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Research dispute prompts patient-trials debate_Seattle Times

Mon, 19 May 2003

Newhouse News Service reports that the continuing dispute about the ethics and design of a multi-site lung ventilation experiment sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and conducted by the ARDSNetwork on 861 critically ill patients with acute respiratory distress syndrome (ARDS) without their informed consent, "has mushroomed into a rancorous national debate over how patients ought to be protected in medical experiments." The patients in the experiment were withdrawn from standard treatment to test two methods of air ventilation.

Its defenders are mostly scientists who had approved the experiment as members of one or another committee of scientists. They have taken the position that scientists conducting human experiments should be exempt from independent, public scrutiny.

Dr. Jeffrey Drazen, editor of The New England Journal of Medicine, who is a member of an NIH advisory committee that reviewed the experiment, wrote an editorial denouncing the Office of Human Research Protection (OHRP) for conducting an investigation. He told Newhouse News Service that "questions about study design should be left to scientific review panels at the NIH, not OHRP" which he claimed "should focus on compliance once studies are under way." [See AHRP letter to the editor submitted to the NEJM: http://www.ahrp.org/ahrpspeaks/ARDSletterNEJ041003.php ]

But that claim is illegitimate--the scientific community cannot exempt itself from independent review and oversight. Decisions about the safety of human subjects cannot be left to those who have a stake in the enterprise. The scientific community has not been authorized to be a law onto itself. Indeed, that attitude has resulted in an experiment that put critically ill patients at increased risk of their lives. OHRP is the authorized federal regulatory agency charged with oversight of all government funded human research--not research stakeholders such as the NIH.

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Research dispute prompts patient-trials debate
http://seattletimes.nwsource.com/html/nationworld/134766946_medical19.html

By Bruce Taylor Seeman
Newhouse News Service

WASHINGTON; A dispute among prominent researchers has mushroomed into a rancorous national debate over how patients ought to be protected in medical experiments.

Central to the conflict is a compelling question: Did design flaws in a landmark series of clinical trials, one including Seattle's Harborview Medical Center, put some patients at greater risk of death?

The outcome could have broad impact. The nation's medical researchers could be forced to rethink basic rules for the design of studies involving vulnerable patients.

The dispute stems from an investigation of a respected research team that has spent more than $37 million in federal funds to test new therapies for acute respiratory distress syndrome, or ARDS, an often fatal inflammatory-lung condition.

The federal government's Office for Human Research Protections last summer forced the shutdown of one study by the team, which is known as the ARDS Network or ARDSNet. In October, the agency demanded data on more than 1,800 subjects from that study and two earlier, completed ones.

Since then, the dispute has been a hot topic in medical journals, symposia and in the halls of the National Institutes of Health (NIH), the nation's foremost center for clinical research.

The prestigious New England Journal of Medicine has taken the unusual step of criticizing the Office for Human Research Protections (OHRP), saying it overstepped its bounds in investigating the design of the ARDSNet studies. And the American Thoracic Society, which is meeting in Seattle this week, has complained to the Health and Human Services Department, parent agency of the OHRP, that the investigation could impede research.

Control group

The federal investigation began when scientists at the National Institutes of Health charged that the ARDSNet team made flawed use of a basic scientific tool: the control group. In a classic medical experiment, some patients receive the therapy being tested while others, in the control group, get current standard treatment. The control group allows researchers to make meaningful comparisons between experimental therapies and traditional treatment - including comparisons on patient safety.

But Drs. Charles Natanson and Peter Eichacker, the NIH scientists who have led the criticism of ARDSNet, contended in a published paper that the research team inappropriately placed patients in control groups that represent treatment extremes, not routine care.

The consequences could have been serious, Natanson and Eichacker reason in their latest analysis, a letter in the March 1 edition of the American Journal of Respiratory and Critical Care Medicine. During one ARDSNet study of 861 patients, they said, control-group subjects died at a significantly higher rate--40 percent--than eligible patients who refused to participate, among whom the death rate was 31 percent.

