration rate (GFR) is normal or increased ( ≥ 90 mL/min/1.73 m 2 ), but there are other chronic pathologic findings of damage. In Stage 2 disease, the glomerular filtration rate is minimally decreased (60-89 mL/min/1.73 m 2 ) and there are other chronic pathologic findings of damage. In Stages 3 and 4, the glomerular filtration rates are minimally decreased to 30-59 mL/min/1.73 m 2 and 15-29 mL/min/1.73 m 2 . In Stage 5 disease, the glomerular filtration rate is less than 15 mL/min/1.73 m 2 and/or dialysis is required for management of electrolytes, fluids, and/or uremic toxins. (For claims purposes, A further distinction is made in patients with endstage renal disease via the ICD-9 codes: Stage 5 585.5 for those with a GFR less than 15 ml/min1.73 m 2 and not on dialysis and Stage 6 585.6 for those on chronic dialysis.) Symptoms, primarily attributable to uremia, reduced fluid clearance, urinary protein loss, and secondary hypertension may present when glomerular filtration is below 30 mL/min/1.73 m 2 and become more noticeable with further declines in renal function. Symptoms include alterations in sleep patterns, anorexia, bruising, chest discomfort, dysgeusia (abnormal taste), dyspnea, edema, fatigue, gastrointestinal bleeding, itching, impaired cognitive function, insomnia, muscle cramps, nausea, and changes in micturition patterns. With the progression of renal disease, patients may lose physical function and independence. Cross-sectional Medicare claims data reveal that use of assistive devices for walking (canes, walkers, wheelchairs) is 16.9% in the pre-dialysis chronic kidney disease population and 32.5% in the incident dialysis population. (USRDS 2008, 2009) The data also reveal that a walking disability (abnormal gait, difficulty walking, fall history) is present in 19.2% of incident dialysis patients and that 40.1% of incident dialysis patients go on to develop a new walking disability during the first year on dialysis. (USRDS 2008, 2009) Chronic kidney disease (pre-dialysis and end-stage renal disease requiring dialysis) has become more common in the U.S over time. Cross-sectional laboratory data (persistent microalbuminuria [ > 30 mg/g creatinine] and calculated glomerular filtration derived from serum creatinine values and the Modification of Diet in Renal Disease equation) from National Health and Nutrition Examination Surveys (NHANES) II (1988-1944) and III (1999-2004) revealed an increase in the prevalence of pre-dialysis kidney disease in the general adult (≥ 20 years) population. (Coresh 2007) The largest prevalence increases were found in patients with Stage 2 disease (2.7% to 3.2%) and Stage 3 disease (5.4% to 7.7%). Cross-sectional claims data revealed an increase in pre-dialysis kidney disease from 2.9% to 7.9% whereas data from the Medical Evidence form (2728) revealed an increase in end-stage renal disease (ESRD) requiring dialysis and/or transplantation from 0.8% to 1.1% in the general Medicare population from 1996 to 2006. (USRDS 2008) The demographics of the end-stage renal disease population in the U.S. have changed over time. The adjusted incident rate for patients 19 years and under has remained relatively low and stable at 13-15/million from 1988 to 2006 (USRDS 2008, 2009). The adjusted incident rate for patients 20 to 44 years of age has increased minimally and gradually from 97/million to 127/million. By contrast the adjusted incident rate for older adults has increased significantly: a) almost double (363/million to 625/million) for patients 45 to 64 years of age, b) more than double (668/million to 1452/million) for patients 65 to 74 years of age, and c) tripled 517/million to 1744/million for patients 75 years and older.(USRDS 2008, 2009) By contrast, ESRD prevalence is highest for patients aged 45 to 64 years of age and the adjusted prevalence rate is highest for patients aged 65 to 74 years of age and reflects the overall mortality associated with age and increased mortality especially within the first year of dialysis respectively.(USRDS 2008, 2009) The causes of end-stage renal disease in the U.S. have also changed over time. Although the major causes of ESRD (diabetes-related, hypertension, glomerulonephritis, and cystic kidney disease) have remained the same, their relative importance has changed. The incidence of diabetes-related and hypertension-related renal disease has increased markedly. Much of the increase in diabetes-related renal disease may reflect the underlying macrovascular disease and hypertension associated with the metabolic derangement of Type 2 diabetes (and not the classic microvascular renal disease associated with Type 1 diabetes). By contrast, glomerulonephritis was the most common cause of renal disease in the prevalent population in the early 1980s, and currently both glomerulonephritis and cystic kidney disease are disproportionately represented