Monday, March 23, 2015

For the record: Dr. Mickey Nardo writes about ethics and the Markingson case at U Minnestoa

link to original post 


Posted on Friday 20 March 2015

    par·a·digm  (pr-dm)
    noun: paradigm; plural noun: paradigms
    1. [technical] a typical example or pattern of something; a model.
The case of Dan Markingson is a paradigm representing something terrible, a period in our medical history when the scientific processes designed to evaluate medications for use in the treatment of illness were perverted and used for commercial purposes. Surely, with the addition of such strong testimony as that of Nikki Gjere, the long avoided investigation of this case will finally become a reality. There are others: Paxil® Study 329, a trial that fallaciously reported that a medication was effective and safe in childhood depression; Seroquel® Study 15, a trial that was definitive but unpublished because the sponsor didn’t like the outcome…
from  a paradigm…  11/30/2014
Well, it seems the investigation[s] were already in the works. First there was the surprise when the external panel appointed by the Association for the Accreditation of Human Research Protection Programs presented their findings about the research program to the faculty senate at the UMN last week [An External Review of the Protection of Human Research Participants at the University of Minnesota with Special Attention to Research with Adults Who May Lack Decision – Making Capacity]. It was more an Indictment than Report [see done nothing wrong… and not trivial stuff!…]. But this week’s report is the bombshell [A Clinical Drug Study at the University of Minnesota Department of Psychiatry: The Dan Markingson Case] from the Office of the Legislature Auditor [OLA]. It goes through the case documenting the form-without-substance way in which the University, the Department of Psychiatry, and the Principals responded to the many calls to action from a variety of sources.
At first, it seems an odd candidate as a symbol for problems with the current clinical trial culture. It’s a trial at an academic center rather than one run at some commercial clinical trial center. The Principle Investigator is the Chairman of Psychiatry at Columbia, the P.I. of the widely quoted NIMH C.A.T.I.E. trial, and the immediate past president of the APA. The C.A.F.E. Trial that Dan Markingson participated in was, in fact, modeled on C.A.T.I.E. – the differences being that it was industry financed and that it focused on acute psychosis rather than chronic cases. Even more unusual for the cause of much other protest, Dan Markingson may well have been under- rather than over-medicated. But there were a few very unusual features that make it stand out:
  1. Suicidal patients were excluded from the C.A.F.E. study. Dan was admitted with expressed homicidality. In psychiatry, there is no distinction between suicidality or homicidality that I’ve ever heard. Commitment laws invariably say "dangerous to self or others" in one breath. The lectures have titles like "The Lethal Patient." The claim that he was eligible because he wasonly homicidal is clinically absurd.
  2. Dan was declared incompetent and involuntarily committed, but within days allowed to enter a voluntary drug study in lieu of going to the State Hospital. Another absurdity.
  3. The outcome parameter for C.A.F.E. was voluntarily continuing the medication, yet Dan’s conditions for avoiding institutionalization were that he stay on the medication. That invalidates any reason for him to be in the study – need I say absurd once again?
  4. In the treatment center where he was staying, the staff saw little to suggest any improvement. Dan’s mother increasingly worried about Dan’s clinical state and yet was told he was doing fine. Then at six months, his involuntary commitment was extended for another six months, the duration of the clinical trial. Further absurdity.
Even the most radical of antipsychiaty activists would’ve likely agreed that Dan should be tried on another drug regimen to control his ongoing and dangerous delusional state. On the face of things, it’s hard to come up with anything that would explain any of the four absurdities listed above. And the most absurd thing of all – up until the day he killed himself, he would’ve been tallied as a treatment success because he was still taking his medications…
from  a mockery…  05/21/2014
People don’t always like it much when I start talking in the psychodynamic way I discovered half my life ago [and never got over], but I don’t know any other way to say what’s on my mind now that this case has finally had a day in court. Back in the 1970s when I came to a psychiatric residency, it was a time like this. We had lots of interdisciplinary meetings and conferences where fur regularly flew around like tumble-weed. We had analysts, biologists, Szaszians, experiential therapists, hippies, suits, etc. and the fights were often anything but civil. I knew almost everybody in the room, and often worked with them in the Grady Hospital Crisis Center – the Emergency Receiving Facility for downtown Atlanta. In that Emergency Room where we all worked, none of the bitter divisions that characterized the conference atmosphere ever came up. It was just the team du jour dealing with difficult cases, and theideological what·evers disappeared. But at the next gathering, we turned back into cardboard icons representing various blind men describing our favorite part of the elephant. We simplified each other, turned others into Straw Men in our zeal to make a  point.
Years later, I had the hobby of translating the jargonized way psych·types sometime talk into everyday language. The residents could say projective identification and splitting, but they really didn’t know what the terms meant. But if I said, "Borderline patients simplify other people", they knew exactly what I was talking about. And I used the difference between how people acted in conferences contrasted with how they worked together in the ER. Then I’d say, "Borderline and Paranoid patients  simplify other people all the time." They got it, [and more importantly] remembered it. When I first read about Dan Markingson in Carl Elliot’s,The Deadly Corruption of Clinical Trials, in Mother Jones back in 2010, I thought about those days long ago. No matter what their favorite part of the elephant, nobody was going to read this case and not know that something was dreadfully wrong in the place where it happened. Nobody. That’s why I call it a paradigm, or a symbol, or a mockery. No matter where you’re positioned in the arguments that fly in conferences, or on blogs, or in the comments here, no matter how much we simplify each other, the something-wrongness with this case is absolute, and that was true from the start.

