Protocol put to the public for review
Once a final decision is made regarding some proposed research involving very young children and an older smallpox vaccine, there could be long-term repercussions for IRBs nationwide. This especially is true now that the entire world can focus a magnifying glass on the IRB approval process with regard to one particular study. The IRB protocol review process was given unusual public attention in November after the Oct. 31 Federal Register notice sought public review and comment on a protocol for administering a smallpox vaccine to children.
Three IRBs had reviewed the same protocol, and while two had approved it, a third IRB narrowly voted against its approval but had made a motion to refer the protocol to the secretary of the Department of Health and Human Services (DHHS) for further action. In response, DHHS has published the study’s protocol, 10-page informed consent form, opinions of 10 experts, partial transcripts of notes from IRB meetings on the protocol, and other information about the vaccine and the study. The information is available on the Internet: http://ohrp.osophs.dhhs.gov/dpanel/dpindex.htm.
The proposed study poses some long-term ethical problems, according to some of the experts convened by DHHS to review the protocol and offer public opinions about whether the protocol should be approved. "I am concerned about the precedent that would be set in allowing this study," wrote Dale E. Hammerschmidt, MD, FACP, associate professor of medicine at the University of Minnesota in Minneapolis, who was one of the 10 national experts who reviewed the protocol.
"It should be unusual that a substantive risk be allowed to be borne without offsetting personal benefit by someone incapable of being his or her own consent authority," he wrote in a five-page letter to Greg Koski, MD, PhD, former director of the Office of Human Research Protections (OHRP) in Rockville, MD, and David Lepay, MD, PhD, senior advisor for clinical sciences and director of the Office for Good Clinical Practice at the U.S. Food and Drug Administration (FDA) in Rockville, MD.
Preschool children are particularly vulnerable to potential ethical abuses during clinical research, notes Mary Faith Marshall, PhD, professor of medicine and bioethics in the School of Medicine at Kansas University Medical Center, and the chair of the DHHS National Human Research Protections Advisory Committee. She was one of the experts consulted by DHHS. "The potential for abuse or exploitation increases when subjects cannot make their own assessments of the relative risks and benefits of the proposed research," Marshall wrote to Koski and Lepay.
"The risk of death based on earlier data is targeted at less than three per million children in this age range," wrote Rosemary B. Quigley, JD, MPH, who also is an expert consulted by DHHS. Quigley is a member of the National Institutes of Health (NIH) Director’s Council of Public Representatives and is a law clerk to Judge Kermit Lipez, who sits on the United States Court of Appeals for the First Circuit. "However, a significant proportion of the trial participants will suffer moderate to severe symptoms of headache, fever, fatigue, and rash, with some requiring medical treatment," Quigley adds. "The risk of these experiences is greater than a child would normally encounter."
The study proposes to evaluate the potency, dose, and safety of vaccinia virus vaccine (Dryvax) when administered to children, ages 2 to 5 years. It would be studied in an undiluted formulation and in a 1:5 dilution, with five skin punctures. Forty participants would be recruited between two sites: the University of California-Los Angeles (UCLA) Center for Vaccine Research and the Cincinnati Children’s Hospital Medical Center.
Two California IRBs reviewed the protocol and came to different conclusions. The Kaiser Permanente Southern California IRB decided in favor of the protocol, and the Harbor-UCLA Medical Center IRB voted 6-to-5 against it. The Cincinnati Children’s Hospital Medical Center IRB voted to approve the protocol after extensive deliberation.
"It’s a tough call because the risks are great," says Irwin Light, MD, IRB chair for the Cincinnati Children’s Hospital Medical Center IRB. "We put in stringent procedures for enrollment and recruitment of subjects," he says. "A third party will be involved in the recruitment process and will screen people to make certain they’re not responding to some unrealistic hysteria and that they are willing to follow through with precautions."
The proposed smallpox vaccination study is loaded with ethical land mines. The risks are severe, while the potential societal and participant benefits are nebulous since smallpox remains eradicated from the world and could not be a threat except in the event of a terrorist attack by an organization that somehow obtained the virus from one of its few remaining sources.
"How do you separate panic from reality?" asks Light, noting that even the history of the protocol dates back to a time of fear over biological warfare. "Our IRB was told in December of 2001, at the height of the anthrax scare, that this protocol was coming our way and that we needed to review it immediately because a terrorist could attack by the next week," he explains. "We called for an IRB meeting for Dec. 28, and the day before the meeting, the FDA called us to say the protocol was withdrawn."
