Tuesday, March 31, 2015

For The Record: Don't let foxes guard the henhouse

U of M human subjects reform: Don't let foxes guard the henhouse

By Teri L. Caraway, David Pellow, Naomi Scheman and Karen-Sue Taussig 

The Board of Regents’ record on oversight does not inspire confidence.
The University of Minnesota has recently received two external reviews of its practices concerning the protection of human subjects participating in medical research. The resulting reports identified many substantive problems both in how the university conducts and oversees human subjects research and in how administrators have responded (or more often failed to respond) to concerns about ethical breaches in medical research.  In response to these scathing reports President Eric Kaler has submitted and on Friday the Board of Regents passed a resolution that outlines “decisive action” to address these problems. 
The proposed actions are not as decisive as they need to be. We applaud the steps that the administration has taken to invest more resources in the University’s Institutional Review Board (IRB), the body charged with balancing the benefit of research with the protection of those participating in research, but it was not primarily concerns about our IRB that led faculty and the public to call for independent investigation. Rather, these calls arose because of the cloud of suspicion hanging over the U caused by the perception that our administration was sweeping research misconduct under the rug.
The legislative auditor’s report presented damning evidence that substantiated these concerns, finding that the administration “dismissed the need for further consideration of the Markingson case by making misleading statements about past reviews.” The external reports suggest that top administrators, with the complicity of the Board of Regents, have repeatedly distorted the facts. They stonewalled requests for information that would have shed light on misconduct and conflicts of interest and ignored repeated warnings by whistleblowers. Their behavior suggests that they placed a higher priority on institutional reputation than on basic ethical principles.  The irony is that in their effort to protect the university’s reputation, they tarnished it.

More of the same?

Now the administration would have us believe that it is ready to tackle these tough problems vigorously and transparently. Unfortunately, the administration’s public responses to the reviews demonstrate that we are in for more of the same. For example, in his response to the Legislative Auditor’s report, President Kaler made the astonishing claim that “our only intent has been to be factual in our responses . . . if [earlier] external reviews were flawed, we were not aware of those shortcomings.”  Yet for years it is precisely these shortcomings that critics have been persistently trying to bring to their attention, only to be dismissed or stonewalled.  In short, if they really were not aware, it was willful ignorance.
We are deeply concerned that the people leading the response to the recommendations of the external reviews are the very people who have insisted all along that there were no problems. 
Not to worry, we are assured, because if you do not trust the administration, you can trust the Board of Regents.  The board’s record, however, does not inspire confidence. In a summer 2014 meeting with President Kaler, Board of Regents Chairman Richard Beeson told former Gov. Arne Carlson that reports of research misconduct had “not risen to the level of our concern” and that the negative publicity had “not hurt our brand.” Regent Patricia Simmons, who now is designated to serve as the Regents’ liaison on this matter, dismissed the legislative auditor’s criticism of the board for never holding public hearings about the Markingson case, arguing that the board received many briefings from the administration and was sufficiently informed.
Given the findings of the external reviews, this assessment of what constitutes adequate oversight is troubling. At Friday’s board meeting, Regents showed no signs of turning over a new leaf. They praised the administration and adopted the resolution it put forward without so much as a single question or critical remark about the handling of the situation to date.

True independence needed

If we cannot trust the administration and the Board of Regents, perhaps faculty and community involvement, which the resolution calls for, will provide the needed oversight of the process. The administration’s extensive past record of dismissing critics from the faculty and community, however, do not give us much confidence that the U will meaningfully include these constituencies in the process of reform. The Board of Regents resolution helpfully calls for the task force to be “comprised primarily of faculty,” but it is crucial that the membership include people — faculty and community members — who are truly independent and capable of providing the critical perspective necessary to restore trust in the institution.
We must be vigilant to ensure that research at the U accords with the highest ethical standards. Both independent reviews singled out U leadership, starting in the Department of Psychiatry and extending all the way up, as the most serious barrier to reform. The “decisive” action the U must take is first and foremost to decisively assure the public that those in charge of implementing reforms are not the same actors who were willfully unaware of past abuses.
Teri L. CarawayDavid PellowNaomi Scheman and Karen-Sue Taussig are faculty members at the University of Minnesota. They were among the faculty senators who helped to introduce and push for the passage of the resolution calling for the external review. The views expressed in this piece are their own and do not reflect those of the university.

Monday, March 30, 2015

Part of the Solution or Part of the Problem?

University of Minnesota

Medical School Dean, President Kaler, Mr. Pfutzenreuter

Sad, but true ...

From a comment in the Star-Tribune on their editorial criticizing the University of Minnesota administration:

",,, As you know, the tragic death of Mr. Markingson has been fully reviewed by the U.S. Food and Drug Administration and has been the subject of proceedings before the Hennepin County District Court and the Minnesota Board of Medical Practice, as well as the University's Office of General Counsel.  None of these investigations or proceedings found that the University in any way contributed to the unfortunate death of Mr. Markingson.  Accordingly, I do not believe additional review is warranted and do not support your petition."
May 29, 2013, letter from Eric W. Kaler to Associate Professor Leigh Turner.

Rarely has a president of the University of Minnesota had to perform as embarrassing a U-turn as has President Kaler on this issue.  To be fair, he inherited the situation from his predecessor.  But there was an obvious lack of interest at the U in getting to the truth of Markingson's case - and at this point it can be justly said that Kaler was part of the problem, not part of the solution.

Sunday, March 29, 2015

For the Record: Leadership and transparency were lacking in research subject’s suicide.- Star-Tribune - #Markingson

Link to original.

(Emphasis added)

Trust but verify' to rebuild trust in the U

  • Article by: EDITORIAL BOARD , Star Tribune 
  • Updated: March 27, 2015 - 7:19 PM
Leadership and transparency were lacking in research subject’s suicide.

Generations of Minnesotans have entrusted their health care to physicians and researchers trained at the state’s flagship educational institution — the University of Minnesota. But two new reports rooted in the 2004 suicide of a patient in a Department of Psychiatry medical study have raised disturbing questions about the U’s transparency and leadership on the case over the past decade.
One report, by the state’s Office of the Legislative Auditor, focused on the death of the patient, Dan Markingson, who suffered from schizophrenia when he was enrolled in a study funded by the drugmaker AstraZeneca. The other report, an external review of clinical trial practices, was set in motion by the Faculty Senate because of its concerns about handling of the case.
In November 2003, Markingson, a recent college graduate, was put under the care of Dr. Stephen Olson, who is still a professor in the U’s Psychiatry Department. Markingson initially responded to a drug called Risperdal. But within days, he agreed to be enrolled in a drug study overseen by Olson. Whether he was competent to provide consent or felt pressured to do so has been at issue.
The study compared the effectiveness of three drugs. Neither Olson nor Markingson and his family knew which drug he would be on. But there was a two-out-of-three chance that it would not be Risperdal — a risk that raises serious questions about the care he received. Markingson did end up on another drug, and the alarms his mother raised about his deterioration went unheeded. He killed himself in May 2004, although it is not possible to say his enrollment in the study caused his death.
It took 11 years for all of the details to come out about Markingson’s suicide and the bungled institutional handling of it. The auditor’s report revealed an institutional failure to adequately investigate the case and concluded that U officials had made “misleading” statements about the rigor of reviews of the case, including one by the U.S. Food and Drug Administration.
Lawmakers have already made a key reform with the 2009 “Dan’s Law,” which prohibits patients facing institutional commitment, as Markingson did, from being enrolled in research studies. But further changes are needed, and the external review launched by the Faculty Senate has offered guidance for implementing these reforms. Among them: ensuring that the U’s Institutional Review Board performs rigorous reviews of research safeguards and adverse outcomes.
It is not enough to finally say that the university is committed to reforms, as U President Eric Kaler, Board of Regents representatives and the medical school’s leadership have done. The Legislative Auditor has also offered pragmatic “trust-but-verify” solutions. Lawmakers should require the U to fully implement reforms outlined by the external review. In addition, lawmakers should authorize the state’s own mental health ombudsman’s office to monitor the U’s psychiatric studies.
Other needed steps include authorizing the legislative auditor to investigate the state Board of Medical Practice, which failed to objectively investigate Markingson’s death. It’s also critical that the U have adequate whistleblower protections in place. University bioethicist Carl Elliott has been marginalized professionally after challenging handling of Markingson’s death.
On Friday, U officials said they had asked Dr. William Tremaine, head of the Mayo Clinic’s Institutional Review Board, to provide independent guidance on its reforms, and he agreed to chair a key reform committee. That’s a sign the U is taking criticism to heart. But more work is needed.
Minnesotans have been ill-served by their flagship university in this tragic affair. Yet the state owes a debt of gratitude to Elliott and others who unrelentingly pushed for truth. Among them: Markingson’s mother, Mary Weiss; his friend Mike Howard; former Gov. Arne Carlson; and state Sen. Terri Bonoff. Their persistence shouldn’t have been necessary, but if lawmakers and Kaler follow through, it will help rebuild the institutional integrity that Minnesotans expect and deserve.

Saturday, March 28, 2015

For the Record: Former Director of the U of M Office of Conflict Resolution calls out President Kaler for skirting the Legislative Auditors Findings on #Markingson

Link to original.

University of Minnesota President Eric Kaler’s response to the Legislative Auditor’s review skirts the heart of the findings and, in doing so, risks losing the university’s opportunity to regain public trust.
The auditor reviewed the experiences of Dan Markingson and other human subjects in drug trials in the department of psychiatry. The report found that drug trials had run amok. Conflicts of interest permeated the management of the trials. Vulnerable individuals were urged, perhaps manipulated, into participating in the trials. And some individuals suffered terribly as a result. Kaler’s March 18 response promises specific, immediate actions to correct the flaws in the department’s research protocols.
By putting the camera up close so that only the substantive research issues fall within the frame, the university sidesteps a blunt criticism. The auditor’s report found that the Markingson case raised serious issues — which university leaders have been consistently unwilling to acknowledge.
In the 10 years since Markingson’s death, the university has had two presidents, several medical school deans and several senior vice presidents of the Academic Health Center. When so many different leaders touch a problem, yet there is no change in the management of the problem, we likely have a systemic cultural pattern rather than an individual proclivity that needs correction.
Report authors throw up their hands in the face of this challenge. The report acknowledges it does not have “a recommendation that would change attitudes at the university about openness, accountability, and transparency”; it is up to the university. Consider bringing this concern into the frame, examining closely the dynamics that led to these missteps, telling us what you learn from your self-reflection and what you plan to do. Reassure us that the auditor’s critique has been received, not sidelined, and will be addressed.
Carolyn Chalmers, Minneapolis
The writer is a former director of the Office for Conflict Resolution at the University of Minnesota.

For the Record: Kaler acknowledges U misstatements on drug study

(emphasis added)
For the first time, President Eric Kaler acknowledged that the University of Minnesota made “misleading or inaccurate” statements in the aftermath of the suicide of Dan Markingson, a psychiatric patient who was in a U drug study at the time of his death.
Kaler made the admission Friday as the Board of Regents took steps to deal with the fallout from a scathing report about the case by Legislative Auditor James Nobles.
Nobles’ report, released last week, stopped short of linking Markingson’s 2004 death to the drug study. But it found that the U had turned a blind eye to conflicts of interest and made “misleading statements” about prior reviews that supposedly cleared the U of wrongdoing.
In response, the regents voted Friday to suspend enrollment in psychiatric drug studies and toughen scrutiny of research involving human subjects.
Kaler, meeting with reporters, acknowledged that the public may have been misled by the university’s repeated claims that it had been investigated, and cleared, by the state attorney general.
“That was not a full-fledged attorney general’s investigation,” Kaler said. He said the attorney general’s office had merely helped the state Board of Medical Practice review a complaint against two U psychiatrists.
“Was there an attorney general’s office investigation? The answer is no,” Kaler said. But he said the university’s assertions, which began before he became president, “would have led somebody to believe” that it was. “In that sense, it was misleading or inaccurate.” He later called it “imprecise,” adding, “I don’t think it was meant to mislead.”
Kaler said it’s impossible to know if Markingson’s death was linked to the study itself, but he issued an apology to Markingson’s mother, Mary Weiss, who had tried to get her son out of the study. “I’m deeply sorry that he passed away while under our care,” Kaler said. “In that sense, we failed his family.” He said he hopes to meet with Weiss “to convey that in person.”
He also vowed to ensure that future research is conducted in “safest and most ethical way possible.”
The resolution approved by the regents Friday calls for suspending enrollment in all psychiatric drug studies until they’re reviewed by an independent board of experts. It also calls for stepping up scrutiny of research involving “vulnerable populations.”
Nobles issued a statement saying he was pleased by the actions.
Mike Howard, a friend of Markingson’s mother, had a mixed reaction.
“This is certainly progress,” he said. But “it would have been nice,” he added, if the university had admitted it was at fault. “You know: ‘We made a mistake and now we want to fix it.’ ”

