i. BACKGROUND Dear Mr. Cotter: DEPARTMENT OF HEALTH &. HUMAN SERVICES Re: Docket No. FDA-2009-P-0426 A. Erythropoiesis-Stimulating Agents

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1 (l t\ strv1c s. ~o/'''''~ DEPARTMENT OF HEALTH &. HUMAN SERVICES Food and Drug Administration Rockvile M D Dennis J. Cotter President, Medical Technology and Practice Patterns Institute 4733 Bethesda Ave., Suite 510 Bethesda, MD JUN Dear Mr. Cotter: Re: Docket No. FDA-2009-P-0426 This letter responds to your citizen petition received on September 1, 2009 (Petition), and supplements received on September 30, 2009 (First Supplement), November 10, 2009 (Second Supplement), November 12,2009 (Third Supplement), March 2,2010 (Fourth Supplement), and April 14, 2010 (Fifth Supplement), regarding EpogenlProcrit (epoetin alfa) and Aranesp (darbepoetin alfa).! Your Petition requests that the Food and Drug Administration (FDA or the Agency) require changes to the labeling for EpogenlProcrit under section 505(0)(4) or other appropriate sections of the Federal Food, Drug, and Cosmetic Act (FD&C Act) "to specify a safer target hematocrit(hct)/hemoglobin (Hb J range and a safer dose in response to new safety information for chronic renal failure (CRFJ adult patients requiring and not requiring dialysis" (Petition at 1). In addition, your Petition requests that FDA require additional boxed warnings related to the target hematocrit/hemoglobin range and dose. Your request for labeling changes regarding the target hematocrit range is based upon clinical trial data describing an increased risk of serious cardiovascular èvents and death among CRF patients randomly assigned to receive doses of EpogenlProcrit or Aranesp sufficient to achieve and maintain a higher as compared to a lower target hematocrit for treatment of anemia. Your request for labeling changes regarding the recommended dose of epoetin alfa is based on a secondary analysis of clinical trial data and the Medical Technology and Practice Patterns Institute's (MTPPI's) unpublished analysis of observational data from the United States Renal Data System evaluating the contribution of dose to an increased risk of cardiovascular events and death. We have carefully reviewed your Petition and each supplement to the Petition, and other relevant information available to us. For the reasons described in detail in this response, your Petition is granted in part and denied in part. We also note that, as with all FDA-approved drug and biological products, FDA will continue to monitor and review available safety information related to licensed epoetin alfa and darbepoetin alfa products throughout the product lifecycles. i. BACKGROUND A. Erythropoiesis-Stimulating Agents Erythropoietin is a glycoprotein hormone produced primarily in the kidney that is responsible for regulating red blood cell maturation and production (erythropoiesis). Red blood cells transport i Although the requests in your Petition are directed to the labeling for Epogen/Procrit, you reference clinical trial data for both Epogen/Procrit and Aranesp. Accordingly, we discuss both EpogeniProcrit and Aranesp in this response.

2 oxygen to body tissues, and are essential for the functioning of vital organs. Erythropoietin binds to its receptor on erythroid progenitor cells and activates signaling pathways that stimulate red blood cell production and inhibit apoptosis (cell death), resulting in an increase in red blood cell levels. An increase in red.blood cell levels is commonly indicated by an increase in the laboratory measures known as the blood hemoglobin level and the blood hematocrit. An abnormally low hemoglobin or hematocrit value is a defining characteristic of anemia. In patients with chronic kidney disease (CKD), anemia is common because production of erythropoietin is impaired by kidney disease. Other conditions that may cause anemia are generally unrelated to a deficiency of erythropoietin (e.g., anemias due to iron deficiency, certain vitamin deficiencies, hemorrhage, and various intrinsic bone marrow disorders).2 Eryhropoiesis-stimulating agents (ESAs) are a class of biological products that stimulate red blood cell production through the same mechanism as endogenous erythropoietin. There are two ESAs currently marketed in the United States: EpogenlProcrie (epoetin alfa) and Aranesp red blood cells (darbepoetin alfa). The goal oftreatment with ESAs is to increase the number of in patients with the specific types of anemia that are responsive to ESAs so that the need for blood transfusions is reduced or avoided. Among other reasons, blood transfusions are considered undesirable for CKD patients who are potential kidney transplant candidates due to the risk of developing immune sensitization (alloimmunization) which may impair graft survival. In 1989, FDA approved Amgen, Inc.'s (Amgen's) biologic license application (BLA) for Epogen (epoetin alfa) for the "treatment of the anemia associated with chronic renal failure,4 including patients on dialysis (end-stage renal disease) and patients not on dialysis." Epogen is indicated "to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients."s Approval of Epogen was based on data from 17 clinical studies enrolling 1,191 patients. Among the key studies supporting approval of Epogen were double-blind, placebo-controlled trials involving patients with chronic renal failure on dialysis and not on dialysis.6 The original approved 2 See Adamson JW, Longo DL. "Chapter 58. Anemia and Polycythemia." In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison's Principles ofintemal Medicine. 17th ed. New York: McGraw Hil, 2008: Epogen and Procrit are different trade names for a single biological product (epoetin alfa) manufactured by Amgen. Amgendistributes Epogen in the United States for use in anemic patients with chronic kidney disease on dialysis, and Centocor Ortho Biotech Products, L.P. (a subsidiary of Johnson & Johnson) distributes Procrit in the United States for use in anemic patients with chronic kidney disease not on dialysis and for use in patients with nomenal indications. We generally refer to "EpogeniProcrit" thoughout this Response. 4 See Epogen product labeling (approved June 1, 1989). The labeling for EpogeniProcrit and Aranesp approved on June 24, 2011, describes use in patients with chronic kidney disease (CKD) rather than chronic renal failure (CRF), reflecting the current preferred terminology. 5 See Summary Basis of Approval for Epogen, licensed on June 1, The First Supplement to the Petition incorrectly describes the conditions of use for which Epogen was initially approved by suggesting that the product was not indicated for hemodialysis patients not dependent on red blood cell transfusion, or for CKD patients not on dialysis (see First Supplement at 1). 6 See Summary Basis of Approval for Epogen, licensed on June 1, The Petition incorrectly suggests that approval of Epogen for CRF patients not requiring dialysis was based on "two small studies (14 and 12 patients, respectively) of short duration (8 and 16 weeks, respectively)" (Petition at 3). FDA reviewed four clinical studies involving 181 CRF patients not requiring dialysis - including two multicenter, double-blind, placebo-controlled 2

