The clinical trial, which was known as the CAFÉ study
(an acronym for Comparison of Atypicals in First-Episode Schizophrenia), was
sponsored by AstraZeneca, the manufacturer of Seroquel (quetiapine), and
managed by Quintiles, a Contract Research Organization. The CAFÉ study was a randomized, double-blind
trial comparing the effectiveness of three different atypical antipsychotic
drugs: Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine.)
The University of Minnesota was one of 26 sites for the trial, which lasted a
full year. After Markingson was enrolled in the CAFÉ study, he spent about two
weeks in Fairview Hospital before being discharged against his mother’s wishes
to a halfway house. Over the next five months Ms. Weiss repeatedly expressed
her concerns about her son’s medical condition, especially his increasing
agitation and rage. Her warnings were largely ignored. Finally, in desperation,
she warned the study coordinator that her son might kill himself.
On May 8, 2004, Markingson mutilated himself with a box cutter so violently that he nearly decapitated himself. His body was found by halfway house workers in the shower, along with a suicide note that said, “I went through this experience smiling.” Blood tests later showed that Markingson had been taking Seroquel.
On May 8, 2004, Markingson mutilated himself with a box cutter so violently that he nearly decapitated himself. His body was found by halfway house workers in the shower, along with a suicide note that said, “I went through this experience smiling.” Blood tests later showed that Markingson had been taking Seroquel.
In the years since Markingson’s suicide became public,
officials at the University of Minnesota have consistently maintained that the
case has been thoroughly investigated, that the university has broken no laws,
and that neither the university nor the CAFÉ study investigators bear any
responsibility for Markingson’s death. However, the CAFÉ study investigators
and the University of Minnesota IRB violated an alarming number of widely
accepted ethical guidelines governing the conduct of medical research, which,
if uncorrected, endanger the welfare of human subjects at the university. Those
violations include the following:
Markingson was coerced into the CAFÉ study by the threat of
involuntary commitment.
Markingson was incompetent to consent to the study.
The CAFE study improperly enrolled psychotic subjects at
risk of homicide or violence.
University of Minnesota investigators ignored warnings that
Markingson was in danger of committing suicide.
University of Minnesota investigators illegally released
private health information to CAFÉ study sponsors.
The CAFÉ study consent form failed to disclose serious risks
to subjects.
The CAFÉ study targeted vulnerable subjects for recruitment.
AstraZeneca and a University of Minnesota investigator
manipulated research results to promote Seroquel.
University of Minnesota investigators failed to disclose
important financial conflicts of interest to subjects.
The CAFÉ study coordinator was given responsibility for
medical duties for which she was unqualified and routinely initialed the medical
chart with the initials of a physician.
University of Minnesota officials have repeatedly refused to
conduct an impartial investigation into the conduct of the CAFÉ study and other
questionable studies in the Department of Psychiatry.
Markingson was incompetent to consent to the study.
Markingson was
coerced into the CAFÉ study by the threat of involuntary commitment.
Because of the fact that Markingson was under a commitment
order, it is unlikely that he was in a position to give his voluntary informed
consent for the CAFÉ study. On November 14, 2003, after Markingson had been admitted
to Fairview Hospital, Dr. Olson signed a document
recommending that he be involuntarily committed to a state mental institution,
on the grounds that he was mentally ill and dangerous. The Dakota County court
agreed. A week later, Olson asked the court to give Markingson a “stay of
commitment” which allowed Markingson to avoid involuntary confinement as long
as he agreed to follow the recommendations of his treatment team. Again, the
court agreed. On November, 20, the court issued a legal
order requiring Markingson to “remain hospitalized, cooperate with the
treatment plan at Fairview University Medical Center until medical discharged,
and follow all of the aftercare recommendations of his treatment team.” The day after the court issued an order
requiring Markingson to comply with the recommendations of his psychiatrist,
Dr. Olson enrolled him in the CAFÉ study. The CAFÉ study coordinator had
Markingson sign a consent form for the study when his mother was not present,
and kept him in the study despite her objections. At no time did Dr. Olson
inform the court that he had enrolled Markingson in a research study. (See the Olson deposition,
pages 79-80.) On December 8, when
Markingson was eventually discharged from Fairview Hospital, he was asked to
sign a document
in which he was warned that the consequences for failing to keep his CAFÉ study
appointments “could result in court commitment to the hospital.”
Markingson was incompetent to consent to the study.
It is very unlikely that Markingson, who was acutely
psychotic, was mentally capable of consenting to the CAFÉ study. During the period leading up to his
enrollment, Markingson had been repeatedly judged incapable of consenting to
neuroleptic (antipsychotic) drugs. On November 14, 2003 Dr. Olson signed a commitment
document stating that Markingson “lacks the ability to make decisions
regarding such treatment.” On November
17, a pre-petition
screening team recommended commitment, noting Markingson’s bizarre beliefs
and his refusal to acknowledge his mental illness. On November 19, a clinical
psychologist, Dr. James Jacobson, confirmed
those assessments, writing that Markingson “is believed not to have the
capacity to make decisions regarding neuroleptic medication.” Yet on November 21, when Markingson was asked
to consent to the CAFÉ study, this assessment of his mental state was reversed
and the CAFÉ study team judged
him competent.
While it is
possible that a psychotic patient’s mental capacity could have improved in two
days, there are good reasons to doubt this happened. First, the final
competence assessment was made not by an independent party, but by the study
coordinator for the CAFÉ study, Jean
Kenney, whose job it was to recruit subjects for the study. This is hardly
an impartial, disinterested assessment. Second, Kenney was a social worker, not
a psychiatrist or psychologist trained to make competence assessments. Third,
even after Mr. Markingson had been judged competent to consent to the CAFÉ
study, his involuntary commitment order was not lifted. This suggests that his
mental state had not changed dramatically. Finally, one of the most persistent features
of Markingson’s psychosis was a lack of insight into his condition. (See for example, page 245 of the Olson’s deposition
and the Occupational Therapy progress
notes.) Markingson did not believe he had a mental illness. It is unlikely
that he could be competent to consent to a study comparing treatments for his
mental illness when he would not even acknowledge that he was mentally ill.
The CAFE study
improperly enrolled psychotic subjects at risk of homicide or violence.
Most clinical trials of antipsychotic drugs prohibit
researchers from enrolling subjects who are at risk of suicide or violence, to
minimize the possibility that these subjects will harm themselves or others in
the trial. While the CAFÉ study
did not allow researchers to recruit subjects at risk of suicide, it permitted
the recruitment of subjects at risk of violence. The University of Minnesota
Institutional Review Board approved the protocol without requiring that
potentially violent subjects be excluded. This allowed the CAFÉ study team to
enroll Markingson, who had been involuntarily committed precisely because he
was threatening homicide. In fact, at the time of his enrollment, there seems
to have been broad agreement that he was at high risk of acting out his
delusions.
University of Minnesota investigators ignored warnings that Markingson was in danger of committing suicide.
Records indicate that Markingson experienced little if any
improvement during the five and a half months he was in the CAFÉ study. The
documents show a subject who, by the most generous interpretation possible,
failed to improve over a period of five and a half months; whose own psychiatrist
acknowledged so little improvement that his stay of commitment could not be
lifted; whose mother was convinced that his condition was spiraling dangerously
downward; and whose life ended in a grisly suicide. As Markingson grew increasingly agitated, Mary
Weiss repeatedly warned the CAFÉ study investigators that he was in danger of
killing himself. On April 15, 2004, Ms. Weiss called
the CAFÉ study coordinator and asked, “Do we have to wait until he kills
himself or someone else before anyone does anything?” After two letters to Dr.
Schulz went unanswered, Ms. Weiss wrote a third
letter on April 26, warning him, “Dan has a rage within him, just below the
surface, and desperately needs help in dealing with it. Please don’t wait until
it comes boiling out!” Nonetheless, the CAFÉ study investigators dismissed the
concerns of Ms. Weiss and left Markingson in the CAFÉ study until he stabbed
himself to death.
CAFÉ study
investigators illegally released private health information to the study sponsors.
According to the Health Insurance Portability and
Accountability Act (HIPAA), health care providers cannot release a patient’s
private health information for use in research without the express written
consent of the patient. Violation of the law is a felony. However, Markingson’s
private health information was given to AstraZeneca and Quintiles without his
authorization. Included in Markingson’s medical records from Fairview Hospital
is an unsigned
authorization form. When Dr. Olson was questioned about possible HIPAA
violations in his deposition,
he replied that he did not know whether Mr. Markingson had authorized the
release of his health information and that he did not know the specifics of
HIPAA requirements (see pages 142-145.)
The CAFÉ study consent
form failed to disclose serious risks to subjects.
According to the informed
consent document for the CAFÉ study, the main risks to study subjects were
the side-effects of the drugs being tested and the possibility that the drugs
would not be effective. However, the
consent document did not mention that subjects in the CAFÉ were also required
to forgo important therapeutic advantages of being treated outside the study.
Ordinarily, if a treatment is not effective or is causing serious side-effects,
the treating psychiatrist can try another treatment or add adjunct treatments.
However, the CAFÉ study placed limits on the kinds of adjunct treatments that
could be used, and subjects could not be changed to another treatment without
being dropped from the study.
Litigation against AstraZeneca has revealed that the company
knew about the risk of diabetes and other metabolic side-effects from Seroquel as
early as 2000, three years before Mr. Markingson was recruited into the
CAFÉ study, and possibly as early
as 1997. But AstraZeneca did not
inform physicians and patients of these risks until January 30, 2004. It was not until May 12, 2004, after
Markingson had committed suicide, that Dr. Olson asked the University of
Minnesota IRB to approve
a new consent form disclosing these risks to subjects.
The CAFÉ study
targeted vulnerable subjects for recruitment.
Before Markingson was enrolled into the CAFÉ study,
Quintiles had placed the University of Minnesota trial site on probation
for being slow to recruit subjects. The Minnesota site was “struggling to get
patients,” according to internal email
correspondence, and Quintiles and was pressuring it to step
up its efforts. However, as the St.
Paul Pioneer Press has reported,
in April 2003 the University of Minnesota’s Department of Psychiatry
established a locked inpatient unit designed for severely psychotic patients.
On this psychosis unit, called Station 12, every patient could be evaluated for
recruitment as a potential research subject.
While the establishment of Station 12 increased
recruitment numbers dramatically, severely psychotic patients on a locked
unit are especially vulnerable to coercion or undue influence.
A University of
Minnesota investigator helped AstraZeneca manipulate research data.
In April 2010, AstraZeneca agreed to pay
$520 million to settle two federal investigations and two whistleblower
lawsuits alleging that it had marketed Seroquel illegally and concealed its
health risks. Documents unsealed in that litigation indicate that Dr. Charles
Schulz, the co-investigator on the CAFÉ study, was involved in the misleading
presentation of least two AstraZeneca studies. As the St. Paul Pioneer Press and the Minneapolis
Star Tribune have reported, an AstraZeneca trial called Study 15 found
that Seroquel performed worse than Haldol, an older, generic antipsychotic
drug, and also that Seroquel increased the risk weight gain and diabetes. Yet
Schulz claimed publicly and in scientific
presentations that Seroquel had been shown superior to Haldol. (For some original
internal AstraZeneca documents about Study 15, see here, here,
here,
here,
and here.)
Later, as reported in City
Pages, Schulz helped AstraZeneca conduct a trial called Study
41, which found that extended-release Seroquel was no more effective than placebo.
AstraZeneca then repeated the study overseas in the developing world, where the
results proved much better. Subsequently,
AstraZeneca enlisted Schulz to publicize the positive study in press
releases, while keeping the negative study quiet. (For internal documents,
see here
and here.)
The design of the CAFÉ study was biased to produce a
favorable result for Seroquel. As a meta-analysis
in the American Journal of Psychiatry
has shown, 90% of similar head-to-head comparisons of atypical antipsychotics
come out positively for whichever company has designed and funded the trial.
