WASHINGTON – Newly unearthed documents show that the Food and Drug Administration failed to use its policing powers to make sure a program to curb improper prescribing of opioids was effective, researchers say.
The lax oversight, they point out, occurred as the epidemic was growing and tens of thousands of people were dying from overdoses each year.
In 2011, the FDA began asking the makers of OxyContin and other addictive long-acting opioids to pay for safety training for more than half the physicians prescribing the drugs, and to track the effectiveness of the training and other measures in reducing addiction, overdoses and deaths.
But the FDA was never able to determine whether the program worked, researchers at Johns Hopkins Bloomberg School of Public Health found in a new review, because the manufacturers did not gather the right kind of data. Although the agency’s approval of OxyContin in 1995 has long come under fire, its efforts to ensure the safe use of opioids since then have not been scrutinized nearly as much.
The documents show that even when deficiencies in these efforts became obvious through the FDA’s own review process, the agency never insisted on improvements to the program, called a risk evaluation and mitigation strategy, or REMS. The new research was published Monday in JAMA Internal Medicine.
“What’s surprising here is the design of the program was deficient from the start,” said Caleb Alexander, the senior author of the study, who serves as a paid expert witness in litigation against opioid manufacturers and distributors. “It’s unclear why the FDA didn’t insist upon a more scientifically rigorous evaluation of this safety program.”
Dr. Andrew Kolodny, the co-director of opioid policy research at the Heller School for Social Policy and Management at Brandeis, said the safety program was a missed opportunity. He is a leader of a group of physicians who had encouraged the FDA to adopt stronger controls, and a frequent critic of the government’s response to the epidemic.
He called the program “a really good example of the way FDA has failed to regulate opioid manufacturers. If FDA had really been doing its job properly, I don’t believe we’d have an opioid crisis today.”
In 2007, Congress gave the agency the authority to require drug manufacturers to train physicians to safely prescribe certain dangerous drugs, and to monitor the companies’ performance. The bill, lawmakers said, was influenced by agency lapses in oversight of drugs like Vioxx, a popular painkiller withdrawn from the market in 2004 after it was found to pose a substantial heart risk.
The main goals of the 2011 program for long-lasting opioids were to train more than half of an estimated 320,000 doctors who prescribed the drugs on how to do so safely, and to inform patients about the significant risks of taking the drugs.
But Hopkins researchers, who relied on thousands of pages of internal FDA documents obtained through the Freedom of Information Act, found the agency repeatedly could not determine whether the companies’ safety strategies were working because of poor study designs, which the agency itself had approved.
In a statement, Jeremy Kahn, a spokesman for the Food and Drug Administration, disputed the authors’ contention that the agency had abandoned efforts to evaluate the success of its program, pointing to a number of steps it had taken in the last three years to study the effects of education on prescribing patterns.
“We understand and acknowledge that there is still much work to do to bring down opioid abuse,” Kahn said in the statement.
About 60 drugs or classes of drugs are subject to such risk-management programs, including the narcolepsy drug sodium oxybate, the antipsychotic drug olanzapine and the acne drug isotretinoin, which used to be branded as Accutane and can cause severe birth defects.
But more than a decade after Congress authorized such safety programs, there is sparse evidence of their effectiveness. And the FDA has come under fire not only for putting pharmaceutical companies in charge of monitoring their own safety practices, but for not doing enough to ensure the quality of the prescriber training it requires the companies to pay for.
There were early warning signs that the safety program for long-acting opioids had weaknesses. In 2010, an FDA advisory committee of experts in the treatment of pain voted 25-10 against the proposed program design. Committee members suggested that the agency require training for prescribers, and that it redesign curriculums to lessen industry influence. The FDA moved forward anyway.
A 2013 report by the inspector general of the Department of Health and Human Services found that only 14% of the safety programs reviewed by the FDA met their goals. And another inspector general report last year noted that the agency did not have the authority to take enforcement actions against companies that don’t provide it with enough information to assess their safety programs — a common problem, it found.
“If FDA does not have comprehensive data to monitor the performance” of the program, the report said, “it cannot ensure that the public is provided maximum protection from a drug’s known or potential risks.”
In the case of long-acting opioids, the FDA wanted 60% of prescribers to take the classes developed as part of the program. But only about 27% did so within the specified time frame, 2012 to 2016. Surveys conducted by manufacturers found “modestly greater” knowledge of safe prescribing practices among doctors who took the classes than among those who did not. But opioid prescribing was dropping overall at that point, and the surveys were not designed in a way that could determine whether doctors who took the classes prescribed less as a result.
Perhaps most important, researchers found that manufacturers didn’t do a good job of assessing whether the safety program led to fewer overdoses and deaths. Instead they relied on broad national data that made no distinction between patients of doctors who had taken the safety classes and those who had not — a problem the FDA pointed out repeatedly, in the third, fourth and fifth years of the program.
Last year, the same Hopkins researchers found failings in a similar safety program the FDA established in 2011 to curb inappropriate use of a small class of fast-acting fentanyl drugs meant only for cancer patients. The program required doctors who prescribed those drugs to take classes and sign forms saying they understood the dangers of prescribing to patients who did not have cancer, but many continued prescribing the drugs much more widely.
The researchers also found that the FDA did nothing to sharpen the safety program for the drugs, known as transmucosal immediate release fentanyls, even though it was aware of the broader prescribing. Top executives of one manufacturer, Insys Therapeutics, were criminally convicted in May of bribing doctors to prescribe and give sham educational talks about its drug Subsys, and of misleading insurers about patients’ need for the drug.
Extended-release, long-acting opioids are a much larger drug class, used by many more people. In addition to OxyContin, they include methadone and the extended-release versions of hydrocodone, hydromorphone and morphine, as well as fentanyl patches and buprenorphine, which, like methadone, is not only for pain but to treat withdrawal in people addicted to opioids.
These drugs are prescribed for pain severe enough to require daily, around the clock, long term opioid treatment. But they have often been diverted for illicit use, with many people crushing and snorting or injecting them for a particularly potent, dangerous high.
Dr. Joshua Sharfstein, a vice dean at Johns Hopkins Bloomberg School of Public Health, and one of the paper’s authors, said it was “extraordinarily important” for the FDA to not only ensure safe prescribing programs are effective, but to keep the public informed if they are not. Sharfstein was the principal deputy commissioner of the FDA from March 2009 to January 2011, and said that while he was not deeply involved in developing the safety program for long-acting opioids, “I wish I had focused on it more.”
In 2017, the FDA began requiring safety programs for all opioid painkillers — not just the long-acting formulations — and updated its blueprint for the programs’ prescriber training. But Kolodny said the revised blueprint still implies that long-acting opioids are safe and effective for chronic pain, contradicting a growing body of research.
Prescription painkillers were the main cause of overdose deaths in the U.S. until heroin, and then fentanyl, surpassed them over the last decade. The national opioid prescribing rate started rising steadily in 2006 and peaked in 2012, at 81.3 prescriptions per 100 people, according to the Centers for Disease Control and Prevention. By 2017, the prescribing rate had fallen to the lowest it had been in more than a decade, at 58.7 prescriptions per 100 people.
But prescribing rates remain high in certain regions, and even as deaths from prescription opioids have dropped, deaths from illicitly manufactured fentanyl have continued to rise.