- IRB —
- institutional review board
- PHE —
- public health emergency
The recent Ebola epidemic exposed critical knowledge gaps about the disease and its impact on different populations, particularly children, which hindered the public health and medical response. For instance, unanswered questions remain about the natural history of Ebola virus disease in young children and its transmissibility in breast milk. Other emerging infectious diseases, such as Middle East Respiratory Syndrome (MERS), remind us that there will always be another pathogen lurking around the corner. Public health emergencies (PHEs) resulting from natural disasters are increasing in ferocity and frequency.1 How can we ensure that we address our current knowledge gaps to better prepare for future disasters?
Awareness of the need to integrate scientific research into PHE response is growing,2 but the discussion of research involving children has been limited. Although several efforts have addressed the unique physical and socio-emotional needs of children in PHEs,3,4 pediatric research during PHEs has been lacking, resulting in significant knowledge gaps for children compared to adults. Conducting research, especially in children, without interfering with the PHE response is challenging. The present article discusses the importance of including children in PHE research and proposes components of a robust infrastructure that need to be in place to facilitate this research.
Barriers to Including Children in PHE Research
Including children in PHE research presents special challenges, including issues with recruitment, informed consent, and enrollment.3,5 Institutional review boards (IRBs) have more stringent requirements for inclusion of children in research than for adults.6 A life course perspective is needed to study the impact of PHEs in children at different developmental stages. The use of medical countermeasures such as vaccines and antimicrobial agents for prophylaxis and treatment of children often requires extrapolation from adult studies and must consider weight-based dosing and different formulations and routes of administration. Despite these complexities, these challenges can be addressed with advanced planning and need not hamper a rapid, effective PHE response.
The Risks and Benefits of Including Children in PHE Research
All research must weigh risks and benefits, and an acceptable risk/benefit ratio for research in children is significantly different from that in adults.6 In the United States, research on specific PHE countermeasures or interventions using child subjects is typically only conducted before a PHE if the research presents "no more than minimal risk," because riskier research is justified only if there is the prospect of direct benefit to the child or the need for the research study is clearly of critical importance.7 In contrast, emergent situations might shift the risk/benefit ratio, making research that would be unethical in a nonemergent situation acceptable, even ethically imperative, during a PHE.5
Understanding the continuum of potential risks and benefits of PHE research is critical to planning for research involving children (Fig 1). At one end of the continuum are observational studies that may not confer direct benefits to the child but are noninvasive or minimally invasive. These studies present fewer ethical challenges because they pose minimal risk, answer important questions, and produce generalizable knowledge. For example, longitudinal cohorts of children were followed after Hurricane Katrina; the tornadoes in Joplin, Missouri, and Tuscaloosa, Alabama; and the Deepwater Horizon oil spill. Before the Deepwater Horizon disaster, we had failed to learn about the health effects on children from the nearly two dozen oil spills in the United States in recent decades because the necessary research infrastructure was lacking.
Toward the other end of the continuum are studies involving novel interventions that may present greater than minimal risk. They might offer direct benefit for the exposed child by reducing immediate or later morbidity and mortality, and they could indirectly benefit children affected by future events by producing generalizable knowledge about a previously untested countermeasure. For instance, because Anthrax Vaccine Adsorbed is not approved for pediatric use, pre-event studies are only possible with age de-escalation protocols, which test the product in progressively younger cohorts as safety is established.8 However, after an intentional release of anthrax spores, the potentially lifesaving benefit of the off-label use of this countermeasure might outweigh the risk of adverse effects in children. Similarly, it would have been unethical to study the Ebola monoclonal antibody ZMapp (Mapp Biopharmaceutical, Inc, San Diego, CA) in healthy children before the West African outbreak; however, during the PHE, the Liberian government and the National Institute of Allergy and Infectious Diseases enrolled children with Ebola virus disease in a clinical trial of this countermeasure.9 Invasive interventional studies at the far end of the ethical complexity continuum might be possible only when the risk/benefit ratio has shifted during a PHE.
Infrastructure to Support Pediatric-Focused Research During PHEs
Developing the required infrastructure to conduct pediatric-focused research during PHEs requires several interrelated efforts. The first effort is the articulation of a cohesive research agenda for use during disasters. This agenda should be developed in the pre-event period and be generic yet flexible enough to be adapted “just in time” for a variety of PHEs. It should identify and prioritize key research questions that could arise during PHEs. By identifying these questions in advance, the agenda should guide data collection efforts, including collection of baseline data immediately after a PHE. Given that children grow and develop, baseline data on mental and physical health are even more important for the pediatric population than for adults, and these data must be collected in an ethical and community-engaged way. The National Institute of Environmental Health Sciences’ Disaster Research Response Web site provides examples of pediatric-relevant instruments for this purpose (http://dr2.nlm.nih.gov/).
