FDA Guidance Documents are Vital in De-Risking REMS

February 2, 2023

The FDA’s risk evaluation and mitigation strategy (REMS) requirements are among the most demanding of a pharmaceutical or biotech manufacturer’s postmarket requirements, and it is important to plan adequately for these programs, given the cost of a failed first attempt. In this blog, we’ll review REMS programs and related FDA guidance, a topic the agency has opined multiple times since the beginning of 2023.

The FDA’s new guidance on the format and content of a REMS document is not the central FDA policy for these programs, but it gives us a reason to examine all the work that goes into developing and deploying a REMS. Perhaps the most essential FDA guidance related to REMS is the 2019 guidance for application of statutory factors for determining necessity. This guidance lists six factors the agency takes into consideration when making such a determination, such as:

  • The seriousness of any known or potential adverse events associated with the therapy;
  • The expected benefit of the therapy;
  • The seriousness of the treated disease/condition;
  • Whether the drug is a new molecular entity (NME);
  • The expected or actual duration of treatment; and
  • The estimated size of the population that would be treated.

Obviously, an NME is statistically more likely to be subject to a REMS requirement, but an abbreviated new drug application (ANDA) for a generic drug may also be subjected to a REMS. The FDA released a guidance in 2018 for development of a REMS that is shared by the holder of the original NDA and the ANDA applicant, which may be required in some but not all circumstances. None of the six REMS factors listed above is sufficient by itself to prompt the imposition of a REMS, but a serious adverse event that is irreversible might be the most significant impetus behind any FDA decision to impose a REMS program. The frequency of adverse events is also a major concern.

Standardized Data Formats Required Going Forward

The FDA believes REMS programs are important enough that it posted two blogs on the subject, the first of which provides an overview. The second blog reviews the challenges and hazards associated with deploying a REMS, principally the question of REMS standardization. The structured product label (SPL) project is designed to aid manufacturers in organizing information about their REMS programs in a manner that facilitates its incorporation into health information technologies. Feedback from stakeholders led the agency to draft and finalize the REMS format and content guidance, which requires the use of an electronic filing format.

Another point of emphasis in this guidance is on a REMS feature known as the elements to assure safe use (ETASU), a set of requirements that also describes the other stakeholders who take part in the REMS. These may include:

  • Training for healthcare professionals that may prescribe the drug product;
  • Certification requirements for entities that dispense the product;
  • Mechanisms to ensure the drug will be dispensed only to patients in clinical settings;
  • Mechanisms to ensure the drug will be dispensed only when need is documented (such as upon confirmatory testing;
  • Mechanisms for patient monitoring; and
  • Enrollment of patients in a registry.

The number of stakeholders and entities that are involved in deploying a REMS program highlights some of the hazards of a program that is not well developed at the outset. In one example, difficulties in migrating the REMS program from one website to another combined with issues with a call center set up for the antipsychotic clozapine to prompt the FDA to provide enforcement discretion regarding administration of the REMS. This REMS has undergone several cycles of enforcement discretion, with the latest round including discretion on both the number of daily doses that can be provided in a single refill, and the ability of a pharmacy to dispense clozapine without having been enrolled in the REMS program.

The periodic requirements for REMS are listed in a program guide, which states that the reporting intervals may be as short as 18 months in some instances. Products with addictive potential such as opioid analgesics are candidates for REMS, but the program guide also indicates that new information about drug product safety can force a redesign of an existing REMS program. Generally speaking, this new guidance on REMS format and content is not retroactive, but any change to an existing REMS program makes that program liable for conformance to the guidance.

Requirements for Disposal of Unused Drug Product May Increase

One of the more potentially burdensome aspects of the format and content guidance is the inclusion of language regarding packaging and disposal requirements for the drug. While the format and content guidance provides little detail on this question, disposal of unused opioid drugs was the subject of an April 2022 FDA communication, which proposed solutions such as prepaid mail-back envelopes. This would be in addition to existing measures such as in-home disposal products, collection kiosks and take-back events, all of which may add considerably to the expense of producing and managing a drug product that is subject to a REMS order.

The FDA maintains a REMS dashboard, which shows that a relatively small percentage of products are subject to REMS requirements. There are only 60 currently active REMS out of approximately 300 total approved since 2008, four of which were approved in 2022. The FDA approved six REMS programs in 2021, a year in which the FDA approved 50 novel drugs. While a large number of drug and biotech products are approved each year without a REMS requirement, it is clear that a manufacturer should consider how it might devise such a program in the event of any uncertainty over whether a REMS program will be necessary, given that the FDA may not permit distribution of an approved drug until the REMS program is in place.