The Dark Side of Industry-Funded Drug Trials

There are many serious problems with the current U.S. mental health system, the most glaring being the over-use or misuse of psychiatric drugs, the warehousing of the mentally ill to prisons and emergency rooms, and the unholy connection between academic researchers and pharmaceutical companies that can result in stilted clinical trials of already-approved drugs and misleading efficacy information that is used to boost sales.

I have written about these issues on HealthBeat before, but no single case demonstrates the convergence of these problems better than the tragic story of Dan Markingson, a young man who suffered his first bout of severe psychosis and schizophrenia in the summer of 2003. In November of that year, Markingson was taken to the University of Minnesota Medical Center in Fairview and against his mother’s wishes, was enrolled into an industry-sponsored drug trial being run by his psychiatrist, Dr. Stephen Olson. Six months later on May 8, 2004, mentally deteriorating and still enrolled in the study, Markingson, 27, committed suicide in the shower of his halfway house by violently stabbing himself in the neck, chest and abdomen.

For several years afterwards, Mary Weiss—Dan Markingson’s mother—pursued his case, e-mailing and writing to numerous agencies and authorities. She called for an investigation by the FDA and the University of Minnesota and eventually filed a lawsuit against two physicians, the U of M and AstraZeneca, the sponsor of the clinical trial, charging that her son was coerced into taking part in the trial and once enrolled received inadequate care. The FDA did eventually investigate the case in 2005   and found “no evidence of misconduct or significant violation of the protocol or regulations.”

Weiss’s lawsuit never got very far either. In 2008, a judge ruled that as a state institution, the university had immunity from such suits and also dismissed the case against AstraZeneca, deciding that there was no convincing proof that Serequel, the company’s drug, had caused Markingson's death. In the end, Weiss settled with Olson, (the only defendant left) for $75,000 that barely paid  her legal bills. To make matters worse, that same year the University of Minnesota filed a countersuit demanding that Weiss pay them $57,000 to cover their legal fees.

Due to the dogged persistence of Mary Weiss, who continued her email and written campaign to get someone—anyone—to investigate the events leading up to her son’s suicide, two reporters from the Twin Cities Pioneer Press finally looked into the case. In 2008 Jeremy Olson and Paul Tosto published a “deeply unsettling” three-part series in the paper that raised questions about whether Markingson’s doctor had followed ethical guidelines and even more troubling, whether the University’s financial relationship with AstraZeneca led them to ignore troubling consent issues and sacrifice the care of this young man.

That’s when Carl Elliott, a bioethics professor at the University of Minnesota got involved. One of the reporters sent him the Pioneer Press series, which “hardly anyone had read,” and Elliott decided to get involved primarily, he says, because “this story had happened at my own institution and no one seemed to be doing anything about it.” He contacted Mary Weiss, and although she was wary of meeting Elliott at first because he was from the U of M, she and a friend eventually provided him with extensive medical records, court records and depositions that told a compelling story. “It looked to me that while the Pioneer Press story had been accurate,” Elliot told William Heisel in a Q&A on USC’s Reporting on Health site, “it didn’t get at this larger issue of how pharmaceutical companies use clinical trials as marketing tools and how dangerous that can be.” 

First, some details on the case—culled from the original Pioneer Press series and a subsequent article by Carl Elliott, "The Deadly Corruption of Clinical Trials" that was published last September in Mother Jones. In 2003, Dan Markingson’s psychosis had reached the point where he was hearing voices that were telling him to kill his mother, and he was involuntarily committed, i.e. taken in handcuffs, to Regions Hospital in St. Paul, MN. With no spare beds in their psychiatric area, the hospital transferred Markingson to a brand new unit at the University of Minnesota Medical Center in Fairview. Called Station 12, the unit was created specifically to treat psychotic patients and screen them for research. According to the Pioneer article, Markingson’s psychiatrist, Dr. Olson (recruited to the unit because of his expertise in schizophrenia), and Dr. Charles Schulz, head of the U of M’s psychiatry department, “helped launch the unit in part to enhance the hospital's startup schizophrenia program and meet the U's mandate to bring in more research dollars.”

