Ensuring Integrity of Studies: Analysis of the Dan Markingson Case

Ramseyer Apau Bediako
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Dan Markingson was a 26-year-old mentally ill young man who violently killed himself while enrolled in a drug-sponsored study (known as the CAFÉ study) at the University of Minnesota’s Department of Psychiatry in 2004. The CAFÉ study was a yearlong double-blind study aimed at comparing three atypical or second-generation antipsychotics among persons experiencing psychosis for the first time.

Dr. Olson, who was the researcher for the CAFÉ study (Minnesota site), was also Markingson’s psychiatrist. Prior to Markingson being enrolled in the CAFÉ study, he was admitted to the University of Minnesota’s Teaching Hospital (Fairview Hospital) through an involuntary commitment order from the court. As part of granting the involuntary commitment order, two clinicians examined Markingson, and both noted that he was dangerous and extremely disorganized in his thinking and behaviour and that he lacked the capacity to make treatment decisions. The court granted the order, and he was then involuntarily confined to get the treatment deemed necessary. While Markingson was receiving treatment at the Fairview hospital, he was enrolled in the CAFÉ study against his mother’s wishes. Surprisingly, despite Markingson’s inability to make a treatment decision, Markingson consented or was made to consent to be enrolled in the CAFÉ study.

Dan Markingson
Dan Markingson and his mother. Photo credit: mprnews.org

Again, when Markingson was being discharged from the hospital to a residential facility, he signed or was made to sign a document stating that if he failed to keep up with his CAFÉ study appointments or failed to take his study medications, he would be returned to involuntary confinement. The Markingson case was the subject of a civil lawsuit and several regulatory reviews.1 2 3 4 5

In this article, I will argue that the researcher failed to protect Dan Markingson and that this compromised the study’s integrity. The researcher failed to balance the need for scientific knowledge of the three antipsychotic medications that were being studied — Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine) — against the moral duty to protect research subjects like Markingson.6 I will also address how Markingson should have been protected as a way to ensure the integrity of the CAFÉ study.

In recent times, research with persons diagnosed as mentally ill has increased to provide better therapeutic options and understanding of current trends in treatment.7 Clinical research with human subjects is key to progress in understanding and improving overall human health.8 On the other hand, mental health research is very often beset with a number of ethical issues relating to informed consent, conflict of interest, therapeutic misconception, exploitation and many more. There have been higher rates of retraction of published psychiatric papers in recent years mainly as a result of some of these ethical breaches and research misconduct.

The World Health Organization estimates that close to 10% of the world’s population is suffering from various forms of mental illnesses and about 25% of persons experience some psychiatric illness during their lifetime.9 This suggests there is a need for research with these populations. However, like Shalala (2000) argues, “if new medicines and new approaches to curing diseases are continuously being tested, we cannot compromise the trust and willingness of patients to participate in clinical trials. Any deterioration in the protective foundation causes direct harm to human research subjects and indirect harm to the reputations of the investigators, their academic institutions, and the entire research community.”10 There is therefore a need to increase and maintain the overall integrity — the quality and the morality — of any research work.

Active adherence to the ethical principles and professional standards essential for the responsible practice of research were missing in the CAFÉ study,11 and commitment on the part of institutions to promote and foster climates supportive of ethical behaviour12 was also somewhat indeterminate. I argue that; i. the informed consent was inconsistent with the principle of respect for a person’s autonomy, ii. the Institutional Review Board (IRB) approved the CAFÉ study even though the study had inadequate safeguards, and iii. the IRB failed to monitor the ongoing study to ensure that ethical issues such as conflict of interest did not compromise Markingson’s safety or Markingson’s best interest. However, in this article I will only focus on how the researcher failed.

The researcher compromised the integrity of the CAFÉ study because the informed consent was inconsistent with the principle of respect for autonomy. Informed consent is a key element of ethical clinical research, and it is grounded in the ethical principle of respect for autonomy.13 It is the role of the researcher to obtain informed consent from a prospective subject. It is also the researcher’s role to ensure that informed consent is consistent with the principle of respect for autonomy.14

Respecting the autonomy of research subjects requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them.15  Additionally, informed consent is a decision to participate in research, taken by a competent individual who has received the necessary information; who has adequately understood information about the research; and who, after considering the information, has arrived at a decision without having been subjected to coercion, undue influence or inducement, or any form of intimidation.16

My point is that, given Dan Markingson’s limited decisional capacity at the time of enrollment (the time between involuntary commitment order and study enrollment), he could not have given informed consent. This is because Dan Markingson was admitted to the Fairview hospital through an involuntary commitment court order because he was deemed to lack the capacity to make an informed decision regarding his treatment. It was at the time of involuntary commitment that he was also enrolled in the CAFÉ study. If Markingson lacked the competence to make treatment decisions, then apparently he lacked the competence to make an informed decision on research participation or study enrollment. Even if the researcher fully disclosed information or fully disclosed what the research was about, Markingson lacked the competence/capacity to give informed consent at the time of enrollment.

In addition to this, Markingson’s participation was not voluntary. Informed consent is based on the principle that competent individuals are entitled to choose freely or voluntarily whether to participate in research or not. The key elements of informed consent are full disclosure of information, competence, understanding, and voluntariness. All these key elements must be present for informed consent to be effective and consistent with the principle of respect for autonomy.17 Beliefs and informed choices shift with time (Beauchamp & Childress, 201318); choices should therefore not be binding.

Beauchamp and Childress argue that competence and voluntariness are preconditions for informed consent. In Markingson’s case, these preconditions were not met or satisfied. Persons diagnosed with severe mental illness like Markingson are highly at risk of impaired consent capacity. Therefore, threat, intimidation or undue influence of any form such as being warned that one would be returned to involuntary confinement if he fails to keep up with his research appointments invalidate the voluntariness of informed consent. This is because informed consent is neither a once-and-for-all event, nor is it a one-time event, but rather an ongoing process and a goal that a researcher strives to achieve. Assuming Markingson had the competence to give informed consent, voluntariness of informed consent means Markingson was free to withdraw from the CAFÉ study at any time without any penalty or loss of benefits to which he may have been entitled. Otherwise, informed consent ceases to be voluntary.

The Tri-Council Policy Statement19 states that, to maintain the element of voluntariness of informed consent, a subject shall be free to withdraw their consent to participate in research at any time, without having to offer any reason for withdrawing or having to suffer any consequence thereafter. The fact that Markingson signed a document threatening that he would be returned to involuntary confinement if he failed to attend his study appointments or failed to take his study drugs invalidated the voluntariness of informed consent, and was inconsistent with the principle of respect for autonomy. Although autonomy is a necessary condition for participation in research, in some instances enrolling people who lack the capacity to make their own decisions can be justified as ethical. For prospective subjects like Markingson, additional measures are needed to protect their interests and to ensure that their wishes are respected. Persons with diminished autonomy like Markingson are entitled to special protections, such as the requirement that the researcher obtains surrogate consent from a close relative of the participant.20

There was the need for a competent authorized third party or a substitute decision maker (SDM) to provide consent for Markingson’s participation or enrollment, and then Markingson would have also needed to voluntarily give an assent. This has been the National Institute of Mental Health (NIMH) requirement in recent years, that is, mentally ill subjects also give an assent alongside consent by an SDM. Markingson could only have consented if he regained his capacity or competence while the study was ongoing. This is the way the researcher ought to have handled the study to ensure its integrity. Highly vulnerable individuals like Markingson should not be taken advantage of in the name of scientific research, and inability to protect such vulnerable subjects compromises the integrity of research.21

Clinical practice guidelines may be based on compromised research. That is why there is a need to ensure the integrity of any research study. If a subject’s safety is compromised, then the whole study is compromised — subject safety cannot be compromised in the name of gathering scientific evidence. If the research enterprise is serious about ensuring the integrity of any study, then they need to pay much more attention to subject safety and protection while participating in a trial, especially vulnerable subjects.