in the prevalent population when compared to the incident population. This reflects the increased mortality associated with diabetes-related renal disease and hypertension as well as the age-of-onset associated with these disorders. (Churchill 1992) The current end-stage renal disease population is currently older and has more co-morbid disease (especially antecedent hypertension, type 2 diabetes, and atherosclerosis-lipids dysfunction). (Knauf 2009, NKF Position Paper 1989, Pedersen 2009, Sorace 2011, USRDS 2008, 2009) Annual mortality rates are higher for older patients. (USRDS 2010) Mortality rates during the first year on dialysis have remained unchanged. (USRDS 2008, 2009) Survival in that first year is approximately 60% in the overall incident dialysis population and 40% in patients who are unable to walk. The five-year survival in the dialysis population is approximately 30%. (USRDS 2008, 2009) Cardiovascular-related mortality, which has fluctuated between 79 deaths/10 3 patient-years in 1991, 94.1 deaths/10 3 patient-years in1999, and 72.1 deaths/10 3 patient-years in 2006, is responsible for approximately 50% of overall mortality. (USRDS 2008, 2009, 2010) Although the number of renal transplants has increased over time, both age and cause of renal disease are factors in whether a patient (with onset of ESRD less than 70 years of age) has received a renal transplant within three years of ESRD registration and these demographic features have changed little since 1991. (USRDS 2008, 2009, 2010) Patients with cystic kidney disease (~ 45-50%) and glomerulonephritis (~35-40%) are more likely to receive a transplant than those with hypertension and diabetes-related renal disease (~ 12-18%). Younger patients (aged < 20 years; ~70%) are more likely to receive a transplant than older patients (age 20-39 years; 47% declining to 31%; age 40-59 years; 25% declining to 18%, and age 60-69 years; 6% increasing to 9%). Anemia in Renal Disease-Etiology There are multiple causes of anemia in patients with renal disease. There is decreased red cell production and increased red cell loss. Uremia reduces erythrocyte survival and suppresses hematopoietic cell production in the bone marrow. (Delwiche 1986, Fukushima 1986, Radtke 1980) Uremia may cause hemorrhagic bleeding, often from the gastrointestinal tract. (Andrassy 1985, Kang 1990, 1993, 1999, Rabiner 1972, Schiller 1989) The hemodialysis procedure and the filters used result in frank blood loss and decreased red blood cell survival. (Handelman 2010) Because of anorexia and dietary restrictions, oral intake of important nutrients, e.g., iron (Fe), may be inadequate. (DeVita 2003, Donnelly 1990, Kotaki 1997, van Wyck 1989) Aluminum (Al), which may be used for phosphate binding and as an antacid to reduce occult bleeding, may have a direct toxic effect on hematopoiesis and an indirect effect impairing iron metabolism. (Bia 1989, Caramelo 1995, Donnelly 1990) Erythropoietin deficiency in many patients with renal disease reduces marrow stimulation of hematopoietic cells although endogenous production (made by the body) of erythropoietin is relatively preserved in some types of renal disease, e.g., polycystic kidney disease. Erythropoietin production and utilization by the body may also be decreased in the setting of other nutritional co-factors, e.g., iron and vitamins. (Altallah 2006 Amato 2005, DeVita 2003, Goicoechea 1998, Keven 2003, MacDougall 1995) There may be resistance to erythropoietin, whether endogenous (made by the body) or exogenous (made outside the body) in the setting of dialysis inadequacy, dysplastic marrow, occult or frank inflammation, infection, anti-erythropoietin antibodies, putative receptor defects, and putative anti-erythropoietin receptor antibodies. (Agarwal 2008, Boven 2005, Casadevall 1996, de la Chapelle 1993, Di Iorio 2003, Drueke 1990, Elliot 2009, Howman 2007, Ifudu 1996, Jacob 2005, Kalantar-Zadeh 2003, Kaysen 2003, 2006, Kilpatrick 2008, Khankin 2010, Kralovics 1997, MacDougall 1995, Markson 1956, Movilli 2003, Nassar 2002, Pedersen 2009, Radtke 1981, Rossert 2007, Ryan 2006, Schellekens 2006, Schreiber 1996, Solomon 2010, Szczech 2008, Wallner 1981, Zappacosta 1982) Hyperparathyroidism, usually present as a secondary phenomenon to hypocalcemia in renal disease, has been postulated to cause anemia via several mechanisms including specific type of marrow fibrosis (osteitis fibrosa cyctica) impairing hematopoietic cell production. (Bhadada 2009, Gallieni 2000, Grutzmacher 1983, Massry 1983, McGonigle 1984, Rao 1993) Medications used in the management of renal disease, e.g., erythropoietic stimulating agents may cause (semi-)reversible marrow fibrosis with different pathologic features. (Akada 2010, Bader 1992, Barosi 2005, Dokal 1989, Epogen label, Gallieni 2000, Hussein 2007, Kakumitsu 2005, Kennedy 2006, Lacout 2006, Levine 2005, Reilly 