How to Treat Schizophrenia

"Many felt that the field had been fully exploited. They were wrong."

“There’s been a search for effective interventions in severe mental illness since Jesus drove evil spirits out of the possessed,” says today’s interviewee. Until remarkably recently, no psychopharmaceutical treatments reduced the symptoms of the severely mentally ill or schizophrenic. The drug chlorpromazine was developed in 1955 and reduced schizophrenic symptoms, but at the cost of giving patients “Parkinson’s-like symptoms” instead: tremors, stiffness, impaired gait, and more. The medical field assumed this tradeoff was the only way to treat schizophrenia. The field was wrong.

What You’ll Learn:

• How a new drug gets developed

• Why the FDA is “the easiest agency for Congress to beat up on”

• How to win over regulators

• When doctors lobby for a drug to be authorized

Our guest today, Dr. Gilbert Honigfeld, led the development and championed the authorization of a drug, clozapine, that treats psychosis in the severely mentally ill. He is the author of Psychiatric Drugs: A Desk Reference. 

Dr. Honigfeld, who is 88, asked me to call him Gil when we spoke by phone for this interview. It’s been lightly edited for clarity.

Dr. Honigfeld with all 327 volumes of clozapine’s New Drug Authorization, 1982

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What’s the story of your connection to clozapine? 

This is my 50th year with clozapine, so I have a long view. 

Psychopharmacology and treatment of the seriously mentally ill with medicine started in 1955 with the introduction of chlorpromazine in this country. Before then, there were a variety of physical interventions that were tried, including lobotomy. But nothing worked until chlorpromazine in 1955. It was astonishing to find something that reliably reduced at least some of the symptomatology of individuals who have serious psychosis.

By the time we studied clozapine in the mid-1980s, chlorpromazine was still the standard agent. In the 1960s, I was at the Department of Veterans Affairs doing multi-center studies, which served as an excellent model for the kind of work I’d eventually do once I entered the industry in 1973. By then, I’d had 12 years of experience doing clinical studies in psychopharmacology in various settings. I decided that it was time to try to take a medicine from beginning to end.

What were the limitations of chlorpromazine that led you and Sandoz to explore different drugs?

Chlorpromazine was the first, but about a dozen patented antipsychotic agents (initially labeled “major tranquilizers”) were introduced between 1955 and 1970. They all were based on mimicking chlorpromazine’s pharmacology, and all induced muscle stiffness and immobility, or Parkinsonism, in animals. 

There had been no new entries in the field between then and clozapine in 1990, mainly because the theory was that the model of drug-induced Parkinsonism was THE mechanism for antipsychotic action. It was understood for many years, incorrectly, that you could not have an effective antipsychotic medicine that did not produce, inadvertently but unavoidably, Parkinson's-like symptoms. That became the prominent model, meaning that when the medicine was used in humans, it would predictably produce symptoms of Parkinsonism. Many felt that the field had been fully exploited. They were wrong. 

There is a general rule of thirds: within the first generation of antipsychotic medicines, about a third of individuals did demonstrably better than they were doing. A third did reasonably well, but not necessarily at a level where they might be considered for leaving the hospital and being treated in the community. A third was in the treatment-resistant category, where there was little or no benefit. 

What prompted you to consider clozapine a potential avenue? 

Well, as with so much in new medicine development, there's a tendency for people not in the field to think that it's a very rational process, and that one derives and builds chemicals based on known mechanisms of action. But it’s primarily good luck, people taking a chance on something new. 

Chlorpromazine was found serendipitously 30 years earlier. And so too with clozapine, it was tried in the hands of German psychiatrists in institutional settings and found to be very effective as an antipsychotic agent, not in proven trials, but in initial clinical exposure. That was done in Europe first, and it was easy then for esteemed psychiatrists to get their hands on a brand-new medicine and simply try it out. 

The appeal to me of clozapine was a) this could be a significant advance clinically, and b) this could blow a significant hole in the theory of the underlying mechanism of action. In 1973, when I decided to go into industry, I had three job offers, and I chose the company that was the furthest from my home and paid the least. I did that because with their drug, clozapine, lab animals in their cages did not get rigid. That was the hook for me. It was rumored from information abroad that patients could conceivably be spared the Parkinson's-like side effects of contemporary antipsychotics.

