In their book, The Courage to Fail, Renee Fox and Judith Swazey describe the tension at the heart of research regulation. “Research physicians,” they write, “can mislead, exploit, or injure their subjects in the name of patient welfare, scientific progress, or public good.” At the same time, they explain, research physicians and study participants “are brought together by their suffering, competence, hope, courage, sense of adventure, quest for knowledge and meaning, and desire to serve.” Fox and Swazey call the tension between the rosy view and diabolical view a “socially structured ambivalence” that arises because research is, ultimately, designed to meet the needs and demands of society. By its nature, research may prioritize societal needs over the rights and integrity of the individual research participant.
Carl Elliott’s book explores this structured ambivalence. The ambivalence is apparent in the case of Dan Markingson, the case that led Elliott to become a medical whistleblower. His experiences in that uncomfortable role then led him to explore the motivations of others who took a similar path and, like him, felt compelled to call out the exploitation, equivocation, and dehumanization that characterizes medical research at its worst.
Mr. Markingson was a 26-year-old who developed schizophrenia. Prior to his illness, he had been a high-achieving student at University of Michigan. He moved to California and hoped to become a screenplay writer. But then he started hearing voices. He became withdrawn. His mother, Mary Weiss, brought him back to Minnesota where he was diagnosed, started on anti-psychotic medication, and offered enrollment in a clinical trial comparing different FDA-approved medications.
Six months later, Markingson took his own life. His mother blamed the researchers for Markingson’s death. Numerous oversight agencies that investigated the study were not so sure.
Elliott’s book is essential reading for anybody concerned about biomedical research and the protection of people who participate in research. This book, and his prior writing on the booming but sometimes shady business of drug development and the failures of research regulation, raise questions about whether we can have medical progress without “the occasional human sacrifice.” Elliott unflinchingly explores the deep rot at the core of both medical education and the biomedical research enterprise. He is following a trail blazed by Samuel Shem whose 1975 novel, House of God, analogized the corruption of our most hallowed medical institutions with the corruption revealed by the Watergate scandal. There are echoes of Sandeep Jauhar’s book, Doctored, an autobiographical tale of Jauhar’s growing disillusionment with the profession that he entered with high ideals, and of Damon Galgut’s book, The Good Doctor, which was inspired by (and takes its title from) Chekov’s bitter short stories.
Elliott’s focus is on the motivations of the whistleblowers. That focus raises questions about the motivations of the researchers upon whom the whistle was blown. It is easy to demonize Big Pharma as rapacious, so it would be convenient if the researchers were all corrupt shills, on the take in conventional ways. Or if they were all patently evil racists and misanthropes. Instead, they are as different from one another as are the whistle-blowers. Saul Krugman, who did studies on the cause of hepatitis and on the safety and efficacy of interventions at the horrendously overcrowded Willowbrook State School, didn’t cause the miserable conditions there. His studies were not funded by drug companies. He seemed to by trying to help the children whom society had neglected. The Cincinnati radiation experiment and the Tuskegee syphilis study were sponsored by the US government, not the drug companies. It is unlikely that the physician-researchers profited from those studies. Furthermore, if America’s corrupt and dysfunctional health care system was to blame for research abuses, we wouldn’t have expected to see similar transgressions in Sweden and New Zealand.
Nor is it clear that the current system of oversight has failed or whether a better one could be devised. Four of the studies that Elliott describes – in Tuskegee, Willowbrook, Cincinnati, and New Zealand all took place before the current IRB system of research oversight was in place. The more modern scandals, such as the fraudulent development of tracheal implants, involved active deception of the IRB rather than an IRB failure.
Markingson’s death is one of the most thoroughly investigated deaths of any research participant in the world. In the end, it was unclear whether his death was caused by his participation in the study or whether the study was itself unethical, as some critics aver. An investigative task force convened by the State of Minnesota reviewed thousands of pages of documents and conducted interviews with people knowledgeable about the study and about psychiatric research. They concluded, “We do not think it is possible to know whether Dan Markingson’s suicide was connected to his participation in the University clinical drug study; the suicide of a person with serious mental illness may involve many contributing factors.”
The problem with attributing Markingson’s death to the study is that he known to be at high risk for suicide. People with schizophrenia often kill themselves. Estimates of suicide rates in schizophrenia range from 5-22%. Many more patients with schizophrenia attempt suicide. The patients at highest risk are younger patients, males, patients with above average intelligence and high levels of achievement. Markingson checked all those boxes.
The standard treatment for such patients is anti-psychotic medication. There are many such medications that have been approved by the FDA. If Markingson had not enrolled in a clinical trial, he likely would have received one or another of the available drugs. To this day, dctors don’t know which is best.
If he had not been in the study, Markingson would likely have been hospitalized at the Anoka Regional Treatment Center. That facility has been plagued by scandals relating to its inability to protect the patients hospitalized there. It is unclear whether his outcome would have been better.
Questions about how to prevent suicide are an active area of research. One key factor is that many of the drugs that are effective in preventing suicide have side effects that lead many patients to stop taking them. Thus, many studies look at the tolerability of such drugs in order to figure out which drug is likely to be taken for long enough to work. A recent review noted, “Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. Thus, there are significant reasons to search for ways to improve effectiveness of current pharmacotherapy.”
So would Markingson have been better off if he had not enrolled in the clinical trial. Hard to know. Critiques focused on three potential harms. The first focused on Markingson’s capacity to consent. At the time, there were no federal guidelines on assessing capacity in patients with schizophrenia. There have been concerns about denying that such patients have capacity to consent or refuse treatment and policies generally assume that patients are competent until proven otherwise. A 2020 review concluded that the majority of patients with schizophrenia or bipolar disorder are capable of treatment related decision making and should be involved in decisions about the care of their health.
Second, there were concerns because a drug company was sponsoring the study and was paying the university based on the number of patients enrolled. But drug companies sponsor at least 70% of the clinical research done in this country. In most studies, the institution that is conducted the study is reimbursed for the costs of research based on their ability to enroll patients. But this is a standard study design. Clinical trial budgets are usually based on an amount per patient enrolled. To determine what amount to request, prepare a line-item budget for all potential costs. It does incentivize enrollment. But it wasn’t enough to allow other centers to enroll sufficient patients to make participation in the study worthwhile.
The third concern was that Markingson’s doctor was also the principal investigator on the study and so had an inherent conflict of interest. This concern has been debated for decades without satisfactory resolution. Morain studied oncologists’ attitudes and discovered that most doctors believe that the clinician investigator is the best person to seek consent, in spite of the potential for conflicts of interest. She concludes that patients prefer that their physician be the one to explain research studies to them, and that “Physician-investigators may be best positioned to provide clinical and scientific context, which can aid patient-participants in distinguishing research from care.”
In the end, we are left with the question implicitly raised by the title of Elliott’s marvelous book. Does medical progress require an occasional human sacrifice? The answer must be as tentative and guarded as the conclusions of the many investigations into Dan Markingson’s death. People will die while they are in research studies. More would die if we didn’t do research studies. It is easier to attribute the deaths of research subjects to their participation in the studies than to assign accountability for deaths that take place because we haven’t done good research. Sadly, research on mental health disorders and treatments for them lags behind research on health problems like cancer or heart disease. The lack of research may be the more important human sacrifice, as we still don’t know, two decades after Markingson’s death, what treatments are most effective to prevent suicide in patients with schizophrenia. Perhaps there is an unfortunate overlap between the view that research requires an occasional human sacrifice, and the view expressed by Fox and Swazey that medical progress can only occur if innovators have the courage to fail.
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