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FDA's Risk Evaluation and Mitigation Strategies: Uncertain Effectiveness in Addressing the Opioid Crisis


While the opioid crisis continued with nearly 47,000 deaths in 2018, FDA used Risk Evaluation and Mitigation Strategies (REMS) as tools to mitigate misuse and abuse of opioids. (A REMS is a drug safety program that is intended to mitigate a specific serious risk associated with the use of a drug.) FDA specifies the requirements and approves the REMS. However, the drug manufacturer is responsible for developing and implementing the program. REMS have the potential to help address the opioid crisis, but previous OIG work from 2013 raised concerns about FDA's oversight and the overall effectiveness of REMS programs. This review determines the extent to which FDA has held drug manufacturers accountable for mitigating the risk of opioid misuse and abuse through REMS. It complements OIG's past work tracking opioid use among Medicare and Medicaid beneficiaries and provides insight into the Federal response to the national opioid crisis.


We analyzed documents related to the REMS for transmucosal immediate-release fentanyl (TIRF) drugs and extended-release/long-acting (ER/LA) opioids from 2011 through 2017, including all drug manufacturer-submitted assessments, FDA decision memoranda, assessment reviews, inspection reports, and other analyses and correspondence. We also interviewed FDA staff about REMS oversight.


While the severity of the opioid crisis became more apparent over time and the Federal Government and States launched initiatives to combat opioid abuse, FDA struggled to measure the effectiveness of the REMS for TIRF drugs and for ER/LA opioids in mitigating the misuse of opioids.

For the REMS for TIRF drugs, FDA found data in the assessments suggesting that the manufacturers were not meeting all their goals and also found the data for some of the REMS goals to be inadequate. From 2014 to 2017, FDA consistently responded to its concerns about the data by requesting better data from the TIRF drug manufacturers or conducting its own analysis. In 2019, FDA announced a proposed modification to the TIRF REMS that places a greater emphasis on ensuring that patients who are prescribed TIRF drugs are opioid-tolerant, including required documentation and a patient registry to capture needed data. However, the new goals no longer say that TIRF drugs should be prescribed and dispensed "only to appropriate patients" (i.e., patients with breakthrough cancer pain), which may signal to prescribers that prescribing TIRF drugs off-label to treat patients with wide-ranging pain symptoms (i.e., low-level chronic pain, post-operative acute pain, etc.) is appropriate.

Similarly, in assessments from 2014 through 2017, poor data left FDA unable to determine whether the REMS for ER/LA opioids was meeting its overarching goal of reducing serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of the drugs. However, FDA did find that manufacturers repeatedly missed the REMS' targets for training prescribers. As it did with the TIRF REMS, FDA requested that manufacturers of ER/LA opioids submit more and better data from different sources. However, FDA was often so late in providing its reviews to the manufacturers that manufacturers had no time to respond to FDA's concerns before their next assessments were due. Finally, in 2018 FDA modified the REMS goals for ER/LA opioids, moving away from an attempt to measure outcomes to measuring voluntary prescriber training meant to educate prescribers about risks.

FDA faced additional challenges to ensuring that these REMS mitigate opioid misuse and abuse. In addition to limitations in the data from the drug manufacturers, FDA faced measurement challenges, such as a lack of baseline data, limited surveillance data, and the inability to distinguish the effects of the REMS separate from the other initiatives addressing opioid misuse and abuse. Further, some opioid manufacturers engaged in deceptive marketing practices that undermined the REMS' educational messages regarding risk. Furthermore, the fact that both REMS are what is known as "shared system" REMS-meaning that they aggregate their data across drugs and product categories-can mask problems with individual drugs or product categories. Finally, FDA has limited authority to enforce manufacturers' compliance with their REMS.


On the basis of our review, REMS are not well-suited to quickly address the opioid crisis. The REMS for TIRF drugs and for ER/LA opioids both rely largely on educating prescribers about the risks of these drugs. This takes time to have an impact on prescribing habits and can be countered by pharmaceutical marketing campaigns designed to increase prescribing. In addition, FDA's deliberate approach to decision-making, which relies on scientifically robust data, focused FDA's attention for years on improving the serious data-quality issues.

Our report had four recommendations. FDA concurred with our recommendations for it to use the new TIRF REMS patient registry to monitor for known areas of risk, such as inappropriate conversions (i.e., switching a patient between different TIRF drugs inappropriately) and off-label prescribing. FDA also concurred with our recommendation for it to enhance its REMS assessment review process by completing its reviews in a timely fashion and seeking information on inappropriate prescribing trends from FDA's Office of Prescription Drug Promotion. FDA did not concur with our recommendation to strengthen the REMS for opioid analgesics (the successor to the REMS for ER/LA opioids) by requiring training for prescribers. Finally, FDA is considering our recommendation to seek additional authority to ensure that manufacturers are held accountable when appropriate.