APA Joins in Negotiations Over New Problematic Clozapine REMS

The new Clozapine Risk Evaluation and Mitigation Strategy (REMS) instituted November 2021 by the Food and Drug Administration (FDA) to monitor prescribing and dispensing of clozapine has led to chaos and confusion for manufacturers, pharmacies, prescribers, and patients. As a result, the FDA has temporarily stopped enforcement of certain requirements in the Clozapine Risk Evaluation and Mitigation Strategy (REMS).

For psychiatrists prescribing clozapine, the new REMS has meant increased administrative time navigating the REMS website seeking authorization for prescriptions and trying to get questions answered. Problems experienced by wholesalers, pharmacies, and prescribers threaten delays, interrupting patient care.

Negotiations between a number of pharmacy and provider stakeholders, including APA, and the FDA are ongoing.

“The changes made to the Clozapine REMS have led to an increased burden for prescribers,” Robert Cotes, M.D., told Psychiatric News. “Compared with other countries, clozapine is already highly underutilized. Additional barriers —or even the perception of additional barriers—contribute to prescribers not using clozapine for patients who may need it. The stakes are very high. If people miss doses because of administrative reasons, it can put people at risk for relapse, rehospitalization, or more catastrophic outcomes.”

Cotes is an associate professor of psychiatry at Emory University School of Medicine and a physician expert with APA’s SMI Adviser. SMI Adviser is APA’s Clinical Support System for Serious Mental Illness.

The Clozapine REMS is a safety program required by the FDA to manage the risk of severe neutropenia associated with clozapine treatment and was originally instituted in September 2015. The REMS applies to all clozapine medicines on the market and requires the use of a centralized system to monitor patients and prevent or manage clozapine-induced neutropenia. Prior to 2015, individual manufacturers operated their own clozapine patient registries.

While the FDA dictates the requirements of the Clozapine REMS, the system is administered by the Clozapine Product Manufacturers Group (CPMG).

Cotes and others who spoke with Psychiatric News said that at least some of the problems associated with the new REMS stem from the fact that CPMG employed a new vendor to operate the REMS website. Wholesalers, pharmacies, and prescribers have experienced multiple problems with the website, confusion about the new requirements, and difficulty resolving problems or getting questions answered in a timely manner.

There has also been some confusion about the status of the new REMS with regard to the COVID-19 public health emergency. In March 2020, the FDA issued guidance stating that the “FDA does not intend to take action against sponsors and others for the duration of the public health emergency for failing to adhere to REMS requirements for certain laboratory testing or imaging studies.”

“The complex nature of the Clozapine REMS touches multiple steps in the patient care process from enrollment to prescribing to monitoring to dispensing to obtaining drug to reimbursement,” said Raymond Love, Pharm.D., a past president of the College of Psychiatric and Neurologic Pharmacists and an advisor to APA’s SMI Adviser “This REMS transition has affected multiple steps in patient care with an incalculable expenditure of scarce resources intended for a most vulnerable population.”

Love said that pharmacies have had problems with the enrollment process and delays and difficulties getting authorization for individual prescriptions. (Even pharmacies that are enrolled in REMS have been required to get a REMS Dispense Authorization, or RDA, for every clozapine prescription).

Lastly, pharmacies have had problems with getting reimbursed for clozapine at a time when community pharmacies are overwhelmed by giving COVID vaccines and boosters, pediatric vaccinations, and annual flu and pneumococcal vaccinations.

Love has been instrumental in negotiations with the FDA on behalf of a group of stakeholders. In addition to APA, the group includes the National Alliance on Mental Illness, College of Psychiatric and Neurologic Pharmacists (CPNP), National Council for Mental Wellbeing, National Association of State Mental Health Program Directors, American Psychiatric Nurses Association, American Pharmacists Association, and American Society of Health-Systems Pharmacists.

The group sent a letter last September in advance of the new REMS, alerting the FDA to many of the problems that pharmacies and prescribers have experienced.

After November 15, the group again communicated to the FDA, which resulted in guidance from the FDA on some of the most immediate and pressing problems. On November 19, the FDA temporarily suspended certain REMS requirements, allowing pharmacists to dispense clozapine without an RDA and allowing wholesalers to continue to ship clozapine to pharmacies and health care settings without confirming enrollment in the REMS.

Yet problems persisted, and on December 2 the stakeholders submitted testimony and recommendations to an FDA Listening Session. “The stakeholders greatly appreciate FDA’s rapid response on November 19 and [its] subsequent actions to suspend parts of the REMS program,” the group wrote. “Unfortunately, the impact of the switch to the new REMS is continuing to disrupt treatment of patients and place excessive burdens on providers. More importantly, it is causing providers to shy away from prescribing clozapine and causing pharmacies to no longer dispense this lifesaving medication.”

The December 2 testimony outlined the problems related to the new REMS and put forward the following recommendations.

Both Love and Cotes said that the REMS should be rethought entirely in light of much evidence that the risk of agranulocytosis is extremely small, largely exaggerated, and limited in duration. “You have an underutilized drug with a questionable need for a monitoring system and a monitoring system that is overly stringent,” Love said.

Cotes agreed. “We are hoping this dialogue with the FDA may be an opportunity to have another conversation about the requirement for lifelong hematologic monitoring, which the literature suggests may not necessary,” he said. ■

Members who wish to submit comments should email them to APA’s Practice Management HelpLine at [email protected]. The Clozapine REMS is posted here.