TRANSPLANT IMMUNOSUPPRESSION

Editor's Note: An article published in the September 2011 issue of the American Journal of Transplantation on the broad topic of regulation by the FDA of drugs, in particular transplant medications is worth a read. Steve Gabardi at the Brigham and Women's Hospital and at Harvard Medical School and his co-authors are experts. Their review is thoughtful and informative about the current scene. Here they discuss their article and add some new thoughts....

COMMENTARY

Managing Risk in Developing Transplant Immunosuppressive agents: The New Regulatory Environment.

Steven Gabardi, PharmD, FCCP, BCPS.

Affiliations: Department of Pharmacy Service, Brigham and Women’s Hospital, Boston, MA, Department of Transplant Surgery, Brigham and Women’s Hospital, Boston, MA, Renal Division, Brigham and Women’s Hospital, Boston, MA, Harvard Medical School, Boston, MA

In this review, we discussed the need to maximize benefits of pharmaceuticals while minimizing their risks (1).  Historically, several landmark regulatory acts and amendments have established the need to require pharmaceuticals be proven safe and effective prior to large-scale human consumption (2).  However, the risks associated with the use of some agents emerge only after approval and marketing.  These experiences have helped create a realization that a medication must be released with a plan that identifies and manages risks and monitors the effectiveness of the strategies intended to reduce these risks.

In 2007, a new era in drug-safety in the US was ushered in with the creation of risk evaluation and mitigation strategies (REMS) (3).  REMS are a strategy to manage known or potential serious risks associated with medications and ensure ongoing pharmacovigilance throughout a medication’s lifecycle (3).  REMS may be a requirement for new drug approvals or may be implemented during the post-approval period based on the emergence of new safety concerns (3,4). Both innovator and generic products are subject to implementation and adherence to Food and Drug Administration (FDA)-mandated REMS programs.  The FDA is empowered to declare a product misbranded, prohibit its marketing, and/or to financially penalize the manufacturer if the approved REMS are not properly implemented (3).

REMS contain certain hierarchal steps that are based on the severity of the known or potential risk (5). The elements of a REMS program contain at least one of the following:

1. Medication Guide (MG):  a MG is required when improved dissemination of informationto patients can help prevent severe adverse events or improve adherence.  MG must be distributed to patients with every prescription fill (5).

2. Communication Plan (CP) for healthcare practitioners (HCP):  this is a specific plan to educate HCP on the appropriate use of a medication.  This may be accomplished via individual mailings, continuing medical education or communication with medical/professional societies (5).

3.  Elements to Assure Safe Use (ETASU):  this is a controlled system that includes restrictions on prescribing and distribution of certain medications.  This tight regulation is deemed necessary to mitigate specific serious risks that, without these restrictions in place, would result in the drug not being approved or withdrawn from the market.  ETASU  is employed when the other REMS elements are not deemed sufficient enough to mitigate these risks (5).

Immunosuppressants are fraught with potential risk, which makes them a high-interest for REMS programs.  REMS are intended to foster the availability of advantageous immunotherapies while creating corrective steps to ensure patient safety.  Everolimus and belatacept are the only current immunosuppressants that are indicated for transplantation with approved REMS (6). Sirolimus was released from its REMS obligations less than seven months after its implementation (7).

The goals of the everolimus REMS are to inform HCP and patients about the potential serious risks associated with its use, including wound-healing complications, hyperlipidemia, proteinuria, graft thrombosis, as well as nephrotoxicity when co-administered with standard dose cyclosporine (8). In order to best achieve these goals, the requirements of the everolimus REMS consists of a MG and CP. 

The goals of the belatacept REMS are to inform HCP and patients about the potential serious risks associated with its use, including the risks of post-transplant lymphoproliferative disease, predominantly in the central nervous system, and serious infections (9). To best achieve these goals, the elements of the belatacept REMS include a MG and CP. 

The process of evaluating medications for REMS was an important directive in drug safety as it empowered the FDA to enforce that the benefits of medications with serious safety risks outweigh those risks.  There is no question that REMS have placed an added burden on the healthcare system, but it is imperative for HCP to realize that they bear this burden in an effort to reduce the potential for serious adverse events and to make outcomes from the treatment of disease safer and more predictable.

References

1. Gabardi S, Halloran PF, Friedewald J. Managing Risk in Developing Transplant Immunosuppressive Agents: The New Regulatory Environment. Am J Transplant 2011.

2. Hamburg MA, Sharfstein JM. The FDA as a public health agency. N Engl J Med 2009;360:2493-5.

3. Food and Drug Administration.  Food and Drug Administration Amendment Act of 2007. 2007. (Accessed November 15, 2010, at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.)

4. Leiderman DB. Risk management of drug products and the U.S. Food and Drug Administration: evolution and context. Drug Alcohol Depend 2009;105 Suppl 1:S9-S13.

5. Food and Drug Administration.  Guidance for industry. Format and content of proposed Risk Evaluation and Mitigation Strategies (REMS), REMS assessments, and proposed REMS modifications. 2009. (Accessed November 15, 2010, at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf.)

6. Food and Drug Administration.  Approved Risk Evaluation and Mitigation Strategies (REMS). 2010. (Accessed November 15, 2010, at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.)

7. Food and Drug Administration.  Approved Risk Evaluation and Mitigation Strategies (REMS). 2011. (Accessed August 15, 2011, at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.)

8. Food and Drug Administration.  NDA 21-560 ZORTRESS^® (everolimus). 2010. (Accessed November 15, 2010, at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM210262.pdf.)

9. Food and Drug Administration.  BLA 125288 Nulojix^® (belatacept) 2011. (Accessed August 15, 2011, at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM261934.pdf.)