SILVER SPRING, Md. -- There was no clear-cut decision at an FDA Friday about whether the Risk Evaluation and Mitigation Strategy (REMS) for transmucosal immediate-release fentanyl (TIRF) is working.
But a number of concerns were raised about whether patients who need the powerful painkillers can get them, and whether they are being prescribed to patients for whom they're not intended. Research on the TIRF REMS has also called into question whether the FDA is properly reacting to warning signs.
"I know the FDA thinks the REMS is working, and I guess that depends on your definition of working," said Lewis Nelson, MD, of Rutgers University in Newark, New Jersey, and the FDA Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC).
"I still think it's yet to be proven that it's working. And I'm not convinced we don't have to actually raise the barrier a little bit," he noted.
Two FDA advisory committees -- the Drug Safety and Risk Management Advisory Committee (DSARM) and AADPAC -- met to discuss the fentanyl oversight program.
In that was not presented orally at the meeting, G. Caleb Alexander, MD, and Joshua Sharfstein, MD, of Johns Hopkins University in Baltimore, submitted documents obtained through the Freedom of Information Act indicating the agency had early clues TIRF drugs were going to patients who did not have cancer or were not opioid-tolerant.
"Our preliminary findings indicate that the TIRF REMS program has generated red flags for years," the Hopkins researchers wrote. "There have been multiple warnings that many providers have been engaged in inappropriate prescribing, placing patients at risk."
TIRF drugs are used to manage breakthrough pain in adult patients with cancer. Because fentanyl's potency can cause life-threatening respiratory depression in patients who are not already taking opioids, TIRF medicines are supposed to be limited to opioid-tolerant patients.
Under the TIRF REMS, which was approved in December 2011, TIRF medicine application holders must ensure that outpatient prescribers and dispensing pharmacies are specially certified, that distributors supply TIRF drugs only to certified pharmacies, and that patients are enrolled in the REMS. Patients must sign a patient-prescriber agreement stating they know about the risks and that they reviewed a product-specific medication guide. Prescribers also must attest that they understand the risks TIRF medicines pose.
But according to Alexander and Sharfstein's findings, the FDA in 2013 supported relaxing the original language in these agreements -- now prescribers no longer have to affirm that their patients have been using opioids "around the clock" for at least a week and are "opioid tolerant."
A pharmacy claims study presented at the meeting indicated that only 58% of patients who started a TIRF medicine were opioid-tolerant, with tolerance defined by the average daily dose of opioids a patient received in the 7 days before a TIRF prescription.
And data from several sources suggested rates of abuse and adverse events had risen from the pre- to post-REMS period. But in many reports presented Friday, findings had small sample sizes or lacked details.
Of 549 deaths reported from August 2016 to August 2017, for example, 355 cases lacked sufficient evidence to determine whether they could have been caused by a TIRF. A selected analysis of 308 of those cases showed TIRF drugs were used for cancer pain in 43% of patients and for noncancer pain in 5%; the reason for TIRF prescription was not reported 52% of the time. In 81% of those selected cases, neither opioid tolerance or concomitant opioid medications were reported.
The initial TIRF REMS included Abstral, Actiq, Fentora, Lazanda, Onsolis, and generic equivalents; , a sublingual fentanyl spray from Insys Therapeutics, joined in January 2012 when it was approved by the FDA. In May 2018, the alleged Insys had paid kickbacks and encouraged physicians to prescribe Subsys for patients who didn't have cancer. The federal government also has pursued criminal cases against Insys employees and Subsys prescribers.
Outpatient TIRF use has dropped significantly since the REMS started: in 2017, fewer than 5,000 people received TIRF prescriptions, a small fraction of people with cancer pain, several physicians speculated. But of those 5,000 patients with TIRF prescriptions, 42% received Subsys.
"Are the numbers of events rising because of some defect in the REMS program? Or is it because we now have a different mix of TIRF products being used?" asked DSARM member Steven Meisel, PharmD, of Fairview Health System in Minneapolis. "This could all be an artifact on the basis of the fact that now we've got Subsys. There's no data one way or another on that, but it's certainly a possibility."
But Alexander told 乌鸦传媒 that agency oversight of TIRF drugs fell short in many ways.
"There are a number of steps that the FDA could have taken -- and still can -- to improve the safe use of TIRFs, including strengthening provider and patient education, improving the written patient-provider agreement form, and disenrolling prescribers who consistently put patients at risk by prescribing TIRFs for individuals lacking opioid tolerance," he said.
Alexander, who said he hopes his research will increase transparency in REMS programs in general, noted, "there is little publicly available information about the TIRF REMS or other REMS programs, meaning that patients, prescribers and policymakers are left guessing how well these programs are working, and how they can be improved."