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  5. FDA’s Role in Managing Medication Risks
  1. Risk Evaluation and Mitigation Strategies | REMS

FDA’s Role in Managing Medication Risks

At FDA, risk management is a key consideration in assessing the benefit-risk balance of a drug. Risk management involves:

  1. Assessing a drug’s benefit-risk balance,
  2. Developing and implementing tools to minimize risks while preserving benefits,
  3. Evaluating the effectiveness of such tools and re-assessing their benefit-risk balance and
  4. Making adjustments, as appropriate, to risk minimization tools to further improve the benefit-risk balance.

FDA’s primary risk management tool is communicating through FDA-approved product labeling, often referred to as the “package insert” or the “prescribing information,” which includes a summary of the essential information needed by health care providers for the safe and effective use of the drug.

Labeling is sufficient for most drugs to ensure that the benefits outweigh the risks. In a limited number of cases, FDA may determine that a Risk Evaluation and Mitigation Strategy (REMS) will also be needed to help ensure that the benefits of the drug outweigh its risks. Within the Center for Drug Evaluation and Research (CDER), the Division of Risk Management (DRISK) serves as the subject matter experts and scientific lead for the review and development of REMS. DRISK is staffed with health care professionals and social scientists who work with other CDER staff, and consult with staff in the Center for Biologics Evaluation and Research (CBER), to determine the risk management approach for prescription drugs and biologics.

A Brief History of Medication Risk Management and REMS

Medication risk management is not a new concept to FDA. A number of earlier drug regulatory initiatives can be viewed as forms of risk management. For example, the designation of a drug product as a prescription drug rather than over-the-counter drug under the Durham-Humphrey Amendment of 1951, is a form of risk management. It ensures that certain drugs require a medical prescription because those drugs can be used safely only under the supervision of a licensed health care practitioner.  

Prior to 2007, FDA occasionally asked companies to develop special safety programs called Risk Management Programs (RMPs) or Risk Minimization Action Plans (RiskMAPs) to mitigate serious risks for a limited number of drug products that offered substantial therapeutic benefits. In 2007, through the Food and Drug Administration Amendments Act (FDAAA), FDA received the explicit authority to require a REMS when necessary to ensure the benefits outweigh the risks of a drug.

Below are some noteworthy milestones over the past 40+ years pertinent to managing the risks of medications.


FDA requires patient package inserts (PPI) for oral contraceptives that must contain information for the patient about specific risks and benefits.


The Accutane Pregnancy Prevention Program (PPP) was established by Hoffman La Roche, Accutane's manufacturer, to attempt to reduce the occurrence of pregnancies exposed to isotretinoin, which could cause birth defects.


FDA approved Clozaril, a first- in-class atypical antipsychotic, approved for the treatment of schizophrenia resistant to other therapies, with a restricted distribution program that requires white blood count monitoring for all patients to mitigate the risk of agranulocytosis, a life-threatening condition. The program was commonly referred to the “No blood, no drug” program.


FDA issued final regulations establishing requirements for the distribution of Medication Guides for certain prescription drug and biological products used primarily on an outpatient basis without direct supervision by a healthcare professional. 

Thalidomide was approved in the United States for the treatment of cutaneous manifestations of erythema nodosum leprosum (a complication of leprosy) under a restricted distribution program called the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S) Program. This program tightly controlled who could prescribe and dispense the drug.  Additionally, patients were advised of and needed to comply with requirements of the program to receive the drug.


FDA publishes the report Managing the Risks from Medical Product Use: Creating a Risk Management Framework: Report to the FDA Commissioner from the Task Force on Risk Management. This report summarizes the task force’s assessment of risk management practices within the overall healthcare delivery system, focusing on the roles and responsibilities of each participant.


The SMART (System to Manage Accutane Related Teratogenicity) Program (previously called the Accutane Pregnancy Prevention Program) is implemented to manage the risk of teratogenicity (birth defects) associated with Accutane.  While participation in the program was voluntary, prescribers enrolled in the SMART program were provided with stickers that were to be affixed to the prescription and signified to the pharmacist that a female patient had undergone pregnancy testing and that contraceptive counseling was provided. Soon after the SMART Program was implemented, generic versions of the drug were approved, each with its own version of the SMART program.


FDA issued final guidance on Development and Use of Risk Minimization Action Plans (RiskMAP) which included recommendations for developing RiskMAPs for situations in which a product may pose a clinically important and unusual type or level of risk.


The iPLEDGE Program (previously called the SMART program), a restricted distribution program, was implemented for brand and generic versions of isotretinoin. This was the agency’s first approval of a single program that was shared by all manufacturers for a drug product. This program tightly controlled who could distribute, prescribe, dispense, and receive isotretinoin.

The Institute of Medicine (IOM) publishes its report, The Future of Drug Safety: Action Steps for Congress, which was an assessment of the U.S. drug safety system and made recommendations to improve risk assessment, surveillance, and the safe use of drugs. The report included several recommendations including recommending that Congress ensure that FDA has the authority to require risk management programs


The Food and Drug Administration Amendments Act (FDAAA) created section 505-1 of the Food, Drug, and Cosmetic Act (FD&C Act), which authorizes FDA to require a REMS for certain drugs if FDA determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks. 

Current REMS

FDA maintains a website listing medications with approved REMS that are currently active and their associated materials, at (REMS@FDA).



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