Most Clozapine Prescribers Satisfied With REMS Program

Most physician prescribers were satisfied with the FDA’s controversial risk evaluation and mitigation strategy (REMS) program for clozapine, survey data showed.

Among 196 doctors who prescribed clozapine, 64% said the positive aspects of the REMS certification process outweighed the negative ones, reported Aaron Kesselheim, MD, JD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues.

Moreover, 68% felt the positives of the drug’s safe use requirement — i.e., scheduled blood testing — outweighed its negatives, the researchers wrote in JAMA Network Open.

First approved in 1989, clozapine is the only medication indicated for treatment-resistant schizophrenia. It’s also indicated for suicidal behavior in those with schizophrenia or schizoaffective disorder. The drug carries a risk for severe neutropenia.

In 2015, the FDA merged the drug’s risk management programs into a centralized REMS, mandating that prescribers undergo a certification process and commit to performing required blood testing.

Patients taking clozapine must undergo weekly blood draws during the first 6 months of treatment, graduating to blood draws every 2 weeks until month 12, and monthly draws thereafter. Prescribers must document a patient’s absolute neutrophil count by fax or the web-based REMS system, which then authorizes a REMS-registered pharmacy to dispense clozapine.

The REMS program has been riddled with problems ranging from technical problems to human error, leading to disruptions in patient care.

“The ramifications of such interruptions in treatment can be stark,” Kesselheim and colleagues wrote. “Discontinuation of clozapine among responders is associated with relapse, hospitalization, and persistent psychosis.”

To understand physicians’ experiences, Kesselheim’s group administered a 57-question survey to U.S. physicians who prescribed clozapine in 2021 or 2022. Surveys were conducted from May 2022 to January 2023.

Most respondents were psychiatrists (86%), followed by internal medicine clinicians (9%), neurologists (4%), and geriatric specialists (1%). Nearly half (47%) had been out of medical school for at least 35 years. Two-thirds were male and 63% were white.

While 77% of respondents agreed that the safe use requirement was clinically necessary, 44% said blood testing under the REMS program was somewhat or very hard. The majority said these requirements were burdensome for patients (71%) and often caused a delay in patients receiving clozapine (60%).

More than half (61%) reported that their patients always or almost always adhered to the blood testing schedule in the REMS program, and 29% said patients did most of the time.

Two-thirds also felt the prescriber certification requirements were reasonable for clozapine and not for other drugs used to treat schizophrenia. Half said the certification process was easy and nearly all said the process clearly explained the testing required of patients taking clozapine. Most (75%) said the certification process provided useful information about the drug, including data about the risk of severe neutropenia (97%).

Prescribers also had thoughts on how the certification process could be improved. Most (89%) agreed that educational materials should include information on all clinically important risks of clozapine, and 72% said a summary of how well clozapine is expected to work should be included. The majority (60%) also said that certification should include a quiz covering knowledge of clozapine risks and required testing.

Only 24% felt prescribed should undergo the certification process each year as opposed to only once as currently mandated.

White respondents were more likely to have a negative perception of the REMS program than American Indian or Alaska Native, Black, Native Hawaiian, or other Pacific Islander respondents. Those who had been in practice for less than 15 years were more likely to have a negative opinion than those in practice longer.

“The diversity of respondents as to practice setting, practice region, professional time in clinical practice, years since graduation from medical school, and frequency of prescribing supports the broad generalizability of the survey findings,” the researchers wrote. “This suggests that strong opposition to the clozapine REMS program may not be widespread or may be limited to the delays that the program may cause.”

In November 2024, a joint FDA advisory committee convened to discuss ongoing issues with the clozapine REMS program. All but one of the 15 voting panel members agreed that testing and certification requirements for patients and prescribers were not necessary. The FDA has yet to take action on the panel’s recommendations.

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