Risk Evaluation and Mitigation Strategy: Tipping the Balance for FDA Approval

In order to be approved by the FDA, a drug must be both safe and effective for the indication(s) and conditions of use stated in its prescribing information (i.e., product label, package insert). However, FDA’s determination of safety does not mean that the drug is without risk; rather, “safety” in this context indicates that the benefits of the therapy outweigh the risks associated with it (i.e., side effects). Risk evaluation and mitigation strategies are required for certain drugs with serious safety concerns to be approved.

What is a Risk Evaluation and Mitigation Strategy?

A Risk Evaluation and Mitigation Strategy (REMS) is a formal plan required by the FDA for certain “riskier” drugs to ensure that the benefits of these drugs outweigh their risks. The Food and Drug Administration Amendments Act of 2007  (FDAAA) created Section 505-1 of the Food, Drug, and Cosmetic (FD&C) Act (21 USC 355-1), which authorizes FDA to require a REMS for certain drugs. As part of this, FDA maintains the REMS@FDA website, which includes a searchable database of approved REMS as well as links to additional REMS information.

FDA’s Benefit-Risk Approach

Before we discuss REMS in more detail, let’s first address how FDA assesses the balance between a therapy’s effectiveness (benefit) and potential safety concerns (risk). This critical assessment underpins both the approval decision and the REMS requirement. Traditionally, FDA’s benefit-risk framework has included the following categories:

  • Analysis of condition
  • Current alternative treatment options
  • Benefit
  • Risk
  • Risk Management

The first two categories concern the therapeutic area, while the remaining three categories represent product-specific concerns. Notice that these categories go beyond just the “good” that a therapy can do and the “harm” that it may cause. Equally important is an understanding of:

  • The condition being treated (e.g., Is this a serious condition? Is there an unmet medical need?)
  • Other therapeutic options (along with their own benefit-risk profiles)
  • If or how risks can be managed in order to shift the balance in favor of benefit.

Within each of these categories are two considerations that inform the regulatory decision:

  • Evidence and uncertainties (i.e., what are the facts, the uncertainties, and the assumptions made to address the uncertainties?)
  • Conclusions and reasons (i.e., what are the regulatory implications of the facts, uncertainties, and assumptions?)

Risk Management

Risk Management is of particular importance for the REMS. Risk management includes both risk assessment and minimization. Risk management is an iterative process involving:

  • Assessing the benefit-risk balance
  • Developing and implementing tools to minimize risks while preserving benefits
  • Evaluating the effectiveness of these tools and reassessing the benefit-risk balance
  • Making needed adjustments to minimize risk and further improve the benefit-risk balance.

Is a REMS Required?

For the majority of products, labeling and routine reporting requirements are sufficient to mitigate risks and preserve benefits. In these cases, a REMS is not required. However, for drugs that include a level of risk that makes labeling and routine reporting insufficient for assuring a favorable benefit-risk profile, a REMS will be required. While a Sponsor can decide to submit a REMS on its own, the FDA will ultimately determine whether a REMS is required. In cases where a REMS is appropriate, the FDA generally requires them to be submitted prior to initial approval, but this does not prevent the FDA from requiring them for already approved drugs. The latter case often results when new safety information comes to light that, in the FDA’s view, necessitates a REMS implementation. When deciding whether a REMS is required, the FDA considers certain key factors as part of their decision-making process. These factors include:

  • The seriousness of any known or potential adverse events that may be related to the drug
  • The background incidence of adverse events in the population likely to use the drug
  • The expected benefit of the drug with respect to the disease or condition
  • The seriousness of the disease or condition that the drug will treat
  • Whether the drug is a new molecular entity
  • The expected or actual duration of treatment with the drug
  • The estimated size of the population likely to use the drug

REMS Elements

REMS is based on the FDA’s assessment of what is needed to ensure that a product’s benefits outweigh its risks. The REMS for one drug may contain different elements than the REMS for another drug. Based upon its interpretation of applicable statutes, in 2009 FDA released a Draft Guidance for Industry to provide direction on the expected format and content of a proposed REMS. This guidance was further revised in October 2017 based upon public feedback and to support submission of REMS documents in structured product labeling (SPL) format. All REMS must include product and contact information (Administrative Information) and a statement of goals (REMS Goals). A timetable for submission of assessments of the REMS by the applicant (REMS Assessment Timetable) is generally also required. Additional elements may be required based on the FDA’s determination of what is needed (REMS Requirements). These additional elements may include:

REMS Requirements

  • Medication guide or patient package insert
    • Patient-friendly information to promote safe and effective use
  • Communication plan for healthcare providers
    • “Dear Healthcare Professional” letters, additional information about the REMS, and other educational materials directed toward the healthcare provider
  • Elements to assure safe use (ETASU)
    • Provider/Pharmacy certifications, dispensing/administration information, patient monitoring, patient enrollment into registries
  • REMS implementation system
    • How ETASU will be enacted, along with requirements for monitoring and evaluating ETASU implementation by healthcare providers, pharmacists, and others

REMS Appended Materials

  • Enrollment forms
  • Training and educational materials
  • Patient care forms
  • Communications materials
  • Other materials mentioned in the REMS Requirements section

As part of the decision process about which elements should be included in the REMS, the FDA considers not only the key factors listed above but also other factors including (but not limited to):

  • The potential increased burden that the REMS could place on patients and/or healthcare providers, given things like patient access limitations, the characteristics, experience, and size of the prescriber pool, and how the drug will be distributed and dispensed
  • Regulatory precedent; for example, whether there are existing REMS elements for drugs with similar risks and how the FDA has previously managed these risks
  • Potential opportunities to standardize risk management approaches and to ensure compatibility with established systems
  • The demonstrated effectiveness of the elements and tools being considered
  • Whether certain elements and tools were already used to evaluate the drug during clinical trials

Over the longer term, even after the REMS has been approved, the FDA continues to monitor the impact of the REMS on patient access and the healthcare delivery system. When warranted, the FDA may require modifications to the REMS based upon information gathered as part of these assessments. Sponsors may also provide the FDA with their own assessments and recommendations for REMS modifications, but any changes must be approved by the FDA.


For certain drugs that might otherwise not be approvable based upon their benefit-risk profile, the REMS may offer a practical solution for tipping the balance in favor of approvability by instituting additional safeguards to mitigate risk. The FDA bases their decision about the REMS and its constituent elements on an integrated benefit-risk framework and several key considerations related to the therapeutic area and the drug itself, as well as any potential negative impacts on patients and healthcare providers that the REMS may cause. If you have questions about how REMS might apply to your own therapeutic product, our senior consultants and former FDA reviewers can assess your development program and provide actionable advice to position your program and submission for success.

FDA REMS Guidance Resources

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