Hopkins study was exempt from FDA - Asthma project tested function of lungs, wasn't a drug trial

Asthma project tested function of lungs, wasn't a drug trial


By Jonathan Bor and Tom Pelton

Sun Staff

Originally published June 22, 2001

The Johns Hopkins asthma experiment in which a previously healthy volunteer died did not require prior approval of the U.S. Food and Drug Administration - exempting it from the intensive safety review given to studies of experimental drugs.

Some critics say the lack of FDA oversight is a deficiency in federal laws governing medical experiments, leaving volunteers without protections needed to ensure that studies are safe.

Dr. Peter Lurie, deputy director of Public Citizen's Health Research Group, said the Hopkins incident points to a significant "loophole" in the laws. "There is no ethical justification for having one kind of chemical get substantial government review and the other kind get very little," he said. "It's a senseless double standard. We think there should be some government agency, perhaps not the FDA, that has jurisdiction."

Because of its enormous responsibility to regulate foods and drugs, the FDA might not be the best agency for that role, Lurie said.

Researchers who conducted the Hopkins experiment received the approval of Hopkins' Institutional Review Board. They also submitted safety data to the National Institutes of Health, which approved the study and issued a $384,000 grant.

But the experiment, in which scientists exposed healthy volunteers to a chemical to learn more about the lungs' functioning, fell into what some scholars call a "gray area" in federal rules.

Jason Brodsky, a spokesman for the FDA, declined to discuss the Hopkins case. But scientists and lawyers familiar with FDA regulations say the use of the chemical in the Hopkins experiment would not have required FDA approval. Researchers who are not testing compounds as possible therapeutics are not required to obtain prior approval from the FDA, which conducts exhaustive safety reviews of drug trials involving human subjects. "If this were a drug trial, the FDA would be looking at everything they did," said Dr. Francis Palumbo, a professor of pharmacy law at the University of Maryland who said he had no direct knowledge of the Hopkins study.

Experiments that explore how the body works do not require federal approval, he said.

"There certainly is a huge gap in the protection of human subjects," said Alan Millstein, a Camden, N.J., lawyer who represented the family of a teen-ager who died in 1999 in a gene therapy experiment at the University of Pennsylvania.

But some ethicists say injecting more bureaucracy into medical research would be wasteful.

"It would cost a fortune to have a Washington bureaucrat go out and look at every challenge study, every bit of pesticide research, every placebo investigation, every surgical innovation," said Dr. Arthur Caplan, who heads the bioethics center at the University of Pennsylvania. A challenge study, the type done by the Hopkins asthma researchers, is one in which volunteers are given a substance to provoke a reaction.

"What we need is better local review" by university review boards, Caplan said. "You're not going to get better review from a Washington conference room."

The volunteer, Ellen Roche of Reisterstown, died June 2 - about a month after inhaling a chemical, hexamethonium, in the trial. She started feeling ill a day after the experiment and was later hospitalized with severe lung complications. She died after her lungs and kidneys shut down, according to one of the researchers. Roche was a lab technician at the Johns Hopkins Asthma and Allergy Center, where the study was done.

Last week, the federal Office for Human Research Protection opened an investigation into the death. In its search for clues, Hopkins performed an autopsy and analyzed medical equipment used in the experiment. Hopkins has not released results of its investigation.

Hexamethonium was an FDA approved drug that was widely used in the 1940s and 1950s to treat hypertension. The drug, however, fell out of favor as more-effective treatments were developed. The FDA withdrew its approval in the 1970s, according to an agency spokesman, who declined to discuss the reasons.

Documents pertaining to the study indicate that the Hopkins review board asked the researchers questions about human safety before approving the study.

"If the hexamethonium is not an FDA approved product, the protocol should describe the source of the [chemical] and how it will be made safe for human use," Dr. Gary Briefel, the board chairman, said in a letter.

Dr. Alkis Togias, the asthma specialist who ran the experiment, answered that the compound would be obtained from a chemical company in a form that was 99.6 percent pure. Hopkins scientists would then pass the substance through a filter to ensure that it is sterile and would test it for the presence of a toxin, he said.

The researchers also gave the review board copies of five studies done outside Hopkins in which researchers gave hexamethonium to volunteers. Those studies mentioned only temporary side effects.

After Roche became ill, the Hopkins scientists told the review board that they were aware of earlier cases in which patients treated with hexamethonium suffered severe lung disease. After Roche died, one of the researchers sent a letter to colleagues across the country warning that the chemical had also been linked to several cases of respiratory failure in the 1950s. He noted, however, that the patients had received larger doses over an extended period of time.

It is not clear when the asthma researchers learned of those cases. In the consent form that Roche signed, she was not warned about the risk of lung disease.

George Annas, a bioethicist at Boston University, said the researchers should have been aware of published reports of severe side effects before they began the experiment. "They had an ethical responsibility to not use [the chemical] if it's risky, and they had a legal obligation to inform the subject of the risk," said Annas.

Karen Rothenberg, dean of the University of Maryland School of Law, said the case will prompt a reappraisal of how studies are reviewed for safety. "We have to instill trust in the public that when they participate in research, there are individuals who are really evaluating the risks and benefits for each individual," said Rothenberg, a professor of health law.