UPDATED 12/10/2010, 5:30 p.m.—Earlier this week eight University of Minnesota bioethicists sent a letter to the Board of Regents calling for an independent investigation into the death of Dan Markingson, a research subject who committed suicide in 2004 while he was part of an AstraZeneca drug study. The letter raised issues such as whether Markingson was competent when he agreed to take part in the study, as he had been deemed incompetent and ordered committed to a state mental hospital days earlier. The eight bioethicists asked that an independent committee review “troubling questions that to day have not been addressed in the University’s response to the death of Mr. Markingson” and “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.”
The University, they said, has yet to look into how financial incentives played a role in enrolling Markingson in the study.
The University of Minnesota has been under fire for both academic freedom and conflict of interest issues regarding the attempt to pull the Troubled Waters documentary. Click here for current developments in this story, including resignation of Vice President Karen Himle.
General Counsel Mark Rotenberg told the Daily Planet that, while the U and the Regents take very seriously the allegations outlined by faculty in two separate letters calling for an investigation, all of the issues raised were subject to previous investigations and none of those investigations found fault by the University or its researchers.
“If you take all of these independent reviews together, the picture is pretty clear that the U and our researchers did not engage in wrongdoing or improprieties,” he said.
The Institutional Review Board “failed”
Dan Markingson and the Seroquel study
On November 14, 2003, Dr. Stephen Olson diagnosed Dan Markingson with schizophrenia, told a court that he was incompetent to make decisions, and recommended commitment to a state hospital. In a 2008 series, the Pioneer Press reported that Olson changed his mind in less than a week, and decided that Markingson did not need to be committed, but rather was competent to consent to participate in a year-long drug study. On May 8, 2004, Dan Markingson killed himself.
Three of the signatories to the letter-Dr. Carl Elliott; Dr. Leigh Turner; and Dr. Mary Faith Marshall-spoke with the Daily Planet and all maintain that the issue of conflict of interest and how financial incentives played a role in enrolling Markingson in the study need to be investigated. Dr. Charles Schulz, the chairman of the U’s psychiatry department, and Dr. Stephen Olson, were paid by AstraZeneca for their research on Seroquel. At the time Markingson was enrolled in the Seroquel drug study, the U was in danger of losing the study, unless it could find additional research subjects.
According to a three-part 2008 Pioneer Press series, “The CAFE study was fairly prominent, involving 26 academic institutions and 400 schizophrenic patients. Financed by the pharmaceutical company AstraZeneca, it was worth up to $327,000 to the U, with some of those funds going to Olson’s salary and other study personnel. “
The independent investigators, Rotenberg said, included the federal Food and Drug Administration, the Hennepin County District Court (in which Markingson’s mom, Mary Weiss, filed a wrongful death suit-she settled out of court for $75,000 to pay her attorney’s fees), the Minnesota Board of Medical Practices, and the U of M’s internal Institutional Review Board (IRB).
Regarding investigations of conflict of interest, Rotenberg said, “The issue of conflict of interest has to be broken down. If by that you question whether a physician can enroll one of his patients in a clinical study that he is also engaged in, yes, that was looked at.”
Dr. Carl Elliott, a U of M bioethics professor whose Mother Jones story on Markingson prompted the professors to draft their letter, said the university did not go far enough in addressing the conflicts of interest and that the IRB should have never been the body to investigate whether there were serious ethical violations in the clinical trial.
“If the IRB was part of what went wrong, why was the IRB in charge of an investigation?” he asked.
The IRB is the primary oversight committee for human research subjects. Yet Elliott, who has previously served on the IRB, said that IRBs often do not investigate conflicts of interest. What’s more, he said, if there was an investigation of alleged ethics violations by the IRB or a Conflict of Interest committee, the University has failed to make it public.
“The IRB looks at the design of the study,” Elliott said. “They are not typically in the business of being on site. The fact that subjects who are involuntarily committed are being recruited, that is not something the IRB would look at, for example.”
According to the IRB site, its role is to review research projects to ensure first, that subjects are not placed at undue risk; second, that they give uncoerced, informed consent to their participation. According to the site, the IRB’s role doesn’t include investigating conflict-of-interest claims.
Elliott added that the IRB failed in ensuring Markingson’s safety, and said the IRB should not be in the role of investigating itself for what he perceives to be serious ethical violations. “The director of IRB said under oath, ‘It’s not our job to protect human subjects,'” Elliott says. “So whose job is it? It’s the investigators’ job to protect subjects from themselves? That doesn’t make any sense.”
The IRB director could not be reached for comment.
Following the (research) money
According to a 2009 article in the Star Tribune, Dr. Charles Schulz made strong statements about Seroquel’s comparative superiority to other drugs in 2000, though internal AstraZeneca emails questioned his conclusions. The research relationship continued, with Schulz publishing a more measured report in 2003, and AstraZeneca paying Schulz “at least $88,000″ over a ten-year period. (Schulz was the the chair of the U’s psychiatry department, who, along with Markinson’s doctor, Dr. Stephen Olson, were paid by AstraZeneca for their research on Seroquel.)
Dr. Frank Cerra, the university’s senior vice president for health sciences, told the Strib that he saw no problem in the relationship:
[Cerra] said he was not familiar with details of the Schulz study, but that there was nothing unusual about his relationship with AstraZeneca. “I think the role of university professors, particularly in health sciences, is to engage with the pharmaceutical industry and the device industry,” he said. As long as Schulz disclosed his ties, he said, “then the university is OK with this.”
Elliott says the new conflict of interest policy-which wasn’t in place at the time of Markingson’s death-still does not go far enough in protecting the integrity of research and the health of subjects from conflicts of interest.
“The idea that you, by reporting the money you are receiving, you are managing a conflict of interest is laughable,” Elliott said. “Researchers love it. Universities love it. Doctors love it. And the reason they love it is that it allows doctors to keep getting paid. So Schulz had to report half a million [in total earnings] before, and he will report half million now. I don’t see the difference.”
Rotenberg said that he could not say whether the Regents would call for an additional investigation of the Markingson case, but that the professors’ letter will be presented to them when they meet. “It’s just one of many things we will be addressing,” he said. “It will be up to them how to proceed, if at all.”
The bottom line, Rotenberg added, is to ensure the trust of research subjects. “We have to ensure that research subjects trust us,” Rotenberg says. “We can’t have funding if we don’t have research subjects.”
Reporter’s Notes: Documents, notes and discussion posted at Tiny Yurt, Molly Priesmeyer’s blog.
Updated 12/10/2010 at 5:30 p.m. to expand and clarify Dr. Elliott’s comments.