FDA Eliminates REMS Requirement for ESAs

The FDA has eliminated the need for risk evaluation and mitigation strategy (REMS) certification prior to the administration of erythropoiesis-stimulating agents (ESAs) for anemia due to myelosuppressive chemotherapy. The decision applied specifically to the agents epoetin alfa (Epogen/Procrit) and darbepoetin alfa (Aranesp).

"The FDA has released the REMS requirements for the ESA products, Epogen/Procrit and Aranesp, and the risks can be communicated by the current product prescribing information," the agency noted. "The appropriate use of ESAs is supported by the CMS National Coverage Determination, the American Society of Clinical Oncology and American Society of Hematology clinical guidelines, which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology."

Epoetin alfa was initially approved in 1989 for patients with anemia associated with chronic renal failure. This indication was expanded to include those with anemia following treatment with myelosuppressive chemotherapy in 1993. Darbepoetin alfa was initially approved in 2001, with inclusion of the chemotherapy indication in 2006.

In the clinical studies leading to the approvals for the ESAs it was determined that treatment with the agents led to a shorter overall survival and/or increased risk of progression or recurrence in patients with breast cancer, non—small cell lung cancer, head and neck cancer, lymphoid cancer, and cervical cancers. Additionally, in chronic kidney disease trials, patients with a hemoglobin level greater than 11 g/dl treated with ESAs were more likely to die or have a serious cardiovascular adverse event or stroke.

Based on these data, a REMS was approved in 2010 for both medications, as a means of ensuring that the benefits of the therapies outweighed the associated risks. The REMS was fully implemented in 2011. Under this program, providers and hospitals were required to become certified in the ESA REMS, provide counseling to each patient, and have each patient complete a Patient and Healthcare Provider Acknowledgement Form prior to treatment.

Amgen, the company marketing darbepoetin alfa, submitted the data for removal of the REMS. The data that led to the decision were from surveys showing that prescribers were aware of the risks associated with ESAs and that the agents were being used appropriately and according to the approved indication.

In data from 2006 to 2014, Amgen showed a decrease in the number of patients receiving chemotherapy who warranted ESAs, showing a lower overall risk. Additionally, of those receiving ESAs, more started at an appropriate dose at a hemoglobin level <10g/dl. Moreover, the trend analysis showed that the introduction of the REMS in 2011 had little impact ESA usage trends.

"While the REMS is no longer necessary to ensure the benefits outweigh the risks, the serious risks of shortened overall survival and/or increased risk of tumor progression or recurrence associated with Epogen/Procrit remains a concern," the FDA noted. "The prescribing information continues to note an increased risk of tumor progression or recurrence, as well as death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access."

The labels for both therapies specify that the agents should only be used with myelosuppressive chemotherapy when at least 2 months of treatment with chemotherapy are planned. Additionally, the labels noted that the agents are not meant to be used in combination with hormonal agents, biologic products, or radiotherapy, unless the patient is also receiving myelosuppressive chemotherapy.