Drugs of 4 Patients Subbed Without Ok
The Boston Globe 11/10/03
A doctor at a state mental health facility changed patients' medications last year so that they would be eligible for a study of a new psychiatric drug, violating basic guidelines for research on human subjects and causing dangerous side effects in a 43-year-old man with schizophrenia, a state investigation has found.
The Disabled Persons Protection Commission uncovered numerous ethical violations at the Solomon Carter Fuller Mental Health Center by Boston Medical Center physicians contracted to treat patients there.
According to a DPPC report, patients' medications were switched without informed consent and without a clear medical need, the changes were made more than two months before the human-studies review boards approved the research protocol, and the patients involved were clearly not eligible under the criteria for the study, which specified that subjects be outpatients.
One of the four patients whose medication was switched, a man who had been stable for 10 years on the drug Clozaril, became so ill and acutely psychotic that he spent months in and out of hospital wards. He was diagnosed with neuroleptic malignant syndrome, a rare, sometimes lethal side effect of medication changes, according to the commission's report.
When the man's health problems grew serious enough to discuss in a Department of Mental Health case conference, a top state mental health official expressed shock that there was a plan to use patients as human research subjects.
"The incident . . . was an egregious series of events that led to a patient experiencing debilitating psychiatric and medical symptoms," wrote Clifford Robinson, Department of Mental Health area director, in a September memorandum about the investigation. The incident "delineated what can happen when a research project is introduced into a clinical environment that is unprepared for it."
The DPPC is an independent state agency that investigates alleged abuse against any disabled person in the Commonwealth. A year ago, Janssen Pharmaceutica was preparing to introduce Risperdal Consta, a two-week injectible form of Risperdal, its drug to treat schizophrenia.
To troubleshoot its instructions for physicians switching patients from oral Risperdal to Consta injections, Janssen asked a number of researchers
-- among them Dr. Domenic Ciraulo, Boston Medical Center's chief of psychiatry -- to test the transition on a total of 60 adult patients who were on oral Risperdal, said Carol Goodrich, a Janssen spokeswoman.
Each site would be paid on completion of the trial, Goodrich said. Janssen declined to reveal the amount.
Ciraulo turned to the Fuller as a site for the study, delegating authority to its medical director, Dr. Douglas Hughes. The prospect of a clinical trial at the Fuller promised to bring prestige to a downtown community health center that, situated among many august research centers, "had not been an attractive place for residents and medical students," Hughes later told investigators. "We saw the Consta study as an opportunity."
But as they looked for eligible subjects, one doctor began asking patients about participating in the trial. Last fall, months before review boards for Boston University and the Department of Mental Health had approved the study, the doctor switched four patients to oral Risperdal so they could be enrolled in the trial, the report said.
By late January, one of the four became so confused and delusional that he was sent to the emergency room and frequently needed to be restrained. Months later, when he returned to the Fuller, he was emotionally drained and sensitive to any antipsychotic medication. Known among the staff as an avid and "very knowledgeable" Red Sox fan, the patient was asked by a state investigator for a favorite player on the current team. He mentioned Carl Yastrzemski, who retired from baseball 20 years ago, and had no response to the names "Nomar," "Manny," or "Pedro," the report said.
The clinical trial at the Fuller was halted in February, and no patients there ever received Consta. The other three patients switched to Risperdal suffered no ill effects.
Changing medications for research without the patients' consent is unethical, and it's especially questionable in a state institution, said Dr. Peter Lurie, a medical researcher with Public Citizen's Health Research Group, which monitors research ethics.
Institutionalized patients, like prisoners, may feel pressure to become subjects, and researchers, as well as their institutions, could benefit financially from recruiting subjects, Lurie said. As soon as medication changes were made, the clinical trial was effectively underway, without oversight to protect subjects' rights -- "a flagrant violation of clinical ethics," he said.
The names of doctors involved were deleted from the commission report, but Department of Mental Health officials and Hughes acknowledged their identities.
