When Drug Trials Go Horribly Wrong

December 6, 2010 9:38 AM

In 2004, Minnesota student Dan Markingson committed suicide while participating in a clinical drug trial for various mood disorders. Trial sponsors the University of Minnesota and AstraZeneca were cleared of blame by the FDA in 2005. Last week, a group of faculty members at the university wrote an open letter to the university's Board of Regents requesting further investigation due to "troubling questions" that remain unanswered and a concern over "conflicts of interest" in the Academic Health Center.
posted by modernnomad (21 comments total)

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Reminds me of the TGN1412 disaster. Makes me shudder just to think about it.
posted by kmz at 9:51 AM on December 6, 2010 [2 favorites]

He'd been given a directive warning that if he failed to continue in the trial, he would be put in a regional treatment center.

Somebody should be in jail for that.
posted by enn at 9:53 AM on December 6, 2010 [4 favorites]

This reminded me of a Law & Order episode which did air in 2004, but was apparently inspired by a string of suicides at NYU under similar circumstances.
posted by inturnaround at 10:03 AM on December 6, 2010

It is tragic, I agree. And while every piece of legistlation should be utilised to prevent this from happening again here, major pharmies still outsource their drug trials to places where the consequences of their misdeeds will not be so easily punishable by law.
posted by mooselini at 10:03 AM on December 6, 2010

It frankly surprises me that the Board of Regents wrote the letter 6 years after the fact. I don't say this because I think it's too late, just that this must have had a huge impact on people to be brought back 6 years later, apparently unprompted. Does anyone know if there's a reason they've put the letter out now? It sounded a bit like it could be a response to the fact that, 6 years down the line, nothing much seems to have changed within the university's system. I just wonder if they've been trying all these years behind the scenes and finally went with the open letter.

I fully support his mother, but I have to admit this quote struck a strange chord with me:

"... I want to work to make people understand the danger of what the pharmaceutical companies are attempting to do—indeed are doing—to infiltrate our lives with drugs for whatever may ail us on a particular Tuesday morning."

I don't want this statement to undermine what she is working for in terms of safer clinical trials, but if her son really was schizophrenic (another thing that's kind of vague in the links) he wasn't just suffering a 'Tuesday morning' ailment. I understand in this scenario he maybe should not have been in that trial, but if he truly was schizophrenic and suffering a clinical trial could have helped him immensely. Some drugs are really necessary for some people to lead a normal life.

We can't give a free pass to the drug companies when something like this happens, but neither does it mean we should dismiss drugs as nothing more than commercial inventions. I just worry she's toeing that line with this particular quote.
posted by six-or-six-thirty at 10:06 AM on December 6, 2010 [3 favorites]

The Mother Jones article about the case, which is based on actual medical and court records.
posted by sarahnade at 10:15 AM on December 6, 2010 [2 favorites]

He'd been given a directive warning that if he failed to continue in the trial, he would be put in a regional treatment center.

This is fucking nauseating. Any clinical trial worth fucking anything allows for a patient to bail out at any time for any reason, without any weird pressure to continue.
posted by Skot at 10:28 AM on December 6, 2010

"... I want to work to make people understand the danger of what the pharmaceutical companies are attempting to do—indeed are doing—to infiltrate our lives with drugs for whatever may ail us on a particular Tuesday morning."

I don't think she's referring to her son specifically, but rather to the fact that a drug with well-known fatal side-effects is being trialed to treat public speaking anxiety, among other conditions that should not warrant treatment by such a risky drug. It's a symptom of a much larger problem.

Honestly, it's a bit surprising (and refreshing) to see the Board of Regents address the issue so directly, especially given that it's likely to have a significant adverse impact on the university's funding and reputation.
posted by schmod at 10:32 AM on December 6, 2010

sarahnade: "The Mother Jones article about the case, which is based on actual medical and court records"

That article is a pretty good read:

But what if a research study is not really aimed at producing genuine scientific knowledge at all? The documents emerging in litigation suggest that pharmaceutical companies are designing, analyzing, and publishing trials primarily as a way of positioning their drugs in the marketplace. This raises a question unconsidered in any current code of research ethics. How much risk to human subjects is justified in a study whose principal aim is to "generate commercially attractive messages"? ...