3 product labeling for Epogen recommended a target hematocrit range of30-33% (max 36%), and stated that the "dose of Epogen should be reduced when the hematocrit reaches the target range of3q-33% or increases by more than 4 points in any two-week period."? FDA subsequently approved EpogenlProcrit for the following nonrenal indications: treatment of anemia due to zidovudine in HIV-infected patients (1990); treatment of anemia due to chemotherapy in patients with cancer (1993); and reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery (1996). In 2001, FDA approved Amgen's BLA for Aranesp (darbepoetin alfa) for the treatment of anemia associated with chronic renal failure, including patients on dialysis or not on dialysis. Aranesp has a longer half-life than EpogenlProcrit and is administered according to a different dose and schedule. Approval was based on clinical trial data demonstrating that Aranesp raised the hemoglobin level and reduced use of red blood cell transfusions to about the same extent as Epogen/Procrit. The initial Aranesp product labeling recommended that the "dose should be adjusted for each patient to achieve and maintain a target hemoglobin level not to exceed 12 g/dl (grams/deciliterj,"s In 2002, FDA approved Aranesp for treatment of anemia due to chemotherapy in patients with cancer. The nonrena1indications for EpogenlProcrit and Aranesp are not relevant to the Petition and are not discussed further in this Response. B. Cardiovascular Events in Patients Treated with ESAs for Anemia Due to Chronic Kidney Disease FDA has closely monitored and analyzed postmarketing data on the benefits and risks ofesa use in patients with CKD since licensure of Epogen in The potential for adverse cardiovascular reactions associated with ESAs was not recognized at the time of Epogen licensure, although it was known that ESAs could cause hypertension. CKD and cardiovascular disease are closely interrelated: principal risk factors for developing CKD such as hypertension and diabetes melltus are also risk factors for atherosclerotic cardiovascular disease, and the most significant complications ofckd (and leading cause of death) are cardiovascular in nature.9 trials - and determned that CRF patients not requiring dialysis had a similar response to Epogen as observed in patients on dialysis. It appears that the published references cited by the petitioner describe data from single centers within multicenter trials or exploratory studies. 7 See Epogen product labeling (approved June 1, 1989). 8 See Aranesp product labeling (approved Sept. 17,2001), available at htt://ww.accessdata. fda. gov/drugsatfda _ docs/labe1l200 1 / darbamg LB.htr. 9 See Bargman JM, Skorecki K. "Chapter 274. Chronic Kidney Disease." In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harison's Principles ofintemal Medicine. 17th ed. New York: McGraw Hil, 2008:

4 In the late 1980s and 1990s, small studies suggested that higher hemoglobin levels were beneficial for patients with CKD, and it was hoped that use of ESAs to raise hemoglobin levels would reduce the risk of cardiovascular events. Subsequently, four randomized, controlled trials were conducted in patients with CKD that compared use of ESAs to target higher and lower hemoglobin levels. These trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels (reflecting the observation that patients with CKD and higher hemoglobin levels had better cardiovascular outcomes). However, in each of these trials, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to end stage renal disease (ESRD). These four trials are described below. "Normal Hematocrit" Study (NHS) ( ): The NHS was a prospective, randomized, open-label trial designed to test the hypothesis that a higher target hematocrit/hemoglobin in subjects receiving hemodialysis with a history of either chronic heart failure or ischemic heart disease would result in improved outcomes as compared with a lower target hematocrit/emoglobin.io The trial enrolled 1,265 patientsll with ESRD who had been receiving epoetin alfa and were being maintained at a hematocrit of 30:13% (Hb of 10:11 g/dl). Patients were randomized to epoetin alfa doses sufficient to maintain a target hemoglobin of 14:11 g/dl or to maintain a target hemoglobin of 10:11 g/dl.!2 The primary endpoint was time to death or first nonfatal myocardial infarction (MI). The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. For all-cause mortality, the hazard ratio (HR) was 1.27 (95% Confidence Interval (CI): ; p=0.018). The incidence of nonfatal MI, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dl.13 This information was added to the EpogenlProcrit labeling as a WARNING, and included in the Aranesp labeling upon its licensure in Besarab A, Bolton WK, Browne JK, et a1. "The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin." N Engl J Med 1998;339(9): (NHS article). ii The NHS article describes an interim analysis of data available for 1,233 patients; data on 1,265 patients was analyzed in the final study report. 12 For consistency throughout this response, we describe the hemoglobin concentration rather than the hematocrit value. In the NHS, hematocrit values (in percentage points) were calculated by multiplying the hemoglobin concentrations (in g/dl) by 3 (see NHS article at 585). 13 The HR was 1.28 (95% CI: ) for all-cause mortality or nonfatal MI (see Epogen/Procrit and Aranesp labeling; see also Petition at 2, Table 1). 4

5 Correction of Hemoglobin and Outcomes in Renal Insuffciency (CHOIR) Trial ( ): The CHOIR trial was a prospective randomized trial of 1,432 patients with anemia (Hb 0: 11.0 g/dl) due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy.!4 Patients were randomized to receive epoetin alfa to maintain a target hemoglobin of either 13.5 g/dl (high Hb group) or 11.3 g/dl (low Hb group). The primary endpoint was the composite of time to death, nonfatal MI, hospitalization for congestive heart failure (CHF), and stroke. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, MI,hospitalization for CHF, or stroke) occurred in 125 of the 715 patients (18 percent) in the higher hemoglobin group compared to 97 of the 717 patients (14 percent) in the lower hemoglobin group (HR: 1.34; 95% CI: ; p=0.03). Death and hospitalization for CHF accounted for 75 percent of the composite events. There were 52 deaths (7.3 percent) in the higher hemoglobin group and 36 deaths (5.0 percent) in the lower hemoglobin group, with a hazard ratio for time to death of 1.48 (95% CI: ; p=0.067).!5 Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta16 (CREATE) Trial ( ): The CREATE tral randomized 603 patients with CKD and anemia (Hb lito 12.5 g/dl) to a high hemoglobin target (13 to 15 g/dl) or a low hemoglobin target (10.5 to 11.5 g/dl).17 The primary endpoint was the timeto a first cardiovascular event (including sudden death, MI, acute hear failure, stroke, transient ischemic attack, angina pectoris resulting in hospitalization for 24 hours or more or prolongation of hospitalization, complication of peripheral vascular disease (amputation or necrosis), or cardiac arrhythmia resulting in hospitalization for 24 hours or more). Overall, a primary endpoint event was reported in 58 of 301 (19.3 percent) patients in the high hemoglobin group and 47 of302 (15.6 percent) patients in the low hemoglobin group (HR: 1.28; 95% CI: ; p=0.20).!8 The increased rate of cardiovascular events among patients in the high hemoglobin target group was not statistically significant in this relatively small trial, but the findings trended in the same direction as the CHOIR trial.. In March 2007, a boxed warning was added to EpogenlProcrit and Aranesp labeling to describe, among other things, the increased risk for death and serious cardiovascular events when ESAs were administered to target a hemoglobin of greater than 12 g/dl: "Use the lowest dose of (ESAJ 14 Singh AK, Szczech L, Tang KL, et al. "Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease." N Engl J Med 2006;355(20): (CHOIR article). 15 See CHOIR article at 2094, Table 2. We note that Table 1 of the Petition (p. 2) refers to a HR of 1.47 for CV- Mortality Risk. 16 Epoetin beta is an ESA, but is not approved in the United States; the CREATE study was conducted in Europe. 17 Drueke TB, Locatelli F, Clyne N, et al. "Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia." N Engl J Med 2006;355(20): (CREATE article). 18 The CREATE article describes the hazard ratio for time to a first cardiovascular event in patients in the low hemoglobin group as compared to the high hemoglobin group (HR: 0.78; 95% CI: ; p=0.20), whereas the NHS, CHOIR, and TREAT trial findings are presented for the high hemoglobin group as compared to the low hemoglobin or placebo group. For consistency with the presentation of other data in this response, we are showing the reciprocal hazard ratio and 95% confidence interval of that presented in the CREATE article (see CREATE article at ). Table 1 of the Petition (p. 2) refers to a HR of 1.51 for the high Hb CV-Mortality Risk Group in the CREATE trial The source of this calculation and the specific analysis to which it refers are unclear. 5

