FDA Panel Votes Overwhelmingly to Abolish Clozapine REMS

Tiffany R. Farchione, M.D., director of the FDA’s psychiatry division, testified to the panel that since its approval 35 years ago, clozapine remains the sole antipsychotic approved for treatment-resistant schizophrenia and to treat suicidal ideation. People with treatment-resistant schizophrenia experience more severe symptoms, worse cognitive functioning, lower quality of life, and greater health care utilization, compared with those who respond to first-line antipsychotic medications, she said.

Yet Farchione said clozapine is prescribed to only 148,000 of the estimated 814,000 to 1.2 million people with treatment-resistant schizophrenia in the United States as of 2023, according to FDA analysis.

“Psychiatrists are sufficiently capable and confident to appropriately monitor a patient’s hematologic status and intervene when appropriate without central reporting,” said Kathryn K. Erickson-Ridout, M.D., Ph.D., a member of APA’s Council on Quality Care, who testified on behalf of APA. “Giving patients more autonomy into their care and daily living is vital to decreasing morbidity and mortality rates in this vulnerable population.

“I have been treating patients with treatment-resistant schizophrenia for 12 years and have seen the life-transforming benefit of this medication—controlling otherwise treatment-resistant psychotic symptoms and providing cognitive clarity,” Erickson-Ridout added. She has not come across a single case of agranulocytosis in her years of prescribing clozapine to patients.

“The REMS program, while well-intentioned and -designed, does create a barrier,” said Erickson-Ridout, who is also an inpatient psychiatrist and researcher for Kaiser Permanente.

In fact, 66% of prescribers have reported trouble getting the drug for patients since the last change to the Clozapine REMS in November 2021. The barriers posed by the REMS can lead to interruptions in patient access to clozapine, often with disastrous results, Erickson-Ridout said.

Dozens of patients and their caregivers offered similar testimonials of rapid decompensation, relapsed psychosis, psychosis-induced self-harm, suicide, or other violence after being denied a refill for their prescribed clozapine—often despite completing required bloodwork—due to reporting errors, missing paperwork, or lack of training among pharmacy personnel. Most commonly, patients and their loved ones simply could not find a willing clinician, pharmacy, and/or lab to prescribe the drug or manage the administrative work of REMS compliance.

FDA’s outpatient dispensing records show that 25% to 35% of patients currently taking clozapine are doing so entirely outside of the REMS program, Farchione said. However, many clinicians and the public testified that they had not been able to bypass the REMS and refuted the existence of any flexibility or process to obtain temporary waivers to access clozapine in an emergency.

“Some of the most distressing calls I receive as a clinician are from patients at the pharmacy where pharmacists are unwilling to fill their clozapine,” said Brian Scott Barnett, M.D., clinical director of the Psychiatric Treatment-Resistance Program and assistant professor of psychiatry at Lerner College of Medicine, both at Cleveland Clinic.

“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,” Barnett said. “I have observed multiple cases of clozapine withdrawal psychosis, delirium, catatonia in long-stable patients, due to this rigid, myopic approach, which jeopardizes patient lives and livelihoods…. Many pharmacists are either unwilling or unable to cooperate, even when the FDA has granted flexibility.”

Robert O. Cotes, M.D., founder and co-director of the Clinical and Research Program for Psychosis at Grady Health System and professor of psychiatry and behavioral sciences at Emory University School of Medicine, testified that REMS compliance “occurs in a delicate and complicated system that involves the patient, prescriber, pharmacies, lab testing facilities, insurance, and distributors. Any breakdown in any part of this highly interconnected system related to the REMS itself—or misconceptions about the REMS—can result in missed clozapine doses.”

Some large pharmacy chains impose even more stringent requirements than those imposed by the REMS, Cotes added. “The lack of standardization can also trigger errors, making missed doses more likely, which can have significant consequences for patients.”

Panelist Gopal R. Vyas, D.O., an adjunct assistant professor of psychiatry at the University of Maryland School of Medicine, took issue with testimony from a handful of large, well-resourced academic medical centers, who implied that their clozapine administration runs like a well-oiled machine. “I don’t think that any of this goes smoothly. To do our best job treating the people that we’re charged to care for, REMS is like pouring a little bit of gravel into that well-oiled machine,” Vyas said. “What’s important is reducing every barrier, and the only way to do that I think now is elimination of [the REMS].”

“The participants who presented … made it clear that for some patients, the greatest risk of clozapine is not getting clozapine,” testified panelist Jess Fiedorowicz, M.D., Ph.D., head and chief of mental health at the Ottawa Hospital and a professor and senior research chair of psychiatry at the University of Ottawa, echoing the exact phrase used by dozens of members of the public who spoke earlier at the meeting. “It’s important for us to remove these obstacles.” ■