Flawed FDA safety requirements are hamstringing a highly effective treatment for severe schizophrenia

For medications with serious safety concerns the Food and Drug Administration mandates a Risk Evaluation and Mitigation Strategy (REMS) “to help ensure the benefits of the medication outweigh its risks.”

Sixty-three medications currently have REMS programs, 57 of which require “elements to assure safe use.” For providers and pharmacies, these elements often mean becoming certified to prescribe and dispense the medication, as well as using online systems to verify that patients are complying with the safety requirements. For patients, they can range from monthly pregnancy tests for the anti-acne medicine Accutane to periodic vision monitoring for the anti-seizure medication vigabatrin to — until recently — in-person dispensing from a certified provider instead of a pharmacy for mifepristone, a drug used to end early pregnancy.

These stipulations are well-meaning attempts to protect people from serious side effects of otherwise effective drugs. But for many people, they all too often delay access to treatment, or prevent it all together.

As a psychiatrist, the REMS program my patients and I most often encounter is for clozapine, the only drug the FDA has approved for treatment-resistant schizophrenia.

Schizophrenia, an often-devastating mental health condition that causes delusions, hallucinations, and cognitive impairment, affects nearly 3 million Americans, severely burdening those affected and their loved ones, while sapping nearly $300 billion dollars each year from the U.S. economy. Antipsychotic medications help many people with schizophrenia lead more functional lives by controlling their symptoms, though some have problematic side effects such as weight gain. Unfortunately, more than one-fifth of people with schizophrenia are treatment resistant, meaning they respond poorly to two or more antipsychotics. For them, clozapine is the gold standard treatment.

Despite having impressive efficacy and being a relatively inexpensive generic drug, clozapine is rarely prescribed in the U.S. largely because of its onerous REMS requirements. At issue is a rare but potentially life-threatening side effect called agranulocytosis, a serious decline in neutrophils, a type of blood cell important for fighting infection.

To prevent and rapidly address cases of agranulocytosis, the FDA requires clozapine’s manufacturers to jointly administer the clozapine REMS program. This aims to verify patients’ recent proof of normal neutrophil counts before pharmacies can dispense clozapine, meaning patients must visit a lab for blood draws as frequently as once a week.

I see the clozapine REMS system as the biggest barrier to starting patients on this potentially life-saving drug, indirectly causing more harm than good for people with schizophrenia.

A poorly executed attempt to update the clunky clozapine REMS program’s online interface has led to more scrutiny than ever of clozapine REMS requirements, and provided yet more evidence for why they should be scrapped altogether.

In November 2021, that upgrade left many prescribers on the phone for hours as they sought to overcome technical difficulties and get their patients registered in the REMS program. Incredibly, the new system did not carry forward any information on patients or providers from the old system, requiring both to re-register. Such poor preparation by the FDA and clozapine’s manufacturers was shocking — when people abruptly stop taking clozapine they can experience well-known serious adverse events, including rebound psychosis, catatonia, and delirium.

The technical issues proved so severe that the FDA quickly suspended some REMS requirements, allowing for more flexibility in dispensing clozapine to patients until the system could be repaired. Nearly six months later, those suspensions remain in place.

In a February 2022 letter to Congress, the American Psychiatric Association (APA) and allies asked that the entire clozapine REMS program “be suspended immediately and undergo thorough reviews.” The following month, the APA filed a Freedom of Information Act request to gain information about the clozapine REMS system, including clarification of the relationships between the FDA, clozapine’s manufacturers, and the administrators of the program’s web portal. This advocacy to improve the clozapine REMS program is important, but the better choice for patients is for the FDA to cancel the clozapine REMS, as it has done for the HIV medication Truvada and other drugs.

Clozapine improves symptoms for approximately 40% of patients taking it, yet fewer than 6% of eligible patients in the U.S. receive it. In a 2019 national survey of mental health clinicians, 76% agreed that clozapine is the most effective antipsychotic yet 43% had not started a single patient on it within the last year. Why is that?

