Guinea Pigs in the ER

Researchers debate the ethics and logistics of performing emergency research without patients' consent

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Article: Artificial-Blood Study Has Critics Seeing Red

Colloquy: Should research without consent be allowed? Read the transcript of a live online discussion with with Lynne D. Richardson, an associate professor of emergency medicine at the Mount Sinai School of Medicine.

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By LILA GUTERMAN

In late 1997, the ethical frontline of emergency medicine was located in the back of an ambulance barreling toward Lehigh Valley Hospital, in Allentown, Pa. At that moment, paramedics were struggling to keep a trauma victim alive, trying to prevent the patient from bleeding to death before reaching the hospital.

Ambulances don't carry blood, so paramedics normally have only one choice in those situations: to pump the patient full of saline in order to keep the victim's blood pressure from plummeting. But this particular ambulance stocked a special fluid, designed to mimic some of the benefits of blood. The paramedics injected the blood substitute into one of the patient's veins as the vehicle hurtled on.

It was a bit of a medical gamble because nobody knew whether the experimental fluid actually worked. It was being tested at the time. And as part of the study protocol, paramedics were administering the blood substitute to some patients and saline to others.

The trial was not a success. Only a few months into the study, the manufacturer stopped the experiment because the substitute actually performed worse than normal saline. Of the 112 patients who had participated in the experiment, 24 had died after receiving the substitute. Only nine had died after getting saline.

Although some of the patients or their family members had consented to participate in the research, most of the participants were unconscious and could not give their permission, nor did they have family members present who could speak for them. Yet the experiment was entirely legal.

The clinical trial was the first to proceed without informed consent under a rule the Food and Drug Administration released in 1996. The rule allows human research without approval from subjects, but only with life-threatening conditions that must be dealt with quickly and that have no proven treatment. Researchers also have to create a safety-monitoring board — an independent group that can recommend that the study stop early, as it did in the blood-substitute trial.

Many doctors support these studies. "The alternative," says Roger J. Lewis, a professor of medicine at the University of California at Los Angeles, "is not doing this sort of research, which condemns our children, if they're struck with these illnesses, to receive the same unproven therapies that we use today." Dr. Lewis was chairman of the blood-replacement study's safety board.

The trials have provoked controversy throughout their 10 years of existence. Some researchers find the FDA requirements too onerous, and think that, as a result, too few studies have taken place. Others think that the requirements do too little to protect patients.

Doctors who participate in this kind of research say they are most concerned not about whether these experiments are right or wrong but about how to discuss them with the public. The FDA requires that before scientists start a clinical trial without informed consent, they must confer with people who are likely to become subjects and must notify the larger public. But meeting those requirements has turned out to be extremely difficult, say several scientists.

"Investigators, even those of us who think we identify strongly with our communities, are not very good at communicating with lay people about research issues," says Lynne D. Richardson, an associate professor of emergency medicine at the Mount Sinai School of Medicine, "and especially very complicated issues about research without consent."

Michelle H. Biros, a professor of emergency medicine at the University of Minnesota Medical School, agrees: "The concept is great but the execution is difficult."

No Longer 'Under the Rug'

For years, medical researchers performed studies without the consent of unconscious patients, but without explicit rules. They justified their studies by saying they were obtaining "deferred consent" after the treatment, until the government clamped down on such research in 1993.

"We'd been sweeping something under the rug," says Susan S. Ellenberg, who at the time was an official at the FDA and is now a professor of biostatistics and associate dean for clinical research at the University of Pennsylvania School of Medicine. "We needed to bite the bullet and admit that we were doing research without informed consent."

However, the research need was clear. In situations like sudden heart attacks, just 5 percent or 10 percent of patients survive, and only if they receive treatment in the first few minutes after they go into cardiac arrest. If treatment comes later, patients endure far worse odds. And none can consent to a research trial. If someone legally allowed to consent for a patient were actually present at the scene of a person's collapse, says Dr. Richardson, "I don't even have enough time to explain the study in the five-minute window where I have a chance to intervene."

Faced with an end to such research, advocates banded together. Dr. Biros organized a group of researchers, ethicists, medical organizations, and patient-advocacy groups to delineate when research without consent might be ethical. The FDA used their ideas to produce the 1996 rule.

The rule sets many requirements for the trials, some of the most important ones being:

• The patient's disease or condition must be unpredictable and life threatening.

• No effective or proven therapy may exist.

• Subjects must be unable, because of their condition, to give consent, and getting consent from a family member or legal representative must not be feasible.

• The trial must provide the prospect of direct benefit to the patient.

• Researchers must try to obtain consent from the patient or from a legal representative.

