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Controversy over U of M clinical trial has heated up again

seroquel pills
CC/Flickr/hopeless128
Dan Markingson committed suicide in 2004 while enrolled in a University of Minnesota clinical trial of the antipsychotic Seroquel.

The complicated and disturbing case of Dan Markingson, the mentally ill young man from St. Paul who committed suicide in 2004 while enrolled in a University of Minnesota clinical trial of the antipsychotic drug Seroquel, has become embroiled in even more controversy in recent weeks.

elliott portrait
Dr. Carl Elliott

Last month, University of Minnesota bioethicist Dr. Carl Elliott, who has written about the Markingson case extensively, raised concerns in his blog, Fear and Loathing in Bioethics, that the “evaluation to consent” form found in Markingon’s file appears to have been filled out in identical ways to the consent form in another patient’s file.

If the forms were filled out identically, it would mean that the patients had not been individually evaluated to determine whether they were mentally capable of giving their consent to be in the study. Markingon’s mother, Mary Weiss, has long contended that her son was incapable at the time of giving informed consent. Indeed, in the days leading up to his enrollment in the study, he had been found repeatedly incompetent of consenting to treatment.

“Most alarming of all,” wrote Elliott, “the ‘answers’ supposedly given by the research subjects appear identical. But the new form has no date, no subject ID, no subject initials, and no mention of Unit 12, the ward in Fairview Hospital where Dan Markingson was hospitalized.”

“I find these documents so alarming that they demand an investigation,” he concluded. “How many research subjects in the Department of Psychiatry have this same form in their charts?  Were any of those subjects in studies subject to federal oversight, such as the CATIE study? Did any of those subjects suffer serious injuries or death?"

A petition for an independent investigation

Soon after Elliott raised these and other new questions about documents in Markingson’s files, Weiss launched a petition to ask Gov. Mark Dayton to appoint an independent panel of experts to investigate the university for possible research misconduct. That petition has now been signed by more than 1,000 people, including dozens of physicians, bioethicists and other medical experts.

In an article published Wednesday in the Star Tribune, the university’s chief counsel, Mark Rotenberg, said, “There is no evidence that any of [the consent forms] contained predetermined, photocopied answers.” 

Rotenberg suggested to Strib reporter Jeremy Olson that the family with the duplicate form may have downloaded it from the Internet.

That charge incensed Elliott. If that is the case, he wrote on his blog Thursday, then the university should make the redacted forms public. The controversy could be easily resolved, he stressed, if the patients’ families could compare the university’s records with their own.

“But [university officials] are not letting anyone else look at the study records,” Elliott added. “They want us to take their word for it.”

Unanswered questions

The Food and Drug Administration conducted an investigation into Markingson’s suicide in 2005; it found no evidence of wrongdoing by the university. Elliott has called the FDA report from that investigation “occasionally misleading, remarkably uncritical, and often simply baffling.”

Weiss filed a lawsuit against the university, the manufacturer of Seroquel (AstraZeneca) and the two university scientists who led the study, Drs. Charles Schulz and Stephen Olson. The suit was dismissed in 2008 with a partial summary judgment. As I've reported here before, 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. Weiss did settle a separate malpractice suit with Olson for $75,000 (an amount that Elliott reported did not cover her legal costs).

“As the controversy over this study has grown louder, the university has tried to portray it as a dispute from the distant past,” wrote Elliott in an op-ed for the Pharmalot blog earlier this week. “Nothing could be farther from the truth. We still do not know if Dan’s suicide was an isolated case. It is possible that other psychiatric research subjects at the university have been seriously harmed or mistreated. Last fall, the Minnesota Board of Social Work found that the study coordinator for the CAFÉ study (the AstraZeneca clinical trial in which Dan died) as well as the federally funded CATIE study had faked the initials of an investigator on study records, failed to inform Dan of new drug risks, failed to heed the warnings that Dan was in danger of killing himself, and had been given medical responsibilities beyond her training. If University of Minnesota officials were truly concerned about the welfare of research subjects, would they not at least want to investigate?"

This is a complex story. For a recent summary of the case and the issues involved I recommend, in addition to the links above, Dr. Judy Stone's series in her Scientific American blog, beginning with Part I, published last December.

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Comments (7)

“Completely false,” says the U of M

... after its own investigation. (As Minnpost's Glean author pointed out yesterday.)

"Ay, there's the rub."

It is well nigh impossible for the average person to make sense of what has been going on at the University of Minnesota in the Markingson case. And my, perhaps cynical, view is because that is how they like it.

