SAFEGUARDING 

CHILDREN

Pediatric Medical 

Countermeasure Research

March 2013
On the cover: Under a high magnification of 

12,483X, this scanning electron micrograph 

(SEM) depicted spores from the Sterne strain 

of Bacillus anthracis bacteria. 

Adapted from: CDC/Laura Rose, 2002
SAFEGUARDING 

CHILDREN

Pediatric Medical 

Countermeasure Research

Washington, D.C.

March 2013

http://www.bioethics.gov
SAFEGUARDING CHILDREN SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research Pediatric Medical Countermeasure Research

iiii

ABOUT THE PRESIDENTIAL COMMISSION FOR 

THE STUDY OF BIOETHICAL ISSUES

The Presidential Commission for the Study of Bioethical Issues (the Bioethics 

Commission) is an advisory panel of the nation’s leaders in medicine, science, 

ethics, religion, law, and engineering. The Bioethics Commission advises the 

President on bioethical issues arising from advances in biomedicine and related 

areas of science and technology. The Bioethics Commission seeks to identify 

and promote policies and practices that ensure scientific research, health care 

delivery, and technological innovation are conducted in a socially and ethically 

responsible manner. 

For more information about the Bioethics Commission, please see http://www.

bioethics.gov.
iii

CONTENTS

Letter of Transmittal to the President and the Secretary ................................................ v

Letter from the Secretary to the Bioethics Commission ...............................................vii

Members of the Bioethics Commission ..............................................................................ix

Bioethics Commission Staff and Consultants .................................................................... x

Acknowledgements ...................................................................................................................xi

EXECUTIVE SUMMARY ......................................................................................................1

Pre-event Research ...............................................................................................................4

Application to Trials of AVA with Children: Pre-event Research ............................6

Post-event Research .............................................................................................................7

Application to Trials of AVA with Children: Post-event Research ..........................9

CHAPTER 1: Introduction...................................................................................................11

Anthrax Vaccine Adsorbed ..............................................................................................15

Scientific Recommendation by the National Biodefense Science Board ..............16

The Bioethics Commission’s Charge .............................................................................17

Ethical and Regulatory Framework for Pediatric Research ....................................18

About this Report ..............................................................................................................19

CHAPTER 2: Current Ethical and Regulatory Framework for Pediatric Research ....21

Ethical Underpinnings: Guiding Principles ................................................................23

Development of the Central Tenet of Pediatric Research ........................................24

Respect for Persons .........................................................................................................24

Beneficence ......................................................................................................................30

Justice ...............................................................................................................................33

Democratic Deliberation ..............................................................................................34

Current Regulations for Conducting Pediatric Research ........................................37

Pediatric Research Subject to Local IRB Approval ..................................................39

Pediatric Research Requiring National-Level Review—Higher Risk and No 

Prospect of Direct Benefit to Healthy Participants (Section 407) ..........................43

Conclusion ...........................................................................................................................46

CHAPTER 3: Ethical Considerations for Pediatric Medical Countermeasure 

Research .....................................................................................................................................47

Ethical Grounding .............................................................................................................48

Pre-event Studies ................................................................................................................51
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

iv

Pre-event Studies Posing No More Than Minimal Risk Approvable 

under Section 404..........................................................................................................52

Application to Trials of AVA with Children: Minimal Risk Pre-event 

Trials of AVA with Children........................................................................................57

Pre-event Studies Posing No More Than a Minor Increase over Minimal 

Risk Approvable under Section 407............................................................................59

Application to Trials of AVA with Children: No More Than a Minor 

Increase over Minimal Risk Pre-event Trials of AVA with Children....................87

Post-event Studies..............................................................................................................89

Ethical Issues in Post-event Research...........................................................................90

Challenges in Post-event Research Design..................................................................93

Community Engagement in Post-event Research......................................................95

Authorizing Distribution of Unapproved Drugs in an Emergency.......................97

Application to Post-event Trials of AVA with Children........................................102

Conclusion.........................................................................................................................104

ENDNOTES...........................................................................................................................107

APPENDICES........................................................................................................................125

Appendix I: Sources of Pediatric Vulnerability.........................................................126

Appendix II: Summary of Pediatric Research Protocols Reviewed under 45 

C.F.R. § 46.407 and/or 21 C.F.R. § 50.54 (1991-2012)........................................127

Appendix III: Characteristics of Category A Biological Agents...........................133

Appendix IV: An Ethical Framework to Guide National-Level Review of 

Pediatric Medical Countermeasure Research under 45 C.F.R. § 46.407

 and/or 21 C.F.R. § 50.54..............................................................................................138

Appendix V: Example of Differences between Active and Passive Surveillance 

Studies.................................................................................................................................139

Appendix VI: Glossary of Key Terms Related to Pediatric Medical 

Countermeasure Research .............................................................................................140

Appendix VII: Guest Presenters to the Bioethics Commission Regarding 

Pediatric Medical Countermeasure Research ...........................................................143
v

Presidential Commission for the Study of Bioethical Issues

President Barack Obama

The White House

1600 Pennsylvania Avenue, NW

Washington, DC 20500

Secretary Kathleen Sebelius

U.S. Department of Health and Human Services

200 Independence Avenue, SW

Washington, DC 20201

Dear Mr. President and Madame Secretary:

On behalf of the Presidential Commission for the Study of Bioethical Issues, we 

present to you Safeguarding Children: Pediatric Medical Countermeasure Research. 

In response to the January 6, 2012 request by Health and Human Services 

Secretary Kathleen Sebelius, the Bioethics Commission conducted a thorough 

review of the ethical considerations of conducting clinical trials of medical countermeasures (MCMs) with children, including the ethical considerations involved 

in conducting a pre- and post-event study of anthrax vaccine adsorbed (AVA) for 

post-exposure prophylaxis with children.

The Bioethics Commission held four public meetings on this topic and heard from 

many speakers addressing a wide range of issues related to this report. At Secretary 

Sebelius’s request, the Bioethics Commission sought the advice of bioethics and 

public health ethics scholars, members of stakeholder communities, pediatric 

research scientists, and officers of local government and federal regulatory agencies. 

In addition, the Bioethics Commission solicited public comment and received 

many informative responses.

Safeguarding children is one of our nation’s foremost obligations, and the ethical 

conduct of pediatric MCM research is one of the ways in which our society fulfills 

its duty to protect children both as individual research participants and as members 

of society to the greatest extent ethically and practically possible in the event of 

an attack. Because children substantially lack the developed capacities necessary 

for adequately informed and voluntary decision making, they cannot consent to 

participate in research in the relevant ethical and legal sense. Extra protections are 

therefore necessary to ensure that children are not placed at excessive risk for the 

benefit of others. The Bioethics Commission offered six recommendations to guide 

the ethical conduct of pediatric MCM research.

1425 New York Avenue, NW, Suite C-100, Washington, DC 20005

Phone 202-233-3960 Fax 202-233-3990 www.bioethics.gov
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

The Bioethics Commission concluded that in the case of pre-event pediatric MCM 

research, absent exceptional circumstances, all research must be designed to pose 

only minimal risk to child participants. When pre-event pediatric MCM research 

cannot be conducted as a minimal risk study, only research that poses no more 

than a minor increase over minimal risk—a level that is still very limited and poses 

no substantial risk to health or well-being—should proceed to national-level ethical 

review under current regulations (45 C.F.R. § 46.407/21 C.F.R. § 50.54). The 

Bioethics Commission proposed an ethical framework to ensure the thoroughness 

and ethical rigor of such national-level review. Regardless of whether pre-event 

research is conducted, post-event pediatric MCM research should be planned in 

advance and conducted when MCMs are administered to children in an emergency. 

When untested MCMs are made available to children in an emergency, research 

protections should be in place.

In addition to generally reviewing the ethical considerations of MCM research, 

Secretary Sebelius requested that the Bioethics Commission specifically address the 

ethical considerations of pediatric testing of AVA. (The Bioethics Commission has 

not been provided a protocol to review, nor is it within the purview of the Bioethics 

Commission to sit as an institutional review board or a national-level review 

panel under 45 C.F.R. § 46.407/21 C.F.R. § 50.54.) The Bioethics Commission 

concluded that before ethical pre-event pediatric AVA trials can be considered, 

further steps must be taken, including additional minimal risk research with adult 

participants, in order to determine whether the research risks to children—who 

do not stand to benefit directly from it—can be reduced to a level that poses no 

substantial risk to their health or well-being. 

The Bioethics Commission is honored by the trust you have placed in us and we are 

grateful for the opportunity to serve you and the nation in this way.

Sincerely,

Amy Gutmann, Ph.D. 

Chair 

James W. Wagner, Ph.D.

Vice Chair

1425 New York Avenue, NW, Suite C-100, Washington, DC 20005

Phone 202-233-3960 Fax 202-233-3990 www.bioethics.gov vi
vii

THE SECRETARY OF HEALTH AND HUMAN SERVICES

WASHINGTON, D.C. 20201

January 6, 2012

Amy Gutmann, Ph.D.

Commission Chair

Presidential Commission for the

 Study of Bioethical Issues

U.S. Department of Health and Human Services

1425 New York Ave, NW

Suite C100

Washington, DC 20005

Dear Dr. Gutmann,

The U.S. Department of Health and Human Services is responsible for developing and 

stockpiling safe and effective medical countermeasures to protect the nation from bioterror 

attacks. While it has made significant progress toward this goal for adults, the development of 

appropriate medical countermeasures for children lags, in part due to challenges in collecting 

basic dose and immunogenicity studies in pediatric populations.

On October 28, 2011, the HHS’s National Biodefense Science Board (NBSB) released its report 

and recommendation on the “Challenges in the Use of Anthrax Vaccine Adsorbed (AVA) in the 

Pediatric Population as a Component of Post-Exposure Prophylaxis (PEP).” The NBSB debated 

how best to obtain scientifically valid safety and immunogenicity data about AVA PEP for 

children, a complex issue with ethical, scientific, medical, legal, regulatory, and administrative 

challenges. In its recommendation, the NBSB concludes that it would be in the best interests of 

children to gather safety and immunogenicity data about AVA PEP in children prior to an 

anthrax event, rather than during a future crisis when the vaccine may be needed. The NBSB 

also recommends that such data be obtained only after the ethical considerations are adequately 

addressed and reviewed by an appropriate body.

To address this issue and the broader question of how best to obtain clinical data on medical 

countermeasures in children, I ask you, as the Chair of the Presidential Commission for the 

Study of Bioethical Issues, to convene a panel to conduct a thorough review of the ethical 

considerations of conducting clinical trials of medical countermeasures in children. I also ask 

that the Commission include the ethical considerations in conducting a pre- and post-event study 

of AVA PEP in children as part of its review.

Given the complexity and sensitivity of this issue, I ask that the Commission consult with a 

range of experts within and outside the United States Government, to include the medical and 

scientific communities in addition to non-profit organizations and other public constituencies. I 

ask that the Commission provide me with a report of its findings, as well as any 

recommendations and suggestions the Commission deems appropriate.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

viii

Amy Gutmann, Ph.D.

January 6, 2012

Page 2

I would welcome the opportunity to further discuss a timeframe for this project that is mutually 

agreeable, taking into consideration both the urgency and complexity of the issue. The safety of 

our children is paramount, and it is vital that we thoroughly address any and all ethical

considerations relative to having adequate and available safety and immunogenicity data on our 

medical countermeasures to protect them before, during, or after an event.

I look forward to reviewing the Commissions’s recommendations on this critical component of 

improving and advancing our nation’s resilience, preparedness, and response efforts.

Sincerely,

Kathleen Sebelius
ix

PRESIDENTIAL COMMISSION FOR THE STUDY OF BIOETHICAL ISSUES

AMY GUTMANN, Ph.D., CHAIR

President and Christopher H. Browne

Distinguished Professor of Political Science, University of Pennsylvania

JAMES W. WAGNER, Ph.D., VICE CHAIR

President, Emory University

YOLANDA ALI, M.B.A.

Michael J. Fox Foundation

Founder’s Council; 

Emory Neurosciences

Community Advisory Board

ANITA L. ALLEN, J.D., Ph.D.

Henry R. Silverman Professor of Law 

and Professor of Philosophy, 

University of Pennsylvania Law School

JOHN D. ARRAS, Ph.D.

Porterfield Professor of Biomedical

Ethics, Professor of Philosophy,

University of Virginia

BARBAR A F. ATKINSON, M.D.

Executive Vice Chancellor Emeritus, 

University of Kansas Medical Center;

Professor Emeritus of Pathology and 

Laboratory Medicine, University of

Kansas School of Medicine

NITA A. FAR AHANY, J.D., Ph.D.

Professor of Law and Philosophy, 

Professor of Genome Sciences and Policy,

Duke University

ALEXANDER G. GARZA, M.D., M.P.H.

Assistant Secretary, Office of Health

Affairs and Chief Medical Officer,

Department of Homeland Security

CHRISTINE GR ADY, R.N., Ph.D.

Chief, Department of Bioethics, 

National Institutes of Health 

Clinical Center

STEPHEN L. HAUSER, M.D.

Robert A. Fishman Distinguished 

Professor and Chair of the Department 

of Neurology, University of California, 

San Francisco

R AJU S. KUCHERLAPATI, Ph.D.

Paul C. Cabot Professor, Department 

of Genetics, Harvard Medical School; 

Professor, Department of Medicine, 

Brigham and Women’s Hospital

NELSON L. MICHAEL, M.D., Ph.D.

Colonel, Medical Corps, U.S. Army;

Director, U.S. Military HIV Research 

Program, Walter Reed Army Institute 

of Research

DANIEL P. SULMASY, M.D., Ph.D., FACP

Kilbride-Clinton Professor of Medicine

and Ethics, Department of Medicine

and Divinity School; Associate Director,

The MacLean Center for Clinical Medical

Ethics, University of Chicago
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

x

PRESIDENTIAL COMMISSION FOR THE STUDY OF BIOETHICAL ISSUES 

STAFF* AND CONSULTANTS

Executive Director

Lisa M. Lee, Ph.D., M.S.

Associate Directors

Michelle Groman, J.D.

Kayte Spector-Bagdady, J.D., M. Bioethics

Communications Director

Hillary Wicai Viers, M.S.J.

Senior Advisors

David DeGrazia, Ph.D.

Paul A. Lombardo, Ph.D., J.D.

Jonathan D. Moreno, Ph.D.

Research Staff

Misti Ault Anderson, M.S., M.A.

Kavita M. Berger, Ph.D.

Rachel S. Bressler, J.D.

Eleanor Celeste, B.A.

Chris Havasy, Sc.B.

Eleanor Mayer, J.D., M. Bioethics

Karen Meagher, Ph.D.

Olivia Nevitt, M.P.H.

Anne C. Pierson, J.D.

Elizabeth R. Pike, J.D., LL.M.

Michelle Spektor, B.S.