1997, Shiozawa 2010, Snide 2008, Tulliez 1989, Wernig 2006) In addition, many patients with renal dysfunction have co-morbid conditions that are the underlying cause(s) of their anemia. For example, cytokines associated with the anemia of chronic disease may impair hematopoietic nutrient utilization, erythropoietin production, and erythropoietin efficacy. (Means 1992, Pedersen 2009) The presence of a mild anemia in type 2 diabetes is only now being recognized and may be a variant of the anemia of chronic disease. (Ishimuura 1998, Thomas 2003) Anemia can be attributed to renal dysfunction only when there is significant renal dysfunction (Figure 3). (Radtke 1979) Mild anemia (mean hematocrit ~ 37 volume %) may be present when the glomerular filtration rate is between 30 and 40 ml/min/173 m 2 . It is more common (mean hematocrit ~ 33 volume %) when the clearance is between 20 and 30 ml/min/173 m 2 . Modest anemia (mean hematocrit ~ 30 volume %) is present when the clearance is between 10 and 20 ml/min/173 m 2 . Longitudinal data demonstrate that hematocrit levels decline in the 6 months prior to the initiation of dialysis and rebound, without exogenous erythropoietin, in the months immediately subsequent to the initiation of dialysis (Figure 4; Panel A). (Erbes 1978, Radtke 1979, 1980) Concomitant longitudinal data show that endogenous erythropoietin levels rise in the 6 month prior to the initiation of dialysis and decline in the months immediately subsequent to the initiation of dialysis (Figure 4; Panel B). (Radtke 1979) In the six to twelve months after the initiation of dialysis, both hematocrit and endogenous erythropoietin levels decline and remain low in most patients-even when dialysis is adequate. (Radtke 1979) Select patients, including those with polycystic kidney disease, retain some erythropoietin-production capacity. (Brown 1980, Eckardt 1991, Koch 1979, Radtke 1977, Ross 1994, Zeier 1996) Such data suggest that the uremia is the primary underlying etiologic agent for anemia in the pre-dialysis patient and that the kidney (and extra-renal tissue) respond to the challenge of anemia with increased production of the erythropoietin hormone in the pre-dialysis patient. Consistent with classic hormone feedback loops, the removal/reduction of the anemia-causing toxins, via dialysis and other renal management measures, decreases the need for erythropoietin secretion. Then, with continued deterioration of the renal parenchyma over time, the functional capacity for both filtration and erythropoietin production is lost (for most patients). The hormonal feed-back loop ceases to function in patients with well-established chronic renal failure. At this stage, erythropoietin deficiency becomes a major underlying cause of anemia. Figure 3: Hematocrit Level and Renal Function (Radtke 1979) Figure 4:Hematocrit, Erythropoietin, and Renal Function (Radtke 1979) Panel A Changes in Hematocrit in Response to Uremic State Panel B Changes in Erythropoietin in Response to Hematocrit and Uremic State Anemia in Renal Disease-Demographics Features The severity of anemia in end-stage renal disease patients appears to have changed over time. Secular changes suggest that hemoglobin/hematocrit levels are currently higher in ESA-naïve patients. Data from the 2008 USRDS annual publication suggest that 51% of incident ESRD patients have hemoglobin levels < 10 g/dl (hematocrit ~ 30 volume%) (and 9% unknown) whereas 1990 Congressional-Office of Technology (OTA) data indicate that 74% had hematocrit levels < 30 volume % (hemoglobin ~10 g/dl) (Figures 5 and 6). Forty-one percent of these had hematocrit levels 25 to < 30 volume %; thirty percent had hematocrit levels from 20 to < 25 volume %; three percent had hematocrit levels under 20 volume %. These differences may reflect changes in patient management, patient composition, and/or some other unknown factor. (Eggers 2000) Figure 5: Level of Anemia Prior to Significant ESA Use in U.S. Figure 6: Level of Anemia in Current Pre- dialysis Patients (Population not treated by a nephrologist. ESA use in 5.7%) Historical Treatment of Anemia It was long presumed that anemia contributed to the fatigue and poor level of functioning in renal disease and that therapeutic intervention was warranted although the level at which anemia requires intervention is not well established. By tradition, patients have been transfused with packed red blood cells (PRBCs) at the hemoglobin level of 7 or 8 g/dl to avoid symptoms and physiologic complications. (Churchill 1992, Ibrahim 2008, 2009) A transfusion of two or more units of PRBCs would result in an increase of at least 2 g/dl of hemoglobin (6 volume % units of hematocrit). Most of these practices, however, are based on empiric observations and not clinical trials. Anemia in renal disease prior to the development of ESAs was primarily treated with transfusions. In 