Clozapine REMS: Regulatory Discrimination Against Psychiatrists?

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COMMENTARY

“It took almost 2 weeks to get my son’s clozapine prescription filled. I called REMS myself 3 times. They told me exactly what the issue was which happened to be the doctor and his assistant not sending in the Patient Status Form, and then not filling it out correctly. The people at REMS told me the doctor could get online and answer 4 questions instead of trying to fax the paper over, which takes longer. The gatekeeper at his office swore up and down she knew what she was doing and that it was the pharmacy’s fault. It was a huge hassle getting him started on it. He has to get blood work once a week and is prescribed the medicine 1 week at a time. I have my fingers crossed that his next refill on Friday will be there.”

-Anonymous caregiver on ‘Angry Moms’ website: July 2024

With 2 entirely unique US Food and Drug Administration (FDA)-approved indications—treatment-resistant schizophrenia and suicide risk reduction in schizophrenia or schizoaffective psychosis—clozapine has no therapeutic peers.¹ Clozapine’s position as the gold standard among second-generation antipsychotics is based on proven superior efficacy to all other agents in its class, an advantage that has persisted for well over 30 years, since the introduction of Clozaril in 1990.²

Yet in the United States, this irreplaceable therapy is massively underutilized. A recent meta-analysis based on per capita utilization rates revealed that among 14 major countries, the US is at the bottom of the list at only 41 patients/100,00 population, while Finland heads the list at 189/100,000, over 4 times the rate of clozapine adoption in the US.³ The Table shows clozapine utilization by country.³

Table. Clozapine Utilization by Country (Rates per 100,000 population)³

The following overview is not designed to address every possible reason for a national underutilization problem that results in short-changing a very vulnerable group of those with mental illnesses. For example, there are shortcomings in clozapine exposure during residency training.⁴ Updating and simplifying white blood cell testing recommendations in light of accumulated clinical experience is certainly overdue,⁵ but these are not the focus of this report.

We address here a different but correctable issue that contributes substantially to clozapine underutilization: the FDA’s mandatory Clozapine Risk Evaluation and Mitigation System (REMS) and its inequitable treatment of psychiatrists by federal regulators vis a vis all other medical specialists.⁶

How does the clozapine REMS work? The following 15-step list provides a sense of the cumbersome processes involved in simply getting patients their first and second doses of clozapine under FDA’s regulatory mandate:

1. Psychiatrist takes and passes clozapine physician information and certification test.
2. Pharmacist takes and passes clozapine pharmacist information and certification test.
3. Patient is registered in the care of a REMS-certified clozapine physician.
4. Patient has blood drawn for absolute neutrophil count (ANC) determination.
5. Psychiatrist reports to the REMS administrator the patient’s ANC results and clinical condition on the Patient Status Form (PSF).
6. Patient’s registered psychiatrist reviews ANC and, if acceptable, sends initial clozapine prescription to REMS-certified pharmacy.
7. Pharmacy submits a REMS Dispense Authorization (RDA) request to the REMS vendor prior to filling clozapine prescription.
8. Patient goes to pharmacy to pick up initial prescription.
9. If RDA was approved via REMS algorithm, pharmacist dispenses the initial 7-day supply of clozapine.
10. Between treatment days 5 and 6, patient returns to lab for next ANC blood test.
11. Lab reports ANC value to certified psychiatrist.
12. Patient’s registered psychiatrist reviews ANC and, if it is acceptable, writes prescription and sends to pharmacy.
13. Pharmacy submits an RDA to the REMS vendor for approval prior to filling second clozapine prescription.
14. Patient reports to certified pharmacist for second week’s medication, etc.
15. If RDA was approved via REMS algorithm, pharmacist dispenses the next 7-day supply of clozapine, etc, repeated throughout treatment.

Clozapine is certainly not the only medicine available to physicians and patients in the US with agranulocytosis as a potential adverse effect. But how many of these other medicines require a REMS program for prescribing and dispensing? None.

In a recent review, Rattay and Benndorf identified 94 medicines with established potential for inducing agranulocytosis.⁷ These ranged from abacavir to zidovudine, spanning over a dozen different drug classes across all medical specialties. But only 1 medicine of the 94 with this potential adverse effect is encumbered with an FDA REMS mandate—clozapine—and thus only 1 group of physicians, psychiatrists.

Of the other 93 medicines with notable agranulocytosis potential but no REMS overlay, we will take a closer look at just 1: carbamazepine (Tegretol). Patients treated with carbamazepine face a far broader spectrum of potential hematologic adversities than with clozapine.

Carbamazepine product labeling includes Black Box Warnings for both agranulocytosis and aplastic anemia… the potential not only to reduce or eliminate white blood cells, but red blood cells and platelets as well.⁸ Yet neurologists are free to prescribe carbamazepine without mandatory federal oversight.

From the point of view of professional equity alone then, clozapine REMS is clearly discriminatory and should be eliminated immediately. 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.⁹

Next steps? The evidence is clear that the FDA has taken a position that discriminates against psychiatrists, reflecting an implicit bias that psychiatrists are somehow less capable of caring for their patients than physicians in all other specialties… and in the case of carbamazepine, specifically neurologists.

There are altogether about 20,000 medicines approved by FDA for use in the US, but clozapine is the only medicine with significant agranulocytosis potential that is burdened with a REMS.

After 30+ years of clinical experience in the US, it is time to petition the FDA for immediate discontinuation of the discriminatory clozapine REMS program. 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. 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.

Dr Honigfeld is a psychopharmacologist and clinical researcher who led the development of clozapine. He is also the author of Psychiatric Drugs: A Desk Reference.

References

1. Clozapine package insert. US Food and Drug Administration. Accessed October 2, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf

2. Qubad M, Bittner R. Second to none: rationale, timing and clinical management of clozapine use in schizophrenia. Ther Adv Psychopharmacol. 2023;13:20451253231158152.

3. Bachmann CJ, Aagaard L, Bernardo M, et al. International trends in clozapine use: a study of 17 countries. Acta Psychiatr Scandinav. 2017;136(1):37-51.

4. Zarzar TR. Clozapine proficiency as a milestone in psychiatric training. JAMA Psychiatry. 2024;81(7):639-640.

5. Schulte PFJ, Veerman SRT, Bakker B, et al. Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring: can the regulations be relaxed? Schizoph Res. 2024;268:74-81.

6. What is the clozapine REMS? Clozapine REMS. Accessed October 2, 2024. https://www.newclozapinerems.com/home#

7. Rattay B, Benndorf RA. Drug-induced idiosyncratic agranulocytosis - infrequent but dangerous. Front Pharmacol. 2021;12:727717.

8. Carbamazepine package insert. US Food and Drug Administration. Accessed October 2, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/016608s097,018281s045,018927s038,020234s026lbl.pdf

9. Vermeulen JM, van Roojien G, van de Kerkhof MPJ, et al. Clozapine and long-term mortality risk: a systematic review and meta-analysis of studies lasting 1.1-12.5 years. Schizophr Bull. 2019;45(2):315-329.