For nearly half his life, 32-year-old Kevin Buchberger was tormented by the imaginary voices and vivid hallucinations that are the hallmarks of paranoid schizophrenia. None of the powerful anti-psychotic drugs -- among them Navane, Prolixin, Thorazine -- he took during and after a dozen hospitalizations helped much. While the drugs moderated the worst of his delusions, they caused him to shake, to pace and to see double.
Nearly three years ago, Buchberger, who lives in Cleveland, volunteered to take clozapine, an experimental schizophrenia drug, as part of a study at Case Western Reserve School of Medicine. For the first time, Buchberger said, he was allowed the "small miracle of being normal."
"I'm not paranoid anymore," said Buchberger, who had been unable to hold a job before taking the drug. "I can drive. I can go to sporting events. I'm working as a custodian . . . It's really changed my life."
For every Kevin Buchberger, mental health advocates say, there are thousands of patients with chronic schizophrenia who could benefit from what mental health officials regard as one of the most promising anti-psychotic drugs in years.
For reasons that are unclear, between 20 and 30 percent of the 2.5 million Americans who suffer from schizophrenia, a disabling and incurable thought and mood disorder, are unable to take the antipsychotic medicines that work for others. For some patients, standard anti-psychotic drugs cause serious side effects, such as tardive dyskinesia, an irreversible condition that produces facial tics and other involuntary movements. Other schizophrenics find that the drugs simply have little or no effect.
For these patients, traditionally labeled "treatment resistant" by the medical establishment, clozapine, also known as Clozaril, offers hope. But standing between them and relative normalcy is a hefty pricetag: nearly $9,000 per year.
The issues at the heart of the controversy over Clozaril are not new; they mirror the furor that has surrounded the marketing of AZT, the only approved therapy to treat AIDS, which cost about $12,000 annually when it was first released. (It now costs about $8,000).
Central to the debate is the question of access to a drug -- possibly the only drug -- to treat a disabling, life-threatening illness. Also at issue are the profits a pharmaceutical company should reasonably be expected to reap.
Clozaril is manufactured by Sandoz Pharmaceuticals Corp., the New Jersey-based subsidiary of the Swiss pharmaceutical conglomerate, which holds the exclusive patent on the drug through 1994.
The drug, first synthesized in the 1950s, is estimated to cost between $2,000 and $3,000; the remainder of the cost is earmarked for a costly monitoring program that consists of a weekly blood test administered by a company hired by Sandoz. A monitoring program was required by the Food and Drug Administration when the drug was approved last year. It is designed to prevent agranulocytosis, a potentially fatal drop in the white blood count, which has been associated with clozapine. The condition is reversible if detected early enough.
In 1975, eight Finnish patients who were being treated with clozapine died from complications associated with the blood infection. As a result, clinical trials of the drug then scheduled to begin in the U.S. were canceled; clozapine was subsequently re-marketed in Europe with a monitoring system. Sandoz officials said that during the 1980s nearly one third of the 116 European patients found to be developing agranulocytosis died as a result.
Subsequent trials of 1,800 U.S. patients have yielded positive results and few side effects. No deaths associated with clozapine have been reported in the U.S., according to the FDA. Sandoz officials say that 18 U.S. patients who have developed agranulocytosis have stopped taking the drug and have recovered.
Because of its potential toxicity, Clozaril is being prescribed only for those who do not respond to other anti-psychotic medications. These drugs can also cause agranulocytosis -- but at a rate far lower than Clozaril. Researchers have estimated one out of every 1,500 people treated with drugs such as Haldol may develop the disease. With Clozaril, the risk is estimated to be one in 100.
One of the chief reasons that patients and physicians are willing to risk the disease is the fact that clozapine acts on the hallucinations and delusions of schizophrenia -- the so-called "positive" symptoms, as well as improves passivity and withdrawal -- the "negative symptoms" that are much harder to treat.
Although other drugs have a plethora of side effects ranging from weight gain to tardive dyskinesia, so far, clozapine does not appear to produce any of these.
Because of its chief drawback -- agranulocytosis -- the FDA last year approved the sale of the drug with the unusual requirement of a monitoring system, although not necessarily one overseen by Sandoz.
But Sandoz, which has been selling Clozaril in the U.S. since February, is tying drug sales to the purchase of its monitoring system.
Two weeks ago, FDA officials wrote to the company, protesting that its labeling of the drug appears to require monitoring by Sandoz alone. The agency ordered that it be changed to permit monitoring by others. Sandoz has not responded, according to FDA spokesmen.
Mental health advocates and the U.S. Department of Veterans Affairs protest that the price of clozapine makes it inaccessible to those who need it most: longtime and often indigent sufferers of schizophrenia.
"We want the drug available, and we want it available with the monitoring," said Thomas Posey, president of the Arlington-based National Alliance for the Mentally Ill (NAMI), an advocacy group composed primarily of relatives of the mentally ill, which has 140,000 members. "But as long as there's some kind of proof that there is monitoring, we don't see why it has to be Sandoz."
About 5,000 patients are currently taking clozapine; NAMI estimates an additional 100,000 patients could benefit significantly if the drug were more affordable.
"The price of the drug without the monitoring system could be quite reasonable," said Anthony J. Principi, deputy secretary of Veterans Affairs. "With it, Clozaril is exorbitant. It's a marketing strategy."
Sandoz officials dispute that and say that the cost, while high, is justified by the best possible monitoring system. "We want to give people access," said Gilbert Honigfeld, Sandoz's strategic business director, "but access in the safest possible manner. We don't want to get into trouble here. And getting into trouble with a new drug basically means people die and the drug is pulled off the market."
The VA, which estimates that 3,600 of its patients could benefit from clozapine, says it has developed its own computerized monitoring program that would be as effective as Sandoz's system.
Earlier this month, the VA cut off negotiations with Sandoz. Last week, it wrote to Attorney General Dick Thornburgh to ask for an investigation into possible anti-trust violations by Sandoz for "tying the sales of its patented drug to an unpatented and medically common blood test."
The 83 VA patients who have been taking clozapine since February will continue to do so, according to the VA, using the company's monitoring system.
The cost of the drug is also a problem for non-military patients. NAMI claims that the cost makes clozapine inaccessible to patients at state mental hospitals and those who are dependent on Medicaid because they are too disabled to work.
So far, the District and 28 states, including Maryland,have agreed to pay for clozapine for patients in state hospitals. And 20 states, but not Maryland, Virginia and the District, have agreed to cover it under their Medicaid programs.
Several other states have indicated they want to use the drug but say they cannot afford to pay for a therapy that costs $172 per week. California officials, who estimate that 400 state hospital patients alone could be helped by the drug, have appealed to Sandoz for a price reduction. They say they are willing to pay $117 a week per patient. Sandoz has declined to reduce the price, citing its costs and need for a "reasonable return on investment."
Mental health advocates question how the company can market the drug in Europe, where national health care systems provide monitoring, for as little as $20 to $30 a week.
Sandoz officials say that such comparisons are misleading because European countries establish drug prices and dispense medications in government-run clinics that absorb the cost of monitoring.