We only discovered later some of the other adversaries we had to negotiate with, like the FDA (U.S. Food and Drug Administration) and physicians. For example, the FDA initially considered our clinical work in Europe supportive but only partially definitive. There’s a more up-to-date process now called the International Committee on Harmonization, which may be more rational.

Why did doctors advocate for the rapid approval of clozapine despite its serious severe side effects?

The idea that doctors urgently pushed for clozapine’s approval in the 1970s isn’t quite right. After discovering that clozapine could cause a dangerous blood reaction called agranulocytosis, U.S. trials came to a halt. There wasn’t much pressure to keep going because clozapine was seen as too risky. The word on the street was that it was “too toxic to develop.” Most new drugs never make it to market, and clozapine seemed destined to be one of them. 

However, through compassionate use programs, clozapine was still being given to some patients who desperately needed it. Their doctors said, and we agreed, “Do not take this medicine away from our currently benefiting patients… they have no other choice.” This kept the studies alive on ethical grounds, eventually leading to renewed clinical trials.

Break down the FDA approval process for me. What did Sandoz go through to get the drug approved?

The rules say a medicine can only come to market if proven safe and effective. That covers a multitude of sins and is open to a variety of interpretations. Ultimately, the FDA's external advisory body reviews all relevant safety and efficacy information and then votes up or down on new drug applications (NDAs). The FDA generally accepts those recommendations, but is not obliged to do so. Outside advisors must agree that a medicine is safe enough to introduce.

The FDA provided plenty of input on the effectiveness of the design of the most critical study that led to the product's approval. They insisted on specific protocol features I would not have gone for if I had a choice. These all biased the potential outcome of the study against clozapine showing a difference vs. chlorpromazine. As a clinical researcher, you'd want to ensure the study design is not biased against your medicine. 

In the end, we limited clozapine's use to treatment-resistant patients only, aligning with the FDA's cautious stance due to the severe risk of agranulocytosis. Our preference was to manage this risk through labeling, letting doctors know it’s an effective antipsychotic medicine with a range of adverse effects. But the FDA insisted that the research be done exclusively on patients resistant to existing antipsychotics.

This requirement significantly challenged our study design, but in the end the medicine performed beautifully. 

Could you elaborate on the FDA's reasoning? Why’d they insist on those specific trial conditions?

You have to understand the perspective of the major players in this type of process. Of all federal agencies, perhaps the FDA is the easiest for Congress to beat up on. 

If the FDA seems to drag its heels on getting a medicine approved, Congress will question why these medicines are available sooner overseas. On the other hand, they'll get beaten up if a drug comes to market and is unexpectedly found to be far more toxic than it was known to be during the approval process. Congress will then ask, “What were you thinking? Couldn't you tell this medicine was dangerous?” 

Why would Dr. Paul Leber, the FDA official most responsible then for the approval of psychiatric drugs, insist on using only a treatment-resistant patient population in our pivotal research? It was a way of ensuring that if he was brave enough to recommend approval, it would be under the strictest possible standards. That protected him. Several features in the trial design defended the FDA from potential criticism by both professionals and by Congress.

Where did you and Dr. Leber not see eye-to-eye on clozapine’s pivotal study development?

Initially, both we and the FDA concurred that clozapine's potential product label should be restricted to patients resistant to previous treatments due to risk/benefit considerations. I had hoped for a traditional study on general schizophrenia patients, later restricting prescribing through product labeling and physician education. However, Dr. Leber insisted on limiting study participants to those proven treatment-resistant.

The question then arose about identifying and classifying “treatment-resistant” patients. Dr. Leber demanded documented historical evidence of treatment resistance to at least three prior medications followed by a proactive period of high-dose haloperidol for six weeks. Anyone responding to haloperidol would be excluded from the study.

Restricting study candidates to those who had failed multiple treatments was challenging. When the FDA speaks, arguments can only last so long. I thought if Dr. Leber was demanding to include only extremely treatment-resistant patients, we might still claim a “win” if we could show clozapine had significant advantages, like fewer extrapyramidal (Parkinson-like) side effects, over control patients receiving chlorpromazine.

Dr. Leber also required us to prove clozapine's superiority to chlorpromazine, not just “equivalence,” for FDA approval. This exceeded the FDA's official regulatory standard of simply establishing that a new medicine is “effective.” Despite my objections, Dr. Leber's stance prevailed.

In the end, since Dr. Leber was the eminence grise behind this pivotal clinical trial, the FDA had no choice but to embrace the impressive study findings and — with the blessing of the Agency’s outside advisors — approve clozapine for commercial distribution in the U.S.

