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Bioethicists ask U of M Regents to appoint outside panel to review ethics of 2004 Dan Markingson case

How the patient was recruited to a psychiatric study, 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 ethicists say.

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.

Leigh Turner
Leigh Turner

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.

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“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.

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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.”

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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.