Definition of REMS
Title IX, Subtitle A, Section 901 of FDAAA created Section 505–1 of the Federal Food, Drug, and Cosmetic Act (FDCA) grants the FDA authority to require manufacturers to submit a proposed REMS as part of the drug approval process if the FDA determines that REMS is necessary to ensure that the benefits of a drug outweigh its risks (3). Subtitle A took effect on March 25, 2008 and defined REMS as a strategy to manage known or potential serious risks associated with the use of a pharmaceutical product. FDAAA also authorized the FDA to require postmarketing studies or clinical trials (i.e. PMRs) to assess known serious risks or signals of serious risks related to a medication, or to identify an unexpected serious risk when data indicate the potential for a serious risk.
Approaches to optimizing risk-benefit profiles in the postmarketing setting are not a novel concept. Prior to the advent of REMS the FDA had approved a small number of medications with Risk Management Programs (RMPs) or Risk Minimization Action Plans (RiskMAPs). RMPs were introduced in the context of the approval of isotretinoin and clozapine in the late 1980s. RiskMAPs formally replaced RMPs in 2005. In a guidance to industry, the FDA defined RiskMAPs as a strategic safety program formulated to minimize known risks of a medication while preserving its benefits (4); RiskMAPs implemented a four-step process to target one or more safety-related health outcomes that continues throughout the life cycle of the pharmaceutical. Although REMS may appear similar in design to RMPs and RiskMAPs, FDAAA provided the FDA with the authority to enforce REMS, including the power to declare the product misbranded, to prohibit the introduction of the product into interstate commerce and to financially penalize manufacturers, if the implementation and adherence to an approved REMS program is not done properly. FDCA, as amended by FDAAA, allows for significant monetary penalties to be assessed for such violations, which escalate with time if not addressed (5). Currently, there are no penalties assessed to healthcare practitioners for failure to comply with the elements of an approved REMS program.
Components of REMS
All REMS must have specific goals and contain one or more elements to achieve these goals. Goals are established to evaluate predefined safety-related health outcomes or to improve the understanding by patients and/or healthcare providers of the serious risks targeted by the program (5). The elements of the REMS constitute the tools through which the goals are achieved and must include a timetable for submission of assessments of the REMS. Based on a hierarchical schema according to the severity of the identified risk(s), the REMS elements may include one or more of the following:
- 1Medication guide and/or Patient Package Insert (PPI). Medication guides are designed to instruct patients about the safe use of a drug product. A medication guide is required if the FDA determines that improved distribution of medication-specific information can help prevent serious adverse effects or could affect a patient's decision to use or continue using a medication, or when specific patient instructions can aid in improving patient adherence and subsequently maximize the medication's effectiveness. Similar to medication guides, PPIs are designed to instruct patients about the safe use of the drug product. A REMS may include a PPI if the FDA determines that it may help mitigate serious risk. The medication guide, but not the PPI, must be provided to the patient every time the product is dispensed, including refills (5).
- 2Communication Plan for Healthcare Providers. Communication plans are designed to educate healthcare providers on the appropriate and safe use of a pharmaceutical product. The communication plan entails distribution of letters to healthcare providers that provide detailed information regarding the REMS elements to encourage implementation by healthcare providers. Dissemination of REMS-specific information to healthcare providers may also be accomplished through distribution of information to professional societies. All materials related to the communication plan must be submitted for approval as part of the proposed REMS (5).
- 3Elements to Assure Safe Use (ETASU). ETASUs are implemented when they are deemed necessary in order to ensure safe access for patients to products with known serious risks that would otherwise be unavailable. Specific components of an ETASU may include special certification of healthcare providers who prescribe the product, special certification of pharmacies that dispense the product and restrictions on product distribution (i.e. limited to patients enrolled in a registry, in specific treatment settings and/or with documentation of safe-use conditions). In order to require an ETASU, the FDA must determine that other REMS elements are not sufficient to mitigate the serious risk(s) (5). An example of an ETASU is described later for eculizumab.
Regular assessments of REMS must be completed by the manufacturer and the FDA no less frequent than 18 months, 3 years and 7 years post-REMS approval or at another frequency specified in the strategy. This evaluation should assess whether the REMS elements employed are achieving their goals and that they are not excessively burdensome on the patient or healthcare system. With an evaluation, any proposed modifications to the REMS can be submitted to the FDA (5).
Since FDAAA became effective in March 2008, approximately 35% of all new drug approvals have required REMS. Out of 174 approved REMS, the majority have consisted of a medication guide only. Along with medication guides, 48 REMS have required communication plans and 21 have included an ETASU (6). Drugs approved before March 25, 2008 may have also been deemed to require an REMS. The FDA notified the holders of 16 previously approved new drug and biological licenses on March 27, 2008 that those products required the submission of a proposed REMS to the FDA by September 21, 2008 (7). Those medications were determined to require an REMS because they had been approved with procedures that effectively represented an ETASU. According to the FDCA as amended by FDAAA, both innovator and generic medications will share the same REMS, including the systems required by an ETASU, unless the burden of creating a single, shared system outweighs the benefit of that system.