Markingson was hospitalized and given antipsychotic medication to help reduce his psychosis. In Minnesota at that time, some patients who had been involuntarily committed were given a choice; they could be confined to a mental institution or they could agree to a "stay of commitment." This “stay of commitment” meant that they could remain in the community as long as they complied with a court-ordered, supervised treatment program laid out by their psychiatrist.

In notes obtained by Mary Weiss’s lawyers; on Nov. 14, 2003, Dr. Olson recommended that a Dakota County District Court commit Markingson to the state treatment center because he was not competent to make decisions about his care. He told the court that Markingson was convinced his delusions were real and that he didn’t believe he was mentally ill.

According to the Pioneer Press, “The doctor changed his opinion about the commitment in less than a week, telling the court Markingson had started to acknowledge the need for help. The court granted the stay for six months, stipulating that Dan had to follow the recommendations of Dr. Olson and his treatment team.”

Here’s where the serious ethics concerns begin to arise. Olson didn’t recommend that Markingson receive standard medical treatment. Instead Elliott writes in Mother Jones, Olson “proposed that Dan take part in an industry-funded study of antipsychotic drugs. The university's study coordinator, Jean Kenney, had Dan sign a consent form when Mary (his mother) wasn't present, and on November 21, he was enrolled in the study.”

The intent of this study, funded by AstraZeneca, “was to compare the effectiveness of three ‘atypical’ antipsychotic drugs, each of which had already been approved by the FDA: Seroquel (quetiapine), Zyprexa (olanzapine), and Risperdal (risperidone.) The study was designed and funded by AstraZeneca, the manufacturer of Seroquel, and it called for 400 subjects experiencing their first psychotic episode to take one of the three drugs for a year. AstraZeneca called it the ‘CAFÉ’ study.” Oddly, though the study—like most for antipsychotics—excluded schizophrenic patients who were suicidal, it accepted those, like Dan, that had threatened to kill others.

Although the University of Minnesota was paid more than $15,000 by AstraZeneca for each patient that they enrolled in the trial, researchers were having trouble finding schizophrenic patients who were experiencing their first psychotic episode and were willing to enroll in the study. The Pioneer reporters write, “Exchanges between local and national study officials made it clear that there was pressure for results and a 'risk' that the study would be shut down if it didn't recruit enough patients.”

“The opening of Station 12 — which evaluated every patient for research — made a difference, Olson and Schulz said. One-third of the U's patients for CAFE came from this unit. By mid-2003, CAFE leaders were praising Olson and his recruiter, Jeannie Kenney, and asking them to share recruiting tips.”

In total, Olson and Kenney brought in $327,000 for their department by recruiting patients for the CAFÉ trial. Dr. Olson was also part of AstraZeneca’s “speaker’s bureau,” earning a total of nearly $150,000 between 2002 and 2008 from the company. In a deposition, Dr. Schulz testified that between 1999 and 2004 he earned an estimated $150,000 to $180,000 from various drug firms. (A recent article on Schulz by Andy Mannix in City Pages, finds that from 2005 to 2010, the U of M psychiatrist “received at least $522,000 from pharmaceutical companies for research, consulting fees, and other compensation… He'd been paid more than $86,000 by AstraZeneca alone.”)

Meanwhile, Mary Weiss did not want her son to be part of this trial, and she felt that he was definitely not competent enough to make that decision himself. In fact, Weiss—and now, bioethicist Elliott—felt that Dr. Olson was using coercion to get Dan to make the choice to enter the trial. Delusional and convinced that he wasn’t mentally ill, Dan was told that he would be institutionalized in a state hospital if he did not sign up for the CAFÉ trial.

What he likely didn’t understand was that once he was enrolled in the trial, he, like other subjects, could not be taken off his assigned drug until the end of the 52-week study period. The protocol didn't allow trial participants to be switched to another drug if their assigned drug was not working; and it didn’t allow subjects to take additional drugs that might be given to manage side effects and symptoms such as depression, anxiety, or agitation. By design, the study was randomized and double-blinded: Subjects were assigned a drug randomly by a computer, and neither the subjects nor the researchers knew which drug it was. The net result was that by enrolling in this trial, Dan Markingson had fewer therapeutic options than he would have had outside the study and receiving standard treatment.

