US researchers guilty of breaking safety rules

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US researchers guilty of breaking safety rules

Deborah Josefson San Francisco

The US Food and Drug Administration (FDA) has found researchers from Johns Hopkins University guilty of violating safety procedures in an asthma study that resulted in the death of a healthy volunteer.

The FDA's investigation was launched last month after Ellen Roche, a previously healthy 24 year old, died while participating in the experiment (BMJ 2001;322:1565). The federally financed study was designed to induce asthmatic reactions in people without asthma in order to study the possible protective physiological mechanisms of deep breathing on normal lungs.

The researchers, led by Dr Alkis Togias, an associate professor and clinical immunologist at the Johns Hopkins Medical Institutions, asked volunteers to inhale a known bronchoconstrictor, methacholine, before and after deep breathing. In a second phase of the experiment, a subset of volunteers, including Ms Roche, was instructed to inhale hexamethonium, a ganglion blocker that would disable the protective effect of deep inhalations.

Ms Roche became ill during this phase of the experiment. In a preliminary report the FDA cited Dr Togias as failing to report that the first volunteer to inhale hexamethonium developed an adverse reaction—a persistent cough—within a day of participating in the experiment. The failure to report the cough may be important, because Ms Roche also developed a cough after inhaling hexamethonium. Dr Togias reportedly thought that the first volunteer’s cough was due to a respiratory infection going around the Hopkins Bayview campus at the time.

The FDA also cited Dr Togias as failing to seek the FDA's approval for using inhaled hexamethonium, an experimental drug that has not been approved by the administration, on human subjects. In addition, it found that the researchers failed to inform the volunteers that they would be inhaling an experimental, unapproved drug.

Finally, the agency cited Dr Togias as changing the formulation of hexamethonium without first informing the Johns Hopkins institutional review board. Dr Togias added sodium bicarbonate to hexamethonium to change the drug’s acidity and make it more comfortable to inhale. The change in formulation may or may not have contributed to Ms Roche’s death, but it represented a departure from the approved protocol and therefore broke federal rules, said the FDA.

In a statement, university officials said that the researchers and the institutional review board did not believe that FDA approval for hexamethonium was necessary because it was not a new drug and was not being tested in the study for therapeutic effect.

The review board also believed that the lengthy consent form signed by the volunteers, which warned of possible side effects of the drugs used in the experiment, was adequate.

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

Hexamethonium was licensed in pill form as an antihypertensive agent in the 1950s but was withdrawn from the market in the 1970s, when safer, more effective antihypertensive drugs became available. It was never approved in inhaled form.

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US researchers guilty of breaking safety rules

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