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UMN: How many deaths have occurred during your clinical trials?

The views expressed are those of the author and are not necessarily those of Scientific American.


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Angel of Grief

This series uses the story of Dan Markingson’s participation in a clinical trial of anti-psychotic drugs at the University of Minnesota, his suicide in 2004 while participating on the study, and subsequent events as a case study in which to explore various aspects of clinical trial conduct. In previous posts, I’ve looked at issues of “good clinical practices” and ethics: consent, investigator responsibilities and conflicts of interest. Then I examined the university’s response. Later, I turned to the importance of careful documentation of consent. I’ve shared reactions to the announcement that Mark Rotenberg, the UMN’s General Counsel, was leaving Minnesota to assume a similar post, now as Counsel and Vice-President at Johns Hopkins University. Finally, I explained how I was transformed by Dan’s story from looking at it simply as an objective case lesson in clinical trial ethics, to becoming an advocate urging an independent investigation of the University of Minnesota.

It is 10 years since Dan Markingson committed suicide while participating in a clinical trial conducted by the UMN’s Department of Psychiatry, ten years of denial and stonewalling by the university.

Dan’s death was tragic, and raises numerous questions about the safety and ethics of research conducted at the UMN. To summarize events:

Dan began to show signs of paranoia and delusions in 2003, believing that he needed to murder his mother. In 2003, he was committed to Fairview Hospital involuntarily after being evaluated by Dr. Stephen Olson, of the University of Minnesota. At that time (Nov 12), it was “noted that Mr. Markingson was felt to not have the capacity to make decisions regarding neuroleptic medication.” A clinical psychologist confirmed this assessment on November 19.  Yet that same day, Olson enrolled Dan on a clinical trial of antipsychotic drugs—despite protests from his mother.

On November 20, the judge elected to stay Mr. Markingson’s commitment for a period of six months, “so long as he followed certain conditions: …(a) that he remain hospitalized, cooperative with the treatment plan at Fairview University Medical Center until medically discharged and follow all of the aftercare recommendations of the treatment team…”

On November 21—just two days after being deemed incapable of consenting to Risperdal (antipsychotic treatment), he was suddenly determined by Jeanne Kenney, his social worker, to be capable of consenting to a clinical trial of antipsychotic medications.

Concerned by her son’s deterioration on the trial, Mary Weiss, Dan’s mother, left multiple messages for the study team. On April 15, in a final message for the study coordinator, Jeanne Kenney, Mary pleaded, “Do we have to wait until he kills himself or someone else before anyone else does anything?”

Mrs. Weiss never received a response. Her son committed suicide a short time thereafter.

Key questions surround the case. Let us focus on the issue of consent here:

How can a “volunteer” consent to participate when he has been deemed incompetent to make decisions? How well did he understand the risks of the study?

How voluntary was Dan’s consent, given that his alternative was commitment to a state institution?

How was the ability of a subject to consent determined? While we have Kenney’s form with answers Dan reportedly gave to signify his understanding, we also have had the disturbing discovery that these answers were identical to those she claims were given by other subjects, and the forms were apparently duplicated boilerplate responses. We also know that Kenney forged Olson’s signature on documents—something she was rebuked for by the Minnesota Board of Social Work.

UMN Department of Psychiatry under scrutiny

Dr. Charles Schulz has been chair of the Department of Psychiatry and a Principle Investigator on studies at the UMN since 1999. Dr. Steve Olson, Principle Investigator responsible for Dan’s care, has conducted 83 trials between 2001 and 2013. How many other serious adverse events and deaths have occurred on those trials? The U does not want you to know.

While the UMN tried to dismiss critics such as Carl Elliott, Professor of Bioethics and most persistent critic of the University’s handling of this case, as being crazy or wackos, it is they who are behaving delusionally, ignoring the rising tide of worldwide criticism and questioning.