So there was informal dialogue between the FDA and companies trying to bring a drug to market. Did that involve physical meetings with Leber and others? 

Yes, we were discussing the trial structure face-to-face.

Traditional communication lines involve the pharmaceutical company, the regulatory agency, and their intermediaries. Typically, there's a designated regulatory affairs person from the industry and one from the Agency, the Consumer Safety Officer. These mid-level operators handle communications between the Agency and Sponsor. 

We received casual word through this channel that Paul Leber signaled that the FDA does not have a fixed policy against medicines with serious adverse effects. If we could show that the significant side effects were controllable and the medicine offered exceptional benefit, they were open to considering its approval. We used this informal tip as leverage with our higher-ups, conveying that the FDA was potentially on board with our proposal.

By 1981, five years after we paused our work, we had learned much more about how to safely manage agranulocytosis. That additional knowledge gave me enough leverage to convince our management to approach the FDA again. We accumulated more evidence on managing side effects, and clinical reports continued to paint a beautiful picture of unheralded benefits for treatment-resistant patients. We now had a stronger case.

Tell me more about the three phases of clozapine clinical trials. 

In clinical pharmaceutical research, we usually talk about three, sometimes even four, phases of trials.

Phase I involves recruiting healthy volunteers, like college students willing to donate their time and bodies to science. These early studies are crucial. They help us determine the maximum dose someone can take without serious side effects. These volunteers are informed about the known risk profile and can opt out anytime, but it's vital to find what's tolerable.

After establishing this, we proceed to early Phase II. This is where we give the drug to patients who might benefit from it. We're still in the early days, so these aren't full-blown controlled trials yet; that's part of the later Phase II process. Here, we start shaping the studies for Phase III, which are more extensive.

By the end of Phase II, we have a reasonable certainty that the drug works with a good grasp on the correct dosages, but a more complete safety data profile still needs to emerge. Crucially, each phase's progression requires both internal approval and the FDA's consent. It's a partnership with the Agency.

In these clinical research phases, tracking adverse events is intensely thorough and needs to be complete. The penalties for withholding bad news during pre-commercialization are severe, both formally and informally. Safety inquiries might be routine or not, but they're a crucial aspect of approval review. Often, the Agency assigns separate reviewers for the Safety and Efficacy dossiers. They may or may not make an actual approval recommendation before putting the full New Drug Application (NDA) to their Advisory Committee of outside experts and patient advocates. The Agency overrules recommendations of its advisors only rarely, and at its peril. 

Once medicines hit the general market, a new safety chapter begins, Phase 4. Now, thousands of patients, a broad spectrum unlike the research phase, are exposed to the new molecule. Predictably, issues arise. Many significant adverse effects only emerge after widespread post-commercialization exposure, often in people with specific physical problems affecting tolerance. The bottom line is that many new adverse effects are identified, and the incidence of established reactions might increase, sometimes selectively, in certain demographic groups.

But a real question is how much of this new adverse experience is reported to the FDA. The answer is very little. While there's an expectation that doctors, pharmacists, nurses, and patients will report these effects using the FDA's reporting system, the reality needs to be improved. Maybe 1 in 10, 1 in 20, or even 1 in 100 cases are reported. The process takes effort, and much goes unreported.

When did you start having issues with the agranulocytosis cases observed abroad?

Clozapine was a tough drug from the start. In Phase I, there was a moment when I thought we were done with it, and this was before we even got to agranulocytosis issues. We had healthy volunteers who would just collapse suddenly — they fainted because their blood pressure plunged so low that not enough blood was getting to the brain.

When the blood pressure fell, the heart would start racing to try and make up for it. That's a scary response because your blood isn't circulating adequately. The heart tries to pump harder and faster to fix it, and sometimes you faint, i.e. your body spontaneously falls to a horizontal position to improve blood flow to the brain.

What steps did you take to overcome these issues?

Well, building a relationship with the FDA was crucial. Here’s what I did, which was quite unusual then — I was pretty new to all this in 1973. I said, look, we've got a problem here that looks almost impossible to handle. Low doses were causing significant cardiovascular side effects in healthy volunteers. How to get past that? That wasn’t immediately clear.