Michael N. Tennison, M.A.

Victoria Wilbur, B.A.

Consultants

Burness Communications

Kathi E. Hanna, M.S., Ph.D.

Communications Staff

Elizabeth Schaub, B.S.

Administrative Staff

Svetlana Cicale, M.A., M.P.H.

Tynetta Dreher

Esther E. Yoo

Interns

Eleanor Gilmore-Szott, B.A.

Taylor Goodspeed, B.A.

Laura Guidry-Grimes, B.A.

Olwen Jaffe, B.A.

Kathleen O’Connor, M.B.A., M.S.W.

Kristina Pyclik, B.A.

Sarah Salama, B.A.

Nicolle Strand, M. Bioethics

*Includes former interns and research staff
xi

ACKNOWLEDGEMENTS

The Bioethics Commission is grateful to all those who contributed their time, 

insight, and expertise to this report. A wide-ranging group of exceptional speakers 

participated in our public meetings, shared their wisdom, and engaged in 

consistently productive and thought-provoking discussions. We greatly appreciate 

their public service. 

The Bioethics Commission also thanks our talented staff for their dedicated 

support, careful research, and thoughtful insights on the ethics of pediatric 

medical countermeasure research. We extend our special thanks to Senior 

Advisor David DeGrazia for his important contributions to our deliberations and 

drafting, and to Executive Director Lisa M. Lee who has been a constant and 

thoughtful guiding force as the Bioethics Commission confronted a particularly 

challenging set of issues. The Bioethics Commission also is enormously grateful 

for the impeccable judgment and timely and tireless contributions of Associate 

Director Michelle Groman. We also extend great thanks to staff leads Kavita 

Berger, who led the project in its early phases, and Anne Pierson, who led it to 

completion, for their outstanding efforts on our behalf, which ensured a nuanced 

and thorough assessment of this weighty issue.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

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1

EXECUTIVE SUMMARY
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

2

Safeguarding children is one of our nation’s foremost obligations. We have 

both a fundamental duty to protect individual children from undue 

risk during research and an obligation to protect all children during an 

emergency—to the extent ethically and practically possible—by being 

prepared both with the fruits of scientifically and ethically sound research 

and with a fulsome national readiness to respond.

In January 2012, the Secretary of Health and Human Services (HHS) asked 

the Presidential Commission for the Study of Bioethical Issues (the Bioethics 

Commission) to advise the U.S. government—in its mission to be fully 

prepared to mitigate the impact of bioterrorism attacks—on ethical considerations in evaluating and conducting pediatric medical countermeasure 

(MCM) research.1

 The Secretary also asked that the Bioethics Commission 

“include the ethical considerations in conducting a pre- and post-event study 

of [anthrax vaccine adsorbed (AVA) post-exposure prophylaxis] in children as 

part of its review.”2

Pediatric MCM research involves testing interventions with children that will 

be used in response to an attack either before an attack occurs (i.e., pre-event 

research) or testing such interventions following an attack (i.e., post-event 

research). Pre- and post-event pediatric MCM research poses risks to the 

individual children enrolled in research who, in many cases, do not stand to 

benefit directly from the research. 

Research with children differs from that with adults because children cannot 

consent in the relevant sense; they are substantially lacking in the developed 

capacities necessary for adequately informed and voluntary decision making, 

making them a vulnerable population. Although this incapacity is most often 

attributed to their level of cognitive development, the vulnerability of children 

can derive from multiple sources (such as expectations of deference to adult 

authority, lack of independent resources for autonomous decision making, and 

longstanding institutionalized relationships of adult authority and power). For 

this reason, extra protections are warranted to ensure that children are not 

placed at excessive risk for the benefit of others. These additional safeguards 

include: parental permission, meaningful child assent, and limits on the 

degree of permissible research-related risk.
EXECUTIVE SUMMARY

3

The Bioethics Commission’s ethical analysis lies at the intersection of the 

unique characteristics of MCM research and pediatric research. In its 

1977 report, Research Involving Children, the National Commission for the 

Protection of Human Subjects of Biomedical and Behavioral Research (the 

National Commission) presciently described this type of challenge: “The 

ethical principles at stake are the moral obligation to protect the community...

and the moral prohibition against using unconsenting persons, at considerable 

risk to their well-being, for the promotion of the common good.”3

The four ethical principles that guides the Bioethics Commission’s discussion of pediatric research protections are respect for persons, beneficence, and 

justice—as outlined in the Belmont Report 4—and democratic deliberation, 

which was implicit both in the way the National Commission carried out its 

work and also in its recommendations regarding the process of reviewing and 

approving pediatric research. 

HHS (and later the U.S. Food and Drug Administration (FDA)) adopted the 

National Commission’s recommendations almost verbatim, and the regulations subsequently promulgated concerning research with children remain 

largely the same today, comprising Subpart D of HHS regulations at 45 

C.F.R. Part 46 and FDA regulations at 21 C.F.R. Part 50.5

The National Commission’s most straightforward recommendations 

addressed research that poses only minimal risk or that offers the prospect of 

direct benefit to participants. These recommendations would subsequently be 

codified in sections 404 and 405 of the HHS regulations. More complicated, 

but still ethically tractable, was research posing greater than minimal risk 

but likely to yield generalizable knowledge about the participants’ condition. 

Research that is greater than minimal risk with no prospect of direct benefit 

to subjects or benefit to others with their condition was considered decidedly 

more controversial and ethically problematic. In the regulations, this last type 

of research was reserved for evaluation and approval by a national panel of 

experts and the Secretary of HHS for HHS-supported research (section 407).6
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

4

Pre-event Research

Pediatric research that presents no prospect of direct benefit to participants 

or that is not likely to yield generalizable knowledge about the participants’ 

condition generally can only be conducted if it presents no more than 

minimal risk, except in extraordinary circumstances. Thus, the Bioethics 

Commission concluded that pre-event pediatric MCM research—which 

presents no prospect of direct benefit because no children are affected by 

the condition being studied—generally cannot proceed unless it is minimal 

risk research. Pre-event research might in some cases be designed in a way 

that would permit it to be judged minimal risk through an age de-escalation 

process in which risks are assessed and evaluated at each step. Robust research 

with young adults might support the conclusion that research with the oldest 

children is minimal risk. Similarly, research with the oldest children that 

further characterizes research risk might support an inference that research 

with the next oldest group of children is minimal risk as well. 

Recommendation 1: Pre-event Pediatric Medical Countermeasure Research 

Risk Limited to Minimal Except under Extraordinary Circumstances 

Pre-event pediatric medical countermeasure testing should be conducted with 

a research design posing only a minimal level of research risk except under 

extraordinary circumstances. If pre-event pediatric medical countermeasure 

research cannot be conducted as a minimal risk study, research that exposes 

children to no more than a minor increase over minimal risk—a level that 

is still very limited and poses no substantial risk to health or well-being—

should proceed to a national-level review under Department of Health and 

Human Services regulations at 45 C.F.R. § 46.407 and/or U.S. Food and 

Drug Administration regulations at 21 C.F.R. § 50.54.

Recommendation 2: Risk in Pre-event Pediatric Medical Countermeasure 

Research

Before beginning pre-event medical countermeasure studies with children, 

ethically sound modeling, testing with animals, and testing with the 

youngest adults must be completed to identify, understand, and characterize 

research risks. If pediatric research is determined to be minimal risk and is 

to be conducted, progressive age de-escalation should be employed whenever 
EXECUTIVE SUMMARY

5

possible from the oldest age group of children to the youngest group necessary 

to provide additional protection to the youngest and most vulnerable children, 

and to ensure that data from an older age group can inform the research design 

and the estimate of risk level for the next younger age group. 

There will be instances in which it will be impossible to design minimal risk 

pre-event MCM research. In such cases, national-level review under section 

407 would be required, but review should proceed only if researchers can 

demonstrate that the research poses no more than a minor increase over 

minimal risk to participants. 

Recommendation 3: Pre-conditions to National-Level Review of Pre-event 

Pediatric Medical Countermeasure Research

Pre-event pediatric medical countermeasure research may proceed to nationallevel review under Department of Health and Human Services regulations at 

45 C.F.R. § 46.407 and/or U.S. Food and Drug Administration regulations 

at 21 C.F.R. § 50.54 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. 

In part because of the inherent uncertainty of a bioterrorism attack, preevent pediatric medical countermeasure research posing greater than a minor 

increase over minimal risk should not be approved under 45 C.F.R. § 46.407 

or 21 C.F.R. § 50.54.

The Bioethics Commission’s recommended framework, structured around 

the three conditions for national-level review, clarifies the circumstances in 

which proposed research presents a “reasonable opportunity” to address a 

“serious problem,” specifies a rigorous set of conditions necessary to determine 

whether the research would be conducted in accordance with “sound ethical 

principles,” and reiterates the importance of informed parental permission and 

meaningful and developmentally appropriate child assent. Decision makers 

should assess proposed pre-event pediatric MCM research that poses more 

than minimal risk using this framework in order to ensure that all the necessary aspects of a study have been evaluated and found ethically permissible 

before moving forward.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

6

Recommendation 4: Ethical Framework for National-Level Review of 

Pre-event Pediatric Medical Countermeasure Research

To ensure the thoroughness and ethical rigor of national-level review, 

reviewers should apply the Bioethics Commission’s recommended ethical 

framework for reviewing pre-event pediatric medical countermeasure 

research that poses greater than minimal risk, but no more than a minor 

increase over minimal risk, under Department of Health and Human Services 

regulations at 45 C.F.R. § 46.407 and/or U.S. Food and Drug Administration 

regulations at 21 C.F.R. § 50.54. A proposed protocol must meet the requirements of the framework outlined in this report to be approved.

The framework clarifies the circumstances in which proposed research presents 

a “reasonable opportunity” to address a “serious problem,” in particular, that 

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 specifies a rigorous set of conditions necessary to 

determine whether the research would be conducted in accordance with the 

required “sound ethical principles” that fall into five general categories: (1) 

ethical threshold of acceptable risk and adequate protection from harm; (2) 

ethical research design, for example, scientific necessity, valid research plan 

using small trials and age de-escalation with appropriate monitoring, and 

planning for post-event research; (3) post-trial requirements to ensure ethical 

distribution of medical countermeasures in the event of an attack, as well as a 

plan for treatment or compensation for research-related injury; (4) community 

engagement; and (5) transparency and accountability. Finally, the framework 

reiterates the importance of informed parental permission and meaningful and 

developmentally appropriate child assent.

Application to Trials of AVA with Children: Pre-event Research 

In confronting the ethical questions surrounding MCM testing in pediatric 

populations, the Bioethics Commission concluded that before ethical preevent pediatric AVA trials can be considered, further steps must be taken, 

including additional minimal risk research with adult participants to determine whether the research risks to children—who do not stand to benefit 

directly from it—pose no substantial risk to their health or well-being.
EXECUTIVE SUMMARY

7

Given the amount of safety, immunogenicity, and dosing information about 

AVA in young adults aged 18 to 25 years, and given the widespread distribution 

of AVA in this population, it is possible that with additional testing in adults 

aged 18 to 20 years—testing to determine adverse effects, alternative dosing 

methods, and immunogenicity—testing of AVA with the oldest children (e.g., 

adolescents who are 16 to 17 years of age) could be considered no more than 

minimal risk. Consequently, it would be reviewed under section 404.

Informed, careful age de-escalation might allow researchers to infer minimal 

risk studies down the age scale. However, if data suggest that the use of AVA 

is affected, for example, by a child’s developmental stage (e.g., infancy or 

puberty), or if an inference of minimal risk from an older group of children 

to the next younger group is not possible, a study designed to pose a minor 

increase over minimal risk might be appropriate for national-level review. 

Post-event Research

Public health officials must be prepared to conduct post-event research when 

a bioterrorism attack occurs regardless of whether pre-event pediatric MCM 

research trials were conducted. In contrast to pre-event testing, in which 

ethical deliberations focus on whether any research with children would 

be ethically permissible, in post-event circumstances, research is ethically 

required to safeguard the well-being of current and future children. If a pediatric MCM research trial were completed pre-event, data should be collected 

following the administration of the tested intervention to acquire necessary 

additional safety information. In the absence of a pre-event investigation, 

an emergency situation might warrant administering an untested MCM to 

children in an effort to save lives. When children receive an untested MCM, 

it is ethically imperative that health officials collect data to learn as much as 

possible about the use of the untested MCM from the event. 

Recommendation 5: Post-event Pediatric Medical Countermeasure Research

Post-event research should be planned in advance and conducted when 

untested medical countermeasures are administered to children in an emergency or when limited pre-event medical countermeasure studies have already 

occurred. Institutional review boards must be cognizant of the exigencies 

imposed upon research under emergency conditions, and when reviewing 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

8

post-event medical countermeasure research proposals, ensure that adequate 

processes are in place for informed parental permission and meaningful child 

assent. Institutional review boards must also ensure that the research design is 

scientifically sound, children enrolled in research have access to the best available care, adequate plans are in place to treat or compensate children injured 

by research, and provisions are made to engage communities throughout the 

course of research.

In the event of a bioterrorism attack, the U.S government has emergency 

preparedness plans to mobilize medical interventions, drugs, vaccines, and 

supplies from the Strategic National Stockpile for distribution to affected 

portions of the population. The federal government delivers supplies to the 

states, which have individualized distribution strategies based on localized need 

and infrastructure. In the event that the MCM needed is either still in clinical 

trials or has not yet been approved for the specified application, there are two 

mechanisms available—an emergency use authorization (EUA) and an investigational new drug application (IND)—that allow the government to distribute 

an unapproved intervention to help people in an emergency. Underlying the 

motivation for these mechanisms are a host of ethical principles including 

respect for persons, beneficence, and justice. Together, the EUA and IND 

provide mechanisms to supply necessary MCMs with varying levels of clinical 

and research protections to ensure adequate respect for persons, as appropriate.

Recommendation 6: Regulatory Mechanisms for Post-event Pediatric Medical 

Countermeasure Research and Distribution

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. 

When a medical countermeasure is distributed broadly to children using a 

treatment IND, it is essential that the U.S. government also conduct a concurrent small-scale study under an investigator IND to obtain data that can 

potentially be used to support an emergency use authorization for pediatric 

use of the medical countermeasure in a future event. To expedite post-event 

research and ensure the availability of appropriate medical countermeasures 
EXECUTIVE SUMMARY

9

for children, a pre-IND consultation and approval should be put in place 

before an event.

Application to Trials of AVA with Children: Post-event Research 

In an event involving the release of weaponized anthrax, or other large-scale 

release of spores, a plan exists to provide children, like adults, treatment with 

a 60-day course of antibiotics as well as AVA.7

 FDA and the U.S. Centers 

for Disease Control and Prevention (CDC) have a treatment IND in place 

to allow for broad access to AVA for children in the event of an emergency. 

