Wednesday, February 27, 2013

Thursday, February 14, 2013

New evidence of privacy violations in the CAFE study

Last week I posted a HIPAA form for Dan Markingson which the University of Minnesota had produced in response to a complaint by Mike Howard.  What was so puzzling about this HIPAA form was that it had never emerged  during the lawsuit by Mary Weiss, despite her charge that Markingson had not consented to the release of his health information to CAFÉ study sponsors.  In fact, when Stephen Olson was deposed, he was repeatedly questioned about HIPAA regulations (and was unable to give good answers.) At the time, the only relevant document found in Markingson’s medical records was an unsigned “consent for service” document from Fairview Hospital. But the new HIPAA form produced by the university contained a dated signature by Markingson. If the university had been in possession of a signed, dated HIPAA authorization form from Dan Markingson all along, why didn’t it produce that HIPAA form in the lawsuit?

Today the family of another CAFÉ study subject has allowed me to post the HIPAA authorization form found in the medical records of their family member. As you can see, this form appears to be the same form that was given to Mike Howard, and it appears to be specifically written for the CAFÉ study. But it has no signature. The absence of a signature suggests that the private health information of this subject may have been provided to the CAFÉ study sponsors (AstraZeneca and Quintiles) without the consent of the subject.

Another odd feature appears on both forms: a sentence that reads “This authorization does not have an expiration date.” Yet to be valid, all HIPAA authorization forms must specify an expiration date or event. Investigators cannot require subjects to release their health information in perpetuity.

What does this mean?  Well, at a minimum, a single unsigned form suggests a HIPAA violation, which is a felony.  Of course it is possible that, if pressured, the university could produce a signed HIPAA form for this subject. But so far it has not. Still, I would think that the presence of an unsigned form would at least be enough to warrant some hard questions – specifically, did the other subjects in the CAFÉ study authorize the release of their health information, or were their HIPAA forms left unsigned as well?

Perhaps the more alarming question relates to the absence of an expiration date.  That suggests a more systemic problem.  If the HIPAA forms for two subjects in the CAFÉ study contain the sentence “This authorization does not have an expiration date,” it seems likely that all of the HIPAA forms did.  And if that is true, then I would think there is a case to be made that the privacy rights of all 17 of the CAFÉ study subjects were violated. I am not a lawyer, nor am I an expert on HIPAA. But my sense is that these forms would probably prove very difficult for the university to justify in court.

Wednesday, February 13, 2013

Has the Department of Psychiatry been faking research subject records? New evidence comes to light.

Two weeks ago, I posted about a curiosity in the medical file of Dan Markingson.  University officials have repeatedly argued that Markingson was fully competent to give his informed consent to the study, pointing to an “evaluation to consent” form located in his chart.  According to this form, which was signed and initialed by Jean Kenney, Markingson had given rational, informed answers to all of the questions he had been asked before he gave informed consent.  The curiosity was that Markingson’s file actually contained two slightly different versions of the same form (here and here.)  I asked readers to help me figure out what could account for the differences.

This request produced a startling response. Within hours, several people had posted on Facebook and written by email to say that the charts of their family members contained exactly the same “evaluation to consent” form.  Today, one family has agreed to let me post the form that was given to them by the Department of Psychiatry. 

In most ways, this form looks identical to one of the forms that allegedly came from Dan Markingson.  The signature of the study coordinator, Jean Kenney appears identical; the signature of the witness, Elizabeth Lemke, appears identical; and the rubbed-out marks located at the top of two of the documents appear identical.  Most alarming of all, the “answers” supposedly given by the research subjects appear identical.  But the new form has no date, no subject ID, no subject initials, and no mention of Unit 12, the ward in Fairview Hospital where Dan Markingson was hospitalized.

At the risk of provoking a legal action against me by my employer, let me speculate about what this could mean.  Judging from this admittedly circumstantial evidence, it appears as if someone in the Department of Psychiatry may have been using a generic, photocopied form with pre-determined answers as documentation that mentally ill research subjects were competent to consent to research studies.  Such forms would have been particularly important for the CAFÉ study, because they would have allowed the enrollment of acutely psychotic subjects without getting proxy consent from their family members.  For example, Dan Markingson was enrolled in the CAFÉ study over the objections of his mother, Mary Weiss.

It is worth pointing out that these “evaluation to consent” forms have been submitted to official research oversight bodies, which have relied on them to make judgments about the conduct of the studies.  For example, in a March 2004 letter to the University of Minnesota IRB, Dr. Stephen Olson wrote that Dan Markingson had been given an “evaluation to consent” and had answered all the questions satisfactorily.  Also, when the FDA investigated Markingson’s suicide in 2005, it cited the “evaluation to consent” form as evidence of Markingson’s competence (see page 9.)  Submission of false evidence to the FDA can lead to disqualification as a clinical investigator.

I want to be cautious here.  I have only seen three of these “evaluation to consent” forms: this one, and the two that appeared in the file of Dan Markingson.  And although I have no reason to doubt that the families of other research subjects have found the same forms, I have not seen those forms for myself.  That said, I find these documents so alarming that they demand an investigation. How many research subjects in the Department of Psychiatry have this same form in their charts?  Were any of those subjects in studies subject to federal oversight, such as the CATIE study? Did any of those subjects suffer serious injuries or death?

Tuesday, February 12, 2013

"Respect for person, beneficence and -- mental block": a conversation with the head of research subject protection at the University of Minnesota

From the deposition of Richard Bianco in 2007, when he was the institutional official responsible for research subject protection at the University of Minnesota.

Q. Are you aware of any physician at the University of Minnesota who has ever, in any of the research studies you're aware of, attempted to commit a patient and a few days after that sign them into a research study?

A. I'm not personally aware of that.

Q. Okay. Are you aware of the Belmont report?

A. Yes.

Q. Are you aware of any statements in the Belmont report with regard to importance of having independent assessments of the ability of patients to give informed consent?

A. No.

Q, Are you aware of the Declaration of Helsinki?

A. Yes.

Q. What do you know about it? Can you tell me a little bit about what you know about that?

A. It is one of -- it's a document, I don't remember when it came out, but it provides guidance, in the author's opinion, on how IRBs should relate to certain types of situations. It's basically a statement of ethical principles, similar to the Belmont but a little more detailed.

Q. Who's the author of the Declaration of Helsinki?

A. I think it's a group. I don't know.

Q.  Do you know which group?

A. No.

Q. And you don't know when that was adopted.

A. It's been around a while, but I don't know the dates, no.

Q. Do you have any idea at all?

A. Within the last 20 years.

Q. How about the Belmont report? Who drafted the Belmont report?

A. Well, I met one of the authors, and I can't remember his name, but again, It was another group of ethicists that met and developed some basic principles.

Q. What are the basic principles in the Belmont report?

A. Respect for person, beneficence and-- mental block.  Well, the third one escapes me right this second. Basically, it's a set of principles. Common sense principles.

Q. When was the Belmont report adopted?

A. I believe 15 or so years ago.

Q. Have you ever heard of the Nuremberg Code?

A. Uh-huh. Yes. I'm sorry.

Q. When was that adopted?

A. I don't know.

Q. Do you have any idea at all?

A. No. Sometime after World War II, I would assume.

Q. What does the Nuremberg Code say?

A. Frankly, I'm not that familiar with the Nuremberg Code.

Q. Okay. Have you ever had any training in the ethics of human subjects, experimentation?

A. Yes.

Q. What kind of training have you had?

A. Well, it's continuous training. I served on the IRB for 15 years or so, and some of that as a vice chair. I am very active in the Public Responsibility of Medicine and Research Organization, which is continuous education and those sorts of things. So did I attend a specific class? No. But I'm very involved and with PRMR and other organizations.

Q. Have you had any training in ethics, bioethics?

A. Formal?

Q. Yes, sir.

A. No.

Q. Can you tell me some of the major philosophical schools and thoughts, schools of thought with regard to bioethics?

A. Arthur Caplan school and there's the Jeff Khan school.

Friday, February 8, 2013

A make-believe investigation at the University of Minnesota

From the day that questions first began emerging about the suicide of Dan Markingson, the University of Minnesota’s General Counsel, Mark Rotenberg, has insisted that the university has already investigated the case. Most recently, in a public statement to City Pages, Rotenberg claimed that the university's Institutional Review Board (among other bodies) investigated the case and found no fault with the university, no fault with the researchers, and no “causal link between the CAFE trial and the death of Mr. Markingson." Local reporters have simply taken Rotenberg’s claim at face value, yet I have never been able to find any evidence that the Institutional Review Board did in fact investigate.

