Monday, August 23, 2010

Alliance For Human Research Protection


Carl Elliot's Making a Killing

Monday, 23 August 2010

The catalyst for Dr. Elliott's article was the tragic case of Dan Markingson, a 26-year old who committed suicide in May 2004, while prescribed Seroquel in the CAFE trial.

Kudos to Carl Elliott, MD, PhD, whose insightful article, "Making a Killing ," published in Mother Jones, is a searing indictment of the morally bankrupt prevailing culture in academia and government oversight agencies that has lent the veneer of legitimacy to dubious commercially-driven clinical trials that are designed to promote drug marketing goals--NOT to produce scientific knowledge for the benefit of society--as mandated by ethical standards, such as the Nuremberg Code.

The Nuremberg Code stipulates that an “experiment should be such as to yield fruitful results for the good of society,” and “the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.”

But, Dr. Elliott identifies a fundamental moral deviation from universal ethical codes governing clinical research: the assumption that medical research is being conducted to produce scientific knowledge is no longer valid.

Dr. Elliott's article focuses on AstraZeneca's CAFÉ study which was designed to promote the marketing of its antipsychotic drug, Seroquel. The study was sponsored by AstraZeneca and the University of North Carolina--it was conducted at 26 sites, involving 400 patients. Of these, all but 119 stopped taking the drug before the yearlong study was finished. Such trials lack a scientific raison d'etre. They are, by definition, immoral.

Indeed, when shown the published report of the CAFÉ study, Dr. Peter Tyrer, the editor of the British Journal of Psychiatry, Dr. Tyrer indicated:

“I would have major problems accepting a manuscript of that nature....“In scientific terms this study is of very little value.”

Internal AstraZeneca documents indicate that the CAFÉ study was designed to serve two purposes: a “regulatory” purpose and a “commercial” purpose. The regulatory purpose was to “produce data that will help us defend the Seroquel label.”

The commercial purpose was to “produce data that will enable us to generate commercially attractive and competitive messages in relation to diabetes and weight.”

So, Dr. Elliott cuts to the chase when he asks:

"... if a research study is not really aimed at producing genuine scientific knowledge at all...How much risk to human subjects is justified in a study whose principal aim is to “generate commercially attractive messages”?

The catalyst for Dr. Elliott's article was the tragic case of Dan Markingson, a 26-year old who committed suicide in May 2004, while prescribed Seroquel in the CAFE trial. AstraZeneca reported 18 "serious adverse events" in the trial, including an alleged homicide, five suicide attempts, of which two were successful suicides--both by patients taking Seroquel.

Dan was enrolled in the CAFÉ study at the University of Minnesota--while he was in the thows of a psychotic episode. In that mental state, he was, by definition mentally incapacitated--and therefore, incapable of giving informed consent. Within 6 months of being in the study, he committed suicide. Those involved in his enrollment were violating fundamental national and international ethical standards.

Documented evidence shows that Dan was enrolled in the trial under duress--threatened with involuntary commitment to a mental hospital. Furthermore, university psychiatrists kept him in the trial despite the vigorous opposition of his mother who expressed concern about his deteriorating mental condition and explosive rage. Mary Weiss' relentless effort to protect her son from the risks involved in the trial were ignored by senior university psychiatrists--Dr. Stephen Olson and Dr. Charles Schultz, chairman of psychiatry. She wrote numerous letters asking that Dan be released from the study, to no avail.

Ten days before he killed himself, his mother left a voice message for the CAFÉ study coordinator saying:

“Do we have to wait until he kills himself or someone else before anyone does anything?”

This case encapsulates the tragic consequences of a broken system which is not designed to detect the hazards for human subjects posed by market-driven research. Nor is the system designed to take steps to prevent predictable hazards. Indeed, the authorized academics and government officials charged with protecting human subjects from unjustifiable risks of harm and / or exploitation, whose responsibility is to ensure that clinical trialists adhere to federal regulations for the protection of human subjects, are violating their public mandate. Instead of protecting human subjects from exploitation, they shield the commercial and academic stakeholders.

