October 2001 • Volume 7 • Number 10
Researchers, ethicist ponder clinical trial safety issues
BY TONI LAPP
The recent death of a healthy 24-year-old volunteer in a Johns Hopkins University asthma trial has some family practice researchers re-evaluating safeguards and others fearing a backlash among potential study volunteers.
The aim of the trial was to study how normal lungs function when exposed to factors that constrict them. Lab technician Ellen Roche took hexamethonium, a chemical that causes asthma-like symptoms and is not approved by the FDA for use in humans. Roche, who was paid $365 for her participation, developed a cough within 24 hours of taking the drug and later lapsed into a coma. She died less than a month later. Those familiar with the case say the informed consent failed to tell patients about the risks of the drug, which was described as a "medicine."
Protecting your patients
With so many persons participating in clinical trials, it's likely there are patients within every family practice who are volunteers, whether their FPs know it or not. But if a patient asks for your opinion about participating in a trial, researchers say there are a few things to consider.
- Ensure that an institutional review board has approved the trial.
- Read over the informed consent document; make sure the patient under-stands the risks.
- If the patient has a condition that could benefit from being in a clinical trial, know what the treatment arms are.
- Does the patient have a mild condition so that receiving a placebo wouldn't pose a great risk?
- In some cases, volunteers suffer from conditions for which there is no cure and therefore have nothing to lose by participating in trials. In this case, the advantage is that the patient is getting the very best of care in the control group -- and even better care if the intervention turns out.
But for the most part, studies today are safer than ever, many researchers say.
One physician who worries about repercussions is Barbara Yawn, M.D., M.Sc., of Rochester, Minn., a member of AAFP's Commission on Clinical Policies and Research. Not only was the death a tragedy, but it also "was a disaster for research," says Yawn.
"I think people are going to be very fearful," she says. "And that's why we need to get as much out and known about the Hopkins study as possible. Let people know about what type of safeguards are in place. There are a lot of people participating in studies, and the risk is low -- but with so many people participating, sometime, somewhere, someone will have a bad reaction."
By some counts, 2.2 million people are currently participating in clinical research trials in the United States. Institutional review boards have the responsibility of evaluating these trials for safety and adherence to ethical guidelines. These review boards ideally include laypersons and clinical experts.
Even though Johns Hopkins is a research-oriented institution, it is not immune from errors, says Yawn. Indeed, the sheer number of research projects conducted by such institutions make it more likely that one of them would have a tragedy, she says.
One researcher who was not surprised by the event at Johns Hopkins is Stephen Spann, M.D., of Houston, chair of the AAFP Task Force to Enhance Family Practice Research.
"Adverse reactions can happen anywhere," says Spann. "It's not necessarily a negative comment on the institution where it happened."
IRB PROBLEMS
However, one medical ethicist says institutional hubris could have played a role. "The more prominent the research institute, the bigger the problem," says Don Reynolds, a program associate with Midwest Bioethics Center in Kansas City, Mo.
"In theory, IRBs are supposed to be populated by community members to dilute the presence of institutional bias," he says. "But in truth, we've done a poor job of recruiting. Often (IRBs) don't represent the kind of distance that's needed."
A lawyer by training, Reynolds sits on several IRBs for the University of Missouri-Kansas City. He notes that the safeguards that are in place are fallible. In Johns Hopkins' case, he says, the institution streamlined the process by which its IRB worked, possibly circumventing a key safeguard in the review process. If investigators had done a complete review of the literature, they would have found reports of adverse events with hexamethonium, says Reynolds. But even when the boards adhere to the complete process, many are overworked by the sheer number of trials. In one case, an acquaintance on another review board told him her board had 12,000 adverse events to evaluate.
PLACEBO RISK
Spann notes that individuals in the placebo group may not be at risk of an adverse reaction from an experimental treatment, but they face another risk: not receiving treatment while participating in a placebo-controlled trial.
Just such a risk caused one physician to experience conflict between his role as a researcher and his role as a physician. Bernard Ewigman, M.D., director of the Center for Family Medicine Science at the Department of Family and Community Medicine, University of Missouri-Columbia, says that in one study, "the potential benefit did not justify the risk of going without treatment for the patients." He declined to work on the study.
TO PAY OR NOT TO PAY
In studies he has been involved with, Ewigman has paid volunteers for their time and effort. But patients should never be compensated for taking risks, he says.
Reynolds concurs. The woman in the Johns Hopkins trial received payment for her participation. "In studies like this one, where there is no benefit to the person, you want to be sure that the person understands the known risks and that they aren't being influenced (by money) to enter the study," he says.
That the volunteer was also an employee of Johns Hopkins is also a concern. "You want to be careful there's not a culture of everyone participating at an institution," Reynolds says.
And even though clinical trials pose a risk, they are an improvement over the days when drugs were tried experimentally without formal data collection or control groups, says Ewigman. They are the foundation of evidence-based medicine.
"It's important to emphasize the gold standard of evaluating a treatment is clinical trials," says Spann. "We must do everything we can to minimize the risks, but the trials must go on."
FP Report is published by the AAFP News Department.
Copyright © 2001 by American Academy of Family Physicians.
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