1992, in the year post initiation of dialysis, approximately 19% of patients received a single transfusion, 8% received two transfusions, and 7% received three or more transfusions. (USRDS 2008). Other therapeutic interventions included androgens, e.g., nandrolone and nutrients, e.g., iron (oral or intravenous). In 1906, erythropoietin was identified as a regulatory hormone for red cell production and, in 1957, its source identified as the kidneys. (Gurney 1957, Reissman 1960) Commercialization was limited by the availability of processes for extraction, replication, and purification of the protein. In the 1980s, with the advent of recombinant technology, several companies, e.g., Amgen and Genetics Institute, attempted commercialization of a therapeutic product. Amgen and the Genetics Institute received Orphan Drug status from the FDA for their respective products, erythropoietin α and erythropoietin β. (Asbury 1991) Amgen partnered with Ortho Pharmaceutical Company. Amgen retained marketing rights for erythropoietin in the U.S. dialysis population. (Coster 1992, NKF Position Paper 1989) Genetics Institute partnered with Chugai (Japan) and Chugai-Upjohn with the latter holding the marketing rights to erythropoietin in the U.S.(Coster 1992, NKF Position Paper 1989) In 1989, the FDA approved recombinant erythropoietin α to manage anemia decrease transfusions in dialysis patients and in pre-dialysis patients in whom hemoglobin levels were less than < 10 g/dl. In 2001, darbepoetin alpha (α) was approved by the FDA to increase hemoglobin. Over time, ESAs became used in a greater proportion of dialysis patients, a greater proportion of pre-dialysis patients, and in renal patients with less severe anemia (Figure 7). (Besarab 1993, USRDS 2008) The dose of ESAs has increased over time (Figure 8). (Collins 1997, USRDS 2008, 2009) Dosing in the U.S. differs from that of Europe, where dosing is approximately 50% less for equivalent hemoglobin levels (Tables 29, 30, and 31). (Burton 2000, Jacob 2005, Pisoni 2004, Richardson 2009) Figure 7: Change in Hemoglobin Levels and ESA Use over Time Figure 8: Change in ESA Doses over Time III. History of Medicare Coverage The end stage renal disease program in Medicare was established by the Social Security Amendments of 1972, Public Law 92-603, Section 299I (1972). Medicare coverage of dialysis typically started during the fourth month of dialysis. Services and items covered by the program include dialysis procedures whether in-patient or out-patient, dialysis supplies, blood transfusions, transplantation, some transplantation-related costs, and drugs associated with dialysis, e.g., heparin and ESAs. These medications are paid under Medicare Part B. There is no national coverage determination (NCD) concerning the use of ESAs in beneficiaries with renal disease treated with dialysis and beneficiaries with renal disease in pre-dialysis stages. A. Current Request On June 16, 2010 CMS accepted a formal request for a NCD with respect to Medicare coverage of ESAs for treatment of chronic kidney disease (CKD) and dialysis-related anemia from Mr. Dennis Cotter, President, Medical Technology & Practice Patterns Institute (MTPPI.) His letter is available at the following link: http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id245.pdf . B. Benefit Category 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) and §1861(s) (Definition of Medical and Other Health Services) of the Act. ESAs fall within the benefits categories specified in §1861(s)(2)(O)of the Social Security Act. IV. Timeline of Recent Activities September 2009 CMS commissioned a technology assessment (TA) to search the literature for ESA clinical trials. November 2009 CMS commissioned a TA that would describe ESA utilization in Medicare beneficiaries with renal disease. The information was presented at the March 24, 2010 MEDCAC. June 16, 2010 CMS accepted a formal request for an NCA to evaluate erythropoiesis stimulating agents (ESAs) for treatment of anemia in adults with CKD including both patients on dialysis and patients not on dialysis. A tracking sheet was posted on the web site and the initial 30 day public comment period commenced. CMS commissioned a technology assessment to delineate the role and impact of blood transfusion on renal transplantation. July 16, 2010 The initial 30 day public comment period ended. Nine timely comments were received. January 19, 2011 CMS held a Medicare Evidence Development and Advisory Committee (MEDCAC) meeting to discuss the role and impact of blood transfusion on renal transplantation. ( www.cms.gov/ medicare-coverage-database/details/medcac-meeting-details.aspx?MEDCACId=57&bc =BAAQAAAAAAAA& ; accessed January 21, 2011.) March 16, 2011 Proposed decision memorandum posted on the CMS website. V. FDA Status A. In 1989, the FDA approved erythropoietin-alpha for the treatment