While prescriber anxiety about agranulocytosis and other side effects certainly plays a role in underprescribing clozapine, as does a lack of centralized services to manage people taking it, the complexity of navigating the REMS requirements is the biggest deterrent. In the same national survey, 68% of respondents said prescribing clozapine was an administrative burden for clinicians, while 61% said being prescribed clozapine was a burden for patients.

For patients, this burden means blood draws every week for their first six months on clozapine, then every two weeks for the next six months, and then monthly for the duration of treatment. Getting such frequent blood draws on time is a challenge for even the most high-functioning individuals, and more so for people with schizophrenia, given its associated cognitive impairments. They also pose an additional financial barrier for people who are not insured.

On top of this hurdle, prescribers must coordinate getting blood test results from labs to dispensing pharmacies. Because of the poor design of the clozapine REMS system, many pharmacists aren’t aware that prescribers can enter lab results into the REMS system, allowing for instant transmission to pharmacies. This has resulted in a redundant system in which prescribers enter lab values into the online clozapine REMS system to meet FDA requirements while also faxing hard copies to pharmacies.

Until the recent debacle, there was no flexibility in the REMS program, so even if a patient had recently completed blood tests, they were denied their medication if the results had not been faxed to their pharmacy, in line with the autocratic “No Blood, No Drug” motto that once graced the top of the clozapine REMS website.

Thanks to this morass, even though treatment guidelines recommend clozapine after two other antipsychotics have failed, I find that in my practice, patients eligible for clozapine rarely to come to me already taking it. Instead, they have often unsuccessfully tried five or more other antipsychotics and many have never even heard of clozapine, which is a tragedy, since I’ve seen this medication help patients maintain jobs, homes, and relationships that would have otherwise been lost.

Someone dying from a medication side effect is devastating, but the FDA’s singular focus on agranulocytosis is myopic. Agranulocytosis occurs in just 8 of every 1,000 people taking clozapine, and 97% of them survive it. Importantly, the risk of death from agranulocytosis after the first six months on clozapine is about the same as general life mortality risks such as traffic or occupational accidents. Furthermore, given clozapine’s unique anti-suicidal properties and the fact that approximately 6% of people with schizophrenia die by suicide, expanding access to the drug would actually prevent more deaths from suicide in eligible patients than lives lost to agranulocytosis.

The economic case for expanding clozapine access by ending the REMS program also should not be overlooked. A 2016 study concluded that prescribing clozapine to all eligible patients in the Veterans Affairs system would save the V.A. nearly $300 million in the first year of expansion.

Other countries have been more discerning about clozapine’s public health calculus, resulting in less-stringent monitoring regulations and more widespread clozapine prescribing. A 2014 study of 17 countries found that clozapine prescribing was highest in Finland, which has less-frequent monitoring requirements than the U.S., and lowest among privately insured U.S. patients, with a nearly 14-fold difference in prescribing frequency. Another study that year revealed that clozapine was prescribed to only 6% of people with treatment-resistant schizophrenia covered by Medicaid compared to 23% of such patients in Australia. In China, which has no mandated neutrophil monitoring requirements, clozapine is a first-line treatment for schizophrenia. Prescribers there still routinely check neutrophil counts, but clinical judgment guides the frequency of testing.

That the FDA has mandated such a flawed clozapine risk mitigation approach for so long without more opposition from within medicine speaks to the extreme marginalization of people with schizophrenia in our health care system. What else could explain why a highly effective antipsychotic is saddled with such cumbersome regulations, while providers routinely prescribe many other medications with similar agranulocytosis risks that have no REMS requirements?

To remedy this situation, the FDA should immediately relinquish decision-making around clozapine neutrophil monitoring and place it entirely into the hands of prescribers. Furthermore, with recent isotretinoin REMS technical difficulties and the FDA’s December 2021 removal of mifepristone’s in-person dispensing requirement following legal action also in mind, the entire REMS enterprise appears in need of an urgent, comprehensive inspection by new FDA Commissioner Robert Califf and his team.

Brian Barnett is psychiatrist and clinical researcher in Cleveland, Ohio.