Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 1 of 32 Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Contents 1. New Evidence 2. Lack of ESA and blood transfusion comparability 3. Legal considerations 4. Policy and process issues 5. Recommendations 6. Material misinterpretations 7. References Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 2 of 32 New Evidence 1. Data concerning the hemoglobin (Hb) concentrations at which patients receive transfusions. A FDA Medical Officer report supporting once-weekly epoetin alfa approval, recently published studies, and a review of data from existing clinical trials help characterize the Hb concentrations at which chemotherapy induced anemia patients require transfusions. These data demonstrate that a subset of chemotherapy-treated cancer patients require transfusion support when their pre-transfusion Hb levels are greater than 10 g/dL, and a substantial number require transfusion when their Hb concentrations are above 9 g/dL. Twenty-three percent of the transfusion episodes in Medicare recipients included in an ESA registry occurred with a pre-transfusion Hb value greater than or equal to 9.0 g/dL. Review of these transfusion events reveals that the majority have occurred in patients with symptoms of anemia e.g. dyspnea, fatigue, etc and/or co- morbid conditions confirming the medical necessity for these transfusions. The NCD states: “...Transfusions are not required for hemoglobin levels 10.0 g/dL or greater. There are no definitive data regarding transfusion need, and by extension ESA need for patients with hemoglobin levels between 7 and 10 g/dL.” (NCD p. 21) While such a statement may be relevant to other populations (e.g., patients in the intensive care unit or postoperative setting), experience shows that cancer patients receiving chemotherapy have different transfusion support needs and differing Hb levels at which transfusions are required. This is not unexpected, given malignancy-related and therapy- related side effects experienced by ambulatory cancer patients who strive to maintain the premorbid functional status. The FDA Medical Officer Report of the placebo-controlled epoetin alfa weekly dosing trial described patients with pre- transfusion Hb levels up to 10.7 g/dL prior to study entry (FDA Medical Officer Report p. 16) with a similar finding during the study (FDA Medical Officer Report p. 27). Two to 3% of transfusion episodes occurred at a pre-transfusion Hb level > 10 g/dL (FDA Medical Officer Report p.27). Similar finding have been reported with the published literature and analyses of controlled clinical trials. Dernedde (2007) reported increases in the transfusion trigger in the oncology population from 2001-2004. “...Looking at the hemoglobin levels preceding transfusion (trigger levels) on two separate occasions, the mean trigger hemoglobin level rose from 8.53 g/dL in the first year of the audit to 8.86 g/dl in the third year (p< 0.001, t test)...” (Dernedde 2007) Additionally, 4% of transfusions were administered for patients with a pre-transfusion Hb level of 10-11.9 g/dL. Controlled ESA clinical trials have reported similar findings with regard to transfusion trigger including 10-14% of transfusions with pretransfusion Hb > 9 g/dL as described in the table below (Ortho Biotech data on file) Review of events prior to transfusion reported anemia-related symptoms including fatigue, shortness of breath, dyspnea on exertion, and chest palpitations, which provides supporting evidence that the transfusions were medically necessary. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 3 of 32 Proportion of transfusion episodes stratified by pretransfusion Hb level Published ESA clinical trial Hb 9.1-10 g/dL Hb > 10 g/dL Witzig (2005) 6.7% 3.6% Waltzman (2005) 10.3% 1.6% Henry (2006) 10.0% 3.8% Data from an ongoing registry, which reflects real world practice, reported that 19% of transfusion episodes occurred at a pre-transfusion Hb level of > 9 g/dL. In a subset analysis of the Medicare population from this registry, 23% of transfusion episodes occurred at a Hb level > 9 g/dL. Review of these transfusion events reveals that the majority have occurred in patients with symptoms of anemia e.g. dyspnea, fatigue, etc and/or co-morbid conditions confirming the medical necessity for these transfusions Pre-transfusion Hb reported from ongoing ESA registry in chemotherapy-treated cancer patients Transfusion trigger (g/dL) <7 7-7.9 8-8.9 9-9.9 10-10.9 11-11.9 Total number of transfusions 14 (4%) 96 (31%) 141 (45%) 48 (15%) 14 (4%) 1 (0.3%) (%) (N=314) Medicare Patients (n=150) 8 (5%) 47 (31%) 61 (41%) 22 (15%) 12 (8%) 0 (0%) 2. Data concerning transfusion risks associated with various hemoglobin concentrations at which ESA therapy is initiated. New data from an ongoing ESA registry of patients with chemotherapy-induced anemia demonstrates that a significantly greater proportion of chemotherapy-treated cancer patients initiated on ESAs at baseline Hb below 10 g/dL required transfusion compared with those initiated on ESAs at baseline Hb 10-11 g/dL. Additionally, a recent integrated analysis of patient-level data from three clinical trials reports significantly greater transfusion requirements in patients initiated at lower Hb levels, including 165% higher transfusion risk in patients with ESA initiation at Hb < 10 g/dL versusHb 10-11 g/dL. New medical claims analyses of ESA-treated cancer patients receiving chemotherapy report significantly greater hospitalization risk, length of hospital stay and transfusion rates in patients whose ESA treatment was initiated at a Hb ≤10 g/dL compared with those whose ESA treatment was initiated at a Hb >10 g/dL. The Dosing and Outcomes Study of Erythropoiesis Stimulating Therapies (DOSE) is an ongoing registry of oncology patients treated in U.S. community clinics and hospital centers. The registry provides observational outcomes data in oncology patients receiving chemotherapy from over eighty sites that provide a national representation. In a new analysis of > 960 patients, a significantly greater proportion of chemotherapy-treated cancer patients required transfusion in those initiated on ESAs at baseline Hb < 10 g/dL compared with baseline Hb 10-11 g/dL. This analysis also reported significantly greater blood utilization in patients initiated at baseline Hb < 10 g/dL compared with a baseline Hb of 10-11 g/dL. Baseline Hb < 10 g/dL 10-11 g/dL p value Proportion of patients requiring blood transfusion 31% 14% <0.0001 Blood utilization (Units/study patient) 0.89 0.44 < 0.0001 Similar findings have been reported in clinical trial analyses in data previously reported to CMS (June 13th submission) comparing patients initiated at a Hb < 10 g/dL compared with those with ESA initiation of 10-11 g/dL. The table below summarizes clinical trial data that reported a higher proportion of patients requiring blood transfusion in the groups with Hb levels at ESA initiation of < 10 g/dL compared with Hb levels of 10-11 g/dL. Proportion of patients requiring blood transfusion stratified by baseline Hb Proportion of patients transfused stratified by Hb at ESA Author initiation Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 4 of 32 < 10 g/dL 10-11 g/dL Vadhan-Raj (2003) 39% (33,34) 16% (14,19) Vansteenkiste (2004) 31% (17,45) 15% (8,22) Boccia (2006) 28% (24,32) 12% (9,14) Szczudlo (2007) 36% (24,48) 9% (3,15) Szczudlo (2007) 29% (18,40) 3% (0,7) Quirt (2006) evaluated patient level data from three clinical trials to assess transfusion patterns in patients treated with epoetin alfa based on prior transfusion use and hemoglobin at time of ESA initiation. Baseline Hb was found to be a significant predictor of transfusion risk. The authors stated: “...As anticipated, patients with baseline Hb levels <10 g/dl had a significantly higher risk for subsequent transfusion than patients with baseline Hb levels of 10–11 g/dl. When directly comparing Hb level strata at which epoetin alfa treatment was initiated, patients were found to have a 165% higher risk for transfusion from day 29 to the end of study (RR, 2.65; 95% CI, 1.54–4.56) at a baseline Hb level <10 g/dl compared with a baseline Hb level of 10–11 g/dl...patients who were treated at a baseline Hb level < 10 g/dl having a higher chance of being transfused than patients in whom epoetin alfa was initiated at baseline Hb levels of 10–11 g/dl. In addition, when the total units transfused in patients receiving epoetin alfa at different baseline Hb levels were analyzed, >85% of the units of blood transfused were received by patients with baseline Hb levels < 10 g/dl...” This was also demonstrated in modeling of transfusion requirements and baseline Hb. The figure below represents the number of units transfused per patient based on Hb level at initiation of ESA administration for all patients. The findings of greater red blood cell utilization with lower Hb levels prior to ESA administration were even greater in those patients who had a transfusion requirement within 28 days of initiating ESA (baseline pre-transfusion). An analysis of medical claims and laboratory data in 820 ESA-treated cancer patients receiving chemotherapy stratified by baseline Hb level (Hb ≤10 g/dL versus Hb >10 g/dL within 28 days of treatment initiation) was conducted. Treatment groups were similar with regard to age, gender distribution, and mean ESA treatment duration. Outcomes measures for the analyses included hospitalization rates, hospital length of stay (LOS) and transfusion rates during ESA treatment. The incidence rates (number of events divided by the person-time of observation) were compared between the two groups. ESA initiation with lower Hb levels increased the risk of hospitalization by 47% (95% CI: 17%- 85%, p<0.001) compared to initiating treatment at Hb>10 g/dL. The hospital LOS and blood transfusion rates were also significantly different between groups, revealing a 53% increased in hospital LOS (95% CI: 38%-69%, p < 0.001) and a 3.6-fold increase in the risk of blood transfusion (95% CI: 2.4-5.4, p < 0.001) for patients whose ESA treatment was initiated at a Hb value ≤10 g/dL compared to those with Hb value >10 g/dL. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 5 of 32 3. Data correlating maximum Hb limits to achieved Hb concentration. Observational data from the ESA registry demonstrate that mean Hb levels achieved in ESA-treated cancer patients are usually 1-1.5 g/dL below the recommended Hb ceiling, i.e. the Hb value at which recommendation is made to suspend ESA dosing (the FDA-recommended prescribing information recommended a Hb ceiling of 13 g/dL during the majority of the data collection period). Modeling Hb changes (+/- SD) over time and applying the potential impact in the downward shift of the Hb limit to 10 g/dL, indicates that approximately 50% of ESA-treated patients’ Hb values would fall in the range of 8-9 g/dL, a Hb range that is seen in 41% of patients who receive blood transfusions in the same registry. The graph below reported the data from 1257 patients treated in oncology clinics between 2004-2007. During this time, FDA-approved prescribing information recommended a Hb cap of 13 g/dL during the majority of the data collection period. As illustrated, mean Hb levels approximated 11 g/dL however evaluation of the standard deviation (vertical bars) reported excursions to Hb > 12 g/dL during ESA treatment. Prescribing information now clearly articulate the recommendations to stop ESA administration for Hb > 12 g/dL 13 12 Hemoglobin (g/dL) 11 10 9 8 7 0 4 8 12 16 ESA treatment week The following graph describes the estimated mean Hb values and standard deviations with Hb cap of 12 g/dL which suggest minimal Hb values > 12 g/dL and modest number of Hb values in the Hb range of 8-9 g/dL, where the transfusion risk is greater. 13 12 Hemoglobin (g/dL) 11 10 9 8 0 4 8 12 16 ESA Treatment Week Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 6 of 32 Estimated Hb values and standard deviation with Hb cap of 11 g/dL, which suggests a large number of patients in the Hb range of 8-9 g/dL, where the transfusion risk is greatest. 