of anemia in renal disease. It was the first erythropoiesis stimulating agent (ESA) approved by the FDA. B. In 1993, the FDA approved erythropoietin-alpha for the management of the anemia due to myelosuppressive cancer chemotherapy of solid tumors. C. On September 17, 2001, the FDA approved the long-acting erythropoietin analogue, darbepoetin, to increase hemoglobin in renal disease patients. ( www.accessdata.fda.gov/drugsatfda_docs/appletter/2001/darbamg091701L.htm , www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080442.htm, www.accessdata.fda.gov/drugsatfda_docs/label/2001/darbamg091701LB.htm ; accessed July 19, 2010.) D. On July 19, 2002, the FDA approved darbepoetin for the management of the anemia due to concomitantly administered chemotherapy for non-myeloid cancer. See www.accessdata.fda. gov/drugsatfda_docs/appletter/2002/darbamg071902L.htm and www.accessdata.fda.gov/drugsatfda_docs/label/2002/darbamg071902LB.pdf . (Accessed July 19, 2010.) E. In 1997, 2004, 2005, 2007, and 2008, ESA product labeling underwent substantial revisions. (Accessed July 19, 2010.) 1-Epogen/Procrit www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080580.htm (revised pediatric use section for renal disease; 4 studies in dialysis patients (EPO 9118 single arm n = 74, EPO 8702 single arm n = 5, EPO 8905 double-blind n = 10, EPO 9902 double-blind n = 112 ) www.accessdata.fda.gov/drugsatfda_docs/label/2000/epoamg072699lb.pdf (request for literature on pharmacokinetic data in neonatal use) www.accessdata.fda.gov/drugsatfda_docs/appletter/biologics/2004/103234-5033ltr.pdf (phase 4 commitment N93-004 to assess ESA effect on solid tumor growth completed; agreement made with 1993 approval; agreement to conduct survival/time to tumor progression study in metastatic breast cancer patients; update warnings and precautions sections for cancer patients; dear doctor letter.) www.accessdata.fda.gov/drugsatfda_docs/nda/2004/103234s5033.pdf (review of BEST trial; advised recent proposed label changes not acceptable; request for information on thrombosis-vascular events, tumor progression, and cancer treatment response rates in randomized, placebo controlled studies with patients with a single tumor type and anti-cancer treatment regimen. www.accessdata.fda.gov/drugsatfda_docs/appletter/biologics/2004/103234_5053ltr.pdf (acknowledgement that study PR99- 11-034/044, a study of anemia and quality-of-life children with solid tumors, Hodgkin s disease, ALL, or NHL and undergoing myelosuppressive chemotherapy, has been completed, but not yet received for review; request for deferred studies in pediatric cancer patients five years and under) www.accessdata.fda.gov/drugsatfda_docs/nda/2004/103234s5053.pdf (review of several studies in cancer patients for weekly dosing and hemoglobin, time to transfusion, and quality-of-life parameters; survival curve in PR98-27-008 appears to diverge after approximately 500 days and favors the placebo arm) www.accessdata.fda.gov/drugsatfda_docs/label/2004/103234_5053_Epogen_lbl.pdf (alternative weekly dosing was added for cancer patients) www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/103234_5076ltr.pdf (acknowledgement of submission of literature search for pharmacokinetic information on use in neonates in response to a 1997 commitment)(use in children based on literature, renal: Campos 1992, Montini 1990, Offner 1990, Muller-Wiefel 1988, Sharer 1993; HIV: Mueller 1994, Zuccotti 1996; cancer: Beck 1995, Bennettts 1995.) www.accessdata.fda.gov/drugsatfda_docs/nda/2004/103234s5076_AP_PKG.pdf (literature submitted: Kling and Widness 1992 case report of infant with urinary tract obstruction, Widness 1996 seven premature infants and ten adults) www.accessdata.fda.gov/drugsatfda_docs/label/2004/103234_5076lbl.pdf (two studies above included in label) www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/103234s5093ltr.pdf (added information about pure red cell aplasia for renal disease section, update renal section of patient insert, distribute dear doctor letter to hematology-oncology care providers) www.accessdata.fda.gov/drugsatfda_docs/nda/2005/103234s5093_AP_PKG.pdf (pure red cell aplasia case reports in system and packaging issues resulting in administration errors viewed) www.accessdata.fda.gov/drugsatfda_docs/label/2005/103234s5093lbl.pdf (IV route recommended for hemodialysis patients to possibly reduce risk of pure red cell aplasia) www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/103234s5104_LTR.pdf (unspecified label and patient insert changes) www.accessdata.fda.gov/drugsatfda_docs/label/2006/103234s5104_LBL.pdf (unspecified label changes) www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103234s5122ltr.pdf (increased warnings and precautions; removed quality of life claims, requested substantiation of any patient-related outcome (PRO) claims in accordance with the FDA