Another disaster waiting to happen

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This article appeared on the now-defunct BioMedNet News.

The entire framework for regulating clinical trials in the US is flawed and long overdue for reform, says a leading bioethicist. The current review process is “somewhere between inadequate and pathetic,” Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania told BioMedNet News today. “The whole system is clearly broken.”

Federally funded clinical trials are monitored by Institutional Review Boards (IRBs), which are responsible for ensuring that trials meet federal standards for safety and are located within individual institutions. But the system, devised in the 1980s, is simply not up to tackling the volume of clinical research that now exists, Caplan says.

IRBs are “overworked, underappreciated and undersupported,” agreed John M. Falletta, a professor of pediatrics and chairman of the IRB at Duke University. Duke, for example, has 4 IRBs (with a 5th rapid-response group), each with some 20 members.

But the IRBs meet once a month, their members contribute less than 20 hours a month and, together, are responsible for reviewing the university’s 2,500 trials.

Falletta says the IRBs at Duke can manage although “it wouldn’t be inappropriate to have more [IRBs].” Not long ago, however, the university had only one IRB.

“We were there 2 years ago,” said Falletta, referring to an incident in May 1999 when the federal government shut down human research at Duke. “And that’s when [the Office for Protection from Research Risks(OPRR)] came to visit and helped us to recognize that we needed more IRBs.”

The year before, the office of the inspector-general at the department of Health and Human Services (HHS) had detailed the limitations relating to IRB review and called for widespread reform. Following the report, Falletta said, “OPRR became more vigilant and the rest is history.”

OPRR, then within the National Institutes of Health (NIH), has since been moved to the department of Health and Human Services. Now called the Office of Human Research Protection (OHRP), the agency has a larger budget and staff, and was responsible for halting clinical trials at Johns Hopkins University (JHU) last month.

Still, “OHRP is a mosquito chasing an elephant,” Caplan said. The agency is managing disasters after the fact rather than doing crucial maintenance work, he says. Representatives from the OHRP were unavailable for comment.

The entire system is plagued by minimal budgets, lack of centralized auditing, no communication between IRBs and a lack of guidelines on how many trials each IRB can handle, Caplan says. Because IRBs function at a local level, members are also often torn between institutional loyalty and the problems they might see with clinical trials.

What’s needed is a task force with tough recommendations and the attention of Congress, Caplan suggests. “There is much more systematic lobbying for animal research than there is for human research so there is no political pressure,” he said.

At a minimum, human trials should have spot inspection and audits on par with those for animal research. They should also carry a better range of penalties. “Shutting down the whole school [over one trial] is loony, it’s intolerable,” he said.

To combat their limitations, IRBs are taking some matters into their own hands. At Duke, all investigators, their staff and the IRB staff are required to take tutorials about aspects of clinical trials, such as informed consent.

At the University of Pennsylvania, members conduct their preliminary discussions on specific trials via general email alerts through listservs. According to Joe Sherwin, the university’s director of regulatory affairs, the preliminary discussions allow for more thorough review without bypassing the in-person discussions and decision-making mandated by the OHRP.

IRBs at institutions that are engaged in the same trial are also beginning to communicate with each other, rather than generate duplicate reviews, he says.

Scientists agree that incidents like the one at JHU aren’t completely preventable. At the University of Pennsylvania, for example, the gene therapy trial that resulted in the death of 18-year-old Jesse Gelsinger was reviewed by 2 IRBs, the DNA recombinant advisory committee or RAC (which functions within the NIH) and the Food and Drug Administration.

“It’s an illusion that you’re going to prevent such mistakes but that’s not the point,” said Caplan. The real issue, he cautions, is that the entire system is “fundamentally flawed” and if left unfixed, will result in many more disasters.

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