The suicide of Dan Markingson, a 26 year old man participating in a psychiatric trial, has again made the news, and will serve us for a life-time of study and discussion of research ethics, along with the TeGenero and Jesse Gelsinger cases.
Markingson began to show signs of paranoia and delusions in 2003, believing that he needed to murder his mother. He was committed to Fairview Hospital involuntarily after being evaluated by Dr. Stephen Olson, of the University of Minnesota. He was subsequently enrolled on a clinical trial of antipsychotic drugs—despite protests from his mother. This study was a comparison of atypical antipsychotics for the treatment of first episodes of schizophrenia (aka the CAFÉ study), sponsored by AstraZeneca. The study’s structure was that of a Phase 4 randomized, double-blind trial comparing the effectiveness of three different atypical antipsychotic drugs: Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine), with each patient to be treated for a year.
After about two weeks on study treatment in the hospital, Markingson was discharged to a halfway house—again over his mother’s objections. Over the coming months, Dan’s mother, Mary Weiss, continued to express concerns about her son’s deterioration, even asking if her son might have to kill himself before anyone else would take notice…then, in fact, her son violently committed suicide on May 7, 2004, mutilating himself with a box cutter.
The University of Minnesota and their IRB have maintained that the study was conducted appropriately and that they have no responsibility for Dan’s death. Dan’s mother and bioethicist Carl Elliott believe otherwise. Elliott has written passionately about the case regularly, with major articles being here and here.
We’ll explore some of the major issues of contention in this case over several posts, as illustrative of basic clinical research principles, including adequacy of informed consent, IRB oversight, conflicts of interest, and coercion, including threats to a bioethicist whistleblower.
First, let’s look at making an “informed consent” to participate in a clinical trial. What is this supposed to mean?
Consent is supposed to be more than just a signed document. It should be a process of explaining a trial to a volunteer, including procedures to be performed, risks and benefits, and alternatives to participation. While a consent is an agreement to participate in a trial, it is different than a contract in that the volunteer may opt out of participation in a study at any time, without any adverse consequences or penalties.
While the study coordinator sometimes obtains a consent, because of the grave responsibility associated with ensuring adequate consent, I did not delegate this responsibility. I can't speak for others.
The following elements of the informed consent agreement are required by the FDA and the International Conference on Harmonisation and are further detailed in the “Informed Consent Form Requirements Checklist” from my text, “Conducting Clinical Research: A Practical Guide…”:
- A statement that the study involves research
- The purpose of the research
- A description of the study procedures
- The time frame in which participation will occur
- A description of the procedures or treatments that are experimental
- A description of anticipated risks and discomforts, and a caveat that there may be significant unknown risks
- A description of what, if any, benefits might be reasonably expected
- Alternatives to participation that are available
- A confidentiality statement, explaining who will have access to the records and for what purpose
- An explanation of compensation (and limits) for treatment or injury
- Direction as to whom to contact for further information, including both the Principal Investigator and the IRB
- A declaration by the volunteer acknowledging that his or her participation is voluntary, that he or she is aware that no benefits will be lost should he or she choose not to participate, and that there is no penalty for early withdrawal from the study
Other elements are strongly suggested. The following elements are optional under the FDA regulations but are required by the ICH:
- An explanation that the volunteer may be dropped from the study without his or her consent, by the investigator or by the sponsor, should that appear to be in the volunteer’s medical interest or should the study be terminated early
- A description of any costs that might be incurred by the volunteer
- An assurance that the volunteer will be informed of significant new findings during the study that might affect his or her decision to continue participation
- A statement that the volunteer has received a copy of the informed consent document
The ability to provide an informed consent is dependent on a number of factors, including educational status and beliefs that derive from cultural, social, and family influences and evolve over time. An in-depth, highly recommended review is the IOM’s report Health Literacy: A Prescription to End Confusion.
Frighteningly, the level of general health literacy is quite dismal, although it is critical to accessing even routine health care. In an often-cited white paper, the Joint Commission reported that 44 percent of patients who signed an surgical consent form did not know the exact nature of the operation to be performed, and 60 to 70 percent did not read or understand the information on the form. Imagine how much worse this is likely to be for investigational clinical trials.
Consent and Research Ethics
We’ve talked before about the basic ethical principles outlined in the Belmont report:
Respect for persons, or the voluntariness of participation;
Beneficience, or benefit to the specific individual;
Justice, that “vulnerable” populations—groups including children, the indigent, the military, prisoners, pregnant women, and institutionalized—require additional protections as they are particularly vulnerable to coercion,
Consent for Vulnerable Populations
The first major question regarding Dan Markingson’s participation in this clinical trial was whether the consent was informed and properly obtained. The US Common Rule directs Institutional Review Boards (IRBs) “to include ‘additional safeguards...to protect the rights and welfare’ of ‘mentally disabled persons.’” There certainly appears to have been none here. After all, Markingson had just been involuntarily committed to psychiatric treatment. A look at the time course related to Dan's participation raises disturbing questions.
November 12: Dan Markingson was hospitalized on a psychiatric ward. “The diagnosis at that time was psychosis and mood disorder, and to rule out bipolar affective disorder with psychosis and schizophrenia.”Dr. Olson’s “differential diagnosis includes paranoid schizophrenia, schizoaffective disorder, and bipolar disorder with manic psychosis.” At that time, it was “noted that Mr. Markingson was felt to not have the capacity to make decisions regarding neuroleptic medication” and that he was refusing to take the prescribed Risperdal.