If an institution can spend fifty grand for a spans and layers analysis (+ half a million to come) then surely they can expend time and energy to get to the bottom of this mess.

And that is why a petition to the Governor of Minnesota has been started by the Markingson family to call for an independent investigation. I'd urge readers to consult the petition web site and consider signing it.

Here is a link: http://ow.ly/jiz65

I'd also point out that more than 1,123 people have signed the petition so far. These go from three former editors at the New England Journal of Medicine, internationally known bioethicists and psychiatrists, and U of M faculty, to ordinary Minnesota residents who find these events extremely disturbing.

To give a few examples:

Dan Markingson was a vulnerable patient made more vulnerable by this drug trial. Significant concerns raised have not been adequately addressed by the University. A number of issues were newly identified in a recent corrective action by the State Board of Social Work, which concluded that Dan Markingson's (already disputed) informed consent (functionally coerced consent?), was also subsequently invalidated (http://www.socialwork.state.mn.us/Portals/0/SO-ACA/ACA_Kenney-13622-1108...). This also implies a failure in the IRB system concerning adequate monitoring in this case. While signing in my private capacity I direct the Program in Human Rights and Health at the University of Minnesota the concern of which is vulnerable patient populations.

As a Senior Associate Dean for Academic Affairs at a Big Ten medical school and a practicing physician, I think medical researchers and their sponsoring institutions should be held to a high standard of ethical behavior and transparency.

Attended U of MN Medical School. then U of MN Psychiatry Residency - ashamed of the Psychiatry Department - have been in private practice since 1977 - Have seen first hand the hijacking of Psychiatry by BigPharma.

As an alumnus of the University of Minnesota and a former Student Representative to the Board of Regents, I believe strongly that the University has an obligation to conduct itself in the most ethical way possible. My own investigations into the matter of the Markingson case and the CAFE trial indicate that there were serious ethical lapses on the part of the University and especially the Department of Psychiatry. Further documentation by my friend Carl Elliott, one of the premier bioethicists in America, have convinced me that an outside investigation is necessary to remedy serious structural problems with the relationship between the University and industry in conducting scientific research. A man has died; a mother grieves; and I cannot sit idly by and do nothing as a community I care about - the University of Minnesota - does nothing to make this right. I urge Governor Dayton to launch and investigation to help bring this matter to an ethical conclusion.

For more damning comments, please see: http://ow.ly/jiA6Y

Bill Gleason, U of M faculty and alum

The petition to investigate psychiatric research at the U

The petition to investigate these research scandals has attracted the support of three former editors of the New England Journal of Medicine, two former members of the President's Council on Bioethics, the scholar who uncovered the US-led Guatemala syphilis study (which led to a presidential apology in 2010), and well over 150 academic experts in medical ethics, health law and related disciplines. It has also gotten a tremendous amount of support from the citizens of Minnesota. Please consider signing at this address:

http://chn.ge/13TtenX

Please sign the petition to investigate the University

Here's a cut from the Star Tribune regarding another psychiatry study scandal and how the University tried to hide and cover-up data. Same General Counsel was involved with this attempted cover-up as the the dealing with the issues surrounding Dan Markingson.

H'mmmm.

"For almost four years, the University of Minnesota covered up its findings that Dr. Barry
Garfinkel knew about and participated in scientific misconduct, including fraud, in a drug study,
according to a report obtained Wednesday.

"As recently as last August the university said it had found no evidence of intentional
wrongdoing by the psychiatrist. The university had claimed repeatedly that Garfinkel was merely
negligent in supervising the research.

"But a November 1989 report by the university's official investigating committee flatly stated
that Garfinkel, a nationally recognized expert in teen suicide, had taken part in fabricating
records about one patient, either knew or should have known about other falsification of data and
failed to current widespread misconduct of the study.

"The 65-page report, which was kept secret, was released to the Star Tribune yesterday by court
order after the newspaper sued the university for access to the Garfinkel file.

"Garfinkel was found guilty last week in U.S. District Court in Minneapolis of five counts of
mail fraud and filing false statements in connections with his research on Anafranil, an
antidepressant drug that was used on patients with obsessive- compulsive disorder. He was
acquitted on 18 other changed. He was accused of faking reports on patient exams that either
never took place or were conducted by a research assistant, Michelle Rennie, who had no
medical training." (pp. 1A-9A)

Unanswered questions prompt petition to investigate UMN research

Thank you for your balanced report. I would add a couple of details, in part from my long experience conducting clinical research, and in part from my own attempts to get concrete, referenced answers from the University:

Based on my own review of publicly available depositions and the lack of adequate responses to my questions, I have concluded that the only way to arrive at answers to troubling questions is to have an outside, independent, inquiry.

