With the country in the throes of the opioid epidemic, the Food and Drug Administration started a risk evaluation and mitigation strategy (REMS) in 2012 to restrict prescribing of quick-absorbing fentanyl to appropriate patients. At the time, these were the most potent and riskiest opioid-based medications available. The program should have worked, but was undermined by one company, Insys, whose top executives were convicted last week of bribing doctors to prescribe this type of painkiller to people who weren’t supposed to get it.
These fast-acting fentanyl medications, also known transmucosal immediate-release fentanyl (TIRF), are taken by mouth. They were approved to treat breakthrough cancer pain. In the months after the risk evaluation and mitigation strategy known as TIRF-REMS was launched, there were large decreases in prescribing this type of fentanyl. But as we and colleagues reported in JAMA Network Open, what then followed is a cautionary tale that’s emblematic of the influence the pharmaceutical industry can have over physicians’ clinical decisions.
While some TIRF products were already part of restricted-use programs, most of those prescribed in the U.S. were older, generic products and not restricted. These drugs were only supposed to be prescribed to patients with cancer pain, but were being widely prescribed for those without cancer. And warnings issued by the FDA had linked several deaths to their use.
The FDA program included the strongest protective action the agency could have taken short of banning the drugs. Doctors who wanted to prescribe these powerful medications needed to pass a test to demonstrate they knew which patients were appropriate candidates for them (those with cancer for whom less powerful opioids were not effective). Patients needed to review information on the risks of TIRF. Pharmacies had to commit to dispense this kind of fentanyl only to verified patients with prescriptions from participating prescribers. And drug distributors had to commit to sell these products only to approved pharmacies.
It was, and still is, the strictest risk evaluation and mitigation strategy the FDA has undertaken related to opioids, and at first it seemed to work.
We evaluated the impact of the program on Medicare beneficiaries who received prescription drug benefits through Medicare’s Part D program from 2010 through 2014 — approximately two years before the program started and two years after. In its first months, there was a 27% decline in fentanyl prescriptions. After a year, though, prescribing rebounded to pre-program levels.
We can’t be sure why the rebound occurred, but we have some ideas. It might simply have taken time for prescribers, patients, and pharmacies to sign up and adjust to the program before everyone returned to the status quo. That explanation doesn’t really fit, though, because there were large decreases in both the number of prescribers and the number of prescriptions after the TIRF-REMS was implemented, yet there was no subsequent increase in the number of prescribers when fentanyl prescriptions rebounded.
A more likely explanation was the 2012 approval of Subsys, a quick-absorbing fentanyl spray that soon dominated the market. Its maker, Insys, used fake medical lectures, bribes, and even falsifying patients’ medical histories to make it look like they had cancer. Several people have been convicted, and some are already in prison for these schemes, including doctors, physician assistants, and former and current Insys executives, including CEO John Kapoor. As researchers who study the promotion of prescription drugs, we found the Insys actions to be eye-opening, but not shocking.
Payments for fake lectures may be attention-grabbing, but most drug marketing is far more mundane, like a drug company representative bringing lunch to a doctor’s office to promote the company’s products. Most payments by pharmaceutical manufacturers to doctors are for meals and beverages, and average just $13 in value. Yet even small payments for lunch are associated with changes in prescribing.
In a study of prescriptions for oral anticoagulants and non-insulin diabetes drugs, we found that an average $13 payment from a drug maker was associated with an additional 100 days of prescribing of the promoted drug. Other studies have found correlations between payments and prescribing for cholesterol and eye medications. We also found that payments from opioid manufacturers were associated with patients receiving higher doses of opioids.
Outrage over what Insys did to boost Subsys sales of won’t fix the underlying problem of influence peddling by pharmaceutical manufacturers, just like the outrage over Martin Shkreli jacking up the price of a generic medication did not fix the underlying problems that contribute to high drug prices. Instead, what’s needed is bold action to curtail the legal world of prescriber influencing.
First, we believe all payments to prescribers that are not related to research should be banned so clinicians can care for their patients without the burden of potentially being influenced by pharmaceutical manufacturers. Second, when implementing risk reduction programs such as the TIRF-REMS, real-time monitoring is needed. That way, if the program is not achieving its intended goals, rapid modifications can be made, including penalties for those subverting it. Third, for dangerous drugs such as opioids, we believe the FDA should be more aggressive in investigating and penalizing companies that illegally market their products for off-label use. Fourth, we urge Congress to ensure that the FDA and law enforcement have adequate resources for faster, more aggressive responses to bad actors like Insys.
In March, the FDA announced plans to strengthen the TIRF-REMS program by requiring prescribers and pharmacies to verify and document patients’ tolerance for opioids (based on their prior opioid prescriptions) before each prescription is written and filled. Also planned is a new database that will follow patients taking these drugs and enable better monitoring for safety issues. We applaud these efforts, and hope these changes, along with the increased scrutiny of past, present, and future marketing efforts by pharmaceutical manufacturers, will better protect patients’ and the public’s health.
William Fleischman, M.D., is the director of quality and implementation science in the Department of Patient Safety and Quality at Hackensack Meridian Health and previously served as a medical officer in the Center for Program Integrity at the Centers for Medicare and Medicaid Services. Joseph S. Ross, M.D., is an associate professor of medicine and public health at Yale University and receives research funding from the Food and Drug Administration. The views expressed here are those of the authors and do not necessarily represent the views of their employers, CMS, or the U.S. government.