What is REMS?

A pivotal role of the FDA is to protect public health by ensuring the safety and efficacy of drug products. In this pursuit, one of the  key tools used by the Agency is the Risk Evaluation and Mitigation Strategies (REMS) program, established in 2007 under the Food and Drug Administration Amendments Act (FDAAA).    The program was developed as a response to several well-documented cases of medication-related harm, including deaths and serious side effects, to manage risks associated with specific medications with a higher potential for harm or misuse.

The primary objective of the REMS program is to manage serious risks associated with certain drugs by informing, educating, and/or reinforcing actions to prevent or reduce the frequency of serious an adverse event.  FDA may decide a REMS is necessary as condition of approval of a marketing application if mitigation measures beyond standard labeling are required to ensure the benefits of the drug outweigh the risk.  Likewise, the Agency is also authorized to mandate a post-market REMS from the sponsor if new issues of safety arise for the drug for which require additional measures are required to control and monitor the risk.

What are the Key Components of  REMS?

When preparing a REMS, several key components can be leveraged by the sponsor to lower the probability of occurrence of a risk. Deciding whether to use any or all of the components in a REMS is dependent on the severity and  complexity of the risk.

• Medication Guide: A guidance document developed by the drug sponsor communicating essential information about the safe use, risks, and potential side effects of a medication. The document is disseminated to patients and healthcare providers to ensure the drug is safely administered and prescribed to the correct patient population
• Elements to Assure Safe Use (ETASU): The most stringent and complex REMS component reserved for risks where a medication guide alone is insufficient for adequately managing a risk. An ETASU requires a specific medical intervention or other action by Healthcare Practitioner to be performed prior to prescribing or dispensing a drug.   An example of an ETASU would be requiring a patient to take a pregnancy test prior to administering a drug with known risks for birth defects or requiring a healthcare practitioner to be formally trained prior to prescribing a drug.
• Implementation System: An infrastructure developed by the drug sponsor to ensure proper execution, monitoring, and assessment of the risk mitigation strategies.
• Communication Plan: A plan for communicating strategies to inform healthcare professionals, patients, and the public about the risks and benefits associated with the medication.

Which Components to Use?

In 2020, a review of the REMS program was published in Journal of the American Medical Association (JAMA) evaluating 222 different drugs .  The study included a review of the individual REMS initiated between 2008 and 2019 and their effectiveness in preventing adverse events.  While the overall effectiveness of the program could not be determined based in the information available, certain trends were noted.  Specifically, a conclusion was drawn that the use of medication and communication plans alone are ineffective in educating patients and clinicians about drug risks and that the prevalence of ETASU in REMS has steadily increased over time.

When Should REMS Development Begin?

Given the complexity with designing and implementing a REMS, planning should begin as early in the drug development process as possible when the drug sponsor is made aware of the potential for a serious adverse event.  If a REMS is delayed until it is requested from FDA during the review of the marketing application, there is chance the strategy may be rushed and hasty decisions made, potentially resulting in an unnecessarily burdensome measures on stakeholders. Likewise, procrastination of an REMS could lead to delayed approval of a marketing application, should FDA reject the first draft require the sponsor to make modifications.

Should Sponsors Meet with FDA Prior to Submitting a REMS?

If the sponsor believes a REMS may be required for their drug product, it is strongly advisable to engage with FDA as early as possible to solicit feedback.  Being proactive with addressing potential safety concerns early in drug development will not only result in a more streamlined approach to designing an effective program but will also result in a collaborative effort to prevent adverse events while minimizing  the burden of REMS implementation and monitoring.

Conclusion

Designing an effective REMS for a new drug product can be a complicated endeavor, but with early planning and engagement with FDA, the process can result in the approval of a drug marketing application that otherwise might be denied because of an unfavorable benefit-risk ratio.