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System's serious flaws have led many to call for regulatory reform

By Duff Wilson and David Heath
Seattle Times staff reporters

Copyright © 2001 The Seattle Times Company

IT'S BEEN MORE than a half-century since horrifying human experiments by the Nazis prompted the first code of ethics for medical research. Yet enforcement of ethics today remains largely an honor system.

On the agenda

Here's what's on the agenda in the national effort for reform of medical research:

Sunday through Tuesday: Medical Research Summit, a privately sponsored forum in Washington, D.C., for industry and regulators, on the regulation and ethics of medical research in the U.S.

April 9-10: Second meeting of the National
Human Research
Protection Advisory
, a panel appointed by then-Secretary of Health and Human Services Donna Shalala.

• Late April or early May: one or two days of hearings on human research and financial conflicts of interest, by a subcommittee of the U.S. Senate Commerce Committee.

In this country, government regulators leave it to research centers to police themselves. And even when regulators learn that rules have been broken, they rarely mete out stiff punishments.

This has led to inconsistent, lax standards - and, sometimes, patients dying in questionable experiments.

Birth defects caused by the drug thalidomide, prescribed without patients always being told it was experimental, led in 1962 to the first U.S. law requiring informed consent for medical research. A decade later, news that 399 black men in Tuskegee, Ala., had been deceptively denied treatment for syphilis as part of a government experiment ultimately led to major reforms.

Yet the system still has serious flaws.

"Unfortunately, because the current system of protections has, in large measure, been cobbled together in the wake of abuses, it is both more cumbersome and less effective than it must be both to support research and protect participants," the National Bioethics Advisory Commission, appointed by then-President Clinton, said in a recent report.

But critics fear that pharmaceutical and biotechnology companies, which pay for much medical research these days, will be able to thwart major reforms. Abbey Meyers, president of the National Organization for Rare Disorders, expected few results from the myriad commissions and studies calling for changes.

"I think we're probably headed toward another catastrophic event like a Tuskegee experiment" before that will happen, Meyers said.

'The science has been lost'

Of particular concern these days is the relationship of physician-researchers and their medical centers to for-profit companies.

Since Congress in 1980 made it much easier for universities and researchers to cash in on their discoveries, "the science has been lost in the rush for money," said Dr. Thomas Bodenheimer of the University of California, San Francisco, who decried this trend in The New England Journal of Medicine.

Momentum to reform conflict-of-interest rules has grown since the highly publicized death of a young man in a clinical trial at the University of Pennsylvania.

Eighteen-year-old Jesse Gelsinger agreed to participate in a gene-therapy trial even though it offered him no benefits. He slipped into a coma after being infused with a gene-therapy substance and died four days later on Sept. 17, 1999.

Unknown to Gelsinger, the researcher, Dr. James Wilson, owned 30 percent of Genovo, whose gene-therapy substance he was testing. Wilson reportedly made $13.5 million when the company was later sold to Targeted Genetics of Seattle.

Gelsinger's death has prompted many universities and medical-research centers to rethink their financial-conflict policies. Most follow federal rules requiring researchers to disclose financial conflicts to someone in administration, but none ban such conflicts outright.

Critics worry, too, that financial conflicts are compromising the validity of medical research.

"Teaching hospitals and medical schools are becoming increasingly compromised in that they are behaving like research outposts for the pharmaceutical industry," said Marcia Angell, former editor in chief of The New England Journal of Medicine.

A report in The New England Journal said 96 percent of studies in medical journals advocating the use of heart and blood-pressure drugs called calcium-channel blockers were funded by the drug manufacturers. Only 37 percent of the studies critical of those drugs had financial ties.

Another study said that in medical journals, only 5 percent of studies sponsored by the makers of six oncology drugs were critical of the drugs, vs. 38 percent of independent studies.

Review boards are pressured

The burden of protecting patients falls to so-called institutional review boards, or IRBs. But these local boards, appointed by the institution they police, are often overwhelmed and lack expertise.

And even if an IRB wants to get tough, its members may lack the time to do it. Studies by the federal General Accounting Office and the Department of Health and Human Services (DHHS) have found IRBs to be severely overworked.

"In some cases, the sheer number of studies necessitates that IRBs spend only one or two minutes of review per study," said a 1996 GAO report. For continuing studies, "these reviews are typically either superficial or not done at all."

An IRB member at one institution explained to federal investigators that for continuing studies, he usually just checks to see if there have been any deaths.

"If no patient has died, then he generally will not raise questions," said a 1998 DHHS report.

There are also financial pressures to approve research because delays could cost an institution grants or commercial partnerships. One federal report described the process used by some pharmaceutical companies as "IRB shopping." A drug company shops around for an IRB that will give it quick approval on proposed research.

Two years ago at the University of Illinois at Chicago, 10 members of the IRB quit, complaining that they felt pressure from the school not to interfere with lucrative studies. One said, "They thought we were overly scrupulous, nitpicking obstructionists who were spoiling the research-enterprise system."

The federal Office for Protection from Research Risks (OPRR), under fire for rarely inspecting research centers, signaled a new get-tough attitude in May 1999 when it temporarily shut down federally funded research at Duke University because the school wasn't adequately tracking experiments to ensure the safety of patients. It later suspended research at several other universities, including the University of Illinois at Chicago.

Dr. Greg Koski, director of the revamped Office for Human Research Protections, the federal successor to the OPRR, said that shutting down Duke and other universities caught the attention of academic centers and led to better compliance.

When the National Institutes of Health recently reminded grant recipients they were required by contract to report any deaths or other "adverse events" in gene-therapy trials, more than 500 previously undisclosed problems were reported.

However, no such reports are made public in the many clinical trials that don't involve gene therapy. The Food and Drug Administration treats those as confidential "trade secrets."

Efforts toward reform

Many of the reforms being proposed nationally focus on educating and certifying anyone involved in research and on accreditation for research centers. There's also a push to reduce paperwork.

"The mindless way to try to protect from any injury to subjects is to build a wall that's higher and thicker that makes it more difficult to do research," said Koski.

"By and large, most human research is done by very well-intentioned individuals according to high standards. The institutional review boards by and large take their responsibilities very seriously."

A U.S. Senate subcommittee is expected to hold hearings on human-research protection this spring.

Previous efforts to reform the system have fallen short. There have been several stinging reports about the failure of IRBs in recent years, including one by the DHHS in 1998.

Last year, that office issued another report, saying that virtually none of the changes it had recommended had been made.

Said Dr. Sydney Wolfe of the consumer group Public Citizen, "They are almost begging for deaths and serious injuries as the prerequisite to making further changes."

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