6 that wil gradually increase the hemoglobin concentration to the lowest level suffcient to avoid the need for red blood cell transfusion... ESAs increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dl..." In September 2007, FDA convened ajoint session ofthe Cardiovascular and Renal Drugs Advisory Committee (CRDAC) and the Drug Safety and Risk Management Advisory Committee to discuss updated information on the risks and benefits of ESAs when used to treat anemia due to chronic kidney disease, including data from the NHS, CHOIR, and CREATE trials. After the 2007 Advisory Committee meeting, the boxed warning in ESA product labeling was updated to advise: "Patients experienced greater risks for death and serious cardiovascular events when administered (ESAsJ to target higher versus lower hemoglobin levels (13.5 vs g/dl; 14 vs. 10 g/dl) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dl." Subsequently, preliminary findings from a fourth randomized, controlled trial (the TREAT trial) became available and are described below. Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) ( ): TREAT was a randomized, double-blind, placebo-controlled, prospective trial of 4,038 patients with CKD not on dialysis, anemia (Hb levels ~ 11 g/dl), and type 2 diabetes melltus.!9 Patients were randomized to receive treatment with darbepoetin alfa to a target hemoglobin level of 13.0 g/dl or to receive placebo, with "rescue" darbepoetin alfa when the hemoglobin level was less than 9.0 g/dl. The trial was performed to determine whether administration of darbepoetin alfa to achieve a higher target hemoglobin level would reduce the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (nonfatal MI, nonfatal stroke, CHF, or hospitalization for myocardial ischemia); or (2) a composite renal endpoint of all-cause mortality or progression to ESRD. In the TREAT protocol, the darbepoetin alfa group attained a sustained median hemoglobin of 12.5 g/dl whereas the placebo group had a median hemoglobin of 10.6 g/dl. The overall risks foreach of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment, but the risk of stroke was increased nearly two-fold in the darbepoetin alfa-treated group as compared to the placebo group (HR: 1.92; 95% CI: ). In January 2010, EpogenlProcrit and Aranesp labeling was updated to reflect preliminary findings from the TREAT trial in the context of the other randomized, controlled trials that compared use of ESAs to target higher and lower hemoglobin levels. The boxed waring was revised to state, in part: "In clinical studies, patients experienced greater risks for death, serious cardiovascular events, and stroke when administered (ESAs J to target hemoglobin levels of 13 g/dl and above. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dl." In addition, the WARNINGS section ofesa product labeling also was revised at this time to highlight the increased risk for stroke. 19 Pfeffer MA, Burdmaii EA, Chen C-Y, et al. "A Trial of Kidney Disease." N Engl J Med 2009;361 : Dar be poet in Alfa in Type 2 Diabetes and Chronic 6

7 In February 2010, FDA required a risk evaluation and mitigation strategy (REMS) for EpogenlProcrit and Aranesp to ensure that the benefits of the drugs outweigh their risks.20 The REMS requires the BLA holder to ensure that a Medication Guide2! explaining the risks and benefits of ESAs is distributed to all patients treated with an ESA, including anemic patients with CKD; additional requirements pertain to the use ofesas in patients with cancer. In October 2010, FDA convened a meeting of the CRDAC, as a follow-up to the 2007 advisory committee meeting, to discuss the results and analyses of the TREAT trial. The CRDAC provided recommendations regarding the benefit/risk profile ofaranesp, additional trial(s) to determine an effective dose regimen of Aranesp with an acceptable safety profile, and potential revisions to ESA product labeling to improve safe use. On June 24,2011, FDA approved revised labeling for EpogenlProcrit and Aranesp that includes, among other things, an updated boxed warning, an updated WARNINGS AND PRECAUTIONS section, and a revised DOSAGE AND ADMINISTRATION section to reflect outcome data from clinical trials with ESAs, including the TREAT trial. In addition, conforming revisions have been made to the Medication Guides for these products. The revised product labeling appears in the updated format described by the Physician Labeling Rule, which is easier for health care professionals to access, read, and use.22 c. Regulations on Warnings in Prescription Drug and Biological Product Labeling FDA regulations state that the WARNINGS AND PRECAUTIONS section of prescription drug and biological product labeling (including the product's package insert) must describe clinically 20 Title IX, Subtitle A, section 901 of the Food and Drug Administration Amendments Act of2007 (FDAA) added section 505-1(a)(2) to the FD&C Act (21 U.S.C (a)(2)), which authorizes FDA to require the submission ofa REMS for an approved drug product if FDA becomes aware of new safety information and makes a determination that such a REMS is necessary to ensure that the benefits of the drug outweigh its risks (see section of the FD&C Act for more information about REMS). Section applies to applications submitted under section 505(b) and (j) of the FD&C Act and applications submitted under section 351 of the Public Health Service Act (PHS Act). 21 A Medication Guide is FDA-approved patient labeling that meets the standards and requirements in 21 CFR par 208 and other applicable regulations. FDA wil require a manufacturer of a prescription drug or biological product to develop a Medication Guide for distribution to patients when FDA determines: the product is one for which patient labeling could help prevent serious adverse effects; the product is one that has serious risk(s)(relative to benefits) of which patients should be made aware because information concernng the risks could affect patients' decision to use, or to continue to use, the product; or the product is important to health and patient adherence to directions for use is crucial to the product's effectiveness (see 208.l(c)). In some cases, FDA may require a Medication Guide as part ofa REMS under section of the FD&C Act. For more information, see FDA's draft guidance for industry entitled "Medication Guides -- Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS)." (This draft guidance, when finalized, will represent FDA's current thinking on this topic. Guidance documents are available on FDA's Web site at htt://ww.fda.govldrugs/guidancecomplianceregulatoryinformationiguidances/default.htm. ) 22 See "Requirements on Content and Format of Final Rule" (71 FR 3922, January 24,2006). Labeling for Human Prescription Drug and Biological Products; 7

