healthy4u: atypical anti-psychotics

Minimizing Legal Liability or Upholding the Mission? - the Markingson Case Redux

There are new, and troubling developments in the long running case of Dan Markingson, the psychiatric patient and research subject who committed suicide while enrolled in a trial of anti-psychotic drugs at the University of Minnesota nearly 10 years ago. Summary of the Case A good quick summary of this case just <a href="http://blogs.law.stanford.edu/lawandbiosciences/2013/03/14/the-markingson-case-investigate-the-university-of-minnesota/">appeared </a>in the Center for Law and Bioscience blob out of the Stanford Law School.  <blockquote class="tr_bq">Dan Markingson – a vulnerable, psychotic young man – was forced to choose between enrolling in a Pharma-funded drug study or being involuntarily committed (in other words, locked up).  A UMN [University of Minnesota]  doctor enrolled him in the study despite having just determined that Dan 'lack[ed] the capacity to make decisions regarding [his] treatment,' rendering it highly unlikely that Dan could have given valid informed consent to participate.  As Dan's mother, Mary Weiss, observed his mental condition deteriorating, she repeatedly tried to have Dan removed from the trial – at one point asking  'Do we have to wait until he kills himself or someone else before anyone does anything?'  But the UMN co-investigators in the drug study refused to terminate his participation.  Shortly after Ms. Weiss made her desperate plea, Dan Markingson killed himself by cutting his own throat.</blockquote> Our most recent (2011) post on the case was <a href="http://hcrenewal.blogspot.com/2011/02/university-of-minnesota-where-nothing.html">here</a>.  In it we also noted that there was reason to think: -  The design of the controlled trial was flawed. -  Financial conflicts of interests may have influenced the trial investigators' actions, particularly their questionable enrollment of Mr Markingson in the trial and their retention of him in it despite his apparent clinical deterioration. Despite that, when bioethicists and the University of Minnesota called for a new investigation of the trial and what happened to Mr Markingson, the university rebuffed them. Worse, as detailed in a 2012 <a href="http://blogs.law.stanford.edu/lawandbiosciences/2012/12/14/how-not-to-run-a-drug-study-the-university-of-minnesota-puts-on-a-clinic/">post</a> in the Center for Law and Bioscience blog, not only did university officials rebuff this call, but the university general counsel, who had been operating at the heart of this case, appeared to threaten the leading bioethicist dissident, Dr Carl Elliott: <blockquote class="tr_bq"> After Carl Elliott, the University of Minnesota bioethicist, refused to drop the matter, Rotenberg asked the university’s Academic Freedom and Tenure Committee to take up the question of '[w]hat is the faculty[’s] collective role in addressing factually incorrect attacks on particular university faculty research activities?' – a question that appeared both to accuse Elliott of 'factually incorrect attacks' and to call for some unspecified action to 'address' them.  Other faculty, including the president of the Minnesota chapter of the American Association of University Professors, viewed this as an attempt to intimidate Elliott into silence.  If so, it backfired.  The story <a href="http://goo.gl/4BIuM">ended up in the press</a>, putting the Markingson case back in the public eye and once again making the University of Minnesota look really bad.</blockquote> New Evidence Unearthed In 2013, Dr Elliott made public what may be important new evidence in the case.  As <a href="http://www.startribune.com/local/193447511.html">summarized</a> by the Minneapolis Star-Tribune, <blockquote class="tr_bq">The professor, Carl Elliott, says he has obtained consent documents for two separate schizophrenic patients that appear to be exact copies — not just in the subjects’ apparent replies, but in the positions of the lettering on the pages. Elliott said it is improbable that separate patients would provide identical responses to the questionnaire, which includes open-ended questions about the risks and requirements of clinical research. And that, he said, raises questions about whether the university was really examining patients to determine their ability to consent to research.