Evolving Regulatory Landscape with Erythropoiesis-Stimulating Agents and Impact on Managed Care

March 17, 2010
Hugh Fatodu, RPh, MBA

Supplements and Featured Publications, Issues in Improving the Treatment of Anemia: Negotiating the Shifting Regulatory and Clinical Landsc, Volume 16, Issue 3 Suppl


Erythropoiesis-stimulating agents (ESAs) are a very effective treatment for reducing the need for transfusions in patients affected by anemia and either chronic kidney disease (CKD) or cancer. However, many clinicians remain wary of its use due to safety concerns. It has been shown that higher doses are associated with cardiovascular disease, stroke, or death. These concerns have spurred the US Food and Drug Administration to order Risk Evaluation and Mitigation Strategies (REMS) for clinicians prescribing ESAs to their patients. REMS are a method to ensure safety and provide clinicians and patients with an appropriate gauge of the risks and benefits associated with the administration of ESAs. Whether this restricts its use or lowers costs remains to be determined.

(Am J Manag Care. 2010;16:S74-S79)


Erythropoiesis-stimulating agents (ESAs) are very effective in reducing the need for transfusions in patients with anemia of either chronic kidney disease (CKD) or cancer.1 However, a plethora of clinical studies,2-6 meta-analyses,7-9 and US Food and Drug Administration (FDA) announcements10-12 have many physicians concerned about the safety of ESAs. Generally, these reports show that higher doses of ESAs and/or targeting higher hemoglobin (Hb) levels are associated with an increased risk of cardiovascular disease, stroke, or death.

Shortly after the publication of safety concerns with ESAs, the FDA made appropriate prescribing information changes to ensure proper dosing schedules and monitoring procedures. At present, if clinicians adhere to the prescribing information for ESAs, the risk to patients is minimal. However, the recent concerns about safety may deter some clinicians from prescribing ESAs to patients who could benefit from them. Of further concern are the changes in Medicare rules and reimbursement policies13,14 and the recent FDA requests for Risk Evaluation and Mitigation Strategies (REMS) for ESAs15 that further dissuade clinicians from prescribing ESAs to patients who may benefit from them.

To address clinicians' concerns in balancing the advantages and risks associated with ESAs, this article offers a brief review of the efficacy, safety, and regulatory aspects of ESAs. This article will also address the recent FDA request that REMS be employed, and what the implementation of REMS means for healthcare professionals treating patients with anemia.

Efficacy and Safety of ESAs

Use of ESAs in Anemia of Chronic Kidney Disease

Table 1

Numerous randomized controlled trials, beginning with the landmark study by Eschbach et al,16 have shown that ESAs increase Hb levels in patients with CKD who manifest anemia ().17

With the initial approval of epoetin alfa in 1989, the primary goal of treatment of anemia in patients with CKD was to increase Hb concentration to greater than 10 g/dL, thus avoiding transfusion. Over the years, clinical practice guidelines may have contributed to use of ESAs in attaining higher Hb targets.17,18 Concern over the increased risk of stroke, cardiovascular events, or death in patients given ESAs to achieve higher Hb levels (>13 g/dL) have led to the current dosing recommendations, which are designed to obtain Hb levels in the range of 10 to 12 g/dL.1,19

Use of ESAs in Anemia and Cancer

It is well established that ESAs reduce the number of transfusions necessary in patients receiving chemotherapy1 and improve patients' quality of life.9

Table 2

Studies have reported reduced survival and increased tumor progression and thrombotic events in patients with cancer and anemia given ESAs.1 These serious safety concerns have been documented over time by the FDA and other organizations ().15,20

The plethora of data showing increased risk for serious adverse events following ESA use has resulted in 2 major regulatory changes that are applicable to healthcare professionals. First, the Centers for Medicare & Medicaid Services significantly tightened reimbursement rules on the use of ESAs in patients this year.13,14 Second, the FDA recently stated that all ESAs prescribed must be part of a REMS to ensure the safe use of these drugs.15 Both of these regulatory changes are discussed below.

ESA Safety and Reimbursement Implications

All of these safety concerns have led to many changes in the prescribing information for ESAs as well as significant changes by Medicare regarding reimbursement. As stated in the previous article, Medicare updated its policy with limits on the use of ESAs. In patients with cancer and anemia, ESA treatment should not begin until Hb levels are less than 10 g/dL.14 In patients with end-stage renal disease, payment will be removed unless the dose is lowered by 25% or 50% once Hb levels exceed 13 g/dL for 3 billing cycles.13

Medicare will not cover the use of ESAs for (1) any anemia due to folate deficiency, B12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis in patients with cancer; (2) anemia associated with the treatment of acute myelogenous leukemia and chronic myelogenous leukemia, or erythroid cancers; (3) anemia of cancer not related to cancer treatment; (4) any anemia associated only with radiotherapy; (5) prophylactic use to prevent chemotherapy-induced anemia; (6) prophylactic use to reduce tumor hypoxia; (7) patients with erythropoietin-type resistance due to neutralizing antibodies; and (8) anemia due to cancer treatment if patients have uncontrolled hypertension.14

Risk Evaluation and Mitigation Strategies

The recent request by the FDA that all ESAs be prescribed and used under REMS is appropriate based on the recent safety reports for ESAs. Many medications and biologic products that are deemed to have a "higher than average risk" have been placed into REMS or "active" monitoring systems. REMS inform healthcare professionals and patients about the risks associated with a medication. In many cases, the strategy of REMS is fairly straightforward and simply requires that patients receive a medication guide each time the drug is dispensed (or at the beginning of treatment). For medications with significant safety concerns, REMS involve increased surveillance and/or performance/safety assessment programs. For the latter, a patient registry may be employed, and that is what the FDA is establishing in coordination with Amgen Inc, the manufacturer of ESAs.

In February 2010, the FDA stated that all ESAs must be part of a REMS.15 More specifically, the FDA stated the program should provide patients with material and guidance to understand the risks associated with ESAs. For patients with cancer, these risks include: (1) ESAs may cause tumors to grow faster; (2) ESA use may be associated with earlier death; and (3) ESAs may cause some patients to develop blood clots and serious heart problems such as a heart attack, heart failure, or stroke. Patients without cancer should know: (1) that the use of ESAs can increase the risk for stroke, heart attack, heart failure, blood clots, and death; and (2) that their healthcare professional has received special training about the use of ESAs in patients with cancer.

All patients receiving ESAs are instructed to read the medication guide to understand the benefits and risks of using an ESA, and to talk with their healthcare professional if they have any questions.15 Also, patients with cancer will be asked to sign an acknowledgment form that states that they have talked with their healthcare professional about the risks associated with ESAs. This form must be signed before patients begin a course of ESA treatment. Patients without cancer will be asked to get blood tests while using ESAs to help guide the course of therapy and lower the risk of serious adverse events.

The FDA also stated that healthcare professionals who prescribe ESAs for anemia in patients with cancer must: (1) complete a training module that covers the use of ESAs; (2) be enrolled in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program following completion of the training module; (3) sign the patient/healthcare professional acknowledgment form prior to the patient receiving an ESA; and (4) re-enroll in the ESA APPRISE Oncology program every 3 years.15 Healthcare professionals not enrolled in the ESA APPRISE Oncology program will not be able to prescribe ESAs for use in patients with cancer.

In addition, the FDA requires that hospitals using ESAs for anemia in cancer patients must be enrolled in the ESA APPRISE Oncology program and have a system in place that ensures that all healthcare providers who prescribe ESAs in the hospital are enrolled and comply with the ESA APPRISE Oncology program. Healthcare professionals who prescribe ESAs for anemia in patients without cancer are required to provide a copy of the medication guide to each patient or their representative when an ESA is dispensed; they are not required to enroll in the ESA APPRISE Oncology program.

A preliminary draft of the REMS developed by Amgen Inc21 states that the goals of the REMS are as follows: (1) to support informed decisions between patients and their healthcare providers who are considering treatment with ESAs by educating them about the risks associated with their use; and (2) to mitigate the risk of decreased survival and or poorer tumor outcomes in patients with cancer (through the ESA APPRISE Oncology program). Amgen will also be responsible for conducting real-time monitoring of prescribing and purchases in private-practice settings and clinic audits, and auditing hospitals to ensure compliance with the ESA APPRISE Oncology program. Failure to comply will result in a suspension of access to ESAs.

Table 3

The draft of the REMS being developed by Amgen shows that it is going to be a very detailed program requiring many parties to maintain records of ESA use. How this will alter ESA prescriptions remains to be seen. However, REMS are becoming more common. A presentation by Gilsenan et al22 reported that as of July 2009, there were 69 medications with REMS. Of those, 52% (n = 36) required only medication guides, 28% (n = 19) required communication plans, 28% (n = 19) required elements of safe use (13/19 are for drugs deemed to have approved REMS), and 13% (n = 9) required an implementation system similar to the one proposed by Amgen ().

Impact of REMS on Managed Care

Implementation of REMS for ESAs is appropriate based on the safety concerns with these medications. It is very likely that the introduction of REMS to the treatment regimen for anemia will be a time-consuming and cumbersome addition; however, these proactive measures should result in reduced incidence of serious adverse events, emergency department visits, and hospitalizations. The net result will hopefully be reduced overall costs to accompany the reduced incidence of adverse events. Whether or not the increased effort associated with REMS prevents some patients from benefiting from ESAs remains to be seen. Also uncertain at this stage is whether the increased emphasis on laboratory results will prevent patients from receiving individualized care. As ESA manufacturers implement their new REMS programs, payers will have to figure out how to integrate these programs into their utilization management practices.


ESAs are an effective means to treat anemia. However, concern for the safety of patients receiving ESAs has dramatically altered the administration of ESAs in recent years. The FDA's request to require REMS for ESA prescribers is a proactive measure to improve safety outcomes and provide both healthcare professionals and patients with an evidenced-based assessment of the risks and benefits associated with ESA use. Whether the restricted distribution program limits ESA use for some patients or reduces overall costs remains to be determined.

Author Affiliation: Department of Pharmacy, Johns Hopkins Healthcare, Glen Burnie, MD.

Funding Source: Financial support for this work was provided by Centocor Ortho Biotech Services, LLC.

Author Disclosure: Mr Fatodu reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design; analysis and interpretation of data; and critical revision of the manuscript for important intellectual content.

Address correspondence to: Hugh Fatodu, RPh, MBA, Director of Pharmacy, Johns Hopkins Healthcare, 6704 Curtis Ct, Glen Burnie, MD 21060. E-mail: fatoduh@jhhc.com.

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