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Bethesda, Md—New moves are coming to protect human research subjects. Greg Koski, PhD, newly appointed director of the Office of Human Research Protection, has put clinical researchers on notice that if they fail to ensure that participants in their studies are properly protected, they will be put out of business. Since he has just taken on the job, Koski was not able to spell out how this mandate might be implemented, but his intention was clear. (The office he heads was recently transferred from the National Institutes of Health, where it was called the Office for Protection From Research Risks, to the Department of Health and Human Services [DHHS].)
Speaking at a meeting on "Human Subject Protection and Financial Conflict of Interest," held at the National Institutes of Health in August, Koski said, "Research has to be based on the highest standards of responsible conduct, based on ethical principles by each and every individual taking part. Let me make it unmistakably clear, in case anyone has any doubts. If institutions and individuals fail to truly accept their responsibilities and in good faith work to achieve them, then they simply should not be permitted to engage in this endeavor."
As several speakers noted, the meeting was called in response to public concern over the disclosure that the principal investigator of an experimental human gene transfer study at the University of Pennsylvania was a major stockholder in the company that sponsored the research.
Conflict and resolution
Before the first coffee break, it was clear that the issue was not limited to the emoluments and stock options of clinical investigators. Conflicting interests involve the entire research endeavor. "They are real, serious, and a threat to the enterprise. They have intensified over the past 5 years and the situation may be out of control," warned Koski. He and other speakers made it clear that the situation had to be addressed. It was less clear what steps would be both practicable and effective.
One step has already been taken. In May, the American Society for Gene Therapy issued a statement making it plain that financial conflicts are unacceptable for investigators engaged in gene therapy trials. In part, the statement reads: "All investigators and team members directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements in companies sponsoring the trial."
At the meeting, Savio L. C. Woo, PhD, the society's president, summarized the events leading to the death of Jesse Gelsinger, a subject in the gene therapy trial at the University of Pennsylvania. Woo read the society's statement—which was widely praised at the meeting—and urged other organizations to follow suit. "If the investigator's interests and the patient's interests are not on the same side of the fence, there is no way that clinical studies can proceed," said Woo, who is director of the Institute for Gene Therapy and Molecular Medicine at Mount Sinai School of Medicine in New York City.
Conflicts of interest are ubiquitous. Koski called them "pervasive," noting the sometimes conflicting roles of the physician investigator and the patient subject. Such conflicts cannot be eliminated, he said: "They are intrinsic to the research process."
Academic advancement, professional acclaim, prestigious prizes—all may be more powerful in influencing behavior than the prospect of material enrichment, said David Korn, MD, vice president of the Association of American Medical Colleges. Korn described academic conflicts as intellectual and of not much public concern, although widely recognized. However, he noted that financial conflicts often go unrecognized until they are specifically disclosed, and said that when they are, they are well understood by the public. For this reason they pose a special vulnerability and risk to the research enterprise, he said.
Changes hinder protection
Other speakers pointed out that protecting human subjects is an integral part of protecting research in general. But by the end of the day-and-a-half meeting, it was clear that real protection is going to be uphill work. There have been major changes in the way clinical research is conducted in recent years. Academic medical centers, which used to design, conduct, and control findings from clinical studies, are now often hired hands in the business of providing data for companies seeking drug approval from the US Food and Drug Administration.
"The companies own the data, analyze it, and control publication," said Marcia Angell, MD, former editor of the New England Journal of Medicine. She made a number of recommendations for academic researchers to follow and urged that institutions make them common policy. Among Angell's suggestions are that no investigator who receives research support from industry should have other financial ties to the company concerned; no strings should be attached to the research; investigators should design, analyze, and publish their own studies; and institutions and senior officials should not hold investments in any health care industry.
Angell acknowledged that academic medical centers are currently in difficult times financially. "I sympathize with their plight," she said. "But the answer cannot be to sell themselves and their patients to industry. Patients should not have to wonder whether an investigator is motivated by financial gain, and the public should not have to wonder whether medical research can be believed."
Experimentation an industry
But even as the conduct of research at academic centers has changed, another new trend has emerged—privately conducted clinical research. The traditional route is being bypassed by the private sector. "There is a growing human experimentation industry. It is transforming medical research into a business," said Sidney Wolfe, MD, director of Public Citizen's Health Research Group, Washington, DC, a consumer organization.
Wolfe cited a report, Recruiting Subjects in Industry Sponsored Research, published in June by the DHHS Inspector General's Office, that has examined this development. An increasing number of contract research organizations called "human experimentation corporations" have sprung up that can recruit patients for drug company trials and do it more efficiently and rapidly than can universities. These organizations engage in what Wolfe described as "highly questionable recruiting practices, using individuals from among the uninsured and in foreign countries."
In 1993, only 20% of drug company research was done privately; by 1998, 50% was being done outside academic centers. The number of private practice–based investigators has grown from just over 3000 in 1990 to more than 11,000 in 1995—almost a four-fold increase. This change is a response to pressure to get new drugs approved. A difference of 1 month in getting a drug to market can mean tens of millions of dollars in additional revenue before the drug's patent expires, said Wolfe.
Granted that conflicts of interest cannot be eliminated, they must be managed. Effective mechanisms to ensure this are needed, said Koski. He indicated that while many institutions try to manage these conflicts, many other organizations work outside the academic arena, so guidance must be at the national level. "If guidance is not effective, rules and regulations must follow," he said.
But compliance in itself is insufficient, added Koski. "What we want to establish is a culture of conscience and responsibility so that each of us in the research enterprise is doing the right thing because it's the right thing to do," he said. "If we do that, compliance will not be an issue."
Marwick C. New Head of Federal Office Clear on Protecting Human Research Participants. JAMA. 2000;284(12):1501–1502. doi:10.1001/jama.284.12.1501
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