Fighting the FDA for Clozapine Access

WebMD has hidden the identity and location of Mary M. and Andrew in order to protect the mental health and safety of Andrew and his family. It’s May 13, 2022, and Mary M. is in a panic. Just a day earlier, a hospital admitted her adult son Andrew in a deep state of psychosis. Against her guidance, the hospital has given her son haloperidol (Haldol), which worsens his symptoms, rather than the one drug she says keeps his paranoid delusions at bay: clozapine.
Now, hospital staff tell her over the phone, he has hurt himself. “What’s he done?” she asks. But they won’t give more details until she gets there. She rushes to the hospital to find out more.  
Mary hasn’t seen her son this sick since 2018, when the FDA’s iron-clad rules on clozapine cut off his medication after he missed a single routine blood test.
Now, after 4 relatively stable years, Andrew is back in the hospital. This time, he started to miss blood tests and skip medication in a self-perpetuating loop after a misguided primary care doctor told him he “doesn’t need clozapine” and he’s “just depressed.” The result was the same: lost access to clozapine followed by delusions, threatening voices, paranoia, hospitalization, physical restraints, and months of recovery. But this time there is something more.
Somehow, even with the requirement that staff watch him closely, Andrew has managed to remove his right eyeball with his fingers and completely sever the optic nerve – no easy thing to accomplish in the 15 minutes between required room checks.
Months later, when he’s back on clozapine and stable, he tells his mother he’s horrified at what he has done. He tells her a voice kept demanding he do it. He tried to ignore the voice, but it got louder and meaner until he complied.   These weren’t the only times that Mary couldn’t get doctors to give her son clozapine. Just finding a psychiatrist who would prescribe it for him in the first place had taken months of begging and pleading. On the face of it, it’s hard to see why.   Clozapine is the gold standard fashion for treatment-resistant schizophrenia, Andrew’s undisputed diagnosis. 
It’s the only FDA-approved medication for the condition, and it is clearly cited in American Psychiatric Association treatment guidelines as the only medication to use after poor response from two other medications — a threshold Andrew passed long ago.   And the research shows that it works. Even compared to other antipsychotics, studies show clozapine results in less suicide and depression, less agitation, less psychosis, less substance abuse, and better quality of life.
“Used correctly, it’s the most effective antipsychotic we have — by far — and it’s changed lives for many people,” says Deanna Kelly, PharmD, director of the Treatment Research Program at the Maryland Psychiatric Research Center.
Treatment-resistant psychosis disorders like Andrew’s make up 30% to 50% of psychosis disorders, but only about 4% of them are treated with clozapine in the U.S. (In other countries, especially Western ones, clozapine use tracks more closely with the rate of treatment resistance: 20% to 35%.)
So why are doctors so reluctant to use it?
The root of the problem, Kelly says, is the FDA’s Risk Evaluation and Mitigation Strategy, or REMS, for clozapine. (It’s derived from the testing guidelines that came with clozapine when the FDA approved the drug in 1989, followed by the slogan “No Blood, No Drug.”)   There are only about 70 drugs that require REMS – an extra layer of regulation – out of thousands of FDA-approved medications. The clozapine REMS requires, among other things, a weekly blood draw with a needle. This tapers down to biweekly after 6 months and monthly after a year, but any interruption means you have to start the process all over again.
The sole reason for the requirement is to protect against a condition called severe neutropenia – a large drop in a type of white blood cells (neutrophils) that can lead to life-threatening infection.  
But the risk is extremely low. The death rate from clozapine-induced severe neutropenia is around 50 per 100,000, or  1/20th of 1%. And it is likely much lower in the younger populations most likely to benefit from the drug.   Numerous medications with no FDA REMS or mandatory blood tests carry a far greater risk of neutropenia, including several cancer drugs with rates 10 to 100 times higher. One common antipsychotic, olanzapine, showed neutropenia-related adverse events at a rate five times higher than clozapine in patients under 45, according to the FDA’s own database.  
More importantly, says Kelly, even after 30 years, there is no evidence the REMS blood-draw requirement helps reduce deaths from severe neutropenia. (During COVID, when the FDA relaxed blood testing requirements, deaths and other adverse events from severe neutropenia remained unchanged.)   What is clear, says Kelly, is that interruption or delay in clozapine use can have serious consequences.   “People with schizophrenia are far more likely to die from suicide due to lack of clozapine than from severe neutropenia if they take it,” says Robert Laitman, MD, a clinician in New York. Laitman, a nephrologist, developed a model for psychosis treatment with clozapine called the Meaningful Recovery Protocol.
And the numbers seem to bear this out. The rate of suicide in people with schizophrenia is tragically high – as many as 5,000 people per 100,000, most of them in the first year after diagnosis, compared to around 14 in the general population. Clozapine is the only medication FDA-approved to reduce suicide attempts in those with psychosis, and studies show this saves thousands of lives, even compared to other antipsychotic options.
Then there are the well-known dangers of trying to stop clozapine too quickly. “It can cause a rebound effect,” says Laitman, who has treated hundreds of people with psychosis disorders over the last 10-plus years. Within just a day or so of missing a dose, someone with schizophrenia can start to “decompensate” into a psychotic state, he says.
