Can the FDA Be Trusted With Clozapine?

The FDA has issued a formal response* to U.S. Representative Brad Sherman’s ‘Dear Colleague’ letter co-signed by nine members of Congress regarding the clozapine Risk Evaluation and Management System (REMS). The FDA reiterated their public announcement on Sept. 21, 2023 that they will conduct a “thorough reevaluation of the Clozapine REMS” within the next year.

The FDA states that they have funded a study by the Brigham and Women’s Hospital to analyze clozapine utilization, REMS adherence, and outcomes. The FDA is also collaborating with the Veteran’s Health Administration to better understand neutropenia incidence and severity in clozapine patients. They are also conducting an internal study of the Sentinel System, the FDA's national medical product monitoring system.

While this may sound hopeful, The Angry Moms have one problem:

We don’t trust the FDA.

Lisa C. has a son, Daniel, in prison in California. Growing up, Daniel was an avid reader, an accomplished chess player, compassionate, and active in youth programs. At age 18 he developed severe psychosis. Daniel’s illness caused him to hallucinate “voices” and “cameras in the walls.” He developed delusions that he could “protect abused children” by starting fires. These symptoms caused violent and self-harming behaviors. The initial psychiatric treatments were ineffective. Eventually, Daniel’s illness caused him to commit a violent crime. He was arrested and jailed but found incompetent to stand trial. He was ordered to participate in a competency restoration program. During this process, Daniel was treated with clozapine. Like a third of individuals with schizophrenia, Daniel has Treatment-Resistant Schizophrenia (TRS), and clozapine is the only medication that works for him.

Daniel’s condition improved, and he became well enough to participate in his criminal case. He accepted a plea agreement for 20 years in prison with the opportunity to be released on probation with mental health terms after ten years.

Unfortunately, Daniel was transferred to a prison that did not continue his clozapine treatment. Like many incarceration programs, the prison where Daniel was placed did not have the resources to comply with the rigorous blood tests and REMS requirements. Upon his arrival at the prison, Daniel was transitioned to other antipsychotics that were not effective for his TRS. His condition deteriorated, and his violent behaviors resurfaced. Daniel accrued additional charges, his 10-year parole date has passed, and he will likely remain in prison for the rest of his life. Lisa is heartbroken.

Lisa C. walks on the beach with her two sons, a few months before her son Daniel (left) developed a psychosis disorder that resulted in his incarceration. Daniel will endure a significantly prolonged prison sentence because the correctional facility was unable to comply with the FDA’s rigid clozapine restrictions, and his necessary treatment was discontinued.

How does the FDA plan to capture the devastating impact of REMS regulations on the prison population? How will an in-depth analysis of “neutropenia incidence and severity in clozapine patients” in any way reflect the added decades that individuals like Daniel will spend in prison?

Does the FDA even know this is a problem?

Lisa’s son Daniel is not alone. It is not unusual for clozapine to be conveniently used for restoration purposes and then promptly abandoned once inmates are placed in prison. As a young, established clozapine patient the risk of Daniel developing neutropenia was near zero at the time of his imprisonment. However, the risks of failing to treat Daniel with clozapine were enormous.

Dr. Ted Zarzar, Associate Professor of Psychiatry at the University of North Carolina School of Medicine, says Daniel’s situation is not uncommon. Dr. Zarzar spoke with The Angry Moms about his experience with trying to expand the use of clozapine for incarcerated populations. He participated in a 2019 survey of clozapine utilization in state prison systems. This survey, the first of its kind, discovered that among respondents, more than a third of state prison systems didn’t even carry clozapine in their formularies.

This finding is shocking. In the US, our jails and prisons have become the largest mental health provider in the country. Clozapine has unique applications for both TRS and recurrent suicidal behavior. Suicide is the leading cause of death in US prisons. How can this medication be entirely excluded from use for inmates?

Dr. Zarzar and his colleagues have been asking this same question. They believe incarcerated individuals with TRS have a statutory and constitutional right to treatment with clozapine, given that this is the only medication approved for TRS and for preventing suicide. Their publications have also referenced literature suggesting clozapine’s efficacy for reducing self-harm in personality disorders and for reducing impulsivity and aggressive behaviors, even in patients without a psychotic disorder.

“It’s what I imagined a state hospital was like in the 1980s,” says Dr. Zarzar of his first experience working in the prison hospital in 2016. He observed many severe cases of treatment-resistant psychoses, aggression and self-injury. His first thought was, “There seem to be a lot of clozapine candidates here.” But he was shocked to find that, at the time, only a dozen or so inmates out of 37,000 in the entire North Carolina prison system were on clozapine. He has been engaged in a quest to improve clozapine utilization ever since.

Beyond the original indication for TRS, in 2002 clozapine became the first and only medication to earn an FDA-approved indication for preventing suicide. Schizophrenia and psychosis disorders are the leading psychiatric diagnoses for suicide deaths. Recent analyses predict sufferers have a 5% lifetime suicide risk and clozapine dramatically reduces suicide rates to the level of the general population. “I call it the ‘forgotten’ indication,” says Dr. Zarar, describing clozapine’s woeful under-utilization, even in suicidal patients.