In that first year, I decided to shake things up. I brought together a bunch of experts from around the world because while we were just starting to test this drug, it was already in use in a number of countries. We all met in Manhattan. I had invited folks from other countries and the U.S. to discuss what they’d seen, what worked, what didn’t.

And then I tried something new. I invited the FDA’s director of the neuropharmacology division — Paul Leber's predecessor, Tom Hayes — to our meeting. You don’t usually mix those worlds — industry and FDA — but I did. He was right there, hearing all our discussions.

The first day was all about laying out the issues. There was a certain amount of hand-wringing and hair-pulling. But the next day, I introduced a new dosing idea that might solve our problem. The group was into it. It was a creative solution. That plan – essentially starting at very low doses and building up gradually to an effective range – was a winner and is still a standard part of clozapine treatment.

Bringing the FDA into our strategy session from the start was a game-changer. It built a lot of trust and credibility. When the FDA trusts you, they don’t second-guess every data element you show them. That matters a lot because the FDA will accept what you're saying if you have credibility. They won’t necessarily assume, as they generally do, that “these bastards out there are trying to trick us in some way, so we have to tear their figures apart to find the devil in the data they're trying to hide.”

They knew that I’d be upfront with them, which earned me a lot of credibility. That came in handy when we hit another major snag with agranulocytosis side effects a year later.

Most people might assume the process to be faceless and bureaucratic. But it sounds like personal relationships were central to your success.

Strict attention to managing adverse reactions fostered a lot of mutual trust, which certainly helped the product’s approval. But it might not have helped the product's commercialization. It was a double-edged sword. I focused a lot on pinpointing every adverse effect and figuring out how to manage them. That was my shtick. Like with the dosage regimen, I'd spot a problem and find a solution. We found a workable fix for each issue that came up, like an “early warning system” for agranulocytosis. But this approach didn't necessarily benefit me or the product after approval, because it had to be sold.

My method for introducing doctors to clozapine — or “Clozaril,” as the brand was known then — didn't quite match the marketing and sales veterans’ strategies. And they might have had a point. Without getting too deep into the weeds, I’ll share a bit about commercialization and the competitive marketplace.

A year or two after Clozaril hit the market, my strategy was: inform doctors upfront about the side effects, like hypotension, tachycardia, seizures, agranulocytosis, and a couple of others, but, at the same time, show them how to manage these issues with dose adjustments or concurrent medications.

When we got to the commercial stage, I trained about 140 sales reps. They needed materials for their discussions with doctors, nurses, clinical staff, and pharmacists. I prepared videos — remember, this was before everything went digital; we're talking late ‘80s here. Sales reps didn't have smartphones with videos at the ready.

I handed out Super 8 players, along with analog tapes, that could all fit into a briefcase. Each tape covered a different topic: seizures, agranulocytosis, tachycardia, you name it. We had doctors on these videos explaining these problems and how to manage them. Every sales rep has one of these players. The plan was simple: place it on the doctor's desk, play the video, and teach them about managing side effects.

However, the US sales manager for Clozaril had a different plan. He insisted that the reps never use those tapes — ever. His message was clear: we don't emphasize side effects. All my ideas about what sales reps should be doing were dismissed by their higher-ups, who believed that discussing side effects would scare doctors away. They thought it would make Clozaril seem too risky, not only to develop but also to prescribe. They might have been right, even though I was convinced I was on the right track.

When those overseas reports of agranulocytosis started coming in, where exactly were you in the FDA approval process for clozapine?

Okay, so regarding the NDA for clozapine, we weren't even close to that stage. We were in the early to mid-phase of the second set of trials. We were conducting controlled studies and comparing clozapine to chlorpromazine, the standard treatment at the time, and we were hoping to demonstrate that clozapine was at least as effective as chlorpromazine and hopefully with fewer neurological side effects.

We ran the study across six different centers in the country, aiming for 300 patients. When the agranulocytosis reports surfaced overseas, we were right at halfway, with 151 patients enrolled. The company's response was swift; they halted the clinical studies: this medicine was too toxic to develop. We needed to stop right there. This was back in 1975.

However, the studies that continued were the open-label, compassionate-use ones. These were critical for patients who had tried everything else and were finally seeing improvements with clozapine. Doctors pleaded to continue access to the drug. As the clinical project leader, I'd get calls from sites asking to add patients to the compassionate-use protocol, and I always said yes.

