Death of Dan Markingson

In addition, as the Legislative Auditor pointed out, AstraZeneca prorated its payments to the University of Minnesota based on the number of subjects enrolled and how long they remained in the study, creating “an incentive to enroll and keep subjects enrolled in the CAFÉ study.” The Legislative Auditor went on to note that “Olson kept Markingson in the study despite Mary Weiss’ repeated warnings that Dan was not well and the study medication was not working.”

On February 10, 2016, a consultant hired by the University of Minnesota found over forty critical violations of research and safety policy in the Department of Psychiatry. The consultant also reported being verbally abused and intimidated by faculty members, and said university administrators had instructed her not to put her critical findings in writing.

In April 2016, Rep. Cindy Pugh, Rep. Connie Bernardy, and Rep. Abigail Whelan, members of the Minnesota House of Representative Higher Education Finance and Policy committee, introduced a bill that would have research studies in the Department of Psychiatry monitored by the Ombudsman for Mental Health and Developmental Disabilities. Brian Herman, Vice-President for Research at the University of Minnesota, testified against the bill on April 13, 2016. The bill is currently still under consideration.

On February 27, 2015, the university released an external review commissioned in light of the Faculty Senate resolution and managed by the Association for the Accreditation of Human Research Protection Programs. The review leveled harsh criticism at the university for a number of problems, including inadequate scientific review of research studies by the Institutional Review Board, poor training of researchers, a defensive posture by university officials toward criticism, and a “culture of fear” in the Department of Psychiatry, where staff members provided “stories of intimidation” and “fear of retaliation” if they spoke up about safety violations.

On April 17, 2015, the New York Times reported that Charles Schulz, who had recently stepped down as Chair of the Department of Psychiatry, had enrolled two residents of a sex offender facility in a study of quetiapine (Seroquel) for Borderline Personality Disorder. According to the director of the facility, however, neither resident had a diagnosis of Borderline Personality Disorder. One resident, a cook at the facility, had crushed up a large quantity of Seroquel and mixed it into the morning oatmeal. According to the Times, this episode “did not seem to ruffle the university oversight board that is charged with looking into such episodes.” A complaint was submitted to the Food and Drug Administration.

On May 16, 2013, Aaron Friedman, the Dean of the University of Minnesota Medical School and Vice-President for Health Sciences, published an editorial in the Minneapolis Star Tribune stating that the death of Dan Markingson was “not a scandal” and that “it is time to stop blaming our university and our researchers.”

On December 5, 2013, the University of Minnesota Faculty Senate voted to endorse a “Resolution on the Matter of the Markingson Case,” in response to a letter from 175 scholars in bioethics and related disciplines asking for an investigation of Markingson's death. Eric Kaler, the president of the University of Minnesota, agreed to commission an external review, but excluded the Markingson case from the investigation.

In November 2012, the Minnesota Board of Social Work issued a “corrective action” against the CAFÉ study coordinator, Jean Kenney, for numerous lapses. Among its findings were that Kenney had performed medical tasks beyond her competency and failed to inform Markingson of new metabolic risks of quetiapine (Seroquel) when the study sponsor notified investigators.

In August 2010, Mother Jones magazine published an article on the Markingson case by Carl Elliott, a professor in the University of Minnesota's Center for Bioethics. AstraZeneca, the sponsor of the CAFÉ study, had paid $520 million to settle a federal lawsuit for fraudulent marketing of its antipsychotic, Seroquel. Unsealed documents provided evidence that AstraZeneca had suppressed unfavorable research studies and manipulated study results. Elliott cited the opinion of several experts that the CAFÉ study had been designed to produce a positive result for Seroquel.

In 2009, the Minnesota state legislature passed “Dan’s Law,” which placed significant restrictions on the ability of psychiatrists to recruit patients under civil commitment (involuntary commitment) orders into psychiatric drug studies.

The Markingson case was first brought to public attention when the St. Paul Pioneer Press published a 3-part series in May 2008. The Pioneer Press series raised concerns about the financial ties Olson and his CAFÉ study co-investigator, Charles Schulz, the Chair of the Department of Psychiatry, had to AstraZeneca and other pharmaceutical companies. It also noted that recruitment into the CAFÉ study had increased dramatically after the University of Minnesota had established a special unit for psychotic patients called Station 12 in which every patient was evaluated for potential recruitment into a research study.

In January, 2007, Mary Weiss filed a lawsuit against the University of Minnesota, but a Hennepin County judge ruled that the university had statutory (or discretionary) immunity. The judge allowed a malpractice suit against Olson to proceed, which was settled for $75,000. The University of Minnesota then filed a notice to assess costs against Mary Weiss, demanding $57,000. The university agreed to drop the demand if Weiss agreed not to appeal the immunity ruling.

The University of Minnesota Institutional Review Board received a Serious Adverse Event report from Olson, but did not review any medical records or interview anyone other than Olson. On July 22, 2005 the Food and Drug Administration issued an Establishment Inspection Report. The FDA inspector, Sharon Matson, found no violations.

