Improving clozapine utilization will require continued advocacy, drug sponsor interest, and FDA support to address REMS issues

1. Introduction

Significant research and clinical efforts have improved the safety of clozapine since FDA approval. This includes work resulting in strategies to prevent, detect, and manage clozapine-related adverse drug reactions (ADRs) such as gastrointestinal hypomotility and inflammatory reactions [1–4]. Tools and guidelines to screen for clozapine-related ADRs and awareness of how clozapine clinics help support the use of clozapine have also advanced care [5–7]. Continued efforts to improve clozapine prescribing are critical as clozapine is the only FDA approved medication indicated for treatment-resistant schizophrenia and reduction of suicidality in schizophrenia or schizoaffective disorder. Unfortunately, literature suggests clozapine use remains suboptimal in the US and throughout parts of the world [8,9].

In the US, the Clozapine Risk Evaluation and Mitigation Strategy (REMS), implemented to ensure completion of hematologic monitoring, remains a major barrier to clozapine use. Prior to the turbulent rollout of the 2021 REMS, the REMS website displayed the trademarked phrase, ‘No blood, no drug,’ which may still be engrained in the minds of healthcare professionals, caretakers, and patients. Not only is this phrase not true, as exceptions existed, it could be interpreted that hematologic risks remain constant throughout the duration of clozapine exposure. This is also not true [10]. Unfortunately, the ‘No blood, no drug’ slogan continues to have real-world negative impacts through the refusal to dispense clozapine from community pharmacists unaware of REMS flexibilities. This was highlighted by situations encountered during the COVID-19 pandemic (e.g. patient in quarantine without access to a laboratory) and the 2021 REMS rollout (e.g. inaccessible call center, preventing enrollment). During these times, some pharmacies denied clozapine prescriptions despite clear guidance from the FDA and international expert consensus to allow and justify monitoring variance in certain patients (e.g. every 3-month monitoring for patients on clozapine at least 1 year without prior hematologic abnormalities) [11]. Yet, given perceived liabilities, prescribers in many countries likely grappled with how to adopt variance from the usual hematologic monitoring requirements. With some REMS parameters still suspended by the FDA, now may be a time for major reformation.

2. How did we get here?

The complex history of clozapine has been described in detail by Crilly [12]. In short, the manufacturer (i.e. Sandoz) of branded clozapine in 1989 established the Clozaril Patient Management System (CPMS) following FDA requirements to ensure prescribers completed hematologic monitoring. To do this, Sandoz contracted with Caremark to collect and analyze blood samples before clozapine could be dispensed to a patient. Required participation in CPMS was discontinued following federal antitrust action [12]. A merger involving Sandoz in 1996 led to the creation of the pharmaceutical company, Novartis, who would manage what was known as the Clozaril National Registry (CNR). The CNR was a master listing of all patients prescribed clozapine for the purpose of ensuring hematologic monitoring. The Clozapine REMS resulted from the FDA Amendments ACT of 2007 which gave the FDA power to require REMS programs. Some medications, including clozapine, approved prior to 2007 were ‘deemed to have in effect’ a REMS type of program, and New Drug Application (NDA) holders were required to submit process of a REMS to the FDA [13]. For clozapine, the REMS was officially implemented and mentioned in prescribing information (PI) in 2015, retiring the CNR and changing control of hematologic monitoring oversight from individual manufacturers to a group of all US clozapine manufacturers, the Clozapine Product Manufacturers’ Group (CPMG). While there are varying degrees of REMS programs, clozapine was approved under the most rigorous, a REMS with Elements to Assure Safe Use (ETASU) which restricts access unless certain conditions are met [14]. As it stands, CPMG still operates the Clozapine REMS.

3. 2021 Clozapine REMS left still to fix

Even before the 2021 REMS rollout, the program has not been fully functional or enforced since the beginning of the COVID-19 pandemic. During the pandemic, the FDA permitted prescriber discretion regarding laboratory testing for all medication REMS programs. However, community pharmacies may have unnecessarily maintained barriers to obtaining clozapine due to no formal change to the PI or REMS program, combined with an unawareness or lack of understanding of the FDA’s action/announcements.

The updated 2021 REMS launched 15 November 2021 but was only in effect for about 1 week. Given concerns for patient harm, stakeholders (i.e. College of Psychiatric and Neurologic Pharmacists, American Psychiatric Association, National Association of State Mental Health Program Directors, American Pharmacists Association, National Alliance on Mental Illness, American Psychiatric Nurses Association, and National Council for Mental Wellbeing) took action with the FDA [11]. On 19 November 2021, the FDA decided not to enforce multiple provisions of the REMS program including aspects related to purchasing, the Patient Status Form (PSF), and the REMS Dispense Authorization (RDA).

With initial CPMS and original 2015 REMS processes, community pharmacists could track and submit laboratory values allowing clozapine dispensing. However, the new 2021 REMS required the prescriber or a prescriber’s designee to submit data via the PSF every 37 days or less. REMS no longer requires pharmacies to have ‘in hand’ current labs if the PSF is up to date. Unfortunately, many community pharmacies still will not dispense clozapine, unless the prescriber submits a current ANC with the prescription. This may be due to lack of familiarity with the new system and the FDA’s enforcement discretion, fear that the laboratory value will be required to obtain an RDA, or due to non-regulatory decisions by chain pharmacy management or pharmacy benefit managers. Due to ongoing problems with the clozapine REMS rollout, the RDA requirement remains suspended as of January 2023.

