Managing Risk in Developing Transplant Immunosuppressive Agents: The New Regulatory Environment


  • S. Gabardi,

    Corresponding author
    1. Departments of Transplant Surgery and Pharmacy Services and Renal Division, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA
      Steven Gabardi,
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  • P. F. Halloran,

    1. Department of Medicine, Division of Nephrology and Transplantation Immunology, Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Canada
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  • J. Friedewald

    1. Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL
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Steven Gabardi,


Recent adverse experience with a number of medications after their approval, including rofecoxib, erythropoietin and rosiglitazone, has led to an increased focus on safety in drug development in the postmarketing setting. The result was implementation of new measures to address perceived deficits in the system for drug approval and postmarketing safety. The resulting legislation introduced risk evaluation and mitigation strategies (REMS) and postmarketing requirements (PMRs). Although these initiatives have the potential to improve patient outcomes, many healthcare practitioners are not yet familiar with REMS or PMRs or may have misconceptions regarding their goals and limitations. REMS is a program to manage known or potential serious risks associated with pharmaceutical products and is designed to ensure that the benefits of using a particular product outweigh the risks. Although the concepts underlying REMS and PMRs are not novel, the FDA now has legal authority to enforce such measures as part of the drug approval process. This article outlines the objectives and limitations of REMS and PMRs, with a focus on how these regulatory measures may impact the clinical specialty of transplantation. The article also briefly describes efforts to address aspects of drug safety less amenable to management through REMS and PMRs.


adverse event reporting system


elements to assure safe use


Food and Drug Administration


Food and Drug Administration Amendment Act


Food, Drug and Cosmetic Act


Institute of Medicine


observational medical outcomes partnership


mycophenolic acid


mammalian target of rapamycin


posttransplant lymphoproliferative disorder


postmarketing commitment


progressive multifocal leukoencephalopathy


postmarketing requirement


patient package insert


randomized controlled trials


risk evaluation and mitigation strategies


risk minimization action plans


risk management program


Randomized clinical trials (RCTs) adequately powered to evaluate an appropriate primary endpoint represent the most appropriate means to establish the efficacy of newer immunosuppressive agents in transplantation. Such trials also capture critical information with which to evaluate the safety of a novel product: the trials typically describe the common adverse events and sometimes provide the first evidence of more attenuated safety signals related to the use of the agent. Safety data from RCTs may lead to strategies designed to limit the established risks associated with the product and to identify specific areas requiring additional investigation. Full elucidation of the safety profile associated with a novel product may require more data than premarketing trials can provide, particularly in the transplant arena, where the size of RCTs is limited by the relatively small patient population, and where safety outcomes such as lymphomas and rare infections often require long-term follow-up.

Over the past decade, a series of safety issues that emerged in the postmarketing experience with several newer medications emphasized the importance of giving equal consideration to both efficacy and safety. Responding to adverse experience with a number of drugs after their approval, including rofecoxib, erythropoietin, rosiglitazone, natalizumab and others, the Food and Drug Administration (FDA) requested input from the Institute of Medicine (IOM) regarding the evaluation and dissemination of safety data with pharmaceutical products. The subsequent IOM report outlined recommendations for improvements in elucidating and communicating data regarding the safety of medications (1). Provisions included in the Food and Drugs Administration Amendments Act (FDAAA) of 2007 reflected many of the recommendations of the IOM, including those related to risk evaluation and mitigation strategies (REMS) and postmarketing requirements (PMRs, Ref. 2). Both REMS and PMRs have the potential to lead to improvements in patient management and safe use of pharmaceuticals. However, informing healthcare practitioners regarding the goals and limitations of the programs is critical to ensuring the effectiveness of these interventions. REMS and PMRs are not designed to detect or prevent unanticipated safety issues, but rather to elucidate and/or mitigate recognized or predicted safety signals. The goal of this article is to discuss the application of REMS and PMRs in the field of transplantation, and to describe additional efforts to address aspects of safety, less amenable to management through REMS and PMRs.

Risk Evaluation and Mitigation Strategies

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).