Tuesday, March 24, 2015

For the Record: Dr. Mickey Nardo writes about "making sense" and the Markingson case at U Minnesota

Link to original post. 

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 theRisperdal® 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 toSeroque. 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 wasdecompensating.

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 wasdecompensating with all of the primary symptoms – often referred to as becomingdisorganized

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.

Friday, March 20, 2015

For the Record: Legislative auditor says U should suspend psychiatric drug trials

Jeremy Olson has written the following piece in the Star-Tribune.  It should be noted that Mr. Olson and Mr. Paul Tosto first broke the Markingson story in the Pioneer Press while both were there. For this work they received the Premack Award from the University of Minnesota Journalism School.

See an earlier pieceOpennness, Transparency, and Avoiding Conflict of Interest at the University of Minnesota?


Premack Award to Pioneer Press for "The Death of Patient 13"

From the press release:
Excellence in investigative or analytical reporting about public affairs (7 county metro):
The St. Paul Pioneer Press and reporters Jeremy Olson and Paul Tosto are the winners of the investigative or analytical reporting award for their series “The Death of Subject 13” published May 18, 19 and 20, 2008.
In this piece, Olson and Tosto reported for the first time on schizophrenia patient Dan Markingson’s death and the resulting lawsuit and probes. In the process, they pulled back the curtain on the rarely viewed world of industry-funded clinical research and the financial incentives that can compromise a doctor’s decision-making.
Premack judges in this category said: “Through the eyes of one patient, this story shed considerable light on the complicated and competing interests between the development and path to market of new drugs, funding needs of the University and the integrity of medical research. 

The judges are hopeful that the new ethics task force implemented at the U of M is resulting in changes in conflict of interest policies.”

Hearty congratulations to Paul Tosto and Jeremy Olson. Over the years they have demonstrated outstanding journalistic skills and the perseverance to dig out information in the public interest. These qualities are shared by colleagues at many other papers including the Strib and our beloved Daily.
The scrutiny of a free press is essential to exposing practices that need to be improved, especially at our beloved University of Minnesota. Truly realigning our priorities with those of a land grant institution needs to be done now. Let's work for a university that we can all be proud of.

Legislative auditor says U should suspend psychiatric drug trials

  • Article by: JEREMY OLSON , Star Tribune 
  • Updated: March 20, 2015 - 2:31 AM
Legislative auditor troubled by University’s response to 2004 suicide of Dan Markingson.

