How Does the FDA’s Risk Evaluation and Mitigation Strategies (REMS) Program Work?
Key takeaways:
Risk Evaluation and Mitigation Strategies (REMS) is a drug safety program designed to help ensure that the benefits of a medication outweigh its risks.
Without REMS, many medications — including those that treat rare diseases — may not be on the market due to their risks.
Your cooperation is essential for REMS to work properly and fulfill its purpose — protecting you from serious risks.
Over the past decades, hundreds of new medications have become available. Many of them can improve our quality of life, and some even treat rare diseases. However, there are those that can also cause severe or potentially life-threatening side effects. Even if a medication has great promise, it’s hard to ensure its safe use if it has serious risks.
To better navigate this problem, the FDA established the Risk Evaluation and Mitigation Strategies (REMS) program to help manage potentially dangerous side effects of certain medications — while still allowing access to them.
Here we’ll cover what the REMS program is, how it works, and how it might affect you.
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What is the Risk Evaluation and Mitigation Strategies (REMS) program?
When a medication is FDA-approved, it means that it’s determined to be safe and effective. However, “safe” doesn’t mean there aren’t any risks. Every medication comes with its own side effects. These side effects and risks are usually detailed in the medication’s FDA-approved labeling.
Some side effects — such as an upset stomach and dry cough — are usually minor. Others — such as liver failure, infertility, and death — can be very serious.
If a medication’s benefits don’t clearly outweigh its risks, the FDA looks deeper into the medication. If it offers a significant benefit and the risks can be minimized with careful management, a REMS program may be required.
REMS is a drug safety program that the FDA established in 2007 to help ensure that medications are used safely, and risks of serious side effects are minimized. Through the REMS program, the FDA can require pharmaceutical companies (manufacturers) to design strategies to mitigate risks for healthcare providers, people taking the medication, and other stakeholders.
When does a medication require a REMS?
It’s important to know that not every medication requires a REMS.
When the FDA decides a medication needs a REMS program, it is a complex situation. There are many reasons why a REMS may be needed, but three of the most important are:
The medication is highly effective, but it can cause serious side effects.
It can treat serious and rare diseases, but the risk of taking the medication is high.
It contains new chemical structures that haven’t been used in the past.
With any of these situations, additional safety measures — such as REMS — are used so that the benefits of the medication can outweigh its risks. While still possible, the goal is to make these risks less frequent or severe.
How does REMS work?
If the FDA determines that a REMS program is necessary for a medication, they may require the manufacturer to implement strategies to help manage its risks.
Let’s review the process.
Step 1: The FDA decides a REMS is needed
When a new medication is submitted for FDA approval — or when new adverse events are reported for an FDA-approved medication — the FDA will assess the benefit and risk balance and decide if a REMS program is needed.
Step 2: The manufacturer develops a specific REMS
After the FDA requests a REMS program, the manufacturer usually has 120 days to design and submit a REMS proposal.
A REMS program needs to have a risk mitigation strategy. In other words, a plan of what the program is looking to achieve and how it will do so. It will also detail any requirements — for both manufacturers and REMS participants — and materials needed to facilitate the program. To ensure that the REMS program is meeting its goal, the company must include an assessment timeframe.
Step 3: The FDA reviews and approves the REMS program
After a REMS program proposal is submitted, the FDA reviews it. If the proposal meets FDA medication safety requirements, the REMS program can be approved. However, back-and-forth discussions between the FDA and manufacturer are common until the program meets necessary requirements.
Step 4: The manufacturer implements REMS with different stakeholders
The manufacturer implements the REMS program by communicating with different parties involved in the healthcare delivery process.
Healthcare providers: Healthcare providers may need to be trained or certified to prescribe the medication.
Pharmacies and other healthcare settings: Certain healthcare settings may need to have certification, training, and specific processes in place to dispense or administer the medication.
Patients and caregivers: People taking the medication may receive specific information about its risks. They may also be required to enroll in the REMS program, get routine lab tests, or have the medication administered in a certified healthcare setting.
Step 5: Review & Revise
Manufacturers require feedback from different stakeholders to assess the REMS program’s effectiveness. In some cases, it may need to be changed and submitted to the FDA for review. The REMS can be revised over time even after the initial program is agreed upon.
Different strategies used by REMS
REMS programs typically include two components — communication and required activities. Depending on the program, one or both components may be needed to help ensure the medication’s benefits outweigh its risks.
Communication
This REMS component requires manufacturers to communicate a medication’s safety concerns and potential risks.
Certain REMS programs may require a manufacturer to develop handouts, like Medication Guides, to help people know how to use a medication safely and understand its risks.
A Medication Guide should be provided alongside a dispensed medication. It can also be accessed at the FDA’s Medication Guide webpage — just search for a medication name.
A REMS program may also require the manufacturer to send its communication plan to various healthcare professionals. This communication plan describes safety risks associated with medication and required activities that are needed to support the REMS.
Required Activities
This REMS component includes activities to complete before a medication can be administered or dispensed. These activities — known as “Elements to Assure Safe Use (ETASU)” — are used to support medication safety.
Examples of ETASU can include:
Needing to sign a form acknowledging that you understand the risks before starting a medication
Getting routine lab testing
Enrolling in a registry that monitors if a specific side effect occurs
Needing to go to a certified healthcare setting to have your medication administered
It’s important that all requirements are followed to receive a medication with a REMS program. You also may need to take surveys to help the FDA make sure the program is effective.
