Patient Safety / Quality

Understanding FDA’s Risk Evaluation and Mitigation Strategy

In 2007, the Food and Drug Administration Amendments Act (FDAAA) became law, giving the FDA new authority to require certain product manufacturers to comply with an FDA-approved risk management plan. Called a Risk Evaluation and Mitigation Strategy (REMS), this plan uses tools beyond a medication’s package insert to help assure a drug’s benefits outweigh its risks.

A REMS can be applied to new drugs, generics, and biologics but not to over-the-counter drugs. FDA may require a REMS on a previously approved product if new or additional safety information becomes available. A REMS isn’t a postmarketing study, which FDA sometimes requires of applicants to monitor a known risk or detect a suspected risk.

In light of the nurse’s vital role in patient care, you need to understand the REMS program and how you can help patients and physicians to work with its requirements.

Reporting new safety information

FDA becomes aware of new or additional safety information about approved products from various sources, including product manufacturers, the MedWatch program, peer-reviewed literature, and postmarketing studies. MedWatch is FDA’s voluntary program through which patients and healthcare providers report adverse events, product quality problems, product use errors, therapeutic nonequivalence or failure, and counterfeit medical products. Patients and providers also can report these issues to the product manufacturer. Manufacturers are required to report product safety information, including adverse events, to FDA.

FDA relies on MedWatch and manufacturer reports for safety surveillance. It reviews this information to determine new or increased risks, which may lead to modification in use or design of the drug or other product in question. The information also improves the product knowledge, in turn helping to increase patient safety. You can learn more about MedWatch and how to file a report at MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

Elements of a REMS

The only element required in a REMS is a timetable for submitting assessments of the REMS that help FDA determine whether it is meeting its goals or needs to be modified. A REMS may include a medication guide or patient package inserts. It also may include a communication plan to healthcare providers, if it supports REMS implementation.


FDA also can require a REMS to include certain elements to promote its safe use. These elements are tools or activities manufacturers must provide that are beyond what’s normally required for a product approved for marketing, due to a serious risk with the drug. Without these elements, FDA may not approve the drug, or the drug may need to be withdrawn. (See the box below.)

REMS elements to assure safe use

Elements to assure safe use (ETASU) may include one or more of the following:

  • training materials
  • specified procedures
  • patient/physician agreements or informed consent
  • patient education materials
  • safety protocols
  • medical monitoring procedures
  • required laboratory testing
  • data collection
  • certification of hospitals, pharmacies, and other healthcare settings that dispense or administer the drug.

Besides possibly requiring certain elements in a REMS, FDA considers the impact of those elements on access to the product. When certain safe-use elements are required, manufacturers may need to monitor and evaluate physicians, nurses, and other healthcare professionals to make sure they’re properly implementing the ETASU. Manufacturers also may need to make improvements in how healthcare professionals execute these elements. For instance, as a nurse in a certified facility, you might be required to input the results of patient medical monitoring testing or other information into databases maintained and monitored by the manufacturer with a REMS.

When is a REMS required?

FDA considers several factors when deciding whether to require a REMS:

  • the number of people most likely to use the product
  • seriousness of the disease
  • drug’s benefit to persons with the disease
  • expected duration of treatment.

For example, is the patient’s condition life threatening (such as lung cancer) or chronic (such as type 2 diabetes)? FDA calls this assessment the risk-benefit analysis. Traditionally, the agency has had a higher risk tolerance for products that treat life-threatening conditions than for those that treat chronic conditions. It also considers any known or potential adverse events caused by the drug, particularly if it’s a new molecular entity.

Examples of a REMS at work

As a nurse, you need to understand how a REMS affects your patients and your practice. Patients may come to you for assistance in navigating REMS requirements, or a physician may ask you to assist patients. Let’s look at two examples of a REMS—one for a new product and one for an existing product.

A REMS for a new product

An example of a product approved with a REMS is Zyprexa Relprevv (olanzapine). A long-acting atypical antipsychotic, this drug is given I.M. to treat schizophrenia. Before approval, clinical trials showed that after it was injected, some patients experienced confusion, muscle weakness, increased sleepiness, and elevated blood pressure. Life-threatening adverse effects, such as seizures, loss of consciousness, and coma, also occurred. What’s more, elderly patients with dementia-induced psychosis had higher death rates. These specific effects, termed post-injection delirium sedation syndrome (PDSS), result from quick absorption of the drug into the bloodstream. As a result, FDA limited the drug’s approval to adults with schizophrenia and required a REMS, called the Zyprexa Relprevv Patient Care Program. Prescribers enrolled in the program are certified after completing training and complying with the requirements. Patients enrolled in the program complete a patient registration form and receive a medication guide, which the prescriber reviews with them before starting the medication. The pharmacy or healthcare facility dispensing the drug also enrolls in the program. Nurses and other staff members may play an important role by confirming that patients have someone to escort them after injection, having a crash cart stocked and ready, and giving the patient a medication guide before each injection. Nurses also may monitor patients for at least 3 hours after injection for signs or symptoms of PDSS, as required by the REMS.

