Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-Release Fentanyl Products

Abstract

IMPORTANCE Transmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately. OBJECTIVES To evaluate knowledge assessments of pharmacists, prescribers, and patients regarding appropriate TIRF use; to describe sponsor assessments, based on claims data, of whether the REMS program was meeting its goals; and to characterize how the FDA responded to REMS assessments. DESIGN, SETTING, AND PARTICIPANTS Qualitative analysis of 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. EXPOSURE A REMS program to reduce the risk of adverse outcomes, including misuse, abuse, addiction, and overdose, arising from use of TIRFs. MAIN OUTCOMES AND MEASURES (1) Knowledge assessments of pharmacists, prescribers, and patients; (2) survey and claims-based prescribing assessments; (3) FDA and TIRF sponsor communications; (4) modifications to the REMS program; and (5) disenrollment of noncompliant prescribers. RESULTS Twelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing. CONCLUSIONS AND RELEVANCE In this review of FDA documents pertaining to the TIRF REMS, surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge regarding proper TIRF prescribing, yet some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program.

The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies

“…A United States FDA Risk Evaluation and Mitigation Strategy (REMS) program was also implemented to assess transmucosal immediate-release fentanyls (TIRFs) and found that substantial rates of TIRFs were prescribed inappropriately 145,146 . With the findings of deficiencies in the structure and administration of TIRFs, the development of other REMSs is needed to ensure the safe and appropriate use of approved drugs, especially dangerous opioid drugs 147 .…”

Inappropriate use of transmucosal immediate-release fentanyl is common

“…In a recent issue of JAMA, Rollman and colleagues evaluated almost 5,000 pages of FDA documents obtained via a Freedom of Information Act request to assess whether the REMS program for TIRF products was meeting its goals. 1 Specifically, the researchers reviewed 6 years of REMS data from 2012 to 2017 for the TIRF products, which included REMS-mandated knowledge surveys of pharmacists and patients.…”

“…A n analysis of FDA documents, including 6 years of REMS assessment reports, indicated that many prescribers are using transmucosal immediate-release fentanyl (TIRF) inappropriately in opioid-nontolerant patients and in those with chronic, noncancer pain. 1 In March 2019, FDA announced changes to the REMS program for TIRF products, citing a further need to mitigate the risks associated with use of these medications. 2 In an FDA statement, former FDA Commissioner Scott Gottlieb, MD, said, "The prescribing of these medicines for non-FDA-approved uses to [opioid nontolerant] patients tells us that there may be a disconnect between prescriber knowledge and prescribing behavior.…”

Comparative effectiveness of risk mitigation strategies to prevent fetal exposure to mycophenolate

“…Furthermore, with predominant focus on assessment of patient and provider knowledge, evidence on REMS’ effectiveness on actual drug use behaviour and reduced risk of adverse events is scarce. Indeed, a recently completed evaluation of FDA internal documents related to a REMS programme for transmucosal immediate-release fentanyl products reported substantial inappropriate prescribing despite high level of risk awareness among patients and providers 6. Thus, research that compares the net benefit of various ETASUs in terms of patient outcomes is crucial to inform risk management policies in the USA.…”