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A Clinical Trial and Suicide Leave Many Questions: Part 3: Conflict of Interest


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Dan Markingson and mom, Mary Weiss

We’ve touched on some of the many disturbing things that happened during the clinical trial on which Dan Markingson committed suicide. In my first post, I asked how a psychotic, homicidal patient who was involuntarily hospitalized in a psychiatric hospital could give an informed consent for participation in a clinical trial. There appeared to have been abuse of a vulnerable patient and extraordinary coercion—participate in this trial or be committed to a psych hospital seems to have been the bottom line.

In my second post, we looked at investigator responsibilities, delegation of authority, and Good Clinical Practice tenets, all of which were violated with no consequences.

Now we turn to the need to disclose conflicts of interest (COI), again a basic clinical research ethics principle that was violated. There are so many obvious conflicts of interest that it is hard to know quite where to start.

Physicians

The most obvious and egregious COI was that shown by Dr. Stephen Olson, who acted as both Dan Markingson’s treating physician and as Principle Investigator on the CAFÉ study. As Dr. Harrison Pope, a Harvard expert, concluded in his testimony, Olson “failed to meet the standards for good clinical practice both as a principal investigator and as the study physician for Mr. Markingson.” He failed his ethical responsibilities to Dan by:

—Enrolling him in a clinical trial he was incapable of consenting to, particularly over the objections of Dan’s mother, Mary Weiss.

— Not dropping Dan from the protocol when Dan was clearly not showing improvement.

Not examining Dan closely and regularly. “Dr. Olson’s signature appears only twice throughout all of the study documents” from 12/8/2003 until his death 5/8/2004. (p 30, Pope testimony). According to Ms. Weiss, Dan had told her “that Dr. Olson would, at most, ‘stick his head in occasionally at study visits. The medical records confirm that impression.’” Olson likely would have had to examine Dan more frequently if he were not on a study, as he would not have had the additional staffing funded by the study to have a surrogate see his patients.

—Improperly acting as both Markingson’s study physician and treating physician

The conflict between Dr. Olson’s roles as Dan’s personal physician and as researcher is further detailed by Dr. Pope. For example, it likely kept Dan from getting a second opinion and from getting additional medications. The protocol also prohibited Olson from measuring blood levels of the anti-psychotic, which would have shown if he were being compliant in taking his meds.

Olson reportedly mislead the IRB, leading them to believe that Markingson’s enrollment had been agreed to by his case manager, when he hadn’t yet been seen by Mr. Pettit. He also failed to inform them of information about Dan’s inability to consent and that the judge had granted a stay of commitment for Dan if he followed recommendations.

The NIH website summarizes the problem succinctly: “If an investigator is also the personal health provider of the potential research participant, there may be an additional conflict of interest. A physician’s duty is to honor the best interests of the patient. An investigator must do what is best for the study. These two objectives are not always consonant. Further, potential participants may be reluctant to question the advice of a health provider on whom they depend for care.”

Olson’s involvement, and that of the department chairman and coinvestigator, Dr. Charles Schulz, appear to have been significantly driven by financial interests, though they had other incentives, too, such as increased prestige and publications.

Financial Conflicts of Interest

Sweetheart deal

There were major financial incentives for both Drs. Olson and Schulz, as well as for the university.

Dan Markingson—aka Subject 13—was worth over $15,000 to the university, had he completed the study. The CAFÉ study not only yielded $327,000, but helped generate more attention (and probably more trials) for the university’s schizophrenia program.

This particular study was structured so that patients had to complete the trial in order for the full payment to be received by the institution. Thus, dropping the patient because the study drug was ineffective, or adding additional medications, was prohibited and would have resulted in significant financial penalties—and this was not explained in the “informed consent.” Because the study period was one year, Olson had to keep Markingson on the trial to get the full payment; I suspect this contributed to his recommendation that Dan’s stay of commitment be extended to keep Dan a captive participant.

