http://www.nytimes.com/2001/06/16/health/16RESE.html

June 16, 2001

U.S. to Investigate Death in an Asthma Study

By LAWRENCE K. ALTMAN

ederal health officials said yesterday that they would investigate the death of a healthy volunteer in an asthma experiment at Johns Hopkins University in Baltimore.

The Office for Human Research Protections, a unit of the Department of Health and Human Services, said it would formally notify Johns Hopkins officials of the investigation next week. The office plans to examine the circumstances of the volunteer's recent death after inhaling an experimental drug, a spokesman for the department said.

Informal notice was given on Thursday night, the spokesman, Bill Hall, said.

Yesterday, Johns Hopkins posted on its Web site documents related to the experiment. The experiment consent form showed that volunteers were paid up to $365 for the seven to nine visits needed for the study.

The Web site posting came a day after the Office for Human Research Protections, responding to a Freedom of Information request filed by The New York Times, released letters it had received from Johns Hopkins officials. Ethicists and asthma experts not affiliated with Johns Hopkins have criticized the university for releasing only sketchy details of the experiment.

Johns Hopkins has suspended the study. Its goal was to determine how the airways in the lungs of nonasthmatic individuals can stay open even when irritating chemicals are inhaled. Participants were given two drugs, methacholine and hexamethonium, at different times in part to determine their effect on the airways after shallow and deep breathing.

The unidentified volunteer developed a flu-like illness 24 hours after inhaling hexamethonium, which the Food and Drug Administration classifies as an experimental drug, and was admitted to the hospital.

The drug was obtained from Fluka, a Swiss subsidiary of the Sigma-Aldrich Corporation of St. Louis, according to the newly released documents.

Rod Kelley, a spokesman for Sigma-Aldrich, said that his company's hexamethonium was not generally intended for human use and that he could not immediately find any record that Johns Hopkins had been provided human-grade material.

"Our primary purpose is to provide products to research chemists," Mr. Kelley said.

But Joann Rodgers, a spokeswoman for Johns Hopkins, called it "standard practice" to use chemicals labeled not intended for human use if they had received F.D.A. approval for experimental testing, as was the case for hexamethonium.

The drug had been used without adverse effect in human experiments elsewhere, Ms. Rodgers said.

The Johns Hopkins experiment was paid for by the National Heart, Lung and Blood Institute, a federal agency in Bethesda, Md.

Before they are started, all federally financed experiments on humans require ethical review by a committee generally known as an institutional review board, maintained by the researching university. Such permission was given for the breathing study at Johns Hopkins on Sept. 18.

But on Aug. 10, Dr. Gary Briefel, the review board chairman, had written Dr. Alkis Togias, a principal investigator of the study, asking about "the source of the hexamethonium and how it will be made safe for human use" since it was not an F.D.A.-approved drug.

On Sept. 14, the review board received a letter from Dr. Togias pledging that a physician would be present throughout the period that hexamethonium was administered, in part to monitor vital signs because the drug is known to lower blood pressure.

Dr. Togias also said that Fluka had certified that its hexamethonium was 99.6 percent pure and that his team would filter the material and test it for a bacterial impurity known as endotoxin before each administration of the drug.

Still, the possibility existed that impurities in the drug could have caused adverse effects. After the volunteer's illness, Johns Hopkins asked a laboratory to test the hexamethonium, Dr. Chi V. Dang, vice dean for research at the university, wrote in a letter to the Office for Human Research Protections.

Mr. Kelley of Sigma-Aldrich said the company first learned of the death of the volunteer and plans for the testing when he was called for comment.

"We were unaware of what has happened" at Johns Hopkins, Mr. Kelley said.

ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.