Scrap Clozapine’s REMS Program, FDA Advisors Say

A joint FDA advisory committee on Tuesday overwhelming voted to eliminate the risk evaluation and mitigation strategy (REMS) program designed around the risk for severe neutropenia associated with clozapine, a drug used to treat schizophrenia and schizoaffective disorder.

All but one of the 15 voting panel members said the current requirements for prescribers to document absolute neutrophil count (ANC) results and for pharmacies to verify results are not necessary to ensure safe use of the atypical antipsychotic.

Likewise, in a vote of 14-1, the Drug Safety and Risk Management Advisory Committee and the Psychopharmacologic Drugs Advisory Committee said the education requirements for healthcare providers on clozapine’s neutropenia risk weren’t necessary.

“I have fantasized for years about abolishing clozapine REMS, and so I very enthusiastically voted no,” said panelist Jacob Ballon, MD, MPH, of Stanford University in California.

“I do not believe that the REMS approach to documenting and enforcing that is serving the health of the patients, the needs of the community, or the well-being of providers,” added Sascha Dublin, MD, PhD, of Kaiser Permanente Washington Health Research Institute in Seattle. “I hope we can find better ways to support appropriate monitoring that don’t have a sort of punitive and technocratic approach that are a burden.”

Severe neutropenia, which is associated with an increased risk of serious and potentially fatal infections, occurs in a small percentage of patients taking clozapine.

The current REMS program requires patients to undergo weekly blood draws in 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 ANC by fax or the web-based REMS system, which then authorizes the REMS-registered pharmacy to dispense clozapine.

But the program — plagued by technical issues and human error — has created access barriers to the only drug approved for treatment-resistant schizophrenia.

As the sole panelist voting in favor of the REMS, Walter Dunn, MD, PhD, of University of California Los Angeles, called for a “more streamlined” option that does away with the ANC documentation requirements, but said there was a role for regular blood work within the first 18 weeks of treatment when neutropenia risk is highest.

Some panel members pointed out that the REMS creates an undue burden on providers and discourages them from prescribing clozapine. REMS also places a heavy burden on patients, likely disproportionately affecting the most vulnerable populations who don’t have easy access to weekly lab work, panelists noted.

Gopal Vyas, DO, of the University of Maryland School of Medicine in Baltimore, said he changed his vote after the emotional public hearing session in which advocates explained how patients struggled to fill prescriptions due to REMS. Speakers recounted arduous tales of treatment withdrawal due to disruptions in care, leading some patients to suicide attempts, institutionalization, and incarceration.

“I would have said yes” to ANC monitoring at 18 weeks, Vyas said, but added that it was more important to reduce “every barrier” to clozapine. “The only way to do that … is elimination of [the REMS].”

Panelists also said healthcare providers were fully capable — and personally responsible as clinicians — of educating themselves on important medications, and this education didn’t need to be part of a regulated program. Some suggested providers may have shied away from participating in REMS due to liability fears.

“I trust our physicians … to take care of their patients. They have the ability and skills to do that outside of a REMS program,” said John Hertig, PharmD, MS, of Butler University College of Pharmacy and Health Science in Indianapolis.

Megan Ehret, PharmD, of the University of Maryland School of Pharmacy in Baltimore, said no study presented during the meeting convinced her that knowledge learned through the REMS prevented severe neutropenia. “Providers are not learning about the risks and benefits of clozapine from the REMS itself. They know this material prior to taking that assessment,” she said.

The general consensus among panelists was that everything prescribing clinicians need to know is on clozapine’s label.

While FDA isn’t required to follow the recommendations of its advisory committees, it typically does.