Dan was far more valuable to the University and psychiatrists as a study patient than as a regular psychiatric inpatient. As Dr. Pope noted, above, ancillary personnel could do many of the assessments. And Dan was destitute, so any care they provided him outside of the study would have had minimal reimbursement—we often didn’t feel that the payments from Medical Assistance even covered the cost of billing, let alone the medical care provided. (Note: not all of the grant money goes to the investigator. Much of it then has to be disbursed to the university for direct costs and for their administrative overhead charge, often 50% of the total grant. Physicians are also expected to generate monies to cover much of their salaries.)

According to the Pioneer Press in 2008, “Olson received $220,000 from six companies since 2002, including $149,000 from AstraZeneca, according to the state records. Schulz received $562,000, including $112,000 as a researcher and consultant to AstraZeneca.

Yet these significant COIs were not disclosed to study participants. When Dr. Schulz replied to anguished Ms. Weiss’ 3rd letter (her first two went unanswered), he did not disclose that he was a principal investigator, nor did he forward her serious concerns to the IRB.

I was shocked to read Dr. Schulz’s testimony that he hadn’t even read the consent form for a study in which he was a co-investigator (and was listed on the FDA Form 1572 as being a responsible party). (p 156 Schulz deposition).

Nor was Schulz, a leading schizophrenia researcher, aware that informed consent requires disclosure of financial COIs:

“At another point, plaintiff attorney “Barden read an excerpt from a bioethics book arguing for the importance of informing patients about a doctor’s financial ties to drug companies.

“Do you agree or disagree with that statement?” asked Barden.

“I don’t agree with that statement,” replied Schulz, arguing that disclosing this information could “confuse” the situation.

“Have you had any training in biomedical ethics?” pressed Barden.

“I’ve taken the courses at the University of Minnesota that are required for us to participate in clinical research.”

“And isn’t this part of that training?”

“I’m not aware,” said Schulz. “I don’t recall that.”

CROs

Contract research organizations (CROs) are intermediaries hired by a sponsor (generally pharmaceutical) to administer a clinical trial. This used to be done by the pharma company itself. As business has gotten more competitive, they generally farm that work out now, to avoid having to have their own staff. Quintiles, responsible for the CAFÉ study, is the largest CRO, capturing 14 percent of the lucrative $11.4 billion global market.

CROs put a lot of pressure on sites to enroll. Delays in completing the approval of a new drug cost from $684,931 to $1 million per day and slow recruitment is the major factor. So they try to motivate their sites to enroll patients, sometimes with encouragement (holding them up as examples to other sites or similar recognition) or promises of further studies, sometimes by threats of having the trial taken away. They employed both tactics to manipulate the study coordinator, Jeanne Kenney, illustrated by their e-mails here and here.

While CROs can often provide helpful tips from their experience doing trials, I was flabbergasted to read, “In the CAFÉ study, for instance, a Quintiles study monitor suggested that each of the CAFÉ study site coordinators try recruiting subjects at homeless shelters.” This is so coercive and unethical, it almost defies belief. . .but the longer I am in this field (and in medicine), the more disillusioned I have become. I should no longer be surprised by anything, I’m afraid.

University

It’s not just individual researchers who benefit from industry-sponsored research. The entire university feeds happily at the trough. At University of Minnesota alone, “In fiscal 2010, business and industry sponsored $35.4 million in research spending at the U — 5.4 percent of total research expenditures of $653.6 million.

And between 2002-8, drug companies gave “$88 million in gifts, grants and fees to Minnesota doctors and caregivers,” including $782,000 just to the University’s two psychiatrists.

The CAFÉ study initially suffered from poor enrollment—so much so that Quintiles, the CRO administering the study, had placed the site on probation and threatened to terminate it.

One Flew Over the Cuckoo's Nest

So the university established a 16 bed specialty psychosis unit at Fairview hospital, known as “Station 12,”  “in part to enhance the hospital’s startup schizophrenia program and meet the U’s mandate to bring in more research dollars.” According to a CAFÉ Study Coordinator Teleconference, on this unit “All patients are reviewed for possible research candidacy.  Research staff are in contact with nurses, case managers, and attending psychiatrists daily   Research staff attend morning report before inpatient rounds take place.  The focus is to identify any possible subjects that may be eligible for studies. This is also focused on building a repertoire [sic] with psychiatry residents, who are often much easier to approach than attendings.”

