Vaccine, drug development link IRBs and researchers
Key is to not repeat past mistakes
Depending on a person’s level of confidence in the current human research protections, the answer is either: "It will never happen again" or "We need to be careful or it’s possible." The question is: "Could the United States trample human subjects’ rights in the push to produce a vaccine for a bioterrorism threat?"
IRBs and researchers may be loathe to be reminded of past research transgressions, such as the World War II outbreak of jaundice that was connected to a yellow fever vaccine administered to soldiers and civilians. To find out what was wrong with the vaccine, government health officials intentionally inoculated healthy people at a Lynchburg, VA, facility for the mentally disabled and studied what happened, says Paul Lombardo, PhD, JD, director of the program of law and medicine for the Center for Biomedical Ethics at the University of Virginia in Charlottesville. Lombardo also is an associate professor in the School of Law and is a member of an IRB. He has studied and written about the eugenics movement.
"Several hundred people were enrolled as volunteers in this study with knowledge that they were legally unable to volunteer, the capability of many of the people to understand what was going on was limited, and protections were limited," Lombardo says. It turned out that the vaccine was contaminated with hepatitis, which caused the jaundice and eventually also infected the institutionalized Lynchburg population.
Lombardo and other experts on vaccine policy and prevention spoke about this topic at the Bioethics and Bioterrorism Conference, presented by the Center for Bioethics at the University of Pennsylvania and the Center for Biomedical Ethics at the University of Virginia, held in February at the National Press Club in Washington, DC.
Things are different today
The Lynchburg incident is irrelevant to today’s discussion about producing a vaccine to prevent widespread bioterrorism of anthrax, smallpox, or other agents, says David Weiner, PhD, an associate professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine in Philadelphia. Weiner also spoke at the bioterrorism conference, and has been involved extensively with HIV vaccine and West Nile virus vaccine research.
Today’s situation is entirely different because there is no pressure to pull out all stops in producing a vaccine, Weiner says. "We have so many more options than we used to have, and vaccine is only one option." For example, the recent anthrax scare was frightening, but not dire because of the availability of powerful antibiotics that can be used to successfully treat the infection, Weiner says.
Even with a smallpox threat, there are about 20 drugs that might inhibit the growth of smallpox, Weiner says. "And actually inhibiting it may be enough to prevent death, and so this is a different time," Weiner adds. "This country and the world are much more sophisticated now; and we have a lot of resources, and we have to put them all to use."
Also there is a stockpile of smallpox vaccine that could be diluted to where it could be supplied to 75 million people, Weiner says. These resources include vaccine trials, which should be conducted under the same stringent human subjects’ protections that are accorded every other human subject, Weiner says. For instance, the government is working on developing vaccines for the Ebola virus and other subtropical viruses that could be used in a bioterrorism threat.
However, there still remains a concern that during a time of national emergency, just as the Lynchburg incident occurred during a time of national emergency, that a vaccine trial or new drug development could be rushed, Lombardo says. "What is the impact of that kind of emergency on the usual rules of research?" Lombardo asks. "And if we had a national emergency that was somehow equivalent to World War II, would we feel free to dispense with rules we’ve had in the last 50 years to protect human subjects?"
IRBs should consider this question, Lombardo suggests: "What kind of national emergency might justify relaxation in the rules and whether or not these relaxations would be appropriate?" Lombardo and Weiner offer these ethical and practical considerations that IRBs may encounter should a significant bioterrorism threat occur:
• How much risk is acceptable with a vaccine? The smallpox vaccine had a risk rate of one in 10,000 serious adverse events in the 1960s and 1970s, Weiner says. "And it’s likely that due to AIDS and immune deficiency that risk would go up," Weiner adds. "So we need newer vaccines that are safer."
Science leaps forward
Most current vaccine technologies use recombinant vectors that are considered safe in the lab. "So in theory, depending on the experiment, one could work with these vectors with genes from pathogens that are separated from the whole pathogenic organism in a relatively safe way," Weiner explains. "And they permit a lot of experimentation of vaccine testing and development in absence of pathogen challenge." Side effects from recombinant approaches would be due to the protein use, and research testing of these vaccines would go through a relatively similar toxicology and safety evaluation as any other vaccine, Weiner says.
