It’s time to wake up from the REMS cycle

July 1st, 2019

The opioid crisis has shown the potential risks of unregulated prescribing of dangerous drugs. In the past few years, tens of thousands of Americans have died of drug overdoses, fueled in part by irresponsible prescribing of powerful synthetic opioids like fentanyl. How did fentanyl get into the hands of so many people that could be harmed? Part of the answer lies in a little-known program called Risk Evaluation and Mitigation Strategies (REMS).

What is a REMS?

When the Food and Drug Administration (FDA) wants to approve a medication that has the potential for misuse, abuse, or other risks, they can require a Risk Evaluation and Mitigation Strategy (REMS) for that drug. A REMS is a drug safety program designed to mitigate certain serious risks, by making sure the medication is being used safely. A REMS may require health care professionals to undergo training or certification before prescribing, patient education or dissemination of informational materials, confirmation of a certain diagnosis or condition before prescribing, limits on where the drug administered, and or other interventions.

When the Food and Drug Administration (FDA) approved fentanyl sprays and lozenges, products that are 100 times as potent as morphine, they recognized the potential danger for misuse and overdose, so they required a REMS. Prescribers and patients were informed that the product was only to be used for “breakthrough” cancer pain to patients who had developed a tolerance to opioids. Drug companies and the FDA would monitor prescribing to make sure that only this small subset of patients received the fentanyl, and drug companies were supposed to cut any providers who prescribed the drug inappropriately.

Unfortunately, that’s not how the REMS program worked in practice, as a JAMA study earlier this year revealed. Researchers at Johns Hopkins School of Public Health reviewed the FDA’s REMS documents from 2012 to 2017 and found that between 34.6% and 55.4% of patients who were prescribed fast-acting fentanyl were not meant to receive it. Although there was documentation that providers were prescribing fentanyl inappropriately, the drug makers did not revoke certification from any of them, allowing them to keep giving out the drug. 

This may not come as a surprise to those who followed the trial of opioid-maker Insys CEO John Kapoor. The trial revealed extremely unethical practices, such as encouraging employees to lie about a patient’s condition to approve insurance coverage of their fentanyl spray. Insys was in charge of monitoring and reporting non-compliant prescribers according to the REMS, but in practice they did the exact opposite, encouraging doctors to give out fentanyl inappropriately

The REMS drug safety system is clearly broken. It relies on the drug manufacturers to monitor how the REMS program is going, submit assessment reports to the FDA, and recommend any changes. The FDA’s role is to review the REMS assessment reports, determine if the REMS is meeting its goals, and if the REMS plan should be modified. The drug manufacturers have no incentive to strictly regulate the prescribing of their drug, because their goal is to sell as much of the drug as possible. In fact, drug companies spend millions to market their drug to doctors and patients, and to suggest off-label uses for drugs.

The REMS cycle

The intention to safely monitor the use of potentially dangerous drugs is a good one. However, some worry that the REMS system is being used to justify the approval of drugs for which the harm outweighs the benefit. For example, earlier this year, the FDA approved esketamine for treatment-resistant depression, which can have serious side effects and has a high potential for abuse. In fact, FDA panel members expressed significant concern about the potential for diversion (patients selling or giving away the drugs to others) and misuse.

What swayed these FDA panel members was the promise of a strict REMS program that would require esketamine to be administered only in a health care setting, so patients would not sell the drug to someone else or potentially overdose. Now that the Department of Veteran’s Affairs has approved the use of esketamine at VA clinics (a decision that has alarmed some politicians and VA officials), the strict REMS program promised by the makers of esketamine will be put to the test in the real world. 

Another recent example of REMS justifying an FDA approval was the approval of opioid painkiller Dsuvia, which is ten times more powerful than fentanyl. Although some FDA panelists and others noted that Dsuvia could easily be prescribed inappropriately or diverted illegally, the FDA approved it based on its “unique features” that would be useful on the battlefield. In response to criticism, FDA commissioner Scott Gottlieb “insisted the risk management program, known as a REMS, will ensure the drug is only used in a medically supervised settings.”

It is evident that the REMS system is not robust enough to combat the forces pushing for inappropriate use. The FDA should be in charge of developing REMS, monitoring prescriptions, and given real methods of enforcement. Drug companies should not be policing themselves; we cannot keep putting the fox in charge of the henhouse. And there should be restrictions on drug company marketing for any drug that requires a REMS, including giving money to doctors for speaker fees or continuing medical education. 

Without substantive changes to the REMS program, we will continue with the cycle of dubious drug approval, non-enforced REMS, immense harm, then promises from drug companies to do better. Rinse, repeat. After what we know happened with fentanyl, can we really make the same mistake again and again?