Patient's Suicide by Antipsychotic Drug Trial Raises Questions About Psychiatrist's Ethics - Part 2 of 3 - Minnesota

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St. Pioneer Press (Minnesota)

The safety net that didn't save him

Patient's suicide raises questions about psychiatrist's ethics

By Tosto and Olson

May 19, 2008

When people enter drug studies at the University of Minnesota, they're

supposed to be protected by a safety net keeping watch that the

vulnerable are not coerced, that standards of conduct are met and When

people enter drug studies at the University of Minnesota, they're

supposed to be protected by a safety net keeping watch that the

vulnerable are not coerced, that standards of conduct are met and that

researchers aren't tangled in conflicts that might influence their

decision-making.

That system was supposed to protect Dan Markingson.

A schizophrenic, Markingson killed himself in 2004 while enrolled in a

study at the U comparing anti-psychotic drugs. Documents surfacing the

past year in a lawsuit over his death have raised questions about

whether the U psychiatrist running the study followed university ethical

guidelines. They also raise questions about why the Institutional Review

Board, the internal group charged with protecting people in university

studies, didn't intervene.

University officials say their nationally accredited review board - a

volunteer panel of 57 experts in medicine and other disciplines - works

well and rigorously reviews studies. They would not talk specifically

about the Markingson case to the Pioneer Press. A judge ruled in

February that as a state agency, the university and its IRB are immune

from the lawsuit.

The legal ruling didn't allow questions to be explored about who's

ultimately responsible for the safety of research subjects and whether

the university did everything reasonable to protect Markingson from

harm.

According to the U's human subjects protection guide, the IRB's first

charge is " to protect human subjects involved in research at the

university from inappropriate risk. "

In reality, the IRB operates largely on trust. Trust that researchers

will follow the rules. Trust that people will speak up when a safety

plan is violated, even if they have professional or financial pressures

to stay quiet.

" It's the people who implement the plan who are responsible for

protecting the subjects, " said Moira Keane, the U's director of research

subjects protection programs.

The IRB approves all clinical research - modifying safety rules when

necessary - and samples study records every year or so to make sure its

conditions are met. It also has the power to shut down projects that

aren't complying with safety requirements or have caused " unexpected

serious harm " to subjects.

Keane recalled four studies out of thousands at the U over the past two

decades that the IRB stopped.

The lawsuit by Markingson's mother, Weiss, alleged that the IRB's

trust was misplaced in the so-called CAFE study, led by Dr.

Olson, a U psychiatrist.

A central allegation was whether Olson had too much power over

Markingson, and too many conflicts that obscured his clinical judgment.

Olson recruited Markingson into the study at the same time he served as

Markingson's treating doctor and advised a Dakota County judge on

whether Markingson should be committed to a psychiatric hospital.

Had the IRB followed its own guidelines, it would have discouraged Olson

from recruiting his own patient. The IRB Web site states that

" doctor-patient relationships between the investigator and participants

should be avoided, when possible, to eliminate any power-based

coercion. "

It's impossible to know whether Markingson would have killed himself if

he hadn't enrolled in the research study. He was in a sensitive early

stage of his schizophrenia diagnosis, during which the suicide risk is

greatest. Even so, the study's rigid guidelines meant that Markingson

received only one anti-psychotic drug to help control his delusions.

Experts hired by Weiss' attorneys said in court depositions that the IRB

missed opportunities to make the study safer.

Dr. on Pope from Harvard Medical School called the IRB's role an

" essential link in the chain of causation that improperly admitted Mr.

Markingson into the CAFE study, improperly held Mr. Markingson within

the CAFE study, prohibited effective treatment of Mr. Markingson, and

thus became a substantial, proximate cause of Mr. Markingson's death. "

The IRB could insist researchers turn over all complaints about their

studies, which might have raised concerns in this case. Weiss had

complained in letters to Olson and Dr. Schulz, head of the U's

Department of Psychiatry, that her son wasn't getting better and was at

risk for harm. She had requested that the doctors try other treatments,

even if he had to be withdrawn from the study.

The U hired its own national IRB expert to refute Pope's claims. The IRB

had no legal obligation to require someone other than Olson to evaluate

Markingson's competency or his ability to consent to research, said

Ernest Prentice, associate vice chancellor at the University of Nebraska

Medical Center.

Nor is there a requirement that complaints such as Weiss' letters be

forwarded to the IRB unless there is some unanticipated risk. Had the

IRB received complaints, it could have investigated, he said.

Weiss said she'd never heard of an IRB.

The CAFE study was fairly prominent, involving 26 academic institutions

and 400 schizophrenic patients. Financed by the pharmaceutical company

AstraZeneca, it was worth up to $327,000 to the U, with some of those

funds going to Olson's salary and other study personnel.

U officials said the IRB acted ethically and within its obligations and

federal regulations to protect human subjects in this study.

After the suicide, the IRB sought information from Olson on how

Markingson consented to the study. But IRB officials said in depositions

for the lawsuit that the review board never formally investigated

Markingson's death.

The IRB investigates when there is evidence of misconduct. There was no

evidence of that in the Markingson case, said Dr. Bianco, a U

physician who oversaw the U's research subjects program at the time

Markingson participated in the study.

Bianco declined a Pioneer Press interview request. But in a court

deposition, he acknowledged that the U has some 8,000 studies involving

humans - research he estimated was worth about $15 million - but that

the IRB doesn't track the number of people enrolled in U research, only

the number of projects approved.

Bianco agreed with Keane that the IRB system operates largely on

self-disclosure by researchers.

The U's top research official says researchers and IRB reviewers " are

aware and understand their ethical and moral obligations to do the right

thing.

" If people write with concerns and issues, they will be reviewed, " said

Tim Mulcahy, the U's vice president of research. " If the IRB were to

become aware of a suggestion of coercion or heavy handedness, " he added,

" we have an obligation to act promptly and very directly. "

Olson declined to talk to the Pioneer Press about Markingson's care.

He said it would be difficult for any researcher to get away with

violating research rules because they are observed by so many medical

students, residents, nurses and others. However, a 2006 internal audit

of the U's psychiatry department challenges the notion that those

workers would speak up.

Nearly 40 percent of the psychiatry department staff responding to the

auditor survey said they did not believe they would be protected from

retaliation for blowing the whistle on a suspected violation in the

department.

Some experts believe the nation's system of review boards is

dysfunctional and in need of reform.

" We have a very haphazard way of overseeing (IRBs) and collecting data

on adverse events, " said Dr. Ezekiel Emanuel, bioethics chair at the

Clinical Center of the National Institutes of Health and a national

expert on institutional review boards.

" There's no one in America who can tell you how many people are enrolled

in clinical research, " he said. " No one can tell you how many people

died in (ways) attributable to clinical research. No one can tell you

how many people got injured, and no one can tell you over time whether

the system is getting less safe. "

Link: http://www.twincities.com/ci_9306735?nclick_check=1

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