Yet another problem with the CAFE study is its failure to compare Seroquel to any older antipsychotics. "It's quite a marketing exercise to put all patients in the CAFE study on atypical antipsychotics," says Dr. Glen Spielmans, an associate professor of psychology at Minnesota's Metropolitan State University. "It removes the older drugs from the discussion." One reason AstraZeneca may have done this, he suggests, is that Study 15 had already shown Seroquel to be inferior to the older antipsychotic, Haldol.

The bluntest assessment of the study came from Dr. David Healy, a senior psychiatrist at Cardiff University in Wales. Healy is a former consultant to AstraZeneca, among other pharmaceutical companies, and a prominent critic of the industry. "This is a non-study of the worst kind," he said. "It is designed not to pick up a difference between the three drugs. It looks like an entirely marketing-driven exercise."

If these experts are right, then the study in which Dan Markingson committed suicide was not simply a matter of inadequate informed consent, or financial conflicts of interest, or even failure to monitor a subject's care. The ethical breach was built into the study from the start. It is one thing to ask people to take risks for science, or the common good, or to help other people. It is another thing entirely to ask them to risk their lives for the marketing goals of AstraZeneca.

posted by Blazecock Pileon at 10:32 AM on December 6, 2010 [4 favorites]

It frankly surprises me that the Board of Regents wrote the letter 6 years after the fact.

Honestly, it's a bit surprising (and refreshing) to see the Board of Regents address the issue so directly

Am I missing something? The linked letter is described as being addressed to the Board of Regents, from various faculty members. The regents have not taken any action that I can find mentioned in the link.
posted by enn at 10:42 AM on December 6, 2010 [2 favorites]

Full quote: Over 70% of patients in the trial dropped out. But Dan was strongly dissuaded from doing so and remained in it for five months. He'd been given a directive warning that if he failed to continue in the trial, he would be put in a regional treatment center.

The dissuasion wasn't systemic in the clinical trial if 70% of patients bailed out. His psychiatrist and the local study director sound more at fault than AstraZeneca.

From the Mother Jones article: Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother's throat, but had not threatened to harm himself—was a legitimate target for recruitment.

Ouch -- even if this was not part of the study design, it seems like a pretty big fuckup to allow this guy into the trial.
posted by benzenedream at 10:43 AM on December 6, 2010

Yet another problem with the CAFE study is its failure to compare Seroquel to any older antipsychotics.

Unfortunately this is standard practice these days, as a lot of contemporary drugs are barely better than placebo after you consider their side-effects, let alone the conventional generics they hope to replace. Their benefit is, of course, that they're under patent. How do you think the pharmaceutical industry maintains its profit margins?
posted by mek at 10:44 AM on December 6, 2010

Sorry enn, you're right, it's the faculty not the board that wrote it. I don't know why I kept reading it wrong.

Thanks for the Mother Jones article, sarahnade. It helped clear some things up.

From the Pioneer Press: Weiss wasn't expecting a schizophrenia diagnosis. At Regions, her son responded well to a medication for bipolar disorder. The family has a history of that disorder as well.

In the interest of full disclosure I feel like I should mention that I am diagnosed bipolar, medicated, and much better now thank you. If I were not on drugs I would be dead. Hands-down. However, earlier in my life I was also misdiagnosed and put on a drug that I should not have been on. It did have very bad effects. So this story resonates pretty strongly to me on a variety of levels.

I am also deeply suspicious of most anything driven by commercial interests. The Mother Jones report is damning, as is the open letter from the faculty.

Another strange thing (from the Pioneer):
An autopsy showed no medication in Markingson's bloodstream, and a coroner's photo showed a sealed bottle of his medication. Had he been taking his drugs?
He was supposed to be on the AstraZeneca medication as they found out after the study blind was listed, the MJ article says. I feel like they should have to monitor these things somehow. If he had for whatever reason made it through this study fine without actually taking the medication, he would be an erroneous datapoint.

It sounds like things were not handled correctly on a variety of levels, even putting aside the fact that he was basically coerced into staying in the study. Help from someone outside the system didn't save him. I can't even imagine what this could do to someone without a person who cares for them keeping an eye on how they're doing, and that's no small amount chilling.
posted by six-or-six-thirty at 10:51 AM on December 6, 2010

to infiltrate our lives with drugs for whatever may ail us on a particular Tuesday morning

It seems like every other day I read a story like this, or one of those New York Times pieces about some doctor caught failing to disclose payments from a drug company in his influential study singing the praises of the company's products (of course, the doctors who are paid to pimp drugs like this but do disclose the payments don't even make the news, because what could possibly be problematic about that?). It seems pretty clear to me that the entire process of developing, testing, prescribing, and selling pharmaceuticals in the US is thoroughly corrupt at this point, and I can't really blame anyone for retreating to a position of wholesale skepticism. Certainly there are drugs out there that are helping real people with real problems, but there is so much well-financed noise that you have increasingly little chance of finding the signal.
posted by enn at 10:57 AM on December 6, 2010 [1 favorite]

At Regions, her son responded well to a medication for bipolar disorder. The family has a history of that disorder as well.

In the interest of full disclosure I feel like I should mention that I am diagnosed bipolar, medicated, and much better now thank you. If I were not on drugs I would be dead. Hands-down.

I've known several people who were successfully treated for bipolar disorder. It's quite common and the treatments are simple - heck, I knew someone who was prescribed good old lithium and it worked great. That's what is so destructive about drug development - new lesser-known drugs of dubious effectiveness are seeking to displace well-understood medications for exclusively financial reasons. There is always a risk to prescribing a newer medication, be it Seroquel or Vioxx or thalidomide, simply because their interactions and side-effects are not fully understood; despite clinical trials we really need decades of historical record to really know what's going on. The current industry will continue to try to sell us stuff like Vioxx (which was probably less effective than ibuprofen, once you discount all the fabricated efficacy studies) for as long as we let them.
posted by mek at 11:12 AM on December 6, 2010

FWIW, I do not work for the UMinn IRB, but I do work for the IRB of a different large reserach university and, reading these articles, this was a grade A fuck-up.

From the article and the subsequent bill "Dan's Law" bill, it sounds like he was under a stay of civil commitment, apparently pending treatment. This alone should have been excluded him from participation, since any consent to participate would have been under duress, and therefore not freely and voluntarily given. Adding that in with the explicit notice that dropping out of the CAFE study would put into involuntary treatment, and there is a clear lack of ability to freely consent to stay in the study.

Then there's the question of who actually gave consent for him to be in the study in the first place. One moment Dan is apparently incapable of making rational decisions about his life, and the next moment he's apparently able to give consent to participate in research? Any researcher, particularly psychiatric researcher, should know that schizophrenia and related disorders are key flags for not being competent to give consent. The choice should have immediately devolved to the Dan's mother, who quite clearly was against it.

As for the money, it's not uncommon for sponsors (AstraZeneca, in this case) to pay universities to conduct trials. Ostensibly this covers administrative costs as well as time and effort on the part of the investigators. Institutional conflict of interest is one of the many shady areas in large well-funded research trials, and one that is handled differently (but almost universally poorly) by just about every institution.

There is no doubt, however, that Dr. Olson should have been a long arm's length away from making decisions about Dan's participation in this study. Current federal guidelines for researchers require that they report any amount over $10K annually they receive from a sponsor. Averaging what Dr. Olson got over 6 years comes out to about $24-25K/year, definitely reportable. This would not bar him from working on the study, nor would it keep him from continuing to provide care for Dan, but it should have definitely barred him from enrolling subjects in the trial.

Still, I can't say this is surprising. Dr. Olson probably thought he had the best interests of his patient in mind by having Dan on the study. It's a common error among clinicians to mistake enrolling their patients in new and possibly exciting forms of treatment with giving them the best and newest care. However, clinical trials are, by their very nature, not better care. They are not worse care, either; they are research. The whole point of clinical trial is to see if one treatment is better or worse than another, and no one can know that answer until the trial is over. Yet, doctors make this mistake all the time, and present these studies as new breakthroughs, when, in fact, they are more like Schrodinger's Treatment Plan.
posted by Panjandrum at 11:27 AM on December 6, 2010 [11 favorites]

And yes, the whole process behind pharmaceutical testing is seriously seriously seriously (no, really, it's triple serious) flawed. Neuropharmaceuticals doubly so.
posted by Panjandrum at 11:30 AM on December 6, 2010

That Psychology Today blog betrays complete ignorance of the subject. It's ignorant agitation. Why is

Christopher Lane ... the Pearce Miller Research Professor of Literature

the best person a magazine allegedly focused on psychology can find to write on this subject?

At Regions, her son responded well to a medication for bipolar disorder. The family has a history of that disorder as well.

There is overlap in medical treatment for bipolar and schizophrenia. Good response to a bipolar drug isn't surprising. Hell, Seroquel is indicated for bipolar.

Unfortunately this is standard practice these days, as a lot of contemporary drugs are barely better than placebo after you consider their side-effects, let alone the conventional generics they hope to replace. Their benefit is, of course, that they're under patent. How do you think the pharmaceutical industry maintains its profit margins?

Well, the benefit of newer drugs is reduced side effects. Compliance is huge problem with schizophrenia. Reduced side effects are worth reduced effectiveness. Via compliance, relatively ineffective drugs with reduced side effects can be more effective.

He was supposed to be on the AstraZeneca medication as they found out after the study blind was listed, the MJ article says. I feel like they should have to monitor these things somehow. If he had for whatever reason made it through this study fine without actually taking the medication, he would be an erroneous datapoint.

I don't know about that. Like I said, compliance is a huge issue in treatment of schizophrenia. What if you were to do a study of Seroquel versus placebo, and throw out all of the noncompliant Seroquel patients? Of course, you couldn't tell with a blood test whether the placebo patients were compliant or not. Or what if you excluded all non-compliant patients from a side-by-side comparison like this? How could you actually evaluate adverse effects, since noncompliance can easily be a surrogate for side effects?

Astra-Zeneca set up a study in the hopes that it would make their drug look good; they funded the study. This, unfortunately, is pretty much standard operating procedure, and if any politician supports raising taxes in order to support more independent academic research, they've got my vote.

Despite Lane's assertions, Seroquel is an anti-psychotic, Markingson was diagnosed with schizophrenia (for which Seroquel is indicated), reduced incidence of suicidal ideation is a GREAT surrogate outcome for evaluating anti-psychotics, and people with schizophrenia commit suicide frequently-- when you run a trial full of schizophrenics, you can expect some suicides.

It was completely out of line for Olson to serve on the trial and to recruit and manage Markingson at the same time. It introduces many opportunities for undetectable and seriously inethical behavior. That's why it's against the rules.

Because I don't see it linked yet, and because it's the best article I found on the subject, here's the twin cities article.
posted by nathan v at 11:49 AM on December 6, 2010 [5 favorites]

The whole relationship between big pharma and universities is broken. Not only do the drug companies inadequately compensate academic institutions for the research, but the studies themselves are so closely (and paranoidly) controlled by the companies that I don't consider them valid scientific studies by any stretch of the imagination. Their purpose is solely commercial: if the FDA didn't exist, most of their trials would cease to exist as well.

I believe that as a socially progressive measure all trials to evaluate pharmaceuticals should be run as grants to academically controlled trial groups such as the cooperative oncology groups for cancer therapies. This would not only be more fiscally viable for universities, which right now are struggling mightily in the face of reduced government funding, but would also provide more credible information regarding the performance of new (and existing) pharmaceutical products.

Of course, since this runs directly counter to the "ohmygodgummintcan'tdoanythingrightletprivateindustryhaveitsway" ideology which holds our country in thrall right now, it will never happen.
posted by Mental Wimp at 11:58 AM on December 6, 2010

Nth-ing the Mother Jones article. I've seen that appear (grimly) in more than one best-of-2010 journalism list.
posted by intermod at 8:11 PM on December 6, 2010

Statements like this pepper the articles I have read: "The university's study coordinator, Jean Kenney, had Dan sign a consent form when Mary wasn't present, and on November 21, he was enrolled in the study." It is continually implied that Dan's mother should have been allowed to be more involved in his treatment, and in fact even make decisions for him. She seems to have cared about him the way the articles portrays it, but even if that is true, that does not automatically give her either the the ability or the legal right to run his life or be involved in his private medical life as assured by HIPAA. This whole thing was a tragedy, but the fault does not lie in any failure to inform the mother or to ask her opinion on her adult son's treatment. It was, quite simply, none of her business if he didn't want to make it her business.

I have a real problem with the ethic that says all decision-making ability and autonomy should be taken away from people that society considers mentally ill. And I don't understand why people who accurately see that it was unfair for Dan to be coerced into study participation with the threat of incarceration think it would have been more ethical for his mother to have made decisions for him against his will. Either way, the autonomy he should have as an adult is taken from him. If Dan's threats to slit his mother's throat were credible (IF), he should be physically prevented from doing so, perhaps by incarceration. That's about the extent of the control that should have been exerted over his life, to prevent him from harming anyone else. Forcing people to consume medications is a serious violation of human rights. Handing over decision-making abilities to someone's relative is also a total violation of an adult's rights.
posted by parrot_person at 8:44 PM on December 8, 2010