Insights and Expertise
White Paper: Understanding Adaptive Designs for Clinical Trials
Rapidly evolving safety risk management processes increasingly dictate drug approval and post-marketing surveillance1. To meet FDA requirements of developing and implementing changes to risk-evaluation and mitigation strategies (REMS), and to streamline this complicated process, we have detailed a framework of key concepts, standards and submission procedures.
In 2007, the FDA Amendments Act (FDAAA), which amends the Federal Food, Drug and Cosmetics Act (FFDCA) to include post-market safety activities in the process for the review of human drug applications or supplements, introduced REMS to assure safe use of certain drugs. As defined by the FDA, “A REMS is a required risk management plan that uses tools beyond the prescribing information (the package inserts) to ensure that all benefits of certain drugs outweigh their risks.” (U.S. Food and Drug Administration, 2019, p. 2). Without REMS, some drugs could not be approved because of high safety risks. Prior to the REMS programs, a few products used risk minimization action plans (RiskMAPs) to the same end2. REMS supersedes RiskMAPs. The most extensive components of a REMS program are elements to assure safe use (ETASU), developed to mitigate specific and serious risks. Examples of common ETASU include:
Safety measures of a REMS are unique to a drug’s associated safety risks. The FDA can require a REMS at any time, pre- or post- approval, and a REMS can be required for a single drug, or for a class of drugs. While the FDA is responsible for reviewing and approving REMS programs, sponsors are responsible for developing them. When deciding if a REMS is needed, consider the following factors3:
When new safety information becomes available, changes to a REMS may be proposed to ensure that a drug’s risk-to-benefit ratio is acceptable. Changes to a REMS may also be proposed to reduce the burden on health care professionals of complying with the REMS. Changes to a REMS are categorized as REMS revisions, minor REMS modifications and major REMS modifications, depending on the degree of potential effect on serious risk, safe use and the actions necessary to comply with the REMS4. Each REMS category has different submission criteria and regulatory action requirements (see the table below).
Did you know that our safety risk management experts have been successfully submitting REMS programs and changes to the U.S. FDA since the program’s start in 2007? Our safety and pharmacovigilance team can take your product through even the most complicated REMS program changes.
During a public health emergency (PHE), the FDA may impose temporary policies for certain REMS requirements. To ensure that timely response efforts meet patient needs in such situations, health care professionals, sponsors, regulators and other relevant parties should closely monitor FDA announcements and communicate with the FDA if needed.
In March 2020, specific to the COVID-19 pandemic, the FDA issued a new guidance addressing completion of REMS program ETASU requirements that may negate public health interventions for self-isolation and quarantine. This guidance states that laboratory testing or imaging studies required by some REMS can put patients and the public at risk of COVID-19 transmission and advises that “healthcare providers prescribing and/or dispensing these drugs should consider whether there are compelling reasons not to complete these tests or studies during the PHE, and use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing and imaging studies.” (U.S. Food and Drug Administration, 2020, p. 7). The guidance indicates that these accommodations should be documented and summarized in the REMS Assessment Report.
As information becomes available on COVID-19 and safety risk management, other temporary policies for certain REMS requirements may arise.
We cannot over-emphasize the importance of safety risk management. Regulators have expanded submission requirements to include REMS programs for certain high-risk products to maintain patient safety, and sponsors must keep up with the rapidly evolving changes.
To navigate complex REMS requirements and challenges, let our safety and pharmacovigilance experts plot your REMS strategy course. We have extensive experience designing, executing and managing a broad range of REMS programs across many therapeutic areas. Dedicated to patient safety, our staff proactively tracks risk-management-related regulatory, legislative and market concerns, keeping us ahead of safety issues. Since 1998, we have developed efficient, cost-effective product development solutions, tailored to our clients’ needs.
Deborah Cole, Marketing Associate, Amarex Clinical Research, LLC, an NSF International company
Shide Badri, Safety and Pharmacovigilance Professional
1 Balian, J. D., Wherry, J. C., Malhotra, R., & Perentesis, V. (2010). Roadmap to risk evaluation and mitigation strategies (REMS) success. Therapeutic advances in drug safety, 1(1), 21–38. https://doi.org/10.1177/2042098610381419
2 U.S. Food and Drug Administration. Center for Drug Evaluation and Research. (2016) Background Materials for REMS Standardization and Evaluation Public Meeting. Retrieved from https://www.fda.gov/media/86199/download
3 Lippmann, E. (2017). FDA, CDER, Office of Regulatory Policy. Risk Evaluation and Mitigation Strategies (REMS) [PowerPoint slides]. Retrieved from https://www.fda.gov/media/105565/download
4 U. S. Food and Drug Administration. Center for Drug Evaluation and Research. (2019). Risk Evaluation and Mitigation Strategies: Modifications and Revisions. Guidance for Industry. Retrieved from https://www.fda.gov/media/128651/download
5 U. S. Food and Drug Administration. Center for Drug Evaluation and Research. (2020). Policy for Certain REMS Requirements During the COVID-19 Public Health Emergency. Guidance for Industry and Healthcare Professionals. Retrieved from https://www.fda.gov/media/136317/download