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The FDA did not take action when evidence emerged that potentially lethal fentanyl products were being prescribed inappropriately to patients, researchers suggested.

Based on a review of 4,877 pages of FDA reports and other documents obtained through the Freedom of Information Act (FOIA), as many as half of the patients taking highly potent transmucosal immediate-release fentanyl (TIRF) drugs should not have been prescribed them, reported G. Caleb Alexander, MD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues in .

And when this evidence emerged, the FDA and fentanyl makers did not review prescribing records of any physicians or consider disqualifying them from a special certification program to prevent them from prescribing the drugs, Alexander said.

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 designed to be limited to opioid-tolerant patients.

"Not only did we see that large numbers of patients were unsafely prescribed these products, but we also found that the FDA and manufacturers missed opportunities to revise the program once these deficiencies were identified," Alexander told 麻豆传媒.

"Rather than having rapid, iterative assessments and revisions to the program to ensure safe use, we found that the identification of unsafe, off-label prescribing was delayed; it didn't occur until 3 years in," he added. "And even when it occurred, even the FDA and manufacturers failed to substantially overhaul the program."

Under the FDA's Risk Evaluation and Mitigation Strategy (REMS) for the drugs, 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. Prescribers also must attest that they understand the risks TIRF medicines pose.

The TIRF REMS program was approved in December 2011. In their analysis, Alexander and colleagues examined six annual REMS assessment reports from 2012 to 2017, the FDA evaluations of these reports, and FDA correspondence about safety issues. They found:

• In the second-year report (2013), 39.4% of responding prescribers reported prescribing TIRFs off-label for patients with chronic, non-cancer pain. Comparable levels of prescribers responded this way in subsequent years.
• After the third-year report (2014), the FDA asked TIRF makers to analyze health insurance claims to provide a clearer picture of the level of inappropriate prescribing.
• These claims-based assessments, provided as part of the fourth-year report (2015), showed 51% of patients who received TIRFs (12,916 of 25,322 people) lacked opioid tolerance.
• The fifth-year report (2016) showed the problem persisted: on a product-by-product basis, between 34.6% and 55.4% of TIRF patients lacked opioid tolerance.

While surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge about proper TIRF prescribing, some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use, Alexander and colleagues concluded.

"Despite these findings, the FDA did not require substantive changes to the program," they wrote.

The analysis mirrors findings presented in August 2018, when FDA advisory committee members reviewed problems in TIRF REMS program that seemingly had been apparent for years.

"These findings -- that many people who received these TIRF products did not have breakthrough cancer pain, or in fact did not have cancer, and nearly half were not tolerant to opioids -- show that the REMS was ineffective at doing what it was supposed to do, which is protecting the public," said Raeford Brown Jr., MD, chair of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee.

"Fifty percent is not good enough when you're talking agents that can kill people almost instantly," Brown told 麻豆传媒.

The initial TIRF REMS included Abstral, Actiq, Fentora, Lazanda, Onsolis, and generic equivalents. Subsys, a sublingual fentanyl spray from Insys Therapeutics, joined in January 2012 when it was approved by the FDA.

During the period covered by the study, Insys was found to have engaged in a nationwide to prescribe Subsys for off-label use. "The U.S. Attorney's Office of the District of Massachusetts brought a criminal indictment against seven executives at the company for this scheme and has secured ," noted Ameet Sarpatwari, JD, PhD, of the Program on Regulation, Therapeutics, and Law at Brigham and Women's Hospital and Harvard Medical School, and Gregory Curfman, MD, JAMA deputy editor, in an .

"But there's a thread that suggests the problem is not just with Insys," Alexander noted. The follow-up claims analysis showed that from 34.6% to 55.4% of patients lacked opioid tolerance, depending on the specific TIRF drug, he pointed out: "That means that even the lowest level of use among opioid-naïve patients was far higher than should ever have occurred."

The study has several limitations, the authors noted. Some of the information requested was redacted, and the context for regulatory decisions may not have been visible. There may be additional documents not provided that could give a clearer picture of the history or relevant advice provided by the FDA.

The documents viewed also did not measure the potential burdens the REMS program placed on prescribers, pharmacists, and patients, they added, and did not assess whether additional requirements might pose undue restrictions in the future.