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
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.
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."
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
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.
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
"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.
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
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
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.
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."
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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