How not to run a drug study: The University of Minnesota puts on a clinic

At Scientific American, Dr. Judy Stone is using a notorious case of research misconduct at the University of Minnesota (where I studied bioethics) to walk through the requirements of ethical research on human subjects and the many ways they can be violated.  It can be difficult to keep up with the research scandals at Minnesota’s Psychiatry Department over the years, so for the sake of clarity: this is the one involving Dan Markingson, a young man who killed himself while participating in an industry-funded clinical trial of Seroquel (the “CAFE” study).

The problems with the CAFE study and the way Markingson was treated would fill a book.  Carl Elliott, a bioethicist (and my former academic advisor) at the University of Minnesota, has been relentless in seeking to keep Markingson’s story in the public eye and to hold his own university accountable for its conduct.  You can read Elliott’s account here, but here are some of the lowlights:

In 2003, 26 year-old Dan Markingson was suffering from psychosis and was threatening to kill people, including his own mother.  A judge ordered Markingson involuntarily committed on the recommendation of a UMN doctor named Stephen Olson.  Dr. Olson then persuaded the judge to release Markingson, but only on the condition that he followed Olson’s treatment program.

But rather than simply caring for Markingson, Olson’s “treatment program” consisted of enrolling him in a clinical trial in which Olson was serving as an investigator.  In other words, Markingson was given a choice between participating in the study or being involuntarily committed.  Moreover, Markingson clearly lacked the capacity to consent to participate in the study – just days before Markingson was enrolled in the trial, Dr. Olson himself had attested that Markingson “lack[ed] the capacity to make decisions regarding [his] treatment.”

Needless to say, this is a novel and outrageous way to “recruit” study participants (and one that is now prohibited by Minnesota law).  But Olson had enormous incentives to get subjects enrolled and keep them in the study.  Under the university’s arrangement with AstraZeneca (Seroquel’s manufacturer and the study’s sponsor), the psychiatry department earned more than $15,000 for each subject who completed the CAFE study.  In addition, the Minnesota study site had previously been placed on probation for failing to recruit an adequate number of participants.

In his conduct of the drug trial, Dr. Olson delegated important responsibilities to a social worker named Jeanne Kenney:

“despite the fact that Kenney had no formal medical training, she apparently administered prescription drugs to research subjects and made formal judgments of the side-effects. She frequently assessed the severity of potentially dangerous adverse events such as akathisia [disturbing feeling of inner restlessness and inability to be still], and sometimes she even assigned the job to a social work intern she was supervising. According to the [Minnesota Board of Social Work], her record-keeping was “devoid of any clearly articulated, consistent set of treatment goals” and she omitted crucial information relevant to suicide prevention. When Markingson’s mother, Mary Weiss, left “alarming voicemail messages” about her son’s condition, Kenney did not respond adequately.  Kenney also made significant mistakes about medication dosage and a medical diagnosis, and these mistakes remained in the chart until well after Markingson’s suicide, when Kenney went back and changed them. To top it all off, Kenney often signed the chart with the initials of a physician.”

Dan’s mother, Mary Weiss, wanted Markingson to be treated for his illness, not enrolled in a drug study.  As time went by she observed her son’s mental condition deteriorating and went to great lengths to try to get Dan removed from the study.  But Olson and Dr. Charles Shultz (a co-investigator in the study and chairman of the university’s psychiatry department) declined.  Finally, Ms. Weiss left Kenney a voicemail message asking “Do we have to wait until he kills himself or someone else before anyone does anything?”  Yet, notes Stone, “neither Kenney nor Dr. Olson thought this was worrisome enough to even notify the IRB, let alone to drop Dan from their clinical trial and place him on other medications, such as the Risperdal he had initially stabilized on, or Haldol, an older antipsychotic.”

Shortly after Ms. Weiss made her desperate plea, Dan Markinson killed himself by cutting his own throat.

Unbelievably, Mary Weiss’ ordeal didn’t end there.  Rather than taking any actions to right the wrongs done to Markingson, to discipline the responsible university employees, or to prevent such gross abuses from occurring again, the University of Minnesota lawyered-up and denied all wrongdoing.  When Weiss sued the university, the university won summary judgment on the basis that it was immune from suit under state law.  To this day, the University of Minnesota cites the court’s ruling as clearing the university of wrongdoing – which is a bit like a diplomat claiming he was “exonerated” for murder by virtue of diplomatic immunity.

But wait, there’s more.  Having hidden behind statutory immunity to avoid being held responsible for Markingson’s death, the University of Minnesota then stuck Markingson’s mother with the bill for the university’s litigation costs – more than $56,000.  It then used those costs as leverage to force Ms. Weiss to abandon an appeal of the trial court’s ruling.  (For more on this aspect of the case, check out my earlier post on this issue.)

Just to recap: A University of Minnesota employee forced Dan Markingson – a vulnerable, delusional young man – into a clinical trial.  That employee then delegated responsibility for Markingson’s treatment to a social worker with no medical training, ignored his deteriorating condition, and ignored his mother’s urgent pleas for help.  After Markingson killed himself, the university denied any wrongdoing and any responsibility for his death, hid behind statutory immunity from suit, and then sought to make Markingson’s mother pay the university $56,000 for its troubles.

It doesn’t end there.  A group of bioethicists at the University of Minnesota then called on the university’s Board of Regents to conduct an independent investigation into the CAFE study and the treatment of Dan Markingson.  When your own bioethicists – i.e., the people whose job is to assess whether doctors have acted ethically – are urging you to investigate your institution’s role in a patient’s death, you might want to heed that advice.  But instead the Board took the advice of its General Counsel Mark Rotenberg – the same lawyer who defended the university from Weiss’ lawsuit and stuck her with its court costs.  Not surprisingly, Rotenberg determined no investigation was necessary.

And yet, there’s more!  After Carl Elliott, the University of Minnesota bioethicist, refused to drop the matter, Rotenberg asked the university’s Academic Freedom and Tenure Committee to take up the question of “[w]hat is the faculty[’s] collective role in addressing factually incorrect attacks on particular university faculty research activities?” – a question that appeared both to accuse Elliott of “factually incorrect attacks” and to call for some unspecified action to “address[]” them.  Other faculty, including the president of the Minnesota chapter of the American Association of University Professors, viewed this as an attempt to intimidate Elliott into silence.  If so, it backfired.  The story ended up in the press, putting the Markingson case back in the public eye and once again making the University of Minnesota look really bad.

That’s the short version.  For more information, check out Elliot’s article, The Deadly Corruption of Clinical Trials, as well as Dr. Stone’s analysis for Scientific American.  Part 1 of Dr. Stone’s series looks at informed consent – in particular, the absence of it in Markingson’s case.  Part 2 examines investigators’ responsibilities, Olson’s failure to fulfill them, and the total absence of any consequences for the people responsible for the Markingson tragedy.

Matt Lamkin
Twitter: @lawbioethics

See also:

Carl Elliott, “A referenced summary of the Dan Markingson case

When Drug Trials Go Terribly Wrong: Lessons from a Bereaved Mother

Carl Elliott, “I Was Just Following Orders”: a Seroquel Suicide, a Study Coordinator, and a “Corrective Action.

Dan Markingson’s 2004 suicide: ‘Corrective Action’ issued to former U of M employee


What Problems? Seroquel Research & A University

University Exonerates Itself Over Seroquel Trial