Reading a bit like a trashy whodunit, with a bloody corpse and a series of coverups, lies, and stonewalling, is the sordid story of Dan Markingson’s suicide and the shameful response of Minnesota’s flagship university, the UMN. But this is more than an isolated case. How the UMN handled medical research, a volunteer patient’s injuries, and investigator misconduct is a cautionary tale for all clinical research and for all of us who rely on honest clinical trials to provide us with safe medicines.
Dan was a young man who developed a psychosis. (For more background see readings, linked below.) A judge offered him a choice of going to a state mental institution or of following the advice of his doctor—which was to enroll in a clinical trial of antipsychotic medication. No coercion here…Despite clinically worsening on the study drug and a dire warning from his mother that he was at risk of suicide, the principal investigator, Dr. Stephen Olson, kept him on the trial. Dan committed suicide in a horrifically gory manner.
The University has been stonewalling for all the intervening years, despite the dogged persistence of its own ethics professor, Dr. Carl Elliott. Elliott has filed multiple information requests, reviewed thousands of pages of documents, and meticulously documented his findings in his writings, making key documents available for all to review on Scribd. His reward? Ostracism by some other faculty and a seemingly retaliatory rebuke from the administration. While the UMN administration’s motto is “Driven to Discover,” they clearly didn’t believe this applied to their own misdeeds.
Finally, after more than ten years, there have been recent successes. First came a letter from more than 175 academic ethicists, legal scholars, and others, including former editors of the New England Journal of Medicine, calling for an independent investigation.
This spring brought a review from the Association for the Accreditation of Human Research Protection Programs (AAHRPP), an organization that also accredited the UMN’s research program. Their findings were damning, particularly given their close relationship to the UMN, including:
—“there is a notable absence of specific objectives relevant to human subject protections or research ethics more broadly.” P 23
—an “apparent lack of rigor and consistency in departmental-level scientific review” p 50
—“evidence of weak and often inadequately expert review of research” (by the Institutional Review Board, or IRB, the committee charged with overseeing protections for volunteers in research) p 9
—“The review process, as documented in the minutes, does not reflect a meaningful discussion of the risks and benefits of research protocols and the necessary steps taken to protect human subjects in the face of scientific or ethical concerns.” P 35
AAHRPP failed to note many problems, including the breathtaking conflicts of interest on the IRB, especially concerning Dr. David Adson, who also received funding from AstraZeneca (sponsor of the clinical trial, known CAFÉ, on which Dan killed himself). Adson chaired the IRB that approved the CAFÉ study, and then chaired the panel that “examined” the report of Markingson’s death although he was a colleague of Olson and Adson’s boss, Dr. Charles Schulz (the Psychiatry Department Chair) was the co-investigator on this trial.
Bizarrely, President Kaler responded to the AAHRPP report, exclaiming, “I am particularly gratified—but not surprised—that the panel found no legal or compliance violations…”
Next came the report of the Minnesota Legislative Auditor. The Nobles report skewered the UMN. P. 3 of pdf: “we concluded that the case involves serious ethical issues and numerous conflicts of interest...We are especially troubled by the response of University leaders to the case; they have made misleading statements about previous reviews and been consistently unwilling to discuss or even acknowledge that serious ethical issues and conflicts are involved.”
Former Governor Arne Carlson and many alumni have called for Kaler’s resignation or firing because of his “subverting the truth and stonewalling ... and ultimately deceiving.”
Despite this series of biting reports from external reviewers about research at the UMN recently, their “leadership” continue to operate in denial.
It’s not just the CAFÉ trial that is of concern. Another patient, Robert, told Fox News’ Jeff Baillon that he was similarly coerced into participating in a Bifupronex trial for schizophrenia, and was not believed when he developed serious pain and side effects. He filed a complaint with the IRB, who dismissed it without even interviewing him. The latest outside review of UMN, by FTI Consulting, found serious non-compliance by Olson—jeopardizing the rights and welfare of participants— with conduct of this study, including that participants were not told of the FDA’s decision not to approve bifupronex. Why has there been no disciplinary action taken against Olson?
And the U? They have appointed a committee to make recommendations as to how to improve trial conduct, comprised of many of the same people who failed to address repeated complaints about these psychiatry trials. Given their history of inaction and coverups, and of multiple ethical breaches just recapped by Carl Elliott in the NYTimes, why should we trust them now?
How this impacts others
I have often said that this case offers a life-time of learning about clinical trials—there were egregious errors in informed consent, coercion, COIs, documentation, IRB oversight and protection of research subjects. It will attain notoriety, like the deaths of Ellen Roche at Johns Hopkins and Jesse Gelsinger on a University of Pennsylvania clinical trial, or the TeGenero “elephant man” debacle. Faculty all over the world are already using Dan Markingson’s death as a case study on how not to conduct clinical trials.
