PEDIATRICS Volume 137 , number 2 , February 2016 :e 20153611

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.

Planning for Research on Children During Public Health EmergenciesLaura J. Faherty, MD, MPH,a,b Sonja A. Rasmussen, MD, MS,c Nicole Lurie, MD, MSPHd

PEDIATRICS PERSPECTIVES

aRobert Wood Johnson Foundation Clinical Scholars Program,

University of Pennsylvania, Philadelphia, Pennsylvania; bLeonard Davis

Institute of Health Economics, University of Pennsylvania, Philadelphia,

Pennsylvania; cCenter for Surveillance, Epidemiology and Laboratory

Services, Centers for Disease Control and Prevention, Atlanta, Georgia;

and dOffi ce of the Assistant Secretary for Preparedness and Response,

Department of Health and Human Services, Washington, DC

Dr Faherty refi ned the conceptualization of the Perspective,

drafted the initial manuscript, and revised subsequent drafts;

Dr Rasmussen conceptualized the Perspective, outlined an

initial organization of the manuscript, and reviewed and

revised subsequent drafts; and Dr Lurie conceptualized the

Perspective and reviewed and revised the manuscript. All

authors approved the fi nal manuscript as submitted.

The fi ndings and conclusions in this report are those of

the authors and do not necessarily represent the offi cial

positions of the Centers for Disease Control and Prevention or

the Department of Health and Human Services.

DOI: 10.1542/peds.2015-3611

Accepted for publication Oct 28, 2015

Address correspondence to Laura J. Faherty, MD, MPH,

Blockley Hall, 13th Floor, Room 1310, 423 Guardian Dr,

Philadelphia, PA 19104. E-mail: lajohns@mail.med.upenn.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-

4275).

Copyright © 2016 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they

have no fi nancial relationships relevant to this article to

disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have

indicated they have no potential confl icts of interest to

disclose.

To cite: Faherty LJ, Rasmussen SA, Lurie N. Planning for

Research on Children During Public Health Emergencies.

Pediatrics. 2016;137(2):e20153611

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FAHERTY et al

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

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PEDIATRICS Volume 137 , number 2 , February 2016

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

3

FIGURE 1A continuum of risks and benefi ts and examples of knowledge gaps for pediatric-specifi c research in PHEs.

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FAHERTY et al

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.

CONCLUSIONS

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.

ACKNOWLEDGMENTS

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.

ABBREVIATIONS

IRB:  institutional review board

PHE:  public health emergency

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Laura J. Faherty, Sonja A. Rasmussen and Nicole LuriePlanning for Research on Children During Public Health Emergencies

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