Message to the FDA on ESAs: REMS is not enough, more studies are needed.

S ince March 24, 2010, the Food and Drug Administration (FDA) has been requiring a “Risk Evaluation and Mitigation Strategy” (REMS) for all patients who are treated with erythropoiesis-stimulating agents (ESAs) (1). Although regulatory authorities elsewhere in the world have not as yet taken this approach, experience suggests that these agencies often take their cues from the FDA. Most nephrologists are unaware that the FDA now requires distribution to both dialysis and nondialysis patients of a medication guide that explains the risks and benefits of ESAs. The FDA is also mandating that oncologists—but not nephrologists, at least thus far—register and participate in a program called Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs (APPRISE) (2); however, APPRISE for ESAs in cancer could herald a similar program for ESAs in the anemia of kidney disease. What is REMS? Should nephrologists be required to register in an APPRISE-like program? Should the FDA be doing more to address safety concerns with ESAs? REMS was announced in February for all patients who receive ESAs, and notices have been sent to ESRD networks asking that medication guides be distributed to patients (3). In addition, for the ESA cancer indication, oncologists need to undergo training on the risks and benefits of ESAs to continue prescribing them. This involves discussion about ESAs with patients who have cancer before beginning a course of treatment. Oncologists have to document that this discussion took place. A health care provider enrollment form that was developed by Amgen and Centocor Ortho Biotech and approved by the FDA must be completed for oncologists to prescribe ESAs (4). The FDA gained authority to require REMS under the Food and Drug Administration Amendments Act (FDAAA) of 2007 (5). The goal of REMS is to manage a known or potentially serious risk associated with a drug or biologic product. REMS can be a part of a new drug application, abbreviated new drug application, or biologics license application; however, the FDA also has the authority to require REMS from the drug manufacturer if new safety information becomes available. This is clearly the case with both anemia of kidney disease and cancerinduced anemia. REMS can include a medication guide, patient package insert, a communication plan, elements to ensure safe use, and an implementation system and must include a timetable for assessment. The “elements to ensure safe use” provision entails the setting up of a restricted distribution program for the drug. Currently, the FDA has 97 drugs that are a part of its REMS program. Sixty-nine drugs have only a medication guide requirement; 18 require a medication guide and a communication plan; and 10 require a medication guide, development of a communication plan, elements to ensure safe use, and an implementation system—two of these 10 drugs are epogen and darbepoetin, listed for their cancer-induced anemia indication. It is quite possible that the FDA will expand REMS to include “elements to ensure safe use” for ESAs in patients with chronic kidney disease (CKD). Some will argue that because all active drugs carry safety risks, the government’s seemingly singular concern with ESAs might be financially motivated. This seems very unlikely because, in the United States at least, the regulatory and reimbursement functions are separated, the latter being the domain of the Centers for Medicare and Medicaid Services. In fact, despite the publication of studies demonstrating higher risk for death and/or cardiovascular complications in patients who have a higher hemoglobin (Hb) target (6–9), as well as warnings by the FDA in the ESA label (10,11), extensive off-label use of ESAs continues. The percentage of dialysis patients with a Hb level of 12 g/dl remains at approximately 40% (12)—above what is recommended in the ESA label and by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines (13) (Figure 1). Indeed, since the approval of Epogen in the United States in 1989, there has been a steep increase in the mean Hb concentration and average ESA dosage used in dialysis patients (12) (Figure 2). ESA use in the United States is more than twofold greater than in other Western countries (Figure 3) (14). Some have speculated that this is because of Medicare reimbursement policies (15); others have presented data that there are economic incentives for overuse of ESAs (16), especially among for-profit dialysis chains. Biologic mechanisms have also been invoked, such as Hb variability (17). Recently, the publication of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (9) has precipitated another round of safety review for ESAs in patients with kidney disease. Although TREAT was neutral for its primary end points of mortality and cardiovascular complications or mortality and the incidence of ESRD, it Published online ahead of print. Publication date available at www.cjasn.org.