13 12 Hemoglobin (g/dL) 11 10 9 8 7 0 4 8 12 16 ESA treatment week 4. Recent product labeling reviews in the EMEA and in the United States. Following an exhaustive review of available data, the EMEA’s Committee for Medicinal Products for Human Use (CHMP) and its Pharmacovigilance Working Party (PhVWP) concluded that the benefits of these products continue to outweigh their risks in the approved indications, but recommended the following changes to the product information: (1) Changes to the ‘Indication’ section (section 4.1), saying that epoetins should be used in the treatment of anaemia only if associated with symptoms and (2) Changes, stipulating a uniform target haemoglobin range for all epoetins of 10 g/dL to 12 g/dL with a warning not to exceed a concentration of 12 g/dL. (European Medicines Agency press release, October 23, 2007). The updated FDA-approved erythropoietic stimulating agent (ESA) prescribing information (November 2007) maintains a Hb upper safety limit of 12 g/dL, permitting appropriate flexibility of ESA dosing based on individual patient need and response for various clinical scenarios. The updated label does not restrict ESA initiation or maintenance to Hb limits of < 10 g/dL. As described in the October 2007 EMEA press release: “The European Medicines Agency (EMEA) has recently reviewed the safety of epoetins. These medicines are used for the treatment of anaemia in patients with chronic renal failure and for the treatment of patients with non-myeloid malignancies receiving chemotherapy. The safety review was initiated because data from recent clinical trials show a consistent unexplained excess mortality in patients with anaemia associated with cancer who have been treated with epoetins. In addition, the results of two studies and a meta-analysis have recently been published suggest that treatment of anaemia with epoetins in patients with chronic kidney disease to achieve relatively high target haemoglobin concentrations may be associated with an increase in the risk of mortality and cardiovascular morbidity...” Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 7 of 32 Johnson & Johnson has been in close collaboration with the FDA regarding new clinical trial evidence and recommendations of the May 2007 Oncology Drug Advisory Committee meeting regarding ESAs. The prescribing information was updated in March 2007 with the following dosing recommendations for cancer chemotherapy patients. March 2007 Epoetin alfa prescribing information TIW Dosing Starting Dose: Adults 150 Units/kg SC TIW; Reduce Dose by 25% when: 1. Hgb approaches 12 g/dL or, 2. Hgb increases > 1 g/dL in any 2-week period Withhold Dose if: Hgb exceeds 12 g/dL, until the hemoglobin falls below 11 g/dL, and restart dose at 25% below the previous dose. Increase Dose to 300 Units/kg TIW if: response is not satisfactory (no reduction in transfusion requirements or rise in hemoglobin) after 8 weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed 12 g/dL Weekly Dosing Starting Dose: Adults 40,000 Units SC; Pediatrics 600 Units/kg IV (maximum 40,000 Units); Reduce Dose by 25% when: Hgb approaches 12 g/dL or increases > 1 g/dL in any 2 weeks Withhold Dose if: Hgb exceeds 12 g/dL, until the hemoglobin falls below 11 g/dL, and restart dose at 25% below the previous dose Increase Dose if: response is not satisfactory (no increase in hemoglobin by ≥1g/dL after 4 weeks of therapy, in the absence of a RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed 12 g/dL: Adults: 60,000 Units SC Weekly Pediatrics: 900 Units/kg IV (maximum 60,000 Units) The FDA-approved ESA prescribing information, updated in October 2007, continued recommendations to avoid ESA administration for Hb levels > 12 g/dL, however, no recommendations or clinical data were incorporated to initiate or maintain Hb levels at <10 g/dL during ESA treatment. November 2007 Epoetin alfa prescribing information TIW Dosing Starting Dose: Adults 150 Units/kg SC TIW; Reduce Dose by 25% when: Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-week period; Withhold Dose if: Hemoglobin exceeds 12 g/dL and restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required; Increase Dose to 300 Units/kg TIW if: Response is not satisfactory (no reduction in transfusion requirements or rise in hemoglobin) after 8 weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed the upper safety limit of 12 g/dL Weekly Dosing Starting Dose: Adults 40,000 Units SC; Pediatrics 600 Units/kg IV (maximum 40,000 Units) Reduce Dose by 25% when: Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-weeks Withhold Dose if: Hemoglobin exceeds 12 g/dL and restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required Increase Dose if: For Adults: 60,000 Units SC Weekly For Pediatrics: 900 Units/kg IV (maximum 60,000 Units) if: Response is not satisfactory (no increase in hemoglobin by ≥ 1 g/dL after 4 weeks of therapy, in the absence of a RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed the upper safety limit of 12 g/dL 5. New National Practice Guidelines. October 2007 evidence-based anemia treatment guidelines, issued by the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) support ESA initiation at Hb< 10 g/dL or 10- 12 g/dL in special populations (“including but not limited to elderly individuals with limited cardiopulmonary reserve, those with underlying coronary artery disease or symptomatic angina, or substantially reduced exercise capacity, energy, or ability to carry out activities of daily living)”, treatment to hemoglobin concentration to (or near) 12 g/dL, and dose adjustments consistent with prescribing information. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 8 of 32 Updated ASH/ASCO recommendations are consistent with 2007 National Comprehensive Cancer Network (NCCN) anemia treatment guidelines. The American Society of Hematology and American Society of Clinical Oncology established a joint committee to update the clinical practice guidelines on the use of the erythropoietic stimulating agents. The committee reviewed clinical literature available through July 2007, which included clinical trials, systematic reviews and meta-analyses including the 2006 Cochrane Review and the 2006 Agency for Healthcare Research and Quality-sponsored comparative effectiveness systematic review. Additionally discussions/publications of the 2004 and 2007 Oncology Drug Advisory Committee meeting regarding ESAs and FDA-approved prescribing information were considered. The 2007 ASH/ASCO ESA guidelines (Rizzo 2007) included the following: Hb initiation “...The use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy- associated anemia and a Hb concentration that is approaching, or has fallen below, 10 g/dL to increase Hb and decrease transfusion...For patients with declining Hb levels but less severe anemia (those with Hb concentration < 12 g/dL, but who have never fallen near 10 g/dL), the decision of whether to use epoetin or darbepoetin immediately or wait until the H levels fall close to 10 g/dL, should be determined by clinical circumstances (including but not limited to elderly individuals with limited cardiopulmonary reserved, those with underlying coronary artery disease or symptomatic angina, or substantially reduced exercise capacity, energy, or ability to carry out activities of daily living [ADLS])...” Hb target “...Hb can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin and darbepoetin should be titrated to maintain that level...” Dose adjustment “...Dose escalation should follow FDA recommendations...Dose reductions are also recommended when Hb rise exceeds 1 g/dl in any 2 wk period or when Hb exceeds 11 g/dL....” It is relevant to note that the NCD (p. 21 of 61) quoted the 2002 American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) guidelines; however, only a portion of the guidelines was included. The NCD stated: “...ASCO and ASH guidelines recommended evaluating patients for the need for ESA therapy when the hemoglobin is at or below 10 g/dL…” It is unclear why the second portion of this guideline was not mentioned in the CMS NCD, as it includes information relevant to the Medicare population. They specifically recommend ESA initiation at an Hb of 10-12 g/dL in certain clinical conditions, such as the elderly. “...The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances... Examples of patients at this higher degree of absolute risk, who may be considered reasonable candidates for this agent, based on clinical judgment, include but are not limited to elderly individuals with limited cardiopulmonary reserve or patients with underlying coronary artery disease and symptomatic angina...” (Rizzo 2002) The NCD reference list included the NCCN anemia treatment guidelines (accessed 4/5/07), however such guidelines are not mentioned in the evidence section describing ESA intervention (NCD p. 21 of 61). It is unclear why such anemia guidelines were not explicitly considered in the evidence supporting the NCD. Additionally, updated NCCN anemia treatment guidelines were issued since the version referenced in the NCD document. The more recent NCCN anemia treatment guidelines (v. 3.2007, dated 4/10/07) recommended ESA initiation at a hemoglobin level of < 11 g/dL for cancer patients with chemotherapy-induced anemia: Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 9 of 32 “Following the identification of anemia (defined for the purpose of considering intervention as hemoglobin levels equal to or less than 11 g/dL) and the evaluation for anemia specific causes, an initial risk assessment should be completed...The history should assess whether accompanying symptoms are present, such as chest pain or dyspnea. Comorbidities such as cardiac disease or underlying pulmonary disease must be considered...Observation or erythropoietic therapy should be considered for asymptomatic patients with risk factors for developing anemia. The decision of whether to use epoetin immediately or to wait until hemoglobin levels fall closer to 10 g/dL should be determined by clinical circumstances. For symptomatic patients, transfusion and/or erythropoietic therapy are recommended. If the patient's hemoglobin level is between 10- 11 g/dL, the panel recommends the consideration of erythropoietic therapy with or without transfusion. If the patient's hemoglobin level is <10 g/dL, the panel strongly recommends erythropoietic therapy...” (NCCN anemia treatment guidelines v.3.2007) The updated NCCN anemia treatment guidelines highlighted changes from previous versions, which included the following: “.... The target hemoglobin was changed from 12 g/dL to 11-12 g/dL throughout the guidelines. The recommendation threshold for holding therapy was changed from 13 g/dL to 12 g/dL...” (NCCN anemia treatment guidelines v.3.2007 6. Further information concerning ESA U.S. registration trials. The FDA Medical Officer Report regarding weekly epoetin alfa dosing in cancer chemotherapy patients was recently (September 27, 2007) posted to FDA’s website and provides new data for CMS’s consideration, including comments on safety and efficacy of once weekly epoetin alfa dosing and comparable safety of TIW and QW epoetin alfa dosing. Additionally, the Johnson & Johnson Pharmaceutical Research and Development clinical study report of once weekly epoetin alfa in the oncology population has been made available to CMS as part of this reconsideration request (The information contained within this study report includes commercial trade secret information and is proprietary and confidential. This information should not be disclosed to any third party without the prior written consent of Ortho Biotech Products, LP. The trade secrets and commercial proprietary and confidential information herein are exempt from disclosure under 20 CFR § 402.90 and 5 USC 552(b)(4). The Center for Drug Evaluation and Research FDA Medical Officer Report provided new insights regarding the clinical data supporting the FDA-approved use of once-weekly dosing for epoetin alfa. The report summarized the data evaluated by the FDA review team. The recommendation of clinical approvability included the following: “...Results demonstrated that Epogen/Procrit therapy reduce the proportion of patients transfused in day 29 through week 16 of the study as compared to placebo. Twenty-five patients (14%) in the Epogen/Procrit group received transfusion compared to 48 patients (28%) in the placebo group (p=-.0010) between day 29 and week 16 or the last day on study. The safety data from this study were comparable between the placebo and the treatment arm study...” (FDA Medical Officer review p. 5) Additionally, reviewers commented on safety data from the EPO-PHI-377 trial that compared epoetin alfa TIW and QW dosing. The reviewers stated, “...As can be seen, the adverse events profile in this small study showed comparability between the two study arms...” (FDA Medical Officer review p. 66) 7. Placebo-controlled trial data from an unplanned interim analysis reported similar tumor-related and survival outcomes in Hodgkin’s lymphoma patients in ESA- and placebo-treated groups An unplanned interim analysis of a placebo-controlled trial (planned N=1,500) that included data from 688 patients with advanced stage Hodgkin’s lymphoma receiving chemotherapy was reported in November 2007. The trial was conducted to evaluate safety and efficacy of three different dose/schedules of BEACOPP combination chemotherapy. A second randomization assigned patients to epoetin alfa 40,000 Units weekly or placebo. ESA administered when the Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 10 of 32 Hb level was < 14 g/dL and dose hold for Hb > 14 g/dL. The Hb level of ESA initiation was changed to Hb level < 13 g/dL following protocol amendment in February 2004. For a maximum of six weeks following chemotherapy completion, Hb levels were targeted to 12 g/dL This analysis at 30 month follow-up (mean) reported no significant difference between epoetin alfa and placebo groups in tumor response rate, freedom from treatment failure, or overall survival. Compared to placebo, epoetin alfa treatment significantly reduced the number of RBC units transfused. Preliminary results of this Hodgkin’s lymphoma placebo-controlled ESA trial were consistent with multiple randomized, controlled trials of ESAs in tumor-specific clinical trials (lung cancer, head and neck cancer, breast cancer, cervical cancer). These trials reported similar tumor-related and/or survival outcomes in the ESA- and placebo-treated groups. Such findings were reported to CMS in the June 13th Ortho Biotech clinical white paper and described in the table below. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 11 of 32 Epoetin alfa Pharmacovigilance Program Evaluating Safety in Epoetin alfa Safety in Patients with Chemotherapy-induced Anemia STUDY # Tumor Type Primary Secondary Safety Results Status (n, Endpoint Endpoint accrual/ planned) Tumor response (designed to Objective Tumor response: EPO 72% (95%CI: exclude an 64-81%), placebo 67% (95% CI: 58-76%). No Lung cancer, treated with absolute more than a 6% difference in RR between the 2 Stopped in agreement with FDA due to slow N93-004 Overall chemotherapy, Target Hb reduction of groups was ruled out therefore primary endpoint accrual secondary to changing standard of (224/400) survival 14-16 g/dL 15% in RR was met. care ; Manuscript published (Grote 2005) between the Overall survival (months): EPO 10.5, control EPO and 10.4, (p=0.264) control groups) Lung cancer, Target Hb 12- Significant difference in the median survival in EPO- Terminated November 2003 based on 14 g/dL (anemia of cancer; Quality of life Hemoglobin favor of the patients on the placebo arm of the CAN-20 unplanned interim analysis; Manuscript not candidates for further change trial (EPO 63 v placebo 129 days; hazard ratio, (70/300) published (Wright 2007) chemotherapy) 1.84; P .04) No survival disadvantage for EPO group; Closed to accrual December 2005; Lung cancer treated with Ger-22 2 year survival Local tumor Interim analysis, median survival 2-year survival data mature 4Q07(Debus chemotherapy, target 12- (389/612) rate control EPO 338 days (95% CI 242-434) 2006) 14 g/dL1 Control 299 (95% CI 234-364) Closed in November 2003 based on RTOG 99- Head and neck cancer Local-regional Overall 1 yr local-regional control HR 1.18 (95% CI unplanned interim analysis; Abstract 03 receiving RT; Target Hb failure survival 0.67-2.09); published (Machtay 2004); Manuscript (148/372) 14-16 g/dL 1 yr overall survival HR 1.57 (95% CI 0.76-3.27) submitted EPO- Closed to accrual April 2002 due to slow Head and neck cancer 2 year local No effect on local tumor control GBR-7 Overall accrual; 5 year follow-up ongoing; Last patient receiving RT; Target Hb disease free 1 year survival EPO 77.3%, control 79.9% (301/800) survival out 2Q07 (Data on file #9, JJPRD; FDA 12.5-15 g/dL survival (p=0.867) ODAC Briefing Information, May 10, 2007) KEY: Hb, hemoglobin; EPO, epoetin alfa RT,radiation therapy; HR, Hazard Ratio, 1 Protocol amended in October 2003 to target Hb range of 12-13 g/dL Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 12 of 32 Epoetin alfa Pharmacovigilance Program Evaluating Safety in Epoetin alfa Safety in Patients with Chemotherapy-induced Anemia STUDY # Tumor Type Primary Secondary Safety Results Status (n, accrual/ Endpoint Endpoint planned) Closed to accrual October 2002; 5 5 yr DFS, 5yr disease free survival: EPO 72%, control 71% (p=0.86) Breast cancer; 2 year disease yr survival data mature 2Q2008; Moebus 5 yr Overall overall survival as of Apr. ‘07: EPO 81%, control 83% Target Hb 12.5 -13 g/dl free survival Abstract published (Data on file #7, survival (p=0.89) JJPRD; Moebus 2007) Accrual ongoing (JJPRD trial Breast cancer EPO-ANE- Progression- Overall available at Target Hb not to exceed Patient accrual ongoing 3010 12 g/dl free survival survival www.clinicaltrials.gov - ID NCT00338286) EPO-CAN- Breast cancer, treated A total of 55 subjects died (27 in the epoetin alfa group and Closed to accrual May 2003; 2 yr Overall 17 with chemotherapy Quality of life 28 in the SOC group). Kaplan-Meier estimates of the Clinical Study Report Submitted to survival (354/350) Target Hb 12-14 g/dL survival curves were similar (log rank test, p=0.82) FDA (Chang 2005) Interim analyses Recurrence rate: EPO 11%, control 22% (p=0.04), AGO/ Cervical cancer, treated 5 year relapse Median observation time: 64 weeks Closed to accrual March 2001; NOGGO with chemotherapy Overall free survival Follow-up ongoing, 5 yr relapse (264/264) Target Hb 13 g/dL survival The difference in recurrence between the groups at the free survival data available 3Q’07 105-week observation was less (25% versus 17% for the (Blohmer 2003) control and epoetin alfa groups, respectively), but trended toward significance (p=0.074) KEY: Hb, hemoglobin; EPO, epoetin alfa; JJPRD: Johnson & Johnson Pharmaceutical Research & Development, L.L.C; RT, radiation therapy; Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 13 of 32 Lack of ESA and transfusion comparability The NCD assumes incorrectly that transfusions and ESA treatment are interchangeable. Clinical studies reported inferior cancer-related and mortality outcomes in transfused patients compared with non-transfused patients. CMS’ national coverage policy for ESAs positions ESAs and transfusions as interchangeable substitutes for one other. In their communications, CMS has even suggested that transfusions are at best preferred, or at worst “not a big deal” for cancer patients with chemotherapy-induced anemia (CIA). This approach ignores the fundamental differences between the therapeutic goals, patient experience, timing, effects, and known and theorized risks of each. The NCD forces a singular and substituted judgment on all Medicare beneficiaries with chemotherapy-induced anemia (CIA). This judgment is levied in the presence of incomplete evidence of differential harm, yet tangible differences, in why the treatments are used, and how they are perceived by and delivered to patients. In addition, the potential for unintended and harmful consequences for other patients -- those who urgently require blood or time in an infusion chair/hospital bed -- appear to have been ignored. ESAs are pharmacologic treatments whose primary therapeutic goal is to reduce the risks of transfusion, with a secondary goal of reducing the signs and symptoms of anemia. The decision of when to treat with ESAs is driven by the primary therapeutic goal, and a Hb trigger of 10g/dL is not uncommon because ESA treatment effects are not seen until 2-6 weeks after treatment initiation, during which time hematopoietic stimulation and the production of red blood cells occurs. The onset of action has been well described in the FDA Medical Officer report of weekly epoetin alfa in this population: “...Following exogenous erythropoietin administration, a clinically significant increase in hemoglobin is usually not observed in less than 2 weeks and may require up to 6 weeks because of the length of time required for erythropoiesis-several days for erythroid progenitors to mature and be released in the circulation...” (FDA Medical Officer report, p. 9) Evidence in randomized controlled trials shows that transfusion avoidance is maintained with continuous treatment and a hemoglobin target of 10-12g/dL (Abels 1996, Witzig 2005, Vansteenkiste 2002, Canon 2006). There is no evidence that intermittent ESA treatment or limiting ESA administration to Hb levels <10 g/dL following the initial four weeks of ESA treatment is effective or safe in avoiding blood transfusions. There are data on the inability of blood transfusions to sustain Hb levels over time. The chart below depicts Hb levels over time in 11 multiple myeloma patients treated with either 150 IU/kg TIW epoetin alfa or blood transfusion. The vertical arrows indicate time points of allogeneic blood transfusion. The ‘without epoetin alfa’ line shows patients not receiving epoetin alfa who are repeatedly subjected to allogeneic red blood cell transfusions. (Couture 2005). It is apparent that blood transfusions provide only transient relief and fail to maintain Hb levels compared to continuous epoetin alfa therapy. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 14 of 32 ESAs are readily available, and their use can spare blood consumption in cancer chemotherapy patients in whom transfusion can be avoided. ESA treatment is typically delivered at a doctor’s office 2-4 times a month via subcutaneous injection, during a visit that is routinely scheduled for physician consultation, therapeutic treatment or diagnostic monitoring. Known risks include thrombovascular events (TVEs) when patients are treated to Hb levels above 12g/dL in clinical trials. In those trials, higher mortality has been observed. While that outcome is partially attributable to TVEs, it is also hypothesized to be the result of tumor proliferation. Blood transfusion is a medical procedure with therapeutic goals of hemodynamic stability and alleviation of anemia-related signs and symptoms. The decision to intervene with transfusion is usually driven by the patient’s clinical condition, inclusive of tumor- and treatment-related side effects, comorbidities, and the severity/rapidity of anemia onset. A Hb trigger of 8-10 g/dL is not uncommon in the cancer chemotherapy population, as seen in clinical trials and observational studies. Treatment effects are seen immediately, with response rate and duration dictated by the clinical scenario and alloimmunization from previous blood transfusions. Blood is a very limited resource, most of which is consumed in urgent settings such as trauma and surgery. Transfusion for CIA requires patients to wait for scheduling availability, travel to the hospital, provide informed consent, undergo multiple tests, experience venous access, occupy one of a limited number of infusion chairs or beds while receiving blood, spend from 12-24 hours in the hospital, and occasionally be admitted. From a humanistic perspective, patient perceptions of blood transfusion elicit intermediate ratings of dread and severity similar to reactions of genetically modified food, nuclear reactors, and pesticides (Lee 2006). Known risks of blood transfusion include blood type mismatches, infection, thrombovascular events, immunomodulation, transfusion-related acute lung injury (TRALI), and fluid or iron overload as described in th the Ortho Biotech June 13 clinical white paper submitted to CMS. Adverse patient outcomes have been associated with transfusion in multiple patient