Medical experiment disclosure hinges on a flawed honor system Hopkins worker death raises wider questions


By Tom Pelton, Sun Staff, August 12, 2001

Are volunteers hurt or killed in medical experiments more often than scientists acknowledge? The question has been percolating in laboratories across the United States since investigations into a healthy woman's death in a Johns Hopkins asthma experiment turned up suggestions that two previous illnesses involving the same chemical might have been improperly concealed.

Scholars and federal officials say it's inherently difficult to measure how often problems are not reported. But many say there's enough anecdotal evidence from lawsuits and complaints to suggest that the nation's system for monitoring "adverse events" during experiments should be improved. Some research institutions, including Johns Hopkins, refuse to release information to the public about the frequency of health problems suffered by their research volunteers, even though they ask the public to submit to their experiments.

At one end of the spectrum, University of Maryland biochemist Adil E. Shamoo sees hints of a whitewash that he believes has been tainting the ethics of the nation's scientific community for years. Shamoo calculates that as many as 5,000 people a year might be dying in federally funded medical experiments across the country and that tens of thousands could be hurt during the studies.

But he says researchers report only a handful of cases for reasons ranging from denial to desire for career advancement. "The researchers and research institutions are not complying with federal regulations and are not reporting deaths and adverse events to the federal authorities as they should," said Shamoo, editor of the journal Accountability in Research. "The consequences are very serious, especially when the problems are also not reported in medical journals. The numbers that scientists count on for our research are not dependable, and the integrity of the research and the researchers themselves is brought into question," said Shamoo.

Other scientists dismiss Shamoo's numbers, with some saying he's interpreting the law incorrectly or engaging in guesswork. The government doesn't try to keep a running tally of deaths and injuries in medical experiments, federal officials say.

Drug companies and universities report problems to different agencies that don't always share data with each other or the public. Moreover, a certain number of deaths are expected in experiments because many volunteers have terminal illnesses and know they face risks with new treatments, many researchers say.

Problems at Hopkins

Dr. Greg Koski, director of the federal Office of Human Research Protections, said he doesn't know how accurate Shamoo's figures might be, but he acknowledges that the underreporting of "adverse events" could be a problem. Koski's agency recently suspended most experiments at Johns Hopkins when it found systemic problems with the review of experiments after the death June 2 of volunteer Ellen Roche.

Koski said his agency will work with the National Institute of Health and the Food and Drug Administration this fall to improve the national system for monitoring experiments and collecting and sharing reports of deaths and injuries. "It's difficult to know how much is underreported," Koski said. "Many of these adverse events are being handled at the local level, and I don't know if they are being handled in the optimal way. There is no question that there is room for improvement." Koski added, however, that federal law does not require researchers to report all injuries and deaths among study subjects to his agency.

It requires reports only of regulatory violations and health problems that are unexpected and likely a result of the treatment. The agency leaves it up to researchers and university review boards to sort through the sticky problem of separating which health problems are a product of illnesses and which are side effects of the drugs. Koski's agency, with only 45 employees, would be overwhelmed with paperwork if every research institution in the United States sent in every report of problems in the thousands of federally funded experiments across the country, said Bill Hall, a spokesman for the agency.

The number of incident reports flowing into the agency has almost tripled in recent years, rising from 100 in 1997 to 290 in 2000, with at least a third of these detailing unexpected health problems suffered by volunteers, according to the agency. The increase stems from increasing awareness of federal reporting requirements and a surging amont of medical research, Koski said. In contrast to Johns Hopkins, the University of Maryland released its adverse-events numbers when asked by The Sun.

The review boards that monitor experiments at the university's medical school received 880 reports of "serious adverse events" to volunteers during more than 1,000 experiments last year. The university defines "serious adverse events" as "any untoward medical outcome occurring in the context of research" - which could include anything from vomiting to the deaths of seriously ill cancer or cardiac patients, according to school spokesman Larry Roberts.

The majority of these health problems, in 728 cases, were judged to be unrelated to the studies - for example, volunteers injured in car accidents while away from the hospital, Roberts said. The university reported only two cases to the federal agency because they were the only cases that were unexpected and probably linked to the treatment, and not to an underlying illness, Roberts said. One was a blood infection that a researcher mistakenly gave to a 24-year-old volunteer in a metabolism study.