8 significant adverse reactions,23 other potential safety hazards, limitations in use imposed by them, and steps that should be taken if these situations occur ( (c)(6)(i); see also 21 CFR (e) through (f)). Labeling mustbe revised to include a warning as soon as there is reasonable evidence of a causal association of a clinically significant hazard with the product the most (see (c)(6)(i)). For products described in 21 CFR , a summary of clinically significant warnings and precautions information must be included in the Highlights of prescribing information (Highlights) for the product ( (a)(1 0)). Under (c)(1), a boxed warning may be required for certain contraindications or serious warnings, particularly those that may lead to death or serious injury (see also (e)). A boxed warning briefly explains the risk and refers to more detailed information in the CONTRAINDICATIONS or WARNINGS AND PRECAUTIONS section ( (c)(1)). A summary of a boxed warning (with the heading WARNING and other words identifying the subject ofthe warning) must be included in the Highlights in a box and in bold type ( (d)(1) and (a)(4)). II. DISCUSSION A. Hemoglobin/Hematocrit Target Range 1. Requested Revisions to Boxed Warning In your Petition, you request that FDA require EpogenlProcrit labeling to include the following statement in the boxed warning: "Patients experienced greater risks for death and serious myocardial infarct events when administered individualized epoetin dosing to target higher versus lower hematocrit levels (42% vs. 30%)" (Petition at 1 to 2). Your request for labeling revisions regarding the target hematocrit range is based upon clinical data from the NHS, CHOIR, CREATE, and TREAT trials describing an increased risk of serious cardiovascular" events and death among CKD patients randomly assigned to receive doses of EpogenlProcrit or Aranesp sufficient to achieve and maintain a higher as compared to a lower target hematocrit for treatment of anemia (see Petition at 2, Second Supplement at 1). 23 The regulation at 21 CFR (c)(7) defines adverse reaction as an undesirable effect, reasonably associated with use of a drg, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. FDA's draft guidance for industr entitled Warnings and Precautions, Contra indications, and Boxed Warning Sections of Labe ling for Human Prescription Drug and Biological Products - Content and Format (Warnings Draft Guidance) (p. 11) defines serious adverse reaction as any reaction occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect (see also definition of serious adverse experience at 21 CFR (a)). The Warnings Draft Guidance (p. 2) states that the clinically significant adverse reactions observed in association with use of a drug that should be listed in the WARINGS AN PRECAUTIONS section (see 201.7(c)(6)) include those involving a serious adverse reaction, an adverse reaction that does not meet the definition of a serious adverse reaction but is otherwise clinically significant (e.g., requires discontinuation, dosage or regimen adjustment, could be prevented with appropriate patient selection, significantly affects patient compliance), and product interference with a laboratory test. (Guidances are available on FDA's Web site at htt://ww.fda.gov/drugs/guidancecomplianceregulatorvlnformationiguidances/default.htm. The Warnngs Draft Guidance, when finalized, will represent FDA's current thinkng on this topic.) 8

9 In addition, your Petition requests that FDA require Epogen/Procrit labeling to include the following statement in the boxed warning: "A maintenance target Hg/Hct range has not been established for either predialysis or dialysis dependent chronic renal failure (CRF) patients" (Petition at 1 ). You assert that this revision to the boxed warning is necessary because the 2009 labeling did not contain a risk warning for dialysis patients despite similar risks to predialysis patients (see Petition at 3). FDA Response Based on FDA's review and analysis of the TREAT trial, outcome data from other clinical trials with ESAs, and the recommendations of the CRDAC, FDA has concluded that labeling for all ESA products should be updated to include a strengthened boxed warning describing the increased risk of death, serious adverse cardiovascular reactions, and stroke when ESAs are administered to target a hemoglobin level of greater than 1 19/dL. Although the TREAT trial involved Aranesp, these clinical trial findings are relevant to the use of EpogenlProcrit, another ESA in the product class. On June 24, 2011, FDA approved labeling for EpogenlProcrit and Aranesp that includes the following text in the boxed warning: Chronic Kidney Disease:. In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dl.. No trial has identified a hemoglobin target level, (EpogenlProcrit or Aranesp J dose, or dosing strategy that does not increase these risks.. Use the lowest (EpogenlProcrit or Aranesp J dose suffcient to reduce the need for red blood cell (RBC) transfusions. As with previous boxed warnings, this part of the boxed warning is directed to use of ESAs in all patients with CKD, including patients on dialysis and patients not on dialysis. The basis for your assertion that an 'earlier boxed warning did not contain a risk warning for patients on dialysis is unclear, because the text of that boxed warning described risk findings from both the NHS trial (patients on dialysis) and the CHOIR trial (patients not on dialysis),z4 FDA's determination regarding the necessary revisions to the boxed warning regarding the target hemoglobin level for ESAs differs from certain labeling revisions requested in your Petition. The revised boxed warning emphasizes that clinical trial data has shown that targeting a 24 At the time of submission of your Petition, the boxed warning for EpogeniProcrit contained the following statement: "Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered eryhropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11. g/dl (CHOIR); 14 vs. 10 g/dl (NSJ) in two clinical studies. Individualize dosing to achieve and maintain this hemoglobin levels within the range of 10 to 12 g/dl"; see also Petition at 3. As described in section LB of response, the boxed warnng was updated in January 2010 to incorporate certain data from the TREAT study describe the greater risk for death, serious cardiovascular reactions, and stroke experienced by patients when administered ESAs to target hemoglobin levels of 13 g/dl and above. and 9