First off, it was an experimercial rather than a scientific study. AstraZenica was looking for a selling point. It was a poor design, First Episode Psychotic Illness is no place for a blinded study with no initial stabilization. And Dan Markingson was not exactly a typical First Episode case. He’d been ill for a while, and had many characteristics of a chronic case with complex and lethal delusions. And then there were all those absurdities listed above, and in the findings of the OLA [from Minnesota: Dan Markingson revealed…]. And the way this case and Dan’s survivors have been dealt with from the highest level of the University of Minnesota down to Dan’s day-to-day management were insensitive, dismissive, and at times, devious. Until nurse Nikki Gjere [INVESTIGATORS: Nurse questions integrity of U of M drug researchers] finally came forward, there was no break in the clouds. Apparently, the staff was up in arms about this case all along, but the climate of things kept that off the radar. Also, the OLA Report makes it clear that he never improved on treatment, in fact, becoming visibly worse towards the end of the study [and his life]. So, nobody, no matter their discipline, has ever defended how he was treated in any comments, or engaged this story except to decry the deadly corruption of clinical trials – this trial in particular.

In the external panel’s report, they say:
While there is no explicit requirement for ethics education for investigators imposed by the federal research regulations, such education is a requirement of NIH and NSF supported research and is widely considered to be a valuable element of a research protection program. The external review team noted the University’s recent introduction of policy changes that mandate additional training of IRB members. However, the broader educational policies and practices at the University fulfill minimal standards but represent a missed opportunity for a richer and more sophisticated institution ? wide approach to investigator training.
In my mind, ethics are the common threads that bind people of diverse opinion and temperament together in the face of real situations. I said it this way recently:
Surely ethics refers to more than a code of conduct, or the rules of right and wrong, or even the letter of the law. It comes from the word ethos, the culture of a place, and should offer a compass for navigating situations where there are no standing rules or precedents – something more felt than transcribed, something conveyed by example rather than memoranda or training manual…
In a Clinical Trial of a new medication, it’s incumbent on the trialist to be vigilant that the subject’s health and medical care is not compromised by participation…
Carl Elliot, Leigh Turner, Mike Howard, and Dan’s mother, Mary Weis, have done something remarkable. They’ve moved rhetorical deliberations about medical ethics out if the ivory towers of academia; breathed a new life into them with this paradigmatic real world case; and taken their campaign to the streets.
from  done nothing wrong…  03/10/2015
I made that up, but what I was getting at was that I’m not sure you can really teach ethics. You can discuss ethics in a seminar, refine the concepts, model ethical behavior, but I guess I see it as more a part of a person than something one chooses or teaches or learns. And in a system, it comes from the top down into the ethos. It’s sadly missing in this story where we hear and see adherence to the letter of the law if necessary, but don’t find an ethical soul. Carl Elliot and Leigh Turner are Bioethicists, but they’re also obviously ethical people. And while I’m aware that this is the worst thing I can possibly say, it’s missing in the people at the upper levels at "the U" in this story, including the Institutional Review Board [IRB]. And I kind of doubt that will change unless somebody’s looking. The Board of Regents put all kind of external supports in place [external ethical oversight], suggesting they have the same concerns. I wonder about a place where it takes eleven years, a group of dedicated campaigners, a faculty Senate revolt, an ex-Governor’s intervention, and international outrage to finally get the ball rolling. So some are already calling for a change of administration and I would anticipate that cry will become louder.