November 13-14: Dan agrees to take Risperdal
On November 19, Dr. Olson discussed the CAFÉ study with Dan. This same day, in a pre-petition screening, a clinical psychologist, Dr. James Jacobson, confirmed Dr. Olson’s assessment that Markingson failed to acknowledge having a mental illness and that he “is believed not to have the capacity to make decisions regarding neuroleptic medication.”
On November 20, the judge elected to stay Mr. Markingson's commitment for a period of six months, “so long as he followed certain conditions: …(a) that he remain hospitalized, cooperative with the treatment plan at Fairview University Medical Center until medically discharged and follow all of the aftercare recommendations of the treatment team; (b) that Mr. Markingson participate in and satisfactorily complete the inpatient/outpatient treatment program and aftercare recommendations as determined by his social worker…”
On November 21—just two days after being deemed incapable of consenting to Risperdal (antipsychotic treatment), he was suddenly determined by Jeanne Kenney, his social worker, to be capable of consenting to a clinical trial of antipsychotic medications. The 10 page CAFÉ study “consent form was read to him verbatim.” Dan then signed the consent, witnessed by Kenney, who also had responsibility for study recruitment. Curiously, he remained on Risperdal until December 5.
On December 11, when Dan had his first study visit, Dr. Olson diagnosed him with schizophrenia—conveniently one of the criteria for participation in the trial on which he had already been enrolled.
March 15, Ms. Weiss sent a certified letter expressing her concerns to the study investigators, and never received a reply.
April 9: Meeting with Dr. Olson, Jeanne Kenney, David Pettit (Dan’s Dakota County case manager), Markingson, and Ms. Weiss, who again expressed increased concerns about her son’s lack of improvement on the study medication. Dr. Olson concurred that Dan’s “ADLs had deteriorated over the last few months, and often looked more disheveled.”
An agreement was reached to extend Dan’s stay of commitment for another six months.
April 15: message left by Dan's mother, Mary Weiss, to the study coordinator, Jeanne Kenney, which warned, “Do we have to wait until he kills himself or someone else before anyone else does anything?”
April 15-26, Ms. Weiss wrote three letters to Dr. Schulz, the study’s co-investigator, begging for help with her son’s deterioration and increasing agitation and “rage…desperately needs help in dealing with it. Please don’t wait until it comes boiling out!”
May 5, Ms. Weiss informed others that she would seek conservatorship of her son; Dan told Pettit, his case manager, that he did not want that.
May 8, 2004 Dan Markingson committed suicide.
Should Dan Markingson have been enrolled on this clinical trial?
There are several issues here. Before the obvious, “Was Dan capable of consenting?” is the question of the enrollment criteria for the trial. This was a trial for patients with the first episode of schizophrenia. Dan was initially diagnosed as having a psychosis “NOS,” or not clearly defined. It was not until December 11—almost 3 weeks after his enrollment—that Dr. Olson clearly labelled him as having schizophrenia. Also, patients with schizophrenia are at increased risk for suicide or violence, so violent ideation is typically an exclusion criteria on clinical trials. Why wasn’t homicidal ideation an exclusion on the CAFÉ trial?
What was the adequacy of Dan Markingson’s Consent?
Do you believe that Dan was able to provide an informed consent? I certainly have a number of concerns.
First, was Dan competent? After all, he was just institutionalized for being delusional and homicidal, and was denying that he had any mental illness. Several evaluations had concluded that he was incapable of consenting to taking neuroleptic (antipsychotic) drugs. The social worker, Jeanne Kenney, did the evaluation that determined that he was capable of consenting—but she was certainly not unbiased, being the study coordinator working under Dr. Olson and responsible for study recruitment. The study was on probation for poor enrollment, so there was also considerable pressure on her to boost enrollment.
There appears to have been an overwhelming level of coercion.
Dr. Olson discussed the protocol with Dan and then, the very next day, the judge stays the commitment with the condition that he cooperate with treatment plans.
Two other problems with the written consent vs. reality of what happened are immediately evident. One is that the consent states, “If the study antipsychotic medication is not effective for you…you will discontinue from the study.” Markingson, who did not believe nor understand that he was mentally ill, was not likely able to ask to be dropped from the study, particularly when he believed that would lead to his being institutionalized. Ethically, investigators are bound to drop patients who are not improving on a study regimen. Yet this was never done.
Similarly, a standard clause in consents says, “What if we learn about new risks during the study? You will be given any new information gained during the course of this study that might affect your willingness to continue your participation. “On March 17, 2004, the study sponsor warned investigators of a new risk of Seroquel – specifically, the hyperglycemia and weight gain.” The increased risks of diabetes and metabolic abnormalities from Seroquel were never disclosed to Markingson. He should have been reconsented when this information came to light, but Kenney failed to do so.
The problems with consent are but the tip of the iceberg in this tragic story. In upcoming posts, we’ll look at the responsibilities of Principle Investigators, delegation of responsibility, conflicts of interest, and much more.
Elliott, Carl. "The Deadly Corruption of Clinical Trials"
Elliott, Carl. "A referenced summary of the Dan Markingson case"
William Heisel also has excellent coverage at http://www.reportingonhealth.org, which I will be citing in upcoming posts.
Original documents including the study protocol, consent, and testimonies of expert witnesses can be found at http://www.scribd.com/MarkingsonCase/documents
Correction: This was a Phase 4 study.
Photo of Dan and mom, courtesy Mary Weiss
Seroquel clock image - rexdownham
Esquizofrenia - RxHxS
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