On Sept. 29, Hughes resigned his position as medical director of the Fuller, explaining in a letter to center director Dr. Mary Louise White that he believed he "share[d] responsibility" for the change of medication, which he ascribed to a "failure of communication between the principal investigator and the physicians . . . at the SCFMHC."
Hughes, who was listed as one of Boston magazine's "Best Doctors" in 2000, is now associate director of training and medical director of outpatient services at BMC's department of psychiatry. He is a paid speaker for Janssen Pharmaceuticals, and earned more than $30,000 in speaking fees last year, he said.
The attending physician who switched the four patients, Dr. Valentina Jalynytchev, is still working at the Fuller, said Lester Blumberg, chief of staff at the Department of Mental Health.
Jalynytchev did not respond to requests to be interviewed for this article, but told investigators that she believed preparing the patient to receive Consta -- the first injectible form of a newer-generation antipsychotic -- was a "good treatment option," made with "nothing but his best interest in mind."
Both doctors plan to appeal the report's findings, said Ellen Berlin, a Boston Medical Center spokeswoman. Berlin would not say whether either doctor had been disciplined.
The doctors could also be disciplined through the Massachusetts Board of Registration in Medicine, which reviews complaints of misconduct and regulates doctors' licenses to practice medicine. No public information is available about action in this case, said Nancy Achin Audesse, the board's executive director.
In an interview, Hughes said Ciraulo had given him authority over the study at the Fuller, but he had received no training in working with human subjects. The physicians at the Fuller, he said, believed that it was permissible to switch patients' medications so they could be eligible for the study. When staff members complained that the switch was unethical, Hughes said, he asked Ciraulo informally whether informed consent was necessary.
"I said, `Is this OK? Is this a problem? Can we not switch people's medications from one approved atypical [antipsychotic medication] to another?' " Hughes recalled in a telephone interview last week. Ciraulo, he said, told him doctors were free to do that.
Through Berlin, Ciraulo declined requests to be interviewed for this article. But in the state report, Ciraulo was quoted as saying that he had "no clinical responsibility" over Fuller psychiatrists.
His attorney told the Disabled Persons Protection Commission that the Fuller "does not allow [Ciraulo] . . . the authority necessary to deal with situations that may be regarded as his responsibility" as the leader of the study.
Ciraulo, a well-published researcher, has received research grant funding from Janssen Pharmaceutica, served as a Janssen consultant, and received support from Janssen for the department of psychiatry, a Boston University faculty disclosure report said.
Top officials of the Department of Mental Health first learned of the study in February, during a medical staff conference to discuss patients. After the meeting, the area medical director, Dr. David Hoffman, wrote of his shock to discover that a trial was underway: "I was never cc'd on any of this, and I didn't know anything about a drug study at the Fuller involving our patients as human subjects. At that point, I began to realize how problematic this was. The medication switch from Clozaril to Risperdal was a violation of the drug study's protocols."
Within weeks, investigations were underway at the commission, the Department of Mental Health, and Boston Medical Center. The Consta study was terminated by the DMH's Research Review Committee on Feb. 21.
In its review, the Department of Mental Health determined that neither Jalynytchev nor Hughes, her supervisor, intentionally jeopardized patients.
"This was a physician who was poorly informed and poorly supervised about conducting research," said Blumberg, the chief of staff. "Her direct supervisor should have known, if he didn't know."
Instead, Robinson, the Department of Mental Health area director, wrote a blistering memorandum pointing to a "major systems failure" in Boston Medical Center's patient safeguards.
Robinson also criticized the hospital's internal review, which "failed to identify, in any material way, what went wrong, how broad the breakdown was and what could be learned from it." The review did not address the fact that Jalynytchev had switched the medication of four patients, not just the one who was injured, he wrote.
"The absence of a sense of remorse in any document reviewed is another noteworthy commentary on the failure of this process to attend to the harm that resulted," Robinson noted.
Berlin, the BMC spokeswoman, did not respond to the criticism of the internal review.