If you look at a deposition in the lawsuit brought against the university, you will see testimony that directly contradicts Rotenberg’s account. According to Richard Bianco, the official then responsible for overseeing research subject protection at the university, neither the IRB nor any other university body has investigated Markingson’s death.

What follows is an exchange between Bianco and Chris Barden, an attorney representing Mary Weiss.  (It begins on page 41 of the deposition.)

Q: Has the IRB done any investigation into the death of Dan Markingson?

A: Not a formal investigation, no.

Q: Has the university done any investigation into the death of Dan Markingson?

A: No.

And later:

Q: To the best of your knowledge, did anyone at the IRB, at the University of Minnesota, or anyone under your office investigate this case, actually look at the records and see the court documents that I’m describing, and if so, could you give me the name of that person?

A: Not to my knowledge.

Q: Nobody did that.

A: No.

Both of these accounts cannot be correct.  One University of Minnesota official is not telling the truth.  My guess is that no investigation was done.  But if Rotenberg is right and the university did investigate, why has that investigation never been made public?

Thursday, February 7, 2013

The deepening mystery over Seroquel Study 41 and Charles Schulz

The mystery over AstraZeneca’s notorious Study 41 has deepened.

Study 41, if you recall, was one of the contested studies of Seroquel that emerged in litigation against AstraZeneca.  Internal emails and documents suggested that the study was buried and the results spun, and that Charles Schulz appeared to be involved.  Here is what I wrote about the study last month for the Mad in America blog:

“Later, in a trial known as Study 41, AstraZeneca compared Seroquel XR – the extended release version of Seroquel – to placebo in patients experiencing acute schizophrenia. The University of Minnesota was one of the study sites, and Charles Schulz was the site investigator. Remarkably, Study 41 showed Seroquel XR performing no better than placebo for schizophrenia.  In emails, AstraZeneca officials refer to Study 41 as a “failed study,” or “code red.” Advisors (such as Schulz) and employees were instructed not to discuss the study. So what did AstraZeneca do? They buried it and tried it again, this time in India, Bulgaria, Romania, the Philippines, Russia, Greece and South Africa. That trial was called Study 132, and it turned out positively. So in 2007 AstraZeneca published that study in the Journal of Clinical Psychiatry. The second author of that study was Charles Schulz, who presented the data at the annual meeting of the American Psychiatric Association and served as the academic point man in company press releases.”

Mike Howard filed a complaint with the university about Schulz’s involvement in Study 41, pointing not only to the hiding of research results but to the fact that the study randomized some acutely psychotic patients to placebos, effectively depriving them of treatment for the duration of the study.  The response  to Howard came from Mark Rotenberg, the General Counsel, who wrote, “Dr. Schulz did not participate in Study 41, because no subjects were enrolled at the University.”

Rotenberg’s statement that Schulz was not involved appears to be at odds with the published study itself, which appeared in Psychopharmacology Bulletin in 2008.  In that journal article, Schulz is listed as a Study 41 investigator.  In fact, the published article has another surprise: Steven Olson is also listed as an investigator for Study 41.  Olson, of course, was the University of Minnesota principal investigator for the CAFÉ study in which Dan Markingson died.

This news raises a number of intriguing questions.  Did Study 41 actually take place at the University of Minnesota?  Was the protocol approved by the IRB?  Did Schulz and Olson each sign a Form 1572 for the FDA?  And why would Rotenberg claim that Schulz did not participate in the study when the published literature indicates that he did?

Wednesday, February 6, 2013

What the Sunshine Act really means

Alice Dreger explains.

Another day, another plagiarized dissertation

"Germany's education minister has been stripped of her doctorate after a committee of academics concluded that she plagiarised substantial parts of her 1980 thesis, which dealt with the formation of conscience." Read about it here.

Sunday, February 3, 2013

"Unethical clinical trial" by Minneapolis police?

"A half-dozen Minnesotans have sued the state and numerous law enforcement agencies, claiming that they were used as 'guinea pigs' when officers supplied them with drugs as part of a controversial police training program."  The story is in the Strib.

