Opioid Resource Center
Opioid Resource Center
February 19, 2019
2 min read

FDA made ‘few’ changes to certain REMS, despite possible abuses

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There were “few substantive changes” made to an FDA Risk Evaluation Mitigation Strategy to acknowledge the evidence of high rates of off-label transmucosal immediate-release fentanyl use, according to findings recently published in JAMA.

“Because of their potency and potential for overdose if used inappropriately, on Dec. 28, 2011, the FDA approved a highly restrictive REMS or all transmucosal immediate-release fentanyl (TIRF) products, a class of short-acting fentanyls delivered through sublingual and buccal tablets, lozenges, and sprays approved solely for the management of breakthrough cancer pain in opioid-tolerant patients,” Jeffrey Eric Rollman, MPH, NRP, of the Center for Drug Safety and Effectiveness at Johns Hopkins Bloomberg School of Public Health, and colleagues wrote.

Rollman and colleagues analyzed annual assessment reports regarding this REMS from 2012 to 2017, the FDA evaluations of these reports, and correspondence about safety issues from FDA sponsors. The partially-redacted documents were obtained through a Freedom of Information Act.

They found in the 12 months since the Dec. 28, 2011 REMS order, 11.6% of prescribers, 7.9% of pharmacists and 2.6% of patients wrongly reported that TIRF products can be prescribed to opioid-nontolerant patients. Nearly identical levels of understanding were observed in the 48-month and 60-month surveys.

Researchers also wrote the 48-month survey showed 34.2% of prescribers reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 18.4% of prescribers and 47.7% of patients wrongly reported the FDA had approved TIRFs for such use.

In addition, Rollman and colleagues found during the 60-month period examined, product-specific analysis of claims data signified that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. Also, there were “few substantive changes” made to the REMS to acknowledge the evidence of high rates of off-label TIRF use and no report of prescribers being removed from the REMS program even though it had a noncompliance component.

A FDA committee has since “acknowledged that off-label prescribing appeared common and provided several recommendations to strengthen the program, including the conduct of additional claims-based analyses and more rigorous educational programs to mitigate ‘knowledge attrition’ among trained TIRF prescribers,” Rollman and colleagues wrote.

In a related editorial, Ameet Sarpatwari, JD, of the Program On Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, Harvard Medical School in Boston, wrote two employees at one of the companies that Rollman et al studied have plead guilty to charges connected to a “nationwide conspiracy” of bribing physicians to prescribe Subsys for off-label use.


Sarpatwari also suggested the FDA shouldcreate REMS, only allow product creators to serve in advisory roles, a neutral third party, and related available without having to go through a Freedom of Information Act request. He also wrote the “FDA will need to be more assertive in requesting specific analyses pertaining to the performance of REMS programs and in restructuring elements to assure safe use in response to concerns the analyses raise.”

“In November 2018, the FDA took the controversial step of approving the transmucosal opioid sufentanil (Dsuvia) — a product 10 times more potent than fentanyl — with a

REMS, based in part on the argued need for the drug in the treatment of injured soldiers. If the FDA is going to continue to rely on REMS when approving such dangerous drugs, better systems are needed to ensure that REMS programs work as intended,” Sarpatwari concluded. – by Janel Miller

Disclosures: Rollman reports no relevant financial disclosures. Sarpatwari reports his work is supported by institutional grants from the Engelberg Foundation, the Harvard Program in Therapeutic Science, the Laura and John Arnold Foundation, and the Open Society. Please see the study for all other relevant financial disclosures.