… have gathered a good number of faculty at the University of Minnesota to request a review of Markingson’s case. The Regents will at least look at the letter Elliott and others have written to them. Maybe the Regents will act on it. This blog will follow the story.
University of Minnesota counsel Mark Rotenberg will meet with the Board of Regents to discuss a letter requesting an independent investigation into events surrounding Dan Markingson’s 2004 suicide.
Eight U of M bioethicists sent the letter last week detailing potential ethical lapses that may have led to Markingson taking his own life while enrolled in a clinical study at the college. Several more faculty members have since sent a subsequent letter to the Regents supporting the call for an investigation.
The story is complicated and long, but essentially involves a claim that University of Minnesota researchers, eager to enroll subjects in an experiment, enrolled Markingson, even though he was reportedly in no mental shape to give informed consent.
Long article by Carl Elliott about the Markingson case here.
December 8th, 2010 at 7:42PM
This is a long and sad story.
The Academic Health Center, the Medical School Dean, and the University of Minnesota General Counsel do not seem to understand the fact that an act may be legal, but still may be unethical and immoral.
They’d like this matter to go away.
Thanks to Carl Elliot and other courageous faculty at the University, it won’t.
To read the letter from the bioethics faculty, please see:
http://bit.ly/f0wrzv
December 8th, 2010 at 7:45PM
thank you for the Mozart the other day and now the link to the Elliott story
“the number of children and adolescents treated for bipolar disorder rose 40-fold between 1994 and 2003. Another study found that nearly one in five children who visited a psychiatrist came away with a prescription for an antipsychotic drug, despite early reports of alarming side effects.”
-this is just evil!
i think i am going to have to go back to the Requiem once i am done with the article- a must read but it makes your blood boil- what are we doing to these kids!
December 8th, 2010 at 9:00PM
You’re welcome, cloudminder. And yes, the Elliott article in Mother Jones makes for very melancholy and angering reading.
December 9th, 2010 at 3:48PM
The articles are here (http://bit.ly/f1bMDe), here (http://bit.ly/gPvE9e), and here (http://bit.ly/fSX4PA). The clinicaltrials.gov is here (http://bit.ly/gsBeTO).
Multiple publications from one study is called the salami tactic.
In an ideal world, journals that publish articles that may have been ghostwritten would (1) make their articles ungated (good news here-2 of the 3 are ungated) and (2) make the database public (if there is a public database, I can’t find it). Shouldn’t someone besides the ghostwriters look at the data?
There’s a common bias involving IRBs and ICFs (informed consent forms). These were set up to discourage unethical studies. I think they may worked in that regard. What was said to clinical investigators was “For you to do clinical research, you need to have IRB approval and have the subjects sign ICFs (informed consent form).” Here’s the bias, and it is a weird sort of “regulatory capture.” The claim is this: “Look, I got IRB approval and the subject signed the consent form, therefore this is ethical. This case challenges that assumption.
These studies have inclusion-exclusion criteria. In other words, they are specifying the kind of patient they want (for whatever reason) they want in the study. For a phase III study, the FDA is often intimately involved in this, as the purpose of the study is get eligibility to market the drug in the US. This is a post-marketing, or phase IV study. Drug companies do phase IV studies for various reasons. For instance, they might want to get doctors to prescribe their drug, they might want to establish a new indication, they might want to establish their drug has better efficacy, or they might want to show their drug is safer or better tolerated. It looks like this study was done to get a publication so that doctors would prescribe their drug.
More later…
The primary endpoint in the study was time on
December 9th, 2010 at 4:20PM
There are a few questions that arise when you look at the inclusion-criteria. Why didn’t they want people who had been on prolonged anti-psychotics before? Why is 15 weeks on a prior antipsychotic OK, but 17 weeks not? Why didn’t they want people who were suicidal? Why were homicidal patients OK but suicidal not? They accepted patients who had been psychotic for up to 5 years (as long as they had not take an antipsychotic for more than 16 weeks). What, people can be clinically psychotic for 5 years and basically not be on treatment?!
Another thing you have to consider is the Would I put my relative in this study? question. It too involves many unknowns. Schizophrenia involves people in their 20s and 30s often, in the early stages of their career. So it can be devastating. Young people like this may not have insurance. They may not be able to afford hospitalization if it’s needed, or medication. You may say that Medicaid is available, but sometimes there’s restrictions if you move from one state to another. I know I had a patient named Jesus who’s life was ruined by intractable epilepsy due to a condition called mesial temporal sclerosis. This can be cured by surgery. I thought I could cure Jesus, but it turns out, as a migrant, his Medicaid coverage did not include this type of surgery. I am just saying things are real quirky in this area, so you have to give his doctor some latitude. Suppose the patient was homicidal, needed medicine, needed hospitalization, but basically did not have access because of insurance issues? Suppose he’d tried an antipsychotic for 15 weeks and it didn’t work? Sometimes you try one medicine in a category, and if it doesn’t work or the guy has side effects, try another in the same category. You could put the guy in a study and get him medicine at no charge. Maybe he could get some hospitalization too. You just don’t know.
More coming later…
December 9th, 2010 at 5:16PM
I’m at home, in bed, sick. Shaking chills, fever, headache. Sorry about blathering on.
The endpoint of the study was Treatment Discontinuation. Arthur Caplan, a medical ethicist who used to be at the U of Minn but is now at Penn, put himself in a clinical trial. Midway through, he asked to get out of the study. The investigator said he couldn’t. You see, ethically, study participants should be allowed to get out of the study any time they want, for any reason. There’s no retribution. No harm, no foul.
I’ve never heard of Treatment Discontinuation as a primary endpoint. It looks like they pay the doctor on the basis of the patient staying in the study. And, as I say, many clinical investigators are not aware of the rule that patients can exit studies when they want. So doctors are encouraged to judge that patients are helped by the drug and should stay in the study. Also, in this case, if the doctor said the medicine wasn’t working and the guy was insane, then as I assume his mother had Power of Attorney, she would have been able to get him out of the study.
So how do the clinical research ethics mesh with Minnesota laws (“In Minnesota, patients who have been involuntarily committed are given another option: a “stay of commitment.” Patients can avoid being confined to a mental institution as long as they agree to comply with the treatment program laid out by their psychiatrist. On November 20, Olson asked for a stay of commitment. The court granted the stay for six months, stipulating that Dan had to follow the recommendations of his treatment team.”)? They don’t. In other words, by clinical research ethics, a person can get out of a study no harm no foul. Minnesota law says that, if the doctor wants the person to stay in the study, they have to, or be committed. The study itself or the IRB should have addressed issue. The evidence is this psychotic guy stayed in the study even though the drug wasn’t working. There were professional and financial incentives for his doctor to maintain that the drug was working.
Another issue is the “caregiver issue.” I would think that, if you have a study in which a patient might be judged competent at first, but incompetent later, you would want the close cooperation of a caregiver with Power of Attorney, for several reasons. It’s not clear this study did that. From Elliott’s column, it looks like U of Minn discouraged involvement of caregivers, or at least, this particular caregiver. So this is another issue the study or the IRB should have addressed.
December 9th, 2010 at 5:48PM
Mr. Evans,
You’ve asked a lot of technical questions whose answers might not be brief or of general readers. If you want to follow up on these matter off line, please contact me by going to the University of Minnesota web site and entering my name in the people search window.
My best,
Bill Gleason (William B. Gleason in the directory)
ps. Hope you’re feeling better.
December 9th, 2010 at 7:13PM
Yes, well, I’m not an insider and I’m not an expert on psychiatric clinical research. Even so, here’s my opinion:
The last step-publication-is the key step. If people thought thought that peer review would detect and journal editors reject articles, then they wouldn’t try in the 1st place. However, as a non-expert outsider, it looks to me like journals, except the British Journal of Psychiatry, compete vigorously to publish these types of articles.
People here, looking on, would probably describe this whole episode as a near miss at best. Despite that, I think if you offered the journal editor a do-over, I think he’d decline. I don’t think they would have the authors change their assertion that “These events (suicides and suicide attempts) occurred despite the close attention provided in clinical research aftercare programs.” (Personally, I’d like some documentation of that)
My guess is that if you gave AstraZeneca a do-over, a Mulligan, they’d take it. They are still going to design a study that will minimize the chance that their drug will be shown to be inferior to comparison drugs. It’s only logical. They would probably keep the study in R&D, rather than marketing, assuming R&D has more clinical research experience. They would exclude both suicidal and homicidal patients, because they don’t want deaths during the trial. They would require a caregiver and caregiver consent. They would minimize incentives to keep people in the trial, when the medicine might not be working or might be causing intolerable side effects. At least I think they would do these things to minimize the risk of bad PR.