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Harvard Public Health Review/Summer 2002

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Truly Informed Consent

Since the Nuremberg Code established the ground rules for ethical research almost 50 years ago, researchers have been required to get informed consent from people participating in studies. Putting the requirement into practice stirs up a swarm of difficult questions. How much information does a person need to be informed? Do the study participants really understand the information? Is their consent genuine?

George R. Seage III wants not only to answer those difficult questions, but also to apply them to one of the biggest challenges in public health today--development and testing of an AIDS vaccine, particularly one that will help AIDS- ravaged Africa. To do so, Seage, associate professor in the Harvard School of Public Health's epidemiology department, is working closely with Max Essex, John LaPorte Given Professor of Infectious Diseases and chair of the Harvard AIDS Institute. Essex spent seven months last year in Botswana, setting up a state-of-the-art laboratory and various programs of the Botswana-Harvard Partnership for HIV Research and Education, a joint effort of the AIDS institute and the government of Botswana.

Westerners working with African researchers and health officials to enroll people in AIDS vaccine trials must be, both ethically and scientifically, above reproach, says Seage. Otherwise, he adds, "we'll be accused of exploiting people." Researchers, therefore, need to strive for truly informed consent but that entails them telling subjects things they might not like to discuss: uncertain outcomes and possible dangers. "The most important aspect of informed consent," he asserts, "is that people need to understand that this is an experiment."

Seage came to the School in 1999 from Boston University. His career in AIDS research started in the mid-1980s with groundbreaking work on HIV transmission rates and routes among gay men in Boston, including original investigations on the role of nitrite use and the immune response in HIV transmission. That research segued into studies of intravenous drug users--and some insights into the practical problems of studying people who often don't have a steady address or job. Instead of relying on the phone, Seage and his colleagues distributed beepers. They learned to collect information on the mothers of study subjects. Even if people in the study seemingly dropped out of sight, it was a good bet that their mothers would know where to find them. "Moms," quips Seage, "are key."

Like many others in his field, Seage had high hopes in the early 1990s that the National Institute of Allergy and Infectious Disease (NIAID) would fund a Phase 3 trial of an AIDS vaccine in the United States. But in 1994, NIAID Director Anthony Fauci decided against going ahead with a large study. Making a virtue out of necessity, Seage shifted to projects that would lay the groundwork for an eventual Phase 3 trial. These vaccine preparedness studies, as they came to be called, included investigations of the most effective study designs, target populations, recruitment and retention strategies, and ethical issues, such as informed consent.

Gauging people's understanding of a study is one of the trickiest issues in informed consent. Seage helped lead an American vaccine study that quizzed potential participants before enrollment. "Before we did it, no one had ever required people to pass a test to get into a clinical trial," he says. At the same time, expecting too much understanding can backfire and simply confuse. "You don't want to make it too much like going to science class," Seage observes. Researchers must also navigate the built-in conflict between large and rapid recruitment into a study, which reduces the cost of a trial, and high standards for informed consent, which are likely to slow recruitment down. Seage says some experts have proposed that oversight of informed consent should be separated from the rest of a clinical trial.
AIDS vaccine trials pose special problems. Prevention counseling is an ethical requirement. But if counseling results in less risky behavior, it may result in no new infections, which is an excellent public health outcome but makes it more difficult to measure how many infections a test vaccine prevented. Another issue: many experts believe the vaccines may slow disease progression rather than provide so-called sterilizing immunity and prevent them altogether. If that's the case, judging efficacy may be complicated by early treatment of study subjects.

Seage, along with Tonya Villafana of the Botswana-Harvard AIDS Partnership, is now pondering how lessons learned from American vaccine preparedness studies might be applied to Botswana. In the US, investigators have often used videos to educate study volunteers, but such an approach might not be feasible or acceptable in Botswana. Another possibility is some form of modified quiz. A bigger problem is deciding what sorts of people to enroll in a study. To be of any use at all, vaccine studies must be conducted in populations that are vulnerable to HIV infection. But, as Seage points out, identifying yourself as vulnerable to HIV might itself pose risks. In Botswana, researchers need to take into account that some people might lose their jobs, be ostracized by their families, or even worse, if word of their participation in a vaccine trial got out. For this reason and others, he says it will be important to collaborate closely with regional health officials, local ethicists, and community advisory boards.

But regardless of the means, Seage says it's crucial that researchers take steps to document that volunteers clearly understand what they are getting into--that a trial is experimental, that a vaccine may not work, that they may not be getting the vaccine at all, and that they still must do everything possible to follow safe behavior guidelines. "I think if we are going to test an experimental vaccine in a vulnerable population, in an economically poor country, we have an obligation to do this kind of work," he says.

"Be prepared" is the motto of the Boy Scouts, and Seage concedes that vaccine preparedness "sounds, well, sort of hokey." But regardless of the connotations, Seage's groundwork in Botswana, thinking through informed consent issues and other knotty problems, stands to hasten development of an AIDS vaccine and save millions of lives in the process. Preparedness, in this instance, means a lot more than a merit badge.

Peter Wehrwein

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