May 13, 2013 Eric Kaler, PhD President, University of Minnesota 202 Morrill Hall, 100 Church Street S.E.

University of Minnesota Minneapolis, MN, 55455 Re: Open letter regarding an independent investigation of possible psychiatric research misconduct at the University of Minnesota Dear President Kaler: I am writing to you because I want to draw your attention to a petition that will soon be submitted to Governor Dayton. The petition asks Governor Dayton to appoint an independent, impartial panel of experts in research ethics and regulation of human research subjects and then assign them the task of investigating possible psychiatric research misconduct at the University of Minnesota. The petition now has over 2500 signatories and is supported by more than 200 scholars working in such fields as bioethics, medicine, health law, and medical humanities. Citizens from all over the world have signed the petition. Many signatories are from Minnesota and have strong personal ties to the University of Minnesota. I am contacting you because I wish to ask you to sign this petition. I am also requesting that you write to Governor Dayton and express your full support for an independent investigation of possible psychiatric research misconduct at our home institution. I realize that as President of the University of Minnesota you have the authority to initiate an internal investigation of allegations concerning psychiatric research misconduct. While I welcome such an initiative, I fear that prior statements and actions by senior administrators here at the University of Minnesota might in the larger community prompt questions about the legitimacy and thoroughness of such an exercise. Let me explain why I came to conclude that an independent investigation is warranted. Some of my concerns are connected to the death of a research subject, Dan Markingson, in the context of a clinical study that involved University of Minnesota faculty members and took place at the University of Minnesota Medical Center, Fairview. However, this individual “case” involving a young man from St. Paul prompts questions about more systemic issues concerning protections for research participants at the University of Minnesota. It generates concerns that extend beyond this one individual and extend to the institutional governance of psychiatric research. The death of Dan Markingson while he was enrolled in a research study here at the University of Minnesota has been widely reported by news media and there is an extensive record of court-related

2 documents and other material. Given the amount of information already available in the public domain I am confident that there is no need for me to review this case in detail. Rather, I will focus upon several of the most salient issues that need to be the focus of an independent investigation. Let me begin with the subject of informed consent and capacity to engage in autonomous decisionmaking. On November 12, 2003, a University of Minnesota psychiatrist at Fairview Hospital saw Dan Markingson. Markingson started displaying signs of mental illness during the summer of 2003; his mother took him to Fairview because he was acutely psychotic, paranoid, delusional, and making statements indicating that he might commit homicide. At Fairview he was assessed and judged to be incapable of consenting to administration of antipsychotic drugs intended to address his symptoms. He was consistently deemed to lack decision-making capacity. For example, on November 14, 2003, the psychiatrist seeing Markingson signed a commitment document and wrote that Markingson “lacks the ability to make decisions regarding such treatment.” Markingson’s lack of decision-making capacity was also noted on November 17 and November 19. And yet, on November 21, while still under an involuntary commitment order, Markingson was judged to be competent and asked to consent to participation in the CAFÉ study, known by its full name as Comparison of Atypical in First-Episode Schizophrenia. Markingson’s decision-making capacity on November 21, 2003 was assessed by a social worker employed as the clinical trial coordinator. She was not qualified to assess decisionmaking capacity of prospective research participants. Also of note, as clinical trial coordinator she had previously experienced difficulties finding individuals willing to participate in clinical studies. She was under considerable pressure to find individuals who could be enrolled in the study. Given the conflicting duties of the clinical trial coordinator, her lack of training to conduct assessments of decision-making capacity, and the profound importance of making accurate determinations about whether highly vulnerable individuals are able to engage in informed decision-making, it appears that this individual should not have been involved in assessing Dan Markingson’s competency to make decisions about whether or not he wished to participate in the CAFÉ study. The preceding concerns about how an individual diagnosed as psychotic was suddenly deemed capable of providing “consent” to participate in the CAFÉ study are well-known. They have prompted many questions about why Dan Markingson was asked to participate in the study rather than approaching his mother, Mary Weiss, who would have served as surrogate decision-maker had Markingson been deemed incompetent to make decisions about whether to participate in the study. Mary Weiss did not want her son to participate in the study and presumably would not have provided consent for him to enroll as a research participant in the CAFÉ study. An independent investigation of Markingson’s death and the CAFÉ study will have to review all relevant evidence and consider whether Dan Markingson in fact had decision-making capacity or whether a psychotic patient was wrongly deemed competent to consent and then enrolled in a clinical trial against the repeated protestations of his mother. New and disturbing information has recently emerged concerning the “evaluation to consent” form used to assess Dan Markingson’s capacity to engage in autonomous decision-making and consent to participate in research. As the title of this document indicates, it was supposed to be used to evaluate Markingson’s capacity to provide informed consent to participation in human subjects research. Carl Elliott, one of my colleagues at the University of Minnesota Center for Bioethics, has been contacted by numerous family members who report that members of their family had copies of precisely the same “evaluation to consent” forms in their medical files. By “the same form” I do not mean that the questions on the form were the same for each research subject, for of course they were. Rather, what I

3 mean is that family members of individuals who participated in clinical studies conducted here at the University of Minnesota claim that numerous research participants had medical files with a document that gave precisely the same answers—word-for-word and entered in the same handwriting—to the standardized questions. These claims by family members of trial participants suggest the possibility that study subjects were not interviewed, administered an evaluation to consent questionnaire, and carefully asked questions about their decision-making capacity. Rather, there are grounds to ask whether the form was completed once by a member of the research team, photocopied, and then placed in the files of multiple individuals in lieu of carefully asking questions of each individual contacted about the possibility of participating in research. If a photocopied, pre-completed “evaluation to consent” form was used in the CAFÉ study it is possible that thorough assessments of decision-making capacity were not conducted. An investigation that gains access to copies of all the evaluation to consent forms in the CAFÉ study will need to address unresolved questions about how well the ability to provide informed consent was tested, and explore whether, perhaps in the name of expediency, someone pre-completed paperwork instead of having conversations with each prospective study participant. Also related to the subject of informed consent, important information concerning risks related to the trial reportedly was not provided to Markingson and other study subjects. For example, the study consent document failed to state that participants in the CAFÉ study had to forgo the advantages of receiving individually tailored care outside the context of the trial. Increased risks of hyperglycemia and diabetes, risks known to the study sponsor, AstraZeneca, were also not disclosed to study participants in a timely manner. What this failure to disclose known risks means is that even if Dan Markingson had decision-making capacity and provided informed consent to participate, there is reason to examine whether his consent to participate was nullified by the failure to disclose relevant risks. Timing and adequacy of disclosure of research-related risks to participants in the CAFÉ study are both subjects that need to be addressed in an independent investigation. An independent investigation also needs to examine whether Markingson was coerced into the CAFÉ study as a result of fears that if he did not agree to enroll he would face the threat of involuntary commitment. At the time Markingson was enrolled in the CAFÉ study he was under a stay of commitment. A stay of commitment means that he would not be involuntarily committed to a medical facility if he agreed to follow the recommendations of his treating medical team. The court that approved a stay of commitment was not informed that Dan Markingson’s treating physician planned to enroll him in a clinical trial for which that same physician was the principal investigator for the University of Minnesota part of the overall study. Available evidence raises the possibility that Markingson understood that his options were to participate in the CAFÉ study and have the stay of commitment continue or refuse to participate and face involuntary commitment to a state mental health care facility. Participation in human subjects research is supposed to be voluntary and uncoerced. For this reason there are many reasons to be critical of the apparent manner in which an individual under a stay of commitment, faced with the possibility of involuntary commitment, was recruited into the CAFÉ study. It is worth noting that in 2009 the Minnesota Legislature passed legislation—known as “Dan’s Law”—that explicitly prohibits recruiting study participants in clinical trials in the manner that Markingson was enrolled in a clinical study here at the University of Minnesota. The preceding remarks provide a brief summary of why there is a need to investigate Markingson’s decision-making capacity and address whether or not he provided genuinely informed, voluntary, uncoerced consent. I now turn to how Mary Weiss’ numerous requests to have her son removed from

4 the CAFÉ study were largely ignored. Dan Markingson’s health status did not improve during his time as a participant in the CAFÉ study. To the contrary, his mother observed significant deterioration in his health and state of mind while he was in the study. Mary Weiss made repeated efforts to warn the study investigators that her son was at risk of committing suicide or homicide. Her efforts to convey her alarm to them included phone calls and letters to the investigators and study coordinator. Her concerns were not vague or otherwise difficult to understand. To the contrary, during one call to the CAFÉ study coordinator she stated, “Do we have to wait until he kills himself or someone else before anyone does anything?” Mary Weiss’ concerns were not addressed in an adequate and timely manner and Dan Markingson did in fact kill himself. An investigation will have to examine why Mary Weiss’ repeated pleas to have her son removed from the CAFÉ study did not result in him being dropped from the trial. Rather than simply seeing Dan Markingson’s death as a sad but unavoidable tragedy—a death that no one could have foreseen or prevented—an independent investigation of Dan Markingson’s death, the CAFÉ study, and psychiatric research at the University of Minnesota must examine why her concerns were not heeded, why it was so difficult for Mary Weiss to get any responses from the study investigators, and why Dan Markingson remained in the CAFÉ study despite the many efforts his mother made to have him removed from the trial. An independent investigation also needs to examine why a full account of the clinical investigators’ financial conflicts-of-interest was not provided to participants in the CAFÉ study. University of Minnesota faculty members involved in conducting this study had significant financial ties to AstraZeneca, the corporate sponsor of the CAFÉ study, and yet these ties were not disclosed to research participants. Prospective study participants were not told that the Department of Psychiatry was paid $15,648 for each study subject that completed the CAFÉ study. Study subjects were not informed that CAFÉ study in total generated $327,000 for the University of Minnesota’s Department of Psychiatry. Study subjects also had no way of knowing that University of Minnesota researchers were having difficulty recruiting participants to their clinical trials and were under considerable pressure to increase recruitment of study subjects. I mention these points not to insinuate that all ties between university and industry are bad and compromise the integrity of academic research, or to suggest that this trial was nothing more than a revenue generating exercise by the Department of Psychiatry, but to emphasize that important information was not provided to study participants. The researchers benefitted when research subjects were recruited, the Department of Psychiatry benefitted from recruitment, and there were incentives to enroll research participants into clinical trials and, once enrolled, keep them in clinical studies. A full account of these financial interests should have been provided to prospective research participants and incorporated into the informed consent process. There are several additional issues that need to be addressed by an independent investigation. For example, recent allegations suggest that health-related information about research participants was shared with AstraZeneca, and that company’s contract research organization, Quintiles, without proper authorization from research subjects. The Health Insurance Portability and Accountability Act (HIPAA), states that patients must provide express written consent before such information is released. Recent allegations suggest that authorization forms were not signed by research participants, or were signed after information had already been released without prior authorization. More fundamental questions about the CAFÉ study generate concerns about study design and whether the study was structured in a way that it had any possibility of generating meaningful scientific knowledge. There is also reason to examine the study’s inclusion and exclusion criteria given that a potentially violent subject was enrolled in the trial. In short, I have tried to identify just a few of the issues that an

5 independent investigation needs to address rather than providing an exhaustive account of the full scope of such an inquiry. A thorough investigation will, of course, have to go well beyond the brief summary of concerns that I have noted. As previously mentioned, the death of Dan Markingson while he was enrolled in the CAFÉ study prompts many questions about what happened to him while he was a research participant. But many of the concerns related to his individual experience as a research subject generate broader questions about the experiences and treatment of other research subjects in the CAFÉ study. At this more general level of analysis, it is important to ask whether the CAFÉ study was an anomaly at the University of Minnesota or whether alleged problems with that study also occurred in the CATIE study and other psychiatric research studies conducted at the University of Minnesota. The best way to follow this thread is to initiate a full investigation of the CAFÉ study and then let the investigation expand to other clinical studies as evidence warrants. I understand that senior university administrators at the University of Minnesota are opposed to additional investigations of Dan Markingson’s death and the CAFÉ study and are eager to bring to an end public debate about these subjects. Numerous senior university officials have declared that they wish to see this matter closed, with no further attempts to criticize the institution or demand an investigation. They argue that such investigations have already happened. For example, the Dean of the Medical School and Vice President for Health Sciences made it clear in 2011 that he regards the university’s review of Dan Markingson’s death as over. However, contrary to various claims made by the university’s General Counsel, there is no public record that the University of Minnesota has ever conducted a thorough, systematic examination of Markingson’s death and the conduct of clinical researchers involved with the CAFÉ study. If such an investigation was conducted there appears to be no record of it in the public domain. The General Counsel points to the court’s decision in the lawsuit brought by Mary Weiss, but the university prevailed on technical grounds that resulted in summary judgement rather than vindicating itself during the trial process. The General Counsel also claims that the University of Minnesota has been investigated and found to not be at fault by the Attorney General’s Office, but again there is no public record of such an investigation. In short, it appears that a substantial amount of the university’s response to the death of a research subject has consisted of denying the need for an investigation rather than exhibiting a genuine, sustained attempt to determine exactly what happened in the CAFÉ study, whether major violations of federal regulations and research ethics occurred, whether University of Minnesota employees fulfilled their legal and ethical obligations as researchers and clinicians, and whether the university’s governance structure for protecting participants in human subjects research functioned and continues to function as it should. As a faculty member in the University of Minnesota’s Center for Bioethics, there are numerous reasons why I am contacting you and asking you to sign the sign the petition and then write to Governor Dayton and request an independent investigation of possible psychiatric research misconduct at our home institution. Here, I will limit myself to providing just two of these reasons. First, as a faculty member in bioethics, I have a responsibility to draw attention to instances of possible research misconduct and take steps to ensure that they are investigated in a rigorous, thorough, and fair manner. In discharging this obligation I must focus upon supporting the search for truth and justice rather than thinking in terms of “risk minimization strategies” or making calculations about optimal “reputation management” strategies for the University of Minnesota. Based upon available evidence, I

6 am compelled to support an investigation in this case, even though it appears that doing so will trigger a substantial amount of harassment and vitriol, as my friend and colleague Professor Carl Elliott has already endured from faculty members and administrators here. Second, in addition to wanting to support the right course of action, there are now so many unanswered and profoundly disturbing questions related to the CAFÉ study that I suspect faculty members and administrators here are going to become the subject of ridicule among colleagues at other institutions if we do not firmly and clearly state as a matter of public record that there is sufficient evidence to demand an independent investigation of possible psychiatric research misconduct at the University of Minnesota. Colleagues elsewhere are justifiably going to wonder why faculty members in bioethics and other fields of study here were not more outspoken given the gravity of allegations concerning research misconduct at our own institution. Indeed, the evidence is sufficiently alarming to anyone familiar with research ethics and regulatory governance of human subjects research that I wish I had written to you when the petition was first announced rather than waiting until today. Just as I have a responsibility as a faculty member to lend my support to the search for truth and justice in the investigation of episodes of apparent wrongdoing here at the University of Minnesota, you, as President of the University of Minnesota, must regard yourself as duty-bound to support these same values, even if defending them in time leads to the full disclosure of what appears to be a particularly ugly episode in the history of research conducted at our institution. And like me, I am sure that you must be concerned about how your actions will be judged, for while you were not here when the CAFÉ study was conducted, and you have no proximal responsibility for the conduct of psychiatric research, as the President of this institution whether you support or do not support an investigation of possible research violations matters a great deal, and your choices are going to be a matter of public record. Furthermore, delegating this file to the General Counsel or other senior university administrators will not suffice, because in many instances questions about the CAFÉ study are connected to their conduct over the last several years. I close by asking you to sign the petition for an independent investigation of possible psychiatric research misconduct and take the additional step of writing to Governor Dayton and expressing your personal support for such an investigation. I cannot imagine that such a decision will be easy, for it will run counter to many prior decisions that have been made here at the University of Minnesota, but available evidence indicates that it is the right choice to make. Yours sincerely,

Leigh Turner, PhD Associate Professor University of Minnesota Center for Bioethics N520 Boynton, 410 Church Street SE Minneapolis, Minnesota, 55455 Phone: 612.626.4830 Email: turne462@umn.edu

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