Why you should care
Every medicine is developed by going through a series of clinical trials, from test tube to animal studies, to different phases of testing in people.
A quarter of adults in the U.S. are affected by depression and schizophrenia occurs in 1 percent. Another 40 million adults suffer from anxiety.
The use of drugs for mental health conditions in the U.S. is staggering, according to a 2011 mental health report by Medco Health Solutions:
—more than one in 5 adults was on at least one psychiatric med in 2010, up 22% from 2000
—more than 25% of adult women were on mental health meds in 2010 vs. 15% of men; 21% of women were on antidepressants
—11% of women aged 45-65 were on anti-anxiety meds
—4% of adults were on medication for attention deficit hyperactivity disorder (ADHD). There are an estimated 5.4 million children carrying a diagnosis of ADHD
—The figures for use of these anti-depressants in children are even more appalling, being 2-3%. (This is especially scary since the drugs themselves can increase the risk of suicide).
So while the unethical trials at the UMN might not directly impact you, they carry serious implications for us all. One day you or your loved one might need a drug like Seroquel. Imagine how you would feel if your only child was harmed or died while on such a trial—in this case a trial that was primarily for marketing, rather than answering an important scientific question.
You need to know that these studies are done honestly and ethically. If they are dishonest, like only being a marketing study or being conducted fraudulently, this will impact what drugs you will likely take.
If we see an investigator not showing integrity in how she or he obtains consent, can we trust what they say as to what they did and how it worked? Sometimes companies try to dissuade reporting adverse events (AE), especially if they are serious (like death) because this can lead to a cascade of FDA questions and worldwide alerts. If a patient is dropped from a study early, even if due to an AE, there can be a big financial penalty for the investigative research site. I don’t know why Robert was told his symptoms were psychosomatic, but I know such pressure to minimize AEs from a company occurs. Serious symptoms that have not been previously reported are particularly important, as they can be the proverbial canary in the coalmine.
If a trial is not conducted ethically, can we trust the results or reporting? One need only to look at the example of Dr. Schulz and his enthusiastic support for Seroquel. He presented data stating the superiority of Seroquel for acute schizophrenia and that it was a “first-choice antipsychotic,” at the same time as there was considerable data suggesting otherwise. Conclusions are vulnerable to sampling bias and cherry picking. It’s well known that industry-funded trials get more positive outcomes than those that are neutrally sponsored. We need investigators to behave ethically so that we can trust their research conclusions. Similarly, clinical practice guidelines are prone to serious conflicts of interest and industry bias, which are issues which organizations like the FDA need to address.
How the UMN scandal is like Toyota’s
I’d like to leave you with one other analogy, that of Toyota’s cover-up of defects in their auto’s accelerators, causing them to speed up as if possessed, and also resulting in deaths. As ABC/Reuters reported,
Toyota recalled 12 million vehicles worldwide in 2009 and 2010 as the scandal spread and tarnished its once stellar reputation. US attorney-general Eric Holder said Toyota's conduct was "shameful".
"It showed blatant disregard for systems and laws designed to look after the safety of consumers," he said.
"Rather than promptly disclosing and correcting safety issues about which they were aware, Toyota made misleading public statements to consumers and gave inaccurate facts to members of Congress.
"When car owners get behind the wheel, they have a right to expect that their vehicle is safe.
"If part of the automobile turns out to have safety issues, the car company has a duty upfront to tell car customers about them, to fix them quickly and to immediately tell the truth about the problem.
"Toyota violated this basic compact."
Now, imagine instead, that US attorney-general Eric Holder said UMN’s conduct was "shameful." He might have then gone on to say:
It showed blatant disregard for systems and laws designed to look after the safety of patients and research volunteers.
Rather than promptly disclosing and correcting safety (research conduct) issues about which they were aware, UMN’s President Kaler made misleading public statements to the faculty and Minnesotans and gave inaccurate facts to members of the legislature.
When patients participate in a clinical trial, they have a right to expect that it will be conducted safely.
If part of the drug being studied turns out to have safety issues or doesn’t work right, the University and researchers have a duty upfront to tell the public about them, to fix them quickly and to immediately tell the truth about the problem.
UMN has violated this basic compact.
The difference is that Toyota was held somewhat accountable. When will that happen at the UMN?
Suggested readings:
The UMN's Medical Research Mess
A Clinical Trial and Suicide Leave Many Questions: Part 1: Consent?
Part 2: Investigator Responsibilities
Part 4: The University of Minnesota’s Response
Covering Clinical Trials: a message for journalists and critical readers
The Deadly Corruption of Clinical Trials--a classic by Carl Elliott
