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WASHINGTON, DC — “Prior to the mid 1960s, there wasn't much interest in ethics in general and biomedical ethics in particular,” Greg Koski, MD, PhD, told attendees at a session here on protecting human subjects and ethics in clinical trials at the Annual Meeting of the American Society for Experimental NeuroTherapeutics (ASENT) in March. “But scientists, especially clinical trialists, lost their innocence as a result of disclosure of the many abuses of human subjects in research.”


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Dr. Koski, Director of the Department of Health and Human Services (HHS) Office of Human Research Protections, noted that the Tuskegee Syphilis Study, among other examples of moral atrocities, served as a trigger for the current increasingly stringent human subject protections. Nonetheless, he said, in his 18 months in Washington, problem cases involving human subjects continue to mount.


“I receive reports of morally questionable studies conducted in underdeveloped countries because they would not have been permitted here. There are reports of patient deaths in clinical trials, financial conflicts of interest, deaths in physiology studies for which no benefit would accrue to patients, and reports of scientists who, at the behest of pharmaceutical companies, write shadow papers about studies in which they played no part.

“I look at this gigantic pile of clippings and it makes me sick,” Dr. Koski said.

The HHS has been making slow but steady progress in the goal of protecting human subjects, and full protection can come “none too soon,” he said.

“Clinical trials are absolutely essential, and society can reap the benefits of improved medical treatment only through human studies,” he continued, “but we must put the interest of human subjects in a top priority position. Science without ethics can do incredible harm.”

But, Dr. Koski added, “We cannot and should not depend on government alone to protect human subjects because the government itself is in a position of potential conflict of interest. It is one of the nation's largest biomedical and clinical research entities.”


Dr. Koski said that HHS will continue to invest more than $100 million to protect human subjects and decrease financial conflicts of interest. To this end, it engages in a variety of activities: educating the public; training members of institutional review boards and individuals who oversee human trials; and accreditation training for hospitals and other institutions where clinical trials are conducted.

A member of the audience asked what seemed to be on the minds of many at the meeting: What about placebo-controlled trials? Dr. Koski replied that placebos should not be banned outright, but they should be used in a clinical trial only when appropriate – that is, if there is no known effective treatment for the disease under study. “No patient should be denied treatment and subjected to harm if there is already an effective way to treat the disease,” he said.


Striking a more forceful tone, Marcia Angell, MD, Senior Lecturer in the Department of Social Medicine at Harvard University Medical School, said: “I am very critical of the direction in which clinical research has been moving in the past decade.”

Dr. Angell, formerly Editor-in-Chief of the New England Journal of Medicine, said she is “worried about the growing influence of industry on the type of research done in the United States and the way it is conducted.”

Dr. Angell characterized some academics as “hired hands” of pharmaceutical companies that sponsor clinical trials. “Many sponsors control the data produced, they control the decision about when – or even if – to publish, and some even refuse to give investigators access to their own data. And the investigators accede to these restrictions.”


Dr. Angell continued: “Even when academics are not completely in the pocket of their for-profit sponsors, they often have a “revolving door arrangement.” That is, they agree to promote the sponsor's product after a clinical trial is completed – and presumably after the drug goes to market. Drug companies actively seek the imprimatur of well-known and respected medical researchers.

“Academic medical centers run on a star system second only to Hollywood,” she said. “But financial ties can and should be almost completely eliminated, and there should be no need for all the hand-wringing that currently goes on over ‘managing’ conflict of interest. If it's eliminated, it doesn't have to be managed.”

Dr. Angell described what she believes are the negative consequences of the trend toward greater conflicts of interest. Among these consequences, she said, industry, not academic medicine, is setting the American biomedical research agenda, and studies are often biased by industry.

“There are many ways to bias a clinical trial, not all of which are deliberate or obvious,” she said. “I am increasingly concerned about protecting human subjects when an investigator has a financial stake in the research.”


Dr. Angell then proposed three rules that she believes would greatly reduce the amount of financial conflict of interest in human research: (1) Investigators should have no financial ties to the company that supports their research – at the time they conduct the research and forever after; (2) Investigators should not accept grants with strings attached, and they must control their own data and publication terms; and (3) Investigators should adhere to the conflict of interest guidelines established by the institution in which they work. There ought to be no get-rich schemes between academic employees and industry.

This reporter from Neurology Today asked Dr. Angell to respond to this question: Given the close-to-the-edge financial straits in which most universities and medical centers operate, where would the money come from if industry were prevented from providing financial sponsorship of clinical trials, and if it came from the university itself, how would this affect its overall operation?

Dr. Angell replied: “It's not so much that industry sponsors academic medical research, it's the terms under which the financial sponsorship is given and the relationship between the sponsor and the investigator. If a company wants to fund research, it should provide a grant, and then stand back – with hands off the research – and wait for the results.

“Patients shouldn't have to wonder if the investigators to whom they are entrusting their lives are motivated by financial gain, and the public shouldn't have to wonder if research results can be believed.”