A fast-acting class of fentanyl drugs approved only for cancer patients with high opioid tolerance has been prescribed frequently to patients with back pain and migraines, putting them at high risk of accidental overdose and death. The New York Times reports that this is according to documents collected by the US Food and Drug Administration, which established a distribution oversight programme in 2011 to curb inappropriate use of the dangerous medications, but entrusted enforcement to a group of pharmaceutical companies that make and sell the drugs.
Some of the companies have been sued for illegally promoting other uses for the medications and in one case even bribing doctors to prescribe higher doses, the report says. About 5,000 pages of documents, obtained by researchers at the Johns Hopkins Bloomberg School of Public Health through the Freedom of Information Act as how that the FDA had data showing that so-called off-label prescribing was widespread. But officials did little to intervene.
“If any opioids were going to be tightly regulated, it would be these,” Dr Andrew Kolodny, an opioid policy researcher at Brandeis University, who was not involved in the investigation, said in the report. “They had the fox guarding the henhouse, people were getting hurt – and the FDA sat by and watched this happen.”
Officials at the FDA said they had reviewed evidence indicating that many patients without cancer were given the drugs. But they said that piecemeal data from various stakeholders – prescriber surveys, insurance claims and industry reports – made it difficult for the agency to measure potential harm to patients. “The information we have isn’t very good, but it seems to indicate people who aren’t cancer patients are getting this and people who aren’t opioid tolerant are getting this,” Dr Janet Woodcock, the director of the Centre for Drug Evaluation and Research at the FDA, said. “There has been a tremendous back-and-forth with companies on how to get better information.”
The report says the class of drugs – quick-absorbing fentanyl sprays, tablets and lozenges called TIRFs (for transmucosal immediate-release fentanyl) – contain a narcotic up to 50 times stronger than heroin and up to 100 times stronger than morphine. Examples include Actiq and Fentora, made by Cephalon, and Subsys, made by Insys Therapeutics.
The report says the FDA began approving the drugs outside of hospital settings in 1998 to treat cancer patients with “breakthrough” pain – sudden, sharp rushes of pain that overwhelm even a round-the-clock regimen of other opioids. But for people taking the drugs, maintaining a round-the-clock regimen is vital: Without it, patients’ tolerance to them decreases, and they are at risk for accidental overdose, respiratory depression and death.
To restrict the dangerous drugs only to “opioid-tolerant” cancer patients, the FDA in December 2011 established a safety programme, called a risk evaluation and mitigation strategy, for a consortium of TIRF manufacturers. The report says the programme required doctors to undergo training for prescribing TIRFs and to sign a form saying they understood that prescribing to other patients can be dangerous.
To administer the programme, the consortium hired McKesson, a large national distributor that supplies drugs, including TIRFs, to pharmaceutical retailers. According to the report, McKesson said it was doing its job as a third-party administrator of the programme and noted that its requirements were “developed jointly by the manufacturers and the FDA with ultimate approval resting with the FDA. McKesson administers the programme according to these FDA requirements.”
The report says safety programme was discussed in a meeting of an FDA advisory committee, and the Johns Hopkins researchers submitted written testimony.
The report says TIRF sales are lucrative: One prescription for a month’s worth can cost more than $30,000. Woodcock said a stricter oversight programme would be “extremely onerous” and that the harm caused by the drugs is difficult to measure, since “all drugs have risks and cause harm.”
With chronic back pain from two car accidents and a fibromyalgia diagnosis, Sarah Fuller, 31, needed pain medication. The report says she scheduled her medical appointment for a Monday in January 2015, a day her father took off from his job as a baker to accompany her. They met with a doctor – and, unexpectedly, a sales representative from Insys, maker of Subsys, an under-the-tongue narcotic spray. “At no time were we told this drug was for terminally ill cancer patients,” said her mother, Deborah Fuller. “She had complete trust in doctors. I don’t know how they put their heads on their pillows at night.” The report says at her death the fentanyl in her blood was between 15 and 20 times the appropriate level, according to a toxicology report.