populations, including increased cancer recurrence rates in colorectal cancer patients, and increased morality in patients with acute lung injury and trauma patients. In a Cochrane meta-analysis, Amato et al (2006) reported increased cancer recurrence rate in patients that received perioperative transfusion. “...Thirty-six studies on 12,127 patients were included: 23 showed a detrimental effect of PBT (perioperative blood transfusion); 22 used also multivariable analyses, and 14 found PBT to be an independent prognostic factor. Pooled estimates of PBT effect on colorectal cancer recurrence yielded overall OR of 1.42 (95% CI, 1.20 to 1.67) against transfused patients in randomized controlled studies. Stratified meta-analyses confirmed these findings, also when stratifying patients by site and stage of disease. The PBT effect was observed regardless of timing, type, and in a dose-related fashion, although heterogeneity was detected...” (Amato 2006) Netzer (2007) reported transfused of red blood cells in patients with acute lung injury was associated with increased hospitalization. “...RBC transfusion was evaluated as a risk factor using several methods, all of which revealed an association with mortality. As a dichotomous variable, the transfusion of any RBCs (> 1 U) was associated with an unadjusted OR for mortality of 2.90 (95% confidence interval [CI], 1.32 to 6.35; p = 0.008) compared to those never receiving RBCs. This increased OR remained significant (3.12; 95% CI, 1.28 to 7.58; p= 0.012) when adjusted for age, gender, APACHE III score, and precipitating event in a logistic regression model....” (Netzer 2007) Malone (2003) reported blood transfusion as an independent predictor of mortality, ICU admission, ICU length of stay, and hospital length of stay in a study of > 15,000 trauma patients. “...Logistic regression analysis documented a significantly increased risk for mortality in Blood Transfusion patients (OR, 2.83; 95% CI, 1.82–4.40) (Table 5) after controlling for all other confounding variables that affect trauma mortality (including ISS, GCS score, age, and race) and all available shock variables (including lactate, base deficit, and shock index). Blood transfusion was Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 15 of 32 therefore confirmed as a significant independent predictor of adverse trauma outcome, characterized by increased mortality...” (Malone 2003) The pathophysiology of the adverse outcomes in patients requiring transfusion is under investigation; however, may be due in part to red blood cell changes that occur during storage. (Bennett-Guerrero 2007, Reynolds 2007) ESA manufacturers have studies underway to determine if there is an increased risk of tumor proliferation caused by ESAs compared with transfusion. In contrast, there is no parallel research program to determine the excess risk of tumor proliferation caused by transfusion compared to patients who undergo no transfusion. It is often the case when drug and procedure treatments are being compared, even if incorrectly, that there is less high quality evidence available on the risks and benefits of the procedure. However, it is important to recognize that this does not mean that the procedure is a superior choice. Legal Considerations The NCD conflicts with CMS’s obligations under the Social Security Act The NCD conflicts with the plain language of the Social Security Act (“SSA”), 42 U.S.C. §§ 1395d, 1395k, and 1395x. In 1993, Congress amended the SSA to mandate that Medicare must provide coverage for drugs used in connection with an “anticancer chemotherapeutic regimen for a medically accepted indication,” including “any use which has been approved by the [FDA].” 42 U.S.C. § 1395x(t)(2) (emphasis added). Despite Congress’ mandate, the NCD bans Medicare coverage for FDA-approved uses of ESAs in circumstances where they previously were eligible for coverage. Medicare Parts A and B both provide coverage for “drugs” and “biologicals.” E.g., 42 U.S.C. §§ 1395d(a)(1); 1395x(b)(2) (covering “drugs” and “biologicals” under Part A); 42 U.S.C. § 1395x(s)(2)(A)-(B) (covering “drugs and biologicals” under Part B). “Drugs” and “biologicals” are defined to include “any drugs or biologicals used in an anticancer chemotherapeutic regimen for a medically accepted indication.” 42 U.S.C. § 1395x(t)(2)(A). Congress amended the statute in 1993 to define the term “medically accepted indication” to include “any use which has been approved by the [FDA].” Id. § 1395x(t)(2)(B) (emphasis added). Prior to 1993, the SSA’s definition of “drugs” and “biologicals” included only drugs and biologicals listed in specified compendia. See 42 U.S.C. § 1395x(t) (1990); SSA, Pub. L. No. 89-97, § 102, 79 Stat. 286, 322 (1965) (amended 1993). Congress amended the definition in 1993 to mandate that Medicare cover all FDA-approved drugs for all FDA-approved (and certain off-label) uses in an anticancer chemotherapeutic regimen. See 42 U.S.C. § 1395x(t)(2). In introducing a bill that included the provision that was codified with no material change at 42 U.S.C. § 1395x(t)(2), the sponsors explained that “the bill would establish a uniform policy by requiring Medicare to cover any use of an FDA-approved drug in an anticancer therapeutic regimen that . . . appears in the drug’s labeling” Testimony of Sander M. Levin, Congressional Record, Extension of Remarks, 139 Cong. Rec. E992-04, E993-94 (Apr. 21, 1993) (emphasis added). The sponsors further explained that the legislation would ensure that “[a]ny use of an FDA-approved anticancer drug that is approved by FDA . . . is considered a medically accepted indication and must be covered.” Id. (emphasis added). In the NCD, CMS contends that it has authority to restrict coverage of FDA-approved uses of ESAs under 42 U.S.C. § 1395y(a)(1)(A), which states that “no payment may be made under part A or part B for any expenses incurred for items or services” unless they are “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” 42 U.S.C. § 1395y(a)(1)(A). CMS is in error. CMS’ assertion that it retains discretion to determine that certain FDA-approved uses of cancer drugs it deems not “reasonable and necessary,” renders Section 1395x(t)(2) meaningless. If the plain language of Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 16 of 32 § 1395x(t)(2) does not cabin CMS’s discretion with respect to coverage determinations for approved and off-label uses of cancer drugs, it accomplishes nothing at all. CMS’s interpretation thus conflicts with the “‘cardinal principle of statutory construction “that ‘a statute ought, upon the whole, to be so construed that, if it can be prevented, no clause, sentence, or word shall be superfluous, void, or insignificant.” TRW v. Andrews, 534 U.S. 19, 31 (2001) (quoting Duncan v. Walker, 533 U.S. 167, 174 (2001)); see also New York v. EPA, 443 F.3d 880, 887 (D.C. Cir. 2006). Because Congress must have intended its reference to “medically accepted indications” of cancer drugs to have significance, CMS’s interpretation of § 1395y(a)(1)(A) as permitting it to restrict coverage of uses that meet the definition of medically accepted indications is in error. In short, the plain language and legislative history make irrefutably clear that Section 1395x(t)(2) restrains CMS’s discretion to deny coverage of an FDA-approved use of an anticancer drug on the basis of safety and effectiveness. Congress left that determination exclusively to the FDA. Congress’ desire for uniform coverage of anticancer drugs -- and its considered judgment that “any use that has been approved by the Food and Drug Administration” for such drugs must be covered by Medicare -- would be wholly inconsistent with an interpretation of Section 1395y(a)(1)(A) that allows CMS to deny or restrict coverage of anticancer drugs on the basis of safety and effectiveness. The NCD’s failure to cover the FDA-approved use In 2007, following the release of results from additional clinical studies, the FDA required that the Procrit label be changed to strengthen warnings of health risks associated with ESAs when used to treat patients with Hb levels above 12 g/dL. 1 The revised label directs prescribers to use the lowest doses of Procrit necessary to avoid the need for transfusions so long as the Hb is not elevated above 12 g/dL. The revisions to the label did not limit the approved use of the product to instances in which the Hb is below 10 g/dL but, instead, expressly permits use of ESAs when the Hb does not exceed 12 g/dL. Since that time, FDA has confirmed repeatedly that ESAs are safe and effective as long as they are not administered to target Hb of greater than 12 g/dL. In recent testimony to the United States House of Representatives Committee on Ways and Means Subcommittee on Health, for example, John K. Jenkins, M.D.,Director of the Office of New Drugs Center for Drug Evaluation and Research at the FDA, confirmed that the “FDA continues to believe that ESAs are safe and effective when used according to the recently revised product labeling, at the recommended dose and approved indication”,” (June 26, 2007), available at http://www.fda.gov/ola/2007/esa062607.html (hereinafter, “Jenkins Testimony”). The NCD conflicts and is inconsistent with FDA-approved uses of Procrit in many respects: (1) The NCD does not permit a patient to be initiated on Procrit until the patient’s Hb level falls below 10 g/dL, despite the fact that the FDA-approved label permits initiating Procrit any time an individual patient’s Hb is below 12 g/dL if treatment is necessary to avoid transfusion. (2) Once a patient has received an initial ESA regimen, use of Procrit must be withdrawn each time the patient’s Hb level exceeds 10 g/dL, despite the fact that the FDA approves use of Procrit allows for treatment until the patient’s Hb level reaches 12g/dL. 1 In late 2006 and early 2007, the results of several studies regarding investigational uses of ESAs were released (hereinafter, the “Investigational-Use Studies”). According to the FDA, these “studies were evaluating an unapproved dosing regimen, a patient population for which ESAs are not approved, or a new unapproved ESA.” FDA Alert (11/16/2006, Updated 2/16/2007 and 3/9/2007), available at http://www.fda.gov/cder/drug/infopage/RHE/default.htm. (emphasis added). None of the studies reviewed -- or even addressed -- the safety and effectiveness of ESA treatments used only when an chemotherapy-induced anemic cancer patient’s hemoglobin level falls below 10 g/dL. The FDA reviewed the results of these studies and issued revised warnings regarding possible health risks associated with ESA treatment. The FDA did not alter the approved uses for ESAs used in connection with a chemotherapy regimen. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 17 of 32 (3) The NCD establishes dose adjustments for Procrit that are different from and inconsistent with FDA-approved dosage adjustments. (4) The NCD prohibits continued use of Procrit where a patient’s Hb levels increase by less than 1 g/dL after eight weeks of treatment, despite the fact that continued use in such circumstances is consistent with FDA-approved uses. (5) When Procrit is withdrawn because a patient’s Hb level exceeds 12 g/dL, as the FDA Label instructs, the NCD prevents resumption of Procrit treatment until the patient’s Hb level falls below 10 g/dL, despite the fact that the FDA approves resumption of treatment when a patient’s Hb level falls below 11 g/dL. The NCD conflicts with CMS’ obligations under the Administrative and Procedure Act The NCD is also in error under the Administrative Procedure Act (“APA”), 5 U.S.C. § 706(2)(A). CMS has restricted coverage for ESAs to uses that have never been clinically tested and that are contrary to scientific evidence and oncology standards of care confirmed by FDA to be safe and effective. CMS has established no evidentiary record supporting the clinical limitations on ESA coverage in the NCD that are not also contained in the FDA-approved labeling for ESAs. CMS action is therefore arbitrary, capricious, and an abuse of discretion and, as a consequence, must be set aside. A national coverage determination, like other final agency actions, may not be arbitrary, capricious, or an abuse of discretion. See 5 U.S.C. § 706(2)(A). Although a court will not substitute its own judgment for that of the agency, the agency must articulate “a satisfactory explanation for its action including a ‘rational connection between the facts found and the choice made.’” Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 43 (1983) (quoting Burlington Truck Lines v. United States, 371 U.S. 156, 168 (1962)); PPL Wallingford Energy LLC v. FERC, 419 F.3d 1194, 1198 (D.C. Cir. 2005). In accord with the APA, an agency “must cogently explain why it has exercised its discretion in a given manner,” State Farm, 463 U.S. at 48–49, so that a reviewing court is able “to conclude that the agency’s action was the product of reasoned decision-making,” id. at 52. If the agency does not cogently explain its decision, or if it omits consideration of important factors or considers inappropriate factors, its decision must be set aside. Id. at 43, 48; A.L. Pharma v. Shalala, 62 F.3d 1484, 1492 (D.C. Cir. 1995). CMS has failed to articulate an adequate explanation for the NCD’s curtailment of coverage of FDA-approved uses of ESAs. CMS’ decision departs from the standard of care recognized by thousands of oncologists and hematologists, from existing clinical studies, and from FDA’s reasoned and expert conclusion that Procrit is safe and effective for the uses specified in the FDA-approved label. The NCD results in an arbitrary treatment regimen that has not been shown to be safe or effective, which prevents Medicare beneficiaries from receiving treatment consistent with well-established standards of care for the treatment of seriously ill cancer patients. CMS’ action is thus arbitrary and capricious, and CMS should suspend the NCD and reconsider it. CMS has been down this path before. In Estate of Aitken, Medicare beneficiaries and a physician organization challenged a national coverage determination issued by the Health Care Financing Administration (now CMS), arguing that the national coverage determination was arbitrary and capricious because the scientific study upon which it was based did not support the agency’s decision. 986 F. Supp. 57, 61-66 (D. Mass. 1997). The district court agreed, issued a preliminary injunction prohibiting enforcement of the national coverage determination, and remanded the matter to the agency. Estate of Aitken, 986 F. Supp. 57, 61-66 (D. Mass 1997). Here, as in Estate of Aitken, the purported scientific studies underlying the NCD do not provide support for the limitations on coverage imposed in the NCD. Here, as there, the record lacks “‘adequate information to support the validity of the determination’” and runs “‘counter to the evidence before the agency.’” Estate of Aitken, 986 F. Supp. at 64. There is one material difference between the two cases. In the case of ESAs, the NCD provides coverage in circumstances that have never been proven safe and effective. Conversely, Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 18 of 32 whereas the published studies that did not adequately support the agency decision in Estate of Aitken supported a conclusion that the treatment at issue was “about as effective as ‘conventional’ therapy.” 986 F. Supp. at 64. Just as in that case, CMS’ NCD on ESAs is arbitrary and capricious, and should be suspended and reconsidered. Additionally, the NCD is impermissibly arbitrary and capricious because it departs from CMS’ longstanding policy of deferring to FDA on determinations of whether a drug is safe and effective. In fact, CMS’ ill- considered decision that many uses of ESAs are not safe, marks a radical departure from prior Agency policy. CMS has recognized repeatedly that it is the FDA that “must determine that a product is safe and effective.” As the Agency has recognized in the past, Congress charted a different role for CMS: “CMS must determine that the product is reasonable and necessary.” 68 Fed. Reg. 55634, 55636 (Sept. 26, 2003). FDA -- and not CMS -- is the appropriate agency to determine whether a drug is safe and effective: “Drugs or biologicals approved for marketing by the Food and Drug Administration (FDA) are considered safe and effective . . . when used for indications specified on the labeling. Medicare Benefit Policy Manual, Chapter 15, Section 50.4.1. CMS’ departure from its longstanding (and sound) policy of deference to FDA on matters of safety and effectiveness is erroneous, and a proper basis on which to suspend application of the NCD and reconsider it. Policies and Process In addition to the case for reopening the ESA NCD based on new data and material misinterpretations of data, we believe that CMS should consider issues of the fairness and transparency of the process, as well as the unprecedented policy changes the NCD represents, which have not been subject to public comment. Unprecedented Restriction in Coverage for an FDA-approved drug This is the first case where CMS is more restrictive in its coverage policy for a drug than the FDA-approved label. CMS’ coverage policy is based on statutory language stating that Medicare should not cover and reimburse for items and services which “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member…” The agency’s longstanding drug coverage policy has been to cover Part B drugs for the FDA approved use but to leave to local carriers and intermediaries review and coverage of off-label uses. In the ESA NCD, CMS has restricted coverage in an unprecedented way for previously covered drugs and has done so without clinical evidence to support its more restrictive coverage. The agency has migrated from not covering items and services that are proven harmful to asserting theoretical harm and requiring that sponsors and clinicians prove that no harm exists. We strongly urge CMS to continue to give FDA-approved labeling appropriate weight in reaching coverage decisions. In this case, the FDA Oncologic Drug Advisory Committee recently reviewed the issue of Hb treatment limits and chose not to recommend that FDA reduce the limit below 12 g/dL. Restriction in Coverage that Departs from Benefit/Risk Considerations and “Reasonable and Necessary” Requirements In approving drugs, FDA weighs evidence of safety and efficacy and makes a regulatory decision that reflects both the benefits and risks of those drugs. CMS’s rationale for setting a coverage limit when the patient’s Hb reaches 10 g/dL is that such a limit will diminish the risks associated with tumor progression, though CMS has no evidence of tumor progression in the range of 10-12 g/dL. So, unlike other drugs covered by Medicare under both Parts B and D, CMS is imposing with ESAs a limit based on theoretical harm and limiting clinicians’ ability to judge when ESAs are beneficial for individual patients beyond Hb levels of 10g/dL. This approach, considering only potential risk without regard to individual patient benefit is also unprecedented with regard to drugs covered by Medicare. CMS is judging that ESA treatment is not medically necessary above the limit, though the agency does not have evidence to substantiate this position. Absence of Public Comment on the Hb Cap Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 19 of 32 The proposed NCD did not propose a Hb cap. Rather, it proposed that beneficiaries would be eligible for ESA initiation only when their Hb levels were below 9 g/dL. While we understand CMS received many comments critical of such an initiation level, the oncology community had no reason to provide comments on a Hb cap, since none was clearly proposed. As such, the agency reached its conclusion without a full and meaningful discussion of relevant information, such as that contained in the attached Cochrane analysis. (Bohlius 2007) Although CMS did not solicit information on the topic, we know from the pharmacodynamics of ESAs that withholding treatment for Hb values greater than 10 g/dL in the setting of concomitant myelosuppressive chemotherapy will result in wider Hb fluctuations and an increased transfusion frequency for a substantial proportion of patients whose Hb will continue to fall while waiting for the beneficial effect of ESA re-treatment. Multiple interruptions of ESA treatment are likely to compromise the clinical benefit of these agents for Medicare beneficiaries with chemotherapy-induced anemia. Absence of Public Comment on Dose Escalation Likewise, the proposed coverage memorandum contained no discussion of allowing only a onetime escalation of 25% of the starting dose as was included in the final NCD. Had the agency sought such comment, CMS likely would have received evidence relating to the clinical trials that established the dose escalation algorithms contained in the approved product labeling for all ESAs. In fact, we have not been able to determine on what evidence CMS based this limitation. We would suggest that if CMS reached this conclusion it was based on the dose escalation required as part of the label for ESAs used in chronic renal failure, which is directed at patients with very different underlying conditions and responses. Lack of Transparency Johnson & Johnson and many others have commended CMS for advancing “coverage with evidence development,” as a way to provide expedited access to important new treatments with additional data collection, to increase the evidence for refining and improving coverage policy over time. Just as CMS is requiring more data and transparency of results to guide coverage policy, CMS should hold itself accountable to the same standard. The agency should demonstrate in a scientifically appropriate format that the ESA NCD is evidence-based and should not simply list, as justification for its conclusions, an 800-article bibliography. AHRQ’s Evidence-based Practice Centers specify individual studies that were examined and the conclusions that may or may not be reached. Both the United States Preventive Services Task Force and the Cochrane Collaboration use a similar format. We request that CMS provide such an analysis, at a minimum, of the studies used to support the Hb treatment cap of 10 g/dL and the one-time dose escalation algorithm of 25%. Failure to Consult with Clinical Oncologists and other Experts on the Final NCD The safety and efficacy of ESAs is well established in treating chemotherapy-induced anemia. Considering the use in large numbers of cancer patients, the clinical guidelines of the two principal physician specialty societies – the American Society for Clinical Oncology and the American Society for Hematology -- and the impact on patient care, CMS should have included input from clinical oncologists in the review and consideration of the final NCD. The agency’s own Medicare Evidence and Coverage Advisory Committee, (MedCAC) which includes oncologists, would have been an appropriate body with which to consult on a final NCD of this significance. While CMS received public comments from oncologists, public comment is no substitute for having oncologists participate in the data analysis and direct deliberations about the appropriate parameters for ESA coverage. Further, the Agency for Healthcare Research and Quality of HHS completed a comprehensive assessment of ESAs in May 2006. AHRQ’s assessment raised questions about thromboembolic complications, but concluded that the evidence was not sufficient for conclusions on thresholds for initiating treatment or criteria for discontinuing therapy, quality of life, tumor response and progression, survival, or adverse outcomes other than thromboembolic events. Given their recent assessment and expertise in weighing evidence, at a Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 20 of 32 minimum, CMS should have consulted AHRQ in developing the final NCD. AHRQ has conducted many technology assessments for CMS and was well -suited to provide advice on this NCD. Process Concerns While CMS has adhered rigidly to its interpretation of the MMA statutory language regarding issuance of NCDs, including the “immediate” effective date, timeframes, etc., the agency does not have a process governing the issuance of clarifying instructions, even after having a series of calls with stakeholders, where clarifying information was provided. The prescribed timeframe or any obligation to respond to a request for reconsideration are also unclear. Rather than responses to their specific requests for reconsideration, earlier requesters received a letter restating the basis for reopening the NCD and asking specific questions. Following the issuance of the final NCD, concerned stakeholders were told, “if we have made a mistake, we want to fix it.” We are proposing reopening the NCD as a critical first step in doing that. Although the agency leadership has said repeatedly that the NCD policies are not driven by cost considerations, since those policies have not specifically been tied to evidence, CMS leaves the impression that cost containment is a major consideration in formulating this decision. Recommendations 1. CMS should immediately suspend the ESA National Coverage Decision and reconsider the issues of an upper hemoglobin limit of 10 g/dL; the hemoglobin level threshold for initiation therapy; the dose reduction approach; and the one-time 25% dose escalation following the initial 4 week treatment period for patients who do not achieve at least a 1 g/dL rise in hemoglobin concentration. 