</blockquote>  One crucial question about the case is how a patient who was actively psychotic - out of touch with reality - could give true informed consent to participation in a drug trial.  These new documents suggest major irregularities in the process used in the trial to assure that patients did give informed consent.  Furthermore, as <a href="http://www.mndaily.com/news/campus/2013/03/14/10-years-study-scandal-lives">reported</a> by the Minnesota Daily, other documents that Dr Elliott found suggested problems with records that related to whether study investigators would have had legal authority to access Mr Markingson's medical records, also suggesting major problems with trial administration.  These documents, unknown until recently, suggest new concerns with how the study in which Mr Markingson was enrolled, and during which he died, was run.  Yet, the University of Minnesota's official response to them, once again orchestrated by university counsel Mark Rotenberg, attacked the legitimacy of the documents (and indirectly, attacked Prof Elliott again), as reported by the Star-Tribune, <blockquote class="tr_bq">the university’s general counsel, Mark Rotenberg, challenged the authenticity of the documents and disagreed that study recruiters failed to obtain proper and independent consent from mentally ill patients. 'I am challenging these allegations directly,' he said. 'We have no reason to believe the consent forms were prepared inappropriately.'</blockquote> As Matt Lamkin <a href="http://blogs.law.stanford.edu/lawandbiosciences/2013/03/14/the-markingson-case-investigate-the-university-of-minnesota/">wrote</a> in the Stanford Law and Bioscience blog,  the University's responses all through this case have been focused  not on the welfare of patients, maintaining the trust of research participants, or the integrity of clinical trials, but on the legal defense of  the University and its leaders <blockquote class="tr_bq">Despite all this (<a href="http://blogs.law.stanford.edu/lawandbiosciences/2012/12/14/how-not-to-run-a-drug-study-the-university-of-minnesota-puts-on-a-clinic/">and much more</a>), the University has never acknowledged any errors or taken any disciplinary action related to the Markingson case and has repeatedly rejected calls for an independent investigation.  That’s probably because from the start the University has handled this case as a litigation matter.  Rather than trying to determine whether there were problems with the way its personnel treated Markingson, the University has focused on minimizing its potential liability.  Accordingly, the University appears to run every inquiry related to the case through the office of its General Counsel, Mr. Rotenberg.  When Carl Elliott (my mentor as a grad student at UMN) wrote <a href="http://www.motherjones.com/environment/2010/09/dan-markingson-drug-trial-astrazeneca">a damning article about the case</a> in Mother Jones, the University’s response came from Rotenberg.  When <a href="http://www.scribd.com/doc/49659724/U-of-M-Board-of-Regents-Markingson-Letter">UMN bioethicists called on the University’s Board of Regents to launch an independent investigation</a>, the Regents deferred to Rotenberg.  Not surprisingly, he declined. When you turn to your lawyer, you’re going to get a particular kind of response.  The GC isn’t in a position to take an objective look at the circumstances.  He’s an advocate.  His role is not to make sure the client has conducted itself ethically, but to minimize the client’s risk.  Asking your lawyer to respond to allegations of wrongdoing is like asking your PR flacks to do so.  Their job is to make their clients look good, not to make sure they’ve acted properly.</blockquote>Note that this still begs the question of who the client is.  Is it the university, or the university's leaders? Furthermore, as Mr Lamkin pointed out, the general counsel would appear to have a conflict of interest.  