Eliminate Clozapine REMS, FDA Panels Say

Two US Food and Drug Administration (FDA) advisory panels are urging the agency to eliminate the risk management program for the antipsychotic drug clozapine, saying that restrictions are limiting access to a life-changing and life-saving medication for people with schizophrenia.
Members of the Drug Safety and Risk Management and Psychopharmacologic Drugs advisory committees held a joint meeting Tuesday to address whether frequently revised restrictions that have been in place since clozapine was introduced in 1989 should be changed again. Clozapine — the only FDA-approved drug for treatment-resistant schizophrenia — can cause severe neutropenia, so is subject to a Risk Evaluation and Management Strategy (REMS).
Calling the current rules overly burdensome, a majority of committee members voted against continuing a requirement that pharmacies and physicians must provide documentation of a patient’s absolute neutrophil count (ANC) results through the REMS. Monitoring should continue, as directed in the labeling, said the panel.
Panelists also voted overwhelmingly that it is not necessary to mandate physician education about clozapine’s risk of neutropenia and the need for ANC monitoring.
The panel did not vote, however, on whether the REMS should be eliminated altogether. The FDA did not pose that as a voting question for the panels’ consideration.
Following intense lobbying by the American Psychiatric Association (APA), the National Alliance on Mental Illness, and others, the FDA announced in 2022 that the agency would exercise “enforcement discretion” by allowing prescribers and pharmacists to skirt the clozapine REMS rules. But the agency doesn’t know whether the program is meeting its goals, said Tiffany R. Farchione, MD, director of the division of psychiatry at the FDA’s Center for Drug Evaluation and Research.
Among other things, the REMS requires that physicians and pharmacists be certified to prescribe and dispense the drug, that patients be enrolled, and that patient status forms be submitted monthly, showing ANC levels and appropriateness of continuing treatment. 
At the meeting, FDA officials said that 148,000 outpatient clozapine prescriptions were written in 2023. But an estimated 814,000 to 1.2 million Americans have treatment-resistant schizophrenia, the main indication for clozapine.
“We know the drug is being underutilized,” said Farchione, adding that the agency wants to ensure that physicians and pharmacists “can use the drug, use it safely and help the patients who need it.” 
REMS a ‘Hindrance’
As reported by Medscape Medical News, research presented earlier this year at the APA annual meeting showed that the risk of moderate and severe neutropenia is low to minimal in people taking clozapine for treatment-resistant schizophrenia. Those findings prompted the study’s investigators to suggest clozapine REMS should be reconsidered.
In Tuesday’s committee meeting, many panelists said that clozapine was no more dangerous than many antipsychotics and that the administrative requirements were preventing clinicians from prescribing.
“I have fantasized for years about abolishing the clozapine REMS,” said Jacob S. Ballon, MD, MPH, a temporary panel member and associate professor of psychiatry at Stanford University.
Panelists Jess Fiedorowicz, MD, PhD, professor and senior research chair in adult psychiatry at the University of Ottawa, Canada; Megan J. Ehret, PharmD, MS, a panelist and professor at the University of Maryland School of Pharmacy, Baltimore; and Rajesh Narendran, MD, a professor in radiology and psychiatry at the University of Pittsburgh School of Medicine, agreed.
“I strongly feel that the REMS at this point is just a hindrance,” Narendran said. “I think you should get rid of the REMS.”
However, panelist Walter Dunn, MD, PhD, staff psychiatrist at the Veterans Administration Greater Los Angeles Healthcare System, cautioned that modifying or eliminating the REMS might not necessarily increase prescribers. If monitoring ANC levels is still recommended in labeling, clinicians will still regard it as the standard of care, said Dunn. And, he said, “there are a whole host of other issues associated with clozapine,” that he said were “more concerning.” 
Many patients are accessing clozapine without going through the REMS, which is also of concern to the FDA and drug manufacturers. 
“We estimate about 42,000 patients are not participating in the REMS, said James Shamp, VP of data intelligence and program analytics at United BioSource, a company that supports drug makers.
Leah Hart, PharmD, a risk management analyst with the FDA, told the panel that the agency estimates that 25%-35% of patients taking clozapine may not be participating in the REMS. 
“Today, prescribers, pharmacies, and patients do not have to participate in the REMS in order patients to obtain clozapine,” Hart said.
Public Testimony Sways Panel
But psychiatrists, pharmacists, families, and patients who testified during the 90-minute open portion of the meeting disagreed with that assessment, saying the REMS program had a devastatingly chilling effect on clozapine access.
Patty Taggart of Las Vegas said her daughter had nine suicide attempts over the past 14 years, while having tried eight different antipsychotics. In August, after the most-recent attempt, Taggart begged the psychiatrist to prescribe clozapine to her daughter. The clinician refused, citing the REMS. After her daughter’s discharge, Taggart said she found another provider who would prescribe the medication.
Lisa Castellanos said her son Daniel had been treated with a variety of antipsychotics but denied clozapine until he was arrested in 2012 for assault during a psychotic break. The state used the medication to improve Daniel’s mental state so he could stand trial, said Castellanos. But when he went to jail after accepting a plea deal, the prison stopped the clozapine, she said. Daniel has since deteriorated and was recently ruled ineligible for parole, she said.
Patients and families also described being rejected at pharmacies — most of which, despite the FDA’s supposed “enforcement discretion” continue to rigorously follow REMS requirements. 
Many panelists said they were moved by patients and family testimony. A dozen or more members of the public were wearing black t-shirts with white writing that declared, “Clozapine is the safest antipsychotic in the world.” 
‘Blood-for-Drug Program’
Brian Barnett, MD, director of the psychiatric treatment-resistance program at the Cleveland Clinic, said during the public portion of the meeting that “many pharmacies simply refuse to dispense clozapine likely due to the administrative burden and lack of financial incentives.” 
Others want faxed lab results even when the results have been filed electronically, he said. “One of the most dangerous features of the current REMS system is its inflexibility, driven by the so-called ‘no blood, no drug’ ethos which has been baked into the minds of America’s pharmacists,” said Barnett.
“This is a blood-for-drug program,” agreed Rachel Strieff of Tempe, Arizona, who noted that her advocacy group, Angry Moms, and others had submitted 4,000 signatures calling for the end of the REMS. “The largest category of patients harmed by the clozapine REMS have never taken a single dose,” she said, noting that millions of eligible individuals are not getting the drug.
Panel chair James Floyd, MD, professor of medicine at the University of Washington, Seattle, said the public testimony was “very moving.” Families and patients had described “the intensity of suffering that people go through prior to getting to clozapine,” he said.
“We have to listen to that,” said Floyd.
“I want you to know that we hear you,” said FDA’s Farchione. “We’re here today because of you and your loved ones. And your stories are important, and your experience is important, and what you’ve shared today will have an impact on regulatory decision making,” she said.
While the FDA typically follows its panels’ advice, it’s unclear if the agency will do so for clozapine REMS or when it will release its final decision.
Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault. 
 
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