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RPA Letter to FDA re: ESA Labeling Changes

Creation/Revision Date: August 17, 2011

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August 16, 2011 

Robert C. Kane, MD, Acting Deputy Director for Safety 
Division of Hematology Products 
Office of Oncology Drug Products 
Center for Drug Evaluation and Research 
Food and Drug Administration 
White Oak CDER Office Building 22 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 

Dear Dr. Kane: 

The Renal Physicians Association (RPA) is the professional organization of nephrologists whose goals are to insure optimal care under the highest standards of medical practice for patients with renal disease and related disorders. RPA acts as the national representative for physicians engaged in the study and management of patients with renal disease. RPA is writing with regard to the recent labeling change pertaining to the use of Erythropoiesis Stimulating Agents (ESAs) for treatment of anemia in adults with CKD, including patients both on and not on dialysis. 

RPA would first like to express our appreciation for the attention FDA is devoting to the safety risks associated with use of ESAs, as RPA shares the safety concerns associated with ESA prescriptions that result in high hemoglobin (Hb) levels or very high ESA doses. We recognize that recent studies have raised substantial concern about the safety of ESAs when they are used to raise Hb concentrations to the normal or near normal range of Hb greater than 13 grams per deciliter (Gm/dL). In addition, we appreciate FDA’s recognition of the importance of physician-patient relationships and the need to individualize treatments, considering the benefits and risk of ESAs. 

With that said, RPA believes that a statement in the new Epogen label, and conclusions based on this statement, are not supported by published evidence. The new Epogen label includes the following statement:

"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 (5.1)” .

This statement is not correct. In these trials, target hemoglobin levels were higher than 13 g/dL, and achieved hemoglobin levels spanned a range above 11 g/dL. While safety risks have been identified from studies when Hb targets of 13 g/dL or higher have been used, the same is definitively untrue for the FDA’s statement about Hb targets above 11 g/dL. At the 11 g/dL range there can be a reasonable balancing of benefit against potential risk, particularly in hemodialysis patients. There are no studies indicating safety risks for patients being treated at intermediate targets, such as 11-12 gm/dl. While RPA does share concerns about cardiovascular safety risks for patients treated to high Hb levels or using very high ESA doses, we have consistently recommended to policymakers to consider the needs of severely anemic patients at low Hgb levels. As such, we believe that with this label change, concerns about higher levels of hemoglobin and ESA doses may lead to the unintended consequence of underdosing, and inducing severe anemia. 

Indeed, it is our belief that as a result of other policy changes affecting ESA use, most nephrologists have already been reducing doses for ESAs at or around Hb 11 g/dL, which would address the thrust of the FDA labeling to minimize the risks shown at higher Hb levels. RPA is now concerned that the label change and ensuing policies will cause the policy pendulum to swing too far in the opposite direction, with potential harm of causing persistent, severe, or transfusion-dependent anemia in patients at lower hemoglobin levels. As an example, the Centers for Medicare and Medicaid Services (CMS) has already proposed changes in their ESRD Quality Incentive Program (QIP), with a proposal to retire the hemoglobin less than 10 Hb measure previously used in the QIP. Accordingly, it is now our concern that the label change and ensuing policies will unnecessarily create a separate patient safety issue for patients with lower hemoglobin levels, with precipitous drops in individual patients’ hemoglobin levels and persistent, severe or transfusion-dependent anemia, and thus adversely affecting patients not demonstrated to be at risk. 

RPA is also concerned that these policies may result in complex medico-legal problems for nephrology clinicians when adherence to the treatment policies emanating from the labeling change lead to adverse patient outcomes. While we acknowledge that concerns of this nature are separate from the FDA mission to ensure the safety and effectiveness of medical products, RPA is compelled to call attention to this real concern affecting nephrology practitioners. 

Finally, RPA believes that the new policies specifically directing nephrology practitioners to initiate treatment when the hemoglobin level is less than 10 g/dL and reduce or interrupt the dose if the hemoglobin level approaches or exceeds 11 g/dL for dialysis patients, and 10 g/dL for non-dialysis CKD patents will leave little room for clinical judgment and will stifle the ability to pursue innovation in the treatment of patients with CKD. 

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

Thank you, 

Ruben Velez signature

Ruben L. Velez, MD 
President 

CC:      Ann T. Farrell, M.D., Acting Division Director 
Division of Hematology Products 
Office of Oncology Drug Products 
Center for Drug Evaluation and Research 

Patricia Keegan, M.D. Director 
Division of Biologic Oncology Products 
Office of Oncology Drug Products 
Center for Drug Evaluation and Research 

Renal Physicians Association

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Suite 220
Rockville, MD 20852

Phone: 301-468-3515
Fax: 301-468-3511
Email: rpa@renalmd.org

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