U of M Releases New Reports on Human Subjects Research

Friday, May 15, 2015

Three new reports released today by the University of Minnesota shed new light on the ongoing discussions about the Department of Psychiatry and the protection of human subjects in clinical research.  Together, the reports show that while there are areas for improvement, patient safety has not been compromised and many of the allegations of misconduct have been found to be without merit.

The reports come on the heels of two critical reviews that were released earlier this year. An independent review commissioned by the University made a number of recommendations for how the University could improve patient protections.  Those findings were echoed by a report by the Legislative Auditor that focused on the death of Dan Markingson, a drug study participant who took his own life in 2004. 

While the new reports support the University’s position that research safety is a priority in all trials, the findings do not impact the continuing efforts by the University to improve practices going forward.

“We have made it clear that we have an obligation to examine our practices and take steps to do a better job at protecting patients, particularly those with diminished mental capacity,” said Brooks Jackson, MD, dean of the University of Minnesota Medical School and vice president of health sciences. “While these reports provide evidence of our commitment to human subject protection, they do not reduce the urgency of our mission, or our commitment to leaders in human subjects protection.”

The reports were made public with the consent of Dr. Stephen Olson, a University of Minnesota Psychiatrist who was the principal investigator (PI) for all of the trials that were examined. The reports include a new report from the Food and Drug Administration (FDA) that reviewed the CAFÉ study, which has been the focus of discussion for the last 11 years following the death of Dan Markingson while he was participating in the trial.  The FDA also reviewed compliance and consent issues for three other schizophrenia studies – the CATIE study, the TENETS study, and the HALO study.

The other two reports that were released today focused on a 2007 clinical trial looking at the use of the drug bifeprunox as a possible treatment for schizophrenia.  The first report was done by the University IRB, looking into allegations of coercion and mistreatment from a patient who has spoken publicly about his claims.  When that report was complete, Brian Herman, the University’s vice president for research, asked an outside organization, FTI Consulting, to do an additional review of the case. 

FDA Report (http://www.health.umn.edu/sites/default/files/FDA-EI-Report-May-15.pdf)

The FDA Report focused on four studies, with the primary focus being on the CAFÉ study.  The FDA had already conducted a review of the trial in 2005, in the wake of Dan Markingson’s death.  The 2005 concluded, “No evidence of misconduct or significant violation of the protocol or regulations was found in this inspection.”

In the years since this review, some have criticized the initial FDA report as being incomplete, in part for failing to review the role of Jean Kenney, the study coordinator for the CAFÉ study.  In 2012 the State of Minnesota Board of Social Work took corrective action against Kenney for performing tasks that were allegedly inappropriate for her role.

The FDA decided to conduct a second review of the CAFÉ study in November 2014 to review Dr. Olson’s oversight and delegation of responsibilities in light of the Board of Social Work findings. After 9 days of interviews and document review by two experienced investigators, the FDA found that the Board of Social Work allegations were “unfounded and were not corroborated.”

“From the beginning I have made it clear that Jean Kenney was operating in the role of study coordinator, not as a social worker,” said Olson. “The claims against her, including allegations of forgeries and improperly dispensing medications, were simply not supported by the facts. The FDA report clearly shows she performed her research functions properly and ethically under my supervision.”

A second issue related to the CAFÉ study concerned the use of an “Evaluation to Sign Consent Form” for subjects being enrolled in the trial.  The FDA had received allegations that the form had been duplicated and used for multiple subjects rather than being filled out for each patient individually.  The FDA inspectors examined the documents and rejected this allegation, noting, “each was obviously an original form and that there was no duplication or use of one subject’s form for another.”

FDA inspection into the CATIE, TENETS and HALO studies also revealed no violations of protocol or issues related to consent of subjects, although the investigation did note some issues that did not rise to the level of violation, but were discussed with Dr. Olson.

Reports from the IRB (http://www.health.umn.edu/sites/default/files/IRB-Investigation-Report-R...) and FTI (http://www.health.umn.edu/sites/default/files/FTI-Release.pdf)

In February 2014 the IRB launched a formal investigation looking at alleged non-compliance related to a clinical trial for the use of bifeprunox for schizophrenia.  A study participant alleged that he was improperly coerced into the study and that serious side effects from his participation in the trial that were not addressed properly by his physician.

The IRB investigation revealed:

  • “…no serious or continuing non-compliance” with regard to the rights and welfare of research participants
  • Adequate mechanisms to evaluate the capacity of participants to consent
  • The patient was not pressured to participate in the trial and was informed of other treatment options available to him
  • Proper procedures were followed related to handling and reporting adverse events
  • Dr. Olson was attentive to and made adequate attempts to address the patient’s complaints
  • The patient was allowed to withdraw from the study freely and without pressure

The IRB did note areas for improvement related to the consent process. In particular, they noted that the research subject was asked to forego consuming food or liquids overnight in preparation for a blood screening the following morning before written consent had been obtained, although verbal consent had been obtained. The review called this out as non-compliance, but said it did not rise to the level of serious non-compliance. The report did call on the investigator to be sure consent forms are signed before any study-related activity begins.

The IRB also felt there was no requirement to notify the research participants when the FDA decided not to approve bifeprunox.  The FDA decision did not direct the drug company to cease testing of the drug and allowed for additional data to be submitted to establish the drug’s effectiveness.

After the IRB report was completed, FTI Consulting was engaged to give an independent review of the case.  FTI’s conclusions included:

  • There were adequate mechanisms in place to evaluate the capacity for informed consent
  • The complainant had the capacity to provide consent
  • The complainant was not pressured or coerced to participate in the study
  • Adverse events were properly handled and reported
  • The complainant was freely allowed to withdraw from the study

The FTI report disagreed with the IRB on whether the participants should have been notified when the FDA decided against approval of bifeprunox. FTI said this information should have been reported to participants in a timely manner.

FTI also disagreed with the IRB on the seriousness of writing an order for asking the patient to forego food and drinks from midnight to 7AM before he had signed his consent.  FTI felt this practice jeopardized the rights of the patient and constituted serious non-compliance even though the patient had given verbal consent.

Given the longstanding controversy around the CAFÉ study and more recent allegations of non-compliance, Dr. Olson said these reports confirm that he and his research teams were acting appropriately with few exceptions. Now, he hopes these reports, along with the plans that are being developed to improve human subjects protection, will help the University move past the controversies and focus on helping patients.

“Clinical research is not easy, and there will certainly be challenges, but I believe we have the ability to rise to the occasion and do it better,” said Olson. “We must do better. Since Dan Markingson’s death by suicide, more than 7,000 other Minnesotans have taken their own lives.   Tens of thousands have developed severe mental illness.  The problem will only get better when research brings better treatments, just as medical research has changed the landscape of cancer and HIV.”

The University’s efforts to implement changes to human subjects research protections are ongoing.  A draft plan will be released on Monday, May 18 after which there will be a period for public comment.  The final proposal is expected to be presented to the University Board of Regents in June.