Boston Medical Center "immediately implemented" a corrective action plan to improve aspects of patient care at the Fuller, according to a press release from the hospital. The two institutions are discussing a range of changes to prevent a recurrence, from appointing a liaison to oversee joint activities to eliminating all research, the release said.
Researchers at the hospital are also being asked to undergo recertification in the ethics of human research. An e-mail widely circulated last week among medical center psychiatrists and psychologists announced that they will have to take monthly quizzes on such issues as federal regulations, internal review-board policies, and conflict of interest. The e-mail was provided to the Globe.
The quizzes, which will be graded, may be a "bureaucratic hurdle," the letter explains, but the Office of Clinical Research sees it as "a necessary step to keep our researchers current on clinical research information and to provide appropriate protection for the subjects who volunteer for our studies."
Mental health officials could prohibit Boston Medical Center from undertaking clinical trials at state facilities, Blumberg said.
The episode has not jeopardized the mental health agency's contract with the medical center, he said. "It's been a long and positive relationship," he said. "Part of what is so troubling about this is that it's an anomaly in our relationship with them."
Ellen Barry can be reached at firstname.lastname@example.org.
Medical records from the Solomon Carter Fuller Mental Health Center tell the story of a profoundly disabled patient who was ushered into a clinical trial during a single conversation:
On Oct. 31, 2002, Dr. Valentina Jalynytchev sat down with the 43-year-old patient and, as she noted in a progress report, "discussed . . . clinical trial of [Ris perdal]," and agreed that he would participate, according to a state report.
The man had been in psychiatric facilities since his teenage years. Diagnosed with schizophrenia and mild retardation, he had been convicted of sexual assault against staff and habitually masturbated or exposed himself in public.
But the 10 years he had spent at Medfield State before its closure had brought significant improvement. In 1993, his doctors put him on Clozaril, a drug used on hard-to-treat patients. Since then, doctors had described him as "quiet, cooperative, and without any management problems."
He had improved so much, in fact, that in late October Jalynytchev noted that he no longer required hospitalization, and remained committed only because, as a registered sexual offender, he was on a waiting list for supervised housing, according to the report.
Still, his thinking was cloudy, and he needed assistance with daily activities like taking a shower and getting dressed. When he transferred to Solomon Carter after a decade at Medfield State Hospital, he told staff he had been sent there "to watch television," the report said. In 1993, a judge concluded he was mentally incompetent and appointed a legal guardian, who was empowered with making major decisions for him.
In her notes of Oct. 31, Jalynytchev concludes that the patient was enthusiastic about starting Risperdal, which does not require regular blood tests, as Clozaril does: "He will start Risperidone . . . any time soon [it is his treatment plan], but for the study his guardian . . . needs to sign a consent form."
In fact, his treatment plan included other antipsychotic medications but not < Risperdal. No call was made to his guardian. But he was started on Risperdal five days later, on Nov. 4, 2002.
The switch in medications was the beginning of a long slide. He began drinking water in little sips from a fountain and running a slight fever. By Jan. 24, 2003, he was so confused that he "had to be redirected three times to put on his pants correctly." Later, he picked up a coffee table and attempted to throw it at the staff and other patients.
Three days later, his mental state was so altered that staff sent him to Boston Medical Center's emergency room, where the attending physician diagnosed neuroleptic malignant syndrome, a rare but potentially lethal drug reaction. Occurring in about 0.2 percent of patients taking antipsychotics, the untreated syndrome progresses to extreme "lead-pipe" rigidity and fever high enough to cause irreversible brain damage.
Over the next two months, he was often feverish and so psychotic at times that he was "urinating in bed and defecating in his room," according to the report. When the patient returned to the Fuller in March, he was so sensitive to antipsychotic medication that he could take only tiny doses. Doctors prescribed electroconvulsive therapy.
"He was never the most alert, lucid person to begin with," said one acquaintance, who spoke on condition of anonymity. "But he was much more flat. He was extremely passive. He wasn't emanating any energy."