It may be he has an interest in defending his own actions, as well as those of his client(s), whether they are the university, its leaders, or both.  <blockquote class="tr_bq">In addition to Mr. Rotenberg’s role as the University’s top defender and advocate, there is another reason he cannot impartially consider requests for an investigation: the General Counsel’s Office is an important player in some of the disturbing events at issue.  As noted above, Rotenberg himself has been accused of attempting to intimidate and silence the bioethicist who has most doggedly sought an investigation.  The University’s lawyers are also responsible for the disgraceful silencing of Markingson’s mother, Mary Weiss.  After avoiding liability by arguing the University was immune from suit, these lawyers then threatened to force Weiss – whose son had died in a University doctor’s 'care – <a href="http://blogs.law.stanford.edu/lawandbiosciences/2011/09/15/academic-health-centers-bare-knuckled-litigation-tactics/">to pay the University’s legal costs</a> of some $57,000.  The University used that threat as leverage to get Weiss to forgo an appeal of the trial court’s decision.</blockquote> So as the University continues to refuse any new consideration of this this seemingly never-ending case, Dr Elliott has posted an <a href="https://www.change.org/petitions/governor-mark-dayton-of-minnesota-investigate-psychiatric-research-misconduct-at-the-university-of-minnesota-2">online petition</a> calling for an outside investigation.   We will see how Mr Rotenberg reacts to this. Summary A very troubling aspect of this case is that it has shown that the university leadership has seemed to care, at best, more about fending off litigation than upholding the university's mission.  The mission of the university is supposed to be discovering and disseminating the truth in a spirit of free inquiry.  Added to the mission of medical schools and university teaching hospitals is taking good care of patients, and putting the patients' interests ahead of all other concerns.  Yet, in this case, university leaders have not seemed to care whether in their haste to push back legal liability they were stepping on their faculty's academic freedom and free speech, the integrity of the medical research done at the university, and most importantly the rights of their patients and research subjects.  Furthermore, it is not clear whether they mainly feared the impact of litigation on the university, or how litigation might actually end up holding them accountable. As Dr Judy Stone <a href="http://blogs.scientificamerican.com/molecules-to-medicine/2013/03/12/a-clinical-trial-and-suicide-leave-many-questions-part-5-the-case-of-the-mysteriously-appearing-documents/">wrote</a> in her Scientific American blog, <blockquote class="tr_bq">  it appears that UMN believes, as do many other institutions, that protecting itself from scandal and its consequences comes first and foremost and that, like the big banks, that it is too big to be punished.</blockquote> Again, note that UMN cannot itself believe or protect.  People acting ostensibly on its behalf may have been protecting themselves from scandal, and believing that the size and status of their institution gave them, the leaders, impunity. The case of Mr Dan Markingson is a continuing reminder that to reform health care, health care organizations need to be lead by people who put the health care mission first and are willing to be accountable for that mission.   I hope that eventually there is an honest investigation of this case, and a commitment to reform based on its conclusions. See additional thoughts from Dr Howard Brody <a href="http://brodyhooked.blogspot.com/2013/03/latest-on-markingson-case-at-u-minn.html">on the Hooked: Ethics, Medicine and Pharma blog</a>, on the <a href="http://1boringoldman.com/index.php/2013/03/13/intrinsically-flawed-and-dangerous/">1BoringOldMan blog</a>, <a href="http://ptable.blogspot.com/2013/03/online-petition-requesting-governor.html">on the Periodic Table blog</a>, and last but certainly not least, many comments by Dr Carl Elliott on the <a href="http://loathingbioethics.blogspot.com/">Fear and Loathing in Bioethics blog.  </a>

