FDA and drugmakers failed to take action when a federal program designed to ensure potent fentanyl painkillers are distributed and prescribed appropriately showed providers were inappropriately prescribing the drugs to patients who did not qualify for them, according to a study published Tuesday in JAMA.
For the study, researchers from Johns Hopkins Bloomberg School of Public Health analyzed 4,877 pages of FDA reports, such as FDA's Risk Evaluation and Mitigation Strategy (REMS) assessment reports from 2012 to 2017.
The researchers focused their review on transmucosal immediate-release fentanyl (TIRF) drugs, which are intended to treat so-called "breakthrough pain" in opioid-tolerant adults with cancer. According to the Washington Post, the drugs are about 100 times more powerful as morphine, and they "pose a serious risk" of addiction, misuse, and overdose for individuals who have not built up a tolerance to opioids. They also can have life-threatening adverse effects, such as respiratory depression.
FDA in 2011 approved a REMS program for TIRF drugs that requires all physicians, pharmacists, and patients who are involved with either dispensing, prescribing, or using the drugs to certify they understand both how to use the drugs and the associated risks. Under the REMS program, FDA and drugmakers agreed to monitor TIRF prescriptions, and FDA is required to prohibit providers from prescribing TIRF drugs if they are found to have inappropriately prescribed them to non-opioid tolerant patients.
The researchers noted their study had several limitations. For examples, the researchers noted that some of the information they reviewed was redacted, which means they might not have been able to review the full context for FDA's regulatory decisions. The researchers also said they did not assess the potential burden FDA's REMS program placed on prescribers and patients.
The researchers found as many as 50% of patients taking TIRF drugs should not have received a prescription for the drugs. Further, the researchers found that when evidence of inappropriate prescriptions first emerged, FDA and fentanyl makers failed to address the issue by reviewing physicians' prescribing records or considering barring physicians from prescribing the drugs.
Caleb Alexander, one of the study's authors and co-director of the Center for Drug Safety and Effectiveness at the Johns Hopkins University Bloomberg School of Public Health, said, "FDA and manufacturers missed opportunities to revise the [REMS] program once" they identified deficiencies in the program. For example, the researchers found FDA did not revise the REMS program after the agency found that:
- In 2013, 39.4% of prescribers reported prescribing TIRF drugs off-label to patients with chronic, non-cancer pain;
- In 2015, 51% of non-opioid tolerant patients received TIRF drug prescriptions; and
- In 2016, between 34.6% and 55.4% of non-opioid tolerant patients received TIRF drug prescriptions.
Alexander said, "Rather than having rapid, iterative assessments and revisions to the program to ensure safe use," the researchers "found that the identification of unsafe, off-label prescribing was delayed," and it did not "occur until three years in." Alexander added that, when such identifications did occur, "FDA and manufacturers failed to substantially overhaul the [REMS] program."
In addition, Alexander said while "[m]anufacturers agreed to a sort of comprehensive prescriber monitoring," that requirement "clearly … broke down." He added, "If that were working, prescribers would have been rapidly disenrolled who were prescribing inappropriately." Instead, the researchers found FDA did not remove any provider from the REMS program for inappropriately prescribing TIRF drugs.
Overall, Alexander said the researchers found that "[b]oth … FDA and the fentanyl makers failed to design and implement an effective monitoring program."
Raeford Brown, chair of FDA's Anesthetic and Analgesic Drug Products Advisory Committee, said, "These findings—that many people who received these TIRF products did not have breakthrough cancer pain, or in fact did not have cancer, and nearly half were not tolerant to opioids—show that the REMS was ineffective at doing what it was supposed to do, which is protecting the public." Brown said, "50% is not good enough when you're talking agents that can kill people almost instantly."
An FDA spokesperson said the agency "shares the concerns" about how TIRF drug are being prescribed and whether the REMS program for the drugs is effective. The spokesperson said, "These products are medically important for a small group of patients who are opioid-tolerant but also pose serious risks. That's why the agency has sought to ensure that the … program is achieving its public health goal of assuring safe use and mitigating the risks of misuse, abuse, addiction, overdose, and complications due to medication errors" (Bernstein, Washington Post, 2/19; Baker, "Vitals," Axios, 2/20; George, MedPage Today, 2/19; Johns Hopkins release, 2/19).
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