FDA re-examines University of Minnesota psychiatric study recruiting

The U.S. Food and Drug Administration (FDA) has finished a second investigation into antipsychotic drug studies at the University of Minnesota, including the study in which schizophrenia patient Dan Markingson died by suicide, and found no violations of federal research protocols.

While the FDA investigation did not address a central allegation — that vulnerable psychiatric patients such as Markingson were coerced into the so-called CAFE and other research studies — it did address key questions about whether psychiatrist Dr. Stephen Olson provided appropriate oversight, or whether he delegated key medical responsibilities in the study to unqualified staff.

Specifically, federal investigators revisited the role of study coordinator Jean Kenney, who was disciplined by the Minnesota Board of Social Work for her conduct in the CAFE study, including that she forged Olson's initials on documents and dispensed study medications beyond the scope of her practice.

The FDA found no problems with her role or Olson's oversight of the study. Olson said, despite criticisms and claims of wrongdoing by bioethicists from within the university and across the country, the FDA's findings call into question the only formal disciplinary action issued in the case of the CAFE study and of Markingson's death. The FDA also said a complaint that Olson had duplicated or fabricated documents indicating that patients had consented to research was untrue.

"What I would hope is these reports would reassure a large group of people that are undecided or who have been influenced only by the negative publicity," Olson said, "and just show them that in reality some of the [criticisms] that make it look like there is something seriously rotten going on here aren't true."

Markingson's death has been a controversial subject since media reports in 2008 revealed that he was recruited into CAFE (an acronym for comparison of atypicals in first-episode psychosis) while confined to the U's psychiatric unit for delusions and psychotic symptoms. Olson recruited him despite having multiple, potentially conflicting roles as leader of the study, Markingson's doctor and an adviser to a court on whether Markingson should be civilly committed.

Markingson died by suicide in May 2004 while participating in the study, which was funded by drugmaker AstraZeneca to compare the effectiveness of three antipsychotic drugs. His mother had been pleading with Olson to get her son out of the study because she believed he wasn't improving.

Two FDA investigators spent nine days on campus last November interviewing Olson and other U officials and reviewing documents related to CAFE and three other psychiatric drug studies Olson led. They noted a few minor concerns, including the use of whiteout on study documents, but nothing that would require a federal penalty.

The U bioethicist who filed the FDA complaint, Carl Elliott, said he was disappointed with the result, including that federal investigators did not revisit recruiting practices and whether Markingson was coerced into the CAFE study. The federal investigation also didn't examine a 2007 U study of the experimental drug bifeprunox in which another patient with schizophrenia, Robert Huber, alleged that Olson coerced him into signing up while he was confined to inpatient care. Elliott said he was "baffled" by the limitations of the FDA review and how much it relied on Olson's explanations.

Olson said the allegations of coercion in the CAFE study were already resolved by the FDA in 2005, so the agency probably wasn't compelled to examine them again. An FDA spokesperson did not return a call for comment on the scope of this latest investigation.

In addition to the FDA report, the university on Friday also released findings from a consultant it hired to evaluate the bifeprunox study.

The review determined that Huber wasn't coerced, but found that he was prepped for the study before he consented and wasn't given timely information about safety issues that could have changed his decision to remain in the drug trial for months. A U official sent a letter of apology for those errors to Huber earlier this month.

The FDA report comes amid a flurry of activity and investigations of the university's psychiatric research.

In March, the state Legislative Auditor issued a scathing report about the U's recruitment of Markingson — noting that state legislation has since prohibited a researcher from having the kind of multiple roles Olson had with Markingson because of the potential for coercion.

Also in March, an external review ordered by the U's Faculty Senate found problems with the conduct of psychiatric research and concluded that the psychiatry department's program to protect research subjects "does not reflect the best efforts of a university of this caliber." Enrollment into psychiatric drug studies was suspended until the university could adopt recommendations from the review and assure the safety of research subjects.

Recommendations expected Monday include more explicit expectations for the U's Institutional Review Board — which has oversight responsibility to make sure research studies are designed to protect patients — and new guidelines for when substitute decisionmakers can determine whether vulnerable patients can participate in research.

In April, Dr. Charles Schulz stepped down as chairman of the psychiatry department. He is also under pressure from U faculty to resign from an executive clinical role at the hospital.

Olson said the FDA review doesn't absolve the university or psychiatry department of all problems. However, he said it does undermine the disciplinary action issued by the board of social work, and some of the criticisms against his research and department.

Much of the legislative audit featured that board's disciplinary action, he said. "The FDA coming back with a basically clean report like this is very satisfying."

Jeremy Olson • 612-673-7744