The Food and Drug Administration and manufacturers did not take action when evidence emerged that potentially lethal fentanyl products were being inappropriately prescribed to patients, new research from the John Hopkins Bloomberg School of Public Health shows.
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 revealed that, even as evidence emerged that as many as half of patients were taking dangerous medications known as TIRFs that should never have been prescribed to them, the FDA and fentanyl makers did not review prescribing records of even a single physician to consider disqualifying them from the program, which would have prevented them from prescribing the products.
The report comes as America's opioid epidemic continues to claim tens of thousands of lives annually, including nearly 50,000 overdose deaths in 2017, the latest year for which statistics are available. More than two million people living in the U.S. have an active opioid use disorder, and as many as two to three million additional individuals have a lifetime history of such a disorder.
Millions more report non-medical use of opioids, yet may not fulfill formal diagnostic criteria of an opioid use disorder. There is widespread consensus that one major driver of the opioid epidemic has been the oversupply of prescription opioids.
The study focused on Transmucosal Immediate-Release Fentanyls, or TIRFs, which are more dangerous than most prescription opioids on the market due to their very high potency and rapid onset. TIRFs are designed to get into the bloodstream within seconds, and because of their risks, were approved by FDA only for adult cancer patients "who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain."
In late 2011, the FDA started a Risk Evaluation and Mitigation Strategy program that required all doctors, pharmacists and patients to certify their understanding of the risks and proper use of these drugs in order to prescribe, dispense or take a TIRF product.
The program consisted of a "closed distribution system," the most stringent type of REMS the FDA uses. TIRF makers were also required to submit annual reports to the FDA demonstrating their compliance with the REMS risk requirements.
As part of its monitoring program, TIRF makers annually surveyed a sample of TIRF prescribers, pharmacists and patients to help determine if they understood TIRF restrictions and if there was significant unsafe prescribing.
Most survey respondents said they understood that TIRFs are never to be prescribed to patients unless they're already tolerant to opioids. But there were some "red flags" suggesting significant potentially inappropriate prescribing.
In the survey reported at the end of the program's second year in 2013, for example, 39.4 percent of responding TIRF prescribers reported having prescribed TIRFs "off label" for patients with chronic, non-cancer pain -- and similar proportions of prescribers responded this way in the third- and fourth-year surveys.
Following the third-year report from the TIRF makers in 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, which were reported four years after the REMS program began, showed very high levels of inappropriate prescribing -- 51 percent of patients receiving TIRFs were defined as lacking opioid tolerance.
In a subsequent claims-based analysis submitted for their fifth-year report in 2016, the TIRF makers once again found that, depending on the specific TIRF drug, between 34.6 and 55.4 percent of TIRF patients lacked opioid tolerance.
The FDA did not immediately respond to a request for comment.
WHAT ELSE YOU SHOULD KNOW
Although TIRF makers outlined a plan in which they would identify, investigate and even disenroll prescribers who inappropriately prescribed TIRFs to patients without opioid tolerance, the FDA noted in the two-year report, and each subsequent one, that there were no instances in which such prescribers were identified, reported to the FDA or deactivated from the REMS program.
The FDA, in its own fifth-year evaluation of the TIRF REMS program, concluded that it "is not meeting its overall goal or most of the objectives," and requested that TIRF makers do further analyses of TIRF prescribing.
Even the methods by which opioids are administered have come under scrutiny. Findings from May 2018 suggest that while many opioids are administered intravenously, the practice could result in more side effects and potential addiction, while not being more effective than other forms of administration.
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