So we have a University department chairman demonstrating leadership by being unaware of basic research tenets and by saying that disclosure of financial COIs would just cause “confusion.” What an exemplary role model.

Of course, there are other COIs and pressures as well, in that successful enrollment begets publication, more fame, and more research grants from other sponsors as well. It also seems to bring considerable protection from those in power at the university.

IRB

The IRB holds a fair measure of blame in this tragedy, as well, though they have admitted no wrongdoing. The IRB is paid by the study to review the protocol and consent and, in theory, to provide oversight.

IRBs have had their own share of bad press. For example, the Johns Hopkins’ IRB received scathing criticism for failures of oversight in an asthma study that led to the death of a healthy volunteer, Ellen Roche. The Office for Human Research Protections (OHRP) temporarily suspended all federally funded research involving human subjects at Hopkins.

Even back in 1996, alarms were raised by the GAO that the workloads of IRBs were too heavy and precluded thorough review. The load on IRBs is well described in Trials and Tribulations.

Funding for IRBs comes from the study sponsors—in this case, AstraZeneca likely paid the U. Minnesota IRB fee. And while the fees are thousands of dollars, the workload of most IRBs results in just minutes spent on each protocol. (Note, individual members of a committee are not paid for their reviews. The funding goes to the institution for administrative overhead).

There are also nonfinancial ethical conflicts of interest involving IRBs. These may be due either to excessive personal involvement or prejudgment by the experts on the board, or increasingly, from competition between the PI and IRB members.

Academic institutions have an incentive to approve studies, so that they can tout that it is providing “state-of-the-art” medical care and that it has been selected as a research site over its competitors by a leading pharmaceutical company.

But IRBs have certain responsibilities. As noted even on the U Minnesota website, “The IRB reviews research projects which involve human subjects to ensure that two broad standards are upheld: first, that subjects are not placed at undue risk; second, that they give uncoerced, informed consent to their participation. The IRB works with investigators to modify projects to ensure adequate protection for its subjects’ welfare and right of self-determination. The University’s process for protecting human research subjects reflects federal regulations developed in response to such cases as the Public Health Service syphilis study and the U.S. government radiation experiments.”

Yet Moira Keane, the director of the IRB (and now a Board member for PRIM&R), responsible for overseeing the CAFÉ study, was asked in her deposition, “So it’s not the Institutional Review Board’s purpose to protect clinical trial subjects, is that what you’re saying?”

And she replied, “Yes.”

Conclusion

In the Markingson case, there are apparent conflicts of interest on multiple levels. The investigators had significant financial incentives to enroll patients—and to not alter therapy, even if a patient was not responding to therapy. Shockingly, the investigators claimed ignorance of basic ethical principles, including informing potential subjects of financial conflicts of interest.

They all claimed shocking levels of ignorance about basic research ethics, although holding positions of responsibility and authority. And, at each level, they absolved each other of any responsibility for this young man’s death.

With failures at multiple levels of supposed safeguards, and knowing that some of the same staff provided the assessments and care for patients on the AstraZeneca study as on a major NIH trial, the CATIE study, it seems essential that OHRP and an independent review examine not only the CAFÉ study, but take a careful look to see if similar breaches tainted the NIH trials.

Who will step up?

[I will continue this series in early January, looking a bit at the NIH and CATIE concerns and the University's troublesome response to this case. As Matt Lamkin just noted, "It can be difficult to keep up with the research scandals at Minnesota’s Psychiatry Department over the years," so we still have lots of questions to bring up.]

Suggested Readings:

Carl Elliott, A referenced summary of the Dan Markingson case

Jill A. Fisher, “Ready-to-Recruit” or “Ready-to-Consent” Populations?: Informed Consent and the Limits of Subject Autonomy

Jeremy Olson and Paul Tosto, Critics say drug firms’ payments to doctors are conflict of interest

William Heisel, The Markingson Files: Can pressure to recruit patients subvert a clinical trial?