Several experts, including the editor of the British Journal of Psychiatry, have
argued that the CAFÉ study was similarly biased.
University of
Minnesota investigators failed to disclose crucial financial conflicts of
interest to subjects.
Research subjects have a right to know if study
investigators have financial conflicts of interest that might influence their
care. However, subjects in the CAFÉ study were not informed that the study
investigators had significant financial relationships with AstraZeneca, the
CAFÉ study sponsor, as well as the manufacturers of the other atypical
antipsychotics being studied. According to the St. Paul Pioneer Press,
Dr. Charles Schulz, a co-investigator on the CAFÉ study, received over $570,
000 from the pharmaceutical industry from 2002 to 2008, with $112,000 coming
from AstraZeneca. Also, subjects were not informed that the Department of
Psychiatry was paid $15,648 for each subject who completed the CAFÉ study. This
payment was arranged so that the longer a subject stayed in the study, the more
the university would be paid. In total, the CAFÉ study generated
$327,000 for the University of Minnesota’s Department of Psychiatry.
The CAFÉ study
coordinator was given responsibility for medical duties for which she was
unqualified and routinely initialed the medical chart with the initials of a
physician.
In November 2012, the Minnesota Board of Social Work issued
an “agreement
for corrective action” for Jean Kenney, the study coordinator for the CAFÉ study. Among the many disturbing findings of the
Board was that Kenney had responsibility for administering prescription drugs
to research subjects and assessing their side-effects, despite the fact that
she had no medical training. Some of the side-effects whose severity she
had responsibility for assessing could be life-threatening. Kenney made significant mistakes about a
medical diagnosis and medication dosage, and forged the initials of a physician
on the medical chart.
University of
Minnesota officials have repeatedly refused to conduct an impartial
investigation into the conduct of the CAFÉ study and other questionable studies
in the Department of Psychiatry.
Almost as alarming as these ethical violations is the
refusal of University of Minnesota officials to address them. Many of the
violations reflect larger structural problems with the oversight of clinical
research at the institution which continue to place subjects at risk. Ordinarily,
the primary responsibility for protecting human subjects rests with the
Institutional Review Board (IRB). In this case, however, the Institutional
Review Board compounded the problem by failing to address critical problems
with the protocol, such as the inclusion of potentially violent subjects. In a deposition,
the director of the IRB, Moira Keane, claimed that protecting subjects was not
the responsibility of the IRB.
The suicide of Markingson was first made public through a
series of articles in the St. Paul
Pioneer Press in May 2008. Since that time, officials at the University of
Minnesota have repeatedly
asserted that the case has already been reviewed and that the university
has been cleared of any blame. (See also
here.) Yet the University of Minnesota has never
provided evidence of any internal investigation apart from the routine “adverse
event” review by the IRB, which was itself implicated in the case. The only
external investigations have resulted from complaints filed by Mary Weiss and
Mike Howard (a family friend) to agencies which have little if any
responsibility for the protection of human subjects, such as the Minnesota
Board of Medical Practice. While it is true that the FDA investigated the case
in 2005, in response to a complaint by Mary Weiss and Mike Howard, the FDA
inspector restricted its investigation to very narrow grounds and produced a deeply
flawed inspection report.
Two months after a lawsuit filed by Mary Weiss was dismissed
on technical grounds, the University of Minnesota filed a legal action – a notice
to assess costs -- against Ms. Weiss, demanding that she pay the university
$57,000. In December 2010, a group of university faculty members sent a public
letter to the Board of Regents asking for an external investigation. That
request was followed by a supporting letter from a campus organization, Faculty
for the Renewal of Public Education. In February, the Board of Regents refused
that request, claiming that the case had already been investigated. Since
that time, similar communications have come from the Mark
Rotenberg in the Office of the General Counsel; Aaron Friedman,
the Vice-President for Health Sciences and Dean of Medicine; and Tim
Mulcahy, the Vice-President for Research.