10 hemoglobin level above 11 g/dl has been associated with an increased risk of death, serious adverse cardiovascular reactions, and stroke. This text more clearly conveys risk information than a description of the risk associated with the higher target hemoglobin level in the TREAT (13 g/dl), CHOIR (13.5 g/dl), and NHS (14 g/dl) trials, whích may incorrectly suggest that a target hemoglobin below those levels is not also associated with an increased risk of death, serious adverse cardiovascular reactions, and stroke. The risk threshold of 1 1 g/dl described in the FDA-approved boxed warning, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of product labeling is based on the control arm outcomes from the clinical trials noted above. Your request to include in the boxed warning a statement about the increased risk of death and serious myocardial infarct events when administered epoetin alfa to "target higher versus lower hematocrit levels (42% vs. 30%),"25 which equates to a hemoglobin of 14 g/dl vs. 10 g/dl is denied. Your proposed statement does not adequately reflect the available clinical trial data or convey overall risk, and could suggest that hemoglobin levels below 14 g/dl would not increase risk. The labeling approved on June 24, 2011, suggests a considerably lower risk threshold (Hb of 1 1 g/dl). In addition, FDA has concluded that ESA labeling should describe the hemoglobin concentration rather than the hematocrit level in this context based on current usage. FDA is granting your request that FDA require a boxed warning stating that a maintenance target Hb/Hct range has not been established for either predialysis or dialysis-dependent CRF patients (Petition at 1). The revised boxed warning in the labeling approved on June 24,2011 states that "no trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks (of death, serious adverse cardiovascular reactions, or strokej." This statement underscores the collective findings from the large, randomized, controlled clinical trials conducted to date, and FDA considers your request to be addressed by this broader statement in the boxed warning. FDA determined that the boxed warning should highlight the fact that no clinical trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase the risk of death, serious adverse cardiovascular reactions, or stroke. This information is essential for healthcare providers to consider in assessing the risks and benefits of ESA use for individual patients in the context of their medical needs. 25 Petition at 1 to 2. 10

11 Section 901 of the Food and Drug Administration Amendments Act of2007 (FDAAA) added authority for FDA to require, under certain circumstances, postmarketing studies and clinical trials for drugs approved under section 505 of the FD&C Act or section 351 ofthe PHS Act.26 FDA may require a postmarketing study or postmarketing clinical trial of an approved drug or biological product if FDA becomes aware of new safety information and determines that postmarketing studies or clinical trials are needed for any or all of three purposes listed in section 505(0)(3)(B) ofthe FD&C Act: (i) To assess a known serious risk related to the use of the drg involved. (ii) To assess signals of serious risk related to the use of the drug. (iii) To identify an unexpected serious risk when available data indicates the potential for Ii serious risk. Pursuant to section 505(0)(3) of the Act, we are requiring the BLA holder for EpogenlProcrit and Aranesp to assess the known serious risk of adverse cardiovascular reactions and death associated with ESAs through postmarketing clinical trials designed to identify an optimal strategy ofesa dose and schedule in patients with CKD on dialysis and to evaluate different dosing strategies in patients with CKD who are not on dialysis. These clinical trials are intended to better define the safe conditions of use of EpogenlProcrit and Aranesp in anemic patients with CKD. 2. Requested Revisions to DOSAGE AND ADMINISTRATION Section of Labeling In your Petition, you request that FDA require changes to the DOSAGE AND ADMINISTRATION section of EpogenlProcrit product labeling to recommend individualized dosing to achieve and maintain a hemoglobin target range of g/dl, with a maximum of 12 g/dl to "more closely reflect safe Epogen use" (Petition at 2). In support of your request, you state that "(tjo date, no study has reported a safe or clinically appropriate target Hct and no study has provided evidence to justify a change from the original EPOGEN label Hct target range of 30-33% maximum 36% (Hb g/dl maximum 12 g/dlj to the current target of 30-36% (Hb g/dl)" (Petition at 3, see also First Supplement at 2). You assert that the "current label provides the incentive to target the high end of the range resulting in Hct overshoots and findings increased risk to patients" (Petition at 3).27 You also state that the TREAT trial "seriously challenge a claim to treat patients above a (Hb J of 10 g/dl, although this study was not specifically designed to identify an appropriate (Hb J target" (Second Supplement at 1; see also First Supplement at i). 26 Under section 505(0)(3)(D)(i) of the FD&C Act, before requiring a postmarketing study, FDA must find that' adverse event reporting under section 505(k)(1) of the FD&C Act and the new active postmarket risk identification and analysis system that wil be established under section 505(k)(3) wil not be sufficient to meet the purposes described in section 505(0)(3)(B). In addition, under section 505(o)(3)(D)(ii), before requiring a postmarketing clinical trial, FDA must find that a postmarketing study wil not be suffcient to meet the purposes described in section 505(0 )(3)(B). 27 You also reported that "as recently as 2007, providers continue to target patients to the high end of the curent FDA approved 30-36% hematocrit range, causing most patients to over-shoot the target. Approximately 24% of hemodialysis patients now receive high epoetin doses, and account for 56% of epoetin consumption" (First Supplement at 2). 11