From '76 to '81, the number of patients on compassionate use kept growing. Meanwhile, our colleagues in Basel were gathering global data on agranulocytosis cases related to clozapine. They started with an initial 18 cases from Finland and ended up with around 200. This information made it clear that regular white blood cell monitoring could catch issues early, allowing the drug to be stopped in time for patients to recover.

Those who unfortunately didn't make it were usually the ones diagnosed too late for the drug withdrawal to help. So routinely monitoring patients' blood counts became crucial for allowing research to continue and ultimately for allowing Clozaril on the market.

When doctors were asking for compassionate use authorization, were they familiar with clozapine through word of mouth?

Well, there was a small cadre of doctors who, pretty much from the beginning, were the leaders in the field, who knew about clozapine and who requested that we make the medicine available to them, which we did. Initially, this was just a handful of doctors, maybe five or six, who would champion the drug at professional gatherings, telling others about the great results they were seeing. So we’d get calls from other doctors. 

By the time 1981 rolled around, we had an increasing cohort of patients shown to be doing better. And these doctors were adamant about never taking this medicine away from them. They were saying, "Don't ever pull this medication." And we made a promise — the company pledged to keep supplying clozapine no matter what, even though full approval at that time seemed like a long shot. 

And they agreed with that because the idea of actual approval seemed highly unlikely to anyone, but we did commit to open-label, humanitarian, and compassionate use. Doctors would continue to be able to get the medicine for their patients. Otherwise, the results were going to be complicated.

For patients who had found relief with clozapine, relapse was almost inevitable if it was taken away. These are not curative agents. These are agents that have to be taken chronically. The company did the right thing by committing to that group of otherwise treatment-resistant individuals. No, we said, we'll never take this medicine away from you. 

Were you in contact with the FDA through other channels when the trials were stopped?

It felt like a complete stop. At the start of 1976, I thought we were done with clozapine, apart from keeping some patients on it through compassionate use. The thought of jumping back into controlled clinical trials and putting together a formal new drug application seemed extremely far-fetched — until we saw a shift around 1980, 81. This was when our understanding of agranulocytosis management began to change. We reported our findings to the FDA, not because we were gearing up for trials again, but just to keep them in the loop.

Around that time, there was a sense from Leber that they were open to considering drugs with serious side effects, provided they could be managed responsibly. That shifted the landscape. And now, with some hindsight, I think about those initial cases in Finland. What happened there, right? We don't have all the answers. They were mostly older women, and there's debate about whether those cases were typical. But in the grand scheme, it almost doesn’t matter because, in that period, we started seeing hundreds more cases.

The medicine was effective as an antipsychotic, but the risk of agranulocytosis was about ten times higher than with other antipsychotics — roughly one in a hundred instead of one in a thousand. We couldn't ignore that.

So, by '81, we felt these nudges from the FDA, like they might be open to reconsidering clozapine. That's when I let management know that we had a better handle on managing the risk of agranulocytosis and that the FDA might just give us another shot at approval. So management said, “Alright if you think it's possible, go ahead and give it a shot." But we had to do it in a year without extra help.

So, there I was in '81, understaffed and with a brutal amount of work, pulling together clozapine’s first new drug application. I had 1981 to 1982, one calendar year to do it. We weren't betting on approval — without complete Phase III data, it was a long shot. But we had that halfway Phase II study with 151 patients, and the results were promising. It wasn't proof, but it looked good on several crucial fronts.

Sure, we only had half of the Phase II trial finished, but in the big picture, you work with what you have. It wasn't approved, which didn't surprise anyone. But the value was in the feedback. The FDA and its advisory committee were encouraging. They saw potential and said, "Do a proper Phase III study in treatment-resistant patients, and let's see."

It was a rejected application, but with a roadmap to approval. The consensus was clear: This wouldn’t fly without more data, but they gave us a clear sign to keep going, proving the drug's worth in the most challenging cases.

Just to clarify, it wasn’t the FDA who gave us the one-year timeframe; it was our management. They essentially said, "Look, you have other tasks to handle. If you can complete this within a year, go ahead. But it won't cost us extra; you’re already on the payroll. If it’s feasible, do it." So we took on the challenge. It was our management who set that one-year limit, not the FDA.

And when the FDA responded with a conditional rejection, that affected the company's view on the drug, considering the FDA seemed somewhat receptive. It did. There was no doubt left — we were heading to Phase III.

