Feature Recruitment to drug trials

Investigating the fallout of a suicide

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f6039 (Published 08 October 2013) Cite this as: BMJ 2013;347:f6039

This article has a correction. Please see:

  1. Edward Davies, US news and features editor, BMJ
  1. 1New York, USA
  1. edavies{at}bmj.com

In 2004 Dan Markingson committed suicide while he was taking part in the CAFE psychiatric trial. Edward Davies looks at how his death has been dealt with

Almost a decade has passed since Dan Markingson committed suicide while taking part in the CAFE psychiatric drug trial at the University of Minnesota.

After years of pressure and countless fruitless personal and legal battles, however, campaigners still believe that his story is only half told and earlier this year launched a petition demanding Minnesota governor Mark Dayton independently investigate the case.1

The petition makes some grave allegations: “Evidence of fraud and serious privacy violations in psychiatric studies at the university have emerged,” it claims.

“It is possible that other research subjects have died or suffered serious injuries, or that they have been mistreated in other ways. Bioethicists at the University of Minnesota itself have called for an external investigation, yet the university still refuses.”

Nine years of struggle

To understand the most recent developments it’s important to note that many of the protagonists have been at loggerheads since Markingson first entered the CAFE trial in 2003.

Markingson began to show signs of paranoia and delusions in 2003, believing that he needed to murder his mother. He was committed to Fairview Hospital involuntarily after evaluation and was subsequently enrolled on a clinical trial of antipsychotic drugs. This study was a comparison of atypical antipsychotics for the treatment of first episodes of schizophrenia (the CAFE study). The study’s structure was that of a Phase 4 randomized, double blind trial comparing the effectiveness of three different atypical antipsychotic drugs: Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine), with each patient to be treated for a year.

After about two weeks on study treatment in the hospital, Markingson was discharged to a halfway house. His mother, Mary Weiss, raised repeated concerns about his condition, questioning his involvement in the trial, but he eventually committed suicide on 7 May 2004.

The fallout from this point was substantial.

In 2005 the US Food and Drug Administration conducted an inspection of the Center for Drug Evaluation and Research at the university but found “no evidence of misconduct or significant violation of the protocol or regulations,”2 and in 2007 Weiss took the University of Minnesota and AstraZeneca to trial in a wrongful death case. The county court dismissed the case against the university and also the case against AstraZeneca, the trial funders, saying Weiss had failed to establish a causal link between Markingson’s suicide and the drugs.3

In 2009, the Minnesota state legislature passed a new law prohibiting certain people from drug trial participation. It stated that people under state civil commitment “will be prohibited from participating in a psychiatric clinical drug trial while the order is in effect.” The law would allow a patient to participate only if the treating psychiatrist submits an affidavit citing its benefit to the person and the treating psychiatrist must not be the same one conducting the drug trial. The statute was nicknamed Dan’s Law and drew heavily on the experiences and testimony of Weiss.4

In 2010 eight of the University of Minnesota’s own bioethicists sent a letter to the Board of Regents at the University of Minnesota raising concerns about the case asking for “an impartial panel of experts in research ethics” to investigate it.5

Finally, last year the Minnesota Board of Social Work found that the study’s coordinator, Jean Kenney, had consistently fallen “below the minimum standards of practice for a clinical social worker” and among the examples of poor practice quoted in her “agreement for corrective action” were dispensing prescription drugs without authorization, routinely signing off clinical documents with physicians’ initials when the physician failed to do so, and recording diagnoses incorrectly.6

However, in spite of the many allegations it’s important to note that the university has never been found guilty of any wrongdoing, nor taken disciplinary action against anyone in relation to this case.

New evidence

But in recent months, those campaigning on behalf of Markingson claim to have new evidence. Carl Elliot, a professor in the Center for Bioethics at the University of Minnesota and one of the eight signatories on the 2010 letter to the Board of Regents has for some years led the charge against his own employer.

