8 Professors demand independent investigation of death in clinical trial

The disturbing circumstances surrounding the enrollment and subsequent suicide of Dan Markingson (2004) after he was given an experimental antipsychotic drug, Seroquel, as a test subject in AstraZeneca’s CAFE trial–having been enrolled while he was hospitalized under an involuntary commitment order–are continuing to generate outrage and dismay.

The case against AstraZeneca’s corrupt practices is well documented in courts of law and in civil and criminal settlements with the Department of Justice: 

Kickbacks to physicians, rigged clinical trials in which company officials "cherry picked" the data to be disclosed while "burying" unfavorable study findings, the company’s use of "smoke and mirrors" to obscure Seroquel’s failed efficacy, AstraZeneca’s failure to warn that Seroquel can cause diabetes and other health problems, and its illegal off-label marketing of Seroquel.  On April 27, 2010, AstraZeneca and the U.S. Dept. of Justice reached a $520 million settlement.  

But what of the case against the University of Minnesota and the psychiatrists who conducted the trial?
Their actions and the significant financial stake they had in the trial, have never undergone independent scrutiny.

Those familiar with the documented facts in the case, are convinced that the University of Minnesota and the psychiatrists who enrolled Markingson when he was mentally unstable–and who then refused to withdraw him despite his mother’s frantic pleas–are culpable for the tragic results.

This case encapsulates the corrupt practices that ensue when academia and the pharmaceutical industry become partners in joint financial ventures.

 Adding insult to fatal injury, the University of Minnesota treated Dan Markingson’s mother, Mary Weiss, with callous disregard–an attitude comparable to that displayed by the Catholic Church toward victims of sexually abusive priests.

 Over the past several years, articles in the St. Paul Pioneer Press, Minneapolis Post, City Pages, and Mother Jones magazine have suggested an alarming string of ethical violations–including gross conflicts of interest by the psychiatrists and the University;  recruitment of mentally incompetent subjects;  and the integrity of the study itself–which, if true, suggest serious problems in the way that clinical research is conducted and overseen at the university.

 Dr. Charles Schulz, chief of psychiatry, and Stephen Olson, personally earned a combined $811,045 between 2002 and 2008 from pharmaceutical companies, including $261,364 from AstraZeneca, the sponsor of the CAFE Seroquel trial in which Dan Markingson was enrolled.

 The Minneapolis Post reported: “The University of Minnesota benefited financially from the study: More than $300,000 went to the Department of Psychiatry.”

In a searing article in Mother Jones, Dr. Carl Elliott reported that the U of Minnesota Department of Psychiatry had earned $15,648 for each person it enrolled in the AstraZeneca Seroquel study. And at the time that Markingson was enrolled in the study, Dr. Elliott wrote, the University was having a serious problem recruiting subjects–it risked being dropped by AstraZeneca as one of the study’s trial sites.

 In 2000, Charles Schulz, chief of psychiatry at the University of Minnesota, gave a presentation at the American Psychiatric Association meeting in which he made misleading claims about the safety and efficacy of AstraZeneca’s antipsychotic, Seroquel, calling the drug "significantly superior" to Haldol. In an AstraZeneca press release, he stated,
 
"I hope that our findings help physicians better understand the dramatic benefits of newer medications…"

Dr. Schulz’ optimistic, but unsupportable statements belied the manufacturers’ own assessment of the data:

"The data don’t look good," an AstraZeneca official, John Tumas, warned in an e-mail on March 23, 2000. That month, an internal company analysis of the raw data concluded: "It is clear that a claim of superiority for Seroquel over Haloperidol (Haldol) could not be generated using these data."

In a 2009 interview with Pioneer Press , Schulz admitted that his prior statements were "exaggerated" and he acknowledged that his own study did not really show that Seroquel was more effective than the older drug. "That’s a bit of a misunderstanding."
http://www.examiner.com/mental-health-in-minneapolis/u-of-m-psychiatrist-s-charles-schulz-misleading-claims-about-seroquel

But that message, by the chief of psychiatry at the University of Minnesota, carried weight with psychiatrists who were persuaded to prescribe Seroquel. AstraZeneca got the service they had paid him for. His (admitedly false claim about the drug’s efficacy) served as a useful marketing pitch to boost the drug’s  sales, which reached $4.5 billion annually.

Dr. Jerome Kassirer, the former editor of the New England Journal of Medicine, was prompted to express his disgust (September 15, 2010):

"The conflict of interest is disgusting, and it seems quite likely that the boy’s death was an indirect consequence of the financial inducements of the study. At the very least, the university should have appointed an independent review board, dismissed all the hospital charges, and paid the boy’s mother damages."

In November, 2010, eight University of Minnesota faculty members of the Department of Bioethics, sent a letter to the university’s Board of Regents requesting the appointment of an outside panel of experts to investigate gross ethical issues raised by the 2004 suicide of Dan Markingson. (below) 

 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.”

This case sheds light on how the commercialization of medicine devalues both the integrity of medical research and patients’ rights reducing both to a means in the service of a financial end.

Additional background: University of Minnesota corrupt research legacy

In 1994, ten years before the tragic death of Dan Markingson, Dr. Bary Garfunkel, the Director of the University of Minnesota, Department of Child and Adolsescent Psychiatry, was sentenced to prison for falsifying documents related to clinical trials of Anafranil.

In 1995, Dr. John Najarian was indicted by a federal grand jury for theft and tax evasion related to the illegal sale of ALG, an experimental drug whose sales amounted to $80 million most of which went to the University of Minnesota. This resulted in NIH placing severe restrictions on the University’s freedom to use research funds.

 

 Vera Hassner Sharav

 

 

http://www.medcitynews.com/2010/12/university-of-minnesota-profs-demand-investigation-of-drug-trial/

 12.6.10 | Thomas Lee | Minneapolis, Minnesota

U. of Minnesota profs demand investigation of drug trial death

Dr. Carl Elliott, University of Minnesota

A group of University of Minnesota professors want the board of regents to investigate the suicide of a patient enrolled in a university-run drug study.

Led by Dr. Carl Elliott, the professors demand the regents appoint an independent outside panel of experts to examine the death of Dan Markingson, a mentally ill patient who killed himself after taking an experimental psychiatric drug developed by AstraZeneca. The professors accuse the school of several ethics violations, including financial conflict of interest and enrolling Markingson even though he may have been too sick to consent.

“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,” stated a Nov. 29 letter to the regents board. “While it is understandable that some of our colleagues will have little interest in revisiting the case and the ethical questions it raises, we are persuaded that there is a disturbing and unjustifiable gap between how the University responded to this death and the careful, critical investigation it warrants.”

Markingson committed suicide in May 2004 after taking Seroquel, a psychiatric drug developed by AstraZeneca. Mary Weiss, Markingson’s mother, accused the university of of forcibly enrolling her son in the clinical trial even though Markingson was under an involuntary commitment order and may have been mentally incompetent to consent to the treatment.

A series of stories in the St. Paul Pioneer Press and Mother Jones magazine, the latter written by Elliott, suggested an improper financial relationship between university researchers and AstraZeneca, including incentive payments to recruit and retain patients for the study instead of providing standard therapy.

University officials deny the accusations, noting the Food and Drug Administration, Minnesota Attorney General’s Office and Board of Medical Practice all cleared the school.

“None found fault with the University, none found fault with the involved faculty, and none found any causal link between the … trial and the unfortunate death of Dan Markingson,” the university’s general counsel, Mark Rotenberg, wrote in response to the Mother Jones story.

In addition, a federal judge dismissed a lawsuit brought by Weiss.

“Faculty in our department of psychiatry have made great progress in pursuit of effective treatments for mental health disease,” Rotenberg wrote. “The department’s work — much through clinical trial efforts — has made a significant impact through its community clinical outreach and treatment programs. However, these conditions remain today among the most difficult to manage and treat. It is that challenge which our psychiatry faculty is seeking to address with its clinical research.”

In a separate interview, Elliott, who recently wrote a book critical of the drug industry, said the FDA investigation did not address key information.

“There is lots that the FDA report missed, and the FDA refuses to answer questions,” Elliott wrote in an e-mail. “The FDA did not mention the conflicts of interest, the financial incentives to enroll subjects and keep them in the study, the failure to exclude subjects at risk of homicide, the fact that Mary Weiss had tried for months to get her son out of the study, or the fact that Dan Markingson had been threatening murder when he was recruited into the study.”

“Bizarrely, it also concluded that ‘there is nothing different about this subject than others enrolled to suggest that he could not provide voluntary, informed consent,’ ” Elliott wrote. “This, despite the fact that only a few days earlier, the investigators had judged him incapable of consenting to antipsychotic drugs.”

Elliott also said new evidence suggests the company rigged the trial to show positive results.

Last year, the Star Tribune in Minneapolis reported that court documents showed AstraZeneca claimed its drug was superior to standard treatments for schizophrenia, even though the drug maker knew research did not back the claim.

Dr. Charles Schultz, chief of psychiatry at the university, presented research backing AstraZeneca’s claims to a medical conference. Schultz claims the company never shared its concerns with him.

Thomas Lee

Thomas Lee

Thomas Lee is the Minnesota Bureau Chief for MedCityNews.

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City Pages

Lawyers, Drugs, and Money

Is medical research at the U of M compromised?

In a damning new article in the latest issue of Mother Jones magazine, Dr. Carl Elliott, a professor at the University of Minnesota’s Center for Bioethics, argues that the university’s system of clinical research "has been so thoroughly co-opted by market forces that many studies have become little more than covert instruments for promoting drugs." Because of the large sums of money pharmaceutical companies are paying the university, Elliott writes, the institution is too often turning a blind eye to glaring conflicts of interest and serious ethical lapses. In one instance, Elliott contends it may even have lead to the death of a study’s subject. 

What’s been the reaction of your peers to this article?

Well, outside the medical school, and outside the university as a whole: lots of support for me personally, and, as you’d expect, shock that this could happen here. Inside the medical school: silence.

One should perhaps no longer be surprised to find pharmaceutical companies suppressing unfavorable data and manipulating studies to get the results they desire, but to read in your piece that a respected medical institution like the university may be aiding that deception is stunning. Why would the university risk its reputation?

Pharmaceutical industry funding is the norm for academic health centers, not the exception. In academic medicine, working for them is not seen as shameful; it is seen as a mark of status. For a lot of academic physicians, being chosen by a drug company to work as a paid consultant or speaker is like being admitted to an elite private club. 

But when the head of your university’s psychiatric department, for instance, is a well-paid consultant for a pharmaceutical company, and that company, in the interest of increasing profits, fudges results and hides unfavorable data, why wouldn’t top officials at the U of M sound the alarm?

You could ask the same question about any of a number of scandals at the university. A couple of years ago, the Star Tribune discovered that Leo Furcht, the co-chair of an ethics task force at the U working on a new conflict-of-interest policy, had steered a $501,000 pharma grant into a firm he owned and which he later sold for $9.5 million in stock. When the Star Tribune asked Deborah Powell, the dean of the medical school, why she had appointed Furcht to chair the ethics task force, she said it was because of his "extensive experience" devising conflict-of-interest rules. Furcht remains chair of the Department of Laboratory Medicine and Pathology.

You point out that in one case, a 26-year-old man named Dan Markingson was used in a psychiatric drug study after being diagnosed as psychotic. He committed suicide during this study. His mother begged university researchers not to place her son in the study. She believes carelessness on their part led directly to his death. Do you believe this?

I asked this question of my brother, a psychiatrist on the faculty at Wake Forest University. He said, "Look, if a mentally ill young man’s mother keeps calling, begging you to take her son out of a study because she thinks he is going to commit suicide, you don’t just ignore her. You call 911." Did the drug given to Dan in the study cause the suicide? That’s impossible to say; you never know whether a suicide is linked to a drug or the underlying mental illness. Did Dan get poor treatment during the study? Yes. Were there financial incentives to enroll him in the study and keep him in? Yes. I asked Jerome Kassirer, the former editor of the New England Journal of Medicine, to comment on the case for my article, and here’s what he said: "The conflict of interest is disgusting, and it seems quite likely that the boy’s death was an indirect consequence of the financial inducements of the study. At the very least, the university should have appointed an independent review board, dismissed all the hospital charges, and paid the boy’s mother damages."