12 FDA Response FDA has concluded that no clinical trial to date has identified a hemoglobin target that does not increase the risk of death, serious cardiovascular reactions, or stroke; therefore, FDA has concluded that it is no longer appropriate to describe a specific target hemoglobin range to guide ESA dosing. Accordingly, the revised DOSAGE AND ADMINISTRATION section of product labeling (and other sections of the product labeling) approved on June 24,2011, does not include a specific target hemoglobin range,28 and weare denying your request that FDA require this labeling revision. The revised DOSAGE AND ADMINISTRATION section of product labeling recommends, for patients with CKD on dialysis, that healthcare providers "(ijnitiate (EpogenlProcrit or AranespJ treatment when the hemoglobin level is less than 10 g/dl," and reduce or interrpt the dose of EpogenlProcrit or Aranesp if the hemoglobin level approaches or exceeds 11 g/dl. For patients with CKD not on dialysis, the revised DOSAGE and ADMINISTRATION section of product labeling recommends that healthcare providers "( c Jonsider initiating (EpogenlProcrit or Aranesp J treatment only when the hemoglobin level is less than 10 g/dl and the following considerations apply: (aj the rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and, (b J reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal," and reduce or interrpt the dose of EpogenlProcrit or Aranesp ifthe hemoglobin level exceeds 10 g/dl. For all patients with CKD, the labeling recommends use ofthe lowestdose of EpogenlProcrit or Aranesp sufficient to reduce the use of RBC transfusions and directs physicians and patients to weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events associated with use of ESAs.z9 With respect to your request to specify a maximum hemoglobin of 12 g/dl, FDA has determined that this could be excessive. The labeling for EpogenlProcrit and Aranesp approved on June 24, 2011 states that using these products to achieve a hemoglobin greater than 11 g/dl has not been shown to provide a benefit and has been associated with an increased risk of adverse cardiovascular reactions. B. Epogen/Procrit Dose In your Petition, you request that FDA require that EpogenlProcrit labeling include the following statement in the boxed warning: "Patients experienced greater risks for death and serious 28 The INICATIONS AND USAGE section of Epogen/rocrit product labeling approved on June 24, 2011, has been revised to state: "(EpogeniProcrit) is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and not on dialysis to decrease the need for red blood cell (RBC) transfusions)." The reference to use of Epogen/rocrit "to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determnations)" has been removed from the indication for anemia due to chronic kidney disease. 29 It should be noted that the riskienefit assessment for use of ESAs may differ for CKD patients with a history of cancer (compare Second Supplement at 2). Based on FDA's analyses of the TREAT data and consideration of the CRDAC recommendations, physicians prescribing ESAs to CKD patients with a past history of malignancy should consider the risks and benefits applicable to this subpopulation. underlying 12

13 cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) found to have a 57% increase in cardiovascular-mortality events at ~20,000 U/wk (Units/weekJ (subcutaneous administration)" (Petition at 2; see also Petition at 3). In addition, you request that FDA require changes to the DOSAGE AND ADMINISTRATION section of EpogenlProcrit labeling to recommend that users "do not exceed 20,000 U/wk (subcutaneous administration) and the equivalent intravenous administration," noting that clinical practice guidelines describe subcutaneous administration as requiring a dose of one-third less than intravenous dosing of epoetin alfa (Petition at 2). This request to impose an upper bound on the recommended dose of epoetin alfa is based on a secondary analysis by Szczech et al. ofthe CHOIR trial (Re-CHOIR or Szczech study)30 and an unpublished analysis of observational data from the United States Renal Data System by MTPPI (2009) evaluating the contribution of dose to an increased risk of cardiovascular events and death (Petition at 3 to 4). You state that the "MTPPI study (in preparation for publication) controlled for Hct and estimated risk by dose quartiles and found a 26% increase in cardiovascular-mortality events in the high dose quartile group(~40,000 U/wk, intravenous administration)" (Petition at 3 to 4; see also First Supplement at 2). FDA Response Your requests to revise the EpogenlProcrit labeling to impose an upper bound on the recommended dose of epoetin alfa are denied. FDA has concluded that there is insufficient evidence to support your requests. However, FDA agrees that dosing should be limited, especially for patients with CKD not on dialysis, and recommendations for limiting dosing are expressly described in the product labeling approved on June 24,2011. In addition, the recommended limitations on dose escalation for patients with an inadequate response3! to ESA treatment may address certain concerns raised in your Petition.32 There is a complex relationship between the ESA dose, dosing regimen, treatment response (ability to achieve a hemoglobin target), and risk for cardiovascular events and death among patients with CKD. Among other things, the ESA dose is dependent on the hemoglobin target as well as the treatment response, as the dose may be escalated in "hyporesponsive" patients and responsiveness to ESA treatment (and corresponding ESA dose) may change over time. An observed association between the risk for cardiovascular events or death and ESA dose may be confounded by medical comorbidity or other factors associated with "hyporesponse" and the need for greater ESA doses in certain patients. 30 Szczech LA, Barnart HX, Inrig JK, et a1. "Secondary analysis of the CHOIR trial epoetin-a dose and achieved hemoglobin outcomes." Kidney International 2008;74: (Szczech study). 31 Although it is generally acknowledged that a group of patients exist who do not respond adequately to ESA therapy, there is no general agreement on how to define such "hyporesponders" and the optimal management of such individuals is not known. 32 EpogeniProcrit and Aranesp product labeling approved on June 24, 2011, states: "For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dl after 4 weeks of therapy, increase the dose by 25%. For patients who do not respond ádequately over a 12-week escalation period, increasing the (EpogeniProcrit or Aranesp) dose further is unlikely to improve response and may increase risks. Use the lowest dose that wil maintain a hemoglobin level sufficient to reduce the use ofrbc transfusions. Evaluate other causes of anemia. Discontinue (EpogenIrocrit or Aranesp) if responsiveness does not improve." 13