guidance and to be received by June 15, 2007) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103234s5122lbl.pdf (addition of boxed warning for increased risk of death, cardiovascular events, thrombo-embolic events, tumor progression; include information delineating increased risk with use in renal and HIV patients; remove quality of life claims; clarify dosing strategies) www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103234s5158ltr.pdf (strengthen box label warnings and send dear doctor letter) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103234s5158lbl.pdf (cardiovacular-thombotic risk for renal and surgical patients more clearly outlined in boxed warning) www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/103234s5163ltr.pdf (typographical error in table 1 in warning section to be corrected) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103234s5163lbl.pdf (addition of boxed warning for increased risk of death, cardiovascular events, thrombo-embolic events, tumor progression; include information delineating increased risk with use in renal and HIV patients; remove quality of life claims; clarify dosing strategies) www.accessdata.fda.gov/drugsatfda_docs/label/2008/103234s5164lbl.pdf (unspecified changes in label and patient insert) 2-Darbepoetin www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/103951_5069ltr.pdf (thrombosis and tumor progression; dear doctor letter) www.accessdata.fda.gov/drugsatfda_docs/label/2004/103951_5069lbl.pdf (thrombosis and tumor progression; label change) www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/103951s5096ltr.pdf (pure red cell aplasia; dear doctor letter) www.accessdata.fda.gov/drugsatfda_docs/label/2005/103951s5096lbl.pdf (pure red cell aplasia; label change) www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/103951s5088ltr.pdf (agreement to provide information on 20010145 in small cell lung cancer patients, DE 2001-0033 (PREPARE-CIA in chemotherapy patients, DE-2002-0015 (ARA-03) in breast cancer patients, SE-2002-9001 (DAHANCA-10) in head-and-neck cancer patients, FR-2003-3005 (GELA LNH-036B) large B-cell lymphoma patients, adverse events [12/2011]) www.accessdata.fda.gov/drugsatfda_docs/label/2006/103951s5088lbl.pdf (dosing regimen q3 weeks) www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103951s5139ltr.pdf (boxed label warning section for cardiovascular, thrombotic, and tumor growth potential; provide information on survival in cancer patients) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103951s5139lbl.pdf (increase severity of adverse event warnings in label) www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103951s5135ltr%20.pdf (allergic reactions with rubber stoppers for vials) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103951s5135LBL.pdf (allergic reaction; label change) www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103951s5164ltr.pdf (dear doctor letter with new label changes) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103951s5164lbl.pdf (change in label, package insert, patient information) www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/103951s5169ltr.pdf (correction of typographical error in warning section) www.accessdata.fda.gov/drugsatfda_docs/label/2007/103951s5169lbl.pdf (typographical error; label change) www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/103951s5170ltr.pdf (includes data from DE 2001-0033 (PREPARE) and GOG191; dear doctor letter) www.accessdata.fda.gov/drugsatfda_docs/label/2008/103951s5170lbl.pdf (label change to warnings and boxed warnings sections) www.accessdata.fda.gov/drugsatfda_docs/label/2008/103951s5195PI.pdf (updated label) www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/103951s5211ltr.pdf (pure red cell aplasia in setting of hepatitis C treated with ribavirin and HIV and ribavarin and interferon; dear doctor letter) www.accessdata.fda.gov/drugsatfda_docs/label/2009/103951s5211Lbl.pdf (updated warnings section for red cell aplasia in label) F. In 2004, the FDA reviewed results of the Breast Cancer Erythropoietin Trial (BEST) and Henke studies. On May 4, 2004, the FDA convened a meeting of the Oncologic Drugs Advisory Committee May 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. Later that year, concerns regarding an increased rate of tumor progression and increased mortality were incorporated into the precautions section of product labeling. (Accessed July 19, 2010.) G. In February, 2006, the FDA issued a draft guidance for patient report outcomes (PRO). See www.fda.gov/OHRMS/DOCKETS/98fr/06d-0044-gdl0001.pdf and www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm118795.pdf. (Accessed July 19, 2010.) H. On November 16 or 17 (sic), 2006, the FDA issued the first of a series of alerts regarding ESA safety. I. On January 26, 2007, the FDA issued a “Dear Doctor Letter” regarding the use of