In a recent JAMA article, “Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-Release Fentanyl Products,” researchers details how an FDA class-wide Risk Evaluation and Mitigation Strategy (REMS) did not prevent the inappropriate prescribing of transmucosal immediate-release fentanyls (TIRFs), which were approved solely for breakthrough cancer pain in opioid-tolerant patients.
Study
As described in the study’s “Key Points,” the major question in consideration asks if the FDA’s TIRF REMS met its goal of preventing inappropriate use of TIRF products, such as prescribing to patients without opioid tolerance. Since 2007, the FDA has used Risk Evaluation and Mitigation Strategies to support the safe use of prescription medications. Because of their potency and potential for overdose if used inappropriately, on December 28, 2011, the FDA approved a highly restrictive REMS for all transmucosal immediate-release fentanyl 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.
The researched reviewed 4877 pages of FDA documents obtained through a Freedom of Information Act request, including 6 annual REMS assessment reports (2012-2017), FDA evaluations of these reports, and FDA-sponsor correspondence about safety issues. The primary outcomes were results of knowledge, attitudes, and behavior surveys of prescribers, pharmacists, and patients; survey- and claims-based prescribing assessments; iterative communication between the FDA and TIRF manufacturers from March 2012, when the REMS was initiated, to December 2017, the date of the last FDA assessment we received; subsequent modifications to the REMS program; and detection and disenrollment of physicians prescribing TIRFs to opioid-nontolerant patients.
“Analyses of health plan data indicated that thousands of patients receiving TIRFs were opioid-nontolerant,” the study found. Although surveys of pharmacists, prescribers and patients showed high levels of knowledge about proper TIRF prescribing, some survey items and claims-based analyses “indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program,” the researchers wrote. In addition, the REMS program had a noncompliance plan, but there were no reports of prescribers being disenrolled for inappropriate prescribing.
Editorial
Accompanying the study is an editorial from Ameet Sarpatwari, JD, PhD, a professor in the Program On Regulation, Therapeutics, And Law (PORTAL) at Harvard Medical School and Gregory Curfman, the deputy editor of JAMA, who explain how the study raises serious questions.
“These findings highlight not just deficiencies with the structure and administration of the TIRF REMS, but problems with the REMS system more generally. Although the FDA has taken steps to improve this system in recent years, including efforts to standardize, integrate, and evaluate REMS programs, additional action is needed,” the editorial says.
The authors outline three necessary reforms:
“First, REMS should be designed by the FDA with manufacturer input—not vice versa—and be administered by a neutral third party paid by the FDA with newly instituted REMS user fees.”
“Second, REMS assessments submitted to the FDA should be publicly available. It is disturbing that it took 5 years for Rollman et al to secure the FDA documents on which they based their review.”
“Third, for REMS to ensure safe use of clinically useful prescription drugs with potentially significant adverse effects, the FDA will need to be more assertive in requesting specific analyses pertaining to the performance of REMS programs and in restructuring ETASU in response to concerns the analyses raise.”