Medical countermeasures (MCMs) cannot ethically be tested on children in clinical trials before attacks without additional steps designed to minimize the chances of such research taking place, a White House advisory panel concluded in a report released today.
The Presidential Commission for the Study of Bioethical Issues concluded that because children enrolled before attacks in “pre-event” MCM trials do not stand to directly benefit from the research, such trials were ethical only if they presented “no more than minimal risk” to study participants. The panel defined “minimal” as posing no greater risk than that routinely faced by a healthy child in daily life or at a medical check-up.
The commission made an exception to that finding in the case of “extraordinary circumstances,” which according to U.S. Health and Human Services regulations (45 C.F.R. § 46.407 or “Section 407”) are circumstances in which proposed research “presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.”
Where it is impossible to design minimal-risk, pre-event MCM research, trials must undergo a national-level ethical review under Section 407 and/or FDA regulation 21 C.F.R. § 50.54 (Section 54). However, the bioethics commission advised, a national ethical review should occur “only when researchers have demonstrated and reviewers concur that a minimal risk study is impossible and the proposed study poses no more than a minor increase over minimal risk to research participants.”
Procedures with a minor increase over minimal risk, according to the commission, might include a skin biopsy or a chest x-ray, since they present no substantial threat to a child’s health or well-being.
“That would still mean that the risk posed no substantial threat to a child’s health or well-being. One would not want to say that you could have ethical research in children who do not stand to benefit from this research unless the research posed no substantial risk to their health or well-being,” said Commission Chair Amy Gutmann, Ph.D., president of the University of Pennsylvania, said.
The bioethics panel addressed the issue of MCM trials and children in its latest report, Safeguarding Children: Pediatric Medical Countermeasure Research. The 146-page report also concluded that before considering pediatric MCM trials in advance of an attack, drugmakers and other sponsors should conduct additional minimal-risk research with adult volunteers.
Also, sponsors should strive to “identify, understand, and characterize research risks” through ethically sound modeling, testing with animals, and testing with the youngest adults. For example, according to the report, it is possible that with additional testing in adults aged 18 to 20 years, testing of anthrax vaccine adsorbed (AVA) with 16- and 17-year olds could be considered no more than minimal risk.
Pre-event pediatric MCM research posing a greater-than-minor increase over minimal risk should not be approved under Sections 407 or 54, the panel added, in part because of the inherent uncertainty of a bioterrorism attack. Instead, the report stated, regulators should use the commission’s framework, which fleshes out spells out circumstances where proposed research presents a “reasonable opportunity” to address a “serious problem”, and specifies conditions for whether the research would be conducted using “sound ethical principles”.
According to the framework, seriousness must be judged by the consequences of exposure, likelihood (or threat) of exposure, and the “vital importance” of the information to be gained. The framework also spells out conditions necessary to determine whether the research would be conducted in accordance with five “sound ethical principles”: ethical threshold of acceptable risk and adequate protection from harm; ethical research design; post-trial requirements to ensure ethical distribution of MCMs in the event of an attack, as well as a plan for treatment or compensation for research-related injury; community engagement; and transparency and accountability.
The framework—which could also be used for nonpediatric MCM research—also stresses informed parental permission and “meaningful” and developmentally appropriate child assent.
For pre-event pediatric MCM research that poses greater than minimal risk, but no more than a minor increase over minimal risk, the commission’s framework adds that the seriousness of a problem must be judged by the consequences of exposure, likelihood or threat of exposure, and the “vital importance” of information to be gained.
Post-event MCM research, Dr. Gutmann added, may offer the prospect of direct benefit to children. The commission recommended that post-event research be planned now and must be conducted when tested, or minimally tested MCMs are used, in order to protect children in emergencies, noting that the post-event environment poses several logistical challenges for research.
The commission began its study at the request of HHS Secretary Kathleen Sebelius. She made the request in January 2012 after another federal panel, the National Biodefense Science Board (NBSB), recommended that the U.S. government conduct a study to test the safety and effectiveness of AVA in children before an anthrax attack, as long as it withstood a review of ethical issues.
The science board weighed in after the U.S. government conducted its “Dark Zephyr” bioterrorism preparedness exercise, which concluded that in a city the size of San Francisco, officials would have to vaccinate 7.6 million people—of which 1.7 million would be under age 18—in the hypothetical event of release of weaponized anthrax spores.
While AVA has been in commercial production for decades, safely administered to more than 1 million military members, there’s no definitive understanding of its effect directly on children since the vaccine has not been given to them.