ESAs for anemia management in the absence of chemotherapy. See www.fda.gov/medwatch/safety/2007/safety07.htm#Aranesp. (Accessed July 19, 2010.) J. On February 16, 2007, the FDA notified healthcare providers of increased mortality and no transfusion decrease in a study in darbepoetin using cancer patients not receiving chemotherapy. See www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152120.htm. (Accessed July 19, 2010.) K. On March 9, 2007, the FDA notified healthcare providers of increased adverse events including death in four studies of cancer patients. The trials were studying ESA use in an off-label patient population, in an off-label dosing regimen, or with an unapproved ESA. See www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152120.htm. (Accessed July 19, 2010.) L. In March 2007, the FDA sent Amgen a letter requesting that Amgen, in a post-marketing commitment, reassess the data used to make patient report outcomes (PRO) in ESA labels in concordance with the principles laid out in the FDA draft PRO guidance document. Amgen agreed to remove quality-of-life claims (e.g., happiness, life satisfaction, and well-being) from ESA labels. Claims that could be considered would be limited to health-related quality of life claims (physical, psychological, and social functioning that reflect the impact of a disease and its treatment). The sponsor was to provide the information by June 15, 2007. The FDA noted that the instruments for PRO claims must have content validity (documentation that the test items are derived from patient input and are appropriate, clinically meaningful, well-defined, specific to the target population/indication, interpretable, and comprehensive), construct validity, reliability, and the ability to detect change. If instruments are altered or used in different patient populations, they require re-validation. PRO instruments will not provide meaningful information unless they are used in adequately designed studies with blinding and prospective statistical analysis plans. Plans to address missing data and drop-outs must be made. M. On September 11, 2007, the FDA convened a joint meeting of the Cardio-Renal Drugs Advisory Committee (CRDAC) and Drug Safety and Risk Management Advisory Committee to discuss safety issue for ESAs. The briefing information and transcript for the meeting is available at www.fda.gov/ohrms/dockets/ac/cder07.htm#CardiovascularRenal. (Accessed July 19, 2010.) The FDA determined that on the basis of the documents submitted to the FDA by July 2007 that the PRO claims made in the label for erythropoietin were not adequately substantiated. Documents submitted subsequent to July 2007 were to be reviewed after the CRDAC meeting date. N. On November 8, 2007, the FDA notified healthcare professionals of ESA label changes including black box warnings. The warnings noted the tumor growth and shortened survival in study patients with advanced breast cancer, head and neck cancer, lymphoid cancer, and non-small cell cancer in which the ESA was dosed in an attempt to reach a hemoglobin of ≥ 12 g/dl. The warnings noted that ESAs, in the setting of cancer, should be used only when the anemia was due to the chemotherapy and should be discontinued with the cessation of chemotherapy. The notice provided information on management of poor responders to ESAs. See www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm152274.htm. (Accessed July 19, 2010.) O. On November 8, 2007, the FDA notified healthcare professionals of ESA label changes including black box warnings. The warnings noted that maintaining hemoglobin levels higher than 12g/dl increased the risk of death and other adverse events in patients with chronic renal failure. The notice provided information on management of poor responders to ESAs. P. On November 12, 2007, the FDA approved methoxy polyethylene glycol-epoetin beta for the treatment of anemia in renal disease. See www.accessdata.fda.gov/drugsatfda_docs/nda/2007/125164TOC.cfm and www.accessdata.fda.gov/drugsatfda_docs/label/2007/125164lbl.pdf . (Accessed July 19, 2010.) Q. On January 3, 2008, the FDA notified healthcare professionals of additional studies demonstrating tumor growth and shortened survival in patients with breast cancer (Preoperative Epirubicin Paclitaxel Aranesp Study [PREPARE]; Germany; n = 733) and cervical cancer (National Cancer Institute Gynecologic Oncology Group [COG-19] [sic GOG 191]; chemotherapy and radiation; 109 of 460 enrolled) after being notified by Amgen on November 30 and December 4, 2007 respectively. Enrollment was stopped early in the NCI study because of an imbalance in serious blood clots. Healthcare professionals were encouraged to review ESA risks with patients. See www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm152274.htm. (Accessed July 19, 2010.) (PREPARE information filed to clinicaltrials.gov/ct2/show/NCT00544232 