F.D.A. Failed to Ensure Safe Prescribing of Opioids, Documents Show

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 F.D.A. 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 F.D.A. was never able to determine whether the program worked, researchers at the 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 F.D.A.’s own review process, the agency never insisted on improvements to the program, called a risk evaluation and mitigation strategy, or R.E.M.S. 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 F.D.A. 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 F.D.A. to adopt stronger controls.

He called the program “a really good example of the way F.D.A. has failed to regulate opioid manufacturers. If F.D.A. 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 the Hopkins researchers, who relied on thousands of pages of internal F.D.A. 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.

Asked for a response, the F.D.A. had no immediate comment.

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 F.D.A. 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 F.D.A. 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 F.D.A. moved forward anyway.

A 2013 report by the inspector general of the Department of Health and Human Services found that only 14 percent of the safety programs reviewed by the F.D.A. 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 F.D.A. 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 F.D.A. wanted 60 percent of prescribers to take the classes developed as part of the program. But only about 27 percent 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, the 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 F.D.A. 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 F.D.A. 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 F.D.A. 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 the Johns Hopkins Bloomberg School of Public Health, and one of the paper’s authors, said it was “extraordinarily important” for the F.D.A. to not only ensure safe prescribing programs are effective, but to keep the public informed if they are not. Dr. Sharfstein was the principal deputy commissioner of the F.D.A. 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 F.D.A. began requiring safety programs for all opioid painkillers — not just the long-acting formulations — and updated its blueprint for the programs’ prescriber training. But Dr. 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 United States until heroin, and then fentanyl, surpassed them over the last decade. The national opioid prescribing rate starting 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.

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