Human subjects research would use surrogate markers in a comparison of antibodies produced by the newer and the older-style vaccine in cases such as smallpox where there already have been vaccines that work, Weiner adds. "We know the newer vaccines are intrinsically safe because they don’t replicate and don’t spread infection," Weiner says. Still, there probably will be small human trials and not be widespread testing of many of these vaccines once they are researched in animal models, and the resulting product will be produced in a large enough quantity to be deployed if needed, Weiner adds.
• How might IRB members insulate themselves from being swayed by public alarm? "IRBs should try real hard to not be swayed by events that are occurring because those public emergencies tend to make us all leapfrog over the kind of logic that is in place to make sure the science is done well and to make sure that no one is unduly harmed," Lombardo says. "You don’t want to let the fear of further disease blind you to the quality or effectiveness of therapy you have in hand," Lombardo says. "But there still is a line to be drawn in research to discovering its effectiveness."
Also, a bioterrorism threat needs to be put into perspective with other significant health concerns and the sense of urgency some will feel about getting a product quickly to the market. "This is the whole story of IRBs as far as I’m concerned," Lombardo says. "It isn’t even a hard question because if a medicine is being tried out that doesn’t provide much hope, then no one rushes to get it on the market."
Alternatively, when there’s a particularly vicious disease and the potential of very hopeful medication, people will ask why researchers or the government are waiting, Lombardo notes. "The very people whose lives are at stake often are unfortunately talked into a hope which may not be justified by the data, and that’s the whole therapeutic misconception," Lombardo says. "It’s I’m sick and you’ve got the pill, so give it to me.’"
• Which research groups and IRBs are likely to be involved in bioterrorism vaccine research? The research typically would begin in significant federal containment facilities in partnership with the Centers for Disease Control and Prevention (CDC) in Atlanta. Animal challenges would be an important part of the development. The most likely scenario would be for these bioterrorism vaccines to be studied at military hospitals and facilities, although universities and academic centers may be involved in small-scale trials of safety, Weiner says. "I think you might have some sort of surrogate analysis, which may be a small stage 3 trial that is looking for the antibody level or for an elevated spot as an indication of cellular immunity levels in an individual, as well as safety research," he says.
The U.S. Food and Drug Administration, the CDC, and the Department of Defense would provide the oversight of vaccine research, so a single IRB probably would not be alone in deciding ethical considerations. "I believe this is a different situation," Weiner explains. "We’re not going for a commercial license." Rather, the goal would be to develop something that needs to be stored and used in the case of a national emergency. The decision about licensure would be based on a committee agreement that whatever the material is after the studies are complete would be worth stockpiling, Weiner says.
Anthrax scare was a learning opportunity
• How can the risks of new vaccines be adequately communicated to subjects and to the public? "You have a separate concern about application of new therapies and vaccines to populations that are infected or might be," Lombardo says. "So the public health issues of how do you prevent further spread of some infectious agent is really a different issue than how do you protect people from research."
The recent anthrax scare is a good example of how the public might be warned of potential vaccine problems. National Institutes of Health researchers made it clear that the vaccine is not really well understood, so it was offered to people with the hope that some of them would look at the data and make an informed decision about whether or not to take it, Lombardo says.
"Most people didn’t take it because the data were unclear of whether or not it would be a benefit to them since they already were on Ciprofloxacin and other antibiotics and since there wasn’t any apparent renewed threat of exposure," Lombardo adds. "This is a case where you could have had much worse results and the government might have had to coercively vaccinate people," he says.
Educate about the risks
On the other side of the coin, the AIDS vaccine research presents an example of how subjects might be fully informed of an investigational vaccine’s risks. Weiner has been involved with developing an AIDS vaccine that presents no risk of HIV transmission but also may not inoculate subjects against the virus. There is the desire on the part of researchers and IRBs to make certain subjects know that they must continue to take as many precautions as previously or they will place themselves at risk of infection. "In our HIV vaccine trials, we tell subjects that we assume the vaccine doesn’t work," Weiner says. "And actually, they’re counseled to think that as far as we know we have no efficacy in this vaccine at all; that we have no knowledge that the vaccine works at all. So, to really do the study, what they’re really doing is volunteering."
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