2. The NCD as currently formulated is likely to result in avoidable transfusions for some Medicare beneficiaries who receive ESAs. Therefore, the agency should immediately suspend the implementation of the NCD. We have previously indicated that CMS has the flexibility to take this course of action. 3. CMS should convene MedCAC, or an oncology subset of MedCAC, to consider the evidence, comments, and formulate the final NCD policy. 4. CMS should revise the final NCD format so that the evidence base for the final coverage policy is clear. Similar to AHRQ, USPSTF, and the Cochrane Collaboration, the agency should provide linkage from conclusions that may be reached from the studies on which it relied. 5. During its reconsideration process, CMS should solicit recommendations from stakeholders regarding dosing strategies that would encourage providers to use the lowest dose of ESAs to avoid transfusions, without materially increasing the number of Medicare beneficiaries requiring blood transfusions due to chemotherapy-induced anemia. NCD Material Misinterpretations or Lack of Considération of Evidence We agree with the use of erythropoietic stimulating agents (ESAs) supports quality care for Medicare beneficiaries; however, the current ESA NCD represents fundamental misinterpretations of existing evidence regarding safe and effective ESA use. This appendix will highlight areas where CMS has materially misinterpreted the evidence. 1. The totality of evidence regarding ESA safety has been misinterpreted. FDA, EMEA, and the Cochrane Collaboration have all looked at the totality of public data and reached the conclusion that existing evidence establishes an upper safety limit for Hb of 12 g/dL when ESAs are used to treat chemotherapy induced anemia, rather than 10 g/dL. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 21 of 32 EMEA recently reviewed the data in light of the safety concerns and came to the conclusion that an appropriate target Hb concentration is 10-12 g/dL, with an upper Hb limit of 12 g/dL. This view of the totality of data is consistent with the view of nearly every source of expert review cited by CMS as a source of expert opinion. These conclusions are supported by a variety of published clinical trials, including the Cochrane Collaboration meta-analysis (Bohlius 2007) demonstrating that the signal of decreased survival in ESA-treated patients is coming exclusively from “correction beyond anemia studies” i.e. those studies with baseline Hb levels > 12 g/dL. Whereas it is true that a subset of patients never achieve the high target hemoglobin levels in these studies, there is no evidence of adverse survival outcomes in this responding subgroup, nor is it statistically valid to use the findings from the “non- responding” subgroup, which is confounded by numerous comorbidities, as the basis for policy development. Investigational studies have demonstrated adverse safety signals when ESA were initiated and maintained to a Hb > 12 g/dL (Leyland-Jones 2005, DHANCA 2007) or in the anemia of cancer population (Wright 2007, Amgen anemia of cancer study). There is agreement that ESA should not be used in such investigational circumstances. These findings have been discussed with the FDA, which led to a boxed warning contraindicating this use. CMS extrapolated these investigational findings and applied them to all ESA use in the cancer chemotherapy population. This is a material misinterpretation of the evidence. Additionally, speculation of patient outcomes in subsets those dosed in accordance with present FDA-prescribing information may be uninformative as such conclusions are impaired by the use of post hoc subset analyses that was not the primary or secondary objective of the clinical trials. An extensive body of evidence supports that ESA use is safe and effective when used in accordance with the FDA-approved label. (Abels 1993, Witzig 2005, Vansteenkiste 2002, Canon 2006). Witzig (2005) reported the results of a placebo-controlled trial of epoetin alfa in cancer patients receiving chemotherapy. This study was used for FDA registration purposes of weekly epoetin alfa dosing and found no survival differences between epoetin alfa and placebo. “...When the entire group of 330 patients was analyzed, the median overall survival (OS) was 11.2 months for placebo-treated patients compared with 10.4 months for the epoetin alfa group (P= not significant; Fig 4 [below])...” It did demonstrate significantly fewer transfusion requirements and better Hb changes in the epoetin alfa- treated group compared with the placebo group. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 22 of 32 Fig 4. Overall survival of the 330 patients by treatment group (EPO, epoetin alfa) These findings were corroborated by the FDA Medical officer review of epoetin alfa once weekly submission, which stated the following: “...The survival curves are similar, with median survival times of 10.9 months (where 1 month=30 days) in the placebo group and 10.6 months in the epoetin alfa group. The difference was not statistically significant via the logrank test (p=0.429). An updated survival analysis was performed when the 4-month safety data became available...Overall, 119 subjects (70%) in the placebo group and 121 subjects (70%) in the epoetin alfa group died. The median survival times were similar between the placebo and epoetin alf groups (10.9 months and 10.8 months, respectively). (FDA Medical Officer report p. 33) Vansteenkiste (2002), another ESA FDA registration trial, reported the findings of a placebo-controlled darbepoetin alfa clinical trial (baseline Hb < 11 g/dL) that also reported significantly fewer transfusions in the ESA-treated group. No difference in survival was noted as the authors describe in the following: “...All 314 patients who received study drug were included in the analyses of progression-free survival and overall survival. One hundred twenty-nine patients (83%) in the darbepoetin alfa group and 141 patients (89%) in the placebo group had disease progression or died either during the study or during the follow-up period. The median duration of progression-free survival was 22 weeks (95% CI=18 to 31 weeks) in the darbepoetin alfa group and 20 weeks (95% CI = 17 to 23 weeks) in the placebo group (Fig. 5). Ninety-two patients (59%) in the darbepoetin alfa group and 109 patients (69%) in the placebo group died either on study or during the follow-up period. The median duration of survival was 46 weeks (95% CI= 39 to 53 weeks) in the darbepoetin alfa group and 34 weeks (95% CI= 29 to 39 weeks) in the placebo group...” (Vansteenkiste 2002) Grote (2006) reported resulted of a placebo-controlled study of ESA use in lung cancer patients. Survival outcomes were similar between groups as described by the authors. “...A total of 201 of the 224 enrolled patients died before the end of the 3-year follow-up period. The overall mortality rate was 91.7% (100 of 109 patients) in the epoetin alfa group and 87.8% (101 of 115 patients) in the placebo group (hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P _ .264); median survival times (based on Kaplan-Meier estimates) were 10.5 months and 10.4 months, respectively...” (Grote 2006) The above findings are further supported by the independent meta analyses conducted by the Cochrane Group (Bohlius 2006 Cochrane) including all ESAs in which analysis of subgroups of studies found different mortality signals depending on study baseline Hb entry criteria. The hazard ratio for studies with baseline Hb less than 10 g/dL was 1.01 (95% CI: 0.89 to 1.15; 20 studies and 3,765 subjects). For studies with baseline Hb of 10 to 12 g/dL, the hazard ratio was 0.98 (95% CI: 0.82 to 1.16; 8 studies, 1,712 subjects). For studies Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 23 of 32 with baseline Hb greater than 12 g/dL, the hazard ratio for death in the ESA group was 1.27 (95% CI: 1.07 to 2.49, 7 studies, 994 subjects). Baseline Hb at ESA initiation Survival odds ratio (95% CI) Hemoglobin < 10 g/dl 1.01 (0.89, 1.15) Hemoglobin 10-12 g/dl 0.98 (0.82, 1.16) Hemoglobin > 12 g/dl 1.27 (1.05, 1.54) At the May 2007 FDA Oncologic Drugs Advisory Committee (ODAC) meeting, the committee reviewed the evidence surrounding the adverse safety signals and recommended to maintain the current FDA approved label which sets the upper limit of 12 g/dL for Hb in ESA-treated patients. The current NCD is in direct conflict with this in that it restricts use of ESAs to Hb not to exceed 10 g/dL for initiation and maintenance. In recent testimony to the United States House of Representatives Committee on Ways and Means Subcommittee on Health, for example, John K. Jenkins, M.D., Director of the Office of New Drugs Center for Drug Evaluation and Research at the FDA, confirmed that the “FDA continues to believe that ESAs are safe and effective when used according to the recently revised product labeling, at the recommended dose and approved indication”,” (June 26, 2007), available at http://www.fda.gov/ola/2007/esa062607.html Following review of all available data, the EMEA’s Committee for Medicinal Products for Human Use (CHMP) and its Pharmacovigilance Working Party (PhVWP) concluded that the benefits of these products continue to outweigh their risks in the approved indications, but recommended the following changes to the product information: (1) Changes to the ‘Indication’ section (section 4.1), saying that epoetins should be used in the treatment of anaemia only if associated with symptoms and (2) Changes, stipulating a uniform target haemoglobin range for all epoetins of 10 g/dL to 12 g/dL with a warning not to exceed a concentration of 12 g/dL. (European Medicines Agency press release, October 23, 2007) 2. Neither the evidence nor the precision of medical practice support a dosing strategy in which ESAs are uniformly initiated and maintained at a Hb level of 10 g/dL. All of the registration trials for the ESAs currently marketed initiated therapy when Hb fell below a concentration of 10.5 or greater, and none required withholding of therapy when a Hb level of 10 g/dL was exceeded. There is no published literature providing evidence that uniformly withholding ESA therapy until Hb concentrations fall below 10 g/dL will permit successful avoidance of blood transfusion. Indeed, observational studies suggest that across populations more blood transfusions will be avoided when therapy is ordinarily initiated before Hb falls below 10 g/dL. CMS has materially misinterpreted the evidence by setting the initiation and maintenance at Hb 10 g/dL. A review of the current literature and references cited in the NCD fails to show evidence where Hb initiation and maintenance of 10 g/dL is either safe or effective. The clinical studies supporting FDA approval of ESAs did not involve stopping administration of ESAs when a patient’s Hb exceeded 10 g/dL. The pivotal trials that led to FDA approval of ESAs in patients with chemotherapy-induced anemia studied baseline Hb at ESA initiation of 10.5-11.5 g/dL, including FDA approval of one ESA regimen as recently as March 2006. FDA-approved ESA regimen* Year of FDA approval Baseline Hb in