Eight University of Minnesota bioethicists have sent a letter to the university’s Board of Regents, asking it to appoint an outside panel of experts to investigate the ethical issues raised by the case of Dan Markingson, a young man who committed suicide in 2004 while enrolled in a psychiatric research study at the U of M.
“There are a number of unresolved concerns, and I think it’s time there was an outside assessment,” said Leigh Turner, an associate professor in the Center for Bioethics, the School of Public Health and the College of Pharmacy, in a phone interview last week.
Student representatives to the Board of Regents had also intended to raise the issue of conflicts of interest at the U of M — both in the Markingson case and in the university’s handling of the “Troubled Waters” documentary — in a report to the full board this week. Last week, however, the board’s staff objected to “stylistic” concerns about that section of the students’ report, and it has been taken out of the final document that will be presented to the Board on Friday.
A revised version of the deleted section may be part of next semester’s report, according to Matt McGeachy, a graduate student in the U of M’s History of Medicine program. McGeachy, who serves as a student representative to the board, drafted the deleted section.
“I thought [the conflict-of-interest issues surrounding the Markingson case] were sufficiently important to be brought up to the board,” he told me last week.
“It was really troubling to find out that this study, which was entirely funded by the pharmaceutical industry, had resulted in the tragic and unnecessary death of a young man not so far from the age of a number of our graduate and undergraduate students,” McGeachy added.
Several ethical violations cited
As described in a 2008 series of articles in the Pioneer Press and in a lengthy article in Mother Jones last August (written by Dr. Carl Elliott, a professor of bioethics at the U of M and another signator to the letter to the Board of Regents), Dan Markingson was 26 years old and experiencing psychotic episodes when he was recruited into a U of M clinical trial of the antipsychotic drug Seroquel (quetiapine). The study was funded by the drug’s manufacturer, the pharmaceutical giant AstraZeneca.
How Markingson was recruited — as well as other details of the case — “suggest serious problems in the way that clinical research is conducted and overseen at the university,” the eight bioethicists state in their letter to the Board of Regents. “Those ethical violations include: recruiting a mentally ill, possibly incompetent subject into a research study while he was under an involuntary commitment order; large financial conflicts of interest on the part of the university researchers conducting the study; a payment structure for the study which included financial incentives to recruit and retain subjects rather than provide them with standard therapy; an allegedly biased study design aimed at generating positive results for AstraZeneca rather than investigating a genuine scientific question; the failure of university researchers to address the legitimate concerns of Mr. Markingson’s mother, Mary Weiss, who warned that her son was suicidal and who attempted for months to have him removed from the study as his mental condition deteriorated; the apparent development of a specialized unit in Fairview Hospital designed to identify severely mentally ill subjects for recruitment into research studies; and finally, a failure of the institutional oversight system for protecting human subjects of research.”
The letter acknowledges that the U of M and AstraZeneca were cleared of blame by a Food and Drug Administration investigator in 2005, but stresses that the ethical problems surrounding the case remain “serious enough to warrant further investigation.”
“Patients participating in research studies at the University of Minnesota need to be confident that the university is doing everything it can to protect them from harm,” the bioethicists write in the letter. “For this reason, we respectfully request that the Board of Regents appoint an impartial panel of experts in research ethics and university governance of medical research to investigate the Markingson case, particularly any larger structural or financial conditions that might have played a role in his death and which may still be putting patients at risk.”
Potential financial conflicts
“There’s a financial backdrop to all of this,” explained Turner in my interview with him. “The University of Minnesota benefited financially from the study being done here. More than $300,000 went to the Department of Psychiatry.”
According to Elliott’s Mother Jones article, the U of M psychiatry department earned $15,648 for each person it enrolled in the Seroquel study. Elliott also reported that at the time Markingson entered the study, the U of M was having a serious problem recruiting subjects and risked being dropped by AstraZeneca as one of the study’s trial sites.
The two U of M psychiatrists who led the study, Drs. Charles S. Schulz and Stephen C. Olson, personally earned a combined $811,045 between 2002 and 2008 from pharmaceutical companies, including $261,364 from AstraZeneca.
U of M cleared in earlier reviews
In a statement issued last August, after the Mother Jones article appeared, Mark B. Rotenberg, general counsel for the U of M, said that issues raised in that article “have been reviewed by federal, state, and academic bodies over the last five years, including the FDA, the Hennepin County District Court, the Board of Medical Practice and Minnesota Attorney General’s office, and the university and its IRB. None found fault with the university, none found fault with the involved faculty, and none found any causal link between the [Seroquel] trial and the unfortunate death of Dan Markingson.”
Markingson’s mother, Mary Weiss, brought a malpractice suit against Olson, which was eventually settled for $75,000 (an amount that failed to cover Weiss’ legal costs, according to Elliott). A lawsuit against the U of M, AstraZeneca, Olson and Schulz was dismissed, however, in 2008 with a partial summary judgment. The judge ruled that there was no case or statue that supported the contention that AstraZeneca — or any pharmaceutical company — had a duty to put the interest of its research subjects above those of the company.
Does new policy go far enough?
The U of M adopted a new conflict-of-interest policy in August — a policy that now covers all researchers in the Academic Health Center, including those in the Department of Psychiatry.
