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Death of Healthy Research Subject Raises Questions


She noticed the cough almost immediately, began feeling short of breath and achy. Two days after her visit for a research study at the Johns Hopkins Asthma and Allergy Center--two days after inhaling the chemical hexamethonium during what was assumed to be a low-risk test for a healthy young woman--Ellen Roche called back, obviously concerned.

Her symptoms were troubling enough that the staff quickly started monitoring her condition. That was May 7, and Roche's lungs already were functioning at two-thirds capacity. By May 9, doctors admitted her to Johns Hopkins Bayview Medical Center in East Baltimore for observation.

The 24-year-old lab technician died there June 2--the university's first death of a research volunteer since 1986 and its first death ever of a healthy volunteer.

The tragedy, an "adverse event" that officials did not report publicly until mid-June, has raised anew questions about how adequately medical research participants are informed and protected during experiments. It has triggered an internal investigation, a special university review committee and probes by the federal Office for Human Research Protections and the Food and Drug Administration.

All parties will try to determine whether asthma researchers did anything wrong as they studied the physiological mechanics of a normal lung: whether they cut corners during the testing, for instance, or failed to fully disclose important details to Roche and other participants, or endangered their subjects from the start by using a substance that is not FDA-approved, possibly without the required permission.

Or the inquiries could find that, no matter the circumstances, the death could not have been foreseen.

"In the field of clinical investigations, the worst thing that can happen is the death, the unanticipated death, of a normal volunteer," said John Fletcher, professor emeritus of biomedical ethics at the University of Virginia's medical school and founder of the bioethics program at the National Institutes of Health.

"Where there's culpability, it's a life-changing and a career-changing thing. It's at least a nine on a moral Richter scale. But we know in the total universe of human studies, these deaths are extremely rare."

Medical ethicists say the country has made great strides in the last three decades in its oversight of medical research. Institutional review boards must approve a project in advance. Scientists are expected to provide truthful, clearly worded information about risk, which should be minimized as much as possible. And participants must be allowed voluntary consent that they can withdraw any time.

Yet since 1998, a number of serious incidents have shown continuing weaknesses in the system. Concerns about patient safety stopped clinical trials at university medical schools in Oklahoma, Alabama, North Carolina and Massachusetts. After glaring breakdowns in its gene therapy studies, which surfaced only after a teenage participant died, the University of Pennsylvania announced last year that its genetic research would no longer use human subjects.

Just last month, as Roche lay in intensive care, a president-appointed panel recommended major changes in the protections afforded participants in a range of scientific studies. Review boards often are overwhelmed by the volume and technical demands of the work they judge, the panel said; guidelines about researchers' potential conflicts of interest need strengthening, as do provisions for especially vulnerable populations such as children and mentally incompetent elderly.

Though the scale of biomedical research has exploded since 1980, the National Bioethics Advisory Commission noted there are no statistics on how many people are involved in clinical trials or the number of adverse events. It urged that a system be created for reporting those incidents. Some members also advocated establishing a fund to compensate individuals harmed because of their participation.

"It's a matter of simple justice that we cover them if they end up injured," said commission member James Childress, who teaches bioethics at the University of Virginia. They are, he pointed out, "putting their bodies on the line for research."

Roche did so understanding that she would receive no therapeutic benefit from whatever the Hopkins scientists learned. Theirs was a baseline investigation looking at how a normally functioning lung helps keep airways open even when they are exposed to irritants and allergens. If researchers can discover that, they can better grasp how the airways of someone with asthma begin to constrict and possibly develop a drug to prevent it.

Ten million Americans suffer from this potentially life-threatening condition. Roche did not.

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