REMS relevant to transplantation
Immunosuppressants carry a high potential for serious risk, making them possible targets for REMS programs. The details of the approved or proposed REMS relevant to organ transplantation, including those for the mammalian target of rapamycin (mToR) inhibitors, mycophenolic acid (MPA) derivatives and other immunosuppressants with potential uses in transplant, are discussed later. It should be noted that the criteria for targeting an individual pharmaceutical agent or class of agents for a REMS program has not been standardized within a therapeutic indication; therefore, it is difficult for practitioners to understand why one immunosuppressive agent (mToR inhibitors) may require a REMS, while another one (calcineurin inhibitors) with equivalent or more serious associated risk does not.
Everolimus (Zortress®, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) and sirolimus (Rapamune®, Pfizer, NY, USA) are the only products with organ transplant indications that currently have approved REMS. The everolimus REMS was approved as part of its overall FDA-approval, whereas the sirolimus REMS was not approved until November 2010, more than a decade after its initial FDA-approval.
The goals of the everolimus REMS are to inform patients and healthcare providers about the serious risks associated with everolimus use, including wound-healing complications, hyperlipidemia, proteinuria, graft thrombosis and nephrotoxicity seen when everolimus is coadministered with standard doses of cyclosporine (8). To best achieve these goals, the elements of the everolimus REMS include a medication guide and a communication plan. The medication guide is enclosed in all everolimus packaging and is also available on the FDA's and the manufacturer's website. This paperwork should be made available for distribution to all patients with each prescription that is dispensed. The communication plan relies on the US Package Insert, a Dear Healthcare Professional/Professional Association letter and a Dear Pharmacist letter to educate healthcare professionals on the goals of the everolimus REMS. The manufacturer is responsible for submitting REMS assessments to the FDA which should include results from surveys designed to assess patient and healthcare provider understanding of the risks and safety messages addressed through the REMS (8).
The primary objective of the sirolimus REMS is to disseminate patient information regarding the serious risks associated with sirolimus use, including risk for infections, malignancies, wound-healing complications, edema, hyperlipidemia, proteinuria and the potential for nephrotoxicity when cyclosporine is coadministered with sirolimus (9). With the principal focus of the sirolimus REMS being patient education only, the FDA mandated that a medication guide was sufficient to accomplish this goal (9).
The MPA derivatives (Cellcept®, Genentech, San Francisco, CA, USA; Myfortic®, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; and all generic mycophenolate mofetil products) do not currently have an approved REMS. However, in September 2008, the FDA mandated that all of the manufacturers of MPA products (brand and generic) submit a REMS proposal to ensure that the benefits of this therapy outweigh the risk of congenital malformations (10). The current proposed REMS for the MPA products will contain several elements including the already-approved medication guide and an ETASU, which will likely entail physician training and certification, patient education and a pregnancy registry for patients. Once the MPA REMS has been finalized, it is incumbent on the manufacturers, including generic manufacturers, to assure that the elements of the REMS are properly implemented. The ramifications of how a REMS program may impact the willingness of generic MPA manufacturers to continue to market their preparations is not fully understood at this time. At the time of this publication, the full MPA REMS remains under review by the FDA (10).
Eculizumab (Soliris®, Alexion Pharmaceuticals, Cheshire, CT, USA) is indicated for the treatment of paroxysmal nocturnal hemoglobinuria. Despite its labeling, some centers have used eculizumab for the treatment of antibody-mediated rejection, as well as for the posttransplant management of hemolytic-uremic syndrome (11,12). This agent currently has a FDA-approved REMS, the goals of which are to limit the occurrence of and morbidity associated with meningococcal infection and progressive multifocal leukoencephalopathy (PML), as well as to ensure the proper use of the medication. The elements of the eculizumab REMS include both a medication guide and ETASU. The ETASU requires prescriber certification based on an attestation that prescribers will educate their patients, distribute patient educational materials and monitor patients for signs and symptoms of serious infections (13). All patients receiving treatment with eculizumab should be entered into the manufacturer's observation data reporting registry. The manufacturer is responsible for providing all of the product-specific educational materials to certified prescribers annually, ensuring that eculizumab is distributed to approved prescribers only and that the prescribers adhere to the requirements of the REMS (13).
Belatacept, a fusion protein that selectively inhibits T-lymphocyte costimulation, is an agent that could be approved for use in organ transplantation in the near future (14). In March 2010, the Cardiovascular and Renal Drugs Advisory Committee of the FDA recommended approval of belatacept. During this vote, the committee also provided recommendations for a REMS program with this agent (15). The goal of the recommended belatacept REMS would be to manage the risks of posttransplant lymphoproliferative disease (PTLD) and serious infections, including PML. The proposed elements of the REMS would consist of a medication guide and communication plan. The goals of the proposed belatacept REMS would be accomplished through the education of healthcare providers and patients regarding the risk associated with PTLD and infectious complications, as well as providing some insights on potential ways to mitigate the impact of these risks (15).
In May 2010, the FDA delayed the approval of belatacept, asking for further analysis to evaluate the long-term effects of this agent. The FDA also requested information to support the manufacturer's proposed REMS. It is logical to reason that, when and if belatacept is approved, it will be approved with a REMS program. However, the specific elements of its REMS will not be known until after FDA approval (15).