The research, published Tuesday in JAMA: The Journal of the American Medical Association, found that the US Food and Drug Administration and opioid manufacturers failed at multiple levels to adequately monitor the restricted use of these types of fentanyl as part of a federal program — and that few substantive changes were made even after officials discovered problems.
“We found alarming use of these products in patients who never should have received them,” said G. Caleb Alexander, a senior author of the study and director of the Johns Hopkins Bloomberg School of Public Health. “The prescribing of this medicine was supposed to be closely monitored and contained but was not.
“What we found was that several years after the program was started, there were alarming deficiencies identified, and yet little was done by the FDA and drug manufacturers to effectively address these problems.”
The study was based on a review of 4,877 pages of FDA reports and other documents obtained through the Freedom of Information Act from 2012 to 2017. It looked at a class of fentanyl known as transmucosal immediate-release fentanyls or TIRFs, meant only for cancer patients already on around-the-clock opioids with breakthrough pain.
This type of fentanyl — typically delivered through lozenges, sprays and tablets — goes into the bloodstream within seconds. The FDA created the program in 2011 to monitor prescribing due to its potency.
The goal of the program was to reduce the risk of adverse outcomes, misuse, abuse, addiction and overdoses by strictly monitoring whom it was prescribed to and limiting that to a small subset of cancer patients.
The study quoted the FDA as saying in the documents that the program was “not meeting its overall goal or most of the objectives.”
This type of fentanyl is “one of the most highly potent and rapidly acting opioids on the market,” Alexander said, adding that it carries “an unacceptably high risk of fatal overdose” for patients outside of those it’s intended for.
But the study found that thousands of patients received the drug who shouldn’t have. In fact, it says, more than half of those who used the restricted fentanyl should never have been prescribed it.
Over one four-year period, 12,916 of 25,322 (51%) patients who were prescribed these fentanyls were “opioid-nontolerant,” meaning they shouldn’t have been prescribed them. The FDA requested more data for a five-year report, which found that between 34.6% and 55.4% of patients with the prescriptions were opioid-nontolerant, according to the study.
“These drugs are dangerous enough, they should never be used in patients who aren’t already on around-the-clock opioids,” Alexander said.
Alexander said the study wasn’t designed to be able to tell what harm might have been done to the patients who took the fentanyl. But he said everyone should be concerned about the lack of oversight of the program that was meant to restrict its use because “there’s a real risk of fatal overdose.”
“The FDA and opioid manufacturers share the blame for these lapses,” he said.
Andrew Kolodny, the co-director of the Opioid Policy Research Collaborative at Brandeis University, found the study results “very disturbing.”
“What this paper shows is a total failure by the FDA to protect the public,” said Kolodny, who was not involved in this research. “Despite overwhelming evidence of problems with TIRFs, the FDA has done nothing to change and is continuing the status quo.
“The majority of the TIRF patients don’t have cancer and aren’t tolerant of opioids. This is very disturbing.”
FDA spokesman Michael Felberbaum said the agency shares the concerns raised in the study as to whether the program is “working as intended.”
“The agency has been actively assessing the recommendations of our advisory committee on the effectiveness of the [program] and necessary changes,” he wrote in an email. “The FDA will soon be sharing planned next steps, including intended modifications to the current TIRF REMS, to make sure the program is working to mitigate the risks of these medicines and that they’re prescribed only to opioid-tolerant patients, and that those patients understand the risks and how to use TIRF medicines safely.”
In August, the agency held a public advisory committee meeting to look into the latest data about the fentanyl program and to discuss the patterns and adverse events associated with the drugs. At the time, Commissioner Dr. Scott Gottlieb tweeted that the agency knows “there’s more that needs to be done. Making sure this program is working to mitigate the risks of these medicines and that they’re appropriately prescribed is a high priority.”
Gottlieb noted “gaps in data on use of these products and adverse events” were presented to the FDA at the meeting and that he was committed to make improvements and “align our approach to strike better balance between access and safety.”
Raeford Brown, an anesthesiologist at the University of Kentucky who attended the FDA’s August meeting, said the new study “accurately reflects what we found.”
“The TIRF [program] was quite ineffective in providing safety for this class of opioids,” said Brown, who was nominated to serve on the FDA advisory committee in 2015.
He said the advisory committee found that more than 50% of the time, this class of fentanyl was being “prescribed for everything but cancer pain.”
“Arithritis — really anything you can think of,” he said.
The new study comes as America remains gripped in an opioid epidemic. In 2017, more than 47,000 people died from opioid overdoses. The Trump administration has declared a public health emergency over the opioid epidemic, and the president has signed sweeping legislation aimed at combating the problem.
Five high-ranking executives of Insys — one of the makers of a fentanyl called Subsys that is part of the federal program — also stand accused of bribing doctors in exchange for prescriptions of the drug meant for cancer patients. It is the first criminal trial of executives of opioid makers, putting on front and center their tactics and contributions to the nation’s opioid epidemic. The five executives have denied all wrongdoing.
According to media reports, jurors last week were shown a video of Insys employees dancing and rapping about how great the product is.
“I got new patients, and I got a lot of ’em,” they rap.
At one point, a person dressed as a purple-and-white Subsys bottle joins in as the employees dance around the bottle. “If you want to be great, listen to my voice. You can be great, but it’s your choice.”
Toward the end of the video, two employees sitting at a coffee shop high-five. “That’s going to kill, man,” one said.
Kolodny said there’s nothing funny about the potency of these fentanyls: “These are exceptionally dangerous medications.”
Brown added, “it’s not a joke beyond any stretch of the imagination, because these drugs can kill. Under no circumstances should people be laughing and joking about this.”