Study Criticizes FDA Safety Oversight of Rapid-Release Fentanyl

An FDA program to prevent the inappropriate use of immediate-release fentanyl did not meet its goals of preventing off-label use or to patients who were not already using opioids, a JAMA study reported Tuesday.¹

In an accompanying editorial, authors called for reforms to the entire FDA Risk Evaluation and Mitigation Strategy (REMS) program, and criticized the agency for engaging in a 5-year Freedom of Information Act battle with the researchers as they sought to obtain the necessary documents for their study.² The types of fentanyl involved come in forms that release rapidly into the bloodstream, such as consisting of sublingual tablets, lozenges, and sprays.

The researchers reviewed FDA documents from 2012 to 2017 and reviewed surveys of patients, prescribers, and pharmacists about their knowledge of the products and the FDA’s Transmucosal Immediate-Release Fentanyl (TIRF) REMS. They also reviewed prescription claims data for the same period.

Despite data showing widespread weaknesses, the FDA did not take steps to correct matters, the researchers said.

In surveys of 786 individuals 12 months after the TIRF began, 86.1% of pharmacists, 87.4% of prescribers, and 90.6% of patients correctly reported that TIRFs are contraindicated in opioid-nontolerant patients.

However, 60 months after the program, 119 of 302 physicians (39%) reported prescribing TIRFs for chronic, noncancer pain. Moreover, claims-based analyses 60 months after program the TIRF indicated that 34.6% to 55.4% of patients prescribed TIRFs were opioid-nontolerant.

The TIRF REMS was created in 2011 and was the first REMS based on an entire drug class.

There have been concerns about REMS from a variety of quarters. In a 2013 report, the HHS Office of Inspector General issued a report critical of REMS practices. Generic drug companies have complained to the FDA about brand-name pharma makers using REMS to delay entry of competition. And in 2016,

37 states filed a lawsuit against Reckitt, the manufacturer of the partial opioid agonist buprenorphine/naloxone (Suboxone), alleging that the company was not participating in a legally mandated shared REMS program for all makers of a drug.

The editorial suggested 3 reforms:

• Design REMS with manufacturer input and administered it by a neutral third party paid by the FDA with newly instituted REMS user fees.
• Make REMS assessments submitted to the FDA publicly available. The editorial called the FOIA battle “disturbing” and said “greater transparency would likely help keep manufacturers and the FDA more accountable, benefiting public health.”
• Make the FDA accountable to ensure that REMS is working to achieve its goals, even if it takes legislation to do it. In this case, the FDA was not assertive enough in demanding additional information from manufacturers about the performance the REMS TIRF.

References

1. Rollman JE, Heyward J, Olson L, et al. Assessment of the FDA risk evaluation and mitigation strategy for transmucosal immediate-release fentanyl products [published online February 19, 2019]. JAMA. 2019;321(7):676-685. doi:10.1001/jama.2019.0235.

2. Sarpatwari A, Curfman G. Mitigating health risks of prescription drugs: lessons from FDA oversight of opioid products [published online February 19, 2019]. JAMA. 2019;321(7):651-653. doi:10.1001/jama.2019.0236.