Postmarketing Commitments (PMCs) and PMRs

As discussed briefly earlier, FDAAA also increased the authority of the FDA to require postmarketing studies and trials and to enforce those requirements. Before the passage of FDAAA, the FDA and pharmaceutical companies often agreed to PMCs but the FDA lacked the authority to enforce those agreements, except under certain circumstances (e.g. Subpart H and Subpart E accelerated approvals, deferred pediatric studies, and Animal Efficacy Rule Clinical Efficacy and Safety Studies, Refs. 16–18). FDAAA gave the FDA the additional authority to enforce agreements to conduct postmarketing studies and trials to assess known or signals of serious risks, or to identify an unexpected serious risk when available data indicate the potential for a serious risk (19). All required studies or clinical trials that an applicant is required to conduct are now defined as PMRs. FDAAA gave similar powers to the FDA to enforce PMRs as those conferred to enforce REMS, including the authority to declare the relevant product misbranded and impose large monetary penalties (3).

Currently required PMRs relevant to transplant

Everolimus is the only product that has received approval for use in transplantation since the passage of FDAAA. The FDA required a single PMR at the time of its approval, where the manufacturer was required to submit the 24-month study results for a pivotal Phase 3 trial (A2309) by July 20, 2010 (20). Overall, many PMCs from before the passage of FDAAA are outstanding. Although the FDA has the authority to convert these PMCs into PMRs as necessary, it has not yet taken any such actions for any product with an organ transplant indication.

Next Level of Drug Safety Monitoring

REMS represent a significant step forward in improving medication safety in the United States; however, this is not a system without faults (Table 1). One obvious imperfection is that neither REMS nor PMRs are designed to detect or prevent unanticipated safety issues. Systems capable of identifying those signals which eluded detection during development as early as possible in the postmarketing period are critical. The Adverse Event Reporting System (AERS) is an information database which supports FDA monitoring efforts both pre- and postmarketing (21). The AERS database contains adverse events reports submitted by manufacturers as required by regulation. It largely relies, however, on voluntary reports from healthcare professionals and patients. The new legislation in FDAAA included provisions which mandated the creation of a new active postmarketing risk identification system linked to federal and private electronic medical records. In response, the FDA is developing the Sentinel Initiative (22). Although not yet fully implemented, the Sentinel System will provide an important complement to the existing safety surveillance programs at the FDA. The Observational Medical Outcomes Partnership (OMOP) represents another effort to develop active monitoring systems to redress the existing reliance on passive voluntary reporting systems for detecting safety issues in the postmarketing period (23). The OMOP is a public–private partnership through the Foundation for the National Institutes of Health. Such systematic approaches to monitoring patient outcomes and analyzing health information databases may provide a more complete understanding of the safe use of a medication.

Table 1.  The benefits and detriments of REMS
– Allows for medications to receive FDA approval that may not have otherwise been approved.
– Helps ensure that certain medications are used more safely and appropriately.
– Medications with significant associated risk(s) identified postmarketing which may have led to the drug's withdrawal, might now be allowed to remain on the market with REMS.
– In some circumstances (i.e. ETASU), REMS allows systematic data collection, reporting and feedback on medication safety.
– Provides for collaborative opportunities for physicians and pharmacists to improve drug safety.
– Not designed to detect or prevent unanticipated safety issues.
– REMS are not standardized, especially for indication, allowing the potential for confusion on how to implement and adhere to the elements.
– Certain REMS may prove to be burdensome and labor intensive.
– Although an individual medication's REMS may not be burdensome to a prescriber, the cumulative effect of prescribing multiple medications with different REMS to several patients may prove onerous.
– No compensation for the increased work load created by adhering to REMS elements.
– General lack of end user (providers and patients) input to the FDA when REMS are being developed preapproval.
– Potential to influence prescribing patterns if adherence to a medication's REMS is particularly burdensome or time-consuming.

Effect of REMS on Transplant Practitioners

The FDA strives to employ the least restrictive strategy possible when establishing an REMS for individual medications. The FDAAA states that a REMS must attempt to avoid being overly burdensome to patients, healthcare providers and the healthcare system, as a whole. All things considered, some REMS are more or less burdensome than others, similar to some medications’ risks being more or less easily mitigated than others. Unfortunately, there is a general lack of input by practitioners and patients to the FDA when REMS are being developed on the potential added burden to daily clinical practice.

