Our Comments on the FDA Notice Regarding Changes to Third-Party Vendors for Risk Evaluation and Mitigation Strategies (REMS)

July 19, 2023

We are pleased to have the opportunity to share our views with the Food and Drug Administration (FDA) on their notice regarding Changes to Third-Party Vendors for Risk Evaluation and Mitigation Strategies (REMS).

We are a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

Implementing changes in REMS has the potential to cause significant disruptions in the operations of any REMS program, including the ability for prescribers and patients to interact with the tools necessary to fulfill the various REMS requirements. These disruptions can undermine patients’ ability to access a drug in ways that minimize risks. Since the FDA does not approve third-party REMS administrators, or play a major role in the initial development of REMS with elements to assure safe use (ETASU), it is essential that the FDA closely monitors any changes in REMS plans to make sure they are appropriate and yield beneficial outcomes.

We strongly urge that the FDA require drug sponsors and their REMS administrators to test proposed changes to REMS systems prior to implementation with those that actively engage with the system, including but not limited to physicians, patients, and pharmacists. This will ensure that the REMS program will have the intended impact. A less-than-rigorous approach to studying the efficacy of REMS defeats the purpose of REMS and fails to protect patients from predictable harm. The FDA REMS for Transmucosal immediate-release fentanyl (TIRF) drugs and the REMS for Extended Release/Long Acting (ER/LA) opioids provide important examples of how improper implementation of REMS can harm patients. The HHS IG found numerous failures for both these REMS programs, at a time when these REMS were especially important because of the opioid epidemic.1 For example, manufacturers consistently missed the REMS’ targets for training ER/LA prescribers, and the FDA was blamed for not giving manufacturers sufficient time to respond to FDA’s requests for better data before their next assessments were due. As a result, the REMS for ER/LA opioids was changed to primarily measure voluntary prescriber training to educate about risks, a decision that also failed to adequately protect patients.

We also strongly recommend that the sponsor and/or the REMS administrator conduct a Failure Modes and Effects Analysis (FMEA) to identify and plan for system failures. This includes providing for adequate support services in the event that the system fails to work as intended following full implementation of an altered REMS system. Part of the planning should include provisions for an emergency suspension of the REMS or specific parts of the REMS.

Additionally, beyond testing a REMS modification with stakeholders, FDA should require stakeholder input from prescribers in all stages of developing, implementing, and tracking a REMS modification related to changes to third party vendors. This will require greater transparency between drug sponsors, REMS administrators, and stakeholders.

In numerous REMS, the FDA has faced measurement challenges, such as a lack of baseline data and limited surveillance data. These metrics are essential for the sponsor to include when evaluating whether a REMS system was successfully and efficiently implemented. It is also essential to collect data on which types of health professionals are involved in implementing a specific REMS. For REMS that involve training of health professionals, there must be a record of the percentage of prescribers being trained, the percentage who start training who complete it, and what percentage that complete the training will answer training questions correctly.

Finally, we strongly recommend that all future REMS agreements that the FDA enters into with manufacturers and their vendors, require that deidentified REMS data be made available to appropriate outside stakeholders. The availability of this data will reassure the public, patients, and health care providers that each REMS is accomplishing its intended outcomes and promoting the safe use of drugs while minimizing harm, especially serious harm.

  1. U.S. Department of Health and Human Services Office of Inspector General. (2020). FDA’s Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis. https://oig.hhs.gov/oei/reports/OEI-01-17-00510.pdf