The University of Minnesota should suspend new psychiatric drug trials until lapses in patient protections and ethical oversight are addressed in its psychiatry department, the state’s legislative auditor said Thursday.
The recommendation grows out of an ethics controversy that has dogged the U for a decade — the treatment of Dan Markingson, who died by suicide at age 27 in May 2004 while participating in a schizophrenia drug trial.
Legislative Auditor James Nobles reviewed allegations that a delusional Markingson was coercively recruited into the study and remained enrolled after his mother expressed grave concerns and asked that he be disenrolled.
While noting that there is no proven link between the drug trial and Markingson’s death, Nobles’ staff said: “We are especially troubled by the response of University leaders … they have made misleading statements about previous reviews and been consistently unwilling to discuss or even acknowledge that serious ethical issues and conflicts are involved.”
Nobles’ recommendation is not binding, but his conclusions are the strongest corroboration by a government agency of the criticisms raised by Markingson’s family. The U has repeatedly denied allegations of wrongdoing from Markingson’s family and, lately, its own faculty.
At a Senate committee hearing Thursday, University President Eric Kaler challenged some findings in the audit, but apologized to the family for Markingson’s death. He said the U would suspend enrollment in current and upcoming psychiatric drug studies until an independent board reviews them and informs university administrators that they can safely proceed.
Nobles, however, said Kaler’s proposed internal review would be questionable given the university’s “insular” culture.
“I think they’ve lost perspective about what is a conflict of interest,” he said.
Nobles recommended legislation preventing new psychiatric drug studies until the U adopts stronger patient protections outlined in another external review that was ordered by the Faculty Senate due to the Markingson death. That review, released publicly two weeks ago, cited the Psychiatry Department for weak patient protections that do “not reflect the best efforts of a University of this caliber.”
Nobles also recommended that Minnesota’s state mental health ombudsman be given authority and funding to monitor the safety of patients in U psychiatric drug studies.
National drug study
The Markingson case involved a national study, called CAFE, that was funded by drugmaker AstraZeneca to compare three antipsychotic drugs in the treatment of newly diagnosed schizophrenia. A U psychiatrist, Dr. Stephen Olson, was in charge of the local arm of the study and had struggled initially to recruit enough patients.
Nobles cited concerns that Olson recruited Markingson into the study while also serving as his treating psychiatrist and an adviser to the court on whether Markingson needed inpatient commitment.
The state mental health ombudsman raised similar concerns in 2005 about the potential for conflict among the multiple roles. In 2009, the Legislature prohibited doctors from recruiting their patients into their own psychiatric drug studies.
Nobles also found conflicts and problems with those overseeing the safety of CAFE. A review of Markingson’s death by the university’s IRB, for example, consisted of no interviews and a short written statement from Olson.
“This is the review that the IRB conducted,” said Nobles, dangling one piece of paper before the Senate Higher Education Committee.
The audit also raised concerns about the Minnesota Board of Medical Practice, which hired a psychiatrist to review a complaint about Olson’s conduct — even though that psychiatrist led the IRB that oversaw CAFE, was a faculty colleague of Olson, and received financial support from AstraZeneca.
Ruth Martinez, executive director of the Medical Board, said the board probably wouldn’t have hired the doctor “if we knew everything that we all know now.” But the board also needs specialized experts in cases like this who understand whether doctors violated laws in their practices.
Troubled legislators
Taken together, the numerous conflicts bothered Sen. Julianne Ortmann, R-Chanhassen. “Everybody seemed to have a conflict here,” she said at Thursday’s hearing.
A review by the U.S. Food and Drug Administration found no wrongdoing by the U in Markingson’s treatment and death, and no other government agency has publicly penalized the U for its role in the CAFE study. A social worker in charge of recruitment and scheduling was sanctioned, though, for her conduct in the study, including record-keeping errors, exceeding her scope of practice and failing to adequately respond to the concerns of Markingson’s family.
Nobles’ report took issue with the quality of the FDA review, however, because it failed to examine whether the threat of commitment was a coercive influence on Markingson’s decision to enroll in the study. He also said university officials overstated the number of investigations that have exonerated their conduct. The audit is a small measure of justice to Markingson’s family.
“Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice,” wrote Mike Howard, a close friend to Markingson’s mother, in a letter in the audit. “This report is the first step toward accountability.”
While university officials pledged improvements that will put the ethics and safety of research “beyond reproach,” they urged lawmakers not to overreact with measures that could cripple research. Olson said more than 7,000 Minnesotans have died by suicide since Markingson, and that research in acutely mentally ill patients is needed to prevent more.
Bioethicist Leigh Turner, a leading campus critic for the U’s treatment of Markingson, accused U leaders of “crocodile tears” and said they have had years to make the improvements they proposed.
But Sen. Terri Bonoff, DFL-Minnetonka, expressed confidence that the audit will motivate change. Bonoff, who chairs the Senate Higher Education Committee, said she plans to submit the legislation calling for a suspension of psychiatric drug research until changes proposed in the external review are carried out.
“I think we cracked this,” Bonoff said. “I think there will be significant reforms.”

Staff writer Maura Lerner contributed to this report.
Jeremy Olson • 612-673-7744