More and more people are asking these hard questions. Arne Carlson, former Governor of Minnesota, has written to the Board of Regents of the UMN and legislative leaders. He told me⁠ (5/5/14 interview) he has asked for almost a year, “How many research subjects have died or been seriously injured and what were the circumstances surrounding this?” Carlson has asked both for an “independent inquiry and public hearings.” He, too, has not received any answers.

On December 5, 2013, the UMN Faculty Senate voted to request an investigation of “current policies, practices, and oversight of clinical research on human subjects, specifically prompted by the Markingson suicide.

Trudo Lemmens, a professor of law at the University of Toronto, wrote a letter that was signed by more than 175 academic experts in health, law, and research from around the world, including three former editors of the New England Journal of Medicine and Susan Reverby, who exposed the unethical syphilis experiments in Guatemala. The letter requested an independent inquiry into research practices at the UMN.

Eric Kaler, President of the UMN, responded by making a mockery of the “investigation,” putting it out on bid on the same web site the U uses to solicit cleaning bids “or a request to supply light bulbs” from vendors. Further, he is insisting that any recommendations be only “forward looking,” and ignore past travesties. Kaler’s RFP notes that the U will have the “sole discretion” in selecting the Respondent, who will be the one “whose Proposal is the most advantageous to the University.” So Kaler will pick the person to investigate human subjects research, specifically excluding the administration and its handling of problems, and that contractor will report back directly to Kaler. What could possibly go wrong?

Lemmens et al. have responded to Kaler, “The RFP is in our opinion so flawed as to preclude any chance the resulting report will be seen as legitimate, except perhaps by those vindicated by it.”

Additionally, more than 3000 people signed a petition to Governor Mark Dayton, again requesting an independent inquiry. This, too, has thus far fallen on deaf ears.

The UMN Psychiatry Department is no stranger to ethics scandals.

In 1993, the head of child psychiatry, Dr. Garfinkel, was convicted of criminal charges for falsifying data in a clinical trial. According to the Minneapolis Star Tribune, “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”—a report “released to the Star Tribune yesterday by court order after the newspaper sued the university for access to the Garfinkel file.” Ironically then, as in the Markingson case, the university’s general counsel, Mark Rotenberg, vehemently denied any wrongdoing. Using the same playbook we have grown to expect from the UMN, the whistleblower was fired, and the Dean made an agreement with Garfinkel to keep events secret.

Also in 1993, Professor James Halikas was accused of coercing Hmong refugees into participating in a clinical trial of gamma hydroxybutyrate (GHB) and reportedly refusing to give them methadone instead. They were considered a vulnerable population due to their addiction problems and language barriers. Halikas admitted to not having gotten consent from these individuals. Yet he—a member of the university’s IRB—egregiously violated basic research ethics. The UMN did not inform state officials nor bar him from conducting further research. The FDA finally disqualified him in 2000.

Charles Schulz, head of the department now, has come under fire himself for stating that Seroquel “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 Schulz, a paid consultant for AZ, had results that showed Seroquel was not better than the older Haldol.

Then there was Faruk Abuzzahab, responsible for 46 deaths and injuries, seventeen in clinical trials. Per the NY Times, the F.D.A. in 1979 and 1984 concluded that Dr. Abuzzahab had violated the protocols of every study he led that they audited, and reported inaccurate data to drug makers.” Abuzzahab was a former president of the Minnesota Psychiatric Society and for some time was chairman of its ethics committees. (While he was no longer full-time psych faculty when some of these deaths occurred, he still was still teaching at the UMN in multiple departments).

And there was David Adson, chair of the IRB overseeing the CAFE trial and responsible for investigating Dan’s death. Despite also receiving money from AstraZeneca and being in the same department as Olson and Schulz (his department chair), Adson claimed that he had no conflict of interest (COI). His actions in regards to Lilly’s Zyprexa and COI have also come under criticism.

