Legislative auditor says U should suspend psychiatric drug trials

The University of Minnesota should suspend new psychiatric drug trials until lapses in patient protections and ethical oversight are addressed in its psychiatry department, the state's legislative auditor said Thursday.

The recommendation grows out of an ethics controversy that has dogged the U for a decade — the treatment of Dan Markingson, who died by suicide at age 27 in May 2004 while participating in a schizophrenia drug trial.

Legislative Auditor James Nobles reviewed allegations that a delusional Markingson was coercively recruited into the study and remained enrolled after his mother expressed grave concerns and asked that he be disenrolled.

While noting that there is no proven link between the drug trial and Markingson's death, Nobles' staff said: "We are especially troubled by the response of University leaders … 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."

Nobles' recommendation is not binding, but his conclusions are the strongest corroboration by a government agency of the criticisms raised by Markingson's family. The U has repeatedly denied allegations of wrongdoing from Markingson's family and, lately, its own faculty.

At a Senate committee hearing Thursday, University President Eric Kaler challenged some findings in the audit, but apologized to the family for Markingson's death. He said the U would suspend enrollment in current and upcoming psychiatric drug studies until an independent board reviews them and informs university administrators that they can safely proceed.

Nobles, however, said Kaler's proposed internal review would be questionable given the university's "insular" culture.

"I think they've lost perspective about what is a conflict of interest," he said.

Nobles recommended legislation preventing new psychiatric drug studies until the U adopts stronger patient protections outlined in another external review that was ordered by the Faculty Senate due to the Markingson death. That review, released publicly two weeks ago, cited the Psychiatry Department for weak patient protections that do "not reflect the best efforts of a University of this caliber."

Nobles also recommended that Minnesota's state mental health ombudsman be given authority and funding to monitor the safety of patients in U psychiatric drug studies.

The Markingson case involved a national study, called CAFE, that was funded by drugmaker AstraZeneca to compare three antipsychotic drugs in the treatment of newly diagnosed schizophrenia. A U psychiatrist, Dr. Stephen Olson, was in charge of the local arm of the study and had struggled initially to recruit enough patients.

Nobles cited concerns that Olson recruited Markingson into the study while also serving as his treating psychiatrist and an adviser to the court on whether Markingson needed inpatient commitment.

The state mental health ombudsman raised similar concerns in 2005 about the potential for conflict among the multiple roles. In 2009, the Legislature prohibited doctors from recruiting their patients into their own psychiatric drug studies.

Nobles also found conflicts and problems with those overseeing the safety of CAFE. A review of Markingson's death by the university's IRB, for example, consisted of no interviews and a short written statement from Olson.

"This is the review that the IRB conducted," said Nobles, dangling one piece of paper before the Senate Higher Education Committee.

The audit also raised concerns about the Minnesota Board of Medical Practice, which hired a psychiatrist to review a complaint about Olson's conduct — even though that psychiatrist led the IRB that oversaw CAFE, was a faculty colleague of Olson, and received financial support from AstraZeneca.

Ruth Martinez, executive director of the Medical Board, said the board probably wouldn't have hired the doctor "if we knew everything that we all know now." But the board also needs specialized experts in cases like this who understand whether doctors violated laws in their practices.

Taken together, the numerous conflicts bothered Sen. Julianne Ortmann, R-Chanhassen. "Everybody seemed to have a conflict here," she said at Thursday's hearing.

A review by the U.S. Food and Drug Administration found no wrongdoing by the U in Markingson's treatment and death, and no other government agency has publicly penalized the U for its role in the CAFE study. A social worker in charge of recruitment and scheduling was sanctioned, though, for her conduct in the study, including record-keeping errors, exceeding her scope of practice and failing to adequately respond to the concerns of Markingson's family.

Nobles' report took issue with the quality of the FDA review, however, because it failed to examine whether the threat of commitment was a coercive influence on Markingson's decision to enroll in the study. He also said university officials overstated the number of investigations that have exonerated their conduct. The audit is a small measure of justice to Markingson's family.

"Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice," wrote Mike Howard, a close friend to Markingson's mother, in a letter in the audit. "This report is the first step toward accountability."

While university officials pledged improvements that will put the ethics and safety of research "beyond reproach," they urged lawmakers not to overreact with measures that could cripple research. Olson said more than 7,000 Minnesotans have died by suicide since Markingson, and that research in acutely mentally ill patients is needed to prevent more.

Bioethicist Leigh Turner, a leading campus critic for the U's treatment of Markingson, accused U leaders of "crocodile tears" and said they have had years to make the improvements they proposed.

But Sen. Terri Bonoff, DFL-Minnetonka, expressed confidence that the audit will motivate change. Bonoff, who chairs the Senate Higher Education Committee, said she plans to submit the legislation calling for a suspension of psychiatric drug research until changes proposed in the external review are carried out.

"I think we cracked this," Bonoff said. "I think there will be significant reforms."

Staff writer Maura Lerner contributed to this report.

Jeremy Olson • 612-673-7744