par·a·digm (pr-dm)nounnoun: paradigm; plural noun: paradigms1. [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that a medication was effective and safe in childhood depression; Seroquel® Study 15, a trial that was definitive but unpublished because the sponsor didn’t like the outcome…from a paradigm… 11/30/2014
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:
- 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 was only homicidal is clinically absurd.
- 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.
- 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?
- 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
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.
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.
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
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 the
place globe, and who is into cost-accounting, sure would be prone to simplifying the patients into 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.