Work is ongoing to clarify the informed consent process. In addition, FDA 

and CDC are collaborating to develop a nested protocol that would involve 

research and surveillance to better understand immunogenicity and reactogenicity to the vaccine.8

 Both of these mechanisms require IRB approval.

Under the Bioethics Commission’s ethical approach, even if a pre-event study 

of AVA with children is approved, post-event research would be necessary to 

gather additional safety and immunogenicity data beyond the limited amount 

a pre-event study could produce. If a pre-event study is not approved and AVA 

is nonetheless administered to children in the event of an attack, post-event 

research would be ethically required. 

It is important that any post-event distribution of AVA to children, regardless of the specific mechanism, entail democratic deliberation in the form 

of extensive community engagement. Community engagement should begin 

in pre-event research and continue through post-event activities. Moreover, 

it is critical that any post-event research protocol be scientifically sound, 

have adequate processes in place to ensure informed parental permission and 

meaningful child assent, provide for adequate treatment or compensation for 

research-related injuries, and ensure that enrolled children have access to the 

best available care.

* * *

Pediatric MCM research brings into sharp focus the fact that the health and 

security of children are paramount. It highlights the importance of both 

protecting children from unjustifiable research risks and assuring their safety 

as far as possible in the event of an emergency. Grounding its work in the principles of respect for persons, beneficence, justice, and democratic deliberation, 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

10

the Bioethics Commission reaffirmed the ethical foundations of pediatric 

research and applied them to the particularly complex and difficult case of 

pediatric MCM research. As exemplified by the Bioethics Commission’s 

deliberations, such research warrants an ongoing national conversation in 

order to ensure the highest standards of protection for children that reflect 

an unwavering commitment to safeguard all children from unacceptable risks 

in research and through research that promotes their health and well-being.
11

CHAPTER 1

Introduction
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

12

Our sense of justice, beneficence, and respect for human dignity calls 

upon the country to do what it reasonably can to safeguard all children 

in the event of a public health emergency. This protection includes, for 

example, providing medicine, vaccines, and other interventions as needed. 

Our same sense of justice, beneficence, and respect for human dignity calls 

on us to safeguard individual children who participate in scientifically and 

ethically sound clinical research to develop these interventions and to protect 

individual children from participating in research that could impose undue 

risks on them. In other words, as a country, we have both a fundamental 

duty to protect individual children from undue risk during research and 

an obligation to protect all children during an emergency—to the extent 

ethically and practically possible—by being prepared both with the fruits 

of scientifically and ethically sound research and with a fulsome national 

readiness to respond. 

In January 2012, the Secretary of Health and Human Services (HHS) asked 

the Presidential Commission for the Study of Bioethical Issues (the Bioethics 

Commission) to advise the U.S. government—in its mission to be fully 

prepared to mitigate the impact of bioterrorism attacks—on ethical considerations in evaluating and conducting pediatric medical countermeasure 

(MCM) research.9

 Pediatric MCM research involves testing interventions 

with children that will be used in response to an attack either before it occurs 

(i.e., pre-event research) or testing such interventions following an attack (i.e., 

post-event research). Pre- and post-event pediatric MCM research pose risks 

to the individual children enrolled in research who, in many cases, do not 

stand to benefit directly from the research. 

The tension between the need to conduct pediatric MCM research to protect 

children in the event of a future attack and the risks of this research to individual children who do not stand to directly benefit from it creates the central 

ethical challenge of pediatric MCM research. As noted in the Belmont Report, 

the ethical dilemma facing the Bioethics Commission derives in part from the 

principle of beneficence, which “requires that we protect against risk of harm 

to subjects and also that we be concerned about the loss of the substantial 

benefits that might be gained from research.”10 The Bioethics Commission 

addresses this tension in this report.
INTRODUCTION

13

I

A major bioterrorism attack could require deployment of pediatric MCMs. 

To safeguard children in the event of a bioterrorism attack, MCMs should be 

ready and available for pediatric use. Under current federal plans, in the event 

of an emergency, children would be provided with at least some MCMs that 

have been approved for adults, even though many of these treatments have not 

been tested with children. Extrapolating from data in adult populations may 

be insufficient to determine safety and proper doses of MCMs for children. 

Pediatric research might therefore be necessary to determine the safest doses 

and formulations of MCMs for children. 

Pre-event MCM research presents challenges that are distinct from other 

types of research, as it involves research on a hypothetical condition with an 

undefined (and perhaps unknowable) likelihood of occurring. And, while the 

knowledge gained could be profoundly useful, we may never have (and hope 

never to have) occasion to use it. The ramifications of these characteristics are 

discussed in greater detail below.11

Post-event research poses its own challenges because this research generally 

will be conducted in very stressful circumstances. In post-event MCM 

research, the experimental intervention will often be provided in concert with 

additional tested treatments that could confound data collected regarding the 

MCM. Moreover, the stressful circumstances in which post-event research 

likely will be conducted might make safeguards such as obtaining adequate 

informed parental permission and meaningful child assent particularly 

difficult. In this report, the Bioethics Commission also addresses research 

conducted when the threat of an attack is imminent, because, as discussed 

in greater detail below, in these cases the ethical and practical concerns track 

those of a post-event study even if technically conducted pre-event.12

Pediatric research itself presents particular ethical complications. 

Competent adults can generally consent to accept risks for the benefit of 

others during research through the informed consent process. Agreeing to 

place oneself at risk for the good of others is often viewed as admirable, 

generous, and honorable. Children, on the other hand, are ethically and 

legally incompetent to consent on their own behalf, and therefore cannot 

agree to assume research risks for the benefit of others. A child’s reduced 

autonomy and increased vulnerability, along with the inability to provide 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

14

informed consent, necessitates additional protections during research. These 

protections include limits on the level and types of research risks a child can 

be asked to assume, and generally require some prospect of direct benefit to 

the participant if research risks exceed the minimal ones that a healthy child 

living in a safe environment routinely encounters in daily life or during a 

routine medical examination.13

The Bioethics Commission’s ethical analysis lies at the intersection of the 

unique characteristics of MCM research and pediatric research. In its 1977 

report, Research Involving Children, 

the National Commission for the 

Protection of Human Subjects 

of Biomedic a l a nd Behaviora l 

Research (the National Commission) 

presciently described this type of 

challenge: “The ethical principles 

at stake are the moral obligation to 

protect the community...and the 

moral prohibition against using 

unconsenting persons, at considerable risk to their well-being, for the 

promotion of the common good.”14

Although the National Commission 

did not address pediatric MCM 

research specifically, the principles 

it articulated—respect for persons, 

beneficence and its corollary, nonmaleficence, and justice—offer a 

way to frame the complexities of 

MCM research involving children. 

An additional principle implicit in 

the National Commission’s work—

democratic deliberation—further 

informs this analysis. For this report, 

the Bioethics Commission examined 

DISTINGUISHING COMMISSIONS

Presidential Commission for the 

Study of Bioethical Issues 

(the Bioethics Commission)

• 2009-present

• Established by Executive Order

13,521, President Barack Obama

• Scope: advise the President on

bioethical issues that may emerge

as a consequence of advances in

biomedicine and related areas of

science and technology

National Commission for the 

Protection of Human Subjects of 

Biomedical and Behavioral Research 

(the National Commission)

• 1974-1978

• Established by the National Research

Act, 93rd Congress of the United

States

• Scope: identify the basic ethical

principles that should underlie the

conduct of human subjects research

and develop guidelines to govern

such research

Sources: Executive Order No. 13,521, 74 Fed. Reg. 

62,671 (Nov. 24, 2009); National Research Act of 

1974, Pub. L. No. 93-348, 88 Stat. 342.
INTRODUCTION I

15

these existing, well-established ethical 

principles that guide pediatric research 

to enumerate considerations for the 

ethical conduct of pre-event and postevent MCM studies with children. 

The Bioethics Commission f irst 

considered pre-event studies: those 

posing minimal risk (i.e., no greater 

risk than that faced by a healthy child 

in daily life or at a routine medical 

examination) as well as those posing 

greater than minimal risk while offering no direct prospect of benefit to the 

individual child participants—but that are important to the potential future 

benefit of many or all children.15 The Bioethics Commission then considered 

post-event studies: those posing minimal risk as well as those posing some 

additional risk but also offering the prospect of direct benefit to the individual 

children who participate or offering the prospect of generalizable knowledge 

about the participants’ condition. Both pre- and post-event MCM research 

studies with children are ethically challenging. For each of these categories, 

and consistent with its charge, the Bioethics Commission also examined the 

specific ethical issues raised in the context of proposed research on anthrax 

vaccine adsorbed (AVA) with children.

Anthrax Vaccine Adsorbed

The complexities of pediatric MCM research were highlighted by government action surrounding AVA, a particular MCM for anthrax. In early 2011, 

the U.S. government conducted an exercise called Dark Zephyr to test local, 

state, and federal government responses to a large-scale anthrax release in 

a major metropolitan area.16 Dark Zephyr revealed that about 7.6 million 

individuals would be exposed to anthrax during such an event, including as 

many as 1.7 million children, all of whom would require treatment. Although 

the government had plans in place to treat adults, officials involved in the 

exercise quickly realized that there was no evidence supporting a clear course 

of action for the treatment of children. The planned response during the 

exercise involved administering AVA for post-exposure prophylaxis to both 

“Ethical issues about the involvement 

of children arise because of 

competing answers to the following 

question: Under what conditions (if 

any) are these various types 

of research justified?” 

National Commission for the Protection of 

Human Subjects of Biomedical and Behavioral 

Research. (1977). Research Involving Children

(DHEW Publication OS 77-0004). Washington, 

DC: Department of Health, Education, and 

Welfare, p. 91. Retrieved from http://

bioethics.georgetown.edu/pcbe/reports/past_

commissions/Research_involving_children.pdf. 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

16

adults and children, in combination with antibiotics. The U.S. Food and 

Drug Administration (FDA) has approved AVA for use by adults before an 

anthrax exposure, but has not approved AVA for post-exposure prophylaxis 

by adults or for any use by children, and there are no data on the use of 

AVA by children. While antibiotics help prevent or treat immediate infection 

with anthrax—and are the only currently approved post-exposure treatment 

for children—they cannot provide the long-term protection that vaccination 

confers against the persistence of dormant spores.17 Long-term use of antibiotics is also associated with side effects, including gastrointestinal discomfort, 

which can result in intolerance and poor adherence. In addition, evidence 

from animal models suggests that even the initial response to combined antibiotic and vaccine treatment is superior to antibiotics alone.18

In the absence of data on the use of AVA by children, and the corresponding 

lack of FDA approval for its post-exposure use in pediatric populations, 

current HHS plans—based on recommendations by the Advisory Committee 

on Immunization Practices (ACIP)—include making available a three-dose 

course of AVA in combination with antibiotics to children who have been 

exposed to anthrax and conducting post-event observational research with 

a subgroup of those children who received it to better understand the effects 

of AVA.19 Research protections would be in place for all children receiving 

AVA—whether as treatment or as part of a research study. (See Authorizing 

Distribution of Unapproved Drugs in an Emergency, Chapter 3.) 

Scientific Recommendation by the National Biodefense Science Board

In response to the findings of Dark Zephyr—in particular, the nation’s lack 

of preparedness to treat children in the event of an anthrax attack—Dr. 

Nicole Lurie, HHS Assistant Secretary for Preparedness and Response, 

asked the National Biodefense Science Board (NBSB) to recommend 

the “best course of action to prepare for a potential use of AVA vaccine 

in a pediatric population.”20 In addition, Dr. Lurie requested that NBSB 

consider the risks involved in conducting a study of AVA with children 

before or after an attack and the logistical challenges of administering AVA 

to children during an attack.21
INTRODUCTION I

17

In its October 2011 report, NBSB 

considered whether to conduct preevent research to gather safety and 

immunogenicity (degree of immune 

response) data about AVA with 

children, or whether instead to gather 

such data post-event. In conducting 

its analysis, NBSB accepted “the 

[U.S. government’s] threat analysis 

and recognize[d] that the dissemination of B[acillus] anthracis spores 

is a threat to the U.S. population, 

including its large proportion of 

children.”22 NBSB also explicitly 

stated that “administering AVA to 

children would present more than a 

minor increase over minimal risk” 

due specifically to the lack of data 

about AVA with children.23 NBSB 

ultimately recommended that the 

U.S. government conduct a pre-event 

study to test the safety and immunogenicity of AVA with children before 

an anthrax attack occurs, but noted 

that any pre-event AVA study should 

proceed only following a thorough 

review of the ethical considerations involved.24 This ethical review became 

part of the Bioethics Commission’s task outlined here, and NBSB’s scientific 

and technical assessment informed this ethical review.

The Bioethics Commission’s Charge

Catalyzed by NBSB’s recommendation, HHS Secretary Kathleen Sebelius asked 

the Bioethics Commission in January 2012 to “conduct a thorough review of 

the ethical considerations of conducting clinical trials of medical countermeasures in children,” and to “include the ethical considerations in conducting a 

pre- and post-event study of AVA [post-exposure prophylaxis] in children as part 

of its review.”25

THE NATIONAL BIODEFENSE SCIENCE

BOARD

The Pandemic and All-Hazards 

Preparedness Act established NBSB in 

2006. The 13-member board advises 

the Secretary of HHS on “scientific, 

technical, and other matters of special 

interest” to HHS regarding activities 

to prevent, prepare for, and respond 

to adverse health effects of public 

health emergencies resulting from 

“chemical, biological, nuclear, and 

radiological events, whether naturally 

occurring, accidental, or deliberate.” 

NBSB members come from diverse 

backgrounds and a range of experience 

in both medicine and public health. The 

members are required to meet at least 

twice a year in a public forum. 

NBSB has advised the Secretary on many 

issues, including: H1N1 immunization, 

home stockpiling of MCMs, mental 

health issues during a disaster, and 

prioritization in MCM development.

Source: Kathleen Sebelius, Secretary, HHS. 

(2012, July 3). National Biodefense Science Board 

Charter, p. 1. Retrieved from http://www.phe.gov/

Preparedness/legal/boards/nbsb/Documents/2012-

renewed-charter.pdf. 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

18

Although the Bioethics Commission’s 

cha rge stemmed from NBSB’s 

recommendation, the charge was 

significantly broader than a review of 

the ethical considerations associated 

with a pre-event pediatric study of 

AVA. As stated in Secretary Sebelius’s 

request, the Bioethics Commission 

was charged with considering the 

ethical issues associated with pediatric research for all MCMs; that 

is, drugs and vaccines intended to 

treat or prevent physical harm (or 

to diagnose a condition) resulting 

from a bioterrorism attack. The 

Bioethics Commission considered 

the term MCM to encompass all 

FDA-regulated products and interventions used in response to chemical, 

biological, radiological, and nuclear attacks.26

Ethical and Regulatory Framework for Pediatric Research

Pediatric research is critical for identifying safe and effective ways to diagnose, 

prevent, and treat disease and injury in children. Ethical pediatric research 

should minimize risks and, when possible, provide a reasonable prospect 

of direct benefit to individual participants. Unlike research with freely 

consenting adults, in which greater levels of risk might be permissible even 

without the prospect of direct benefit, children who participate in research are 

afforded special protections due to their vulnerability and inability to legally 

consent to participate. Any research conducted with children must therefore 

respect children’s well-being and dignity as persons, as well as their current 

and future capacities for self-determination, and must protect children from 

exploitation. These ethical imperatives are dictated by the foundational principles of respect for persons, beneficence (and its corollary non-maleficence), 

justice, and democratic deliberation.