Minimizing Legal Liability or Upholding the Mission? - the Markingson Case Redux

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15 Mar 2013

Nemeroff, Seroquel, and ACCME

Nemeroff, Seroquel, and ACCME Roy Poses has <a href="http://hcrenewal.blogspot.com/2009/10/more-on-misleading-promotion-of.html">discussed</a> the atypical antipsychotic drug Seroquel (quetiapine) several times on this site, pointing out manipulation of clinical research results to enhance the appearance of efficacy, and suppression of studies with unfavorable results. I call this augmenting the marketed profile of the drug. Daniel Carlat has commented on published Seroquel data <a href="http://carlatpsychiatry.blogspot.com/2009/06/geodon-ineffective-for-bipolar.html">here</a> and ClinPsych <a href="http://clinpsyc.blogspot.com/search?q=Seroquel">here</a>. AstraZeneca, the marketer of Seroquel, has also been busy with continuing medical education (CME) programs that augment Seroquel’s profile. Last December 8, one such program went on line, aired by the provider CME Outfitters. The program’s title was “Atypical Antipsychotics in Major Depressive Disorder: When Current Treatments Are Not Enough.” The corporate logo for CME Outfitters is Education with Integrity. I will allow readers to decide if the company is meeting its mission statement in this respect. The key opinion leader engaged by CME Outfitters to discuss Seroquel and other atypical antipsychotic drugs was Charles Nemeroff of Emory University. He was joined by 2 KOLs-in-training, whom I will not name. The corporate sponsor that paid CME Outfitters and, indirectly, these presenters was AstraZeneca. I do not need to rehearse here the ethical issues that have surrounded Dr. Nemeroff for the past several years. Suffice it to say that, as a result of those issues, Dr. Nemeroff is no longer chair of the department of psychiatry at Emory University, he is no longer editor-in-chief of the ACNP journal Neuropsychopharmacology, he was removed from involvement with ongoing federally funded research grants at Emory University, and he was put on a short leash by the Emory administration. On December 23, 2008 I filed a formal complaint about Dr. Nemeroff’s program with ACCME. My bill of particulars was lengthy, detailed, and backed up by extensive materials. In due course, ACCME investigated the complaint and found that the program did violate ACCME standards. With respect to content, ACCME determined that Dr. Nemeroff’s program lacked sufficient information about possible adverse effects of treatment with atypical antipsychotic drugs; and failed to emphasize sufficiently the efficacy of alternative treatments. With respect to commercial bias, ACCME determined that bias existed as a result of the absence of contrasting therapy data, and through downplaying the drawbacks related to treatment with atypical antipsychotic drugs in depressed patients. Following these findings by ACCME, the provider was notified of the violations in early September 2009, and the program was removed from the provider’s website. The sanitized statement of violations determined by ACCME does not capture the nuances of deceit, ineptitude, and deficient educational content in Dr. Nemeroff’s program. One remarkable example was Dr. Nemeroff’s citation of data, from one of his own publications, that were previously retracted. Did he think no one would notice? A second example involved biased presentation of the sponsor’s data for Seroquel. Two doses of Seroquel (150 mg and 300 mg) were tested. Only the results for the 300 mg dose were statistically significant. Nevertheless, in the video presentation one of the junior presenters stated very clearly that there was “significant improvement in both response and remission with both doses” of Seroquel. That is a falsification of the scientific record. That falsification does not meet ACCME requirements for fair, balanced, truthful, and honest teaching. As moderator, Dr. Nemeroff was required to correct this false statement made by his junior assistant, but Dr. Nemeroff failed to do so. The negative findings and sanction by ACCME against Dr. Nemeroff’s program are welcome, though I have to say it took ACCME an inordinately long time to complete their work. I also presented ACCME with several follow-on questions, which the Council is now considering. These are: • Did ACCME notify the presenters that their program violated ACCME policies? If not, why not? • Will CME credits be clawed back from physicians and other professionals who obtained credits through the noncompliant program? If not, why not? I believe this would be an effective form of negative feedback to the provider and the presenters. • Does ACCME have a process to require the provider and presenters to ascertain whether any patients were injured as a result of the violations that created biased and deficient information in this program? If not, why not? • Does ACCME require the provider to notify physicians and other professionals who completed the noncompliant program that the provider was sanctioned for violation of ACCME standards? If not, why not? • Does ACCME require the provider to furnish corrective materials to such professionals in order to remedy the bias and incompetence to which they were subjected through violation of ACCME standards, and thereby to remove potential danger to future patients? If not, why not? • Why did ACCME allow the noncompliant program to remain available long after the complaint was filed? I suggest that ACCME needs to place a hold on programs that are subject to active complaint. Had such a policy been in effect in December 2008, the violating program would not have been re-aired by the provider in early 2009, it would not have remained on-line for 9 months, and the damage to the continuing education community would have been contained. • Will ACCME issue a public listing of sanctions it has enforced against providers and presenters? If not, why not? State medical boards do exactly that in relation to physicians and other professionals who violate standards of practice. • Finally, I reminded ACCME that its primary constituents are patients, physicians and other professionals, not commercial or academic CME providers. It seems to me that ACCME was altogether too laissez-faire and dilatory in the way it handled this matter. At the time of my initial complaint last December, I requested expedited review precisely because additional airings of this violating program were scheduled. The good news is that ACCME seems to have got the message that things need to change. As one of their officers wrote to me recently, “We sincerely appreciate the time and effort you have put into participating in our complaints and inquiries process. You have raised important issues that the ACCME will review and address.” I await their next communications on the remaining questions. As for Dr. Nemeroff, he is yesterday’s news. The adverse findings by ACCME about his program serve as a reminder to corporate sponsors and CME companies that Dr. Nemeroff is so compromised by now that he has lost effectiveness as a front man for Pharma. Indeed, he is so toxic that he now glows in the dark.

Nemeroff, Seroquel, and ACCME

Nemeroff, Seroquel, and ACCMERoy Poses has discussed the atypical antipsychotic drug Seroquel (quetiapine) several times on this site, pointing out manipulation of clinical research results to enhance…

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11 Oct 2009