• Researchers must consult with "representatives of the communities in which the clinical investigation will be conducted and from which the subjects will be drawn." They must also publicly disclose the experiment's plans, its risks, and its benefits.

• An independent committee must monitor the safety of the trial as it progresses.

• Once the study ends, researchers must notify the public of its results.

• If one institutional review board rejects a study, all other boards that have considered or are considering the study must be notified.

After the rule was announced, the FDA received 90 messages during the public-comment period. Sixteen of the comments opposed the rule, mainly arguing that informed consent should never be sacrificed.

"A big concern was balancing between making sure patients were protected, and not protecting them so much that we could never make research advance," says Ms. Ellenberg. "It's a big deal to give up informed consent. But it seemed unacceptable to most of us to say, Then we can't do research in this arena."

No one has an exact count of how many studies are occurring or have taken place under the rule. Some researchers think the number is around 15. The results of at least five have appeared in the medical literature.

One has provoked so much controversy that the U.S. Senate Committee on Finance is investigating, but most have proceeded quietly.

A few, like the first blood-substitute trial, have been cut short. The full results of another unsuccessful trial will be published in the Journal of the American Medical Association this month. The study tested a device that gives chest compressions to patients whose hearts have stopped.

Before the company terminated the study, 1,071 patients went through the experiment in five cities, receiving CPR with or without the device from emergency responders in fire trucks or ambulances. Ten percent of patients who received regular CPR survived, while less than 6 percent of patients who received CPR using the device survived — suggesting that perhaps 20 more people might have lived had they all received CPR without the device.

"That was disappointing," says Michael R. Sayre, an associate professor of emergency medicine at Ohio State University, who participated in the study. But he justifies the research in part because the device was already on the market at the time of the trial, and still is today. "Had we not done the study," Dr. Sayre says, "it's possible that many devices would have been used on patients that might actually have been detrimental to them."

Saving Heart-Attack Victims

None of the studies have yet changed the way doctors practice medicine, although emergency researchers say such studies will come with time. But proponents of studies done without consent all point to one large trial that has had a significant influence on the public.

The study looked at treating heart-attack victims using automated external defibrillators — the easy-to-use small machines that can shock a stopped heart back into normal rhythms. The machines, better known as AED's, were already widely used in ambulances, but researchers wanted to know if lay people with training and access to a defibrillator could save lives.

"If someone collapses, and I have a defibrillator already hooked up to them, I have a 70 or 80 percent chance of successfully resuscitating them," says Dr. Richardson, who led the portion of the trial that took place in New York City. "With every minute that goes by, the chances drop by 10 or 15 percent." Heart attacks kill some 450,000 people a year in the United States.

The study took place in 24 regions of the United States and Canada, and involved about 19,000 volunteers who received training to give CPR either alone or in conjunction with the defibrillator. The volunteers worked or lived in locations such as shopping malls, office buildings, factories, and apartment complexes, and half of those locations received AED's. Because patients could be taken by ambulance to different hospitals in each region, 76 institutional review boards had to approve the trial.

It required more than three years and perhaps $12-million in research grants and donated AED's. The team of 140 scientists published their results in The New England Journal of Medicine in 2004.

In the end, volunteers treated around 235 heart-attack patients. Thirty of those who received defibrillation and CPR survived, while just 15 survived who received only CPR. Dr. Sayre, who also participated in the study, says it "is helping to convince people that they really ought to have AED's in place in their shopping malls, businesses, and hotels across the United States."

Public Misunderstanding

Despite the trial's medical success, it may have failed on one front: getting the word out to the community of potential test subjects. Dr. Richardson and her colleagues performed the experiment in 59 residential high-rise buildings in New York. She wanted all residents to know what to do if someone had a heart attack: "We needed them to know there was someone on-site trained to respond and to call that person if someone collapsed."

The researchers held meetings, distributed flyers to each apartment, hung posters in lobbies and laundry rooms, mailed newsletters, and held stagings of mock heart attacks.

Two years after the study, she returned to the buildings and talked to people who had lived there during the clinical trial. "Less than half remembered anything about it," she says. "That was kind of discouraging." And of those who did recall the study, she says, only 3 percent identified it as research. The rest did not realize that the study was testing whether lay people could save lives with the device.

In a paper published in Academic Emergency Medicine last November, Dr. Richardson and her colleagues quote a resident who, upon hearing that the study was an experiment, insisted that it "wasn't research — we were helping people!"

"I think we were very careful to explain that this is a research study," says Dr. Richardson. "It's very difficult to get people to comprehend the difference."

What's more, the residents told her that they approved strongly of the trial, but upon hearing hypothetical scenarios of other types of research without consent, their answers varied widely.

The responses resembled those from a larger survey of public attitudes, conducted during the defibrillation trial. Terri A. Schmidt, professor and interim chairwoman of emergency medicine at Oregon Health and Science University, and Dr. Biros, of the University of Minnesota, interviewed 530 people visiting or receiving treatment at two emergency rooms.

At the time, the defibrillation study was enrolling patients in both cities, so members of the public could have become aware of the study through researchers' earlier public-notification efforts: multiple newspaper advertisements and community meetings.

At the emergency rooms, nearly 90 percent of the respondents thought trials should require informed consent. But when asked specifically about the defibrillation trial, 70 percent said they had no objection to entering such a study if they were unable to consent.

Dr. Schmidt says that researchers have struggled to find effective ways of engaging members of the public in discussion about studies. Researchers plan public meetings, she says, and no one comes. More useful in gauging opinions, she finds, are telephone polls. Similarly, scientists have been trying methods to notify the broader public, hoping to find one or a few that work well.

So far, public notification has been the least successful element of studies without consent, says Dr. Biros. In her and Dr. Schmidt's emergency-room survey, just 5 percent of respondents had heard about the continuing defibrillation study.

"People are feeling their way," says Ms. Ellenberg, the former FDA official now at the University of Pennsylvania. "You kind of know that putting a notice on a bulletin board in a couple of grocery stores isn't enough. Do you need a full-page newspaper ad? Do you need a TV thing?" she asks. "It was never the intent of the FDA that everybody in the community would have to know, but you have to make a good-faith effort."

Dr. Richardson hopes that the outreach will eventually become effective, not just a strong effort.

"What we really need are some guidelines about how to do it," she says. "Then I think we need some metrics to figure out whether or not it was done effectively."

Exploiting Patients?

Some researchers express frustration with the lack of direction from the government on this part of its outreach requirements. But Bonnie M. Lee, associate director for human-subject-protection policy at the FDA, says the unspecific requirements were intentional. "We recognize that different communities are different," she says. "We were hoping that by being vague, institutions and sponsors would think of creative ways to involve the communities."

Public consultation and notification tend to add several months, and significant expense, to each trial. Some researchers worry that the requirements discourage sponsors and researchers from carrying out trials.

Studies of another device to assist with CPR, an antibody to treat severe overdoses of antidepressants, and a drug to treat heart attacks never went forward because of concerns about expense or institutional review boards' discomfort with the exception from informed consent. Two reviews have found that the number of heart-attack trials has decreased since the 1996 rule went into effect, compared with before 1993.

Ms. Lee says the agency carefully monitors the trials and the concerns of participants, and may make changes if the agency finds it necessary. However, she says, "We never intended for it to be easy. We don't lightly waive the requirement for informed consent."

Some critics take exception to that statement. Informed consent, says George J. Annas, a professor of health law, bioethics, and human rights at Boston University, "has been the bedrock of human research since World War II. There's no compelling reason to abandon it."

To ethically do a study without consent, he says, would require far more input from the public. "You'd probably have to vote on it," he says. "You could do that! It's interesting to me that most [drug] manufacturers are afraid to ask people, when most Americans are very receptive to research."

Dr. Biros could hardly disagree more, asserting that research without consent is critically important. Mr. Annas, she says, "isn't a physician who has to deal with critically ill and dying patients every day, and who gets real tired of them dying."

But Vernon K. Sondak, chief of the division of cutaneous oncology and director of surgical education at the University of South Florida's H. Lee Moffitt Cancer Center and Research Institute, says researchers should have to prove that studies cannot be performed with consent before they do one without it.

He previously was a member of an institutional review board at the University of Michigan that decided, he recalls, not to accept proposals for research under the FDA's rule allowing an exception from consent. "We would insist on an attempt to do it with consent," he says.

It might take longer to do the research because it would require finding subjects who could give consent or legal representatives who could do so. But "taking three times as long or getting three hospitals together to do [the study] would be better than doing it without consent," he says.

Other critics worry that minority or poor patients could bear the brunt of the research risk. In blood-substitute trials, for instance, the likely subjects are "victims of violence, gunshot wounds in particular," says Karla F.C. Holloway, a professor of English and law at Duke University who is interested in how race and medicine interact. "These are populations that have not traditionally had respect in the medical community and institutions."

Dr. Biros recommends that researchers do the best they can to protect their patients, to contact the public, and to try to develop new ways to save lives. The 1996 rule, she says, "is, right now, all we have." She suggests that critics — and proponents — give recommendations to the FDA about changes they would like to see in the rule.

"It would be devastating," she adds, "to say that only informed-consent trials could go forward."