Credits:

Dan Markingson photo courtesy Mary Weiss

Origami dollar heart -Thomas Hawk/Flickr

One Flew Over the Cuckoo’s Nest – Portland Center Stage

Molecules to Medicine banner © Michelle Banks

Judy Stone About the Author: Judy Stone, MD is an infectious disease specialist, experienced in conducting clinical research. She is the author of Conducting Clinical Research, the essential guide to the topic. She survived 25 years in solo practice in rural Cumberland, Maryland, and is now broadening her horizons. She particularly loves writing about ethical issues, and tilting at windmills in her advocacy for social justice. As part of her overall desire to save the world when she grows up, she has become especially interested in neglected tropical diseases. When not slaving over hot patients, she can be found playing with photography, friends’ dogs, or in her garden. Follow on Twitter @drjudystone or on her website. Follow on Twitter @drjudystone.

The views expressed are those of the author and are not necessarily those of Scientific American.





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  1. 1. kienhua68 6:17 pm 12/18/2012

    If this individual was not capable of living in society, why is it so unfair that they should be in a clinical trial that may offer future benefit? I think we sometimes become so involved with the human condition as to actually hamper the progress of improvement. Then there are the sue happy
    folks who really are more concerned with reaping cash than
    caring about who the victim actually is or the outcome of that individual.
    Odd how we have soldiers killing themselves daily and we accept that even if we disagree about war. But let someone who is no longer viable commit suicide? Oh my goodness that certainly calls for all out attention.

    You really have to wonder…………..

    Ethics? Really?

    Link to this
  2. 2. jgrosay 6:40 pm 12/18/2012

    Clinical trial’s (CTs) entry criteria are sharply defined in the research protocol, and protocols, including informed consent forms, need to be approved by several regulatory bodies before the trial starts enrolling patients, so responsibilities in deaths of patients in the CT, if they were any reponsibility, may be shared between many. A CT on an antidepressant was closed when the experimental group had several suicide attempts, even when the difference to the standard group was not statistically significant, and a psychotic patient lost a court demand, he had stopped taking his medication, his madness came back, and thinking his hand was possesed by a devil, he cutted it with a tool. When arriving to the emergency room, the orthopedic surgeon offered the patient to re-implant the hand. The patient refused, and the extremity was lost forever. When he re-started taking his medication, he realized what he did, and blamed the surgeon, thinking that the doctor should have noticed that nobody sane would have rejected the procedure, and that it was the doctor’s fault to have missed he had a mental disorder, and not treating him in accordance. As said, the patient lost this case, but it can lead to hundreds of pages and hours of discussions. Do surgeons or emergency rooms have an obligation of assessing all diseases the patient may suffer besides the surgically treatable one, and should every case of non-reasonable refusal of therapy, like the one of the man that lost his hand, be assesed by psychiatrists and legal advisors, to know the value of the patient’s decissions, and eventually obtain a fast court or judge’s order for a mandatory treatment? Not providing an adequate care on the patient’s request may be close to a cooperation or assitance in suicide, as withdrawing therapy may be that. Or not?

    Link to this
  3. 3. Judy Stone in reply to Judy Stone 6:45 pm 12/18/2012

    Any suicide is tragic. What is the problem here is the coercion, lack of consent, and shirking of basic responsibilities toward research volunteers shown by the university. Perhaps you should read the details. You seem to have missed important points.

    Link to this
  4. 4. Rocza 10:03 am 12/19/2012

    This really isn’t about “the weak culling themselves” (although implying such is poor form, to say the least), nor is it about soldiers and war – that’s a diversionary tactic trying to shift away from the problem here.

    The problem here is that there were numerous conflicts of interest in the care and treatment of a young man, which lead to tragic results. But this case highlights a serious problem that goes beyond Mr. Markingson: the validity of any data collected from this clinical trial. People are being prescribed Seroquel daily based on very flawed data collected from the CAFE trial, and the Markingson case gives us a window into all of the flaws that invalidate that data.

