To the Editor:
We have recently reported on the management of risk in developing new immunosuppressive agents (1). In particular, we discussed the ever-evolving environment of drug safety and described in detail the process of risk evaluation and mitigation strategies (REMS) and their impact on transplantation. Given the dynamic nature of drug safety, it is not surprising that, since the acceptance of our manuscript, there have been several major developments that must be addressed to provide practitioners with the most up-to-date view of REMS. The two developments include the Food and Drug Administration (FDA) approval of belatacept (Nulojix, Bristol-Myers Squibb, Princeton, NJ, USA) for marketing in the United States and the FDA allowing some medications to be released from their REMS requirements.
Belatacept, a fusion protein that inhibits an important costimulation pathway for T-lymphocyte activation, was FDA-approved on June 15, 2011 with a REMS program. The goals of the belatacept REMS are to inform patients and healthcare providers about the potential serious risks associated with its use, including the risks of posttransplant lymphoproliferative disease (PTLD; predominantly in the central nervous system [CNS]) and serious infections, such as progressive multifocal leukoencephalopathy (PML; Ref. 2). To best achieve these goals, the elements of the belatacept REMS include a medication guide and a communication plan. The medication guide is enclosed in all belatacept packaging and is also available on the product's website. This paperwork must be dispensed to the patient at the time of hospital discharge posttransplant and at the time of each infusion (2).
For their communication plan, the manufacturer identified transplant surgeons, transplant nephrologists, community nephrologists, transplant coordinators, infusion nurses, transplant pharmacists and pharmacists who support infusion clinics to receive belatacept REMS-specific information (2). This plan relies on a Healthcare Provider Letter, a Healthcare Provider Fact Sheet, Infusion Specialist Letter, Preinfusion checklist, a REMS webinar series and a Journal Information Piece to educate healthcare professionals on the goals of the belatacept REMS. The communication plan will also extend to professional societies and organizations that represent the transplant community and those that support infusion centers (2).
The manufacturer of belatacept has established a voluntary registry to further evaluate the safety profile of this agent (3). The primary objective of this registry is to determine the incidence rate of PTLD, CNS PTLD and PML in adult Epstein–Barr virus seropositive transplant recipients treated with belatacept. This registry is not a REMS element and is completely voluntary.
In recent months, the FDA has released some medications from their REMS requirements (4). In situations where manufacturers who currently have a drug-specific REMS that includes a medication guide with or without a communication plan, a proposal to eliminate the REMS can be submitted to the FDA if the manufacturer believes that the REMS is no longer necessary to ensure that the benefits of the medication outweigh the risks (5). The FDA will review these requests to determine whether the REMS is necessary to ensure drug safety. In situations where REMS is eliminated, the medication guide will continue to be part of the approved medication labeling and will still be required to be dispensed to all patients. However, the routine assessment of this element is no longer necessary (5). Since April 2011, 58 medications have been released from their REMS requirements (4). Within organ transplantation, sirolimus (Rapamune, Pfizer, New York, NY, USA) was released from its REMS obligations less than 7 months after its approval and implementation (4).
For completeness, it should be mentioned that in our original publication, weerroneously referred to the eculizumab REMS as providing information about therisk of PML. PML is not an element of the eculizumab REMS, and this complicationhas never been seen in patients receiving this medication.
The FDA's effort to maximize medication safety is a dynamic process. As more immunosuppressive agents emerge, we are likely to see more REMS in the field of transplantation. However, as these REMS programs are continually assessed, changes may be implemented that can impact patients and practitioners. It is imperative for transplant clinicians to stay abreast of changes in REMS regulations, as this can alter clinical practice as it relates to implementation of and adherence to REMS elements.