After just under six months of being part of the CAFÉ study, taking an unknown atypical anti-psychotic and living in a half-way house, Dan’s mother and several social workers who were monitoring his mental state felt that he was not improving, and in fact, they suspected he was getting worse. According to the Pioneer Press article, “Mary Weiss sent five letters and made numerous calls to the researchers, complaining that her son, the 13th enrollee, didn't have the wherewithal to consent to the study and requesting that he be withdrawn.” Study notes obtained by Elliott include several instances when his mother or her close friend alerted U of M staff that Markingson’s paranoia was worse; that he was not going to therapy; and that he was out of control: “Do we have to wait until he kills himself or someone else before anyone does anything?” they asked prophetically.

The university disregarded all the letters and calls. Meanwhile, Dr. Olson, perhaps worried that Markingson would drop out of the study, extended his “stay of commitment” for another six months—or until the study was completed. Not long after, on May 8, 2004, Dan killed himself by violently stabbing himself in the abdomen and neck in the shower of the half-way house. “Later, when the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca,” writes Elliott.

This tragic tale raises several serious issues. First of all, is it ethical for a doctor (in this case Olson) who is solely responsible for a patient’s treatment to recruit him for a study—especially one in which the investigator has a financial stake? Secondly, the U of M had an institutional review board in place (IRB) that approved the study design and the way patients were recruited. In this case it seems clear that by allowing Dan Markingson to consent to the trial, this board was sadly remiss in its stated duty to protect human subjects in medical experiments. In early March, Elliott wrote in the Hastings Center’s Bioethics Forum “there is simply very little protection for human subjects in privately-sponsored clinical trials.” It's worth asking, how effectively do IRBs at other academic medical centers play this advocacy role–or how often do they bow to the financial concerns of their institution?

When patients are recruited into clinical trials they are told that by participating they will help others. In that line of reasoning then, the knowledge obtained from the CAFÉ trial should help doctors determine the best treatment for schizophrenia. But, according to Elliott, this wasn’t really the goal of the CAFÉ trial. All the drugs being tested were already approved by the FDA; in fact by 2008 the atypical antipsychotics were the most profitable class of drugs in the U.S.  The market for AstraZeneca’s Serequel alone was $4 billion in sales, making it the country’s fifth most profitable drug.

AstraZeneca’s interest in funding this trial—which pitted Serequel against its top two competitors—was to gain an edge in marketing. They wanted to be able to tell doctors that their drug had fewer side effects or was slightly less likely to be discontinued (in this and another trial of antipsychotics and schizophrenia—the CATIE trial funded by the National Institute of Mental Health—an average 74% of subjects stopped taking their medicine due to unwanted side-effects or other reasons).

Despite the huge increase in use of atypical antipsychotics, the City Pages’ Mannix reports that a growing number of studies showed that the atypicals had side-effects just as bad as older anti-psychotics like Haldol, including weight gain, movement disorders and diabetes. They also didn’t appear to be more effective than these older (and far less expensive drugs) and in at least one trial conducted by U of M’s Charles Schultz (yet never published), the newer antipsychotics had no more effect on schizophrenia or other serious mental disorders than a placebo.

In fact, in April 2010, AstraZeneca agreed to pay $520 million to settle two federal investigations and two whistleblower lawsuits alleging that it had marketed Seroquel for unapproved uses and hid health risks. The company still faces more than 25,000 civil suits.

More troubling, it looked like industry-funded studies that do prove successful are far from unbiased. Elliott writes in Mother Jones, “A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects.”

How does all this relate to the Markingson case? Elliott says that investigating this tragedy led him to see a larger problem with industry-funded clinical trials. “The danger lies not just in the particular circumstances that led to Dan's death, but in a system of clinical research that has been thoroughly co-opted by market forces, so that many studies have become little more than covert instruments for promoting drugs. The study in which Dan died starkly illustrates the hazards of market-driven research and the inadequacy of our current oversight system to detect them.”

