Asthma study violated safety rules, FDA says

A Johns Hopkins Medical School researcher failed to follow several safety regulations during an asthma experiment that ended with the death of a 24-year-old volunteer, according to a preliminary federal report released yesterday.

Dr. Alkis Togias should have gotten approval of the U.S. Food and Drug Administration before using an experimental drug and should have more fully warned research subjects of the risks involved, the FDA said.

Togias also failed to report to a Hopkins oversight board that another volunteer developed an eight-day cough after inhaling the drug. And he altered the mix of chemicals in the drug without the board's knowledge or approval, the report says.

"We have control points that are critical to protecting human subjects, and when we have numerous compromises of these controls, we have cause for concern," said Dr. David Lepay, FDA senior adviser for clinical sciences.

Lepay, who heads the FDA's review of experiments, said yesterday that the federal inquiry into the June 2 death of Ellen Roche will not be finished for a few more weeks. The inspection form released yesterday is only one piece of evidence that investigators are examining.

Roche, of Reisterstown, a lab technician in the Asthma and Allergy Center at Hopkins' Bayview campus, was one of 10 people who enrolled in a federally funded study of how healthy people's lungs function differently from those of asthmatics.

Doctors found she was healthy before the experiment. But 24 hours after inhaling the chemical hexamethonium on May 6, Roche started coughing, felt short of breath and returned to Bayview, where doctors found her lung capacity had declined by a third, according to documents. The researchers called off the experiment.

After being hospitalized for almost a month with severe respiratory problems, Roche died. It was the first time in more than a decade that a Hopkins experiment had ended with the death of a previously healthy volunteer.

Togias was not available for comment yesterday. Another scientist involved with the research, Dr. Solbert Permutt, declined to respond to the report by FDA investigator J. Diann Schaffer.

Dan Kracov, a Washington attorney who is representing both Hopkins doctors, would not comment on the FDA report.

"It's not something we take lightly, and we don't think it would be appropriate to respond in a newspaper article," he said. "We are responding to and cooperating with the FDA."

The researchers and the Johns Hopkins Institutional Review Board, which monitors and approves experiments on human subjects, believed that they did not need FDA approval, according to a statement released by the university yesterday.

That is because they viewed the FDA's role as scrutinizing the development of new drugs. The Hopkins researchers were not trying to create a new drug, but were instead performing more basic research on how the lungs work, according to the Hopkins statement.

"The death last month of the young woman participating in a Johns Hopkins research study is a terrible tragedy," the statement read. "Since her death, we have been cooperating fully with the FDA ... as well as conducting our own internal review."

Togias failed to inform the review board that his first volunteer - Roche was the third - developed a persistent cough after inhaling hexamethonium, according to the FDA.

"It was his opinion that the cough was due to an upper respiratory ailment going around the campus at the time," said the Hopkins statement. "We are reiterating to faculty that all unanticipated adverse events must be reported."

After the first subject developed the cough, Togias added another substance to the hexamethonium - sodium bicarbonate - to change its acidity and make it more comfortable for the volunteers, according to the FDA report and Hopkins statement.

This change might not have had any impact on the subject. But it broke federal rules, which require scientists to stick to the procedures approved by review boards and to report any changes, according to the FDA.

In addition, Togias failed to warn volunteers on their consent forms that inhaling hexamethonium is an experimental use of a drug that carries unknown risks, said Lepay of the FDA.

"It [hexamethonium] is not an approved drug, and it was never approved in an inhaled form. That should have been part of the information provided to the volunteer as part of informed consent," Lepay said.

The Hopkins review board believed that the lengthy consent form - which mentioned possible side effects, but nothing life-threatening - was adequate, according to the Hopkins statement.

Concerned that asthma is becoming common around the world, Togias and Permutt were trying to understand what prevents the lungs of asthmatics from relaxing after the inhalation of irritants. Part of their study involved stimulating asthma-like constrictions in the lungs of healthy people, such as Roche.

The doctors asked Roche and the other volunteers to inhale hexamethonium, a chemical that doctors in the 1950s used in pill form as a treatment for severe high blood pressure.

The drug had several serious side effects. The label for the hexamethonium chloride tablets marketed by Richlyn Laboratories of Philadelphia in the 1950s warns of fainting, constipation, vomiting and blurred vision.

Several articles in medical journals reported during the 1950s and 1960s that the prolonged use of hexamethonium occasionally led to fatal inflammation of the lungs.

The FDA ruled in 1971 that the drug was "ineffective" in fighting high blood pressure, and in 1972 the agency withdrew its approval. Reports in agency files criticized the "substantial potential toxicity of oral hexamethonium."

In a letter sent to his colleagues after Roche's death, Permutt said he had learned about several cases of respiratory failure attributable to patients taking hexamethonium in the 1950s. But Permutt added that five studies in the 1980s and 1990s showed no ill effects to people inhaling smaller amounts of the chemical during experiments.

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