A Risk Evaluation and Mitigation Strategy (REMS) is a risk management program that serves to inform and educate patients and health care providers about the serious risks of a drug and offer tools and strategies to mitigate those risks. The Food and Drug Administration Amendments Act of 2007 authorizes the FDA to require a REMS if it is determined – either during initial product review or at any point in the post-marketing period – that specific safety measures are needed to ensure that a drug’s benefits outweigh its risks. A REMS may be be associated with a single, specific drug, such as a novel first-in-class molecular entity, or more broadly to a general classification of drugs which share common risk / benefit traits.
The implementation of REMS programs is important because they not only affect pharmaceutical companies and patients, but they have an impact on the entire healthcare system. Many different healthcare and drug supply chain entities are affected by REMS including manufacturers, prescribers, patients, pharmacies, and insurance providers.
Title 21 of the Code of Federal Regulations (CFR) specifies the criteria for determining when the FDA can require a REMS. These guidelines are very broad and are left up to interpretation by the FDA. Size of population, whether the drug is a new molecular entity, the severity of the disease, potential adverse events, and the expected benefit and duration of treatment all factor into the FDA’s decision to require or not require a REMS program.
A REMS can be required both pre- and post-approval. In a pre-approval situation, the FDA would deem a REMS necessary because, without a REMS, the risk of the drug would be greater than the benefits. In this case, the REMS program would be approved with the drug approval letter, which can be very positive for a drug Sponsor. Prior to the REMS program, the Sponsor may have been issued a Complete Response Letter (CRL) and told that, so far, there is an unacceptable risk-benefit profile and more data would be required for an approval. Now, the FDA may approve the drug with an appropriate REMS program instead of letting the drug sit in regulatory approval limbo.
Post-approval REMS can be required if the FDA becomes aware of new safety information and determines that a REMS is necessary to ensure the benefits of the drug outweigh the risks. New safety information often arises through adverse event reporting after a drug’s approval and its use in clinical practice since the number of patients using the drug is greatly increased.
The factors FDA considers when determining the need for a REMS include:
There are five basic components that must be included in a REMS program, which include:
☐ Timetable for Submission of Assessments
☐ Medication Guide
☐ Elements to Assure Safe Use (often referred to as ETASU)
☐ Implementation System
☐ Communication Plan
The Timetable for Submission of Assessments lays out when Sponsors must assess how well the REMS is working and report back to the FDA. They must include certain specific goals that can be used as evaluation metrics. These REMS assessments compare the results of the program to the initial goals, and the minimum requirements are 18 months, three, and seven years.
A Medication Guide may be required if it could help avoid serious adverse events. The purpose of the Guide is to inform patients about serious side effects before they decide to use a drug. Adherence is essential to the drug’s effectiveness since Medication Guides are meant to be read and understood by the average patient. As such, they must be written in non-technical language and be dispensed with the drug.
Many ETASU requirements focus on actions that are performed prior to the drug being dispensed or prescribed to a patient, such as certifications and dispense only requirements. Other elements, such as patient monitoring, may be required for the duration of the treatment.
Certifications are a common ETASU element. This can include certification of healthcare providers by requiring those who may prescribe the drug to be familiar with educational materials and risks. This certification ensures that healthcare providers are aware of any serious risks and know how to look for and control potential adverse events associated with the drug. REMS programs can also require a pharmacist or anyone else who dispenses the drug, perhaps a nurse in a hospital, to be certified.
An implementation System may be required to track certain ETASU elements. The drug’s Sponsor may be required to take reasonable steps to monitor and evaluate those in the healthcare system who are responsible for implementing necessary ETASU measures.
A Communication Plan serves to educate and raise awareness of the risk(s) associated with the drug’s use. They are similar to Medication Guides except Communication Plans are designed for and directed at healthcare providers while, Medication Guides are designed for patients. Communication Plans can also serve to alert healthcare professionals of any changes in the REMS program that they may need to know in order to properly care for their patients taking a specific drug, or determine which patients are a good fit for that drug.
One of the key aspects of a Communication Plan is sending letters to healthcare providers including pharmacists, physicians, and any other relevant healthcare professionals. Communication Plans often include distribution of the informational materials through professional societies.
A REMS is a drug safety program that the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. REMS programs are designed to reinforce medication use behaviors and actions that support the safe use of that medication. While all medications have labeling that informs healthcare stakeholders about medication risks, only a few medications require a REMS.
REMS focuses on preventing, monitoring, and managing a specific serious risk by informing, educating, and reinforcing actions to reduce the frequency and severity of the event. If there is a question as to whether the drug you are developing has risks that may outweigh its benefits, it is crucial that you understand the REMS program so that you can implement it effectively.
Has the FDA required you to develop a REMS program for your product? We can help you develop and implement a successful REMS program in compliance with all of the Agency’s requirements. To learn more about our services and how we can help you achieve successful interactions with the FDA, contact us today.
February 8, 2019
On Wednesday, January 30th, FDA issued a draft guidance which clarifies what information must be shared with the Agency regarding the marketing status of branded and generic drugs. The draft...
November 1, 2018
On Monday, October 12th, FDA issued a draft guidance regarding the role of Pre-IND Meetings in the development of drugs to treat rare diseases. The document, entitled "Rare Diseases: Early Drug...
October 26, 2020
Recruiting clinical studies in a niche disease area can be challenging, but disease registries can provide the solution. The European Medicines Agency (EMA) has issued draft guidance on how...