Saturday, February 2, 2013

How many deaths and injuries were there in the CAFE study?

On May 6, 2004, two days before Dan Markingson committed suicide in the CAFE study at the University of Minnesota, there was another "Serious Adverse Event" in the study.  Here is the letter Steven Olson sent to the IRB, along with the reply.

Friday, February 1, 2013

Crowdsourcing the Markingson mystery, part 2: the picture becomes clearer

Within hours of my posting two mysterious, almost identical “evaluation to consent” forms from the lawsuit involving Dan Markingson, a number of people came forward with an astonishing statement: they too appear to have the identical “evaluation to consent” forms in their files, with the identical answers filled in.  You can see some of their comments on the Facebook page, Community Alliance for Ethics in Minnesota Psychiatry.  (And you don’t need to have a Facebook account to see the page.)

Before I speculate about the consequences of this revelation, let me fill in the story with some background information.

After Dan Markingson killed himself in the CAFÉ study on May 8, 2004, Steven Olson, the site investigator, filed a Serious Adverse Event report with the University of Minnesota Institutional Review Board (IRB).  (This is standard practice; it is done whenever a subject dies or is seriously injured in a study, regardless of the cause.)  On May 13, 2004, the IRB wrote back to Olson  and asked for more information.   Specifically, the IRB wanted to know:  “Was this subject considered competent to provide consent?  How was consent obtained?”  It was in response to this letter that Olson replied.   Olson told the IRB that yes, the subject was fully competent to consent, and as evidence, he submitted the “evaluation to consent” form.

Why is this form important?  Well, it is important because in the weeks leading up to his enrollment in the CAFÉ study, Dan Markingson had repeatedly been judged incompetent to consent to medical treatment.   Every clinician who had seen him, including Olson, had decided that his thinking was so disordered that he could not fully understand and appreciate information well enough to make an informed choice about his medical care.  Ordinarily, this would mean that Dan could not be enrolled in the CAFÉ study without the authorization of a surrogate decision-maker.  That decision-maker should have been his mother, Mary Weiss.  But Mary Weiss had made it clear that she was opposed to Dan’s enrollment in the CAFÉ study.  So to get Dan into the study, Olson needed to show that Dan was competent.  The “evaluation to consent” form was intended to demonstrate that Dan was, in fact, thinking clearly enough to understand the risks and benefits of the CAFÉ study, and thus fully competent to consent.   (I have written more about this here.  I should also point out that this "evaluation to consent" is very poorly constructed and not at all an adequate gauge of competence to consent.)

This morning, Mike Howard pointed out to me that there was not just a single “evaluation to consent” form in Dan’s medical records, but rather two of them, and that the two versions appeared to be slightly different in odd ways.  I posted the two forms this morning, and right away, the family members of other research subjects in the Department of Psychiatry recognized the forms.  Which raises a disturbing question: what could possibly explain the presence of identical forms in the charts of different subjects?

I don’t want to make any accusations, especially without seeing the documents firsthand.  But if someone in the Department of Psychiatry were using a photocopied form with identical, pre-determined answers as evidence that mentally ill research subjects were competent to consent to research, it would be a very serious matter.  Ordinarily, I would think that it would merit an investigation into the protection of human subjects at the university.  Unfortunately, however, there does not seem to be anyone at the University of Minnesota willing to look into such complaints.  

Crowdsourcing a mystery from the Markingson case

Here's a mystery from the case of Dan Markingson. Yesterday I posted some correspondence between Steven Olson and the University of Minnesota's IRB about Dan Markingson's "evaluation to consent" to the CAFE study.  Well, it turns out that there are actually two different versions of that "evaluation to consent." 

In one version, a space at the top labelled "subject initials" has no initials, only a large black mark.  At the bottom right-hand corner of this uninitialed form is the phrase "IRB."

In the other version, the space labelled "subject initials" has a different black mark with the initials "DRM" above it. At the bottom right-hand corner of that form is written the phrase "psy." 

So the mystery is: why would there be two versions of the same form? What is under the blacked-out spot on each form, and why are those spots slightly different? Why does one version have the initials of Dan Markingson while the other one does not?

Any ideas out there? 

Here are links to the two forms: