As we were waiting for our first patients of the morning to be checked in, a colleague and I discussed his experience at a university-wide committee meeting the previous day. He reported vigorous criticism of the University of Minnesota Medical School (and certain Medical School faculty), centered upon the deaths of research subjects in clinical trials. Particularly prominent in the discussion was the suicide a decade ago of Dan Markingson, a patient who became a subject in a comparative trial of newer antipsychotic agents. My colleague perceived this as old news, a lack of understanding of the realities of research into the treatment of life-threatening illnesses, and at a certain level an attack on clinical investigation by faculty from outside the Medical School.
I’m sympathetic to his perception, but I also think there are substantive reasons that the Markingson case continues to cause concern; there are questions raised by it that have never had a satisfying (public) resolution.
Some of the concerns involve the conduct of the study at this site, some involve the study design more broadly, some involve Markingson’s specific experience, and some involve the fundamental issues in conducting research involving the care of vulnerable persons. When these different themes get lumped together, an accusatory tone and defensiveness may get in the way of learning from the events.
Accordingly, I’ll not spend much time here on allegations of site-specific misconduct; I’ve never reviewed that part of the record in detail, and I don’t have much to add. I will register my disappointment, however, at the university’s response. On several occasions, we have been told that the university and its investigators have been “exonerated,” because the attorney general chose not to prosecute and the federal oversight bodies (FDA and OHRP) did not effect any sanctions. I think that most faculty members understand that a decision not to prosecute is quite a few steps shy of “exoneration,” and I think most faculty members would like to see a higher behavioral standard than “freedom from felony prosecution.”
On several occasions, it has been suggested that an outside review panel be convened, to review the case and study in detail; these suggestions have not been taken seriously (at least until very recently), which I think is unfortunate. The careful review of serious misadventures is one of our important tools for improving clinical practice; it should also be one of our key tools for improving research practice. Even if no misconduct is found and no weakness in human subjects’ protection is found, a thorough and independent review would show that the university is taking the matter seriously, rather than sweeping it under the carpet.
Looking beyond the narrow concerns of misconduct per se, there are several questions we might ask that I think are very important:
- Markingson was in an unusual situation, known as “stay of commitment;” that is, a court had ruled in favor of his commitment, but stayed its implementation as long as he co-operated in treatment and did well. Technically, he was his own legal consent authority, but he was demonstrably vulnerable and by definition compromised in his ability to give consent. Routine ethical guidelines and federal regulations* provide that there be special protections for vulnerable research subjects; we might thus ask: Were there adequate protections in place for this vulnerability? What would be the best sort of protections to use in this sort of circumstance in the future?
- A fellow on a stay of commitment is in a dependent position with respect to his treating psychiatrist – the stay is conditioned on co-operation with therapy. This could have a coercive effect if the treating psychiatrist is also the one inviting the patient’s participation in a clinical trial or the one conducting the clinical trial. Here we might ask: Were there adequate protections against this adverse influence? In fact, can there ever be adequate protections for the situation (must the person inviting study enrollment be someone uninvolved in the patient’s care)?
- Because the commitment was stayed, no family member was named as a guardian or decisional surrogate for Markingson, and none had clear legal status with respect to his care. That set the stage for tension (a mild word) when a family member was concerned that he was not doing well on his randomly-assigned therapy. So another question: Were there adequate provisions in place for a response to family concerns? Is there a way that such a scenario can be planned for in the design of this sort of study? Might the person most likely to have been named guardian have been a good choice to serve as a special advocate (as part of the special protections)?
- The study was a drug-company-sponsored comparison among newer (but not experimental) drugs useful in managing major psychiatric illnesses. The interests of the sponsor and the best interests of the participating patients can come into conflict in such a study. An additional concern: Did the incentive structure of the study militate unreasonably against code-breaking or crossing over when a patient was not doing well? In fact, one might well ask if it is ever appropriate for a clinical study comparing competing products in vulnerable subjects to be conducted by the sponsor of one of the products.
If we ask questions like these honestly and critically, we may not like all the answers. We may have to admit that we could do a lot better; we may have to admit that there are circumstances where we really don’t know what’s best. But that’s how we move forward. And improving our research practices is far preferable to abandoning our efforts.
*45 CFR §46.111(b) [Criteria for the approval of research]: When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as … mentally disabled persons …, additional safeguards have been included in the study to protect the rights and welfare of these subjects.
*Identical wording appears in the FDA regulations at 21 CFR §56.111(b)
Dale Hammerschmidt, MD, FACP, is an emeritus professor, Division of Hematology, Oncology and Transplantation, University of Minnesota Department of Medicine.
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