On April 4, 2019, FDA issued final guidance on FDA’s application of the statutory factors in determining when a risk evaluation and mitigation strategy (REMS) is necessary. This guidance clarifies how FDA determines whether a REMS is necessary to ensure that a drug is used in a way where its benefits outweigh its risks.

A drug can only receive FDA approval if it is shown that the drug is safe and effective when used according to its label. However, a determination that a drug is safe does not necessarily mean that the drug is entirely free from harmful or undesirable effects. Instead, it means that the likelihood of a positive treatment outcome outweighs the probability and magnitude of any adverse effects. A REMS is one tool that FDA can develop and utilize to preserve a drug’s benefits while reducing its risks to an acceptable level. For example, a REMS may require health care providers who prescribe the drug to undergo specialized training, or mandate that the drug only be dispensed to patients in certain health care settings, such as hospitals, where the patient can be closely monitored. If FDA determines that a drug’s risks would exceed its benefits even if a REMS is required, FDA will not approve the drug.

Section 505-1(a)(1) of the FDCA requires FDA to consider six factors when determining whether a REMS should be required:

  1. The seriousness and nature of known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug.
  2. The expected benefit of the drug with respect to the disease or condition.
  3. The seriousness of the disease or condition to be treated.
  4. Whether the drug is a new molecular entity.
  5. The expected or actual duration of treatment with the drug.
  6. The estimated size of the population likely to use the drug.

No single factor is determinative, and the relative weight of each factor is a case-specific inquiry. In addition to the six factors listed above, FDA will also consider the potential burdens that a REMS may impose on patients and health care providers, and whether a REMS can be designed that adequately minimizes those burdens.