14 Your request for an additional statement in the boxed warning regarding ESA dose is based on a statistical reanalysis of the CHOIR trial in the Szczech study. The Szczech study sought to utilize the random assignment of subjects in the CHOIR trial to a high (13.5 g/dl) or low (11.3 g/dl) hemoglobin target to examine the relationship between epoetin dose, inability to achieve hemoglobin target (hyporesponse), and a composite cardiovascular event/mortality outcome. The random assignent of subjects to the high or low hemoglobin target group in the CHOIR trial should equally distribute certain baseline medical comorbidities, that could affect epoetin responsiveness (and thus dose requirements), among the two treatment groups in the trial. However, it is not clear whether the statistical modeling used in this reanalysis (which included adjustment for hemoglobin target assignent, failure to achieve hemoglobin target, self-reported hypertension, and use of intravenous iron) adequately addressed the confounding between use of high-dose epoetin and hyporesponse. In the adjusted model, the Szczech study identified an increased risk for a composite cardiovascular event/mortality outcome for highdose epoetin (~ 20,000 U/week)33 in the 4-month landmark analysis (HR: 1.57; 95% CI: ). However, this association no longer reached statistical significance in the 9-month landmark analysis (HR: 1.48; 95% CI: ), although the point estimates and confidence intervals were qualitatively similar.34 The authors ofthe Szczech study stated: "The conclusions of this analysis should... be considered hypothesis generating. And although hyporesponsiveness and high-dose requirements for epoetin significantly attenuated the increased risk associated with a higher hemoglobin target in CHOIR, these factors do not fully explain the increase in risk.,,35 FDA agrees with the Szczech study authors' conclusion that "(pjrospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.,,36 Accordingly, this hypothesis-generating data from the statistical reanalysis of the CHOIR trial is not adequate to support a boxed warning or revisions to the DOSAGE AND ADMINISTRA non section of product labeling to describe an upper bound on the recommended dose of epoetin alfa. Your requested labeling revisions to limit the recommended dose of epoetin alfa also are not supported by data from MTPPI's presentation to FDA in 2009 (see Exhibit 5 to Petition). The MTPPI presentation did not provide substantive evidence that high-dose epoetin was associated with either cardiovascular events or mortality. MTPPI failed to replicate its earlier observatiori37 of a positive correlation between high-dose epoetin and mortality when the data were re~ 33 See Szczech study at 797 ("(ESA) use was categorized as high- or low-dose if the maximum dose (within the first 4 or 9 months of the study for each landmark analysis) was ~20,000 or ~20,000 U (high vs. low dose). This threshold was chosen because CHOIR limited the dose of epoetin-a to 20,000 U/week"). 34 See Szczech study at 794, Table 3 (Model 5). 35 Szczech study at Szczech study at Zhang Y, Thamer M, Stefanik K, et al. "Epoetin requirements predict mortlity in hemodialysis patients." Am J Kidney Dis 2004;44(5):

15 analyzed using a statistical method (inverse probability weighting) to address the potential timedependent confound between epoetin dose and hemoglobin level. 38 In addition, the MTPPI study results described in Table 1 of the Petition are not accompanied by adequate data and methodological details to support your requested labeling revisions (see Exhibit 5 to the Petition). Exhibit 5 in the Petition describes the preliminary results ofmtppi's study, which sought to estimate the effect of high-dose epoetin on the risk of adverse cardiovascular events and mortality among elderly hemodialysis patients in the United States. The Petition states that the MTPPI study controlled for hematocrit and estimated risk by dose quartiles (Petition at 3 to 4). MTPPI's preliminary results suggested that patients who received an intravenous epoetin alfa dose greater than 40,000 U/wk were at greater risk for a composite cardiovascular event/mortality endpoint as compared to patients who received between 20,000 and less than 30,000 U/wk (HR: 1.26; 95% CI: ), although this finding did not reach statistical significance (see Exhibit 5 to the Petition at slide 46).39 FDA has conducted multiple exploratory analyses of possible relationships among ESA dose and risk of cardiovascular events and/or death. The BLA holder for Aranesp also conducted many exploratory analyses of time-dependency and dose-dependency for adverse events in the TREA T tral. All such analyses were confounded by the fact that, during the trials, hemoglobin levels and ESA dosing varied markedly for each patient, rendering aggregate information inconclusive; therefore, no clear dose-toxicity relationship was identified. FDA is continuing to evaluate the relationship between the ESA dose, dosing regimen, treatment response, and risk for cardiovascular events and death among patients with CKD. In addition, as noted above, FDA is requiring under section 505(0)(3) of the FD&C Act that the BLA holder for EpogenlProcrit and Aranesp conduct postmarketing clinical trials to identify an optimal strategy ofesa dose and schedule in patients with CKD on dialysis and to evaluate different dosing strategies in patients with CKD who are not on dialysis. III. CONCLUSION We have carefully reviewed your Petition and each supplement to the Petition, and other relevant information available to us. Based on our review and analysis ofthe data, your Petition is granted in part with respect to your request that FDA require the boxed warning for EpogenlProcrit to state that a maintenance target hemoglobin/ematocrit range has not been established for CKD patients. FDA considers your request to be addressed by the statement in the revised boxed warning for EpogenlProcrit and Aranesp that "no clinical trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase the risk of death, serious adverse cardiovascular reactions, or stroke." FDA's conclusion thatthis statement should be added to the boxed warning was based on its reanalysis of data from controlled clinical 38 Zhang Y, Thamer M, Cotter D, et al. "Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States." Clin J Am Soc Nephrol 2009;4(3): Although the Petition states that the MTPPI study is in preparation for publication (see Petition at 3-4), it does not appear that the study has been published as of the date of this response. 15