Input from experts in disaster-related pediatric research, such as pediatricians, psychologists, public health planners, bioethicists, and federal subject matter experts, is critical to developing this agenda. Ideally, these experts would meet regularly before a PHE to develop prepositioned generic, yet customizable, research agendas that incorporate the perspectives of parents, educators, and child care professionals. Postevent refining of the generic research agenda is imperative. As an example of this strategy, the Institute of Medicine convened a meeting of stakeholders to review existing knowledge regarding Ebola virus disease and set research priorities related to environmental transmission and personal protective equipment (report available at http://www.nap.edu/catalog/19004/research-priorities-to-inform-public-health-and-medical-practice-for-ebola-virus-disease).
Another critical component is the development of a network of pediatric “research responders” who could rapidly execute the research agenda after a PHE. These research responders should be available to quickly mobilize, select questions from the research agenda to address, amend and activate precleared protocols, assemble pretrained research teams, and initiate data collection and analyses as soon as possible during a PHE.
The development of both generic and scenario-specific prepositioned research protocols specific to the needs of children and quickly deployable during a PHE are needed to successfully execute the research agenda. One of the few existing examples is the International Severe Acute Respiratory and Emerging Infection Consortium–World Health Organization’s Clinical Characterization Protocol for severe infections with emerging pathogens, which can be adapted to patients of all ages (https://isaric.tghn.org/protocols/clinical-characterization-protocol/).
Such protocols can be used to build another component of PHE-related research infrastructure: generic minimum data sets. In the adult arena, the United States Critical Illness and Injury Trials Group's Program for Emergency Preparedness network is charged with developing processes for rapid data collection to create a minimum data set during PHEs, real-time analysis of clinical data, and timely dissemination of results. This network could be adapted to include children. An existing pediatric network that could be leveraged and expanded to rapidly collect, analyze, and disseminate pediatric-specific data in a PHE is the Pediatric Acute Lung Injury and Sepsis Investigators network of >78 PICUs throughout North America ((www.palisi.org), which facilitated multicenter trials during the 2009-2010 influenza pandemic. To glean important clinical information about the unique pediatric impact of PHEs, generalizable information could be gained from pooling the experiences and patient numbers from many facilities, as well as including a longitudinal component, to create data sets for analysis during and after a PHE.
Rapid review by an IRB, particularly for multisite studies, is needed for PHE-related research. Revisions to the Federal Policy for the Protection of Human Subjects (“Common Rule”) were proposed in August 2015 (http://www.hhs.gov/ohrp/humansubjects/regulations/nprmhome.html). If approved, these revisions may allow a single IRB review for multicenter studies and are anticipated to simplify aspects of the IRB process. In addition, any US academic institution can designate the nascent Public Health Emergency Research Review Board, housed within the National Institutes of Health, as its IRB of record. IRBs must be prepared to recognize the shifted risk/benefit ratio during a PHE and to consider the particular legal, ethical, and scientific ramifications of involving children in PHE-related research before an event.
Lastly, the issue of funding this infrastructure is complex and situation-dependent. Fortunately, multiple sources of funding exist. The National Science Foundation provides rapid research grants after PHEs. In addition to the National Institutes of Health, other nongovernmental organizations, and philanthropies may also provide support, depending on the circumstance.
We describe the risks and benefits of research involving children during PHEs and the key components of a pediatric-focused research infrastructure. Not all PHE-related research in children is created equal, and certain PHEs alter the risk/benefit ratio for postevent investigations that become both ethically permissible and ethically imperative if untested medical countermeasures are used to save children’s lives. Although these postevent studies must not interfere with the response itself, we owe it to the youngest members of our communities to learn from each event, to fill in our critical knowledge gaps, and to do so through ethically sound research during PHEs.
The authors thank Georgina Peacock, MD, MPH, and Stephanie Griese, MD, MPH, of the Centers for Disease Control and Prevention, and Diane DiEuliis, PhD, of the Office of the Assistant Secretary for Preparedness and Response, for helpful discussions.
- Accepted October 28, 2015.
- Address correspondence to Laura J. Faherty, MD, MPH, Blockley Hall, 13th Floor, Room 1310, 423 Guardian Dr, Philadelphia, PA 19104. E-mail:
The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention or the Department of Health and Human Services.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Peek L
- Presidential Commission for the Study of Bioethical Issues
- The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
- United States Department of Health and Human Services
- Kuehn BM.
- Copyright © 2016 by the American Academy of Pediatrics