FDA-approved registration trial Aranesp 500 mcg Q3W 2006 < 11 g/dL Aranesp 2.25 mcg/kg QW 2002 ≤ 11 g/dL PROCRIT 40,000 U QW 2004 < 10.5 g/dL females, < 11.5 males PROCRIT 150 U/kg TIW 1993 ≤ 10.5 g/dL * PROCRIT Prescribing Information [3/07], Aranesp Prescribing Information [4/07] Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 24 of 32 It is unknown what the risks and benefits of an initiation and maintenance at Hb 10 g/dL may have for Medicare beneficiaries, since it has never been studied and there is no evidence to support this dosing schema. Additionally, there are no practice guidelines supporting use of ESAs in the manner described in the NCD. The National Comprehensive Cancer Network (NCCN) anemia treatment guidelines provide recommendations regarding ESA initiation at a Hb level of < 11 g/dL for cancer patients with chemotherapy- induced anemia: “Following the identification of anemia (defined for the purpose of considering intervention as hemoglobin levels equal to or less than 11 g/dL) and the evaluation for anemia specific causes, an initial risk assessment should be completed...The history should assess whether accompanying symptoms are present, such as chest pain or dyspnea. Comorbidities such as cardiac disease or underlying pulmonary disease must be considered...Observation or erythropoietic therapy should be considered for asymptomatic patients with risk factors for developing anemia. The decision of whether to use epoetin immediately or to wait until hemoglobin levels fall closer to 10 g/dL should be determined by clinical circumstances. For symptomatic patients, transfusion and/or erythropoietic therapy are recommended. If the patient's hemoglobin level is between 10-11 g/dL, the panel recommends the consideration of erythropoietic therapy with or without transfusion. If the patient's hemoglobin level is <10 g/dL, the panel strongly recommends erythropoietic therapy...” (NCCN anemia treatment guidelines v.3.2007) The NCD (p. 21 of 61) quoted the American Society of Hematology/American Society of Clinical Oncology guidelines; however, only a portion of the guidelines was included. The NCD stated: “...ASCO and ASH guidelines recommended evaluating patients for the need for ESA therapy when the hemoglobin is at or below 10 g/dL...” It is unclear why the full guideline was not referenced; as it includes information relevant to the Medicare population as the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) published anemia treatment guidelines recommend ESA initiation at an Hb of 10-12 g/dL in certain clinical conditions, such as the elderly. “...The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances... Examples of patients at this higher degree of absolute risk, who may be considered reasonable candidates for this agent, based on clinical judgment, include but are not limited to elderly individuals with limited cardiopulmonary reserve or patients with underlying coronary artery disease and symptomatic angina...” (Rizzo 2002) The narrow Hb target range of 10 g/dL mandated in the ESA NCD does not allow for clinical flexibility in treating patients. Inter-patient variability and response to medications is well established. In order to provide the best medical care, physicians need discretion to determine the optimal care for each individual patient based on that patient’s specific needs. The NCD as written does not allow for that flexibility and hinders the ability for physicians to safely and effectively tailor ESA use. The FDA-approved prescribing information for ESAs recommends using the lowest dose possible to avoid red blood cell transfusions. This statement allows for flexibility in dosing based on patient differences and physician discretion. It does not dictate Hb initiation or maintenance of 10 g/dL. Practice guidelines also recognize the importance of inter-patient variability and the need to tailor usage based on specific patient needs and physician judgment. This is evidenced in suggesting a target range for Hb of 10-12 g/dL based on patient needs. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 25 of 32 CMS has also fundamentally misinterpreted the difference between Hb target and Hb ceiling (i.e. the Hb value above which ESA treatment should be held). If, as CMS suggests, the optimal benefit of ESAs with respect to transfusion reduction is achieved by targeting Hb levels around 10 g/dL in patients receiving myelosuppressive chemotherapy, then that Hb target can never be achieved by implementing a Hb ceiling of 10 g/dL. Again, this is also counter to ODAC's recommendation that a Hb ceiling not to exceed 12 g/dL was acceptable. It is recognized and understood that 12 g/dL is the upper safety limit that should not be exceeded,; however, setting the level at 10 g/dL is arbitrary and not founded in scientific evidence. CMS categorically misinterpreted the clinical trial evidence and the FDA approved prescribing information by setting the initiation and ceiling for ESAs at Hb 10 g/dL and failed to allow for inter-patient variability when dosing ESAs. 3. The dose escalation and reduction schedules in the NCD are inconsistent with the data referenced by CMS, which described some of the same data relied upon by FDA to approve the labeling for ESAs. No publications or evidence in the ESA NCD call into question the conclusions reached by FDA with respect to dose modifications. CMS materially misinterpreted the data by restricting ESA dose escalation to 25% if the Hb rise is < 1 g/dL. FDA-approved prescribing information and anemia treatment guidelines recommend a dose escalation of 50% [in the PROCRIT (epoetin alfa) weekly dosing regimen] or 100% in the three times weekly PROCRIT (epoetin alfa) dosing regimen. The FDA-approved dose escalation for darbepoetin alfa calls for 100% dose escalation in the once-weekly regimen and no dose escalation is recommended for the 500 mcg every 3- week regimen. As written, the ESA dose adjustments described in the NCD encourages use of ESAs that is contrary to the FDA label and does not preclude a 25% dose escalation for the darbepoetin alfa 500 mcg every 3 week regimen. This would translate to 625 mcg every 3 weeks, a dose higher than what is recommended in the FDA label. The FDA label for darbepoetin has no allowance for dose escalation in this particular regimen. It is unclear what evidence CMS used to recommend a 25% dose escalation for all ESAs. A review of the literature, the studies cited in the NCD and all published clinical guidelines fail to provide evidence for this restriction in the oncology population. A 25% dose escalation has not been studied and it is unknown if such a dosing regimen is safe or effective for Medicare beneficiaries. For dose reduction, the NCD calls for a 25% reduction if there is greater than a 1 g/dL rise in Hb over a two- week period. While this is consistent with the prescribing information for epoetin alfa, it is contrary to the darbepoetin alfa FDA-approved label, which calls for a 40% reduction in dose. The NCD again recommends higher ESA doses than recommended by the FDA. This discrepancy is not supported by clinical evidence and it is unclear why CMS is recommending higher doses that could potentially be harmful to Medicare beneficiaries. It is a clear misinterpretation of the data. 4. Transfusion triggers used in non-mobile ICU patients are not an appropriate basis for predicting transfusion triggers in ambulatory cancer patients receiving chemotherapy. Because the reasoning of the NCD relies heavily upon this prediction, it is a material misinterpretation of the data. Blood transfusion patterns in the chemotherapy-treated cancer population are unique from transfusion patterns in other settings (e.g., critical care) because of the ambulatory status of this population and the ongoing myelosuppression induced with continued chemotherapy. CMS misinterpreted the evidence when it extrapolated transfusion Hb triggers used in non-mobile ICU patients to ambulatory cancer patients. Transfusion needs may vary based on patient age, co-morbid conditions, underlying malignancy, and chronicity of chemotherapy regimen selected. Barrett-Lee et al. (2000) reported that if the Hb was <10 g/dL prior to chemotherapy initiation, the probability of at least one transfusion at some point was markedly increased compared to higher initial Hb levels, with approximately 70% of patents requiring transfusion. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 26 of 32 Similar findings have been reported in analyses comparing patients initiated at a Hb < 10 g/dL compared with those with ESA initiation of 10-11 g/dL. In clinical trials and observation studies, data have reported a higher proportion of patients requiring blood transfusion in the Hb < 10 g/dL versus Hb 10-11 g/dL. In most trials, patients had a two-fold increase in transfusions when they were initiated at a Hb < 10 g/dL compared to those initiation at a Hb 10-11 g/dL. Study Study Type Proportion of patients transfusedHb at ESA initiation < 10 g/dL 10-11 g/dL Vansteenkiste (2004) Clinical trial 31% 15% Boccia (2006) Clinical trial 28% 12 % Szczudlo (2007) Clinical trial 36% 9% Szczudlo (2007) Clinical trial 29% 3% Wang (2007) Observational 31% 13% Lyman (2005) also showed in a systematic review of five controlled trials that the proportion of randomized patients requiring transfusion in the early ESA treatment group (Hb > 10 g/dL) was 14.3% (11.4 – 17.7%) compared to 25.6% (22.2 – 29.2%) in those patients receiving late ESA treatment. This combined analysis provides evidence that patients who are initiated on ESAs when their Hb is <10 g/dL have significantly more transfusions than those who are initiated at higher Hb levels (10 –11 g/dL). As the NCD is written, CMS misinterpreted the evidence when they stated that the NCD would not affect the nation’s blood supply. The evidence shown above supports the fact that transfusions do increase when ESAs are started at lower Hb levels mandated by the NCD. Ortho Biotech performed a modeling simulation to estimate the impact that limiting the use of ESAs in chemotherapy-induced anemia would have on the U.S. blood supply. The excess number of units that would be required if treated patients were not treated with ESAs was compared with the available marginal supply using 2004 data (the most recently available). Model inputs were drawn from the published literature or expert opinion where evidence was lacking. Estimates were developed for a range of scenarios and incorporated into appropriate sensitivity analyses. The model predicts that up to a third of the marginal U.S. blood supply would be required to cover the incremental demand for blood that would arise from a 25% decrease in the use of ESAs. Nearly two-thirds of the marginal blood supply could be compromised with a 50% reduction of ESA use in patients with chemotherapy-induced anemia. Recent Wall Street Analysts report that the CMS Proposed Decision Memo on ESAs as written may decrease ESA sales from 25% to 70% (Porges 2007, Werber 2007, Ende 2007, Hopkins 2007). Such changes in ESA utilization are associated an incremental demand of 118,000-237,000 units of blood. (Data on file, Ortho Biotech) This added pressure on the blood supply could be even greater due to regional variation in the number of available units and the variable frequency of donation. The Association of Community Cancer Centers (ACCC) recently conducted a survey that was sent to 650 ACCC member hospitals. One hundred and fifteen sites responded, including rural (20%), urban (39%), and suburban (41%) hospitals. The survey showed that 40.9% of respondents indicated that a 30% increase in demand would cause problems in carrying out normal transfusion services. Another 16.5% said even a 10% or less increase in demand for blood transfusions would cause problems, and 21.7% said any increase would result in problems. It is clear from the randomized controlled studies that transfusions do occur in patients with Hb greater than 10 g/dL, and that those patients who are initiated at Hb lower than 10 g/dL compared to those initiated at Hb greater than 10 are more likely to get transfused. Based on these data and the new data cited in this paper, transfusion use will increase due to the NCD restrictions and the NCD therefore will have an impact on the nation’s blood supply. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 27 of 32 5. CMS may have misunderstood the relationship between transfusions and subsequent Hb levels as reported in trials comparing ESA to placebo. A review of the Witzig (2005) publication revealed that hemoglobin values were inclusive of transfusion effect and transfusion intervention was physician-determined rather than protocol- specified. CMS has commented that cancer chemotherapy patients treated with transfusion alone will increase Hb levels over the treatment course. However, clinical trials in cancer chemotherapy patients treated with transfusion alone have reported decreases in Hb levels during placebo treatment. A single clinical trial (Witzig 2005) reported Hb increases in placebo group (based on monthly Hb levels inclusive of transfusion), but two other placebo-controlled ESA trials (Pirker 2002, Grote 2005) reported significant Hb level reduction in placebo-treated patients. Witzig (2005) showed a significantly greater proportion of transfusions in the placebo-treated group. Transfusions were administered at the discretion of the treating physician and Hb values obtained subsequent to RBC transfusions were not excluded. While there were significantly greater transfusions and inferior Hb changes in the placebo-treated group, an increase in the Hb concentration was observed in the placebo group, as shown in the figure below. Hb levels inclusive of transfusion impacted the Hb change of the placebo group as noted by the FDA Medical Office Review. “...Because the transfusion rate was higher in the placebo group than in the epoetin alfa group, the effect of transfusion would contribute to Hgb increase to a great degree in the placebo group than in the epoetin alfa group...” (FDA Medical officer report p. 28) Pirker et al (2002) reported a placebo-controlled trial of darbepoetin alfa in lung cancer patients. Inferior outcomes with regard to transfusion frequency and Hb changes were reported in the placebo group compared to the darbepoetin alfa-treated group. Additionally, weekly Hb levels which were controlled for transfusion (Hb values set to missing for 28 days following blood transfusion) reported decrease over baseline in the placebo-treated patients as shown in the figure below Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 28 of 32 Grote (2005) reported a double-blind placebo-controlled study of epoetin alfa in lung cancer patients. Significantly inferior transfusion and Hb changes were reported in the placebo group compared to the epoetin alfa-treated group. Hb change in the placebo group decreased over the course of the study as shown in the figure below. “...Over all chemotherapy cycles, fewer epoetin alfa patients (26 of 109 patients; 24%) than placebo patients (42 of 115 patients; 37%) required RBC transfusions (hazard ratio, 0.597; 95% CI, 0.365 to 0.977)...Mean baseline hemoglobin levels (epoetin alfa group, 12.8 g/dL; placebo group, 13.0 g/dL) were maintained in the epoetin alfa group during the first 22 weeks of study (mean weekly hemoglobin range, 11.3 g/dL to 12.7 g/dL), whereas the mean hemoglobin decreased in the placebo group to a minimum of 9.9 g/dL at week 14 (Fig 2). At the time of median exposure to study drug (13 weeks), mean change in hemoglobin was - 0.2 g/dL in the epoetin alfa group and - 2.9 g/dL in the placebo group. Mean hemoglobin at the end of cycle 3 was 12.5 g/dL and 10.6 g/dL in the epoetin alfa group and placebo groups, respectively, and mean final hemoglobin was 12.2 g/dL and 10.3 g/dL, respectively (mean difference in hemoglobin between groups at both timepoints, 1.9 g/dL; 95% CI, 1.4 to 2.4)...” Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 29 of 32 These data also illustrate that blood transfusions are an inferior substitute to ESAs for Hb maintenance. While blood transfusions readily correct the symptoms of anemia, this effect is transient. ESAs typically require 3-4 weeks of dosing to stimulate sustained erythropoiesis, and patients should be appropriately maintained on ESAs if chemotherapy is ongoing to avoid the cumulative myelosuppressive effects of cancer regimens. Accordingly, withholding ESA treatment because an Hb may transiently fluctuate above 10 g/dL during chemotherapy could result in Hb levels decreasing to the point where a patient would require transfusion support while waiting for resumption of ESA treatment and a sustained erythropoiesis response. Conclusion CMS has fundamentally misinterpreted the evidence in several key areas. In many instances these misinterpretations are putting Medicare beneficiaries at risk because the safety and efficacy of the restrictions are unknown and have never been tested in clinical trials. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 30 of 32 References Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer 1993;29A (Suppl 2):S2-S8. Amato A, Pescatori M. Perioperative blood transfusions for the recurrence of colorectal cancer. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005033. DOI: 10.1002/14651858.CD005033.pub2. www.thecochranelibrary.com Aranesp® (darbepoetin alfa) Prescribing Information. Amgen Inc., Thousand Oaks, CA. Rev’d April 2007. Bennett-Guerro E, Veldman T, Doctor A et al. Evolution of adverse changes in stored RBCs. PNAS 2007; 104: 17063-17068. Boccia R, Malik IA, Raja V, et al. Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia. Oncologist 2006;11:409-17. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Brunskill S, Djulbegovic B, Benett CL, Langensiepen S,Hyde C, Engert A. Erythropoietin or Darbepoetin for patients with cancer. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003407. DOI: 10.1002/14651858.CD003407.pub4. Canon JL, Vansteenkiste J, Bodoky G, et al. Randomized, double-blind, active-controlled trial of every-3- week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst 2006;98(4):273- 84. Case DC, Bukowski RM, Carey RW, et al. Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst 1993;85(10):801-806. Chang J, Couture F, Young S, et al. Weekly epoetin alfa maintains hemoglobin, improves quality of life and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2005;23(12):2597-2605. Couture F, Turner AR, Melosky B, et al. Prior red blood cell transfusions in cancer patients increase the risk of subsequent transfusions with or without recombinant human erythropoietin management. Oncologist 2005;10:63-71. Danish Head and Neck Cancer Group (DAHANCA 10). Study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck. http://www.dahanca.dk/get_media_file.php?mediaid=125 - Accessed October 17, 2007. 3/ 9/2007 Dernedde U, Dernedde R, Shepstone L et al. Three-year single institution audit on transfusion requirements in oncology patients. Clinical Oncology (2007) 19:223-227. Ende E, Newman J, Christiansen P. Amgen Inc: Expect more volatility post-CERA PDUFA. Merill Lynch Research Report. United States: Merill Lynch: May 17, 2007. European Medicines Agency. Public Statement: Epoetins and the risk of tumour growth progression and thromboembolic events in cancer patients and cardiovascular risks in patients with chronic kidney disease (Doc. Ref. EMEA/496188/2007). October 23, 2007. London, UK. http://www.emea.europa.eu/pdfs/human/press/pus/49618807en.pdf. Accessed November 1, 2007 Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 31 of 32 FDA Medical Officer Report: Center for Drug Evaluation and Research Approval for Application Number 103234s5053; Trade Name: Epogen/Procrit; For the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. http://www.fda.gov/cder/foi/nda/2004/103234s5053.pdf - Accessed October 17, 2007 Grote T, Yeilding A L, Castillo R, et al. Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol 2005;23(36):9377-86. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362(9392):1255- 60. Hopkins B. JNJ: Procrit proposal an overhang. Lehman Brothers Research Report. United States: Lehman Brothers: May 15, 2007. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Clinical Study Report; A Phase 3 Randomized Double-Blind Study of Epoetin Alfa Versus Placebo in Anemic Patients With Cancer Undergoing Chemotherapy Protocol PR98-27-008 (NCCTG 97-92-53). Lee D. Perception of Blood Transfusion Risk. Transfusion Medicine Reviews (2006) 20: 141-148. Leyland-Jones B. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005;23(25):5960-72. Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001; 19(11):2865-2874. Lyman GH, Glaspy J. Are there clinical benefits with early erythropoietic intervention for chemotherapy- induced anemia? Cancer 2006; 106(1):223-33. Malone D, Dunne J, Tracy J et al. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54:898-907. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Cancer- and Treatment-Related Anemia v.3.2007. The Complete Library of NCCN Practice Guidelines in Oncology may be found at www.nccn.org. Accessed October 17, 2007 Netzer G, Shah C, Iwashyna T et al. Association of RBC transfusion with mortality in patients with acute lung injury. Chest 2007;132;1116-1123. Pirker R, Vansteenkiste J, Gateley J, et al. A phase III, double-blind, placebo-controlled, randomized study of novel erythropoiesis stimulating protein (NESP) in patients undergoing platinum treatment for lung cancer. Poster presented at the 37th Annual Meeting of the American Society of Clinical Oncology; May 12-15, 2001, San Francisco, CA. Porges GC, Nudell BM, Guha A, Schneider EJ. AMGN, JNJ: End of evidence based regulation - CMS proposal could cut the EPO market by 50% or more. Bernstein Research Report. New York: Sanford Bernstein & Co., LLC, a subsidiary of Alliance Bernstein L.P.; May 15, 2007. PROCRIT (Epoetin alfa) Prescribing Information. Distributed by Ortho Biotech Products, L.P., Raritan, NJ. Rev’d March 2007. Attachment to Ortho Biotech’s ESA NCD Reconsideration Request Page 32 of 32 PROCRIT (Epoetin alfa) Prescribing Information. Distributed by Ortho Biotech Products, L.P., Raritan, NJ. Rev’d October 2007. Quirt I, Kovacs M, Couture F, et al. Patients previously transfused or treated with epoetin alfa at low baseline hemoglobin are at higher risk for subsequent transfusion: an integrated analysis of the Canadian experience. Oncologist 2006;11(1):73-82. Reynolds J, Ahearn G, Angelo M et al S-nitrosohemoglobin deficiency: A mechanism for loss of phyisiological activity in banked blood. PNAS 2007; 104:17058-17062. Rizzo JD, Lichtin AE, Woolf SH, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology (ASH). Blood 2002;100(7):2303-20 and J Clin Oncol 2002;20(19):4083-107. Rizzo J, Somerfield M, Hagerty K et al. American Society of Hematology/American Society of Clinical Oncology clnical practice guideline update on the use of epoetin and darbepoetin. http://jco.ascopubs.org/cgi/content/abstract/JCO.2007.14.3396v1. Accessed October 23, 2007 Szczudlo T, Croot C, McKenzie R, et al. Epoetin alfa initiation at Hb 10-11 or Hb <10 g/dL: analysis of safety and efﬁcacy. J Clin Oncol 2007;25(18S Part 1 of 2).(Abs 19628) Available at: www.asco.org Vadhan-Raj S, Mirtsching B, Charu V, et al. Assessment of hematologic effects and fatigue in cancer patients with chemotherapy-induced anemia given darbepoetin alfa every two weeks. J Support Oncol 2003;1:131- 38. Vansteenskiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94:1211-20. Wang Q. Hematologic outcomes of epoetin-alfa treated cancer patients based on initial intervention of Hb <10 v. Hb 10-11 g/dL: results from a prospective observational study. J Clin Oncol 2007;25(18S Part 1 of 2).(Abs 19542) Available at: www.asco.org Werber Y. Amgen Inc (AMGN): It all comes down to the final CMS NCD decision - cardiorenal panel might not be nearly as bad as ODAC. Citigroup Research Report. North America: Citigroup Global Markets Inc.: May 25, 2007. Witzig TE, Silberstein PT, Loprinzi CL, et al. Phase III, randomized, double-blind study of epoetin alfa versus placebo in anemic patients with cancer undergoing chemotherapy. J Clin Oncol 2005;23(12):2606-2617. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non–small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25(9):1027-32.
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