“Because of the sensitivity of the 

involvement of children in research, 

[NBSB’s] recommendation voiced [its] 

desire to have other focused experts, 

like [the Presidential Commission for 

the Study of Bioethical Issues], formally 

review and address these issues 

from an ethical perspective. ... The 

[NBSB] is confident that the [Bioethics] 

Commission will help us and our nation 

deliberate this very complex issue, 

ensuring safe medical countermeasures 

for our children.”

Parker, J.S., Chair, NBSB. (2012). The National 

Biodefense Science Board Report. Presentation 

to the Presidential Commission for the Study of 

Bioethical Issues, May 17. Retrieved from http://

bioethics.gov/cms/node/715.
INTRODUCTION I

19

The current regulatory framework adopts an approach recommended by the 

National Commission, that is, categorizing pediatric research based on both 

the level of research risk and the prospect of direct benefit to participants. 

Research that poses only minimal risk to participants, research that offers the 

prospect of direct benefit to participants, or research that provides the opportunity to gain generalizable knowledge about the participants’ condition each 

fits neatly into one of the regulatory categories of research approvable at the 

local level, which are intended to govern the majority of pediatric research.27

Some proposed MCM research, however, might involve exposing healthy 

children to greater than minimal risk while offering no prospect of direct 

benefit, and therefore does not fit into one of these categories.28 In its report 

Research Involving Children, the National Commission recognized the 

ethical challenge inherent in considering whether research that poses more 

than minimal risk and offers no prospect of direct benefit to participants 

nevertheless might be justified by the “promise of substantial long-term 

benefit to children in general.”29 The National Commission did not reach 

a conclusion about the permissibility of any such research with healthy 

children, instead recommending that decisions—taking into account “sound 

ethical principles” along with other important considerations—be made at the 

national level on a case-by-case basis. It intended this type of review only for 

rare and exceptional cases.30

About this Report

This report by the Bioethics Commission enumerates the ethical considerations associated with conducting pre- and post-event MCM research with 

children. The Bioethics Commission examined the current ethical and regulatory framework to assess the types of ethically permissible pre- and post-event 

research. It built on the work of the National Commission to provide 

decision makers with the necessary ethical tools to assess whether research 

posing greater than minimal risk with no prospect of direct benefit to healthy 

child participants—the most ethically complex pre-event pediatric MCM 

research—can proceed. Fulfilling its charge, the Bioethics Commission 

applied its analysis to the particular case of AVA as well.

Due to the unique characteristics of pre-event MCM research—including 

uncertainty that the research results will ever be used—and the fact that 
20

SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

children are not legally or ethically competent to consent to participate in 

research, the Bioethics Commission concluded that greater than minimal 

risk pre-event research is ethically unacceptable if valuable information about 

an MCM could be obtained using a study design involving only minimal 

risk. If pre-event pediatric MCM research cannot be designed as minimal 

risk, the proposed research should pose no more than a minor increase over 

minimal risk and proceed to national-level review. Although the regulations 

might allow pediatric research that poses greater than a minor increase over 

minimal risk to be approved if it also meets ethical standards, the Bioethics 

Commission concluded that higher risk is unacceptable in the context of 

pre-event MCM research. Such research does not directly benefit the child 

participants, and the likelihood that the results of such research would benefit 

other children is unknown or unknowable.31

In accordance with its commitment to democratic deliberation and transparency, the Bioethics Commission held four public meetings to address the 

Secretary’s request. Experts addressed a range of ethical, public health, scientific, 

medical, security, and regulatory issues associated with this report, providing 

a wide array of professional and institutional perspectives, including those 

from scientific and medical communities, non-profit organizations, and other 

individuals and groups. The Bioethics Commission published a request for 

information in the Federal Register and received almost 100 written responses. 

In the course of its work, the Bioethics Commission performed an in-depth 

review of relevant literature, and in its deliberations, took into account the 

relevant work of prior commissions, in particular, the National Commission’s 

pathbreaking work in establishing pediatric research protections.

Based on the Bioethics Commission’s detailed examination, Chapter 2 of 

this report provides an overview of the ethical foundations for pediatric 

research protections and the current regulatory structure governing pediatric 

research. Chapter 3 sets forth and analyzes the ethical issues associated with 

conducting pre-event and post-event MCM research with children, and 

applies this ethical analysis to the particular case of AVA.
21

CHAPTER 2

Current Ethical and Regulatory Framework 

for Pediatric Research
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

22

Pediatric research is essential to ensure that children have access to therapies that are safe and effective. “Children are not just small adults.”32

They vary substantially from adults—and from other children of different 

ages—in the ways they process medicines, respond to interventions, and interact with their environment. Drug effects and toxicities, as well as immune 

responses to vaccines, are affected by the rapid growth and development in 

body size, weight, and organ function, as well as the metabolic processes that 

characterize childhood.33 Children behave differently from adults as well, for 

example, they generally spend more time outdoors and put objects in their 

mouths when they are young, increasing their exposure to some environmental contaminants.34 Given these differences, without specific data from 

pediatric research, health care providers often have inadequate information to 

accurately estimate dosages, formulations, and treatment regimens.

The pharmaceutical industry historically has had little incentive to conduct 

systematic clinical trials with children, even when those trials could have 

been conducted with minimal risk to individual children, because childhood 

is relatively short and most children are healthy.35 The market for pediatric 

pharmaceuticals and other medical products is small and subdivided by 

stages of development, often making it difficult to enroll adequate numbers 

of appropriate participants necessary for rigorous trials.36 As of 1997, studies 

showed that up to 80 percent of the drugs used by children had never been 

studied in pediatric populations for safety, dosing, or efficacy.37

Beginning in the late 1990s, out of concern for protecting children through

research rather than from research, Congress passed a series of laws to remedy 

the paucity of pediatric data by creating incentives for ethically sound pediatric clinical research. This legislation, including the Best Pharmaceuticals 

for Children Act of 2002 and the Pediatric Research Equity Act of 2003, 

provided extended market exclusivity for products tested with children and 

enabled the U.S. Food and Drug Administration (FDA) to request drug and 

biologic testing with pediatric populations.38 These incentive programs have 

spurred pediatric research and provided data that contributed to an approximately 50 percent reduction in off-label use of drugs for children.39 This is a 

vast improvement from the recent past, although the rate of off-label use still 

remains high.40
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

23

The current ethical and regulatory 

framework has proven largely capable 

of protecting children in the face of 

increasing pediatric research: promoting 

their welfare and enhancing research 

quality. Medical countermeasure 

(MCM) research, however, presents 

unique ethical challenges to the existing 

regulatory framework. 

This chapter provides an overview of 

the ethical and regulatory framework 

for pediatric research. It begins with an 

overview of the ethical principles that 

form the foundation of current federal 

regulations governing pediatric research 

and concludes with a discussion of how 

those foundational principles animated 

the development and adoption of pediatric research protections.

Ethical Underpinnings: Guiding 

Principles

A core set of ethical principles provides 

the foundation for pediatric research 

protections. Reflecting a consensus on 

the ethical conduct of human subjects 

research, these ethical principles are 

drawn from the National Commission 

for the Protection of Human Subjects of 

Biomedical and Behavioral Research’s 

(the National Commission’s) Belmont Report, and furthered by democratic 

deliberation, which the National Commission and subsequent commissions 

practiced in their work, and this Bioethics Commission explicitly adds as a 

critical principle for publicly accountable decision making.41

HISTORICAL RESEARCH ABUSES

A convergence of research abuses 

influenced the move toward 

regulatory human subjects research 

protections developed in part by the 

National Commission in the 1970s 

and enacted by the Department 

of Health, Education, and Welfare 

(now HHS) in the late 1970s and 

early 1980s. Research abuses, 

including well-known cases such 

as Willowbrook, Tuskegee, and the 

Nazi atrocities, were historically 

important in moving toward regulation. 

Henry Beecher’s publication of an 

article in the New England Journal of 

Medicine, which exposed 22 cases 

of human experimentation abuses, 

also motivated human subjects 

research regulation. Among the cases 

included in Beecher’s publication was 

the Willowbrook study—research 

conducted with institutionalized and 

mentally handicapped children.

Sources: Beecher, H.K. (1966). Ethics in clinical 

research. New England Journal of Medicine, 

274, 1354-1360; Jones, J. (1993). Bad Blood: 

The Tuskegee Syphilis Experiment. New York, 

NY: The Free Press; Lederer, S.E., and M.A. 

Grodin. (1994). Historical Overview: Pediatric 

Experimentation. In Grodin, M.A. and L.H. Glantz. 

(Eds.). Children as Research Subjects (pp. 1-25). 

New York, NY: Oxford University Press, pp. 

15-19; Mellanby, K. (1947). Medical experiments 

on human beings in concentration camps in 

Nazi Germany. British Medical Journal, 1(4490), 

148-150.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

24

In Research Involving Children, the National Commission emphasized the 

importance of including children in research to interrupt what had become 

a long history of untested and harmful pediatric innovations. The National 

Commission recognized that in addition to protecting children from research 

risks, society ought to protect children through research. This need to ensure 

the safety of children was grounded in respect for persons and the inability of 

children to consent to research-related risks. 

The National Commission’s report clarified what became the United States’ 

central tenet of pediatric research: pediatric research generally should be 

allowed only when such research exposes children to minimal risk. Minimal 

risk research entails a level of risk in which the degree and likelihood of 

harm is no greater than that faced by a healthy child in daily life or at a 

routine physical or psychological examination.42 Research risk can be greater 

than minimal only when the research offers the prospect of direct benefit 

to participants themselves or, if a minor increase above minimal risk, when 

research offers the prospect of benefit to others with the same condition.43

Except in extraordinary circumstances, asking children to take on greater risk 

in research when they do not stand to benefit directly pushes the bounds of 

ethical acceptability because children do not have the legal or ethical capacity 

to consent, and society has a duty to protect children from risk of harm to 

which they cannot consent. This view is widely shared, affirmed in leading 

international guidance documents, and reflected in U.S. law.44 It continues 

to serve as the first principle of ethically sound pediatric research around the 

world today.

Development of the Central Tenet of Pediatric Research

The four ethical principles that guided the Bioethics Commission’s discussion of pediatric research protections are respect for persons, beneficence, and 

justice—as outlined in the Belmont Report—and democratic deliberation, 

which was implicit both in the way the National Commission carried out its 

work and also in its recommendations regarding the process of reviewing and 

approving pediatric research. 

Respect for Persons

The Belmont Report delineates the principle of respect for persons, which 

recognizes persons as autonomous and capable of deliberating about their 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

25

personal goals, considering their own choices and opinions, and determining 

their own lives. Respect for persons also establishes “that persons with 

diminished autonomy [including children] are entitled to protection.”45 Some 

commentators believe that the obligation of “protection” in the Belmont 

Report is really a matter of beneficence.46 However, disregard for the wellbeing of children also reflects a lack of respect owed to them as young 

persons. This respect derives in part from the fact that children have and 

will further develop personal values and goals, as well as the capacity for 

self-determination to strive and fulfill them.

Respect for persons requires that research participants with full decision 

making capacity be given the information and the opportunity to consent 

voluntarily and knowingly to what will happen to them as a result of their 

participation. This imperative is often viewed as deriving from the human 

capacity for reason and self-determination. Human beings are generally capable of setting their own ends in accordance with their values and 

priorities and rationally pursuing these ends. Treating others in a way that 

disregards their human capacity for rationality and self-determination constitutes disrespect for those persons, and when we use people only to pursue the 

ends or interests of others—in other words, using them as mere means—we 

fail to respect their human dignity. Coercive uses of research participants—as 

in the Nazi medical atrocities—provide the most obvious instances of the 

impermissible treatment of participants as means only.47 Coercion of adult 

participants in research is a violation of a participant’s autonomy: the rational 

ability to direct the course of one’s own life. 

To treat people merely as means—to exploit them or use them only to further 

the interests of others—is not the same as treating people both as means and

as ends-in-themselves. Ethical human subjects research illustrates this distinction. Participation in research that offers a prospect of direct benefit might 

prove useful to others while simultaneously advancing the interests of individual research participants. In other instances of scientifically and ethically 

sound research, adult research participants are well informed and willing to 

bear personal risks with no expectation of return in order to benefit others. In 

these cases, transparency about risks and benefits allows individuals to make 

their own assessment of whether research participation comports with their 

personal values and pursuits. Accordingly, adults who provide their informed 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

26

consent to participate in otherwise scientifically sound and necessary research 

are not treated only as means, but also as ends in themselves. 

Ethical Safeguards in Pediatric Research Informed by Respect for Persons

Research with children differs from that with adults because children cannot 

consent in the relevant sense; they are substantially lacking in the developed 

capacities necessary for adequately informed and voluntary decision making, 

making them a vulnerable population. Although this incapacity is most often 

attributed to their level of cognitive development, the vulnerability of children 

can derive from multiple sources (such as expectations of deference to adult 

authority, lack of independent resources for autonomous decision making, and 

longstanding institutionalized relationships of adult authority and power).48

For this reason, extra protections are warranted to ensure that children are not 

placed at excessive risk for the benefit of others. These additional safeguards 

include: parental permission, meaningful child assent, and limits on the 

degree of permissible research-related risk.

Parental Permission. Parental 

permission requires that parents 

act on their child’s behalf, operating on their understanding of 

what is in their child’s best or 

essential interests.49 With this 

in mind, parents might allow a 

child to participate in research 

that offers a prospect of direct 

benefit precisely because enrollment appears to promote the 

child’s interests. In the context of 

research that poses no substantial risk to a child’s health or 

well-being but offers no prospect 

of direct benefit, some parents 

will compare short-term risks 

and benefits. For these parents, 

research that provides no direct 

APPLIED ETHICS IN PEDIATRIC RESEARCH

Paternalism constitutes those actions that 

restrict the freedom of others on the grounds 

that those actions are the best way to promote 

or protect their interests. In the case of children, 

such restrictions are not only justified because 

children cannot identify and pursue their own 

interests, but because “such restrictions on 

a child’s freedom guarantee his autonomy in 

either or both of two ways: these restrictions 

protect the child from harm that would limit his 

freedom in the future (being seriously injured, 

or a lack of education), or these restrictions are 

what we think the child will later agree to, what 

he will later see as something he would do in 

his own interest.” 

