Johns Hopkins Researchers Slam FDA for Efforts to Deter Opioid Abuse

Nancy Grover

Sarasota, FL ( – A 5+ year initiative by the Food and Drug Administration to reduce adverse outcomes associated with inappropriate prescribing or use of opioids isn’t getting many accolades from researchers at Johns Hopkins. Their review of nearly 1,000 pages of FDA documents led them to conclude the federal agency fell way short in assessing the effectiveness of the program. Their findings were published in JAMA Internal Medicine.

“In2012, the FDA and extended release/long acting (ER/LA) manufacturers implemented a Risk Evaluation and Mitigation Strategy (REMS) ‘to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse,’” the authors wrote. “Despite a multitude of assessments, 5 years after initiation, the FDA and drug manufacturers could not assess whether the ongoing ER/LA REMS had accomplished this goal. Alternative observational study designs would have allowed for more rigorous estimates of the REMS effectiveness, improving the ability of the FDA and ER/LA manufacturers to critically evaluate and iteratively improve this important program.”

The researchers looked at 9,739 pages of documents obtained through the Freedom of Information Act. They were looking to see whether the agency and drug makers could assess the effectiveness of the program by evaluating manufacturer REMS assessments and FDA oversight of them. The program required the ER/LA manufacturers to:

  • Deliver voluntary REMS-adherent continuing education (CE) to prescribers, with content based on an FDA blueprint for safe ER/LA prescribing
  • Develop medication guides to inform patients about risks associated with ER/LA opioids
  • Monitor and annually report on prescriber knowledge and behavior, as well as patient access and safety

The FDA’s goal was to have 60 percent of the ER/LA prescribers take REMS-adherent CE between 2012 and 2016. But by 2016 just 27.6 percent of the prescribers had done so.

“Nonrepresentative cross-sectional surveys of self-selected prescribers suggested modestly greater ER/LA knowledge among CE completers than noncompleters, and claims-based surveillance indicated slowly declining ER/LA prescribing, although the contribution of the REMS to these trends could not be assessed,”the researchers wrote. “The effectiveness of the REMS program for reducing adverse outcomes also could not be assessed because the analyses used nonrepresentative samples, lacked adequate controls for confounding, and did not link prescribing or clinical outcomes to prescribers’ receipt of CE training. Although the FDA had requested studies tracking adverse outcomes as a function of CE training, the FDA concluded that these studies had not been performed as of the 60-month report in 2017.”

The Program

REMS are drug safety programs the FDA can require for certain medications that pose safety concerns to help ensure the benefits of a particular medication outweigh the risks. They are designed to help reduce the occurrence and/or severity of certain serious risks, by informing and/or supporting the execution of the safe use conditions described in the medication’s FDA-approved prescribing information,” according to the FDA website. “REMS are not designed to mitigate all the adverse events of a medication, these are communicated to health care providers in the medication’s prescribing information. Rather, REMS focus on preventing, monitoring and/or managing a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of the event.”

The REMS program for ER/LA products began because of the association with the products and a greater risk of addiction, unintentional overdose, and death than their immediate-release counterparts. The idea was to “reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics,” according to the researchers.

The authors posed and answered questions related to the program.

“Did the REMS change prescribing?” they asked. “No surveillance at any time contrasted prescribing patterns or other clinician-level or patient level outcomes between CE completers and noncompleters, nor did analyses allow for the effectiveness of the REMS to be isolated from secular trends or a multitude of other factors that may have been associated with adverse outcomes.”

“Did REMS reduce adverse effects, including overdose?” was another question. “As with assessments of the association between REMS receipt and prescribing, ER/LA opioid manufacturers relied on population-level ecological trends to answer this question rather than comparing patient-level outcomes between prescribers who completed REMS-adherent CE and those who did not.”

The researchers pointed to the analysis as having implications “for the conduct of future REMS programs.” They listed several recommendations:

“First, the FDA should establish and release a credible evaluation plan for REMS at the time of a program’s adoption based on a validated, reproducible framework for CE program evaluation,” they wrote. For example, if the primary goal of the education is to change a behavior, then direct assessments of such behaviors should be included.”

“Second, risk management programs like the REMS should be designed to incorporate evolving information while not deviating unduly from the prespecified protocol,” they advised. “The structure of the ER/LA REMS posed potentially as long as a 1-year to 2-year cycle between when a problem would be identified to the FDA and when the FDA would next receive a report with data demonstrating the effectiveness or lack thereof of any remediation effort.”

“Third, as we and others have called for … REMS assessments should automatically be made public given the strong overriding public interest in the issue,” they recommended.

Meanwhile, the FDA changed the program name in Sept. 2018 to Opioid Analgesic REMS, and modified it to include immediate-release (IR) opioid analgesics intended for use in an outpatient setting. Two months ago it was again modified to add medication guides for authorized generics.

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