The report says the FDA documents obtained by researchers included a survey by the industry group in 2013 in which nearly 40% of TIRF prescribers said they had used the drug to treat chronic pain in patients who did not have cancer, like Fuller. In the survey, 42% of pharmacists stated that the drugs were appropriate for those ailments.
In another survey three years later, in February 2017, almost one in five TIRF prescribers (18%) and almost one in two patients (48%) said they believed, wrongly, that the medications were formally approved by the FDA to treat illnesses other than cancer.
Just over half of patients prescribed the drugs were not already taking a round-the-clock opioid regimen, and therefore were susceptible to an accidental overdose, according to an analysis of commercial health plan claims for more than 25,000 patients by the industry group in 2016. A follow-up analysis had a similar result.
The report says in fact, in an effort to address “concern regarding patient access,” the industry group in 2013 had taken steps to make it easier to prescribe to patients without opioid tolerance. The group removed protective language from a mandatory patient-prescriber agreement form attesting that the “patient is opioid tolerant,” and instead required a prescriber only to indicate that “I understand” the meaning of opioid tolerance. The form was also altered to omit a clause that had required patients to affirm that they were already using a round-the-clock opioid regimen.
“It is not open for debate that the risk of these drugs among patients who lack tolerance is unacceptably high. It’s quite clear-cut,” said Dr Caleb Alexander, a physician who co-directs the Centre for Drug Safety and Effectiveness at Johns Hopkins and led the research on the documents.
The report says according to an internal FDA memo, the agency and the industry group held several teleconferences in 2017 to discuss plans to study adverse events in patients who were not opioid-tolerant, as well as accidental poisonings of children.
With companies “actively subverting” the oversight and safety programme, the FFA had authority to mandate a substantial reformation of it, said Dr Joshua M Sharfstein, a former principal deputy commissioner of the agency now at Johns Hopkins, who reviewed the documents. The agency could have sharpened prescriber training programmes and agreement forms, he said, or investigated prescribers. At the least, he and other researchers said, the agency could have made the data from the programme public. “With poor transparency and accountability, policymakers and patients are left guessing,” Alexander said. “This could have all come out years ago.”
The report quotes Scott Gottlieb, the commissioner of the FDA as saying: “We’re taking the issue of how we manage the safe use of these products to our advisory committee, to bring transparency to what we know about how well these post market safety programs are working and to get their advice on how we could strengthen these restrictions to better protect patients.”
The FDA has taken a hands-off approach in the past. The report says the agency tasked the agency Purdue Pharma in the early 2000s with leading a risk management programme for OxyContin, its own product. In 2007, the company pleaded guilty and paid more than $600m in fines related to misleading marketing.
When the narcotic pain reliever tramadol was approved by the FDA in 1995, it allowed Ortho-McNeil of Johnson & Johnson to fund a steering committee to monitor drug abuse instead of classifying the drug as a controlled substance. After two decades of mounting abuse, the report says tramadol was reclassified as a controlled substance in 2014.
In recent years, drug companies have faced legal action for falsely advertising TIRFs. Cephalon paid over $400m in fines for false marketing of its products, including its TIRF lollipops, called Actiq, to treat migraines.
The owner of Insys Therapeutics, which makes Subsys – and five prescribing doctors – were charged in a bribery scheme to boost off-label prescribing. McKesson, the distributor, paid a $150m settlement for failing to report suspicious opioid orders, the report says.
Carolyn Markland of Jacksonville, Florida, wanted to be able to lift her grandchildren despite a degenerative spinal disease. Her doctor prescribed a dose of Subsys to her in July 2014. Markland suffered respiratory distress the following morning and died of drug toxicity, according to court documents.
Joey Caltagirone of Philadelphia was prescribed his first of almost 6,000 Actiq lollipops for migraines in 2005, when he was 30. He developed a lasting addiction, was prescribed methadone to curtail it, and died of methadone toxicity in 2014, according to court records.
Deborah Fuller, Sarah’s mother, is still struggling with the loss of her daughter. “If she had died from disease, I wouldn’t be as angry,” she said. “But knowing how she died – and the manipulation that went on – I get angry. I just don’t know what to do with all that anger.”The New York Times report