4. Privacy issues?

In the 2015 REMS, pharmacists could assist prescribers to update a patient’s REMS status. In the new system, pharmacists cannot update a PSF to generate an RDA, and this responsibility only falls to the prescriber or a prescriber’s designee. Some pharmacies have worked around this by creating a designee account with a generic e-mail address, then requesting electronic authority from a prescriber to allow management of patients and to update PSFs. Prescribers must understand that designees have visibility of their entire patient panel within REMS, whether intended or not. Another privacy concern is that the REMS patient search function allows search by one or partial patient identifier. As an example, search by date of birth alone or last name will display the information of patients not intended to be viewed. Insufficient data protection has been described as a ‘major worry’ to patients using a REMS-based medication [15].

5. Can it change?

To modify a REMS, either the FDA-approved application holder submits a proposal along with justification or the FDA requires modification to ensure benefits outweigh risks or to reduce the healthcare delivery system’s compliance burden [16]. Since clozapine is under a Shared System REMS, CPMG would submit the modification proposal. It is interesting to consider that under Chapter 21 US Code § 355–1, any REMS must assure access and minimize burden. Specifically, the ETASU must ‘not be unduly burdensome on patient access to the drug, considering in particular, 1) patients with serious or life-threatening diseases or conditions, 2) patients who have difficulty accessing health care, and 3) and patients with functional limitations; and shall – to the extent practicable, so as to minimize the burden on the health care delivery system’ [17].

Changes to REMS may face challenges in determining whether REMS elements actually increase safety and whether they are ‘burdensome’ [14]. This was highlighted in the case of mifepristone, which also was approved under a REMS with ETASU. The FDA reviewed requirements twice, keeping its REMS intact despite advocates and drug sponsors recommendations [14]. Even lawsuits (Chelius v. Becerra, American College of Obstetricians and Gynecologists v. FDA) argued of mifepristone REMS burdens [14]. Through continued efforts, the FDA did ultimately determine ‘that the REMS must be modified to reduce burden on the health care delivery system and to ensure the benefits of the product outweigh the risks’ [18]. Stakeholders of clozapine management including patients, caregivers, or health systems may consider aspects of the clozapine REMS program to be unduly burdensome.

6. Expert opinion

The evidence suggests REMS may be more burdensome relative to the risk of neutropenia after 1 year of hematologic monitoring without added harm. The risk of clozapine-induced neutropenia during months 6–12 has been reported as 0.70/1000 patient-years, falling to 0.39/1000 patient-years after 1 year [19]. Other studies provide similar figures and indicate that the delayed neutropenia is not especially severe and in some cases may not be due to clozapine [11]. The risk of fatal neutropenia from clozapine after early exposure is comparable to other medications that do not require indefinite monitoring. This has been used as justification by the Dutch Clozapine Collaboration Group to move toward infrequent monitoring in certain patients [11].

The FDA can reduce clozapine-related REMS barriers. Examples include allowing monthly monitoring after 18 weeks (like other countries), reevaluating the need for indefinite hematologic monitoring, improving how all healthcare members collaborate within the REMS system to mitigate administrative barriers, re-assessing need for a PSF, or removing the ETASU in favor of an educationally oriented REMS. CPMG has previously submitted monitoring data that could be made available for independent analysis to quantify the risk of neutropenia with clozapine. Even allowing REMS data to be available for clinical research purposes, similar to the publicly accessible data found in the FDA Adverse Event Reporting System, could expedite a conclusion supporting or refuting the clinical need to change hematologic monitoring.

The FDA has the authority to modify the Clozapine REMS, the largest perceived barrier to increasing clozapine utilization. Such a precedent could have global impact but noting that there is no standardized international approach to hematologic monitoring [20]. As an example, few countries have adopted the FDA requirement for reporting only ANCs or established separate requirements for those with benign ethnic neutropenia [21]. But as in the United States, regulatory bodies in other countries may have little motive to change the status quo, based on the notion that the current monitoring maintains a threshold of ‘safety,’ although that threshold is likely too high. Finally, it is imperative to not only consider the evidence supporting that less than monthly hematologic monitoring can be appropriate. The benefits of clozapine related to reducing suicidality and mortality should carry important weight when considering REMS changes can improve access and continuation rates of the medication [11]. At least in the United States, continued, coordinated pressure from advocacy groups, healthcare provider organizations, public health systems, and researchers is necessary to force the FDA significantly modify or even abandon the Clozapine REMS with ETASU.

Declaration of interest

RO Cotes is a speaker for Clinical Care Options, has received research funding from Roche, and Alkermes, and has received consulting fees from Saladax Biomedical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Disclosures

A reviewer on this manuscript has disclosed receipt of consultant fees for HLS Therapeutics and Thermo Fisher. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.