Recently, Fox 9/KMSP investigative reporter Jeff Baillon has been focusing on current research misconduct. In addition to the Markingson incident, another person has come forward accusing Dr. Olson of not responding appropriately to a serious adverse event that occurred with a different drug, and on a different trial.

Another case Baillon reported involved Michael Swanson, a young man with bipolar disease who, left untreated, went on to kill two people. Dr. Jonathan Jensen, a UMN psychiatrist, had evaluated Swanson after he had written disturbingly violent notes and diagnosed him as bipolar, recommending anti-psychotic medication, yet none was prescribed. According to Michael’s mother, Kathy Swanson, Jensen instead recommended that the young man be enrolled on a clinical trial at the UMN, and the teen was discharged home, on no treatment. It was 6 weeks before he could be seen at the UMN. In the meantime, Michael went on his shooting spree. Dr. Jensen denies this claim…but why was Michael not immediately institutionalized or started on treatment, since Jensen thought he was dangerous “risk to society” if unmedicated?

Adverse events and trial conduct

While deaths are of major concern, other aspects of inattention to detail on Dr. Olson’s trials are also worrisome. For example, serious adverse events (SAEs) are required to be promptly (within days) reported to the sponsor and the IRB, whether or not the investigator feels that they are attributable to the study medication. On the AstraZeneca CLEARS trial, Dr. Olson did not report SAES to the IRB for almost 6 months after they occurred.

On the same CLEARS trial, the IRB also admonished Dr. Olson for not following up with a patient regarding an SAE for 10 months, and for dispensing expired study medication. (p 31 & 32)

As an experienced investigator myself, I find these lapses incomprehensible and inexcusable.

The requests for an outside investigation of studies by the Psychiatry department are not new, nor only instigated by Dr. Elliott and the Markingson case. In 2009, Susan Berry, Professor and Chair of the IRB, wrote Dr. Tim Mulcahy, VP for Research, and responsible for human subjects protection at the UMN, asking for a review of studies by independent outside experts. She noted that “it is the pattern and frequency of problems” related to consent, SAE reporting to the IRB, and confidentiality problems, among others. A subsequent internal review found no “substantive, systemic issues across the department that would suggest risk to the use of human subjects.”

A pattern emerges

The university derives large amount of money each year from clinical trials, as well as prestige from publications and lectures at national meetings. Looking at these cases, occurring over decades, a pattern emerges. Investigators in the psychiatry department enroll vulnerable subjects—those who may not have the capacity to fully understand what they are agreeing to—in clinical research. In several cases, the study coordinators did medical assessments which they were not qualified to perform (Olson and Garfinkel trials) and the investigators abdicated their responsibility for the safe conduct of the trial. Assessments were sometimes recorded fraudulently.

A whistleblower comes forward, and is marginalized by the administration, dismissed as a troublemaker or wacko. There is a code of silence, with faculty being told to refer outside questions to the general counsel’s office. Questioners are targeted for retaliation. The University, perhaps intent on intimidating others from complaining, sued a grieving family member—Mary Weiss.

Requests for records are stonewalled—either saying they can’t be released, charging exorbitant fees ($9,306 plus $.12/page, payable in advance, for one report) , or saying the records were destroyed as no longer being necessary.

As Arne Carlson aptly concluded, “They (the UMN) are going around trying to pretend that mentally ill people are competent to give consent,” motivated by “the vast amount of money involved.”

So far, the Board of Regents silence has been disappointing, as they have not yet assumed responsibility or a leadership role in insisting on an independent investigation. Similarly, Governor Dayton and Attorney General Swanson have not stepped up to do the right thing. One can only conclude that money is trumping any sense of ethics and decency.

Yahrtzeit candle

Eventually, however, the truth will come out. While progress has been painfully slow, I hope that Mary will see that Dan’s legacy is continuing to grow and will have a lasting impact.