The repercussions from the Markingson story continue. In 2009 the Minnesota Legislature unanimously passed a bill that makes it illegal for a patient under a “stay of commitment” to be enrolled in a clinical trial—it’s called Dan’s Law. Meanwhile, pressure has been building from Mary Weiss and her supporters, including eight members of the University of Minnesota bioethics department, to have an independent panel investigate possible ethics violations at the U of M in regards to their industry-funded drug trials.

As recently as last month, U of M officials “rebuffed” this request for an independent panel of experts to investigate the Markingson case and its ethical issues. The university claims that the FDA’s investigation in 2005 effectively exonerates it of any culpability in the case. A statement from the university’s Board of Regents defends their practice of accepting research funding from corporate sponsors:

“In an era when public funding of our University and its research is limited, we must recognize that critically important medical and health research requires substantial private investment, both from donors and from corporate sponsors,” the letter stated. “Those funding sources provide great opportunities — and pose significant challenges — for the University. We believe our faculty is ideally suited to engage in a rigorous, open, and honest exploration of these opportunities and challenges, and the impact they may have for the integrity of our research mission.”

What do we take away from this tragic tale? First of all, it is absolutely essential that institutional review boards (IRBs) do their stated job of protecting human subjects—and not make decisions that instead promote the financial interests of their institutions. A seriously ill person like Dan Markingson who has already been deemed delusional and unwilling to accept that he needs treatment is not competent of providing informed consent; especially if the alternative to consent is to be locked away in an institution or face criminal charges.

The second lesson from the Markingson case is that academic researchers need to rethink their participation in industry-designed and funded drug trials. The truth is that these trials can be—and often are—designed to cast a company’s drug in the best light; for example, in the CAFÉ trial, there is evidence that participants were given lower, and therefore potentially less effective doses of the competitor drugs Zyprexa and Risperdal, than AstraZeneca’s Seroquel. If the trial results aren’t positive, a company can bury them or recast them to demonstrate a different conclusion. If they are positive, they are published and become a powerful marketing tool.

As Elliott tells Reporting on Health, “I don’t think that the clinical trials and the marketing of the drug should have anything to do with one another.”

He goes on,  “[P]eople have been volunteering to take part in these clinical trials because they think they are contributing to scientific knowledge in some way. They think they are going to save people’s lives or make other people’s lives better. Some of the people in these trials may not be harmed, but a lot of people are harmed and experience side effects, sometimes very severe ones. And sometimes in the case of the antipsychotics, they kill themselves or they kill other people while they are in the trial.”

6 thoughts on “The Dark Side of Industry-Funded Drug Trials

  1. Naomi-
    I am exhausted from reading hundreds of stories and booksfor over a decade now about the morally bankrupt US Pharmaceutical Industry.
    Regulations,fines and lawsuits are not working.
    The only action that I see remaining is jail sentences for some Big PhRMA CEOs
    Dr. Rick Lippin

  2. And some jail time for morally bankrupt researchers.
    What Dr. Olson did was criminal malpractice. . . no regard for the well being of his patient, whose needs and interests should have come first.
    So much for Do no Harm.

  3. A simple definition of the word coerce is “to force to act or think in a certain way by use of pressure or authority without regard to individual wishes or desires.” This certainly played out regarding Dan Markingson. For someone who basically never agreed he was mentally ill, always regarded his “psychosis” as simply being sleep deprived for a few days, and prior to enrolling into and during the study declared himself “completely” well, there is no other explanation for his enrollment other than greed and ego by his so-called treating psychiatrist. Dr. Schulz has made a career out of stumping for AstraZeneca and their drug Seroquel. Always calling it “safe” and “effective.” Well, the simple definition of the word SAFE– “free from danger or the risk of harm” Any competent clinical investigator not being paid by the sponsoring pharmaceutical company would certainly choose different words to describe a very powerful antipsychotic drug, especially now that there are over 25,000 lawsuits resulting from severe side effects of the drug. The psychiatry department at the University of Minnesota has done nothing to find or develop a cure for schizophrenia. They have only prostituted themselves for a bonus check. So much for great research that has cost lives.

  4. Indeed, this story is old news. No one has or probably will pay any significant penalty. Its a yawner. A bunch of bloggers complain, a couple of news stories come out followed by as many supportive news stories the company and healthcare institution can buy or influence. No fuss no muss in the board room or in the halls of power in medicine.