A REMS for an existing product

An example of a REMS for an existing product is the one for erythropoiesis-stimulating agents (ESAs). These drugs, which stimulate red-blood cell production, are approved to treat anemia stemming from chronic renal failure or from certain treatments for HIV/AIDS and cancer. After their approval, FDA learned of clinical studies that showed ESAs stimulate tumor growth in certain cancer patients. Consequently, the agency notified the drug manufacturers that a REMS was necessary to help ensure the drugs’ benefits outweigh their risks. The REMS for ESAs requires that all patients treated with ESAs receive a medication guide.

The ESA APPRISE Oncology Program is part of the REMS for ESAs. Under this program, healthcare providers and hospitals that prescribe or dispense ESAs for cancer patients must have special certification. Also, ESAs can be dispensed to cancer patients only after the healthcare provider and patient discuss their risks and if the patient signs an acknowledgment form before starting treatment. Nurses may assist physicians in educating patients on ESA risks.

Weighing in on REMS

FDA provides for and encourages public input in the regulatory process. On April 19, 2011, the agency announced it will require a REMS for extended-release and long-acting opioids, as previous FDA efforts have failed to minimize misuse and abuse of these drugs.

FDA received the first reports of widespread oxycodone abuse in 2000. By 2008, an estimated 20.1 million Americans older than age 12 (about 8% of the U.S. population) were taking pain relievers for nonmedical reasons. In June 2010, FDA held a joint meeting of the Anesthetic and Life Support and the Drug Safety and Risk Management Advisory Committees, to solicit feedback from panel members and the public on the proposal’s components. Carlton Brown, PhD, RN, AOCN, President of the Oncology Nursing Society, spoke during the open public session on behalf of the organization. He stressed that an opioid REMS should be reasonable and ensure access to this class of drugs for patients with cancer-related pain.

On July 27 and July 28, 2010, FDA held a REMS public meeting to obtain input on issues and challenges associated with developing and implementing a REMS for drugs and biological products. Karen Kiefer, BAIS, RN, spoke on behalf of the New Jersey Chapter of Pain Management Nurses and as an American Pain Foundation Action Network Leader. Providing the nursing and physician perspectives on issues regarding ETASU, she described physician reluctance to prescribe medications that required mandatory training to do so, and suggested integrating healthcare provider, patient, and family education into existing hospital-based training. Kiefer offered the pain resource nurse program as an example.

Since the REMS provisions were implemented, concerns have arisen about the impact of specific REMS, how the growing number of REMS is affecting the healthcare system, and the effects of the REMS program on health professionals, distributors, and patients. With their broad base of knowledge and experience, nurses can help FDA develop effective REMS and provide feedback on the REMS process. If you’d like to be involved, visit Meetings, Conferences, & Workshops on the FDA website for upcoming meeting announcements, including instructions for submitting written comments if you can’t attend.

Lieutenant Commander Christine Merenda, MPH, RN, OCN, U.S. Public Health Service, is a Health Programs Coordinator in the Office of Special Health Issues at the U.S. Food and Drug Administration in Silver Spring, Maryland. The author acknowledges Janelle Derbis, PharmD, Health Programs Coordinator in the FDA’s Office of Special Health Issues, and Claudia Karwoski, Supervisory Interdisciplinary Scientist in the FDA’s Office of Surveillance and Epidemiology, for their assistance in writing and editing this article.

Selected references

U.S. Department of Health & Human Services. Substance Abuse and Mental Health Services Administration. Results from the 2008 National Survey on Drug Use and Health: National Findings. (Office of Applied Studies, NSDUH Series H-36, HHS Publication No. SMA 09-4434). Rockville, MD; 2009. http://oas.samhsa.gov/nsduh/2k8nsduh/2k8Results.cfm. Accessed July 8, 2011.

U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). “www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. Accessed July 8, 2011.

U.S. Food and Drug Administration. A Communication about an Ongoing Safety Review of Erythropoiesis-Stimulating Agents (ESAs) Epoetin alfa (marketed as Procrit, Epogen) Darbepoetin alfa (marketed as Aranesp). www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm072280.htm. Accessed July 8, 2011.

U.S. Food and Drug Administration. Opioid Drugs and Risk Evaluation and Mitigation Strategies (REMS). www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm. Accessed July 8, 2011.

U.S. Food and Drug Administration. Transcript for the July 23, 2010 Joint Meeting of the Anesthetic and Life Support and the Drug Safety and Risk Management Advisory Committees. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM224671.pdf. Accessed July 8, 2011.

U.S. Food and Drug Administration. Transcript for the July 27, 2010 Risk Evaluation and Mitigation Strategy (REMS) Public Meeting. www.fda.gov/downloads/Drugs/NewsEvents/UCM224945.pdf. Accessed July 8, 2011.

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