“Yes’n, how many deaths will it take till he knows…that too many people have died?” – Bob Dylan

Credits:

Angel of Grief image Scott Loftesness

Yahrtzeit candle – Elipongo/wikimedia

“Molecules to Medicine” banner © Michele Banks

 

 

http://www.twincities.com/localnews/ci_6665989 adson

 

http://www.nytimes.com/2007/05/10/health/10psyche.html?pagewanted=all&_r=1&

“Yes’ n’ how many times must a man turn his head / Pretending he just doesn’t see?”[8]

 

 

 

 

1 See Mystery docs post and links

2 interview, 5/5/14

3 www.law.utoronto.ca/sites/default/files/users/lemmenst/Untitled_20140424_011928.pdf

4 http://www.law.utoronto.ca/blog/faculty/markingson-case-update-how-institution-can-transform-request-independent-inquiry

5 http://www.healthintheglobalvillage.com/2014/04…

6 Professor accused of coercing Hmong into ‘U’ drug study

Star Trib (see scribed docs

7 http://www.albany.edu/~scifraud/data/sci_fraud_3239.html

8 Road to Perdition-  http://www.madinamerica.com/2012/12/the-road-to-perdition/

9 Halikas Professor accused of coercing Hmong into ‘U’ drug study

Star Trib

10 Road to perdition  http://www.madinamerica.com/2012/12/the-road-to-perdition/

11 http://www.madinamerica.com/2012/12/the-road-to-perdition/

12 http://www.startribune.com/lifestyle/41470522.html?source=error

13 http://www.nytimes.com/2007/06/03/health/03docs.html?pagewanted=all

14 http://www.newyorker.com/reporting/2008/01/07/080107fa_fact_elliott?currentPage=all

15 http://www.nytimes.com/2007/06/03/health/03docs.html?pagewanted=all&_r=0

16 http://www.xulonpress.com/bookstore/bookdetail.php?PB_ISBN=9781624197475

17 http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=658 2&blogid=140#ixzz2kYfSpw5a

and Trudo’s table of Mark inv

18 http://www.mapsresearch.com/cv.php?id=8

19 http://www.twincities.com/localnews/ci_6665989

20 Fox news Investigators clip

21 http://www.myfoxtwincities.com/story/24811285/investigators-clerk-killer-diagnosed-not-helped

22 http://www.scribd.com/doc/221159920/Serious-Adverse-Event-SAE-reports-for-University-of-Minnesota-site-for-AstraZeneca-CLEARS-study-Cataractogenic-Potential-of-Seroquel-and-Risperdal

23 http://www.scribd.com/doc/221159920/Serious-Adverse-Event-SAE-reports-for-University-of-Minnesota-site-for-AstraZeneca-CLEARS-study-Cataractogenic-Potential-of-Seroquel-and-Risperdal

24 http://www.scribd.com/doc/206162637/Susan-Berry-Letter-to-VP-Tim-Mulcahy-Requesting-External-Review-of-Psychiatry-Research-March-16-2009

25 http://www.scribd.com/doc/212897896/Department-of-Psychiatry-Report-2009

26 http://www.scribd.com/doc/204031600/Unsuccessful-Data-Practices-Act-Requests-to-the-University-of-Minnesota-by-Carl-Elliott

27 http://www.scribd.com/doc/204031600/Unsuccessful-Data-Practices-Act-Requests-to-the-University-of-Minnesota-by-Carl-Elliott

Judy Stone About the Author: Judy Stone, MD is an infectious disease specialist, experienced in conducting clinical research. She is the author of Conducting Clinical Research, the essential guide to the topic. She survived 25 years in solo practice in rural Cumberland, Maryland, and is now broadening her horizons. She particularly loves writing about ethical issues, and tilting at windmills in her advocacy for social justice. As part of her overall desire to save the world when she grows up, she has become especially interested in neglected tropical diseases. When not slaving over hot patients, she can be found playing with photography, friends’ dogs, or in her garden. Follow on Twitter @drjudystone or on her website. Follow on Twitter @drjudystone.

The views expressed are those of the author and are not necessarily those of Scientific American.





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