Hopkins faults safety lapses

A Johns Hopkins panel investigating the death of a 24-year-old woman in an asthma experiment has concluded that she most likely died from a drug given to her in the test, and it faulted both the lead researcher and an internal oversight board for safety lapses.

The panel said the Institutional Review Board at Hopkins' Bayview campus should never have approved the study because the scientist did not present sufficient evidence that the drug used in the experiment was safe.

The consent form signed by volunteers was "misleading" and "inadequate," the panel said, because it failed to disclose that the drug, hexamethonium, was no longer used clinically, lacked approval by the U.S. Food and Drug Administration and could cause severe side effects, even death.

Additionally, Dr. Alkis Togias, the physician who ran the study at the Johns Hopkins Asthma and Allergy Center, should have suspended it after an earlier subject developed a cough that persisted for nine days.

At that point, Togias should have performed more research on the drug's potential toxicity before giving it to other people, the panel said.

Ellen Roche of Reisterstown, who was healthy before participating in the experiment, died June 2 at Bayview of lung damage and multiple organ failure. A lab technician at the asthma center, she was the third volunteer who inhaled the drug in the study.

The experiment was to have included 10 subjects, but Hopkins halted it when Roche was hospitalized with a cough and fever.

Several medical journal articles in the 1950s and 1960s linked hexamethonium to rare cases of fatal lung disease. But Togias did not find these articles until after Roche became ill, according to Hopkins officials.

Her death is being investigated by the FDA and the federal Office of Human Research Protection. A preliminary FDA report two weeks ago faulted Togias for failing to follow safety procedures.

The report prepared by the Hopkins panel was released yesterday at a news briefing on the Hopkins medical campus in East Baltimore.

"I am the father of a 25-year-old daughter and I can imagine what the family is going through," said Dr. Edward D. Miller, Hopkins medical dean and chief executive officer. "We accept full institutional responsibility for her death."

The seven-member panel, all Hopkins professors, was chaired by Dr. Lewis C. Becker, a cardiologist. The committee included an ethicist and specialists in various medical disciplines. Two outside consultants also advised the panel.

"This was a horrible tragedy to have befallen any healthy volunteer," said Becker. "But Ellen gave her life in a truly noble cause, to try to understand asthma and to try to help people who suffer from this condition."

Roche died from adult respiratory distress syndrome, a condition in which small air passages of the lungs break down and lose the ability to supply the blood with oxygen.

The reason this happened might never be known, Becker said, but he said the condition was most likely a reaction to the drug. Tests have shown no evidence that Roche caught an infection in the experiment, though she later developed a secondary infection while being treated at the Bayview medical center.

Hopkins has taken several steps to ensure that further tragedies are avoided in medical experiments, said Dr. Chi Dang, vice dean for research.

These include the creation of a third Institutional Review Board - in addition to Bayview, another board currently operates at the main campus - to monitor the large volume of experiments. Random inspections of studies under way will also be increased, he said.

Dang said the university has suspended 10 additional experiments under the direction of Togias. It has also halted 16 other studies involving the use of drugs not approved by the FDA. The Hopkins investigating panel faulted the Institutional Review Board for not requiring Togias to ask the FDA whether its approval for the experiment was needed.

Reactions to the Hopkins report varied yesterday, with some praising the institution for a thorough review and others criticizing it for approving the experiment in the first place.

Sheldon Krimsky, a science policy analyst at Tufts University, said: "It sounds like the university has not issued a whitewash. It sounds like they are doing some real soul-searching and that they admitted wrongs."

Dr. Frederick Wolff, a professor emeritus at the George Washington School of Medicine, said he found it "foolish" and "lazy" that Togias and the Hopkins review board failed to look up the 1950s medical journal articles warning of lung damage caused by hexamethonium.

"Anyone trained in academic medicine knows how to do this research," Wolff said. "This is just laziness. What happened is not just an indictment of one researcher, but of a system in which people don't bother to research the literature anymore."

Togias had searched an electronic medical database, called PubMed, which lists articles back to about 1960. And he had consulted contemporary edition medical textbooks, but none of them mentioned the 1950s-era reports on hexamethonium's toxicity, according to Hopkins officials.

The Hopkins committee acknowledged, however, that a routine search using two popular Internet search engines, Yahoo and Google, would have produced a French medical school's Web site that listed the past studies.

While the panel believed the researcher made a "good faith effort" to learn of the drug's effects, some members said Togias should have found the articles.

Craig Schoenfeld, a lawyer representing Roche's parents, said the family had no immediate comment. Dr. Gary Briefel, chairman of the Bayview Institutional Review Board, which approved Togias' experiment, also declined to comment, according to a university spokeswoman.

In the fatal experiment, Togias and other doctors were attempting to discover the neurological mechanism - or reflex - that protects the lungs of healthy people against asthma attacks. They administered hexamethonium to see whether it would block the reflex.

Hexamethonium was used as a high blood pressure medication during the 1950s and '60s, but it was taken off the market in 1972 after the FDA ruled that it was ineffective.

Togias designed the study and submitted it to the Bayview review board, which approved it.

According to the investigatory panel, the review board should never have approved the study because Togias did not present enough data demonstrating the safety of hexamethonium. While he did present four studies showing that inhaled hexamethonium produced only temporary problems - such as dizziness - the studies included only 20 patients.

"Small clinical trials give uncertain estimates for even frequent adverse events, and may miss even relatively common toxicity," the report said.

Togias did not have a response yesterday to the Hopkins report, said his attorney, Daniel Kracov.

However, some of Togias' thoughts about Roche's death can be found in a letter that Kracov sent yesterday to the FDA.

On June 28, an FDA investigator faulted Togias for failing to obtain necessary FDA approval, neglecting to warn his subjects of the risks of inhaling a nonapproved drug, and failing to report that the first volunteer in his study coughed for nine days after inhaling hexamethonium.

"It is important to note that while Dr. Togias takes issue with a number of the FDA's regulatory findings, our response is not intended to suggest any diminution in Dr. Togias' deep concern and sorrow regarding the death that occurred," Kracov wrote.

Togias believes it would be "unfair" to point the finger of blame only at him, according to the letter. Togias relied upon the Hopkins review board to guide him on whether to seek FDA approval, and the board did not tell him to consult the federal agency, the letter says.

He did not report the first volunteer's cough because he thought it was caused by a cold, his lawyer said.

According to the Hopkins panel, Roche received two doses of hexamethonium May 4. The drug was administered with a nebulizer, a device that turns a liquid substance into an aerosol.

On May 7, she reported that she had been sick for two days. Her symptoms began with a cough and progressed to a fever. Two days later, on Togias' advice, Roche returned to the asthma center for tests, which revealed a lung inflammation and a 101-degree fever. She was admitted to Bayview.

Within days, her condition worsened, and she was transferred to the intensive care unit. Tests revealed a "ground glass" appearance to her lungs, evidence that they were injured and that tissues were breaking down, the panel said.

A week into her hospital stay, the young woman was placed on a respirator. Later, she developed kidney failure and her blood pressure dropped dangerously low.

"Given her worsening condition and unsupportable oxygenation, the family elected to withdraw [life] support and Ms. Roche died," the report said.

Although Roche worked at the asthma center, she did not report directly to the scientists conducting the experiment. She had participated in several other research studies before enrolling in Togias' project. For that experiment, a doctor drew her name from a registry of past volunteers and called to ask whether she wanted to take part.

Two likely reasons Roche volunteered were an "altruistic desire to help people with asthma" and compensation of $365, the panel said.