An Overview of FDA Risk Evaluation & Mitigation Strategies

When a new drug is developed, the FDA must take many factors into consideration before approving the new compound. These factors may include the seriousness of the disease being treated, number of people affected with the disease, expected drug benefits, expected treatment duration, and seriousness of the known adverse events.

This is where a Risk Evaluation and Mitigation Strategy (REMS) comes into play. REMS are assessments performed throughout the lifecycle of a drug—from preclinical trials to a post-commercialization phase—mandated by regulatory bodies to determine whether additional monitoring beyond product labeling is necessary to ensure the benefits outweigh the risks.

As defined by the FDA, “(REMS) is a drug safety program designed to reinforce medication use behaviors and actions that support the safe use of that medication.”¹

REMS are not intended to minimize all harmful effects of the drug. Rather, the focus is on preventing, tracking, and handling a specific serious risk by informing, educating, and/or enforcing measures that reduce the frequency and/or intensity of the event.

In 2007, the FDA Amendments Act (FDAAA) extended authority to the FDA to require a REMS from pharmaceutical companies to ensure that the safety of their products still outweigh the risks. They may also require post-commercialization studies to ensure that if there is a known or hypothetical risk associated with the product, then it is possible to identify and mitigate that over time. Additionally, the FDAAA enables the FDA to intervene more regularly with the approved package insert to incorporate new safety information as it becomes available.

Prior to the enactment of the FDAAA, the FDA approved a limited number of drug and biological products that included risk minimization action plans (RiskMAPs). A RiskMAP was a strategic safety program focused on minimizing identified risks associated with a product while maintaining its benefits.

Since the FDAAA, 16 products with RiskMAPs transitioned into REMS, including clozapine’s "No Blood, No Drug" program and thalidomide’s "System for Thalidomide Education and Prescribing Safety" program, as well as for isotretinoin and mifepristone.²

If the FDA decides that a REMS is required, the law empowers the agency to request sponsors submitting new drug applications, abbreviated new drug applications, or biologics license applications to send a proposed REMS as part of their application, along with the required REMS elements.³

One of the main elements of the REMS program is the Medication Guide (MG), which is also known as a patient package insert. MG is mandated because it importantly highlights safety information that needs to be distributed with every dispensed drug.

It provides FDA-approved, patient-friendly labeling and should meet the stipulated requirements of 21 Code of Federal Regulations (CFR) 208 if the FDA determines: that patient labeling may assist in preventing serious adverse events; that the product carries significant risks that may influence the patient's decision to use or continue to use; and that patient adherence to instructions is critical to the product's effectiveness.⁴

Another element is the communication plan which is necessary to educate health care professionals (HCPs) on safe and appropriate use of the drug. Communication plans vary among drugs because each has its own requirements based on the risk it presents.

Manufacturers should document how these HCP were educated, including which tools and materials have been provided. Additionally, Elements to Assure Safe Use (ETASU) are necessary medical interventions or acts by health care practitioners before prescribing or dispensing the medication.

ETASU can require any or all of the following, depending on the drug’s risk: HCPs who prescribe the medication must be certified or undergo specialized training; pharmacies or other drug dispensers must also be certified; dispensing/administration of medication in limited distribution networks; only dispense/administer drugs with evidence of safe-use conditions; and patients taking the drug will be monitored and enrolled in patient enrollment registries.⁴

Then comes the implementation plan, which is a description of how the manufacturer wants to implement the ETASU—from physician and patient education to pharmacy implementation.

Each REMS program submission must entail a timetable for submitting an assessment of the program. After the REMS program is initially approved, assessments happen at 18 months, 3 years, and 7 years’ post-launch, which is the bare minimum that is required.

This assessment intends to evaluate the effectiveness of the REMS assessment plan, including metrics that will be used to identify problems with the program, if the programs’ objectives are met, if any modifications are required, and the criteria/methodology or policies that address the programs’ implementation.

If a serious risk is identified in an already-marketed drug, patients will be informed immediately, and the FDA will give the manufacturer a window of 120 days to submit a proposed REMS program. If a serious risk is identified in a new drug application or during a clinical trial process, then the FDA will request manufacturers include a REMS program upon the launch of the new drug. REMS programs put some obligations for both the manufacturer and the FDA in having a shared responsibility to ensure there is an ongoing oversight to mitigate a product’s risks versus the benefits.

Therefore, we may see REMS drugs dispensed through specialty pharmacies because they are more inclined to have capabilities and capacities to do what needs to be done for a limited distribution therapy. Further, limited distribution can qualify as a meaningful component of the ETASU.

The specialty pharmacy model enables manufacturers and physicians to implement FDA-mandated REMS programs by providing patient contacts, specially qualified clinical staff, infrastructure, documentation, and reporting systems.⁵

About the Author

Zakieh Abuelkhair earned her Bachelor Degree of Pharmacy from the University of Sharjah in the UAE and her Master of Pharmacy Business Administration (MPBA) program at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines. In the past 2 years, Zakieh has worked at Novartis Pharmaceuticals as a Disease Education Specialist and completed her 6-month pharmacy internship at Cleveland Clinic Abu Dhabi. Her current role is working as Pharmacy Operations Manager at Al Thiqa Specialty Pharmacy in an effort to transform the practice of Specialty Pharmacy in the Middle East.

References

1. Risk Evaluation and Mitigation Strategies (REMS). (2021). Retrieved 16 April 2021, from https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems
2. (2021). Retrieved from https://fas.org/sgp/crs/misc/R44810.pdf
3. Background Materials for REMS Standardization and Evalution Public Mee. (2021). Retrieved 16 April 2021, from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/background-materials-rems-standardization-and-evalution-public-meeting
4. (2021). Retrieved 16 April 2021, from https://www.fda.gov/media/105565/download
5. Specialty pharmacy's role in REMS, FDA's new drug safety program. (2021). Retrieved 16 April 2021, from https://www.formularywatch.com/view/specialty-pharmacys-role-rems-fdas-new-drug-safety-program