The Markingson case is one of many scandals in the research enterprise that has gained public attention. As research is moving toward pharma-industry or private sponsorship, there is a need for Institutional Review Boards to be extra vigilant and do more with regard to subject safety. Researchers should also not take for granted the trust and willingness of these subjects to participate in clinical trials. Already, research scandals like Tuskegee have left behind a legacy of distrust. It is up to researchers and IRBs to restore and maintain the integrity of the research enterprise. If researchers keep repeating these scandals, they may not have human subjects to recruit in the near future. Maybe this is the time for IRBs to step up and ensure the morality of research involving human subjects.

Show 21 footnotes

  1. Elliott, C. (2012, August 2). When Medical Muckraking Fails, Chronicle of Higher Education. Retrieved from; http://chronicle.com/blogs/brainstorm/when-medical-muckraking-fails/50767.
  2. Elliott, C. (2015, May 26). The University of Minnesota’s Medical Research Mess. The New York Times. Retrieved from; https://www.nytimes.com/2015/05/26/opinion/the-university-of-minnesotas-medical-research-mess.html
  3. Elliott, C. (2017). Institutional Pathology and the Death of Dan Markingson. Accountability in Research, 24(2), 65-79. DOI:10.1080/08989621.2016.1246969
  4. Office of the Legislative Auditor (OLA), The State of Minnesota (March 19, 2015). A Clinical Drug Study at the University of Minnesota Department of Psychiatry: The Dan Markingson Case. Retrieved from; http://www.auditor.leg.state.mn.us/sreview/markingson.pdf
  5. Lamkin, M. (September 29, 2017). The Death of Dan Markingson: A Research Scandal & a Cover-Up at The University of Minnesota. 2017 UT System Legal Conference. The University of Tulsa College of Law.
  6. Kohn, E.S (1984). Ethical Consideration in Protecting Human subjects in Social and Behavioural Research. In J.E Sieber (Ed.), NIH Readings and the Protection of Human Subjects in Social and Behavioural Research. (pp. 159). Fredrick, Maryland; University Publication of America Inc.
  7. Jain, S., Kuppili, P. P., Pattanayak, R. D., & Sagar, R. (2017). Ethics in Psychiatric Research: Issues and Recommendations. Indian Journal of Psychological Medicine, 39(5), 558–565. http://doi.org/10.4103/IJPSYM.IJPSYM_131_17
  8. Grady, C. 2015. Protecting Research Participants: Why, How, and How Much? The Hasting centre report. Volume: 37, Issue: 4
  9. Demyttenaere, K., Bruffaerts, R., Posada-Villa, J., Gasquet, I., Kovess, V., Lepine, J.P., et al. (2004).Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA, 291 (21)  pp. 2581-2590
  10. Shalala, D. 2000. Protecting Research Subjects-What Must Be Done. The New England Journal of Medicine. Vol.343(11), pp.808-810
  11. Korenman, S. G. 2006. Teaching the Responsible Conduct of Research in Humans. Washington, DC: DHHS, Office of Research Integrity, Responsible Conduct of Research Resources Development Program. Retrieved from; https://ori.hhs.gov/education/products/ucla/default.htm
  12. Gunsalus, C. K. 1993. Institutional structure to ensure research integrity. Academic Medicine. 68(9):S33–38.
  13. Sakellari, E. 2003. Patients autonomy and informed consent. ICUS WEBJ issue 13
  14. Ryan, M. K. (1982). IRB Procedures. In R. A. Greenwald et al. (Eds.), Human Subjects Research; a Handbook for Review Boards (pp. 63-70). New York, NY: Plenum Press
  15. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1978). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Bethesda, MD: US Government Printing Office.
  16. Council for International Organizations of Medical Sciences (CIOMS). 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects. pp. 30-42. Geneva. Retrieved from https://web.archive.org/web/20100823205120/http://www.cioms.ch/publications/layout_guide2002.pdf
  17. Drew, C. J., Hardman, M. L. & Hosp, J. L.(Eds). (2008). Ethical issues in conducting research. In Designing and conducting research in education (pp. 57). Thousand Oaks, CA: SAGE Publications Ltd. doi: 10.4135/9781483385648
  18. Beauchamp, T.L. & Childress, J.F. (2013). Principles of Biomedical Ethics. (7th ed.). pp. 150- 241. New York, NY: Oxford University Press.
  19. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, December 2014.
  20. Coughlin, S.S., Soskolne, C.L., & Goodman, K.W. (1997). Studies of Vulnerable Populations. Case Studies in Public Health Ethics (pp. 101-103). Washington, DC: American Public Health Association.
  21. Palmer, B., Savla, G., Roesch, S., & Jeste, D. (2013). Changes in capacity to consent over time in patients involved in psychiatric research. British Journal of Psychiatry, 202(6), 454-458. doi:10.1192/bjp.bp.112.121160

20 COMMENTS

  1. “the researcher failed to protect Dan Markingson”

    Would it not be more accurate to say that Dr. Olson used prisoners as rats for dangerous and toxic experiments? Are you aware that this is precisely one of the reasons why Nazi doctors were executed in Nuremberg?

    “In recent times, research with persons diagnosed as mentally ill has increased to provide better therapeutic options and understanding of current trends in treatment.”

    This is perfectly false: this research is conducted with the aim of commercializing new products, in order to repress mental deviants, but also Latin migrant children. This research has no ethical or scientific basis: there is no mental illness, and the purpose of these products is the control of deviant populations and migrants.

    “The World Health Organization estimates that close to 10% of the world’s population is suffering from various forms of mental illnesses and about 25% of persons experience some psychiatric illness during their lifetime.9 This suggests there is a need for research with these populations.”

    Do you really believe that? In 1880, the United States government launched a large survey, in which nearly 80,000 physicians participated in the census of mental patients across the country, including outside institutions. (Census Office, 1888, pp. IX and X).

    The government found a prevalence of 0.18% of cases of madness in the general population. (Census Office, 1888, pp. XXIX).

    Could you explain how we went from a prevalence of 1 in 500 to 1 in 10 in just over a century? This prevalence of 10% is ridiculous: no species can survive with 10% of “mentally ill”. It’s just the percentage of people that society wants to marginalize with psychiatric “diagnoses”.

    “There is a need to increase and maintain the integrity – the quality and the morality – of any research work.”

    The quality and morality of psychiatric research has always been excruciating. In France, the medical profession (Fond, 2018) is sorry to note that 41% of interns in psychiatry are alcoholics, 22% regularly consume cocaine, 17% hallucinogenic mushroom, 12% cannabis, 10% amphetamines, and 7% LSD. Psychiatric students have always been the most depraved of the medical school. How can you be surprised at their total lack of ethics once they graduate? And for the quality of their research, this huge joke! Psychiatry is the only “medical” discipline where treatments have worse and worse results. Did you know Jääskeläinen (2013)? In 1941-1955 the recovery rate of schizophrenics was 17.7%. In 1996-2012, it was only 6%! It must be said that in the meantime, we had made this superb discovery: the neuroleptics.

    Thank you psychiatric research!

    Census Office (1888). Defective, dependant and delinquent classes of the population of United States, as returned at the thenth census (June 1, 1880). Washington, Government Printing Office. https://www2.census.gov/prod2/decennial/documents/1880a_v21-02.pdf

    Fond G et al. (2018) Psychiatry: a discipline at specific risk of mental health issues and addictive behavior? Results from the national BOURBON study. Journal of Affective Disorders Volume 238, 1 October 2018, Pages 534-538. DOI: 10.1016/j.jad.2018.05.074

    Jääskeläinen, E., Juola, P., Hirvonen, N., McGrath, J. J., Saha , S., Isohanni, M., Veijola, J., Miettunen, J. (2012). A Systematic Review and Meta-Analysis of Recovery in Schizophrenia. Schizophr Bull (2013) 39 (6): 1296-1306. DOI: https://doi.org/10.1093/schbul/sbs130 https://academic.oup.com/schizophreniabulletin/article/39/6/1296/1884290/A-Systematic-Review-and-Meta-Analysis-of-Recovery

  2. I do agree with Sylvain. Ramseyer I can see that you are trying to apply a general medical ethics framework, and you come up against the conundrum of whether there was informed consent.

    My own take on this is pretty simple:
    1. You cannot conduct trials on incarcerated patients at all, because by definition, they don’t have a choice. As Sylvain points out, this has grave echos of the past.
    2. You cannot conduct trials on patients as unstable as this. He is already a danger to himself or others, he is already on drugs for sure, he should be excluded from the study on any number of grounds.
    3. It doesn’t feel to me like there was a controlled washout period prior to the study. It rather sounds as if he was suddenly transitioned from something like haloperidol to Quetiapine, which we now know is not, and could never be an “anti psychotic”. That transition should be under the spotlight. You cannot screw with medication like that.
    4. You cannot overrule the carer , in this case the mother, without very good reason. They put the priority of the study above patient welfare.

    The big picture, as Sylvain points out, is that psychiatry hasnt a clue how to treat psychosis because it doesn’t know what it is, and itself suffers from the delusion that sedatives are “antipsychotic”.

  3. I know, it’s an amazing thing to say, but it’s time Quetiapine was outed!

    If you look at the analysis by Joanna Moncrieff in conjunction with Leucht and Cipriani, the effect size is 0.32, very weak. You hardly need to look further. The most common outcome in a Quetiapine trial is dropout.

    Then consider what Ken Gilman wrote about the proposed mechanism. It does not touch a neurotransmitter that could possibly be implicated in
    psychosis. Shitti Kapur and P Seeman have tried to defend the fact that it doesn’t appear to touch D2 with a “fast off” theory but it’s very tenuous and disproven by Kristoffer Sahlholm. Even the whole D2 psychosis theory is listing dangerously in the water.

    Finally look at what “1BoringOldMan” dug up about the FDA trials. If ever there was a concerted effort to market a drug out of thin air this was it.

    Basically, it’s an antihistamine with some nasty adronergic and muscarinic properties that you really don’t want – and that’s about it!

    I think the games up for Quetiapine. But what of the flagship drug clozapine, with the trial that originally yielded a half decent effect size of 0.88? Leucht recently had this to say “The most surprising finding was that clozapine was not significantly better than most other drugs.” Yes, even the darling of the antipsychotic world is being found out!

  4. “The CAFÉ study was a yearlong double-blind study aimed at comparing three atypical or second-generation antipsychotics among persons experiencing psychosis for the first time.”

    “The researcher failed to balance the need for scientific knowledge of the three antipsychotic medications that were being studied — Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine) — against the moral duty to protect research subjects like Markingson.6” I agree.

    As to the efficacy of antipsychotic treatments in relation to psychosis. The antipsychotics / neuroleptics are anticholingeric drugs. And it is possible for these drugs to cause psychosis, hallucinations, and all the positive symptoms of schizophrenia, via something called the central symptoms of neuroleptic induced anticholingeric intoxication syndrome, aka anticholinergic toxidrome.

    https://www.bing.com/search?q=can+antipsychotics+cause+psychosis&form=APMCS1&PC=APMC
    https://en.wikipedia.org/wiki/Toxidrome

    In other words, the antipsychotics create psychosis.

    The neuroleptics can also create the negative symptoms of “schizophrenia,” via neuroleptic induced deficit syndrome.

    https://en.wikipedia.org/wiki/Neuroleptic-induced_deficit_syndrome

    In other words, “schizophrenia” is actually an iatrogenic illness, created with the antipsychotic/neuroleptic drugs, which are the “gold standard schizophrenia treatments.”

  5. Thanks for your efforts to memorialize and honor Dan, who I agree, was targeted by amoral predators for financial and political gain, under quite similar conditions to Nazi era atrocities. I hope someone that he would approve of doing so will make a youtube video of Dan’s story to make it more widely shareable. This man died a horribly terrifying and painful death that was 100% preventable.