ASN Testifies at FDA Meeting on Future of ESAs

Daniel Kochis
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Representatives convened at a crucial Food and Drug Administration (FDA) meeting of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) recently to determine the future of darbepoetin. ASN Public Policy Board member Wolfgang Winkelmayer, MD, ScD, FASN, presented testimony on the currently available evidence regarding erythropoiesis-stimulating agents (ESAs).

FDA convened the CRDAC meeting to discuss the risks and benefits of the use of ESAs to treat anemia in patients with chronic kidney disease (CKD) based on results from the recent “Trial to Reduce Cardiovascular Events with Aranesp® Therapy” (TREAT). CRDAC reviews and evaluates available data concerning the safety and effectiveness of drug products for use in the treatment of cardiovascular and renal disorders and makes recommendations to the Commissioner of Food and Drugs.

FDA approved darbepoetin in 2001 for the treatment of anemia associated with chronic renal failure, including for patients not on dialysis. In light of TREAT, which failed to demonstrate cardiovascular benefit—and showed risk—when patients with chronic renal failure and anemia were treated with ESAs to target hemoglobin concentrations higher than the current recommended range of 10 to 12 g/dL, FDA requested that the CRDAC provide advice about the benefit-risk profile of darbepoetin, feasibility and necessity of future trials on Aranesp dosing, and on labeling revisions. FDA prepared five specific questions for the panel to vote upon, which will inform FDA’s final decision on this issue.

“The TREAT trial evidence raises considerable doubt about the safety and advisability of using darbepoetin in this manner to raise the hemoglobin in patients with anemia associated with CKD,” concluded FDA’s internal review of evidence in advance of the CRDAC meeting. “No large randomized trial results support the hypothesis that targeting a higher hemoglobin/hematocrit results in an improved cardiovascular or renal outcome.”

Prior to voting, CRDAC heard testimony from Aranesp sponsor Amgen; TREAT principal investigator Marc Pfeffer, MD; internal FDA experts; and public speakers including Winkelmayer. Reviewing the implications of currently available evidence, Winkelmayer’s testimony focused on three key points.

First, all four large ESA trials have shown that if a population is being treated to a target hemoglobin above the upper limit of the current label, 12 g/dL, no meaningful benefits arise and adverse outcomes may occur. Second, he argued that TREAT does not provide evidence that would support reducing the current lower range of the labeled target hemoglobin below 10 g/dL. TREAT intended to study a population of patients with advanced chronic kidney disease and anemia, with the expectation that the patients’ kidney function and—correspondingly—anemia would deteriorate during follow-up. Thus, the inferences that can be made from TREAT about the optimal label range are limited and any justification for a label change based on TREAT is inherently weak. A comparison of achieved mean hemoglobin concentrations among the four large ESA trials puts the low hemoglobin groups in each of them well within the range of the current label.

Third, adjusting a label to a reduced lower hemoglobin boundary could result in more patients receiving transfusions, thereby reducing their likelihood of receiving and maintaining a functioning kidney transplant. Importantly, lowering the labeled hemoglobin target would put women and minorities at particular risk. Overall, Winkelmayer’s testimony on behalf of the society supported the current label, noting that it “is grounded in the best evidence currently available and has been adequate to support individualized treatment decisions among patients and their physicians.”

In addition to testimony by Winkelmayer, the panel also heard from other providers and patient advocacy organizations as well as from dialysis patients. Patients primarily urged the panel to strongly weigh quality of life issues when considering any changes to EPO dosing guidelines. One patient told the panel, “I’m hoping, along with hundreds of thousands of kidney patients like me, that the recommendations you make today will not hinder our ability to live full, meaningful, and productive lives.”

ASN Public Policy Board member Glenn Chertow, MD, FASN, also testified, answering questions from the panel about what, if any, dosing changes the recent clinical trials support for ESAs. Chertow summarized his commentary by stating, “Patients and their physicians need to balance the known risks of ESAs with the potential benefits, including avoidance of transfusion, when deciding whether or not to use these drugs. Patients awaiting kidney transplantation may be those most likely to benefit from transfusion avoidance.”

After hearing testimony, CRDAC considered five prespecified FDA questions relating to darbepoetin dosing guidelines. The first question asked whether based on available evidence the indication for darbepoetin for the treatment of anemia associated with chronic renal failure should be withdrawn; the panel voted 15–1 with one abstention not to withdraw, stating that the scientific evidence available does not support such a move at this time. The panel also voted not to recommend darbepoetin alfa be avoided for all patients with a prior history of stroke. The panel voted no on questions two and four, which asked whether the control arm of the TREAT trial be used as the dose-schedule for use for controlling the anemia associated with CKD in dialysis and nondialysis patients, respectively. Question three asked the panel to describe a prudent approach to designing the next trial for safer use of ESAs in patients with CKD. The panel suggested any future trial would need to study EPO use in patients with CKD versus a true placebo group—an arrangement that, it pointed out, raises serious ethical questions since patients in the placebo group may not suffer unnecessary risks and lower quality of life than the non-placebo group.

While the FDA is not obligated to follow the recommendation of the CRDAC, it is highly unlikely they would not. Following the meeting, current dosing practices remain in effect, with the panel strongly supporting an EPO regimen individualized for each patient through discussions between patients and their physicians on the risks and benefits of drugs that treat anemia associated with CKD. ASN continues to closely monitor the debate over EPO dosing, supporting guideline decisions that take into account patient safety as well as quality of life and the integrity of the patient-physician relationship. To view ASN’s complete comments to the CRDAC please visit ASN Public Policy webpage.