without subsequent change on October 15, 2007. GOG-191 recruitment closure filed to clinicaltrials.gov/archive /NCT00017004/2007_08_06 on August 6, 2007.) (Accessed July 19, 2010) R. On August 14 and 15, 2008, the FDA convened a meeting of the Risk Communication Advisory Committee to discuss methods and procedures to effectively convey and reduce risk to patients. The briefing and transcript information is available at www.fda.gov/ohrms/dockets/ac/08/transcripts/2008-4377t1-01.pdf. (Accessed July 19, 2010.) S. On September 26, 2008, the FDA publically reported preliminary data from a German study in which an erythropoietin product not marketed in the U.S. (40,000 units daily for three days) and recombinant-tPA were used to treat acute ischemic stroke because there was an imbalance in the treatment arms for death. See www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136211.htm. (Accessed July 19, 2010.) T. On April 30, and May 1, 2009, the FDA convened a meeting of the Risk Communication Advisory Committee to discuss methods and procedures to effectively convey and reduce risk to patients. The briefing and transcript information is available at www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/RiskCommunicationAdvisoryCommittee/ucm158758.htm. (Accessed July 19, 2010.) U. On April 30, 2009, the FDA revised the March 2007 boxed warning to address issues regarding ESA use by both patients with cancer and patients with chronic kidney failure. The warning noted that ESA dosing in oncology studies with hemoglobin targets of 12 g/dL or greater, whether the target was achieved or not, has resulted in more rapid cancer progression or shortened overall survival in cancer patients with advanced breast, head and neck, lymphoid and non-small cell lung malignancies and that these risks have not been excluded in cancer patients with hemoglobin targets of less than 12 g/dL The warning noted that ESAs should only be used to treat chemotherapy-induced anemia while patients are undergoing chemotherapy and not other types of anemia. (The indications section indicated that the chemotherapy should be myelosuppressive.) The warning noted that ESA dosing in renal disease studies with higher hemoglobin targets (e.g., 13.5 g/dL versus 11.3 g/dL and 14 g/dL and 10 g/dL), whether the target was achieved or not, has resulted in greater risks of death and serious cardiovascular events including heart attack, stroke and heart failure in pre-dialysis and dialysis patients. (In the non-boxed warning section, the warning noted an increased risk of mortality and cardiovascular complications in renal patients poorly responsive to ESA doses and given high ESA doses [CHOIR and NCHT trials cited.]). V. In December 2009, the FDA issued the final version of the guidance for patient-report outcome measures. See www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM193282.pdf. (Accessed July 19, 2010.) W. In February 2010, the FDA required all ESAs to be prescribed and used under a risk evaluation and mitigation strategy (REMS) to ensure the safe use of these drugs. As part of the REMS, a Medication Guide explaining the risks and benefits of ESAs must be provided to all patients receiving ESAs. Information is available at www.fda.gov/AboutFDA/CentersOffices /CDER/ucm200847.htm, www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109375.htm, www.fda.gov/AboutFDA/CentersOffices/ CDER/ucm200847.htm, www.accessdata.fda.gov/drugsatfda_docs/appletter/2010 /103951s5197ltr.pdf , www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/103234s5199ltr.pdf . (Accessed July 19, 2010) X. On October 18, 2010, the FDA convened a meeting of the Cardio-Renal Drugs Advisory Committee (CRDAC) to discuss safety issues for ESAs in TREAT trial. The briefing information is available at www.fda.gov/downloads/AdvisoryCommittees/.../Drugs/.../UCM236323.pdf. The transcript for the meeting is available at www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM233461.pdf. (Accessed July 19, 2010.) Prior to the CRDAC meeting, Amgen submitted proposed labeling changes to the FDA regarding the use of ESAs in chronic renal failure patients not on dialysis that would limit treatment to patients who are most likely to benefit, specifically those with significant anemia ( < 10 grams per deciliter ["g/dL"), and who are at high risk for transfusion and for whom transfusion avoidance is considered clinically important, including those in whom it is important to preserve kidney transplant eligibility. A more conservative dosing algorithm in these patients was also proposed. The sponsor also recommended against increased dosing in hyporesponsive patients. (See pages 88 and 89 www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM229328.pdf.) (Edgar 10-Q 08/09/10); accessed November 3, 2010) VI. General Methodological Principles When making national coverage