Turner, however, believes the new policy fails to respond in any meaningful way to many of the specific problems that came up in the Markingson case. “It doesn’t in any way address whether [Markingson] had a decision-making capacity or why his mother wasn’t contacted and her concerns addressed,” he said.
Nor does he believe the new policy adequately deals with the financial conflict of interests that arise when researchers — and the university itself — rely so heavily on industry funding. “It’s an important revenue stream,” he said, “and they’re not going to want to see it go away,” particularly now, when government funding of research is decreasing.
Financial conflicts of interest are a long-standing problem at research universities, said Turner, “and the conflict-of-interest policy that the University of Minnesota has drafted doesn’t really get at that problem.”
The U of M’s new policy is “more about managing conflicts of interest than eliminating them,” he added. “Managing usually means disclosure. But some kinds of conflict of interests — financial ones, in particular — just need to be eliminated.”
Won’t go away
Turner said he’s hopeful that the Board of Regents will appoint a panel of experts to do an independent investigation of the Markingson case. “I can understand a sense of reluctance or unwillingness to revisit it and see what was done and why — and what could have been done better,” he said. But the university must resist the temptation to “sweep this under the rug,” he added.
“These things tend to recur when they’re not properly addressed,” he said. “An outside investigation might generate some response. If not, this topic will come back again and again until it is addressed.”
In addition to Turner and Elliott, the U of M bioethicists who signed the letter to the Board of Regents are Dianne Bartels, assistant professor in the Center for Bioethics and Department of Medicine; Joan Liaschenko, professor in the Center for Bioethics and School of Nursing; Mary Faith Marshall, professor in the Center for Bioethics and Department of Family Medicine and Community Health; Dr. John Song, associate professor in the Center for Bioethics and Department of Medicine; Susan Craddock, chair of the Department of Gender, Women, and Sexuality Studies and an afficiliate faculty member in the Center for Bioethics; and Joan Tronto, professor in the Department of Political Science and an affiliate faculty member in the Center for Bioethics.
For more information
A website with a link to the letter to the Board of Regents and other documents can be found here. You can read Elliott’s Mother Jones article about the Markingson case here. (Dan Markingson’s story is also featured in Elliott’s most recent book, “White Coat, Black Hat: Adventures on the Dark Side of Medicine.”) The U of M’s response to the Mother Jones piece can be found here.
I am proud of my faculty colleagues at the University of Minnesota for speaking up on this matter. The disgraceful behavior of my alma mater in the Markingson case has been shameful.
The Academic Health Center Administration does not seem to understand the distinction between illegal and unethical.
For an illustration of this lack of understanding, please see:
“We’re Not Violating a Legal Statute”
Link: http://bit.ly/zLxTA
William B. Gleason, PhD, Associate Professor, University of Minnesota College of Medicine
I used to work on psychiatric units at Fairview University. We saw a lot of this studies and there were frequently problems. The idea of getting informed consent from a mentally ill adult is very tricky issue to begin with. One problematic practice is the use of family to get patients into a study. Frequently family members will be involved in the consent process and encourage patients to enroll in a study, but they then have no legal power to withdraw the patient if it looks like things are going wrong. The ability of a patient withdraw themselves is also quite limited. When a schizophrenic decompensates they usually can’t form any kind of objection to the experimental medication. In fifteen years working psych I don’t think I ever heard of a patient asking to be withdrawn from a study and put back on their previous medications. Family members usually lack the legal standing to make such a demand. Even a mental health advocate or lawyer can run into a wall if the patient themselves is not refusing treatment.
Another problem we had was the difficulty getting anyone to intervene when things were clearly going wrong. Medical directors, hospital administrators, and other physicians are very reluctant to intervene in another Doctors treatment or study.
Psychiatric research is necessary and very difficult to do. A lot of people are trying to conduct very difficult and very commendable research that can lead to much more effective treatments. But too many time I saw all the safety’s fail. Peer review and supervision, review boards, licensing boards, human subjects safe guards, informed consent requirements, and concerned staff can all fail under current regimes with tragic consequences.
A top to bottom bioethics review would be a great idea. There is no actual safety that can be deployed to break a patient out of study regime if they’re decompensating. Nothing triggers an automatic withdrawal. There should some kind of lever that can be pulled by any number of people from unit staff to patients family. Every subject should have some designated person that can pull the plug without repercussions whether the researchers like it or not. At the very least anyone on the treatment team or family member should be able force a chart review at any point. One way might be to designate another doctor in a completely different area of the hospital as an independent reviewer for the course of the study. Any concerned staff or family should be able to register a concern that would trigger a review by that doctor who would have the power to break a patient out of a study. Every review and request for a review needs to be documented and reported.
Another problem not discussed here is the practice of simply not publishing studies that don’t deliver the desired results. You have multiple studies sometimes on the same drug putting patients at risk because previous studies simply weren’t published and researchers aren’t required to share that data with anyone. They can tweak the study until they get good enough results and then publish.
The mere fact that the state legislators found what happened to Dan Markingson appalling and passed Dan’s Law unanimously should have been a wake-up call at the University of Minnesota that things are not right regarding how they conduct research on the mentally ill. The legal counsel never seems to remember that. It seems ethics are a complete joke to the department of psychiatry, with them it’s money buys truth and pharma money buys lots of truth. We don’t care how the human subjects are doing; just how many more have you enrolled.