Source: Redmon, R.B. (1986). How children can be 

respected as ‘ends’ yet still be used as subjects in nontherapeutic research. Journal of Medical Ethics, 12(2), 

80. [Original emphasis]. 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

27

benefit might be out of the question. Other parents might be willing to take 

on risk for themselves but reluctant to subject their child to any research risk 

without the prospect of direct benefit—not knowing what the child will think 

(upon reaching adulthood) about having been subjected to risk for the benefit 

of others without their consent. And still other parents will give greater weight 

to the study’s incremental contribution to long-term scientific or societal 

endeavors, which might eventually result in medical progress that helps their 

child or the child’s potential offspring, as well as other children. Alternatively, 

parents might enroll their children in research that poses no substantial risk 

to their health or well-being to teach them a moral lesson about the value of 

service to others. Parents of older children might wish to give effect to their 

developing autonomy by including them in projects to which they assent and 

which they might later endorse as consistent with their own ethical perspective and interests.50

Meaningful Child Assent. While children are not fully autonomous, they 

nevertheless have varying capacities to make informed, self-regarding choices 

and express their preferences regarding how they will be treated. Children’s 

partial autonomy affords them a developmentally appropriate ability to participate in decisions regarding their involvement in research. Out of respect for 

this developing ability of children, their assent should be solicited, if possible, 

and their dissent respected, if applicable.51 Obtaining the meaningful assent 

of a capable child is one component of respecting that child as a person. It 

must not be interpreted, however, either as informed consent or as a substitute for parental permission. Parental permission is absolutely necessary to 

informed participation in conjunction with meaningful child assent. 

The fact that children have a developing capacity for autonomy lends 

significance to a child’s meaningful assent or dissent and also establishes a 

need to protect this capacity for self-determination. The principle of respect 

for persons permits only those research protocols that preserve and sustain 

the full development of a child’s autonomy, such that the current and future 

aspirations of some children are never unduly compromised merely for the 

sake of benefitting others. This is accomplished in important part by the final 

form of protection discussed here, which limits the degree of risk to which 

children can be exposed in research.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

28

Limiting the Degree of Research-Related Risk. Placing strict limits on the level 

of risk acceptable in pediatric research is a third and critically important way 

to protect children in light of their incomplete autonomy and their inability 

to consent. Child research participants will one day grow up and reflect on 

whether they would have consented to participate in the research, had they 

been capable. While parents may exercise legitimate discretion when granting 

permission for their children to enroll in research, there is no way to know 

whether all participants, once adults, will endorse the decision retrospectively 

(even if they provided meaningful assent as children).52 To reduce the 

possibility that some participants will look back and think they were 

unethically used by their parents or researchers, protections should be in place 

to ensure that participants who reflect on their past research participation will 

be likely to endorse the ways in which they were protected, if not their own 

participation. On this view, past participants might later reflect that even if 

they would not have consented to participate, protections were in place that 

prevented them from being harmed. 

Risk limits are essential to combat the potential for exploitation (of both 

children and adults), however unintended such exploitation may be. Because 

children cannot make an autonomous decision to participate in research, 

from an ethical and legal perspective, great care must be taken to ensure that 

research risks are rigorously limited. In particular, because research is, in part, 

always justified on the basis of potential benefit to others—but not necessarily 

to the children who are subject to risks as research subjects—special efforts 

must be made to ensure that children are not exploited by permitting greater 

research risks to children when society stands to benefit in greater measure.53

The imposition of a rigorous risk ceiling ensures that, no matter how great the 

potential benefit, child research participants are not exposed to a disrespectful 

and exploitative level of risk for the interests of others in society. 

Another reason why it is important to limit the research risks to which 

children are subjected is that the state does not have the same broad latitude 

as parents to make risk-laden decisions on behalf of children. There are public 

obligations to limit both the outer bounds of parental authority (so as to 

prevent negligence) and the outer bounds of governmental authority over 

children (so as to prevent the exploitation of individual children for public 

purposes). One way in which the government defines the outer bounds of its 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

29

own authority over individual children and respects the future autonomy of 

children is by limiting the levels of research risk that parents may be asked 

to accept for their children, especially when that research is above minimal 

risk and does not directly benefit the child. These risk limits are one of the 

core protections that children receive both out of respect for their dignity 

as persons and to help ensure that they will be able to exercise their own 

autonomy as adults.

Interpreting the Scope of Respect for Persons

Given that children are allowed, under clearly delineated circumstances, 

to participate in research without the prospect of direct benefit, current 

regulations implicitly reject one particularly restrictive interpretation of the 

principle of respect for persons. (See Current Regulations for Conducting 

Pediatric Research, Chapter 2.) Under this most restrictive interpretation, 

due to their incapacity to consent, the principle of respect for persons would 

prohibit all research with children (including even minimal risk research) 

that offers no prospect of direct benefit.54 Strong consensus in the field of 

bioethics—including the judgment reflected in the National Commission’s 

position—regards this understanding as overly restrictive. An alternative, 

widely accepted interpretation of respect for persons allows for the participation of children in research that offers no prospect of direct benefit under 

certain carefully defined circumstances—even if the research imposes more 

than minimal risk on pediatric participants, stopping short of posing any 

substantial risk to the fundamental health or well-being of the research 

participants. On this widely accepted interpretation, research without the 

prospect of direct benefit is permissible if it imposes no greater than minimal 

risk—a level of risk comparable to the risks that healthy children living in 

a safe environment routinely encounter in everyday life or during a routine 

medical examination—and, under certain limited circumstances, a slightly 

higher (but still very limited) level of risk, which poses no substantial risk to 

the participants’ health or well-being.55

The widely accepted interpretation of the principle of respect for persons 

should be endorsed on the grounds that research protections can help to 

ensure respect for children by safeguarding their current capacities, guaranteeing their future autonomy (by ensuring they are not treated as mere 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

30

means), and by not subjecting them to undue risk. In addition, this more 

inclusive interpretation receives support from other relevant moral principles. 

The principle of beneficence, further addressed in the next section, calls upon 

society and the research community to advance biomedical knowledge in the 

interest of the public’s welfare. The importance of beneficence in the context 

of pediatric biomedical research counsels against the most restrictive interpretation of respect for persons and in favor of the widely accepted approach to 

pediatric ethics, as reflected in the National Commission’s recommendations 

and current regulations.

* * *

All pediatric research must satisfy the ethical principle of respect for persons. 

This Bioethics Commission articulated a set of conditions under which 

pediatric research without the prospect of direct benefit fully respects and 

ethically protects children as individuals and as a group. (See Pre-event 

Studies Posing No More Than a Minor Increase over Minimal Risk 

Approvable under Section 407, Chapter 3.) By treating the interests of child 

participants as a paramount concern, pediatric research without the prospect 

of direct benefit can respect and uphold the humanity of participants, and 

refuse to view them as objects merely serving the ends of science or society, 

provided that the research risks are strictly limited and parental permission 

and meaningful child assent are obtained. This generally entails permitting 

research that involves no more than minimal risk, but under certain strictly 

limited circumstances, permitting a slightly higher than minimal (but still 

very limited) level of risk, provided that the protocol poses no substantial risk 

to the children’s health or well-being. 

Beneficence

Beneficence, as described in the Belmont Report, is the obligation to undertake 

efforts to secure the well-being of others. In pediatric research, the duty to 

safeguard participants by protecting them from harm and undue risk of harm 

is particularly salient because children have reduced autonomy and cannot 

legally consent, making them a vulnerable population.56 Beneficence requires 

that special safeguards be employed to protect vulnerable populations (e.g., 

the requirement of minimal risk or prospect of direct benefit for most pediatric research). This principle provides additional support for the conclusion 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

31

that some proposed pediatric trials impose excessive risks, too high to ask 

parents to consider having their children bear. These studies would involve 

potential harm that would threaten the basic health or well-being of children 

who, as research participants, would not stand to directly benefit or be able to 

offer their own informed consent.

The Belmont Report includes under beneficence the corollary principle of nonmaleficence, or “do no harm,” an obligation not to cause deliberate harm to 

others.57 This obligation to minimize the risk of harm from research—especially for children in view of their inability to consent—provides an additional 

principled foundation for a firm limit to acceptable research risks. Notably, 

however, there might be cases in which, in order to avoid harm, research is 

needed to discover what is harmful. Similarly, to discover what is beneficial 

might, at times, require exposing some persons to the risk of harm. As stated 

by the National Commission, “The problem posed by these imperatives is to 

decide when it is justifiable to seek certain benefits despite the risks involved, 

and when the benefits should be foregone because of the risks.”58

Beneficence is directed not only at individual research participants, but 

also toward the broader public, seeking to benefit society as a whole. The 

Belmont Report acknowledged this, stating, “The obligations of beneficence 

affect both individual investigators and society at large, because they extend 

both to particular research projects and to the entire enterprise of research.... 

In the case of scientific research in general, members of the larger society 

are obliged to recognize the longer term benefits and risks that may result 

from the improvement of knowledge and from the development of novel 

medical, psychotherapeutic, and social procedures.”59 Those who deliberate 

and consider whether research should proceed ought to take into account the 

duty “of a society and its government to promote individual activities and 

institutional practices, including scientific and biomedical research, that have 

great potential to improve the public’s well-being.”60

Beneficence guides the risk-benefit assessment in research. While “risk” indicates possible harm, “benefit” refers to the anticipated gains resulting from 

the research. The Belmont Report offered five considerations for assessing the 

risk-benefit justification in research with all human participants:

i. Brutal or inhumane treatment of human subjects is never morally 

justified.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

32

ii. Risks should be reduced to those necessary to achieve the research 

objective.... Risk can perhaps never be entirely eliminated, but it can 

often be reduced by careful attention to alternative procedures.

iii. When research involves significant risk of serious impairment, review 

committees should be extraordinarily insistent on the justification of 

the risk (looking usually to the likelihood of benefit to the subject—or, 

in some rare cases, to the manifest voluntariness of the participation).

iv. When vulnerable populations are involved in research, the 

appropriateness of involving them should itself be demonstrated. A 

number of variables go into such judgments, including the nature and 

degree of risk, the condition of the particular population involved, and 

the nature and level of the anticipated benefits. 

v. Relevant risks and benefits must be thoroughly arrayed...in the 

informed consent process.61

Two of these considerations are especially applicable to the question before 

this Bioethics Commission: (ii) reducing risk to that necessary to achieve the 

research objective and to the lowest possible level by considering alternative 

approaches; and (iv) justifying the appropriateness of including vulnerable 

populations, in this case children. Non-maleficence, which requires us 

to reduce research risks as far as possible, becomes especially salient when 

research is planned with children who cannot consent to assume risks on the 

behalf of others. 

Beneficence and non-maleficence—similar to respect for children as 

persons—obligate us to ensure that research risks be necessary and minimized, and to employ alternative approaches that might avoid exposing 

children to risk—for example, using computer and animal models or adult 

participants who can consent to assume risk on behalf of others. Moreover, 

risks should be shown to be minimal in the youngest adults through testing 

them before proceeding with the oldest children. Further, non-maleficence 

toward child research participants and beneficence toward participants and 

toward society as a whole must be jointly considered in determining an 

acceptable level of risk. In general, research-related risks that are greater than 

minimal are ethically permissible only if there is a prospect of direct benefit 

for the child participants or there is the prospect of benefit to the class of 

children from which the participants are drawn. 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

33

Justice

The principle of justice reflects the National Commission’s commitment to 

“‘fairness in distribution’ or ‘what is deserved.’” 62 Ethical distribution of 

research burdens and benefits generally prevents the possibility of asking 

participants and families to consider bearing too heavy a burden on behalf 

of society. More specifically, in the conduct of research, justice requires 

that research participants not be denied a benefit to which they are entitled 

and that no individual participant be burdened with undue risk of harm or 

hardship. These obligations can be met by ensuring that all research participants are treated equitably—for instance, by allocating research burdens and 

benefits according to ethically justifiable criteria.63 In the case of research 

with children, moreover, justice—in combination with respect for persons, 

beneficence, and non-maleficence—requires that children should not bear 

more risk than absolutely necessary during research, and that risks children 

undertake during research may be assumed only in order to address research 

questions that can only be addressed with children. For example, children 

should not be asked to bear research risks solely to benefit adults.

Just distribution of research risks applies not only to the design and conduct 

of research, but also to subject selection. Even when they are treated equitably 

once enrolled in research, children and families might be selected unjustly 

if they are chosen from certain subgroups of the population that are already 

excessively burdened by conditions of socioeconomic disadvantage, that 

have made uncommon sacrifices in the course of public service, or that have 

been subject to repeated recruitment for research enrollment. Reviewers and 

researchers must ensure that all necessary safeguards are in place to avoid 

exploiting participants when enrolling those who might be vulnerable based 

on their age, clinical status, marginalization, economic deprivation, or similarly relevant factors.64 Just as justice requires that similar cases be treated 

similarly, so too does justice require that we be alert to significant differences. 

Researchers, therefore, must be cognizant of the potential for exploitation—

the ability to take unfair advantage of participant vulnerability. The principle 

of justice requires, as noted by the National Commission, that researchers 

adapt their practices to treat cases that differ in “morally relevant respects” 

differently—for example, modifying consent or recruitment practices—in 

order to equalize protection from harm for all participants.65
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

34

Once research has concluded, justice requires equitable distribution of benefits 

that emerge from successful research endeavors. Just distribution takes into 

account not only such factors as who participated in the research, but also 

ensures that children are not excluded from receiving benefits on the basis of 

poverty or other marginalizing factors.

Democratic Deliberation

Democratic deliberation is a process that seeks to clarify and articulate factual and ethical issues at the core of a debate, to create consensus 

whenever possible, and to map the terrain of disagreements in a respectful 

way—when agreement is not immediately attainable—by encouraging 

reciprocity, respect for persons, transparency, publicity, and accountability.66

This principle embraces inclusion of community members—individuals and 

their representatives—in meaningful and active participation in an ongoing 

public exchange of ideas. In research, democratic deliberation is manifest, for 

example, in community engagement and in various aspects of institutional 

research review and approval.

The National Commission valued the principle of democratic deliberation 

and honored it both in its approach as well as its recommendations. While 

studying the matter of research protections for child participants in the 

1970s, the National Commission took extensive measures to involve experts, 

advocates, parents, and other stakeholders. The National Commission invited 

representatives of professional societies, federal agencies, public interest 

groups, parents, and other members of the public to present their views at 

public hearings.67 In addition to creating an open forum for interested individuals and parties to present their views, the National Commission actively 

convened a National Minority Conference on Human Experimentation to 

represent the views of those who might not otherwise be adequately represented.68 The National Commission reviewed papers and surveyed existing 

pediatric research practices to inform its public deliberations and develop 

recommendations for pediatric research.

