On September 11, 2007, the Food and Drug Administration (FDA) Center for Drug Evaluation and Research held a joint session with the Cardiovascular & Renal Drugs Advisory Committee (CRDAC) and the Drug Safety & Risk Management Advisory Committee (DSaRM) to examine the risks and benefits of erythropoesis-stimulating agents (ESAs) when used in the treatment of anemia due to chronic renal failure. The drugs, sold under the brand names Aranesp and Epogen, boost red blood cell production and raise hemoglobin levels in kidney disease and dialysis patients. The hearing was prompted by the “Normal Hematocrit” study and the CHOIR study. The task was to evaluate the appropriate hemoglobin target for patients using ESAs and the identification and management of ESA “hypo-responders.”
You can view further information about the hearing, such as the overall agenda and a list of committee members here, under September 11, 2007.
Drs. Lynda Szczech and Jonathan Himmelfarb represented the ASN and presented testimony during the Open Public Hearing. The ASN Public Policy Board submitted a statement to the FDA prior to the hearing and received an invitation from the FDA to speak at the Open Public Hearing. Dr. Himmelfarb is the chair of ASN's Public Policy Board. Dr. Szczech is a member of the Public Policy Board and chair of ASN's Dialysis Advisory Group. You can read more about their testimony below.*
FDA Invited Speakers (You can view these slides here)
Dwaine Rieves, MD, Acting Director of Medical Imaging and Hematology Products and the FDA introduced the invited speakers.
The first presentation was given by Ajay Singh, MD, Clinical Director of the Renal Division at Brigham & Women's Hospital, who gave an update on Anemia and Chronic Kidney Disease based on results of the CHOIR study.
The second presentation addressed Epoetin Outcomes Research and was given by Dennis Cotter and Yi Zhang from the Medical Technology and Practice Patterns Institute in Bethesda , Maryland and Miguel Herman, Associate Professor of Epidemiology at Harvard University 's School of Public Health.
Sponsor Presentations (You can view their slides here)
Paul Eisenberg, MD, MPH, from Global Regulatory Affairs & Safety at Amgen, Inc. provided the introduction. This was followed by a presentation on the Clinical Perspective provided by Allen Nissenson, MD, Professor of Medicine at UCLA. Preston Klassen, MD, MHS, Global Development, Amgen, Inc. then spoke about the benefits and risks. Paul Eisenberg, MD, then addressed Risk Management.
The Sponsors summarized that:
(1) Hb target is clinically important (label recommendation 10-12 g/dL)
(2) Relationship between dose and outcomes is highly confounded
(3) Additional investigation of hypo responsiveness and outcome required
Ann Marie Trentacosti, MD, Study Endpoints and Labeling, gave an overview of Patient Reported Outcomes (PRO) Claims and the limitations of these studies related to their design. Ellis F. Unger, MD provided the “FDA Perspectives on Erythropoiesis-Stimulating Agents (ESAs) Anemia of Chronic Renal Failure: Hemoglobin Target and Dose Optimization” to include analyses suggesting a relationship between the rate at which hemoglobin rises and risk and a reanalysis of the Normalization of Hematocrit Trial with extended follow-up favoring the low hematocrit group (p=0.01) ( Click here for PDF).
Open Public Hearing
Presenters at the Open Public Hearing included the following:
Roberta Wager, RN, MSN, President of the American Association of Kidney Patients stressed that ESA doses should be decided by a physician and a patient on an individual basis and that the FDA should strive for a “Goldilocks” solution — not to much, not too little, but one that should improve the Quality of Life for kidney disease patients.
*Dr. Himmelfarb, ASN Public Policy Chair, discussed the problems patients encounter when they have become sensitized from blood transfusions given to manage their anemia and as a consequence may lose access to kidney transplantation as a therapeutic modality.
*Dr. Szczech, ASN Dialysis Advisory Group Chair and member of the Public Policy Board, provided the results of new post-hoc analyses of the CHOIR data examining interactions between the dose of administered epoetin alpha, targeted hemoglobin, achieved hemoglobin and patient outcomes. She will be presenting these important results more fully during the late breaking clinical trial session at Renal Week.
Drs. Robert Wolfe and Friedrich Port from the University of Michigan presented new research from Arbor Research Collaborative for Health. The research found that mortality is lower in dialysis facilities having more patients with hematocrit levels greater than or equal to 33%. They cautioned that it is also possible that some facilities have sicker patient populations.
Dr. Robert Provenzano, DaVita, and past president of the Renal Physicians Association, spoke about the risks of cycling. Data from DaVita clinics suggests that holding EPO when the hemoglobin is at 12 or 13 g/dL increases the risk of both low and high hemoglobin levels later. He recommended that EPO should be used to keep the hemoglobin above 11 and to decrease it if above 12.
Michael Lazarus, MD, Fresenius Medical Care, presented data showing that even thoughp hysicians are unable to stop shifting hemoglobin levels, overall the mean level stays around 11g/dL.
David Van Wyck, MD, co-chair of the KDOQI anemia work group recommended that the target range should be 11-12 g/dL, not to exceed 13 g/dL. This recommendation follows the examination of evidence from 27 Randomized Clinical Trials (RCTs).
Alan Kliger, MD, President of the Renal Physicians Association also represented the American Society of Pediatric Nephrology. He spoke to the fact that the doctor-patient relationship should be preserved and that warning should target specific patient populations (pediatrics, CKD, ESRD, cancer). He also testified that Quality of Life should be included in the committee's considerations.
Lori Hartwell, founder of the Renal Support Network, was the final witness. Ms. Hartwell has suffered from chronic kidney disease for 39 years, has had 3 kidney transplants and 12 years of dialysis therapy . As a nurse and a kidney disease patient, Ms. Hartwell has seen the benefits of ESAs and discussed concerns from the patient community about potential lowering of hemoglobin target levels.
Committee Discussion and Voting
The first question posed to the committee was whether the ESAs label should “&be changed to state that the target hemoglobin should not exceed ~11 g/dL for patients on hemodialysis&” The committee voted 14 to 5 against this question. Many Committee members were uncomfortable with the language “shall not exceed” and felt that the 11 g/dL upper target was inappropriate. Several members preferred other options, such as a 10-12 g/dL range or a target of 11 or 11.5 g/dL (omitting the words “not exceed”).
The second question was very similar to the first except it addressed the target hemoglobin for patients NOT on dialysis. The committee again voted 14 to 5 against the question for the same reasons as the first.
The committee omitted the third question, regarding future randomized clinical studies to study hemoglobin targets, due to time constraints.
The fourth question posed to the committee asked whether the “ESA dosages used to achieve the hemoglobin levels in the lower target groups in Normal Hematocrit and CHOIR are sufficient to form the basis for ESA dosage recommendations.” This question garnered a positive vote of 14-3, with 2 abstentions.
The fifth question addressed the identification and dosages for “ESA hypo-responders.” Members noted that the Sponsor presented a recommendation on how to identify these patients.
The final question asked the committee to discuss dosing algorithm hypotheses. Members agreed that additional attention to dosing algorithms would be useful.
The role of the FDA Advisory Committee is strictly to advise the agency and the FDA issues final decisions. However, the recommendations of the committee often have a strong influence on the final decisions. In general, the committee members acknowledged the value of ESAs and hesitated to impose stringent restrictions on their use.
The hearing was covered by several major media outlets including the New York Times , Bloomberg, the Wall Street Journal , the LA Times , CBS News, Inside CMS, the Associated Press, and Reuters, as well as CBS News. Most articles indicated a positive outcome for the kidney disease community.
The ASN Public Policy Board will keep the membership informed of any future developments in the controversies surrounding management of the anemia of chronic kidney disease in subsequent issues of Renal Policy Express.
Thursday, September 13, 2007
FDA Hearing on Erythropoeisis-Stimulating Agents (ESAs)
Via the American Society of Nephrology: