‘Godfather of Clozapine’ Calls for End to REMS

Fifty years ago, Gil Honigfeld, Ph.D., then a young project director for Sandoz Pharmaceuticals, began the first Phase I clinical studies on an interesting molecule called clozapine that seemed to have antipsychotic properties without the neurological side effects of older medicines like chlorpromazine and haloperidol.

Known by some today as the “godfather” of clozapine, Honigfeld saw the new drug through those earliest trials to its approval by the Food and Drug Administration (FDA) in 1989 for patients who have not responded to at least two other antipsychotic medications. (Today, clozapine is also approved for suicide reduction in schizophrenia or schizoaffective psychosis.)

But it was a scientific and regulatory odyssey whose twists, turns, and controversies are still felt today in the lives of patients and in the experiences of prescribers and dispensing pharmacists. Early in that journey, in 1974, in Finland—one of several European countries that had already introduced clozapine—eight patients died of agranulocytosis while taking clozapine in conjunction with other medications.

In the United States, the deaths meant the end of controlled studies on clozapine for the better part of a decade. “The identification of the neutropenia and agranulocytosis problem stopped our U.S. research program in its tracks not long after it had begun,” Honigfeld recalled to Psychiatric News.

But, he said, regular white blood cell testing was found to provide adequate early warning to allow for prompt drug discontinuation and a return to normal hematologic status, and in the early 1980s research began again. “This understanding—safe management of the patient during treatment with clozapine—permitted those of us responsible for overseeing the development of clozapine through the rigors of Phase II and Phase III clinical testing and ultimate FDA approval to begin to move forward again,” Honigfeld said.

In order for the drug to be approved, the FDA insisted on three criteria:

In 1989, the drug was approved along with a Clozaril National Registry System, administered by the manufacturer. As described by Honigfeld in a January 1996 article in Psychiatric Services, the registry system required all patients to have normal baseline white blood cell counts and weekly white blood cell monitoring throughout treatment with clozapine and for four weeks after treatment ended. The medication was dispensed weekly only to patients for whom current data on white blood cell counts was available. Distribution was limited to registered pharmacies.

Fast forward to 2015, when the FDA established the REMS, which took the administration of required blood monitoring out of the hands of manufacturers and created a centralized registry for prescribers and pharmacists.

Fifty years after research first began on that intriguing new molecule, clozapine is widely recognized as the most effective antipsychotic medication, often transformative for patients with otherwise intractable psychosis. Yet it is dramatically underutilized—in large part because of perceived risks associated with the drug and because of onerous administrative and logistical burdens associated with the REMS requirements.

Honigfeld thinks it is long past time to eliminate the Clozapine REMS. “Psychiatrists are now totally familiar with clozapine’s benefits, risks, and patient-management issues,” he said. “In my view, they should be relieved of the encumbrance of the inefficient national monitoring system and take on patient oversight and management of their patients exactly like their counterparts in every other branch of medicine.”

Other medications actually have a higher risk for agranulocytosis, Honigfeld noted, but only clozapine requires regular blood monitoring. “Among all the medical specialties, psychiatrists alone face this unnecessary burden,” he said. “It should be as easy for a psychiatrist to prescribe clozapine as it is, for example, for a neurologist to prescribe carbamazepine or an internist amoxycillin.” ■