Public says no such thing as too much regulation, especially after a fatality

High-profile mistakes linger in people’s minds

The suspension last month and subsequent reactivation of human research programs at Johns Hopkins University in Baltimore dealt a heavy blow to an already bruised industry in the public’s eye. The death of 24-year-old Ellen Roche this past June from an experiment at Johns Hopkins Bayview Medical Center was indeed the proverbial straw that broke a weak camel’s back. The experiment on how healthy lungs respond to asthma triggers led investigators with the Office of Human Research Protections (OHRP) on July 19 to suspend all human studies at Johns Hopkins except for those where interruptions would harm the participants. OHRP later reinstated its multiple project assurance for research at Johns Hopkins on July 21.

A total of 31 findings were reported by the OHRP regarding the research at Johns Hopkins Bayview Medical Center. (For more on what to learn from the incident, see "Focus of findings lost in media spotlight," in this issue.) The death of the patient no doubt further cements attitudes in the public perception of the dangers of medical research. Unfortunately, there are further instances where mishaps taint the public’s confidence in medical research. Consider this partial listing of recent actions from OHRP:

• November 2000: OHRP suspends research at the National Institute of Child Health and Human Development for involving children in an experiment involving greater-than-minimal risk. The experiment measured insulin sensitivity, energy output, and body composition in obese children and average-weight children of obese parents. OHRP investigators concluded that while intravenous lines of glucose and insulin caused no lasting harm, it did not "represent the category of research involving children that is permissible."

• December 2000: OHRP investigators conclude that the National Institute of Mental Health was experimenting on four pediatric participants with the antipsychotic olanzapine — without IRB approval or parental informed consent.

• June 2001: OHRP completes its investigation of the death of 3-year-old Tyler Shelton at the University of Arkansas and Arkansas Children’s Hospital. The patient was enrolled in the National Wilms’ Tumor Study in 1997, but was placed in a stage I tumor category when he should have been placed in the stage II tumor category. The participant died in May 1999 from advanced spread of Wilms’ tumor. OHRP concluded that the therapy "may have contributed to [his] premature death."

Did OHRP need a scapegoat?

Some critics argue that the current oversight system is overburdened and OHRP used the Johns Hopkins incident to establish its existence. Others, however, contend that the death is just one warning of an overburdened system failing to keep pace with mounting pressures.

In the meantime, public awareness about problems and potential ones within medical research is mounting. "I think when you combine a death at a prestigious institution with a government shutdown, it does make a deep impression in the particular city at least," says Michael A. Susko, president of Citizens for Responsible Care in Psychiatry and Research (CIRCARE), a New York-based group lobbying for oversight for patients in research programs, especially those with mental illness. "At present, there is sustained national attention on the issue of human research subjects and their safety, so I think the issue is coming to the national consciousness," he adds.

In fact, the Washington Post published an editorial in its Aug. 2, 2001 edition defending the actions of OHRP and went further by calling for additional staffing at research institutions. "For research to be properly monitored, most universities need at least to double the number of review board personnel," the paper states.

Paul Gelsinger, the father of Jesse Gelsinger, who died in a gene therapy clinical trial at the University of Pennsylvania in 1999, responded to the Johns Hopkins incident by saying that the current system is not fair to anyone. (To see his response, see "Victim’s father speaks out on current system," in this issue.)

How long will they remember?

There likely will be some short-term negative impact on clinical trials, says Susko. Not only in terms of public perception, but in a wariness to participate in a trial "particularly when an ordinary healthy volunteer dies, because the potential participant sees the victim as someone like themselves," he says.

The greater long-term impact, however, would be to continue as is and not provide meaningful informed consent and lose the trust of the general public, explains Susko. "The research institutions should take the medicine now and, after genuine reform, will not have to worry about obtaining subjects. Yet it may be that with genuine informed consent that certain types of challenge studies would not be conducted. But that’s the risk the researchers have to take, just as they are asking their subjects to take risks," he contends.

But others suggest that the OHRP actions toward Johns Hopkins will do nothing to help human research subjects. "Suspensions like the Johns Hopkins case will simply shift research subjects to other sites, many of which will have IRBs less qualified than the existing IRB," says Steven Belknap, MD, assistant professor of clinical pharmacology and medicine at the University of Illinois College of Medicine at Peoria.

Rather than continuing to focus on punishing the institutions, the OHRP should instead focus on investigator competence, suggests Belknap. In addition, FDA guidance over whether the use of hexamethonium required an IND is unclear, says Belknap. Had its guidance been clearer, the investigator — and peers at other medical centers — would likely have submitted investigational new drugs (INDs), he notes.

"If the FDA then denied the Johns Hopkins’ hexamethonium IND, then Ellen Roche would still be alive, but if the FDA had permitted the IND, the outcome would still be the same despite the IND," explains Belknap.