Last Thursday, the Presidential Commission for the Study of Bioethical Issues met in Washington, DC to assess the ethics of a clinical trial on anthrax vaccines for children. Secretary of Health and Human Services Kathleen Sebelius asked the Commission to investigate the issue, after the National Biodefense Science Board (NBSB) voted in favor of pursuing pediatric trials. These trials and other medical countermeasures are intended to prepare the nation in the event of a bioterrorist attack, like the one in 2001 in which letters containing anthrax spores killed five people and infected 17 others. A recent project called Dark Zephyr found that the release of anthrax spores in a city such as San Francisco could result in infection of 7.6 million people, nearly a quarter of which would be children.
More than one million adults, mostly member of the military have received BioThrax, the only FDA-licensed vaccine. Side effects include soreness and redness at the shot site, muscle aches, fatigue, headache, and fever, with a few rare but serious allergic reactions. Uncertainty about the severity of similar side effects in children has led some to believe we should continue to rely on the current standard of care for anthrax, antibiotics, three of which are approved for adults and children.
But there are drawbacks to using antibiotics alone, as NSBS noted. For one thing, they offer only temporary protection; an individual exposed to anthrax would still need to be vaccinated. But a 60-day regimen of antibiotics would be needed before a vaccine would take full protective effect. Given the difficulty complying with such a long-term antibiotic regimen, and the need for vaccination anyway, the NBSB saw advantages to so-called “pre-event” vaccination and recommended a pediatric vaccination trial.
While conducting a trial on an anthrax vaccine for children may well save millions of lives, it raises serious ethical questions. A number of witnesses at the meeting highlighted the fact that we have zero data on how children would react to such a vaccine. Given this scarcity of data, Michael Anderson, vice president and chief medical officer of UH Case Medical Center and representing the American Academy of Pediatrics, argued that it would be unethical not to conduct pediatric trials. He believed a failure to examine the vaccine in children would deprive us of valuable data necessary to save children’s lives.
Several other witnesses were more cautious, particularly since the necessity of such a vaccine is uncertain. Robert “Skip” Nelson, senior pediatric ethicist in the Office of Pediatric Therapeutics of the Food and Drug Administration (FDA), questioned whether a pediatric trial of an anthrax vaccine would meet the FDA’s ethical standards. He highlighted ethical framework that the FDA uses to evaluate pediatric trials, emphasizing three relevant principles. Children should not be enrolled in a clinical trial if the scientific or public health objectives can be achieved by enrolling adults. Absent direct therapeutic benefit to the children enrolled, the risks to them must be low –or no more than a minor increase over minimal a risk, which itself is defined as no greater than the risks that they face in ordinary activities. And children should not be placed at a disadvantage after being enrolled in a clinical trial, either through exposure to excessive risks or by failing to get necessary health care.
Children enrolled in a”pre-event” anthrax trial will not receive direct medical benefit. The benefits–knowledge about how best to protect children from anthrax–would be accrued by future generations. Given the uncertainty of an anthrax attack even occurring, it is not clear how much risks research subjects should be legitimately exposed to or whether vaccination is more effective, or cost-effective, than an antibiotic regimen.
To justify such a study, one would have to presume that an attack is almost certain and that the studies will yield scientific and medical benefits. Even if we can agree on the certainty of a bioterrorist risk and the value of scientific knowledge gained through studies, it remains to be answered who should be enrolled in the clinical trials.
One suggestion at the Commission meeting was that those most at risk of attack, such as military families or individuals living in likely terrorist targets such as Washington, DC or New York City, should be recruited for clinical trials first. Whether this or another approach is pursued, a number of justice-based concerns arise related to the distribution of risks and benefits. James Hodges, professor of health law and ethics at Arizona State University, laid out 10 core principles to help frame emergency public health ethics. These principles lead to consideration of which populations are most vulnerable and those that are most likely to benefit, as well as the equity, transparency, and fairness of scarce resource allocation.
Pediatric trials would also lead to a number of practical and logistical considerations, which also have ethical underpinnings. Nicola Klein, Director of Kaiser Permanente Vaccine Study Center, highlighted some of them. Given the great weight of the decision parents must go through to approve clinical research on their child, she said, parents must be robustly informed about potential risks, benefits, and other consequences of the vaccine as predicted from use in adults; be actively engaged in reporting outcomes; and be committed to the goals of the research. Parents, and children as they get older, must also trust the research process.
Klein also emphasized that while financial and other incentives can be used to encourage participation and compliance of subjects, it must not lead to coercion or pressure. Unlike children with cancer or a rare disease who might be enrolled in an experimental clinical trial with the prospects of extending life or finding a cure, consent to an anthrax vaccine trial appears to be almost entirely altruistic.
Ethical considerations aside, what struck me most about the meeting was the extent to which it seemed as though the Commission was being called upon to issue a “rubber stamp” of ethical approval. The NBSB recommendation stated that approval of pediatric anthrax vaccine studies “should be referred to an appropriate review board to formally address the ethical considerations.” In addition to seeking input from ethicists, NBSB also requires public representation in the decision process. After undertaking an ethical assessment, it said, “HHS should develop a plan for and conduct a pre-event study” of anthrax vaccines in children. It is no surprise that the Commission is the body most suited to undertake such an ethical examination, but should a favorable finding by the Commission fully legitimate pediatric trials?
Given the speaker presentations and subsequent discussions among members of the Commission, I would be surprised if the research is given the ethical green light, but what if it is? Should we be entrusting such a decision, with a great deal of questions still unanswered or even yet known, to one advisory body? As David DeGrazia, professor of philosophy at George Washington University, said when asked if he would approve “pre-event” vaccine trials, we do not yet have a clear enough idea of the probability of a bioterrorist attacks, the associated risks, or the complexity of the situation.
Furthermore, if NSBS is truly concerned about “public representation” and input on ethical issues, the Commission meeting was little evidence of that. Of those in attendance who asked questions, only one was not a member of the scientific, medical, or academic community–she was a mother who expressed concern about such a study after witnessing adverse side effects of vaccinations in her own children. While laypersons are invited to submit official comments to the Commission, those most likely to do so are probably strong opponents on one side or the other, not representative of American citizens who might be called upon to volunteer their child for a study.
I have great admiration for many members of the Commission, but to give them alone the power to stipulate the proposed trials as ethical or not troubles me. Unlike previous tasks given to presidential commissions over the last few decades, which called for largely advisory recommendations, the resulting report in this case could have a more direct impact on whether research proceeds.
Ultimately the decision by the Commission about how to weigh the ethical considerations at stake will likely come down to weighing the risks, burdens, and uncertainty associated with ”pre-event” pediatric anthrax trials against the risks to public health and bioterrorism preparedness of not getting out ahead of threats. This is not an easy balance, but I am of the mind that we should be more concerned about the former than the latter. There will always be threats to our national security and public health posed by individuals with nefarious intentions, but to proceed further down the path of assuming the risks of an anthrax attack than we need to seems premature at this time.
Imposing potentially undue health risks on children is not necessary given our uncertainty of needing such precautions. Those risks should only be assumed by our children and society in the event of an anthrax attack. Unless that happens, we should continue to rely on antibiotics as the standard of care. Given the complexity and uncertainty surrounding this issue today, this seems to be the most ethical and socially responsible approach.
Ross White is the public policy associate at The Hastings Center and a graduate student in philosophy and social policy at George Washington University. Follow him on Twitter @rossswhite.