Dr Olson and Dr. Schulz, who were handsomely paid by AstraZeneca, denied that Dan's condition deteriorated during the trial.

A public database maintained by the Minnesota pharmacy board indicates that "Olson received a total of $240,045 from the pharmaceutical industry between 2002 and 2008, with $149,344 coming from AstraZeneca. Dr. Charles Schulz, his co-investigator and department chair, received an even greater sum: more than $571,000 from the industry, with $112,020 coming from AstraZeneca." The University of Minnesota received $327,000 for the study from AstraZeneca. Clearly, these sums presented a conflict of interest.

Sharon Matson, an FDA investigator exonerated the University of Minnesota, finding no evidence of misconduct: “I did not find any evidence of misconduct, significant violation of the protocol, or regulations governing clinical investigators or IRBs...” She specifically dismissed the suggestion that Dan was mentally incompetent to consent to the study, writing that “there was nothing different about this subject than others enrolled to indicate that he couldn’t provide voluntary, informed consent.” In other words, FDA officials endorse the enrollment of psychotic patients in drug trials--even as such patients are incapable of making sound judgments.

As Dr. Elliott explains, "the study in which Dan Markingson committed suicide was not simply a matter of inadequate informed consent, or financial conflicts of interest, or even failure to monitor a subject’s care. The ethical breach was built into the study from the start. It is one thing to ask people to take risks for science, or the common good, or to help other people. It is another thing entirely to ask them to risk their lives for the marketing goals of AstraZeneca."

Dr. Elliott notes that documents unsealed in related civil suits suggest an alarming pattern of deception. Internal correspondence reveals company officials discussing how to hide or spin potentially damaging studies. “Thus far, we have buried trials 15, 31, 56,” wrote a publications manager in 1999.

“The larger issue is how do we face the outside world when they begin to criticize us for suppressing data.”

Indeed, in 2010, AstraZeneca became the fourth pharmaceutical giant in the last three years to admit to federal charges of illegal marketing of antipsychotic drugs. The company has paid $520 million to settle federal investigation over the illegal marketing claims made about Seroquel.

It faces more than 25,000 civil lawsuits filed on behalf of patients contending that the company did not disclose the drug’s risks.

But what about the culpability of the academics who conducted such commercially-motivated exercises?

The principle investigator of the CAFÉ study was Jeffrey Lieberman MD, chairman of psychiatry, Columbia University (then at Chapel Hill, North Carolina).

How much did AstraZeneca pay him to provide the appearance of legitimacy to this commercially driven exercise whose goal was "to produce data to generate commercially attractive and competitive messages?"

In 2005, Dr. Lieberman rhapsodized to physicians at the World Congress of Biological Psychiatry about the CAFÉ study findings and the value of second generation antipsychotics. He recommended that they explore "even higher doses" on their patients.

"CAFÉ is the first study of this size to compare multiple second generation antipsychotic drugs in first-episode patients. This study provides important new information on the comparative efficacy and safety of these medications that will guide clinicians in their care of these patients. These data underscore the importance of appropriate dosing for agents such as quetiapine [Seroquel] in first-episode psychosis. In individuals with chronic schizophrenia, clinicians should fully explore even higher doses of medications, including quetiapine."

Our own observation is that commercially-driven clinical trials such as the CAFÉ study, foster about as much genuine scientific information as prostitution fosters family values!

Dr. Elliott, who is a Professor at the Center for Bioethics at the University of Minnesota Medical School; and a Professor in the Department of Pediatrics as well in the Department of Philosophy, writes:

"Of all the ways in which Mary Weiss has been damaged by the University of Minnesota, there is one episode that still brings a sting of shame to my face. When the lawsuit over Dan’s death was dismissed, the university filed a legal action against Mary, demanding that she pay the university $57,000 to cover its legal expenses. Gale Pearson, one of Mary’s attorneys, says that while such suits are technically permissible, she had never seen one filed in her previous 14 years of legal practice. The university agreed to drop the lawsuit against Mary only when she agreed not to appeal the judge’s decision.

“Maybe they want to chill anyone who might think of challenging the university, even if her child had died,” Pearson said. “It gave me a sick feeling.”

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