Another was the death of a 61-year-old man with life-threatening heart disease who may have suffered a reaction to medications he was taking in a study, Roberts said. The Johns Hopkins University, unlike Maryland, refused to release information about the number of problems suffered by volunteers in its more than 2,700 experiments last year. Joann Rogers, a spokeswoman for Hopkins, said the university has no evidence of widespread problems with underreporting.

"We are looking to see if there are systemic problems," Rogers said. "If there are, we are going to do whatever it takes to change that." Shamoo and others complain that self-policing invites a lack of candor. "It's an honor system," said Arthur Caplan, director of the University of Pennsylvania's Bioethics Program. "Many adverse events do not get reported because doctors and researchers don't like to think about themselves causing harm. So if there's something else to blame it on, like an illness, they will."

What is an 'adverse event'?

George Annas, chairman of the health law department at the Boston University School of Public Health, said: "Nobody would disagree that there is underreporting. But people do disagree about the definition of 'adverse event,' because there is no common definition.'" The law requires the reporting of "any unanticipated problems involving risks to subjects or others" in federally funded studies. Those who believe underreporting is a problem point to anecdotal evidence and statistical probability.

In a paper to be published this fall called "Adverse Events Reporting: The Tip of an Iceberg," Shamoo writes that 7 million people a year are enrolled in experiments funded by the National Institutes of Health, but fewer than one death a year (eight total since 1990) is reported to the National Office for Human Research Protections. Using the assumption that each subject is enrolled in a study for a month, the natural death rate for this many people during their time in studies would predict that between 500 and 5,100 would die of causes from illness to traffic accidents and suicides, according to Shamoo's analysis.

Shamoo believes that even suicides and traffic accidents among study participants should be reported to the government because the scientific community should have data to determine if depression and perhaps impaired ability to drive might be side effects of drugs. Two possible cases of underreporting came to light during investigations into the Johns Hopkins asthma experiment.

After a university inquiry pointed to the chemical hexamethonium as a probable cause of the volunteer's death, the University of California, San Francisco announced that it would investigate a 1978 asthma study that also used hexamethonium. Officials there want to know why researchers failed to report that two of five volunteers in that study became sick, one seriously enough to be hospitalized. The Hopkins researcher, Dr. Alkis Togias, might not have used the 1978 study as evidence that inhaling hexamethonium is safe had it reported the illnesses, said Togias' lawyer, Daniel Kracov.

"Dr. Togias relied on prior studies," Kracov said. "Science is a very cumulative activity." But Togias failed to look up other journal articles from the 1950s that suggested hexamethonium may cause lung disease, according to a federal report. And he may have been guilty of underreporting in his own experiment. Togias failed to inform his review board that the first volunteer in his asthma study coughed for eight days after inhaling hexamethonium, according to a university investigation.

His third subject, Roche, suffered a cough and then lung failure. A few allegations of nonreporting have surfaced in lawsuits and complaints to federal agencies. Some involve questions of government notification; others, a lack of disclosure in journal articles. UCLA professor Keith Nuechterlein did not report to the federal government the suicide on March 28, 1991, of a 23-year-old patient, Tony Lamadrid, in an aftercare program that followed a schizophrenia study, according to a federal report and officials.

In a lawsuit scheduled for trial Oct. 15 in Los Angeles County, Lamadrid's family contends that Nuechterlein failed to warn Lamadrid of the risks of withdrawing him from drugs as part of the study. Nuechterlein could not be reached for comment. But a UCLA spokesman said there was no reason to report the suicide to the government because it was unrelated to the experiment and because the study was over by the time of the death. Another case involves a malpractice lawsuit in Georgia.

Lawyers there filed court documents contending that a Stanford University surgeon, Dr. Farr Nezhat, and colleagues failed to report serious health problems in a 1991 medical journal article. Nezhat and others had reported in Surgical Laparoscopy, Endoscopy & Percutaneous Techniques that they had successfully operated on 16 women suffering from endometriosis, a uterine disorder, with no major complications.

But the journal retracted the article in February after court records in the suit alleged that four of the 16 suffered serious complications, including incontinence and intestinal injury, according to the San Francisco Chronicle. Nezhat said that none of his subjects suffered major complications and added that his surgical technique was not experimental. Stanford is investigating this and other articles by Nezhat, said Dr. Peter Gregory, senior associate dean for clinical affairs at Stanford Medical School.

Gregory said he believes that most researchers in the nation are diligent about reporting adverse events in medical journal articles. "But there are pressures on researchers," he said, "because journals tend to want to publish the positive rather than the negative, and grants are more likely to go to researchers with positive findings rather than negative findings."