Report: FDA REMS program ineffective at curbing opioid misuse

Regulatory NewsRegulatory News
| 02 October 2020 | By Mary Ellen Schneider 

The US Food and Drug Administration (FDA) has been using the Risk Evaluation and Mitigation Strategies (REMS) program as a way to mitigate adverse events stemming from opioid misuse and abuse, but that program is a poor tool for fighting the opioid epidemic, the Health and Human Services Office of the Inspector General concluded in a new report.
The REMS program is a long-standing drug safety program that has allowed the FDA to require manufacturers to implement specific safety measures that go beyond drug labeling requirements. But the OIG found that data quality issues within the program made it difficult for the FDA to track compliance by prescribers of two major classes of opioid drugs – transmucosal immediate-release fentanyl (TIRF) drugs and extended-release/long-acting (ER/LA) opioids.
The OIG proposed a series of changes to the FDA’s opioid response, including greater accountability for drug manufacturers and greater use of patient registry data.  
In terms of TIRF drugs, data from the REMS program suggested that the manufacturers were not meeting program goals and some REMS goals were inadequate, OIG reported. From 2014 to 2017, the FDA requested better data from drug manufacturers and conducted its own analysis. As a result, in 2019 the agency proposed modifying the REMS for TIRF drugs. The changes placed more emphasis on ensuring patients were opioid tolerant when prescribed TIRF drugs by requiring documentation and a patient registry. However, the modifications also removed language that had stated that TIRF drugs should be prescribed and dispensed “only to appropriate patients.” The OIG said this change could send the signal that it is appropriate to prescribe these drug off-label for wide-ranging pain symptoms. 
The OIG found similar problems with the use of REMS in ER/LA opioids. From 2014 through 2017, the FDA did not have the data to determine whether the REMS was meeting its goal of reducing serious adverse outcomes from inappropriate prescribing, misuse or abuse of these opioids. It was clear, however, that manufacturers were often missing REMS targets for training prescribers. The agency again requested that manufacturers submit more data. In this case, the FDA was frequently late in providing reviews of the information, leaving manufacturers without sufficient time to respond to the agency’s concerns before their next assessment. The agency modified the REMS goals for ER/LA opioids in 2018, shifting from measuring outcomes to measuring voluntary prescriber training programs.
“On the basis of our review, REMS are not well-suited to quickly address the opioid crisis,” the OIG wrote. “The REMS for TIRF drugs and 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.”
OIG recommendations
The OIG made four recommendations for how the FDA could shift its focus in responding to the opioid crisis.  
First, OIG suggested that the FDA use the new TIRF REMS patient registry to monitor for known risks, including switching a patient between different TIRF drug inappropriately and off-label prescribing. Second, OIG urged the FDA to strengthen the REMS for opioid analgesics, which is the successor to the REMS for ER/LA opioids, by requiring prescriber training. Third, OIG suggested that the FDA could enhance its REMS assessment review process by providing more timely feedback and getting information on inappropriate prescribing trends from the agency’s Office of Prescription Drug Promotion. Fourth, OIG said FDA should seek additional authority to hold manufacturers accountable when they do not comply with the REMS.
While the FDA agreed with the recommendations to use the TIRF patient registry and to enhance the REMS review process with more timely feedback, the agency disagreed with the recommendation to strengthen the REMS for opioid analgesics, according to the agency response section of the report. The agency is considered the recommendations to seek additional authority.
Opioid approvals
Meanwhile, a recent study in the Annals of Internal Medicine found that FDA’s approval of opioid products is often based on trials of short duration – no more than 12 weeks -- and narrowly defined patient populations.  
James Hayward of Johns Hopkins University in Baltimore and colleagues examined new drug applications (NDA) for opioid analgesics approved between 1997 and 2018. Of 39 NDAs for treating chronic pain, 21 products were supported by one or more pivotal trials, which had a median duration of 84 days. For acute pain indications, eight of nine NDAs were supported by at least one pivotal trial and the trials had a median duration of 1 day.
The researchers urged the FDA to strengthen its regulatory guidance for opioid applications to specifically require the measurement of populations, duration of therapy and efficacy and safety outcomes. They also called on the agency to be more systematic in how it gathers information on common adverse events.
Additionally, the researchers suggested that the FDA either revise opioid product labeling about efficacy to better align it with current trial evidence or require trials to be at least 24 weeks in duration.
“Ultimately, our findings underscore the evidence gaps that have limited clinicians’ and patients’ full understanding and appreciation of the inherent risks of prescription opioid analgesics,” the researchers wrote. “Optimizing the efficacy and safety data manufacturers provide to the FDA would help ensure more informed prescribing and reduce the public health risk of these products.”
GAO Report


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