Despite commercial concerns about serving a diagnostically-restricted niche market, Sandoz gave the green light. Why? In a commercial environment where the odds are an estimated thousand to one against ever bringing an investigational drug to FDA approval, I assume the business decision was that some revenue to offset the long-running development costs of clozapine would be better than no revenue at all.

What goes into a new drug application? What are the pieces of that application that you submit? 

I've got a picture of me sitting in a room with 327 volumes of material. A volume is about a two inch-thick binder packed with everything known about this medication. In modern times, most of this is submitted electronically, but back then it ranged from raw data to written narrative reports. 

The information pyramid in a pharmaceutical company starts with the chemists, so there's a section for chemistry. Then comes pharmacology, where we study the drug's effects on various animal species. After that, we have the toxicology reports detailing the doses at which 50% of the test animals succumb, providing insight into potential human dosage limits.

The metabolism team steps in next, analyzing how animals and humans metabolize the drug, supported by clinical sample studies. There’s also the manufacturing side, detailed in its section of the NDA. Essentially, every department contributes a piece to the entire picture.

So you got the very qualified note from the FDA, and Sandoz started Phase III trials. Talk to me about that process.

This whole process was familiar territory for me; it took me back to my time at the VA, where I was involved in multi-center studies right from the start. My role, along with my associates, was internal: we were the ones designing what the study protocol would look like. Leber had a big hand in shaping the design of this study. It wasn't just a few disagreements here and there; it was an ongoing collaborative effort to finalize a complex protocol that was many pages long, with many specifications. It’s a rigorous negotiation process. We go back and forth until we reach an agreement that aligns with FDA expectations.

The final product, the protocol, is a comprehensive document that receives the green light from the FDA, allowing us to proceed. It also has to persuade corporate management that the study is well-designed and has the potential to yield the desired outcomes.

How long was the process from the first FDA no to the eventual FDA approval? 

Reflecting on that first attempt with the partial dataset, we indeed submitted the NDA around '82, and it took roughly a year to be assessed. It was in '83 when we received feedback — clear support but not affirmative for approval — yet they provided constructive guidance. Fast forward to '84, and we're in the thick of study design, leading to study number 30. If I recall correctly, this pivotal study ultimately tipped the scales, kicked off in '85, and wrapped up by '87.

Though bound by legal frameworks, the FDA's actions often reflect individual administrators' personalities and proclivities. The agency has a fixed operational rule: when you send in any submission, they must get back to you within 180 days. However, even the most cursory of responses will suffice. 

It could be them telling you they’re still reviewing or having issues with some of your data. But as long as they've replied within that six-month window, they’ve done their job by the book. They’ve got wiggle room to use their judgment, to play it slow if they want to since all they need to do is make sure they've responded by that 180th day. So there's a lot of latitude.

How did your team develop the Clozaril Patient Monitoring System (CPMS) in response to the FDA's recommendations for clozapine approval?

Firstly, the FDA didn't just suggest — they mandated that the company deal with the agranulocytosis issue in the drug's labeling. I implored them for some direction and criteria that would satisfy their requirements, but they wouldn't specify. They essentially took a stance similar to a Supreme Court justice's comment on defining pornography: “I know it when I see it.”

And that's what we heard from Leber: put together a system to protect patients, and we'll decide whether it's adequate. This presented a significant challenge. With the company under time pressure, the goal became to design a foolproof system that the FDA would surely approve, rather than the bare minimum, which risked rejection and further delays due to a lack of guidance.

The complexity of CPMS can be traced back to this problem — although it's impossible to know if a less intricate system would have passed the FDA's scrutiny. However, as detailed in the paper I authored on the CPMS process, it was important that the initial design was not intended to be permanent.

In subsequent years, the system was gradually liberalized. For instance, a white blood cell count was initially required weekly for every patient indefinitely. Within the first year or so after its release, we managed to decrease the testing frequency to every two weeks after six months, and eventually to once a month after one year. These reductions in the frequency of blood draws made the process significantly less burdensome for patients.

Yet, despite our expectations for continued liberalization, the adjustments ceased. This stagnation could be explored through the interplay among the pharmaceutical industry, regulatory bodies, and the public. In this case, the sponsoring company's role was pivotal.

The anticipation was that with growing experience, the program would be progressively liberalized. However, following its approval on September 26th, 1989 — a date etched in my memory — and its market release in March of 1990, the five-year exclusivity period set by the Hatch-Waxman Amendment meant that by 1992 or '93, corporate interest in the drug waned in anticipation of generic competition, which typically results in the original brand losing around 90% of its market share in the first year.