With ETASU, healthcare professionals often need to become certified — or enrolled in the specific REMS program — and undergo training..
How does REMS affect me?
REMS was developed to help protect against serious risks of certain medications. Because of this, it’s important to follow all necessary requirements and cooperate with your healthcare provider.
You play a key role in REMS. Without your cooperation and willingness to adhere to REMS requirements, REMS would not function properly.
It’s important to keep in mind that REMS provides access to certain medications with serious risks that would otherwise not be available.
What are some examples of REMS?
There are currently 61 implemented REMS programs. Most of them have ETASU, and a few require communication between you and your healthcare provider. Below are some examples of common REMS programs.
Medications that require Medication Guides
As mentioned, Medication Guides are handouts that come with the medication’s packaging, and they contain specific information about how to use medication safely. It’s important to read it thoroughly to understand the medication’s risks and how to mitigate them.
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs — such as ibuprofen (Advil) and naproxen (Aleve) — have a REMS program. This Medication Guide’s goal is to provide a better understanding of risks and how to use NSAIDs safely to avoid certain serious side effects (e.g., heart attack, higher risk of bleeding, and stomach ulcers).
Even if NSAIDs don’t have ETASU, you still have an essential role. It’s recommended to take the medicine as directed and read the Medication Guide thoroughly to better understand NSAID risks. It’s also important to report experienced side effects to your healthcare provider.
Medications that require routine testing
Some REMS may require routine lab testing to monitor for serious side effects. If your lab results show that a medication is negatively affecting your body, actions can occur to help intervene (e.g., switching to a different treatment). Below is an example of a REMS medication that requires routine lab testing.
Clozapine
Clozapine is a medication used for schizophrenia that can cause severe neutropenia (abnormally low number of white blood cells). Neutrophils (a type of white blood cell) are a part of the immune system that protects us from unwanted invaders like bacteria and viruses.
When the number of neutrophils is low, people have a higher risk of infection. Certain infections may be severe or lethal. If you already have a low neutrophil level, it may not be safe to use clozapine. Because of this, people taking clozapine may be required to enroll in the Clozapine REMS Program.
Before starting on clozapine, a healthcare provider will check your neutrophil count and medical history to make sure it’s appropriate to prescribe for you. Once on the medication, your provider should check neutrophil levels routinely to make sure it’s still safe to use.
Medications administered at a certified healthcare setting
Some REMS medications may cause serious side effects that require immediate medical attention. Because of this, these medications should be administered in a certified healthcare setting for monitoring purposes. An example of this is discussed next.
Brexanolone
Brexanolone (Zulresso) is a newer medication used for postpartum depression (PPD) in adults. Zulresso is administered by continuous intravenous (IV) infusion over 60 hours.
During the infusion, it’s common to feel sleepy, but some people may pass out or even lose consciousness. This is why it’s important to monitor recipients during an infusion. Because of this, Zulresso can only be administered at a certified healthcare setting that provides monitoring during the infusion.
REMS requires all people receiving the infusion to have a good understanding of its risks and to be enrolled in the Zulresso REMS Program.
The bottom line
REMS is a medication safety program that helps to protect people from serious risks of certain medications. Many medications — including those that treat rare diseases — may not be available without REMS.
You play an essential role in REMS. You may receive specific information about a serious risk associated with a medication, what actions you may need to take to mitigate it, and what symptoms you should watch for and report to your healthcare provider. It’s important to follow all requirements to make sure the benefits of a medication outweigh the risks.
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References
Aurobindo Pharma Limited. (2021). Clozapine- clozapine tablet [package insert].
Batta, A., et al. (2020). Trends in FDA drug approvals over last 2 decades: An observational study. Journal of Family Medicine and Primary Care.
Centers for Disease Control and Prevention. (n.d.). What you need to know: Neutropenia and risk for infection.
Sage Therapeutics, Inc. (2019). Zulresso- brexanolone injection, solution [package insert].
U.S. Food and Drug Administration. (n.d.). Approved risk evaluation and mitigation strategies (REMS).
U.S. Food and Drug Administration. (n.d.). Medication guide for non-steroidal anti-inflammatory drugs (NSAIDS).
U.S. Food and Drug Administration. (2018). FDA’s role in managing medication risks.
U.S. Food and Drug Administration. (2018). What’s in a REMS?
U.S. Food and Drug Administration. (2019). REMS: FDA’s application of statutory factors in determining when a REMS is necessary: Guidance for industry.
U.S. Food and Drug Administration. (2020). Policy and procedures: Risk evaluation and mitigation strategies modifications and revisions.
U.S. Food and Drug Administration. (2020). Risk evaluation and mitigation strategy (REMS) document zulresso (brexanolone) REMS programs.
U.S. Food and Drug Administration. (2021). FDA adverse event reporting system (FAERS) public dashboard.
U.S. Food and Drug Administration. (2021). Risk evaluation and mitigation strategies | REMS.
U.S. Food and Drug Administration. (2021). Risk evaluation and mitigation strategy (REMS) single shared system for clozapine.
U.S. Food and Drug Administration. (2022). Labeling information | drug products.
U.S. Food and Drug Administration. (2022). Medication guides.
U.S. Food and Drug Administration. (2023). Format and content of a REMS document: Guidance for industry.
U.S. Food and Drug Administration. (2023). Medication guides database.
U.S. Food and Drug Administration. (2023). Roles of different participants in REMS.
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