It’s not just the unpredictability of psychosis that is the problem. Decompensation damages the brain, Laitman says. “It’s neurodegenerative. Every time someone has a psychotic episode, they lose some gray matter.”
These issues are harder on certain minority populations in the U.S, says Laitman. People of African or Middle Eastern ancestry in particular can have healthy ranges of neutrophils that run 30% lower than white populations. That makes these groups more likely to fail the blood tests, even though they are less likely to develop severe neutropenia, he says. The result is that they get clozapine less often than average and are discontinued more often. The REMS is a huge burden on doctors, pharmacists, and patients, says Kelly.
“Imagine starting a new medication and now every week you’re gonna go to the lab to get your blood drawn. You can’t pick up your next week’s prescription. You have to go every single week. You have to pick up. It’s a lot.” Kelly helped start a hotline in Maryland to assist providers with all aspects of clozapine dosing and monitoring, which can be a bit tricky if you don’t know the particulars. But that’s not what either patients or providers call about most.
“The most frequent questions we get by a large margin are about how to manage the REMS program itself. There are just so many things that can go wrong,” Kelly says.  
If you miss a blood draw, the clozapine stops. If you can’t find a certified pharmacy, the clozapine stops. If you lose your meds, the clozapine stops. If the pharmacy doesn’t get the report in time, the clozapine stops. If your doctor forgets to submit the monthly “Patient Status Form” (a new requirement for 2021), the clozapine stops. If a provider can’t stock the drug (a common problem due to REMS), the clozapine stops. If the FDA REMS system goes down (as happened in 2021), the clozapine stops. And the list goes on. In December 2021, the FDA issued guidance that temporarily allows a little leeway for certified doctors if they can find a certified pharmacy willing to dispense the drug without a blood test.  
But the lack of clarity and complex logistics have led most doctors and pharmacists and other players (like pharmacy benefit managers) to either continue with the strict patient testing requirements or simply opt out of dealing with clozapine altogether, says Kelly.
In addition, the FDA’s announcement of “additional enforcement discretion” is confusing to many and sometimes interpreted as more restrictive, not less, according to some advocates. In 1976, after 3 years of clinical testing, U.S. research for clozapine stopped due to eight reported clozapine patient deaths in Europe from severe neutropenia, says psychologist and psychopharmacologist Gilbert Honigfeld, PhD, one of the architects of the original clozapine patient monitoring system from the 1990s. That’s what led the FDA to put in place the stringent requirement for blood testing and monitoring. And then it just never went away, even after new research and new medications showed it wasn’t necessary. “It was understandable at the time,” says Honigfeld, who has worked on clozapine for 50 years. But now, he says, “I believe the time for eliminating this kind of mandate has long passed.” 
In the late ‘90s, a comprehensive report by Honigfeld and colleagues showed clozapine-induced severe neutropenia was far less common than thought, and deaths  from the condition were almost unheard of. In addition, by that time, there were much better medications to help treat severe neutropenia, says Honigfeld. 
It’s true, Honigfeld says, that clozapine can be a tricky medication. It does have some serious possible side effects that need to be competently managed.
But, says Honigfeld in an open letter to the president of the American Psychiatric Association (APA) in March 2023, “Psychiatrists are well-equipped to handle clozapine prescribing and patient monitoring without the creaky apparatus of a federal program whose time has come and gone.” On May 24, 2023, 30-year-old Analisa Chase, who has schizophrenia, spoke at a Capitol Hill briefing in Washington, DC, put on by the Schizophrenia & Psychosis Action Alliance and the American Association of Psychiatric Pharmacists. She spoke about the battle to get clozapine in the first place, even after going through numerous other medications with no success. She spoke of the nightmarish months-long journey to get back on her feet after missing a single weekly blood draw in 2018. She pleaded for the FDA to revamp or remove the REMS for clozapine.   The APA, along with a number of prominent psychiatrists like E. Fuller Torrey, Robert Cotes, and Brian Barnett and pharmacologist Raymond Love, have made similar public pleas. They’re joined by a bevy of advocacy groups like the Treatment Advocacy Center, NAMI, and an aptly named group of mothers of children with psychosis disorders, The Angry Moms.
The FDA recently released a new request for feedback about what to consider when changing REMS requirements, including testing of the system, how to evaluate if change was successful, and how to plan for system failures.
We can only hope, says Honigfeld, that’s a sign the FDA is paying attention.  After Andrew lost his eye, he spent several months in and out of the hospital. He had to start all over again with a slow buildup of clozapine and a weekly blood draw. He was terribly depressed about what had happened and doctors kept him heavily sedated. But over time, the clozapine took hold and he stabilized. He’s been back home since October 2022 and lately has been stable, says Mary. “In the hospital and without clozapine, he had two med techs watching him 24/7 and mitts on his hands to prevent him from harming himself. On clozapine, he is living at home, independent.”  
He takes part in family activities and participates voluntarily in a local community mental health program. He takes his meds.
“If you were to meet him on the street, you wouldn’t know he had such a serious illness,” says Mary. “He has coherent conversations. He goes to the gym daily to work out. He plays basketball occasionally and a lot of ping-pong. Surprisingly, he beats most everyone at ping-pong, even with one eye!” The FDA has not responded to WebMD’s request for comment on the issue of REMS for clozapine or the views of experts in this piece.