-- The UMN could answer the question re the authenticity of the evaluations to consent forms by providing redacted copies of the evaluation to consent forms--and should do so not only for the CAFE trial, but for all of the studies involving that investigator and social worker/study coordinator. This includes the CATIE trial, which had federal (NIH) funding.

--The Minnesota Board of Social Work found significant fault with the coordinator’s behavior and record keeping, including the coordinator’s failures of documentation and her signing forms with the investigator’s initials. I address this in my Scientific American series of posts, A Clinical Trial and Suicide Leave Many Questions: Part 2: Investigator Responsibilities (Dec 13, 2012). Again, inadequate documentation on a NIH study has even broader implications and should be investigated.

--The investigation by the FDA was remarkably superficial and limited in scope. I explain in SciAm Part 4: The UMN’s Response (Jan 8, 2013 post). It was woefully inadequate—and more evidence suggestive of wrongdoing has appeared since then, that calls for a reexamination.

--The University was dismissed from the suit on a technicality—that it had sovereign immunity, not that there was no foundation to the Markingson family claims.

--You state, “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.” Perhaps that is technically correct…but it is abhorrent, and it does not abrogate the responsibility of the University, its IRB, investigators, and lawyers, to put the interests of research subjects first. In fact, I was appalled to read the deposition statement that the head of the IRB denied patient protection was an IRB responsibility.

--I would note that for every question I have asked Dr. Elliott or the Markingson family, they have directed me to documentation in the form of depositions (available to all on Scribd) or copies of records, or have given me concrete responses. In contrast, the University has been less than forthcoming with me in response to questions I have posed and I will write about this in an upcoming post. They have yet to provide me with any of the documentation I’ve requested (since March 8) to substantiate their responses. This has markedly affected my assessment of the situation.

--At this point, questions are being framed by the UMN as “allegations” against them and are all fielded by the Office of the General Counsel. While perhaps understandable from their perspective, this creates a climate of intimidation, chilling other faculty dissent. It also defeats any claim they have of transparency.

Because of these concerns, I support Mike Howard, Mary Weiss, and Dr. Elliott in their call for an impartial and independent investigation.

Prof. Elliott and the Markingson family raise many questions that deserve better answers.

Judy Stone, MD
Blogger, Scientific American Blog Network,
"Molecules to Medicine"

Release redacted copies of the evaluation to consent forms

The University of Minnesota can address concerns about the possibility that a photocopied evaluation to consent form was used by releasing redacted copies of all evaluation to consent forms from the CAFE and CATIE studies. While such a step will not address the many other issues that an independent investigation should address, it will resolve one important question by revealing that either a duplicate form was used or such concerns are unfounded.

I'm one of the more than 1,330 individuals who have signed the petition initiated by Mary Weiss and Mike Howard. Others wishing to sign the petition can find it here: https://www.change.org/petitions/governor-mark-dayton-of-minnesota-inves.... Concerned citizens wanting to do some additional background reading before deciding whether to sign the petition will find that the preceding site provides links to informative articles and blog posts that provide history and context.

Coercion of involuntary consent = No consent at all

This case demands that new light be cast on ALL clinical trials at the U, where it seems there is an air of entitlement to working in the dark.

Medical research institutions used to be source of pride.

I remember when Minnesota medical research institutions used to be a source of pride. Then came the day when pharmacuetical companies began to have way too much power. The Star Tribune Reporter who recently committed suicide is but one story that should haunt everyone. He had recently sought treatment. That treatment consisted of a few short days in-patient, more meds and then the suicide. Pharmacuetical companies have successfully perpetuated the myth that drugs are the new treatment. Propublica recently published the 22 doctors who earned $500,000 or more from the drug industry, "Dollars for Doc: Top Earners." Eleven of those practicing doctors were Board Certified in Psychiatry and Neurology.

An independent investigation of the UofM is warranted and appears long over due. Also long overdue is an investigation into the rising suicide rate and the drugs that have been prescribed to these patients prior to the suicide, especially in the military. Long over due is a look at the mentally ill murders and mass shooters to compare the drugs they were prescribed prior to the crimes. The questioning of whether these drugs do more harm than good is not a new one. It doesn't take a rocket scientist to understand that when a person is already in a a severe state of depression or a psychotic state, placing that person on a drug that flattens the affect to the point of removing all ability to empathize with other living creatures might be problematic.

Yes, we have a responsibility to investigate the UofM practices and to hold whomever is responsibile accountable. But we can't stop there because there is more work to be done.