    The data was manipulated, the people involved in the study had numerous conflicts of interest that motivated them to deviate from good clinical practice, and the end result is a significant potential level of harm, not just to the human research subjects within the University of Minnesota system, but anyone who is prescribed Seroquel.

    And yes, it also indicates a much more serious and longterm problem at the University of Minnesota – this is the third major research scandal in their psychiatric department, and the third time the University has gone out of it’s way to protect that department. It’s clear that UMN, despite having some of the best ethicists in the country working for them, has absolutely no interest in following ethical guidelines for human subjects research, and that is deeply problematic in and of itself.

    Link to this
  5. 5. jmardell 6:26 pm 12/20/2012

    I have been following this series with interest, and further disclose that the author and I corresponded by email about some of the ideas presented here. As a teacher of Good Clinical Practice, I want to make a couple of observations about this installment:
    1. There is no US regulatory restriction against a treating physician also serving as an investigator. The NIH website says it *may* “represent a conflict of interest” (emphasis mine), but it is not absolute or automatic; nor is the NIH’s website the binding regulation of the land for industry-sponsored clinical research. Indeed, a compelling argument can be made that such a situation can be in the best interests of a study patient. For example, an exclusionary factor known by the patient’s own physician, but not readily available to a study investigator, could help to keep a patient out of a study that is not appropriate for that patient. While the specifics of the Markingson case indicate that his physician/investigator did not sort out this conflict well, we should not take this out to infer that in all cases a treating physician must not also be an investigator.
    2. The probable reason Dr Shulz was not aware of any informed consent requirement to disclose financial information to subjects is because it is not true. The NIH website says “investigators *should* be required to disclose…” (emphasis mine again), but the US Federal regulations for informed consent (21 CFR Part 50) and financial disclosure (Part 54) have no such requirement, and these are the regulations that governed the CAFE study, its sponsor and investigators. Some institutions are including this information in their consent materials, but it is not yet universally required. Given that this subject was unable to give meaningful consent anyway, the point is almost moot; however the subject’s next-of-kin probably would have found the information useful, had she been allowed to make decisions in her son’s behalf.

    There are a lot of things to find fault with in the Markingson/CAFE case, and this series has done a good job corralling some of these issues into the light. There is quite a bit not brought up here, such as failure of the sponsor to adequately design and monitor the study and bring this investigator and institution into compliance. When we think about this in the context of clinical research though, I caution that we don’t want to use too wide a brush. Society has determined that we want to be provided with safe and effective medicines. Therefore we need clinical research, and we have to address the conflicts and challenges that come with it.

    In my GCP classes at UC Santa Cruz, we review case studies of things that go wrong, like this one. After a quarter of this, sometimes students come to believe that the entire industry is nothing but scoundrels and thieves. Of course that is not true. For every Markingson/CAFE, there are thousands of people tirelessly working every day to make sure their studies are run safely. We learn how to keep airplanes in the air by studying the plane crashes; we learn how to run good clinical research by studying Markingson, and others. Thank you for providing us all with a learning opportunity.

    Jacquie Mardell
    UC Santa Cruz

    Link to this
  6. 6. Judy Stone in reply to Judy Stone 7:22 pm 12/20/2012

    Thank you for your thoughtful comments and corrections, Jacquie. All are greatly appreciated.
    I heartily agree with you that we need clinical trials and, in my text and in other posts, have tried to encourage more participation of both the public and physicians–as even on cancer trials, fewer than 5% of patients participate. I enjoyed helping to develop new antibiotics in my role as a PI and a number of patients were helped through these protocols.

    This is one case study we can all learn from. It is a disturbing example of how not to do a trial, particularly troubling because of the University’s response, which I will be discussing more in an upcoming post. We all make mistakes; it is important to be able to show that you have learned from them and grown. That appears to be missing here.

    Thank you again for your help in understanding this complex case.

    Link to this

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