May 13, 2013 Letter to President Eric Kaler

7/30/2019 May 13, 2013 Letter to President Eric Kaler

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May 13, 2013

Eric Kaler, PhDPresident, University of Minnesota202 Morrill Hall, 100 Church Street S.E.University of MinnesotaMinneapolis, MN, 55455

Re: Open letter regarding an independent investigation of possible psychiatric researchmisconduct at the University of Minnesota

Dear President Kaler:

I am writing to you because I want to draw your attention to apetition that will soon be submitted toGovernor Dayton. The petition asks Governor Dayton to appoint an independent, impartial panel ofexperts in research ethics and regulation of human research subjects and then assign them the task ofinvestigating possible psychiatric research misconduct at the University of Minnesota. The petition nowhas over 2500 signatories and is supported by more than 200 scholars working in such fields asbioethics, 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 ofMinnesota. I am contacting you because I wish to ask you to sign this petition. I am also requesting thatyou write to Governor Dayton and express your full support for an independent investigation ofpossible psychiatric research misconduct at our home institution. I realize that as President of theUniversity of Minnesota you have the authority to initiate an internal investigation of allegationsconcerning psychiatric research misconduct. While I welcome such an initiative, I fear that priorstatements and actions by senior administrators here at the University of Minnesota might in the largercommunity 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 myconcerns are connected to the death of a research subject, Dan Markingson, in the context of a clinicalstudy that involved University of Minnesota faculty members and took place at the University ofMinnesota 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 atthe University of Minnesota. It generates concerns that extend beyond this one individual and extend tothe institutional governance of psychiatric research.

The death of Dan Markingson while he was enrolled in a research study here at the University ofMinnesota has been widely reported by news media and there is an extensive record of court-related


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documents and other material. Given the amount of information already available in the public domainI am confident that there is no need for me to review this case in detail. Rather, I will focus uponseveral 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 decision-

making. On November 12, 2003, a University of Minnesota psychiatrist at Fairview Hospital saw DanMarkingson. Markingson started displaying signs of mental illness during the summer of 2003; hismother took him to Fairview because he was acutely psychotic, paranoid, delusional, and makingstatements indicating that he might commit homicide. At Fairview he was assessed and judged to beincapable of consenting to administration of antipsychotic drugs intended to address his symptoms. Hewas consistently deemed to lack decision-making capacity. For example, on November 14, 2003, thepsychiatrist seeing Markingson signed a commitment document and wrote that Markingson lacks theability to make decisions regarding such treatment. Markingsons lack of decision-making capacitywas also noted on November 17 and November 19. And yet, on November 21, while still under aninvoluntary commitment order, Markingson was judged to be competent and asked to consent toparticipation in the CAF study, known by its full name as Comparison of Atypical in First-Episode

Schizophrenia. Markingsons decision-making capacity on November 21, 2003 was assessed by asocial worker employed as the clinical trial coordinator. She was not qualified to assess decision-making capacity of prospective research participants. Also of note, as clinical trial coordinator she hadpreviously experienced difficulties finding individuals willing to participate in clinical studies. She wasunder considerable pressure to find individuals who could be enrolled in the study. Given theconflicting duties of the clinical trial coordinator, her lack of training to conduct assessments ofdecision-making capacity, and the profound importance of making accurate determinations aboutwhether highly vulnerable individuals are able to engage in informed decision-making, it appears thatthis individual should not have been involved in assessing Dan Markingsons competency to makedecisions about whether or not he wished to participate in the CAF study.

The preceding concerns about how an individual diagnosed as psychotic was suddenly deemed capableof providing consent to participate in the CAF study are well-known. They have prompted manyquestions about why Dan Markingson was asked to participate in the study rather than approaching hismother, Mary Weiss, who would have served as surrogate decision-maker had Markingson beendeemed incompetent to make decisions about whether to participate in the study. Mary Weiss did notwant her son to participate in the study and presumably would not have provided consent for him toenroll as a research participant in the CAF study. An independent investigation of Markingsons deathand the CAF study will have to review all relevant evidence and consider whether Dan Markingson infact had decision-making capacity or whether a psychotic patient was wrongly deemed competent toconsent 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 formused to assess Dan Markingsons capacity to engage in autonomous decision-making and consent toparticipate in research. As the title of this document indicates, it was supposed to be used to evaluateMarkingsons capacity to provide informed consent to participation in human subjects research. CarlElliott, one of my colleagues at the University of Minnesota Center for Bioethics, has been contacted bynumerous family members who report that members of their family had copies of precisely the sameevaluation to consent forms in their medical files. By the same form I do not mean that thequestions on the form were the same for each research subject, for of course they were. Rather, what I