As for the current REMS in organ transplantation, the majority of the burden falls on the manufacturers and, to a lesser extent, the dispensing pharmacies. The burden encumbered by transplant practitioners and patients receiving therapy with medications having approved REMS elements appears to be minimal, for now. For example, the REMS for the mToR inhibitors only attempt to educate transplant practitioners and patients about the serious risks associated with these agents. The burden was placed upon the manufacturer to educate patients (i.e. medication guide) and practitioners (i.e. communication plan). The apparent burden related to the mToR inhibitor REMS on transplant practitioners is minimal. However, the cumulative impact of REMS may be substantial, as adherence to different REMS with other medications may be necessary when utilizing some medications for routine posttransplant care (i.e. antibiotics and opioids). Also, one has to consider the potential burden of adhering to future REMS with the MPA products and newer immunosuppressants. When evaluated as a whole, the burden of REMS on clinical practice within organ transplantation may be considerable.

One aspect of REMS that is not yet well defined but cannot be overlooked is the increased workload. Transplant centers should identify one or more practitioners, be it a pharmacist, transplant coordinator, physician or surgeon, to aid in the implementation and adherence to REMS elements within the institution and/or outpatient setting. Ideally, this can be done in a systematic fashion, allowing for ease of administration as well as uniform application of the REMS. In situations where a prescribed medication has an ETASU, there must be a person responsible for making sure that all prescribers have been certified and all patient registry requirements have been met. The financial impact of this increased workload may be significant and there are no current methods established to receive compensation for meeting these demands.

Some have theorized that REMS may influence prescribing patterns (24). In cases where access restrictions are imposed by certain REMS, some practitioners may seek out alternative medications solely for the purpose of avoiding REMS. For example, if the MPA REMS program requires physician certification and a patient registry, will transplant practitioners increase the use of alternative agents, such as azathioprine, in an attempt to avoid the hassle of completing the REMS requirements? Although this behavior may enable a prescriber to avoid the requirements of a restrictive REMS, it may ultimately have a negative impact on the care of transplant patients.

Finally, how REMS may impact our medical legal system is as yet undefined. Although the primary goal of REMS is patient protection and safe use of therapeutic agents, it is important to continue to examine how these strategies affect liability for the practitioners, pharmacies and hospitals involved.

It is imperative for all healthcare providers to realize that REMS are a permanent part of the development and marketing of pharmaceutical products in the United States. Realization that the ultimate goal of REMS to increase awareness of safety concerns, thereby making patient outcomes from the treatment of disease more predictable, should make the implementation of and adherence to REMS by practitioners more palatable.


In an effort to improve the margin of safety for new drugs after their release, the regulatory environment has changed recently, with legislation like the FDAAA to allow for the management of known risks posed by pharmaceuticals that also have proven benefits for defined patient populations. The tools available to drug makers and regulators include those aimed at educating patients and clinicians as well as those designed to restrict distribution of certain drugs to registered prescribers and pharmacies, and/or specific patient populations where the benefits justify the associated risks. Although those tools should help mitigate known risks, the transplant community and medical community at large must also participate in the process of identifying unknown risks associated with newer therapies in the postapproval setting. Such approaches will likely result in broader and more effective sharing of patient level outcomes and synthesis of disparate events to recognize patterns.

For transplant clinicians, it is important to be familiar with the different elements of drug safety and regulation. As novel immunosuppressive agents emerge, we are likely to see risk mitigation strategies applied to their release to allow access to the drugs while addressing previously identified safety concerns. In addition to these measures to reduce known risks, novel measures to identify previously unrecognized safety signals will continue to be examined, not the least of which is continued vigilance by astute clinicians.


The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Philip Halloran has research relationships with Novartis, Astellas, Bristol-Meyers Squibb and Stromedix. The other authors have no conflicts of interest to disclose as described by the American Journal of Transplantation.