ASN Discusses ESA Label Changes with FDA

When the Food and Drug Administration (FDA) changed the label on erythropoiesis-stimulating agents (ESAs) in July, ASN raised concerns about the modifications to the agency. FDA met with ASN this October to discuss the society’s reservations.

FDA significantly revised the ESA label, most importantly by removing the recommended target hemoglobin range of 10–12 g/dL. The new label states that the dose of ESAs should be “reduced or interrupted” if hemoglobin levels exceed 11 g/dL. The label also states that “In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL.” The revised label caused concern among nephrologists, including those on ASN’s Public Policy Board, on multiple levels. First, no study has ever demonstrated that risk does in fact exist above the specific threshold of 11 g/dL, as stated on the label. Second, the label generates uncertainty about how ESAs should actually be administered. “Interrupting” a medication is not typical when treating patients with chronic disease and variable follow up. How low is it safe to let hemoglobin levels go? And would exceeding 11 g/dL generate risk of a malpractice lawsuit in the case of an adverse event?

Given the confusion and alarm among the nephrology community regarding the changes, ASN was pleased that FDA suggested an in-person meeting to discuss the already-published label—a rare move for the agency. ASN Public Policy Board chair Tom Hostetter, MD, and Public Policy Board member Wolfgang Winkelmayer, MD, ScD, FASN, represented the society at the FDA, along with ASN Manager of Policy and Government Affairs Rachel Shaffer. The key points ASN’s contingent emphasized centered on the agency’s assertion that hemoglobin levels above 11 g/dL have conclusively been proven to increase risk of adverse events.

ASN emphasized that since adverse events were consistently observed in randomization groups targeting only hemoglobin concentrations >13 g/dL, no scientific data are currently available that would either justify dropping the previous hemoglobin target of 10–12 g/dL, or substantiate the statement of risk at 11g/dL (Table 1). An accurate statement would instead read that “In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 13 g/dL.”

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“We recognize that FDA is doing its best to ensure patient safety in an area where evidence is sparse, and with a product that is known to increase safety risks when hemoglobins of 13 g/dL or more are aggressivley targeted,” said Winkelmayer. “But it is fundamentally not true that evidence suggests those risks start at 11 g/dL. It would be more reasonable for the label to state that — based on available trial evidence—the risks of any treatment strategies targeting the range between 11 g/dL and 13 g/dL are currently unknown relative to lower or higher targets. That change would allow patients and their nephrologists to have a conversation about the potential risks and benefits.”

ASN also pointed out the on-the-ground reality that the new dosing recommendation terminology could result in overly conservative, more rigidly enacted ESA dosing practice patterns in some dialysis units, especially in light of recent changes to the ESRD Quality Incentive Program by the Centers for Medicare and Medicaid Services. The label change may place patients at increased risk of anemia and blood transfusions, which could adversely affect health and candidacy for transplantation.

The society also explained that physicians treating chronic disease rarely consider interrupting treatment as it may lead to adverse health outcomes. In the setting of anemia in CKD patients, interruption may place patients at increased risk of transfusions.

ASN’s key request to FDA—a request shared by the Renal Physicians’ Association, which also attended the meeting—is that FDA consider revising the label to reflect that studies actually show that greater risk exists when ESAs target a hemoglobin level of greater than 13 g/dL.

At press time (within a week of the meeting) FDA had not issued any formal responses to ASN. The society will keep members updated about additional communications with the FDA regarding the label. You may view ASN’s letter to the FDA on this issue at www.asn-online.org.

October-November 2011 (Vol. 3, Number 10 & 11)