The Markingson Files: Can pressure to recruit patients subvert a clinical trial?
Universities and research organizations set up institutional review boards to make sure research that involves human subjects is safe, among other things.
In the case of the CAFE Study, which measured the benefits of the AstraZeneca drug Seroquel against its competitors, bioethicist and writer Carl Elliott, a University of Minnesota professor, has suggested that one of the trial participants, Dan Markingson, was urged to sign up for the trial, even though his mental illness may have precluded him from making a fully informed consent.
Through the documents referenced below, most of which were filed as part of a lawsuit by Markingson's mom against the University of Minnesota, you can see how Elliott pieced together a picture of how a research team desperate for patients helped create a pipeline for clinical trial participants by setting up a psychiatric ward.
In an undated letter to CAFE study coordinators, Jeffrey Lieberman of the University of North Carolina, wrote that the study is "behind schedule on enrollment."
This fact was acknowledged in a September 2002 email from Jean Kenney, the social worker who was coordinating the CAFE study at its Minnesota location. Kenney wrote to Quintiles, the clinical research organization, saying that her team was "definitely struggling to get patients" three months after she had started leading the efforts.
Struggling so hard, apparently, that the University of Minnesota site was put on probation for lack of recruitment. Kenney mentioned that the study was "on hold/probation" in an email from September 2002. She wrote that she hoped "we can get CAFE up and running again."
Dr. Charles Schulz, who helped lead the clinical trial at the University of Minnesota, elaborated on this in a deposition for the lawsuit. He said, "My understanding was that Quintiles felt, or indicated that it is expensive to run multiple sites, and that if a site is unable to enter subjects in the study, then what they would prefer to do is work with sites that can."
In late January 2003, Kenney was still worried about recruitment. She wrote in an email, "So, some frustration here because we really need to get more enrollees. We've had none for January and that really concerns me."
She then mentioned that the Department of Psychiatry was planning to open a specialty psychosis inpatient unit in April 2003, which would work as a recruitment vehicle.
She was right.
In a brief prepared for an August 2003 teleconference about the CAFE study, the University of Minnesota team described the establishment of a specialized 16-bed psychosis unit, known as Station 12, which would recruit subjects for the study. The brief says, "All patients are reviewed for possible research candidacy. Research staff are in contact with nurses, case managers, and attending psychiatrists daily Research staff attend morning report before inpatient rounds take place. The focus is to identify any possible subjects that may be eligible for studies."
This focus on recruitment turned things around for the trial.
"One-third of the U's patients for CAFE came from this unit," wrote Paul Tosto and Jeremy Olson in the St. Paul Pioneer-Press. "By mid-2003, CAFE leaders were praising Olson and his recruiter, Jeannie Kenney, and asking them to share recruiting tips."
In an email from October 2003, Kenney mentioned the uptick in recruitment.
And, later that month, Dr. Stephen Olson, Markingson's treating physician and the other lead research for the CAFE study was featured in a webcast for "turning an underperforming site into a well-performing site."
How many of these recruits – who were supposed to be people experiencing their first schizophrenic episode – were able to fully consent for themselves? And were they, like Markingson, under orders to stay in the trial?
When Markingson was discharged from Fairview Hospital in December 2003, where he had been involuntarily committed, he was told in the discharge documents that if he had to follow the treatment plan, meaning the clinical trial, and that "consequences for not following this plan could result in court commitment to the hospital."
Another question raised by Elliott is why a clinical trial like this one would have allowed for a patient who was threatening violence. Most studies of antipsychotic drugs exclude subjects who are dangerous to themselves or others. Markingson had told multiple people that he was being ordered by a Satan-worshipping cult to kill people.
Had he talked about suicide – instead of homicide – he likely would have been excluded. The CAFE Study protocol lists among its exclusion criteria subjects at risk of suicide, not subjects who were a danger to others.
This brings us to one of the oddest facts Elliott unearthed.
The director of the University of Minnesota's IRB overseeing the CAFE Study explained in her deposition that it was not the job of the IRB to protect research subjects. This seems to run counter to the stated purpose of IRBs everywhere, including the University of Minnesota, which states quite clearly on its website (boldface added):
The IRB reviews research projects which involve human subjects to ensure that two broad standards are upheld: first, that subjects are not placed at undue risk; second, that they give uncoerced, informed consent to their participation .The IRB works with investigators to modify projects to ensure adequate protection for its subjects' welfare and right of self-determination. The University's process for protecting human research subjects reflects federal regulations developed in response to such cases as the Public Health Service syphilis study and the U.S. government radiation experiments.
Yet Moira Keane was asked in a sworn deposition, "So it's not the Institutional Review Board's purpose to protect clinical trial subjects, is that what you're saying?"
Her response? "That's true."
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