When it comes to regulatory issues, some are thornier than others. At the approval stage, regulators must ask whether the evidence supports approval, whether a product might be abused, whether use could hide other conditions, or whether other negative externalities exist. And even at the Investigational New Drug (IND) filing phase for drugs, regulators have to consider the safety of patients who could stand to benefit-or be harmed-by prospective treatment.
And those concerns grow ever more difficult when the patients involved are children.
Pediatric testing is broadly governed by the concept of "minimal risk," a term FDA has defined as "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."
Because pediatric populations-a category that includes neonates, infants, children and young adolescents-consent to trials through their legal guardians (often their parents) and in some cases cannot vocalize or even conceptualize non-consent, federal regulations are written to afford them a higher standard of protection than their adult counterparts.
But this minimal risk standard comes with a notable catch, one identified last year by a federal ethics board. The problem lies with efforts to bolster the US' ability to respond to potential safety threats, including nuclear, chemical, biological and pathogenic emergencies.
These events are, by their very nature, exceedingly rare if they happen at all, making preparing for them exceedingly difficult.
Take anthrax, for example. The deadly bacteria has been seen in the US just a small handful of times in the last two decades, but pharmaceutical companies-spurred in part by funding from the Biomedical Advanced Research and Development Authority (BARDA)-have set out to develop therapies for it.
So how do you conduct clinical testing against a rare pathogen that very often kills its host? Prior to 2002, no real method existed. However, in 2002 FDA enacted the Animal Efficacy Rule ("the Animal Rule"), which permits sponsors to deviate from standard clinical testing practices in one important way.
While safety testing for the products still involves human subjects, efficacy testing instead involves only animal subjects known to be genetically similar to humans. For example, Cangene's botulism antitoxin, approved in March 2013, was approved based on safety testing in Rhesus monkeys.
A Tension between Risk and Reward
But that leaves a tension between the Animal Rule and the standard of minimal risk: Are the safety risks associated with human safety testing under the Animal Rule acceptable for pediatric patients given that they are unlikely to ever benefit from the treatment?
In May 2013, the Government Accountability Office (GAO) weighed in with a report, noting that 40% of all stockpiled medical countermeasures in the Strategic National Stockpile (SNS) have not been approved for any children, and the other 60% have in most cases only been approved for some pediatric populations (e.g. for adolescents, but not neonates). This, the report said, raised the prospect that treatments might not function, or worse be harmful, for pediatric patients in situations where the treatment is most needed.
GAO's report had little to say in terms of concrete recommendations, noting that the regulatory hurdles were substantial, but simply said that the government could be doing more to support the needs of children.
A Presidential Commission Weighs in
An earlier March 2013 report by the Presidential Commission for the Study of Bioethical Issues (PCSBI) came to a similar recommendation, noting that "new policies, practices, research and perspectives are needed to study medical countermeasures for and with children."
"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 commission recommended.
The report also calls for a de-escalation approach, in which data obtained from adults is used to support testing in adolescents, which in turn is used to support testing in younger children, and so on and so forth.
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.
The commission also recommended that research trial regulations (45 CFR 46.407, 50.54) be reworded 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.
Now FDA is set to take on the conclusions on that report, announcing in a Federal Register posting on 7 August 2013 that it plans to hold a meeting over two days in September 2013 to "discuss ethical issues in pediatric product development, including medical counter measures, focusing on the concepts of minimal risk, disorder or condition, and exposure of pediatric subjects to risks under 21 CFR 50.54."
The meeting is considerably longer than most, which often occur over a single day-possibly an indication of the difficulty and weight of the ethical issues the meeting is set to address.
For now, details about the meeting are few, with FDA offering its standard explanation that further meeting materials will be available "no later" than two business days prior to the start of the meeting. Approximately one hour of the meeting will be set aside for oral presentations from the public, FDA added.