Clinical trial participant's suicide raises ethical questions for IRBs

Conflict of interest and informed consent issues pondered

A recent legal case involving a clinical trial participant who committed suicide raises a variety of questions for IRBs.

The case stemmed from a clinical trial comparing antipsychotic medications used to treat schizophrenia. Twenty-seven-year-old participant Dan Markingson killed himself about six months into the trial.

Markingson's mother, Mary Weiss, sued the researchers, research institution, and pharmaceutical company after his death in 2004. Earlier this year, a judge ruled that the university had statutory immunity and that the drug company (AstraZeneca of Wilmington, DE) was in the clear because there was no convincing evidence that the drug caused the participant's death. The mother settled with the researcher for $75,000.1(See timeline for Markingson case)

While there have been fewer shockwaves in the clinical trial industry from this case than there were years earlier when Jesse Gelsinger died during a clinical trial, it still highlights ethical concerns about conflicts of interest and informed consent of people with limited decision-making capacity.

In the Markingson case, the study's investigator was also the clinician who diagnosed the young man with schizophrenia, determined his ability to make an informed consent for the study, and decided whether he needed to be placed in an inpatient unit. Weiss had charged that the PI's decisions were made for the convenience of keeping her son in the clinical trial and not an objective determination of what would be best for him medically.1

Weiss also claimed that her son was never mentally sound enough to make adequate informed consent for participation in the research.1

Recognizing this issue as an ongoing concern, the Department of Health and Human Services' Secretary's Advisory Committee on Human Research Protections put on its July 15, 2008, meeting agenda a report from the subcommittee on the inclusion of individuals with impaired decision making in research. [The meeting was held after IRB Advisor's deadline for this issue.]

So IRB Advisor asked IRB and research ethic experts to discuss how IRBs could do a better job of protecting research participants, especially when they are part of a vulnerable population.

"There are a couple of very good resources for considering the ethics related to research with patients with diminished capacity," says Don E. Workman, PhD, interim associate vice president for research operations at Northwestern University in Evanston, IL.

Workman calls it a teeter-totter issue: "On one hand, there are times when people have diminished capacity, and you still need to respect their autonomous decision making," Workman says. "On the other hand, there are people with diminished capacity who need additional protections."

Decisional capacity is a difficult concept to fully understand, Workman notes.

"Do you give a mini-mental status exam and look at the score to see if people are able to consent?" he asks. "It's a gross marker, and we have to be careful about substituting its results for a clinician sitting down and speaking with a patient."

Even in patients with schizophrenia, there are times when these people are as capable of making good decisions as anyone else, he says.

Labeling different people "vulnerable" for research recruitment purposes may not be the most useful of strategies, says Mark S. Schreiner, MD, associate professor of anesthesia in pediatrics at the University of Pennsylvania in Philadelphia, PA. Schreiner also is the chair of the Committees for the Protection of Human Subjects at The Children's Hospital of Philadelphia and a member of the editorial advisory board for IRB Advisor.

People recruited for trials when they are experiencing economic hardship are vulnerable, as are people with terminal illness, Schreiner says.

"I can make a case why everyone is vulnerable in some way," he adds.

The best criteria for whether a person has the capacity to provide informed consent is this question: "Does the patient understand the risks and benefits of participating in research, and does the patient understand they have the option to not participate?" says John Csernansky, MD, Gilman professor and chairman in the department of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine in Chicago, IL.

"There are a variety of different ways to evaluate capacity," Csernansky says. "But basically the concept of evaluating capacity relates to having a dialogue and discussion with the patient where the patient is not passively sitting and listening, but is asking questions and engaging in the informed consent process."

Through active listening, a researcher can determine whether a patient is asking for clarification in a way that will help the prospective study participant to best understand their role and responsibilities in a clinical trial, he adds.

Researchers can use tools to determine a potential participant's capacity for making informed consent, and some studies rely on these when the study population has been diagnosed with a mental illness. For example, the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) is sometimes used for this purpose.2,3

Whether a researcher uses this tool or another one for determining decisional capacity, use of the tool and informed consent process needs to be well-documented, says Alan M. Sugar, MD, chairman of the New England Institutional Review Board and a professor of medicine at the Boston University School of Medicine in Boston, MA. Sugar is a member of the editorial advisory board of IRB Advisor.

"We certainly require that competency be documented so if the principal investigator/doctor says the person is competent, you'd expect that to show up in the medical record as a primary clinical determination," Sugar says. "Preferably, you'd have why the person was [deemed] competent in the source document."

Another avenue IRBs might pursue is to require studies to use patient advocates, who would advise potential study participants about their informed consent decision, particularly when potential participants' decisional capacity might be in doubt.

IRBs could request that patient advocates be used when a study appears to warrant such a measure, Csernansky says.

"I've chaired a committee meeting where an advocate was necessary for a given study," Csernansky says. "And I've also been a principal investigator of a study where an IRB asked me to have an advocate present."

"In general, this is a good approach for some studies — and not just for research with patients with psychiatric disorders, but also for a variety of disorders where patients are vulnerable," Csernansky says.

Other possibilities might be to have surrogate decision makers or family members present during the informed consent process, but these could pose problems, as well, the experts note.

"We have had studies with surrogate decision makers, and in the amazing perspective of time, the decisions made were contrary to what the people would have wanted," Schreiner says. "But at least it was somebody looking out for the subjects' interest."

If researchers were to have family members serve as surrogates or at least be present during informed consent for potential study participants who are mentally ill, then there could be privacy regulation issues, particularly if the participant doesn't want anyone else involved.

"From an autonomy standpoint, HIPAA, for instance, might preclude the physician from commenting or communicating with a subject's mother without her son's permission," Workman says. "If I have a 27-year-old patient, my responsibility is to the patient and only to the patient, and only if the patient is unable to make decisions on his own would I consider overriding his interest."

If a potential research subject in a schizophrenia drug trial doesn't want a family member involved, then the issue for the investigator is how to judge whether the potential subject has the capacity, and not just the legal ability, to consent, Schreiner says.

"They need to have the capacity to protect their own interests," he says.

References

  1. Olson J, Tosto P. Dan Markingson had delusions. His mother feared that the worst would happen. Then it did. St. Paul Pioneer Press May 23, 2008. Available at: www.TwinCities.com.
  2. Kim SY, Appelbaum PS, Swan J, et al. Determining when impairment constitutes incapacity for informed consent in schizophrenia research. Br J Psychiatry 2007;191:38-43.
  3. Appelbaum PS. Assessment of patients' competence to consent to treatment. N Engl J Med 2007;357:1834-1840.