I hypothesize that the company chose to refrain from investing in a product that would soon face generic encroachment. It was a remarkable journey, but it concluded with the prospect of generic alternatives.

Tell me about the state of play for clozapine today. You've mentioned that it's still underused because of the management systems that are still in place today? 

The government has taken over the monitoring system for clozapine through a REMS (Risk Evaluation and Mitigation Strategies) program. It’s the only medication for agranulocytosis with such a program. The current complexity and inflexibility of the REMS program are major barriers to accessing clozapine. That's the first point. Secondly, clozapine was introduced in 1990, and three decades later it’s arguably the safest option we have if you consider the comparative risk of mortality, including the risk of suicide, which is lower compared to other medications. This medicine should be promoted much more broadly from a public health perspective. But it's not happening. Companies need to prepare to invest in getting that message out.

My goal is to rally the psychiatric community. We're capable and knowledgeable about managing side effects and monitoring white blood cells. Through my papers, I hope to stir up the field of psychiatry to challenge the status quo.

After 30 years, the issue remains: some patients desperately need this medication but aren’t receiving it. Those who do have it prescribed often struggle to ensure the pharmacy can provide it when needed.

Are there pressures on the FDA not to liberalize the REMS program right now? 

There are a couple of points to consider. First, is there a party or parties interested in maintaining the complexity of the current system? The answer leans towards yes. The REMS program outsources its execution to third-party vendors, who are vested in the system's complexity. A more intricate system is preferable from the perspective of such a vendor, whose livelihood is tied to administering REMS programs.

On the other hand, are there efforts to simplify this system? There’s a group named “Angry Moms,” individuals who are deeply frustrated with REMS. They’ve recently persuaded ten congress members to endorse legislation to dismantle REMS. There’s a very active and current initiative. These are folks directly affected by severe mental illnesses that require clozapine for treatment, either as patients themselves or as family members. They’re working to make REMS more manageable within the confines of the existing framework. In contrast, the role I’ve carved out for myself is to argue for the complete removal of REMS. My stance is straightforward: abolish it and let psychiatrists practice medicine just like other physicians.

The second group is actively dealing with the ongoing challenge of securing medication for their patients, resorting to extraordinary measures like hoarding medication to create a buffer and support each other.

What did you learn about the FDA approval process through your experience?

Credibility matters. Organization matters. Mutual respect matters. Ultimately, there is not one FDA but individuals in senior roles at the FDA who place their marks on operations, enforcement style, and willingness to back long shots. The most accessible word in the regulatory lexicon is “NO.” Getting to “YES” sometimes takes cojones.

Is there anything I should have asked you that I haven't?

I want to touch on something real quick — how crucial commercial backing is. I owe a lot to Sandoz for their support of me and the product. When you’re relying on grants, you’re always on the hunt for funding. That got old fast, especially since I wasn’t good at it. You end up with a career that’s just bits and pieces, just doing the studies you luck out on getting money for. 

But with a commercial sponsor, you have consistent funding, at least as long as the higher-ups believe in the drug you're working on. We managed to push this through, which would’ve been a no-go without Sandoz’s backing. Impossible.

But after the product hit the market, they took a step back. They didn’t keep up with updating the monitoring system, making it more flexible, and things sort of spiraled from there.

I also want to mention one more point about commercial support: why the case of clozapine being a lifesaver is so critical and rare. In 2002, a study was done that proved that clozapine, compared to the best alternative newer medicine, olanzapine, saves more lives from suicide. But to run a controlled study about suicide risk, man, that's expensive and time-consuming because suicides are pretty rare, and you need long follow-up times. This study was massive — nearly a thousand patients across 17 countries. So, with their advisory committee recommendation, the FDA greenlights clozapine for reducing suicide risk in schizophrenia and schizoaffective psychosis patients.

There are over 20,000 drugs listed in the FDA’s approved drug database, and out of all of them, only clozapine is indicated for lowering suicide risk. We've got people dying who shouldn’t be. It's a monumental missed chance. Saving lives is so atypical for psychiatrists, in particular, to think about. It's unlike cardiology or oncology, where they always consider saving lives. Psychiatrists think about improving lives, but rarely do they have in their hands the potential to save lives.

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Thanks to

Michele

for his judicious edits to this transcript. His Substack is

Borsalino Test by Michele Canzi

.