Do you have any support, inside the medical school, calling for some new approach to medical research?

There are a few people concerned about conflicts of interest, but most of them seem afraid to say much. They prefer to keep their thoughts to themselves. As my brother says, "Doctors fear drug companies like bookies fear the mob."

 (Note: Dan Markingson’s mother sued the University of Minnesota and the pharmaceutical company, Astra Zeneca. It never went to trial. A district judge dismissed the suit with partial summary judgment.) 

 Related Content

 

 

Bioethicists ask U of M Regents to appoint

outside panel to review ethics of 2004

Dan Markingson case

By Susan Perry | Published Mon, Dec 6 2010 9:10 am

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.

“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.

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STAR TRIBUNE

Once-secret drug-company records put U on the spot

Documents raise questions about a drug study by U of M psychiatrist S. Charles Schulz. He says there is a "misunderstanding" about the results he reported.

Last update: March 19, 2009 – 10:10 AM

In the spring of 2000, Dr. S. Charles Schulz attended a national medical conference to present favorable research on a new psychiatric drug called Seroquel.

Schulz, chief of psychiatry at the University of Minnesota, reported that the drug was "significantly superior" to the old gold-standard treatment for schizophrenia. In a press release by the manufacturer, AstraZeneca, he touted the "dramatic benefits" of Seroquel’s class of drugs.

But newly released documents show that AstraZeneca knew the research didn’t support the claim — and knew two months before Schulz went public with it.

The disclosures have raised questions about Schulz’s ties to the company as a paid consultant at a time when Congress and the university itself are intensifying their scrutiny of potential conflicts of interest in medical research.

"The data don’t look good," an AstraZeneca official, John Tumas, warned in an e-mail on March 23, 2000. That month, an internal company analysis of the raw data concluded: "It is clear that a claim of superiority for Seroquel over Haloperidol (Haldol) could not be generated using these data."

In an interview this week, Schulz said the pharmaceutical company never shared its doubts about Seroquel, which went on to become a blockbuster, with annual sales of $4.5 billion today. "I don’t recall anybody calling up and saying, oh my goodness, we have this problem," he said.

At the same time, Schulz acknowledged that his own study did not really show that Seroquel was more effective than the older drug. "That’s a bit of a misunderstanding," he said. "I think the overall message is that it works about the same."

In a statement, AstraZeneca spokesman Tony Jewell said Schulz accurately presented the data at the American Psychiatric Association (APA) meeting in 2000, and "clearly explained the methodology he used.”

 Dr. Frank Cerra, the university’s senior vice president for health sciences, noted that medical research can be interpreted in more than one way, and cautioned against jumping to conclusions based on Internet documents. He 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."

Today, Seroquel is widely used worldwide for a range of psychiatric conditions, from schizophrenia to borderline personality disorders. In fact, next month AstraZeneca, a $32 billion British concern, will ask the Food and Drug Administration for approval to market it for major depression, which could greatly expand the drug’s patient base and sales.

However, experts say doubts remain about the value of the drug. "It does work, but it’s not necessarily better than the pills that are already out there,” said Dr. Daniel Carlat, a psychiatrist at Tufts University in Boston. "And it does have some nasty side effects.”

Ed Blizzard, a Houston lawyer who is handling consumer lawsuits against the company, said he believes AstraZeneca inflated the drug’s value. "They marketed it as having unsurpassed efficacy," he said.

The internal company documents became public last month in connection with a federal court case in Florida over Seroquel’s side effects. Since the documents started circulating on the Internet, at least one outside critic has called for an investigation by the university.

"Is it any wonder that psychiatric research, and by implication psychiatric practice, is losing credibility due to the economic influence of big pharmaceutical companies," wrote Brent Robbins, a psychologist at Point Park University in Pittsburgh, on a blog site of the Society for Humanistic Psychology.

Robbins said he had contacted the Medical School to look into the matter. "How can we trust science when the people who are conducting the science are only publishing or presenting on findings that favor the economic well-being of the company for which they are hired?” Robbins asked.

Schulz denied that his ties to the company affected his research. "I don’t think I would have been comfortable standing in front of a poster that exaggerated the results," he said.