A new report published by the Presidential Commission for the Study of Bioethical Issues calls for the US government to put into place a modified framework that will allow for researchers to conduct pediatric testing of medical countermeasures, part of a framework intended to protect the entire population in the event of an attack using weaponized anthrax or other pathogens.
The announcement comes nearly a year after the commission first announced it would study the issue. In a June 2012 statement, the commission said it had received a request from Department of Health and Human Services Secretary Kathleen Sebelius, who asked it to look into the legal, ethical and social issues associated with testing medical countermeasures on children.
At issue is the use of the Animal Efficacy Rule, a pathway of sorts created shortly after the US postal system was used to mail spores of anthrax around the country, and most notably in Washington, DC. In the wake of that incident, legislators realized the US lacked a means to develop treatments in advance of a realized need, and set about trying to make a regulatory pathway that could account for the ethical complexities of testing a product meant to protect against a dangerous pathogen.
What they came up with was the Animal Rule, which allows regulators to approve products based on preclinical research, a phase I clinical trial on humans, and substantial animal testing instead of phase II trials. The intent of the pathway is to make sure a product would be generally safe for use in humans, while having a reasonable idea about how effective the treatment would be in humans based on animal models.
Testing the safety and efficacy of the products in humans is deemed to be too dangerous given the potential for serious adverse events.
While progress with the pathway has been slow, FDA has recently awarded several approvals to companies based on the pathway, including treatments for anthrax and the plague. A seventh product, Cangene's botulism antitoxin, was recently given a favorable decision by an unanimous FDA advisory council, smoothing its pathway for a likely approval from US regulators.
But the pathway has one potential problem: Adults aren't the only ones with the potential to fall ill during in the event of an outbreak of a dangerous pathogen, be it caused by a malicious actor or simply by circumstance.
"While significant progress has been made in the development of medical countermeasures for adults, the development of similar products for children has lagged, in part because of challenges in conducting safety and immunogenicity studies," the commission explained. "The Commission is particularly interested in policies, practices, research, and perspectives on ethical issues associated with pre- and post-event studies testing the safety, dose, and/or immunogenicity of medical countermeasures for and with children."
At the time, the commission said it was particularly interested in creating a conceptual framework to consider "risk and societal value when reviewing pediatric clinical research in general and for medical countermeasures in particular." It wanted that framework to include different types of information, criteria for proposed studies, ethical issues, scientific and public health strategies, communication strategies and the role of communities in designing and supporting research.
Now the commission is out with its recommendations, saying that the government needs to do a considerable amount of legwork before pediatric trials involving medical countermeasures-anthrax vaccines, specifically-would be ethically warranted.
"The safety of our children is paramount and we have to get this precisely right," Commission Chair Amy Gutmann said in a statement. "The Bioethics Commission concludes that many significant steps would have to be taken, including additional minimal-risk research with adult volunteers, before pediatric anthrax vaccine trials prior to an attack should be considered."
The ethics of involving children in the medical countermeasure trials are in many ways similar to the risks that face adults. Because participants are unlikely to benefit-perhaps ever-from the treatment, risks need to be seen as minimal. This is especially true, though, for children, wrote the commission.
"Out of respect for every individual, our nation must protect children enrolled in research studies while also doing its best to develop the knowledge needed to save children's lives during a possible emergency," Gutmann said.
Minimal Risk Paradigm
That framework for risk is one defined in the word the commission added: Minimal.
"Absent extraordinary circumstances, pre-event MCM research with children is ethical only if it presents 'no more than minimal risk' to study participants, where 'minimal' means no greater risk than that routinely faced by a healthy child in daily life or at a medical check-up."
The best way to start testing in children is through a process known as age de-escalation, whereby a trial would start testing in healthy young adults (e.g. 15-18) based on data obtained in younger adults (18-21). From there, testing would progressively decrease in age-steps so long as the prior trial did not raise any safety issues. The aim of this approach is to prevent a young child from being exposed to unknown risks, the commission said.
The commission conceded that in some rare cases, it will be impossible to demonstrate that a trial would only represent "minimal" risks to children. In those cases, the commission recommended that the researchers be able to show that the risk is still acceptably minor (near-minimum) and represents "no substantial threat to a child's health or well-being" before being allowed to proceed.
Regulatory Changes Needed
The commission also recommended that research trial regulations (45 CFR 46.407, 50.54) be re-worded to remove ambiguity surrounding pediatric medical countermeasure research, which it said would allow more consistent protections for children. The new wording, it said, would require that children be exposed to "minimal risk" and stand to benefit in some way from the research.
In addition, "When there are no data on the administration of a medical countermeasure to children and it will be provided to children in an emergency, the medical countermeasure should be provided under a treatment investigational new drug application (IND) to ensure that rigorous pediatric research protections apply to safeguard those children who receive the medical countermeasure," the commission recommended. This should be done to ensure that the product can be used in an emergency-use situation in any future events, it explained.
Sponsors of the research should make sure to conduct post-event research to gauge its efficacy and safety.