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mean is that family members of individuals who participated in clinical studies conducted here at theUniversity of Minnesota claim that numerous research participants had medical files with a documentthat gave precisely the same answersword-for-word and entered in the same handwritingto thestandardized questions. These claims by family members of trial participants suggest the possibility thatstudy 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 theform was completed once by a member of the research team, photocopied, and then placed in the filesof multiple individuals in lieu of carefully asking questions of each individual contacted about thepossibility of participating in research. If a photocopied, pre-completed evaluation to consent formwas used in the CAF study it is possible that thorough assessments of decision-making capacity werenot conducted. An investigation that gains access to copies of all the evaluation to consent forms in theCAF study will need to address unresolved questions about how well the ability to provide informedconsent was tested, and explore whether, perhaps in the name of expediency, someone pre-completedpaperwork 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 studyconsent document failed to state that participants in the CAF study had to forgo the advantages ofreceiving individually tailored care outside the context of the trial. Increased risks of hyperglycemiaand diabetes, risks known to the study sponsor, AstraZeneca, were also not disclosed to studyparticipants in a timely manner. What this failure to disclose known risks means is that even if DanMarkingson had decision-making capacity and provided informed consent to participate, there is reasonto 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 CAF study are bothsubjects that need to be addressed in an independent investigation.

An independent investigation also needs to examine whether Markingson was coerced into the CAFstudy as a result of fears that if he did not agree to enroll he would face the threat of involuntarycommitment. At the time Markingson was enrolled in the CAF study he was under a stay ofcommitment. A stay of commitment means that he would not be involuntarily committed to a medicalfacility if he agreed to follow the recommendations of his treating medical team. The court thatapproved a stay of commitment was not informed that Dan Markingsons treating physician planned toenroll him in a clinical trial for which that same physician was the principal investigator for theUniversity of Minnesota part of the overall study. Available evidence raises the possibility thatMarkingson understood that his options were to participate in the CAF study and have the stay ofcommitment continue or refuse to participate and face involuntary commitment to a state mental healthcare facility. Participation in human subjects research is supposed to be voluntary and uncoerced. Forthis reason there are many reasons to be critical of the apparent manner in which an individual under astay of commitment, faced with the possibility of involuntary commitment, was recruited into theCAF study. It is worth noting that in 2009 the Minnesota Legislature passed legislationknown asDans Lawthat explicitly prohibits recruiting study participants in clinical trials in the manner thatMarkingson 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 Markingsonsdecision-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


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the CAF study were largely ignored. Dan Markingsons health status did not improve during his timeas a participant in the CAF study. To the contrary, his mother observed significant deterioration in hishealth and state of mind while he was in the study. Mary Weiss made repeated efforts to warn the studyinvestigators that her son was at risk of committing suicide or homicide. Her efforts to convey heralarm 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 CAF studycoordinator she stated, Do we have to wait until he kills himself or someone else before anyone doesanything? Mary Weiss concerns were not addressed in an adequate and timely manner and DanMarkingson did in fact kill himself. An investigation will have to examine why Mary Weiss repeatedpleas to have her son removed from the CAF study did not result in him being dropped from the trial.Rather than simply seeing Dan Markingsons death as a sad but unavoidable tragedya death that noone could have foreseen or preventedan independent investigation of Dan Markingsons death, theCAF study, and psychiatric research at the University of Minnesota must examine why her concernswere not heeded, why it was so difficult for Mary Weiss to get any responses from the studyinvestigators, and why Dan Markingson remained in the CAF study despite the many efforts hismother made to have him removed from the trial.

An independent investigation also needs to examine why a full account of the clinical investigatorsfinancial conflicts-of-interest was not provided to participants in the CAF study. University ofMinnesota faculty members involved in conducting this study had significant financial ties toAstraZeneca, the corporate sponsor of the CAF study, and yet these ties were not disclosed to researchparticipants. Prospective study participants were not told that the Department of Psychiatry was paid$15,648 for each study subject that completed the CAF study. Study subjects were not informed thatCAF study in total generated $327,000 for the University of Minnesotas Department of Psychiatry.Study subjects also had no way of knowing that University of Minnesota researchers were havingdifficulty recruiting participants to their clinical trials and were under considerable pressure to increaserecruitment of study subjects. I mention these points not to insinuate that all ties between university andindustry are bad and compromise the integrity of academic research, or to suggest that this trial wasnothing more than a revenue generating exercise by the Department of Psychiatry, but to emphasizethat important information was not provided to study participants. The researchers benefitted whenresearch subjects were recruited, the Department of Psychiatry benefitted from recruitment, and therewere incentives to enroll research participants into clinical trials and, once enrolled, keep them inclinical studies. A full account of these financial interests should have been provided to prospectiveresearch participants and incorporated into the informed consent process.

There are several additional issues that need to be addressed by an independent investigation. Forexample, recent allegations suggest that health-related information about research participants wasshared with AstraZeneca, and that companys contract research organization, Quintiles, without properauthorization 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 weresigned after information had already been released without prior authorization. More fundamentalquestions about the CAF study generate concerns about study design and whether the study wasstructured in a way that it had any possibility of generating meaningful scientific knowledge. There isalso reason to examine the studys inclusion and exclusion criteria given that a potentially violentsubject was enrolled in the trial. In short, I have tried to identify just a few of the issues that an


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independent investigation needs to address rather than providing an exhaustive account of the full scopeof such an inquiry. A thorough investigation will, of course, have to go well beyond the brief summaryof concerns that I have noted.

As previously mentioned, the death of Dan Markingson while he was enrolled in the CAF study

prompts many questions about what happened to him while he was a research participant. But many ofthe concerns related to his individual experience as a research subject generate broader questions aboutthe experiences and treatment of other research subjects in the CAF study. At this more general levelof analysis, it is important to ask whether the CAF study was an anomaly at the University ofMinnesota or whether alleged problems with that study also occurred in the CATIE study and otherpsychiatric research studies conducted at the University of Minnesota. The best way to follow thisthread is to initiate a full investigation of the CAF study and then let the investigation expand to otherclinical studies as evidence warrants.

I understand that senior university administrators at the University of Minnesota are opposed toadditional investigations of Dan Markingsons death and the CAF study and are eager to bring to an

end public debate about these subjects. Numerous senior university officials have declared that theywish to see this matter closed, with no further attempts to criticize the institution or demand aninvestigation. They argue that such investigations have already happened. For example, the Dean of theMedical School and Vice President for Health Sciences made it clear in 2011 that he regards theuniversitys review of Dan Markingsons death as over. However, contrary to various claims made bythe universitys General Counsel, there is no public record that the University of Minnesota has everconducted a thorough, systematic examination of Markingsons death and the conduct of clinicalresearchers involved with the CAF study. If such an investigation was conducted there appears to beno record of it in the public domain. The General Counsel points to the courts decision in the lawsuitbrought by Mary Weiss, but the university prevailed on technical grounds that resulted in summaryjudgement rather than vindicating itself during the trial process. The General Counsel also claims thatthe University of Minnesota has been investigated and found to not be at fault by the AttorneyGenerals Office, but again there is no public record of such an investigation. In short, it appears that asubstantial amount of the universitys response to the death of a research subject has consisted ofdenying the need for an investigation rather than exhibiting a genuine, sustained attempt to determineexactly what happened in the CAF study, whether major violations of federal regulations and researchethics occurred, whether University of Minnesota employees fulfilled their legal and ethical obligationsas researchers and clinicians, and whether the universitys governance structure for protectingparticipants in human subjects research functioned and continues to function as it should.

As a faculty member in the University of Minnesotas Center for Bioethics, there are numerous reasonswhy I am contacting you and asking you to sign the sign the petition and then write to Governor Daytonand request an independent investigation of possible psychiatric research misconduct at our homeinstitution. 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 possibleresearch misconduct and take steps to ensure that they are investigated in a rigorous, thorough, and fairmanner. In discharging this obligation I must focus upon supporting the search for truth and justicerather than thinking in terms of risk minimization strategies or making calculations about optimalreputation management strategies for the University of Minnesota. Based upon available evidence, I


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am compelled to support an investigation in this case, even though it appears that doing so will trigger asubstantial amount of harassment and vitriol, as my friend and colleague Professor Carl Elliott hasalready 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 CAF study that I suspect faculty members andadministrators here are going to become the subject of ridicule among colleagues at other institutions ifwe do not firmly and clearly state as a matter of public record that there is sufficient evidence todemand an independent investigation of possible psychiatric research misconduct at the University ofMinnesota. Colleagues elsewhere are justifiably going to wonder why faculty members in bioethics andother fields of study here were not more outspoken given the gravity of allegations concerning researchmisconduct at our own institution. Indeed, the evidence is sufficiently alarming to anyone familiar withresearch ethics and regulatory governance of human subjects research that I wish I had written to youwhen 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, asPresident of the University of Minnesota, must regard yourself as duty-bound to support these samevalues, even if defending them in time leads to the full disclosure of what appears to be a particularlyugly episode in the history of research conducted at our institution. And like me, I am sure that youmust be concerned about how your actions will be judged, for while you were not here when the CAFstudy 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 possibleresearch 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 willnot suffice, because in many instances questions about the CAF study are connected to their conductover the last several years.

I close by asking you to sign the petition for an independent investigation of possible psychiatricresearch misconduct and take the additional step of writing to Governor Dayton and expressing yourpersonal support for such an investigation. I cannot imagine that such a decision will be easy, for it willrun counter to many prior decisions that have been made here at the University of Minnesota, butavailable evidence indicates that it is the right choice to make.

Yours sincerely,

Leigh Turner, PhDAssociate ProfessorUniversity of Minnesota Center for BioethicsN520 Boynton, 410 Church Street SEMinneapolis, Minnesota, 55455Phone: 612.626.4830Email: [email protected]

May 13, 2013 Letter to President Eric Kaler

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Transcript of May 13, 2013 Letter to President Eric Kaler