However, an investigation by the state Ombudsman for Mental Health and Mental Retardation found several areas of concern. In a letter on June 17, 2005, the Ombudsman's office pointed out that patients under a civil commitment (involuntary commitment) order are especially vulnerable and need special protection. The letter also noted a conflict of interest, since Olson had served as both Markingson's treating physician and the principal investigator of the study into which he recruited Markingson.

Some critics fault porous oversight by the Food and Drug Administration. When journalist Peter Aldhous compared Food and Drug Administration records with disciplinary actions by state medical boards, he found dozens of doctors conducting research studies after they had been sanctioned or stripped of their licenses for substance abuse, fraud, negligence, or mistreatment of their patients. A report by the Office of the Inspector General of the U.S. Department of Health and Human Services found that the FDA inspects less than one percent of research sites, often long after questionable studies have been completed. In 2005, investigative journalists for Bloomberg Markets magazine discovered that the largest drug testing site in North America was located in a converted motel in Miami, where researchers were paying undocumented immigrants to test unapproved drugs. A former FDA investigator told the magazine, “The FDA’s backbone has been Jell-O. The folks at the FDA stopped enforcing the rules several years ago.”

Over the course of the next five months, Mary Weiss became convinced that Markingson's condition was deteriorating and tried repeatedly to have him removed from the CAFÉ study. She warned the University of Minnesota research team that Markingson was in danger of committing suicide. On April 11, 2004, she left a voice mail message for the study coordinator, Jean Kenney, asking “Do we have to wait until he kills himself or anyone else before anyone does anything?” On May 8, Markingson committed suicide with a box cutter, nearly decapitating himself. Laboratory tests later revealed that he had been taking quetiapine (Seroquel), produced by AstraZeneca.

Dan Markingson was raised in St. Paul, Minnesota by his mother, Mary Weiss, and earned a degree in English literature from the University of Michigan. In the summer of 2003, when he was 26 years old, Markingson was living in Los Angeles, where he hoped to become a screenwriter. During a visit to Los Angeles, Weiss became alarmed at changes in her son's behavior that suggested he was seriously mentally ill. She persuaded him to return to St. Paul. On November 12, 2003, Markingson spoke about an apocalyptic “storm” in which he would be required to murder people, including his mother. As a result, he was admitted to a locked psychiatric unit at Fairview University Medical Center. His treating physician was Dr. Stephen Olson, an associate professor in the University of Minnesota's Department of Psychiatry.

After starting Markingson on risperidone (Risperdal), an antipsychotic drug, Olson wrote in support of a petition for an involuntary commitment order that would send Markingson to Anoka Metropolitan Regional Treatment Center, a long-term state psychiatric hospital. A judge granted the commitment order on November 17, 2003. Two other clinicians examined Markingson as part of the commitment process and both noted Markingson's extremely disordered thinking. Shortly afterward, Olson requested that the court grant Markingson a stay of commitment, which permitted Markingson to avoid involuntary confinement at Anoka as long as he agreed to abide by the Fairview University Medical Center treatment plan. A judge granted that request on November 20, 2003.

On November 21, 2003, one day after the stay of commitment was granted, Jean Kenney, a study coordinator, had Markingson sign an informed consent form for the CAFÉ study when his mother, Mary Weiss, was not present. Weiss strongly objected to her son's enrollment in the research study, but her objections were dismissed.

Six months later, another University of Minnesota research subject, Robert Huber, revealed publicly that he had been recruited into a study of an unapproved antipsychotic drug, bifeprunox, under circumstances similar to those of Dan Markingson. Shortly afterward, the Office of the Legislative Auditor, a state watchdog agency, agreed to investigate the Markingson case. In November, Niki Gjere, a clinical nurse specialist at University of Minnesota Medical Center at Fairview, told Fox 9 News that she had objected to Markingson's enrollment in the CAFÉ study in 2003 but her objections were ignored. She also said that nurses were “badgered and pressured” into finding subjects for psychiatric drug studies.

Dan Markingson (November 25, 1976–May 8, 2004) was a young man from St. Paul, Minnesota who committed suicide in an ethically controversial psychiatric research study at the University of Minnesota while under an involuntary commitment order. For nearly eleven years, University of Minnesota officials defended the conduct of its researchers, despite significant public criticism, numerous news reports, and pressure for an external investigation. In March 2015, however, an investigation by a state watchdog agency found a number of alarming ethical violations in the case, including serious conflicts of interest and financial incentives, poor oversight of the study, pressure on Markingson to join the study while he was in a highly vulnerable state, and a series of misleading public statements by university officials. Shortly afterward, the university suspended recruitment into psychiatric research studies. On April 9, 2015, Charles Schulz, MD, announced his resignation as Chair of the Department of Psychiatry.

The architecture of the current system of human subject protection in the United States was put into place after public outcry over scandals such as the Tuskegee syphilis experiment. The National Research Act was signed into law in 1974, and the federal regulations regarding oversight of biomedical research (the Common Rule) came into effect in 1981. That system includes little direct monitoring of research, but rather depends on researchers to comply with the regulations and conduct research honestly. But today's medical research enterprise may simply be too large, complex and financially powerful for such a system to be sufficient. Elizabeth Woeckner, president of Citizens for Responsible Care and Research, a non-profit watchdog organization, has said, “These are regulations for a world that doesn’t exist anymore.”