Does this case generalize to industry funded, commerce driven, CRO managed, KOL created clinical trials? I think it’s a fair assumption to postulate that a trial conceived for commercial purposes, run by a CRO-in-a-hurry, that partitions it out to sites all over theplace globe, and who is into cost-accounting, sure would be prone to simplifying the patientsinto cardboard subjects or fudging during recruitment to meet a quota, or any number of other things. And I would really worry about Institutional Review Boards becoming rubber stamp approval machines. That same lassitude might be true at any level in the process of conducting a trial.

This case will be in books and textbooks where it belongs long after most of us are no longer around to read them. That was never guaranteed, and getting it there is quite an accomplishment…

++++++++++Some Comments++++++++++

The U of M has been suspended from doing drug trials, which means losing money, which usually gets the attention of the faculty. I hope fear is running like a melting glacier through the hearts of research establishments, because given the lack of ethics to date, I think self-preservation is the only motivator that could lead to significant changes in the way drug trials are carried out by universities.
Hopefully, they’ll make good use of both ethics and science to mend their shabby ways.

@Wiley–I think it’s important to point out that the U of MN has voluntarily suspended only psychiatric drug trials–not all drug trials. My cynical belief is that they took this step to appear like they are being serious about change while trying to limit focus just to issues (which, granted, are appalling) with the Dept of Psychiatry. However, the AAHRPP report demonstrates broad institutional issues–not just issues with the Dept of Psychiatry. I truly do not believe that they ‘get it’ yet. I think the IRB, the administration and the Board of Regents still think that all of this was stirred up by a couple of trouble makers in the Bioethics Dept and all they really want to do is get it swept under the rug as quickly as possible so they can continue with the status quo (i.e. allowing the pharma tail to wag the research dog).
The Markingson tragedy was all but inevitable given two other absurdities highlighted in local press releases that did not make it into either report–namely that the chair of the IRB stated in testimony that she did not believe it was the role of the IRB to protect patients. The woman chairing the U of MN’s IRB does not understand the actual statutory role of an IRB.
The second absurdity is that the Chair of the Board of Regents, Richard Beeson, just recently re-elected to this role, stated publicly that the death of a patient in a U of MN research study ‘did not rise to the level’ of needing attention by the almighty Board of Regents. It is apparently beneath the valuable time of their highnesses to deal with the death of a peasant.
The oversight problems at the U of MN clearly go way beyond issues at the Dept. of Psychiatry. I just hope the OLA report, which was intentionally very narrowly focused, does not inadvertently provide cover for the U of MN to ignore the larger picture. To employ an over-used analogy, shaking up the Dept of Psychiatry is akin to rearranging the deck chairs on the Titanic.

Thank you for a terrific summation of the MN Leg Auditors report. Had you actually been sitting in on the hearing you would noticed right away the only thing missing was a picture of Nixon waving his fingers and declaring that he was not a crook every time someone from the U of M spoke.

Whitewashing in academia is expected. Look at the Kupfer “investigation”. Look at the Penn State investigation of the Climategate emails. No one dare disrupt the money and career gravy train. Those who triumph “civility” and respect of colleagues over honesty understand how the ethics game is played. Cue up Idina Menzel singing “Let it Go” after the results of these things are announced.

No comments: