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Center for Bioethics N504 Boynton

410 Church Street
Minneapolis MN 55455
Fax: 612-624-9108

Dr. Susan Berry
Chair, IRB Executive Committee
University of Minnesota
D528 Mayo Memorial Building
420 Delaware St. SE
Minneapolis, MN 55455-0392

February 13, 2014

Dear Sue:
Thanks for the recent communication about my complaint of January 2. I am glad that the IRB Executive
Committee has agreed to look into the complaint, and I appreciate the meeting with you and Michael
Oakes last week. I just wanted to clarify the points that I raised in our meeting, based on the
information that I was able to gather after writing to you in January. I now believe that the problems
raised by the bifeprunox studies go well beyond the welfare of a single patient and involve serious
lapses in IRB oversight.
According to the information I have received, the patient in question was enrolled in an open-label
bifeprunox study on July 3, 2007. The study was numbered Protocol S154.3.002A and titled “An Open
Label, Flexible Dose, Long term Safety and Efficacy Study of Bifeprunox in the Study of Schizophrenia.”
The site investigator for University of Minnesota Medical Center, Fairview was Dr. Stephen Olson. The
study coordinators listed in the initial application to the IRB were Jean Kenney and Elizabeth Lemke,
although it is unclear to me if they worked on the study once it was approved.
Five weeks later, on August 10, 2007, the sponsor, Solvay Pharmaceuticals, announced that the FDA had
rejected its licensing application for bifeprunox. According to the Solvay press release, the FDA rejected
the drug application for two primary reasons. First, bifeprunox was not as effective as standard therapy
for schizophrenia. Second, the FDA asked for more information about a patient with acute
schizophrenia who had died of hepatorenal failure while taking bifeprunox three years earlier.
Despite the FDA decision not to approve bifeprunox, neither the sponsor nor the University of
Minnesota IRB stopped this study or either of the two other bifeprunox studies that Dr. Olson was
conducting at the time. Dr. Olson continued to recruit subjects until December 17, 2007, when the
sponsor issued a safety alert for bifeprunox and suspended all studies, based on the investigation
requested by the FDA.
According to the safety alert, a patient with schizophrenia and no other previous health problems had
been enrolled in a bifeprunox study in July 2004. Within ten days, the patient had become comatose
and died. The site investigator thought that the death was possibly related to bifeprunox. However,
Solvay apparently did not look further until October 2007, after the FDA asked for more information. In
November 2007 an independent pathologist concluded that the death was most likely caused by
bifeprunox. It was this finding that finally led to the suspension of bifeprunox studies.
I have seen no evidence to suggest that any subjects in these studies were informed that a subject had
died of hepatorenal failure after taking bifeprunox. While the death is mentioned in the Investigator’s
Brochure, along with the site investigator’s assessment that the death was “possibly” related to the
study drug, I cannot see any mention of the death or any such risks in the consent form I was provided.
Nor does it appear that any subjects were informed when the FDA had rejected the drug application in
August 2007. 21 CFR 50.25(b)(5) requires that consent documents for certain studies contain “a
statement that significant new findings developed during the course of the research which may relate to
the subject's willingness to continue participation will be provided to the subject.” I would be very
interested to know whether the subjects were informed of the FDA decision or the safety alert for
bifeprunox when the study was suspended.
I can also see no evidence in the records that I was given that Dr. Olson reported the injuries
experienced by the subject in the KMSP report to the IRB. In the Continuing Review report to the IRB for
the relevant period, dated September 23, 2006 to November 15, 2007, Dr. Olson reported “no serious
and unexpected adverse events” and “no complaints” by subjects. (However, he did report that three
subjects had withdrawn consent for the study.) In the Continuing Review report for the period dated
October 25, 2007 through October 30, 2008, Olson reported no serious and unexpected adverse events,
no complaints about the study and no withdrawals from the study.
If, as claimed, the patient in question suffered adverse effects so severe that he considered suicide, and
which necessitated a visit to the hospital emergency room, it is hard to imagine how a failure to report
this information to the IRB could possibly be justified. Dr. Olson’s apparent failure to report this injury
also raises questions about potential unreported injuries in other studies, especially the two other
bifeprunox studies that were running during this period.
As I mentioned in our meeting, I continue to be disturbed by the apparent indifference of the IRB to the
“corrective action” issued in 2012 by the Minnesota Board of Social Work to Jean Kenney. Although
that corrective action referred only to Kenney’s misconduct regarding the care of Dan Markingson in the
CAFÉ study, the problems identified by the Board were so alarming that they should have prompted
immediate investigation into the other studies in which she and Dr. Olson were involved. Those studies
include the NIMH-sponsored CATIE study and (apparently) the bifeprunox studies. As you are aware,
the Board of Social Work found that Kenny had falsified the initials of physicians, failed to warn subjects
of new risks of antipsychotics according to sponsor’s instructions, failed to attend to warnings that
Markingson was in danger of suicide, and had been given medical responsibilities far beyond her
training as a social worker.
I am attaching the safety alert and the relevant Continuing Review reports for the study, as well as the
Corrective Action for Jean Kenney. I am aware of at least two other bifeprunox studies that were
apparently conducted by Dr. Olson during this period:
Protocol S1543021. A Randomized, Multicenter, Double-Blind, Parallel Group Study to Compare the
Effects of the Bifeprunox and Quetiapine on Weight Changes in Stable Schizophrenia Patients
Protocol S1543020. A Multi-Center, Open-Label, Parallel-Group, Randomized, Flexible Dose Study to
Evaluate the Safety and Tolerability of Switching from Existing Atypical Antipsychotics to Bifeprunox in
Subjects with Schizophrenia or Schizoaffective Disorder.
Thank you for your help.

Yours sincerely,

Carl Elliott MD PhD
Professor, Center for Bioethics