Speaking to the BMJ he claims that there have been recent developments that demand further investigation.

At the start of the year Mike Howard, a family friend, and Weiss contacted Elliot saying they had found two near identical “evaluation to consent forms” in Markingson’s case notes. 7 8

“The purpose of the forms is to evaluate whether subjects are competent to consent to the study,” explains Elliot. “We just couldn’t figure out why there were two or why they were in that form. We had initially thought that one was a photocopy of the other—they seemed pretty much identical apart from the fact that one has subject initials marked on it while the other doesn’t—but then we could not explain why the shapes of the rubbed-out parts at the top of the forms were different.”

Unable to come to a satisfactory answer Elliot posted the documents on an online psychiatry community forum, to see if anyone else might have a theory. He says that he soon heard back from several people who said that their relatives had been enrolled in the same CAFE trial as Markingson and that their “evaluation to consent” forms featured exactly the same answers as appeared in the Markingson forms, written in precisely the same handwriting.

But as he contacted these individuals to investigate further, most said they could not help, although they did not make clear why not. However, one former trial participant did consent to share a form on the grounds of total anonymity—its contents are strikingly similar to Markingson’s form, with the same answers recorded and in the same handwriting, albeit in this case without dates or identifiers.9

What had been going on with the consent forms?

These observations led Elliot to put a serious accusation to the university: “The dark conclusion that you are tempted to leap to is that they are enrolling mentally ill patients in trials, so there will always be questions of patient competency to answer,” says Elliot. “Rather than evaluate these patients properly they use standard forms and pre-ordained, ‘one-size fits all,’ text and add the names in later. Is there a benign explanation for it? There might be but I can’t think of one.”

When Elliot put this to the university and asked them to release the relevant forms themselves, the university issued a strong rebuttal. “Elliott is not in possession of any official clinical or research “file” regarding Markingson. On the other hand, there are many numerous legal proceedings and independent reviews. The implication that there is a single official Markingson file that contains divergent “evaluation to sign consent” forms is false.

“The third document produced by Elliott, supposedly from the family of another study subject, is merely another photocopy of the Markingson form, on which someone has clumsily whited out identifying features.

“There is absolutely no evidence that any of the forms used predetermined photocopied answers. Elliott’s insinuations in this regard are completely false.”

Both before and since this statement was issued the university has repeatedly rejected requests to investigate conduct in the CAFE trial citing the investigations of numerous external bodies. Most recently William Donohue, the university’s current General Counsel, responded to requests from Leigh Turner, another associate professor for bioethics at the university, saying that Turner seemed “simply unwilling or unable to credit the judgment of others who have reviewed the matter, including the US Food and Drug Administration, the state district court and the Minnesota Board of Medical Practice as well as the Office of General Counsel at the University.”

But again campaigners have attacked the line that independent bodies have cleared the university.

“The university has repeatedly made claims about bodies that have cleared them that simply do not stack up,” says Elliot. “For example the Minnesota Board of Medical Practice is a licensing body to investigate individuals—it cannot investigate another body such as a university or the ethics of a study.”

His claims are borne out by a recent letter from Robert Leach, the executive director of the board, to Weiss and Howard that states that: “The Board’s only jurisdiction is over the credential of the individual practitioner. The Board has no jurisdiction over any institution, clinic, facility, hospital, university or medical school. We do not look at anything other than the professional practice of the individual licensee. When the Board closes a case without action, it does not necessarily ‘exonerate’ that individual practitioner and that is a term the Board would not use.”10

Similarly, Minnesota deputy attorney general Karen Olson wrote to Weiss and Howard to confirm that her office had not made “any independent investigation or determination regarding the care rendered to your son.”11

The situation leaves matters unresolved and the campaigners almost out of options—hence now the petition for an independent investigation of this case.

Notes

Cite this as: BMJ 2013;347:f6039

Footnotes

  • Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.

  • Provenance and peer review: Commissioned; not externally peer reviewed.

References