In late September 2020, the United States Department of Health and Human Services Office of Inspector General (HHS OIG) released a study on the Food and Drug Administration’s (FDA) Risk Evaluation and Mitigation Strategies (REMS) addressing the opioid crisis. While FDA specifies the requirements and approves the REMS, the drug manufacturers are responsible for development and implementation of the program. While REMS have the potential to address the opioid crisis, a prior OIG report from 2013 raised concerns about the FDA’s oversight of the programs and their overall effectiveness. Therefore, this new review looks at the extent to which FDA has held drug manufacturers accountable for mitigating the risk of opioid misuse and abuse through REMS.
In conducting the review, HHS OIG 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. The reviewed documents included all drug manufacturer-submitted assessments, FDA decision memoranda, assessment reviews, inspection reports, and other miscellaneous analyses and correspondence. HHS OIG also interviewed FDA staff about REMS oversight.
Findings
After conducting the review, HHS OIG found that the FDA “struggled to measure the effectiveness” of the REMS for TIRF drugs and for ER/LA opioids in mitigating opioid misuse.
TIRF Drugs
TIRF drugs are short-acting and highly potent opioid analgesics that are approved for breakthrough pain in cancer patients who are opioid-tolerant. TIRF drugs are 50 to 100 times more powerful than morphine. The FDA initially approved the TIRF REMS in 2011 and TIRF manufacturers spent the first two years getting the REMS established. However, after those two initial years, FDA found data that suggested that manufacturers were not meeting their goals and that some of the data for the goals were inadequate. From 2014 to 2017, FDA frequently and consistently responded to its concerns about the data by requesting better data from the manufacturers, or in some cases, even conducting its own analyses.
In 2019, FDA announced a modification to the TIRF REMS that put a greater emphasis on making sure that patients who are prescribed TIRF drugs are opioid-tolerant. However, the modification also resulted in a change of phrase – TIRF drugs were not longer recommended to be prescribed and dispensed “only to appropriate patients” (such as those with breakthrough cancer pain), which may wind up giving the wrong idea to doctors who wish to prescribe with TIRF drugs off-label to treat patients with varying pain symptoms.
The below exhibit, found in the report, indicates at which stage the overarching goal and certain subgoals were met, partially met, not met, or if the FDA was unable to determine if the goal was met.
ER/LA Opioids
Similar to the problems with the TIRF REMS, in assessments from 2014 through 2017, FDA could not determine whether the ER/LA opioids REMS was reaching its overarching goals due to bad data. What the FDA did determine, though, was that manufacturers repeatedly missed the REMS’ targets for training prescribers. Also similar to the TIRF REMS, FDA often requested manufacturers submit additional data from different sources, but FDA did not often make such a request in enough time for the manufacturers to respond before their next assessments were due.
In 2018, FDA modified the REMS goals for ER/LA opioids and moved away from an attempt to measure outcomes to measuring voluntary prescriber training that was intended to teach prescribers about risks.
As can be seen below, the FDA has not yet been able to determine whether manufacturers met the overarching goal of the ER/LA opioid REMS.
HHS OIG Recommendations
At the conclusion of the report, HHS OIG recommends the following:
- That FDA use a 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.
- That FDA strengthen the REMS for opioid analgesics by requiring training for prescribers.
- That FDA enhance its REMS assessment review process by completing reviews in a timely manner and seeking information on inappropriate prescribing trends from its own Office of Prescription Drug Promotion (OPDP).
- That FDA seek additional authority to ensure manufacturers are held accountable, if and when appropriate.
The FDA agrees with the first and third recommendations but disagrees with the second. With respect to the fourth and final recommendation, FDA is taking it under advisement and giving it consideration.