Recent estimates show the incidence of severe neutropenia to be between 21 and 40 in 10,000 clozapine patients. Cases are rarely fatal, with only 1 to 7 fatalities per 10,000 individuals who take the drug, even in countries with less stringent monitoring requirements. Yet, unlike any other antipsychotic, clozapine could effectively prevent as many as 500 suicides per 10,000 cases of schizophrenia. The risk-benefit math behind the excessive mandatory neutropenia testing doesn’t add up.

Dr. Zarzar and his colleagues obtained permission to do retrospective analyses on clozapine-treated inmates. They found a marked reduction in assaults, self-injury, infractions, and a significant reduction in time assigned to solitary confinement. “Self-injury is the big one,” says Dr. Zarzar, “it’s very expensive for prisons. Money can be a big argument for prison administrators to support the use of clozapine.”

So, why isn’t it being used?

“It’s all the standard arguments,” he says. “People don’t want to deal with the administrative and logistical burdens. It requires more time, attention, and skill on the part of the prescriber. And then there’s the myth about clozapine being a ‘dangerous medication.’ So many in my profession won’t even touch it. It’s just easier to prescribe other things. They might be willing to maintain someone on clozapine, but less likely to do the initiation.”

Dr. Zarzar is referring to the challenges of just getting clozapine started. The first six months of clozapine treatment requires frequent contact with the patient, strict weekly blood tests, and limits on dispensed quantities. These barriers are insurmountable for most patients, and a major deterrent for most clinicians.

We asked Dr. Zarzar if he had ever seen a patient with true clozapine-induced severe neutropenia. Since 2016, he has observed one non-fatal case. “We had one patient that we couldn’t attribute the neutropenia to anything else but the clozapine.” He stated. “But it’s rare. I’ve seen more cases with Tegretol® and Depakote®.”

Indeed, other antipsychotic medications and some anticonvulsants carry higher risks of causing neutropenia than clozapine. But clozapine is the only medication in FDA history to require frequent, strict, REMS-controlled neutropenia testing for every patient.

And the program is mandatory.

One mother wrote to The Angry Moms that her son “yelled at voices 24/7 for six months in solitary confinement because he was afraid of needles.” Many families tell us their loved ones “can’t do needles” for one reason or another. Sometimes it is paranoia, sometimes they are a “bad stick,” and sometimes it is a lack of transportation or supportive resources. Most of the time there is simply no doctor willing to use clozapine or take on a clozapine patient.

One mother explained that her son thinks the blood tests are “lethal injections” that will kill him. He becomes terrified and unable to cooperate. She requested that some tests be waived, but no providers have been willing to budge. The mother was told that as her son’s legal guardian, she could order a forced blood test using restraints, but she could not authorize the waiving of any routine tests. The explanation given by clinical staff was that “the blood tests are a federal mandate.” Her son has accumulated months of taxpayer-funded hospitalizations solely attributed to REMS-related clozapine restrictions.

The Angry Moms would like to know: how is it possible that for 30-plus years it hasn’t occurred to ANYONE at the FDA, the American Psychiatric Association, or any medical organization to allow a “compassionate use” option for clozapine?

Patients cannot initiate clozapine without being enrolled in the REMS and providing a baseline neutropenia test. There is no option for patients to refuse any of the excessive tests. There are no alternatives – in prison, in hospitals, or any setting – for unrestricted clozapine treatment. Gravely ill patients and families are held hostage by a regulatory program. While the current REMS program has features allowing prescribers to waive some missing tests, very few doctors will use these options, and many facilities have policies prohibiting exceptions. Full participation is required. There is no choice but to comply.

Treatment-resistant schizophrenia, especially in the context of severe illness, violence, and incarceration, carries as many serious consequences as cancer, if not more. Yet cancer medications with 10 to 100 times higher neutropenia risks than clozapine do not mandate frequent weekly blood tests with REMS dispensing restrictions.

Is clozapine treated differently because schizophrenia is “all in your head” and not a physical illness?

Is a suicide death different than a cancer death because suicide is a “choice,” and cancer is not?

Would it ever be acceptable to mandate rigorous blood tests as a condition to receive lifesaving cancer treatment?

The discrimination runs deep.

Over 85% of US patients who need clozapine will instead suffer grave torment without adequate treatment. Most will never hear about the drug. These individuals will not be represented in ANY existing clozapine patient database. Perhaps the FDA can share how they plan to characterize premature deaths, suicides, homicides, mass shootings, patient injuries, caregiver injuries, prolonged suffering, and prolonged prison sentences associated with NOT using clozapine. Such tragedies completely eclipse the minuscule risks of developing a life-threatening case of clozapine-induced neutropenia.

The Clozapine REMS is the most cruel and dangerous FDA regulation ever conceived for individuals with mental disease. The restrictions represent decades of systemic institutional discrimination. Given their dismal track record, we don’t expect the FDA to conduct their “thorough reevaluation of the Clozapine REMS” with a proper perspective or even simple common sense.

-----

The Angry Moms would like to thank Lisa C. for her courage in sharing her son’s story. Our heartfelt thoughts and prayers are with her son Daniel and the hundreds of thousands of inmates in the US suffering from Serious Mental Illness. We would especially like to thank Dr. Ted Zarzar for sharing his experience with us, and for his commitment to clozapine utilization in vulnerable populations. Dr. Zarzar is a second cousin of the Zarzar family of psychiatrists. We are grateful for their many decades of dedication to the field.

*Download the FDA's Letter to Congressman Sherman here:

2023-2552 RESPONSE SHERMAN

.pdf

Download PDF • 115KB