During those weeks of relentless media coverage of anthrax, the potential smallpox vaccination protocol was announced in Cincinnati media outlets, resulting in parents inundating the IRB with requests to participate in the trial, Light notes. Since then, the panic and fervor have resided, and since the trial has not yet begun to recruit children, he says he couldn’t predict what the interest would be.
A potential analogy could be the swine flu panic and vaccine of the late 1970s in which the government pushed forward public immunization for a flu that never materialized. The vaccine resulted in Guillain-Barre syndrome in some of the immunized, and the infectious diseases community and government lost a great deal of credibility when the potential threat was over, says John M. Neff, MD, director for the Center for Children with Special Needs at the Children’s Hospital and Regional Medical Center in Seattle. "I think that’s what’s bothering everybody," he says. "Is that a threat that’s going to materialize or is it anxiety that is getting played out this way."
The threat of smallpox being reintroduced in the world and the United States is a hypothetical unknown, Neff says. "With the potential of war, there’s more of an immediacy in these trials."
Another problem with any smallpox vaccine studies is that the nation’s health has changed considerably since the 1960s and 1970s when the vaccine last was administered, says Anthony Robbins, MD, MPA, professor and chair of the department of family medicine and community health at Tufts University in Boston. "There are a lot more immunocompromised people out there now than in the past because of the presence of HIV and the many anti-cancer drugs that suppress the immune system," he reports. "It’s much more risky now."
Dryvax is a live virus vaccine that is administered by insertions of a needle, causing a blister. Unlike other vaccines, the smallpox vaccine remains present on the person’s skin and can be spread to other individuals. Because of this problem, the study’s investigators say that it will be necessary to have the children remain out of school or daycare for 30 days after vaccination. "So we’re talking about risks to both the person who is vaccinated and the risks to others who might come into contact with that vaccinated individual," Robbins says. "Efforts are being made now to see if a safer vaccine can be produced by changing the virus in a manner that would make it less dangerous to people exposed to it, but so that it still will give protection against smallpox virus," he adds.
Also, the Dryvax trials pose additional ethical considerations since they would include giving some children a diluted vaccine, which may or may not provide any particular child participant with immunity to smallpox. On the other hand, the adult studies have shown that the diluted vaccine provides good protection. Some experts consulted by DHHS have suggested that this information should suffice, and the diluted vaccine should not be studied in children.
Members of the Cincinnati Children’s Hospital IRB, in discussing the protocol at a meeting on July 16 were concerned about the 30-day school/daycare prohibition on children participants. They wondered whether this meant that the children would need to be isolated from all contact with other children and/or adults and whether the children’s parents could become exposed to the vaccine virus through contact with their children, resulting in their own lost wages.
If the children Dryvax trials are finally approved, there will be very stringent exclusion criteria with more than 15 exclusion details, including a history of atopy, eczema, or other exfoliative skin disorders, immunodeficiency disease, use of immunosuppressive medications, allergies to components of the vaccine, thimerosal, cidofovir, or probenecid, and household members or contacts who are pregnant younger than 12 months old or who have the same skin or immunodeficiency disorders that would result in the exclusion of the actual subject.
Anyone who is pregnant or planning to get pregnant should not be exposed to the vaccine or a vaccinated child because the vaccine is associated with fetal death or miscarriage, Neff says. One of the challenges for investigators and IRBs is to make certain the potential subjects and their families are carefully screened for all of the exclusion criteria, both through family histories and medical check-ups, he says. "I wouldn’t vaccinate anyone without knowing their HIV status and T-cell count, and I’d do pregnancy tests and pregnancy counseling," Neff says. "I’d be very cautious on that."
With all of the potential hazards and such poorly understood benefits that could be derived from clinical trials in small children, some of the experts and others question why this research should be pursued. "The truth is I don’t know how you do vaccine trials on children ethically," says Vera Hassner Sharav, president of the Alliance for Human Research Protection in New York City. "I understand the danger of smallpox, but I also know that at a declaration of war time you always wind up with a whole lot of things done that use the war as an opportunity to do what you otherwise can’t," she remarks. "Some research needs to be slowed down."
Once a final decision is made regarding some proposed research involving very young children and an older smallpox vaccine, there could be long-term repercussions for IRBs nationwide.
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