FDA Committees Vote to Dismiss Clozapine REMS

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BREAKING NEWS

In a joint meeting of the US Food and Drug Administration’s Drug Safety and Risk Management Advisory Committee and Psychopharmacologic Drugs Advisory Committee, members decided the clozapine REMS (Risk Evaluation and Mitigation Strategy) protocol was no longer necessary and may even be a barrier to access.¹

The joint panel voted 14 to 1 that the requirement to monitor, document, and verify absolute neutrophil count (ANC) results were unnecessary, essentially dismissing the clozapine REMS.¹

Before the vote, the committees heard testimony and evidence from pharmaceutical representatives as well as leaders in the field—John Kane, MD, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Robert O. Cotes, MD, Emory University School of Medicine. Kane and Cotes discussed the clinical context and implications of clozapine for patient populations.²

Kane noted that “Clozapine is a cornerstone in the treatment of schizophrenia,” detailing its impact on treatment resistant schizophrenia in general as well as its ability to improve functioning, reduce mortality, reduce risk of relapse, among other clinical features.² Kane also described the delays in obtaining clozapine, adding that the US lags behind in its use as compared to other countries.

Kane specifically addressed the risk of clozapine-induced neutropenia, which has been the foundation for the REMS protocol. He explained that the most serious cases occur within the first 18 weeks and that the risk decreases over time, becoming almost negligible after 2 years. “Long-term risk excess is small compared with advantages of clozapine in outcomes, including life expectancy,” he reported. ”Relaxing long-term monitoring could favor the advantages of clozapine use, without incurring risk of neutropenia.”²

Meanwhile, Cotes addressed prescriber, patient, and caregiver concerns, including challenges working with some pharmacies in submitting information. He discussed the results of a study that found 60% of clinicians prescribing clozapine said that “The safe use requirements have often caused delay in my patients receiving medication.” Cotes added that missed doses due to this bureaucracy can lead to the need for re-titration, psychological distress for patients, physical discomfort/withdrawal, symptom exacerbation, and can even lead to hospitalization.²

In addition to expert testimony, patients, caregivers, clinicians, and advocates were given an opportunity to speak before the committee voted.

“The REMS program, while well-intentioned and -designed, does create a barrier to prescribers and patients using clozapine,” said Kathryn K. Erickson-Ridout, MD, a member of APA’s Council on Quality Care who testified on behalf of APA.3 Erickson-Ridout, who is also an inpatient psychiatrist and researcher for Kaiser Permanente, told the committee, ““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.”

She added the disruptions in care resulted from the REMS protocol can lead to “disastrous results.”

Similarly, epidemiologist and panelist Sascha Dublin, MD, PhD, emphasized the need for monitoring and support without “a punitive and technocratic approach.”³

“I do not believe that the REMS’ approach to documenting and enforcing is serving the health of the patients or the needs of the community,” she said.

Although the committee overwhelmingly decided the REMS was no longer appropriate, Walter Dunn, MD, PhD disagreed. Dunn, Health Sciences Assistant Clinical Professor in the department of psychiatry at UCLA David Geffen School of Medicine, director of the Mood Disorders Clinic at West Los Angeles Veterans Affairs Medical Center, preferred monitoring when the risk was the greatest—during the first 18 weeks—instead of completely getting rid of the REMS. He did, however, suggest a more streamlined program without ANC levels.¹

In a recent article for Psychiatric Times, Gilbert Honigfeld, PhD, detailed the onerous process and the delays in treatment that result from REMS, even referring to it as a discriminatory practice against psychiatric clinicians.⁴

“From the point of view of professional equity alone then, clozapine REMS is clearly discriminatory and should be eliminated immediately,” he wrote.⁴ “Psychiatrists are physicians first, specialists second. They are as capable of monitoring the health and well-being of their patients as physicians in all other medical specialties. No medicine is free of significant adversity, and clozapine’s low overall rate of fatal outcomes turns out to be quite comparable to other antipsychotic medicines, if not better.”

“As well intended as it might once have seemed, the federal REMS program is now one of the primary obstacles standing in the way of patients receiving their medicine on time,” he added.⁴ “It is a major factor limiting access to clozapine for individuals with serious mental illnesses whose very lives might well depend on it. Solution? Eliminate FDA’s clozapine REMS program and allow psychiatrists to practice medicine just like their peers in all other medical specialties.”

What do you think of this decision and how will it impact your prescribing strategy and patients? Share your thoughts with us via PTEditor@mmhgroup.com.

References

1. Sutter S. Clozapine REMS A Barrier To Treatment And Unnecessary For Safe Use, US FDA Adcomms Say. The Pink Sheet. November 20, 2024. Accessed November 20, 2024. https://insights.citeline.com/pink-sheet/product-reviews/us-advisory-committees/clozapine-rems-a-barrier-to-treatment-and-unnecessary-for-safe-use-us-fda-adcomms-say-KDK6ICJKNBHPTBGVFFL3C6ME7U/

2. FDA Advisory Committee Meeting Clozapine Risk Evaluation and Mitigation Strategy. November 19, 2024. Accessed November 20, 2024. https://www.fda.gov/media/183655/download

3. FDA Panel Votes 14-1 Against Clozapine REMS. APA News Alert. November 20, 2024. Accessed November 20, 2024. https://alert.psychnews.org/

4. Honigfeld G. Clozapine REMS: Regulatory Discrimination Against Psychiatrists? Psychiatric Times. October 3, 2024. Accessed November 20, 2024. https://www.psychiatrictimes.com/view/clozapine-rems-regulatory-discrimination-against-psychiatrists