A magyar vonatkozású részek:
For patients confined to the locked psychiatric ward at Kutvolgyi Uti Hospital in Budapest, the drug research underway last year offered a brief taste of freedom. It was a chance to make a phone call during a few minutes on an open ward, and it offered patients the vague hope of being able to go home a few days sooner.
That's why Adam Novak, a 25-year-old bartender suffering from schizophrenia, said he signed up. He said he had been locked up for two weeks at the hospital when his doctor asked if he would be willing to test aripiprazole.
The company said he signed a consent form, which he does not dispute, "but when you are being held like that and in such a state, you are not really able to understand it," said Novak, one of 600 patients worldwide expected to test the drug in that study.
Testing mental patients kept under lock and key would put an American researcher on treacherous ethical ground. "You would try to stay away from that because of the fear the patient would be coerced into consenting and you couldn't be sure the consent was really informed," said Lawrence Gostin, a professor of law and public health at Georgetown University.
But in Budapest, "it is easier to find patients here, yes," said Gabor Faludi, the researcher who signed up Novak. "Patients in Western countries -- and in the United States especially -- have an overdeveloped sense of their rights and a fear of being harmed."
He acknowledged that obtaining informed consent from mental patients is "a hard question. . . . But the reality is that scientific research can only be conducted on these patients when they are in a phase where they are getting worse."
Andrea Borbely, a 35-year-old housecleaner who was confined in the same hospital, said she refused several times to participate. Bristol-Myers said it has no record of Borbely being in a test, but Faludi said he enrolled her after getting consent from her family. Borbely contends her medication was changed, and then changed again when the experiment was over. She said it was done simply "for the sake of the test. That is what makes me angry."
Faludi said Borbely received a standard drug being used as a comparison, and her subsequent medication changes were his attempt to find an effective treatment for her.
A spokeswoman for Bristol-Myers Squibb said approaching acute psychiatric patients for testing in locked wards was standard practice in Hungary.
Medical researchers there have been guided by a formal patient bill of rights since 1998. But while its provisions are "very good, no one does it in practice. It is so new," said Judit Harangozo, a Budapest psychiatrist.
Said Gabor Gombos, president of the Mental Health Interest Forum in Budapest, an embryonic patients' rights organization: "Our experience is that patients don't know they have rights, that they can say 'no' and expect not to suffer consequences."
But researchers such as Gyorgy Boszormenyi Nagy, a physician at Hungary's National Institute of Pulmonary Medicine, complain that patient consent forms developed in the United States are too complex.
"There is too much information on it, too much science, too many medical terms. They should be written plainer," he said, without feeling a need "to give every warning so as to cover every possibility if something goes wrong."
The Meanings of Consent
The Meanings of Consent
The drug companies themselves, rather than the regulators, sometimes determine how much test subjects know about the medicines being tested. Communication among international medical test regulators is poor and sometimes nonexistent. Test participants in one country may unknowingly sign up to test a drug whose side effects already worry regulators in another country.
Two years ago, for example, the American pharmaceutical giant Pfizer Inc. had high hopes for its schizophrenia drug Zeldox, which was predicted to earn Pfizer $600 million in profits within four years. But the Food and Drug Administration was concerned about indications that the drug affected heart rhythms and issued a "not approvable" letter, meaning Zeldox required more tests on human subjects before it could be approved for sale in the United States.
Pfizer said it did that further testing primarily in the United States, with one test site in South Africa.
Pfizer was also conducting a large number of other clinical trials as part of its ongoing effort to collect safety and efficacy information on Zeldox.
The Post visited one of those trial sites at a Bulgarian mental institution last spring.
A drug information sheet given to patients at the State University Hospital of Neurology and Psychiatry, a crumbling asylum outside Sofia, the capital, made no mention of the FDA's concerns. Luchezar Hranov, who ran the study for Pfizer, also said he did not inform volunteers of the FDA's action.
"I don't believe anyone would care," Hranov said. "The FDA is out of someone's reach. I would have to do an educational course."
The three-page information sheet told patients Zeldox had "been tested in studies involving more than 3,000 patients, and the results of these studies are currently being reviewed by government regulatory authorities in Europe and the United States." The sheet noted that Zeldox appeared "to slightly affect the electrical activity of the heart in some people."
Pfizer neglected to tell Hungarian regulators about the FDA action, as well, said both Janos Borvendeg, medical director at Hungary's National Institute of Pharmacy, and Tamas L. Paal, head of the institute, which is his country's equivalent of the FDA for drugs. Hungary had been one of the test sites for Zeldox in Pfizer's original round of research before the FDA intervention. Under Hungarian regulations, Pfizer was obliged to report the FDA action to Hungarian officials because Zeldox was part of another ongoing trial last year, Paal said.
In July, an FDA advisory committee recommended approval of Zeldox for sale in the United States, and a final decision is pending.
Borvendeg said Hungarian regulators had a right to know about the FDA's concerns. "I will go to the company to ask about this and see whether it was an oversight or whether they were trying to cheat on me," he said. Pfizer responded that it adheres "to the laws of each country in which clinical research is conducted."
Testing drugs on mentally ill patients makes obtaining informed consent especially problematic. In some cases, doctors who have been paid to recruit subjects are the ones judging when a patient is capable of consent. Other times, patients believe that joining a test is the only way to receive quality care.
Doctors said that in the crowded state-run mental institutions of Eastern and Central Europe, agreeing to participate in a clinical trial can vault a patient to the top of a busy doctor's priority list.
"The patients know there is a hierarchy of patients and that the best deal for them is to be in a trial," said Laszlo Lajtavari, a psychiatrist at the Nyiro Gyula Hospital. "If you're not in a trial, you're part of the big group of people I see and you're not getting as much attention from me. I do not think that would be coercive to get them to say yes, but it is how it is."
Tibor Toth, 58, one of Lajtavari's patients who has been in and out of psychiatric hospitals since 1967, said the doctor's attention was one reason he agreed to take part in a recent drug experiment. "When I got a chance to have tablets and a chance to have continuous monitoring by my doctor, I was happy to take it," Toth said. The consent form he signed was "like a small contract. I had to read it, talk it over with anyone I wanted to, with my family." Toth recalled being told that the only risk in taking either of the drugs in a comparative test would be headaches. "To be honest, I can't remember everything I was told because I was going from one state of illness to another," he said.
In the United States, psychiatric patients could expect more protections, said Ernest D. Prentice, vice chancellor of the University of Nebraska Medical Center and head of its institutional review board. Ethics boards reviewing testing protocols might encourage patients to name a representative to act in their interest or ask that someone from outside the research team be present at all consent discussions. Once a patient regains coherence, researchers might be asked to reaffirm the consent, Prentice said.
Yet, in Eastern Europe, just the words "United States" can be enough on a consent form. Erzsebet Terjek, 45, a Budapest schizophrenia patient who agreed to test a Johnson & Johnson drug called risperidone, said she understood the risks outlined in her consent form but decided to take part because she trusted American products. "I believe they can cure me sooner," she said. "I am honored to be chosen for an American experiment."
Attila Samu, 36, an epileptic who has been part of anti-seizure drug experiments, said he understands the bargain Hungarians make. "I would like to see the day come when Hungarian companies can manufacture drugs like these, so we are not just test subjects," he said. "But for now, I see the new drugs come from America and we're the people who try them out."
Poverty and Choice
The problem of obtaining informed consent becomes even more severe in very poor countries where patients have no decent health care.
"I'd argue you can't do studies ethically in a country where there is no basic health care," said George J. Annas, head of the health law department at Boston University's School of Public Health. "You can tell a person there that this is research, but they hear they have a chance to get care or else refuse their only good chance at care. How can you put them in that position and then say they are giving informed consent?"
Researchers say it can be especially hard to help Third World patients understand such basic drug-testing practices as the use of placebos -- dummy medicines given to some participants in an experiment.