That ARDSNet study tested whether survival rates would improve if ARDS patients on mechanical ventilators were given small breaths rather than large breaths. Its findings--that small breaths were significantly safer--were hailed as a breakthrough and published in May 2000 in the New England Journal of Medicine.

But recent studies suggest most doctors have yet to adopt the small-breath technique as the new standard of care for such patients.

e new Natanson and Eichacker analysis has increased concerns about the ARDSNet study.

"It's shocking to learn that the patients who would not participate in the trial had a much better survival rate," said Vera Hassner Sharav, president of the Alliance for Human Research Protection, a patient-advocacy group. "This was a lethal trial."

Kenneth Steinberg, an associate professor of medicine at the University of Washington, who ran the study at Harborview, told The Seattle Times in December that their clinical trial had ended in 1999.

He said that 76 patients enrolled and about half got experimental treatment. Steinberg said the other group had a few more deaths than the experimental-treatment group.

Alan Milstein, a Philadelphia lawyer who specializes in patient-safety issues, said ARDSNet had "laudable goals" but violated a fundamental rule of research by favoring a study design that would produce strong scientific results over one that would place greater emphasis on the safety of participants.

"Their hearts are in the right place," Milstein said, "but it's the age-old case that the researchers are looking down the road to the patients who could be afflicted with the disease in years to come as opposed to looking at the patients who are on the table right then and there."

ARDSNet's leaders declined to discuss the March letter highlighting mortality among onparticipants. But the designated spokesman among them, Dr. Gordon Bernard of Vanderbilt University, defended the trials in earlier interviews as properly designed, exhaustively reviewed and safe.

Hindsight

To establish a control group for the ventilator study, the ARDSNet researchers drew on information from earlier studies and used professional judgment, Bernard said in December.

At the time, Bernard characterized criticism of ARDSNet as misguided hindsight.

"It's really easy, when you've got the data in your pocket, to poke holes in what we were thinking," he said.

Bernard noted that the ARDSNet trial designs were approved by review boards before the studies began. Even after the controversy erupted, he said, the suspended study was deemed proper and safe last August by a panel of scientists assembled by the National Heart, Lung and Blood Institute, the NIH agency that funded the trials.

Citing that endorsement, the American Thoracic Society in January warned Tommy Thompson, secretary of Health and Human Services, that the government's "completely unnecessary" investigation could discourage scientists from doing research. NIH, like the Office for Human Research Protections, is in Thompson's department. "This is very major, it seems to me," said Dr. Thomas Martin, president of the society that represents some 13,000 lung-disease specialists. "The broad implication is that major trials can be put on hold even when there's not compelling evidence that something incorrect has been done."

Dr. Jeffrey Drazen, editor of the New England Journal of Medicine, penned the journal's challenge of the OHRP in April.

In an interview, he said ARDSNet's ventilator trial did not need a control because no standard treatment was established. The treatments employed were "well within the range that I and other doctors have used," Drazen said.

Drazen said questions about study design should be left to scientific review panels at the NIH, not OHRP, which should focus on compliance once studies are under way. "They don't have the expertise to deal with trial design," he said.

Arthur Lawrence, deputy assistant secretary for health at the Health and Human Services Department, said federal officials have authority to investigate allegations that trial design could have contributed to patient harm. OHRP is equipped for such a review, he said.

"The OHRP staff includes a number of professionals with training and expertise in medicine, human-subjects research and clinical-trial designs," Lawrence said, adding that consultants are used if needed.

ARDS is a rapidly progressing lung problem that piggybacks on other illnesses. About one in three ARDS patients develops the syndrome as a result of sepsis, a bodywide infection. ARDS also can follow a trauma injury, pneumonia, the aspiration of gastric contents, smoke inhalation or a near-drowning.

The life-threatening condition emerges when blood and fluid leak into the lungs' tiny air sacs and patients have trouble breathing.

As many as 150,000 Americans are afflicted each year, though some estimates have been smaller. Death rates have declined steadily to less than 40 percent since the mid-1980s, when well over half of ARDS patients died.

Information from The Seattle Times' archives is included in this report.

Copyright (c) 2003 The Seattle Times Company

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