making sense…

Posted on Monday 23 March 2015

The Board of Regents has closely followed the work of the external review panel and is aware of OLA’s findings. Chair Beeson and Regent Simmons have already created a plan for the Board to take an active role in shaping the University’s action plan. The Board will provide ongoing implementation oversight through its Audit Committee to ensure transparency and accountability. I look forward to demonstrating to the Regents our commitment to improve. To that end we are taking immediate actions:
  • Suspending enrollment in all Department of Psychiatry interventional drug studies currently active or awaiting approval…
  • Using an independent IRB and the University’s post approval monitoring process, we will sample additional interventional clinical studies targeting vulnerable populations…
  • Appointing a Community Oversight Board, comprised of external experts in human subjects research and research ethics…
  • Visiting leading institutions to learn the best practices followed by their IRBs.
  • Implementing new IRB software…
With this letter from the University of Minnesota, President Eric Kaler and the Board of Regents suspended enrollment in all present and future Clinical Trials in the Department of Psychiatry pending review. They were responding to the Report by the Office of the Legislative Auditor released last Thursday. To those of us who have followed this case, this is welcomed news. From first reading, this case has been troubling, and as time passed, every new data point confirmed the need for thorough investigation. But what kind of case is it? Is it a legal case? Is it a research case that relates to the clinical research program at the University of Minnesota? Is it a psychiatric case study of Schizophrenia? Is this a case of the human tragedy of a suicide? Or is this a case that’s an inkblot to contain our various biases and projections? There’s one thing for sure – it was not a case that had been thoroughly investigated!

Over time, Carl Elliot and his colleagues have collected a number of documents [subpoenaed, FOIA, etc] that are collected «here» as Scribe documents. I had looked at some of them, but wanted to look at a few others to see if I could clear up questions I had in my own mind. Let me first admit that although I spend a lot of time on this blog looking at Clinical Trials [groups], by interest and inclination, I am an n=1 type – most at home with case studies, and this is certainly one of those.

For reasons now obvious to us all, I thought from the start that Dan shouldn’t have been allowed into the C.A.F.E. study to begin with. But I had a lingering curiosity about how that happened, and there were comments in various reports that he had responded to the Risperdal® started on his initial admission and that had something to do with it. Where did that information come from? He was admitted to the hospital involuntarily on Nov 12th, 2003 and soon started on Risperdal® 3mg at bedtime. He was committed on November 17th; was approached about CAFE on Nov 19th; was granted a stay of commitment on Nov 20th if he agreed to cooperate with treatment; and he signed up for CAFE on Nov 21st. On Nov 24th, he had a SCID Structured Interview [see Study Visits p. 4] in which his communications were lucid. He said his difficulties began in late July with "inaccurate ideas". He quit his job in early August and "did some traveling." In late September, he wrote the delusional emails that disturbed his mother [see Elliot’s The Deadly Corruption of Clinical Trials p.1]. In the SCID Interview on Nov 24th [CAFE Intake], he said his conditioned worsened two weeks earlier: "episodes of extreme confusion, sleep deprived, tense living situation – two weeks ago, no sleep, inaccurate beliefs" and "gradually beliefs more firmly planted, 12 days ago – things were alarming" [see Study Visits p. 5]. He attributed these symptoms to "lots of work, little sleep. thinks it made him vulnerable to those thoughts. no other problems." My point is that he did respond to the Risperdal®. He may not have ascribed it to an illness, but he was talking about it from a place in our shared reality. Of course he shouldn’t have been accepted into CAFE, but his response to Risperdal® makes the story make more sense.

And speaking of not making sense, this portion of the narrative in the OLA Report doesn’t either [see OLA Report p. 13]:
Mary Weiss and Markingson’s treatment team sharply disagreed over the state of Markingson’s mental health. Mary Weiss frequently reported to Dr. Olson, Kenney, and Pettit that her son was deteriorating and needed help. Generally, Pettit, the medical team, and group home staff reported Markingson was doing well, at least for the first few months after he came to the group home. In the month before Markingson died, however, more observers reported some decline in his condition. One report found that Markingson appeared very inattentive in his group therapy; he sat smiling to himself. Two days later, Markingson said he had never heard of the Easter holiday even though he said he was raised Catholic. Other observers noted that he looked more disheveled and had a mildly “wilder” look in his eyes but still in contact with reality.
In a later deposition where Dr. Olson was being grilled about those latter months of Dan’s life, the lawyer produced Dan’s Journal [hitherto unknown by Dr. Olson]:
Mar 9, 2004: "You’ve been given observation on truth today, Dan. If someone makes an assumption in asking for a confirmation, such as you’ve seen Friday right? You may recast the question by saying, Have I seen Friday or more generously, if you think the assumption might possibly be all right to make concerning the average person, like you’ve seen Star Wars, right. You may answer the question, then say is it good enough to assume that somebody’s seen it." [Olson 2007 p. 465]
Mar 23, 2004: "world walking, you were at a farm house and we’re getting presents from dogs who had presents fastened in plastic bags to their snouts… in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green. That was someone brings a snowslide in summer or midsummer. It has been left behind…" [Olson 2007 p. 467]
Mar 25, 2004: Lawyer, "he says he’s leaving for California as soon as court order expires…" [Olson 2007 p. 471]
In that same Deposition, there were notes from occupational therapy…
Lawyer: "Had you seen any notes in the occupational therapy records that in April of 2004 that said that over time client has become more isolated. He seems to have no interest in interacting with his peers. Personal appearance, disheveled, isolated and withdrawn, poor insight and self awareness. Plan to become an actor in California continues. Delusions seems fixed." [Olson 2007 p. 489]
and the counseling center…
Lawyer: "During the time you were treating Dan, did you see the Eagan Counseling Clinic notes of March 29th, 2004 stating that he is showing slightly more disorganization and thought and stream of speech and risk to self low with plan." [Olson 2007 p. 485]
And this was the time period during which Mary Weiss was raising holy hell about her son’s condition deteriorating. So there’s an even bigger question, "Why was he allowed to stay in the CAFE Study?" The Protocol is quite clear about the criteria for withdrawing subjects from the study [see Protocol p.9]… Criteria for Discontinuation
Patients may be withdrawn from the trial for any of the following reasons:
  1. Inadequate therapeutic effect [requiring alternative treatment]. [Note: subjects shall not be withdrawn due to lack of efficacy if the maximum dose has not been achieved; except if the patient is not having adequate response but higher doses are not tolerated, then this can be considered as a discontinuation for lack of efficacy.]
  2. Unacceptable side effects
  3. Patient decision [examples include but are not limited to]:
    • Withdrawal of informed consent.
    • Subject lost to follow-up [dropouts].
  4. Administrative [examples include but are not limited to]:
    • Site protocol noncompliance [protocol violations or deviations].
    • Other independent external events that preclude further participation in the protocol for a subject who would otherwise continue [e.g. moving, accidental death, pregnancy].
The primary outcome measure was the proportion of patients who withdrew from the study prior to 52 weeks of treatment [“all- cause pharmacological treatment discontinuation”]. The reason for discontinuation was recorded according to a predetermined algorithm: [1] administrative discontinuation due to an independent external event [e.g., moving with family to another state]; [2] a clinician decision to discontinue treatment because of inadequate therapeutic effect or intolerable side effects whether or not the patient wanted to discontinue; or [3] a patient decision to discontinue although the clinician believed the treatment to be adequately efficacious, tolerable, and safe.

The responsibility for withdrawing a subject from the study for inadequate therapeutic effect [efficacy] rested with the clinician, not the patient. Because of the bind Dan was in, he was unlikely to withdraw himself for fear of being sent to the State Hospital under the terms of his Stay of Commitment agreement. As I now read the timeline, he was involuntarily admitted to the hospital with a flagrant psychosis and lethal thoughts. He responded to his initial treatment with Risperdal® [above], and was accepted into the CAFE Trial, randomized to Seroque. He apparently did reasonably well at first – living in a group home, attending Day Treatment, seeing a Counselor. He was driven to these various places by his mother, Mary Weiss, and her friend, Mike Howard. But over the last two months of his Stay of Commitment [and life], he showed signs of progressive deterioration reported from all venues. He was not talking about the delusions as he did on admission, but he instead had primary symptoms [Bleuler]. And he certainly qualified as having an "inadequate therapeutic effect." It wasn’t subtle, and was noted generally. There was some question as to whether he had stopped taking the study medication or not. But whether he had stopped or the Seroque just wasn’t up to the task doesn’t matter. By Protocol, he should’ve been withdrawn by the clinician in charge of the study. He wasn’t just having an "inadequate therapeutic effect." He was decompensating.

The Deposition I have been quoting [Olson 2007] is hard to read because it is so contentious, but when the Lawyer begins to imply that Dan was getting sicker, Dr. Olson seemed shocked:
"To the best of my knowledge, we thought Dan was taking his medication and it was being monitored after January and February by the staff at Theo House. And in terms of the deterioration, there was no evidence that came to light either before his suicide or after that he was suffering a psychotic decompensation. The only deterioration that we noted was some deterioration in his grooming and other negative symptoms which are  manifestations of schizophrenia that do tend to  increase over time, but they’re not amenable to treatment with antipsychotic medications, and there was no indication that he had any return of the behavior being influenced by his delusional thinking. [see Olson 2007  p.451]."
More than 100 years ago, Eugen Bleuler made the distinction between primary symptoms:

  • loosened associations of thought
    ["in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green"]
  • inappropriate or flattened affect
    "he sat smiling to himself"]
  • autistic thinking – as in a private logic
    ["You’ve been given observation on truth today, Dan. If someone makes an assumption in asking for a confirmation, such as you’ve seen Friday right?…"]
  • and ambivalence
    ["Are you asking me or telling me?"]
and secondary symptoms like delusions and hallucinations. When the DSM-III came along, the criteria were organized differently, but all of those things are among them. Dan was decompensating with all of the primary symptoms – often referred to as becoming disorganized
    Bernard Carroll
    March 23, 2015 | 11:47 AM

    It’s pretty clear in your description of events that there was a serious question about whether Dan Markingson was taking his Seroquel medication. Would it have killed them to get a blood level, then? In the context of a clinical trial from which the sponsor expects to profit billions, are they so chintzy that they would not gladly provide that help to the clinicians and to the patients for resolving a clinical issue?

    This is a pervasive failing of the pretend clinical trials that I call experimercials. The posture of the corporation with its deep pockets is not to assist investigators and patients but to extract value from them. If blood levels are not given as an option in the protocol then nobody connects the dots when a situation like this arises.

    On a related note, the marketing departments of the corporations work hard to keep any mention of pharmacokinetics, blood levels, and therapeutic ranges off the table. They want to avoid the impression that use of the drug is “complicated” by such irksome issues, even though the patients would benefit from having blood level testing readily available. Just look at all the Coke v. Pepsi style TV advertisements for the new blood thinners versus the old blood thinners. And the world of academic clinical trialists has colluded in this dumbing down of the clinical science.

    March 23, 2015 | 6:02 PM

    If he had stopped taking the Seroquel, and they had tested him to confirm that, then shouldn’t they have wanted to know why and have documented it as part of the study? Since they were comparing three antipsychotics and subjects were barred from taking any of the other test drugs and only allowed limited additions, wouldn’t that information be important, since compliance is such an issue with psyche meds and schizophrenia and they were comparing antipsychotics?

    Experimercials can be deadly. It’s horrific that a person can die an ugly death for marketing that doesn’t provide sound information.

    James O'Brien, M.D.
    March 24, 2015 | 11:42 AM

    Speaking of experimercials, it’s only a matter of time before the Brawndo Corporation gets into CNS drug marketing, because it’s got electrolytes which is what your serotonin receptors crave:

    If it can give plants when they crave, maybe it can help your mood too!

    “it’s neuroprotective”=”It’s got electrolytes” Sadly, the first statement is not really much dumber than the second.

    James O'Brien, M.D.
    March 24, 2015 | 12:39 PM

    To clarify the above, “neuroprotective” as used to describe SGAs not Lithium.

    March 24, 2015 | 2:18 PM

    Jeffrey Lieberman was at my local bookstore last night. I forgot to go, which may be just as well, since I was thinking of asking him about these reports and this decision. I think that the gist of his new book is about how psychiatry emerged as a modern, scientific enterprise from its less than scientific origins.

    But I don’t want to be a rabble-rouser, and I worry about coming off as anti-psychiatry, which I’m not.

    James O'Brien, M.D.
    March 24, 2015 | 5:15 PM

    “It’s pretty clear in your description of events that there was a serious question about whether Dan Markingson was taking his Seroquel medication. Would it have killed them to get a blood level, then? In the context of a clinical trial from which the sponsor expects to profit billions, are they so chintzy that they would not gladly provide that help to the clinicians and to the patients for resolving a clinical issue?”

    This is more than a bit puzzling and kind of argues against the greed motive theory and more toward the sloppy science/don’t give a damn about getting the independent variable free of noise theory.

    If the pharma greed/positive results uber alles theory is correct, then the motivation is to push out subjects who are not as likely to get better and it would seem that Markingson was probably in that category. Whereas overinclusive “major depression” totally is compatible with SSRIs work uber alles since they are normals who are going to get better anyway (hence the high placebo responses). I would think in an antipsychotic study, a purely greedy pharma/KOL might prefer someone with borderline hypnogogic hallucinations or someone with minimal functional impairment.

    Based on what I’ve read about this case, I’m filing it in the bad scientist category. A well trained researcher trying to eliminate “noise” would have been more careful and certainly more ethical.

    What do you have to do these days to get thrown out of a clinical study?

    March 24, 2015 | 6:49 PM

    Couldn’t someone running a study have greed as a motive AND be a sloppy scientist?

    Let us commend the extraordinary dedication of Carl Elliot, Mary Weiss, and others to exposing this case, where a wide range of abuses clearly occurred.

    March 25, 2015 | 3:44 PM

    I hope that Mary has been able to gain some solace from these developments.

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