This inclusive approach to its deliberations was evident not only in the National 

Commission’s process but also in the content of its report, Research Involving 

Children, which lays out its argument through chapters devoted to each 

level of its inquiry. These chapters include the various surveys to characterize 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

35

contemporary research, review, and consent practices; views presented by 

stakeholders; and discourse by psychology, law, and ethics experts of the day.69

One recommendation in particular demonstrates the importance of democratic 

deliberation to the National Commission, not only in its own work but also in 

the ongoing review and approval of research with children. Although all pediatric research requires review by an Institutional Review Board (IRB)—a form 

of democratic deliberation—the National Commission recommended that 

research involving greater than minimal risk with no prospect of direct benefit 

to healthy children should only be approved after an opportunity for extensive 

public comment and open deliberation. Because the National Commission 

considered this category of research approvable only in extraordinary circumstances and as a matter of societal exigency, it considered soliciting the input of 

citizens essential both to inform and legitimate the work.70

Accordingly, the National Commission recommended that research in 

this category could only be considered for approval by the Secretary of the 

responsible agency after consultation with a panel of experts and opportunity 

for public comment. Observing the principles at stake—(1) the obligation 

to protect the community or come to the aid of those within it, and (2) 

the prohibition against unethically using persons who cannot consent, at 

considerable risk to their well-being, for the common good—the National 

Commission stated, “[t]hese principles are of such moment and their observance so basic to a just and humane society that any debate about their 

application should be held at the most public level of discourse.”71

This Bioethics Commission reaffirms its own commitment to the principle 

and practice of democratic deliberation and its importance in shaping 

pediatric research protections. Given the dual obligations to protect individual 

research participants and to protect children as a class, enhanced transparency 

and accountability and extensive community engagement, for example, are 

essential to informing the review and conduct of pediatric research. By 

fostering meaningful inclusion of the affected communities at all stages of 

the research process, community engagement constitutes a component of 

democratic deliberation that researchers can employ to incorporate the values 

of the community into the research process. The Bioethics Commission 

includes in its recommendations appropriate provision for community 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

36

engagement in both pre- and post-event research.72 Moreover, in all 

stages of pediatric research, democratic deliberation provides an essential 

means of confirming both that the research is consistent with societal and 

community values and also that it achieves socially valuable—and broadly 

valued—goals. Indeed, the Bioethics Commission has begun the community 

engagement process specifically—and the democratic deliberation process 

more generally—through its deliberations, and recognized that communities 

are well-positioned to contribute to the discussion now, before any research 

occurs. A significant test of the social value and importance of pediatric 

research projects—especially when such projects subject individual children to 

some risk for the potential benefit of children as a class—is that a broad range 

of citizens and parents, having been informed and given the opportunity to 

comment, value and support those projects. 

* * *

Foundational ethical principles provide both clarification and guidance in 

formulating strong safeguards for children, both as individuals and as a group. 

Essential research protections that follow from a principled approach often 

involve appeal to more than one ethical principle. One protection central 

to this report—a commitment to repudiating exploitation—provides a clear 

example of such an appeal. This commitment derives from the principle of 

respect for persons and its attendant imperative not to treat others as mere 

means as well as from non-maleficence (the duty to “do no harm”). The 

commitment to avoid exploiting the vulnerable is clearly a matter of justice, 

and deliberative democracy helps to assure a just outcome by promoting 

dialogue with those who have not yet had their chance to voice concerns, 

thereby protecting against exploitation. 

Continuing in the tradition of the National Commission, this Bioethics 

Commission reaffirmed the view that ethical research is not research that 

strikes the appropriate “balance” or “trade-off” among fundamental social 

values, but rather “that all of these principles must be taken together as 

the necessary and sufficient conditions for the ethical conduct of research 

regarding children. Unless research can be designed which reflects all [four], it 

cannot be called ethical.”73 The recommendations of this report therefore are 

informed by and seek to satisfy all four fundamental principles of respect for 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

37

persons, beneficence, justice, and democratic deliberation, which are widely 

affirmed by our society and firmly established in the best practices of scientific 

research with human subjects. 

Current Regulations for Conducting Pediatric Research

The three Belmont principles and the principle of democratic deliberation 

also informed the National Commission’s reasoning and recommendations 

for additional regulatory protections for pediatric research participants. The 

Department of Health and Human Services (HHS) (and later FDA) adopted 

the National Commission’s recommendations almost verbatim, and the 

regulations subsequently promulgated concerning research with children 

remain largely the same today, comprising Subpart D of HHS regulations at 

45 C.F.R. Part 46 and FDA regulations at 21 C.F.R. Part 50.74 The language 

of these two sets of regulations is substantively identical. Although Subpart 

D makes up part of these agencies’ human subjects protections regulations, it 

is separate from and supplementary to Subpart A, referred to as the Common 

Rule—which governs research with adults.75 Subpart D specifies stringent 

protections for children in addition to those provided in the Common Rule.76

The key impetus for a separate regulatory subpart addressing additional 

protections for child participants in research was the recognition that, while 

adults can consent to assume research risks, children cannot. More specific to 

the content of this report, adults can consent to participate in research from 

which they will accrue no benefit for themselves but that benefits others. By 

contrast, children cannot participate in research that poses higher risks than 

those of daily life, except in circumstances where research offers the prospect 

of benefit to participants themselves or to those with the same condition.

For the most part, protections for pediatric research participants are well 

defined and well implemented. The regulations include special protections for 

wards of the state, delineate requirements for parental permission and child 

assent, and provide criteria for IRBs to use in reviewing research depending 

on its level of risk and potential benefit.77 Local IRBs can review and approve 

research with children that: (1) does not involve greater than minimal risk; (2) 

involves greater than minimal risk but presents the prospect of direct benefit to 

individual participants; or (3) involves a minor increase over minimal risk and 

no prospect of direct benefit to individual research participants, but is likely 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

38

Table 2.1 

Regulations Governing Review of Pediatric Human Subjects Research Protocols

Local IRB Review Mechanisms

45 C.F.R. § 46.404

Reflected by FDA at:

21 C.F.R. § 50.51

Minimal risk

HHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is 

presented, only if the IRB finds that adequate provisions are made for soliciting assent of the children and 

the permission of their parents or guardians as set forth in § 46.408.

45 C.F.R. § 46.405

Reflected by FDA at:

21 C.F.R. § 50.52

Prospect of direct benefit to the individual participant

HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented 

by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a 

monitoring procedure that is likely to contribute to the subject’s well-being, only if the IRB finds that:

a. The risk is justified by the anticipated benefit to the subjects;

b. The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented 

by available alternative approaches; and

c. Adequate provisions are made for soliciting the assent of the children and permission of their parents or 

guardians, as set forth in § 46.408.

45 C.F.R. § 46.406

Reflected by FDA at:

21 C.F.R. § 50.53

Likely to yield generalizable knowledge about participants’ condition and only minor increase over 

minimal risk

HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented 

by an intervention or procedure that does not hold out the prospect of direct benefit for the individual 

subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if 

the IRB finds that:

a. The risk represents a minor increase over minimal risk;

b. The intervention or procedure presents experiences to subjects that are reasonably commensurate with 

those inherent in their actual or expected medical, dental, psychological, social, or educational situations;

c. The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or 

condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or 

condition; and

d. Adequate provisions are made for soliciting assent of the children and permission of their parents or 

guardians, as set forth in § 46.408.

National-Level Review Mechanisms

45 C.F.R. § 46.407

Reflected by FDA at:

21 C.F.R. § 50.54

Greater than minimal risk with no prospect of direct benefit to individual participants 

or those participants’ condition

HHS will conduct or fund research that the IRB does not believe meets the requirements of § 46.404, 

§ 46.405, or § 46.406 only if:

a. The IRB finds that the research presents a reasonable opportunity to further the understanding, 

prevention, or alleviation of a serious problem affecting the health or welfare of children; and

b. The Secretary,* after consultation with a panel of experts in pertinent disciplines (for example: science, 

medicine, education, ethics, law) and following opportunity for public review and comment, has 

determined either:

1. That the research in fact satisfies the conditions of § 46.404, § 46.405, or § 46.406, as applicable, or

2. The following:

i. The research presents a reasonable opportunity to further the understanding, prevention, or 

alleviation of a serious problem affecting the health or welfare of children;

ii. The research will be conducted in accordance with sound ethical principles; and

iii. Adequate provisions are made for soliciting the assent of children and the permission of their 

parents or guardians, as set forth in § 46.408.

* Note: In the case of review by FDA under § 50.54, the Commissioner of Food and Drugs convenes the expert panel and makes the final 

determination, which is forwarded to the HHS Secretary. For concurrent review under §§ 46.407 and 50.54, the Secretary makes the 

final determination.
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

39

to yield generalizable knowledge about the children’s disorder or condition.78

Local IRBs are not permitted to approve research outside of these categories, 

but “research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of 

children”—generally higher risk, non-therapeutic research—can nonetheless 

be approved by the Secretary of HHS in consultation with a panel of national 

experts.79 This report refers to such national-level expert review by its HHS 

provision number—45 C.F.R. § 46.407 (section 407)—which is a common 

convention in ethics discourse on this subject.80 Equivalent substantive requirements are found in FDA regulations at 21 C.F.R. § 50.54. Whether the review 

is conducted by the HHS Office for Human Research Protection (OHRP), or 

FDA, or both, the ethical requirements are essentially the same across both 

sets of regulations.81 The regulations governing these review mechanisms are 

included in Table 2.1. 

This report references research regulated by section 407 as research with 

healthy children that poses more than minimal risk with no prospect of 

direct benefit. The Bioethics Commission recognized and considered in its 

work the full range of research that is encompassed by section 407, including 

(1) research with healthy children that poses greater than minimal risk and 

that offers no prospect of direct benefit, (2) research with children affected 

by a disease or condition that poses more than minimal risk and does not 

yield information of vital importance about their disease or condition, and 

(3) research with children affected by a disease or condition that poses greater 

than a minor increase over minimal risk.

Pediatric Research Subject to Local IRB Approval

The National Commission’s most straightforward recommendations 

addressed research that poses only minimal risk (codified in section 404) or 

that offers the prospect of direct benefit to participants (codified in section 

405).82 More complicated, but still ethically tractable, was research posing 

greater than minimal risk but likely to yield generalizable knowledge about 

the participants’ condition (codified in section 406).83 Research that is greater 

than minimal risk with no prospect of direct benefit to subjects or benefit to 

others with their condition was considered decidedly more controversial and 

ethically problematic. 
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Section 404: Minimal Risk Research

Making its recommendation on minimal risk research, the National 

Commission recognized that “the scope of parental responsibility includes 

the right to choose activities and to define a manner of life for their 

children.”84 Finding that “many experiences which parents generally allow 

to their children are somewhat risky and cannot be said, without forcing 

the case, to involve particular benefits,” the National Commission considered 

it uncontroversial that parents should have the opportunity to enroll their 

children in research where the risks “are equivalent to normal risks of 

childhood.”85 The National Commission recommended and the regulations 

allow an IRB to approve minimal risk research that provides for parental 

permission and meaningful assent from child participants as well as standard 

pediatric research safeguards such as risk minimization, privacy and 

confidentiality protections, and equitable subject selection.86 The National 

Commission defined minimal risk as “the probability and magnitude of 

physical or psychological harm that is normally encountered in the daily lives, 

or in the routine medical or psychological examination, of healthy children.”87

As implemented, protections for minimal risk research have been subject to 

ongoing debate—mostly focused on the regulatory definition of “minimal 

risk,” which omits the National Commission’s reference to healthy children. 

While disagreement remains as to whether the standard is intended to be 

objective or subjective, several national committees studying the matter have 

concluded that “minimal risk” should be interpreted as the degree of risk 

encountered in the daily life of a healthy child living in a safe environment or 

the risk to which a healthy child is exposed during a routine examination.88

The Bioethics Commission accepted this shared understanding.

Section 405: Research Presenting the Prospect of Direct Benefit

In considering research that presents greater than minimal risk but also the 

prospect of direct benefit to research participants, the National Commission 

concluded that risk might be justified by “avoidance of greater harm” or 

provision of “important anticipated benefit.”89 Any risk entailed in research, 

however, can be justified only by the potential direct benefits to the 

individual child participant that are associated with the intervention itself 

(not by ancillary benefits such as a medical examination). The risk-benefit 
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41

ratio of the experimental intervention must be at least as good as that of 

available alternatives.90

The relevant regulatory language closely reflects that of the National 

Commission, stating that an IRB may approve a protocol if it finds that 

the risk is greater than minimal but that the research holds the prospect of 

direct benefit to the individual either through the intervention or through “a 

monitoring procedure that is likely to contribute to the subject’s well-being.”91

Beneficial monitoring procedures might include, for example, obtaining 

samples of blood or spinal fluid in order to determine that drug levels are safe 

and effective. A reviewing IRB must also find that (a) “[t]he risk is justified 

by the anticipated benefit to the subject[],” (b) the risk-benefit ratio is at least 

as good as existing alternatives, and (c) all relevant parental permission and 

meaningful child assent provisions are observed.92 There is ongoing debate 

over the extent to which “benefit” should include non-medical benefits, but 

in practice, the scope is most often limited to medical benefits associated with 

the intervention being studied.93

Section 406: More Than Minimal Risk Without the Prospect of Direct 

Benefit but Likely to Yield Knowledge About the Participants’ Condition

The National Commission recognized that some valuable research involving 

children will inevitably present greater than minimal risk with no prospect 

of direct benefit to the individual participants. Prohibiting this type of 

research completely, as initially supported by some members of the National 

Commission, might have come at too great a cost, sacrificing research of 

critical importance to child welfare in order to avoid “only a minor” increased 

risk.94 In developing its recommendations for approval of a limited class of 

research entailing greater than minimal risk and no prospect of direct benefit, 

the National Commission kept in mind the proposition that parents are 

routinely allowed to authorize their child’s involvement in activities, such 

as skiing, where risk is greater than minimal and the potential for benefit is 

debatable.95 Given that information, the National Commission recommended 

that pediatric research with no prospect of direct benefit and presenting no 

more than “a minor increase over minimal risk” could be ethically permissible 

and allowed by regulation if the knowledge likely to be generated by the 

research was of “vital importance” to understand or ameliorate a pediatric 

disorder or condition. 
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Specifically, in light of reports that valuable diagnostic, therapeutic, and 

preventive measures have been discovered in research that entails risk that 

“while minor, would be considered more than minimal,” the National 

Commission recommended that local IRBs could approve research that meets 

the following conditions: (1) “the risk involved must be only a minor increment beyond minimal,” (2) “the procedures to be used must be reasonably 

commensurate with (similar to) those with which prospective subjects have 

had experience,” and (3) “the research must be likely to yield generalizable 

knowledge important for the understanding or amelioration of the subjects’ 

specific disorder or condition.”96 Research that meets these specifications may 

be approved because the minor additional increment of risk to participants is 

acceptable in light of the “foreseeable benefit in the future to an identifiable 

class of children.”97

In making its recommendation, the National Commission emphasized that 

“minor increase over minimal risk” is only a “narrow” expansion and that any 

protocol submitted under this provision should “pose[] no significant threat 

to the child’s health or well-being.”98 HHS and FDA adopted the National 

Commission’s recommendation.99

* * *

Taken together, the three categories of research that can be approved 

by a local IRB constitute the majority of pediatric research approved and 

conducted in the United States. Where a protocol does not fall into one of 

these approvable categories, it is generally amended so that it conforms to 

local review requirements or else it is denied approval. Only rarely is such a 

protocol elevated for national-level review under section 407. (See Pediatric 

Research Requiring National-Level Review—Higher Risk and No Prospect 

of Direct Benefit, Chapter 2.) These regulatory provisions for local IRB review 

place strict, ethically sound limits on the degree of risk to which children can 

be exposed in research, and from the time they have been in place, they have 

permitted and indeed fostered research leading to interventions for the most 

common childhood illnesses and conditions.100
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Pediatric Research Requiring National-Level Review—Higher Risk and No 

Prospect of Direct Benefit to Healthy Participants (Section 407)

Although the National Commission created a mechanism for local approval 

of greater than minimal risk research with children affected by a disorder or 

condition, it did not develop a set of criteria for local IRBs to approve higherrisk research with healthy children or research where the risk is greater than 

a minor increase over minimal risk. This latter type of research was reserved 

for evaluation and approval by a national panel of experts and the Secretary 

of HHS, later codified as section 407. The National Commission struggled 

with the idea of involving children in such research with no prospect of direct 

benefit to the individual child participant, but recognized that there might 

be extraordinary circumstances in which the dangers to children as a class, 

or the community as a whole, that would result from excluding children 

from research would be so great that they might require society reluctantly to 

accept a higher level of research risk. For instance, in the event of a pending 

epidemic that could be stemmed by testing a novel vaccine with children, 

the circumstances might require this reluctant acceptance of levels of risk 

otherwise unacceptable in pediatric research (e.g., higher risks involved in 

determining dosing specifications for particular age groups). 

Acknowledging that every such situation would involve different considerations that could not be precisely resolved in the abstract, the National 

Commission concluded that it would be preferable to debate the matter in 

an actual situation where the “real issues and the likely costs of any solution 

can be more clearly discerned.”101 In providing the opportunity for considered 

debate in light of more specific circumstances, the National Commission went 

a step further, calling for public input as well, stating that the moral obligation to protect the community (to the extent ethically and practically possible) 

and the prohibition against using unconsenting persons at considerable risk to 

their well-being for the promotion of the common good were of such import 

that debate on how to reconcile the obligation and prohibition must be held 

publicly.102 The National Commission recommended that research entailing 

this level of risk could only be approved as an “exception to the general rules” 

(i.e., when “[t]he outright prohibition of such research on grounds of risk 

might have consequences which themselves appear unethical”) and could only 
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44

go forward after (1) an IRB determines that for “urgent or unique” reasons the 

research should be permitted, and (2) the research is reviewed and approved 

at the national level to determine that it does not violate the principles of 

respect for persons, beneficence, and justice, with opportunity for public 

comment.103 Additionally, appropriate parental permission and meaningful 

child assent would be required. The National Commission recommended 

that this national-level review include judgment by the Secretary of the 

responsible agency and that approved research should be delayed pending 

congressional notification and a reasonable opportunity for Congress to take 

action regarding the proposed research.104

As enacted, the regulations provide that research may be approved if (1) an 

IRB determines that the research “presents a reasonable opportunity to further 

the understanding, prevention, or alleviation of a serious problem affecting 

the health or welfare of children” but is not approvable under sections 404 

to 406, and (2) upon convening a panel of experts and soliciting public 

comment, the Secretary of HHS determines that (i) the “research presents a 

reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;” (ii) “the 

research will be conducted in accordance with sound ethical principles;” and 

(iii) adequate provision is made for permission of parents and guardians and 

meaningful assent (or affirmative agreement) of children.105 This structure 

creates three independent bodies that must review or approve any protocol 

submitted for assessment under section 407: (1) the local IRB, (2) the national 

panel of experts, and (3) the Secretary of HHS.

As evidenced by the language of section 407, HHS (and FDA in its regulations) modified the National Commission’s recommendation. The provision 

adopted by HHS (and FDA) does not provide for notification of Congress and 

sufficient delay for Congress to intervene. The reasons for this omission are 

unclear. In addition, the regulations depart from the National Commission’s 

recommendations by providing for an ad hoc panel of experts to conduct the 

national-level review, rather than a standing “[N]ational [E]thical [A]dvisory 

[B]ody.”106 Unlike a standing committee, a system that HHS expected to prove 

“cumbersome, inflexible and unadaptable to the variety of different research 

problems likely to be encountered within the scope of the Department’s activities,” the agency hoped that an ad hoc structure would provide the flexibility 
CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

45

necessary to convene sufficiently expert individuals in a range of scientific 

specialties, ethics concentrations, legal fields, and other relevant disciplines for 

a given protocol.107

Similarly, regulations adopting national-level review, rather than enumerating the principles in the National Commission’s recommendation 

(respect for persons, beneficence, and justice), simply require that research 

be conducted in accordance with “sound ethical principles.”108 Although 

the provision permits necessary flexibility for review of research required 

by extraordinary circumstances, many expert panels have reported great 

uncertainty in determining whether a protocol was consistent with sound 

ethical principles, especially in the context of extraordinary circumstances 

that would justify approval.109

NATIONAL-LEVEL REVIEW CASE STUDY: DRYVAX (SMALLPOX VACCINE) PROTOCOL 

In 2002, an independent panel reviewed a protocol to test smallpox vaccine in 40 children, 

2 to 5 years of age. Because smallpox was eradicated in 1979, no manufacturer still 

produced the vaccine and only a limited supply of stockpiled vaccine doses remained. 

Motivated by concerns about a possible bioterrorism attack using smallpox virus, the 

study was intended to demonstrate the safety of diluted vaccine (and its immune 

response), allowing emergency responders to stretch the existing supply.

Reviewers agreed that the existing evidence about adverse reactions and secondary 

infections in adults suggested that the vaccine trial would pose more than minimal risk 

to children. The experts struggled, however, with putting these risks in context. Because 

they could not foresee the likelihood of a bioterrorism attack, many found it difficult to 

quantify the possibility of future benefit to children as a class. Further complicating the 

reviewers’ considerations was news of a potentially safer, next-generation vaccine in 

development, which might be available by the time a smallpox attack occurred. Reviewers 

also debated subject selection problems that might result if only parents particularly 

concerned about bioterrorism attacks permitted their children to participate.

Ultimately, HHS did not approve the protocol because biopreparedness plans changed, 

meaning that DryVax would not be used for children in an emergency.

Source: Quigley, R. (2004). Uncertain benefit: The public policy of approving smallpox vaccine research. American 

Journal of Public Health, 94(6), 943-946.
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In practice and as permitted by regulation, national-level review is used 

primarily for research that could not otherwise be approved under another 

section in Subpart D (sections 404 to 406), but most of the research to date 

that has been considered under section 407 has not risen to the level of 

extraordinary circumstances. This practice is in tension with both the tenor of 

the National Commission’s discussion and the language of its recommendation. However, the ethical difficulties inherent in enrolling healthy children 

as experimental controls create persistent challenges difficult to resolve in a 

way that would permit approval under sections 404 through 406.110 Healthy 

controls are scientifically essential to ensure high quality scientific results. Such 

broad application of the national-level review process might result from inadequate specification of the term “serious” or from the codification of section 

407 as a “catchall” provision. Nonetheless, while national-level review has been 

used more frequently in recent years, it remains rare. From 1991 to 2012, this 

level of review has been used in only 14 cases, 10 of which were approved.111

Conclusion

The ethical foundations for research with children are rooted in long and 

widely held ethical principles—respect for persons, beneficence (and 

non-maleficence), justice, and democratic deliberation—articulated and 

embodied by the National Commission’s recommendations in 1977 and later 

codified in federal regulations. In general, the current ethical and regulatory 

framework functions well, fostering research and advancing medical progress 

for children while adequately protecting them. Although there are historical 

examples of unethical research with children, most of these predate the 

current regulations. 

The Belmont principles, in conjunction with the principle of democratic 

deliberation, continue to guide contemporary pediatric research and set 

the backdrop for the Bioethics Commission’s deliberations on the ethics of 

MCM research with children. In the next chapter, the Bioethics Commission 

examines how the characteristics of MCM research and these ethical 

principles interact to present unique circumstances to consider when deciding 

whether to proceed with pediatric MCM research in general and with specific 

MCM protocols.
47

CHAPTER 3

Ethical Considerations for 

Pediatric Medical Countermeasure Research
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The Secretary of Health and Human Services (HHS) requested that the 

Bioethics Commission analyze the ethical issues associated with 

conducting medical countermeasure (MCM) research with children, including 

an analysis of both pre- and post-event studies of anthrax vaccine adsorbed 

(AVA). In this chapter, the Bioethics Commission, supported by the long-held 

principles enumerated in Chapter 2, concludes that society’s duty to children 

requires a necessary, even if not sufficient, limit on the level of research risk to 

which children can be exposed for the benefit of others. This risk ceiling, above 

which only limited and previously outlined exceptional circumstances allow us 

to pass, governs even the unique circumstances of MCM research.

Ethical Grounding

Ethical biomedical research is motivated by principles set forth in the 

Belmont Report and embodied by the work of the National Commission for 

the Protection of Human Subjects of Biomedical and Behavioral Research 

(the National Commission)—respect for persons, beneficence (and its 

corollary non-maleficence), justice, and democratic deliberation. Additional 

considerations relating to children are outlined in the National Commission’s 

report Research Involving Children and codified in 45 C.F.R. Part 46, Subpart 

D and 21 C.F.R. Part 50, Subpart D. (In this chapter, as in Chapter 2, the 

Bioethics Commission adopts shorthand, referring only to HHS regulations in 

the text, although the discussion encompasses the provisions of Subpart D as 

codified by both HHS and the U.S. Food and Drug Administration (FDA).)

Central to any analysis of pediatric research is the fact that children are 

ethically and legally unable to consent to assume research risks. Respect 

for persons in the context of pediatric research requires that researchers 

obtain both parental permission and meaningful child assent to participate. 

Although meaningful assent (or dissent) is distinct from consent, it nevertheless plays an important role in respecting children as persons. Young children 

differ from the oldest children in their moral development, which affects their 

ability to meaningfully assent (or dissent) to research participation. Children 

who have the ability to provide meaningful assent for participation in MCM 

research without the prospect of direct benefit, and who instead demonstrate 

meaningful dissent, are entitled to have their dissent respected, regardless of 

their parents’ permission. The critical consideration is that assent and dissent 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

49

be meaningful. For example, a toddler, unable to provide meaningful assent, 

who expresses distaste for an injection is not expressing meaningful dissent.

In conjunction with respect for persons, beneficence obligates us to recognize additional duties owed to children as vulnerable persons. As outlined 

in Chapter 2 of this report, beneficence guides the risk-benefit assessment 

in research. Reducing research risk to children to the lowest possible level 

by considering all possible alternatives—one of five considerations offered in 

the Belmont Report—requires that researchers test interventions as extensively 

as possible with computer models, animals, or adults (individuals who can 

legally and ethically consent) in order to better understand and minimize 

research risks before testing interventions with children.112 Beneficence also 

requires that we safeguard the health of children outside the research context, 

which can include providing evidence-based treatments and, in the case of 

public health preparedness, safe preventive and therapeutic interventions, 

including MCMs. Justice, which calls for equitable distribution of research 

burdens, in combination with respect for persons, beneficence, and nonmaleficence, requires that adults take on greater risk so that children bear no 

more risk than necessary.

Together these principles support the ethical conclusion that research with 

children should generally pose no greater than minimal risk to participants unless it offers the prospect of direct benefit (45 C.F.R. § 46.405 

(section 405)) or is likely to generate vitally important knowledge about the 

participants’ condition (45 C.F.R. § 46.406 (section 406)). In the context 

of pre-event pediatric MCM research where neither exception applies, this 

means that all necessary prior testing should be done to identify, understand, 

and characterize the risks in order to conduct research that could be classified 

reasonably as minimal risk (approvable under 45 C.F.R. § 46.404 (section 

404)); posing risks no greater than those of everyday life or a routine medical 

examination whenever possible.

If it is not possible to conduct an informative minimal risk pre-event pediatric 

MCM study, and the research poses no more than a minor increase over 

minimal risk, the proposed research may go forward only after national-level 

review, as set forth in 45 C.F.R. § 46.407 (section 407) and specified later in 

this chapter. Though section 407 allows for the potential approval of research 
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50

posing more than a minor increase over minimal risk in other circumstances, 

the Bioethics Commission determined that this greater level of research risk 

is ethically impermissible in the MCM context. Certain kinds of pediatric 

MCM research seem to meet the standards of “extraordinary circumstances” 

envisioned by the National Commission. Pediatric MCM research requires 

narrower risk limits than might be permitted in other exceptional types of 

pediatric research under section 407, however, because it is distinct from most 

other pediatric research in ethically relevant ways as highlighted in Chapter 

1 of this report and further discussed below.113 Moreover, because children 

have no legally or ethically recognized capacity to consent to assume risks—

and because they are vulnerable individuals who need to be protected from 

undue risks undertaken for the benefit of others—the Bioethics Commission 

considered this approach to pre-event MCM research with children to be fully 

consistent with established ethical principles.

In the context of post-event pediatric MCM research, research risks also must 

be minimized. Yet the ethical considerations differ from pre-event MCM 

research because pediatric research participants likely will have been exposed 

to an agent, meaning that research could yield vital information about 

their condition (section 406), and participants might have already received 

the MCM under investigation as a treatment measure, reducing research 

risks to minimal (section 404) or creating the potential for direct benefit to 

participants (section 405).114 When children receive an untested MCM, it is 

ethically imperative that researchers collect as much data as possible to inform 

and protect both those who have received it and other children who in the 

future might need such treatment in an emergency. Research protocols must 

be in place for rapid deployment, and groundwork for extensive and effective 

community engagement must be prepared. Also of paramount importance, 

exceptional care must be taken to ensure that research protections such as 

fully informed parental permission and meaningful child assent are observed 

to their fullest extent.

Although pediatric MCM research can be conducted either before a bioterrorism event occurs—as a pre-event study—or after a bioterrorism event 

occurs—as a post-event study, pre- and post-event studies present different 

ethical and logistical concerns. In pre-event research, no research participants 

have yet been exposed to the agent, meaning the research will not offer the 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

51

prospect of direct benefit to individual child participants or the prospect of 

valuable knowledge about the participants’ condition. Participants in postevent research have either already been exposed to the agent or have a greater 

likelihood of being exposed in the near future and might have already received 

the MCM under investigation. Post-event research risks, therefore, are generally limited to those involved in the active or passive surveillance of participant 

reactions to the MCM. Because these types of research raise different ethical 

and logistical concerns, pre- and post-event studies are addressed separately 

and in turn. For the purposes of this report, those studies conducted when a 

threat is imminent (i.e., it is predictably coming quickly and there is little time 

for deliberation) are understood to pose ethical and practical concerns that 

track those of a post-event study even if technically conducted pre-event.115

These concerns will be addressed in greater detail below.116

Pre-event Studies

Pre-event pediatric MCM research will generally be conducted with healthy 

children and offer no prospect of direct benefit to participants. Further 

complicating its conduct, pre-event MCM research presents challenging 

ethical characteristics, involving (1) health conditions that might pose considerable danger to children as a class—but danger that could be mitigated by 

exposing a small group of healthy children to research risks; (2) health conditions that no child has yet contracted and that result from events that have 

an unknown and unknowable likelihood of occurrence; and (3) research that 

would produce results that we expect and hope never to use. Given these 

characteristics, pre-event research cannot be considered to offer the prospect 

of direct benefit to research participants, and therefore cannot be approved 

under section 405. Pre-event MCM research also cannot be approved under 

section 406 because the participants do not have a condition about which 

important generalizable knowledge can be obtained. All such pre-event pediatric MCM research therefore must either be approved under section 404, 

which requires that research risks be minimal, or—in exceptional circumstances, as set forth in greater detail below—under section 407. 

To the extent that sufficient testing in adults or animals can demonstrate that 

the risks of pre-event pediatric MCM research could be considered minimal, 

studies should be reviewed and approved under section 404. If it should prove 
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52

impossible to conduct research that can be reasonably classified as minimal 

risk, then the level of allowable risk must be capped at a minor increase over 

minimal risk, and the pre-event pediatric MCM research proposal must 

undergo national-level review. National-level review under section 407 should 

be permitted only in rare circumstances or, as the National Commission put 

it, in “exceptional situations... in which considerable dangers to children or to 

the community at large might be avoided or prevented by exposing children 

to research attended by more than minimal risk.”117

Pre-event Studies Posing No More Than Minimal Risk Approvable under 

Section 404

Whenever possible, informative pre-event pediatric MCM research should 

be designed in a way that children are only exposed to minimal risk. Such 

research would therefore be approvable under section 404.118 Designing 

MCM studies as minimal risk requires a thoughtful and carefully executed 

research plan. Since most bioterrorism events will affect both adults and 

children, thorough testing in adults, who can consent to assume risk on 

behalf of others, must be completed before conducting research with those 

who cannot consent. Prior testing can help identify, understand, and characterize the risks of research. Once these risks are properly understood, to the 

extent it is possible to design and conduct informative minimal risk research 

with the youngest adults (e.g., 18 years of age), it might be possible that the 

same research design—modified in accordance with information obtained 

from prior research—could form the basis of a study that would similarly be 

minimal risk with the oldest children (e.g., 16 and 17 years of age). Moreover, 

adolescents aged 16 and 17 could provide meaningful assent to participation 

which, along with parental permission, would allow the research to proceed. 

Once minimal risk research is conducted with the oldest children, research 

determined to be minimal risk by incorporating any new data from this prior 

research could be conducted with the next youngest group of children. To the 

extent that it is possible to infer minimal risk from research with the previous 

cohort, “age de-escalation,” a process typical of vaccine development trials, 

would continue as a stepwise series of minimal risk protocols through to the 

youngest group of children.119
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53

It is important to recognize that inferring minimal risk does not depend solely 

on whether an intervention is determined to be “safe” in adults. Adverse event 

data, for example, will not definitively determine whether a study meets the 

regulatory “minimal risk” standard. In addition to the risk associated with the 

intervention itself (which is informed by safety information and adverse event 

data), reviewers and researchers must account for the risks associated with 

research procedures as well (e.g., blood draws, if part of the research design).

Moreover, the Bioethics Commission recognized that, as a general matter, 

studying a previously untested therapeutic with children is often categorically classified as more than a minor increase over minimal risk.120 The age 

de-escalation process contemplated here, however, requires researchers to collect 

data and assess risk on the most similar group and infer the level of risk, when 

possible, to the next youngest age group. If minimal risk studies can be done 

with the youngest adults, for example, it might be possible to infer that a similar 

minimal risk study design can be done with the oldest adolescents. 

Not treating all children (i.e., 0 to 17 years of age) as a single group or class 

enables careful and thoughtful inference. Because very young children differ 

physiologically from adults (and even older children) in significant ways, 

extrapolating adult data about risk to all children (0 to 17 years of age) is quite 

difficult and involves a high degree of uncertainty. While initially there might 

be a dearth of relevant pediatric data, under an age de-escalation approach, 

researchers and reviewers might be able to make an empirical finding that the 

research risk is no greater than minimal or a minor increase over minimal 

for the next lower age group. The Bioethics Commission concluded that 

cautious and scientifically sound age de-escalation, beginning with the 

youngest adults and progressing to the oldest children, can yield important 

data that will better inform the degree of risk posed by research.121 Although 

the data obtained through age de-escalation studies might show that the risks 

of research are still too high to justify its conduct, in other cases, the availability of more targeted and relevant data (and consideration of a more limited 

segment of the pediatric population) may permit extrapolation with greater 

certainty in judging the level of risk posed by a given protocol. 

The specific design of age de-escalation trials will vary depending on the 

intervention being tested and its mechanism of action, as determined through 
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54

early clinical trials and thorough testing in adults. Age de-escalation need 

not and should not be based solely on a participant’s age: additional developmental markers can and should be considered. While pediatric drug dosing is 

typically determined by a combination of age and body weight, maturational 

differences in absorption, metabolism, and elimination of drugs make use of 

age and weight alone less than ideal.122 Similarly, pediatric vaccine dosing is 

sometimes determined on the basis of body weight, route of administration, 

and maturation, but MCM research trials should take into account more 

granular physiological factors. Relevant demarcated steps for the process of 

age de-escalation should be clearly defined in the research plan and might 

be based on appropriate biological characteristics such as chronological age 

or stage of development (e.g., post-pubescent, pubescent, pre-pubescent, 

adolescent, school age, early childhood, toddlerhood, and infancy). For 

example, if the mode of action of the intervention might be affected by the 

metabolic, hormonal, immunological, and body composition changes that 

occur at predictable developmental stages of childhood, such as puberty, then 

age de-escalation should be carefully designed to account for these changes 

rather than solely accounting for age by chronological year.

A focus on informed age de-escalation protocols will help to minimize risk 

in most pre-event pediatric MCM research. There are, however, contextual 

limits to the employment of this strategy. Stepwise age de-escalation studies 

are time-intensive, particularly if the aggregated results of initial studies must 

be analyzed for use in designing the trial with the next lower age group and 

if each new trial requires individual IRB approval. In the event that the U.S. 

government receives credible intelligence on the development and planned 

deployment of a particular bioweapon, there might not be adequate time to 

complete sufficiently cautious age de-escalation protocols. The recommended 

use of age de-escalation assumes a situation in which there is no immediate 

threat of deployment. 

Additionally, there are situations in which age de-escalation trials might not be 

appropriate based on the anticipated difference in impact that an agent could 

have on children compared with adults, or on the possibility that an agent 

might be used specifically to target children. Children, along with adults, 

would be affected in generalized bioterrorism attacks, but children could also 

be targeted specifically.123 Certain biohazardous threat agents could have a 
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55

greater impact on children than on adults. A smallpox outbreak, for example, 

likely would affect children disproportionately due to the waning effects of 

herd immunity since the effective eradication of the disease and cessation of 

immunization in the United States in 1972. Children could also be targeted by 

location (e.g., schools) or through the mechanism of delivery, such as targeting 

the milk distribution system. Given that children between the ages of 2 and 11 

years consume approximately twice as much milk as adults, an attack of this 

nature would pose a significant threat to children.124 While many bioterrorism 

agents affect both adults and children, and thus MCMs should be tested 

in adults first, evidence exists that children could be intentionally targeted 

through both method of distribution and specific agents.125

Although the potential targeting of children in a bioterrorism attack stresses 

the importance of conducting pediatric MCM research, such research, even 

when minimal risk, must be ethically sound. For example, ethical preevent pediatric MCM research must assure a developmentally appropriate, 

meaningful assent process for potential child participants, administered in 

conjunction with the process employed to obtain parental permission.126

Fully informed parental permission and meaningful child assent is especially 

important in the case of MCM research. A person independent of the study 

team should monitor consent or oversee the process of obtaining parental 

consent and meaningful child assent even in minimal risk studies. The 

consent monitor should be an independent entity, without conflict of commitment or conflict of interest in conducting the research. 

Ethically sound pre-event pediatric research must also ensure that the costs of 

any resulting harm or injury do not fall on the injured research participants—

even in minimal risk studies. This means that researchers must ensure that 

compensation for injuries arising from MCM research is accessible under the 

Public Readiness and Emergency Preparedness (PREP) Act or through an alternative mechanism. (See Compensation for Research-Related Injury, Chapter 3.) 

Whenever possible, pre-event pediatric trials should employ age de-escalation 

strategies that provide additional protection to the most vulnerable members 

of the group (the youngest children) by beginning with those who are less 

vulnerable (young adults). If prior testing of young adults makes it reasonable 

to infer that such research would be of minimal risk to the oldest children, 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

56

conducting minimal risk research with those in their late teens would allow 

researchers to identify, characterize, and understand research risks before 

moving to younger, more vulnerable, groups of children. In the event that 

age de-escalation is impossible—due to, for example, an inability to extrapolate the rate of adverse events between adults or older children and younger 

children, or insufficient time available for testing—MCM research might 

need to be considered under section 407, provided it is no more than a minor 

increase over minimal risk. (See Pre-event Studies Posing No More Than a 

Minor Increase over Minimal Risk Approvable under Section 407, Chapter 

3.) In all cases, ethical safeguards such as fully informed parental permission, 

meaningful child assent, and treatment or compensation for research-related 

injuries must be provided.

Recommendation 1: Pre-event Pediatric Medical Countermeasure Research 

Risk Limited to Minimal Except under Extraordinary Circumstances 

Pre-event pediatric medical countermeasure testing should be conducted with 

a research design posing only a minimal level of research risk except under 

extraordinary circumstances. If pre-event pediatric medical countermeasure 

research cannot be conducted as a minimal risk study, research that exposes 

children to no more than a minor increase over minimal risk—a level that 

is still very limited and poses no substantial risk to health or well-being—

should proceed to a national-level review under Department of Health and 

Human Services regulations at 45 C.F.R. § 46.407 and/or U.S. Food and 

Drug regulations at 21 C.F.R. § 50.54.

Recommendation 2: Risk in Pre-event Pediatric Medical Countermeasure 

Research

Before beginning pre-event medical countermeasure studies with children, 

ethically sound modeling, testing with animals, and testing with the 

youngest adults must be completed to identify, understand, and characterize 

research risks. If pediatric research is determined to be minimal risk and is 

to be conducted, progressive age de-escalation should be employed whenever 

possible from the oldest age group of children to the youngest group necessary 

to provide additional protection to the youngest and most vulnerable 

children, and to ensure that data from an older age group can inform the 

research design and the estimate of risk level for the next younger age group. 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

57

Application to Trials of AVA with Children: Minimal Risk Pre-event Trials 

of AVA with Children

An AVA trial with children that is approvable under section 404 must present 

no more than minimal risk to participants. Provided that all necessary 

prior testing of AVA has been conducted in adults, and in the event that 

it is possible to conduct an informative minimal risk pre-event trial with 

the youngest adults (i.e., 18 years of age), it might be possible to design and 

conduct minimal risk pre-event research with the oldest cohort of children 

(i.e., 16 and 17 years of age). Moving from AVA trials in the youngest adults 

to the oldest cohort of children only can proceed under section 404 if the 

research is minimal risk in young adults, and the data collected are sufficient 

to conclude that such research could be considered minimal risk in the oldest 

cohort of children.

Available Data

The safety, immunogenicity (the capability of a vaccine to stimulate a specific 

immune response), and dosing of AVA have been evaluated in both animal 

studies and adult human studies. Based on available data, AVA is approved 

by FDA “for the active immunization for the prevention of disease caused 

by Bacillus anthracis, in persons 18 through 65 years of age whose occupation or other activities place them at high risk of exposure.”127 AVA has been 

distributed widely to adults—as of 2001, approximately 2.1 million doses of 

AVA had been distributed to members of the military.128

AVA safety has been evaluated in adults through both active and passive 

surveillance studies, and its safety is comparable to other vaccines regularly 

administered during routine medical appointments.129 Data in adults indicate 

that the mild and moderate adverse events associated with AVA are no worse 

than for other vaccines.130 Although vaccination with AVA results in a higher 

incidence of mild allergic reactions than some other more routine vaccines 

AVA is less allergenic than vaccines that are produced with eggs (e.g., yellow 

fever vaccine).131 Among mild reactions, tenderness (about 1 person out of 2) 

and redness (about 1 out of 7 men and 1 out of 3 women) near the injection 

site are most common.132 Less common are mild reactions such as itching 

(about 1 out of 50 men and 1 out of 20 women), development of a lump 

(about 1 out of 60 men and 1 out of 16 women), or bruising (about 1 out of 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

58

25 men and 1 out of 22 women) at the injection site. Systemic events—such 

as fever, malaise, and myalgia—although associated with receipt of AVA, 

are much less common than injection site reactions, and are similar in both 

rate and type to events observed following receipt of other vaccines that are 

routinely administered.133 Accordingly, it might be possible to conclude that 

the administration of AVA in adults is minimal risk because “the probability 

and magnitude of harm or discomfort anticipated in the research are not 

greater in and of themselves than those ordinarily encountered ... during the 

performance of routine physical ... examinations or tests.”134

AVA’s immunogenicity has also been evaluated in adults, but the immune 

response it elicits is not as well characterized as its safety. While the mechanism of immunogenicity is understood and has been qualitatively observed, 

the quantitative relationship, or the precise level of antibody that confers 

protection against anthrax, is not known.135

Data regarding the efficacy of AVA come from vaccine trials in animals whose 

immune responses are similar to adults, including rhesus monkeys and, to 

a lesser extent, rabbits.136 These studies have shown that AVA is most effective against anthrax when combined with antibiotics and given before the 

onset of clinical illness.137 Antibiotics treat the immediate infection while the 

vaccine provides protection against future infection from the dormant spores 

that remain after the course of antibiotics has been completed. Information 

regarding the efficacy of AVA in adults also comes from one human study, a 

1962 experiment in which mill workers at risk of cutaneous anthrax exposure 

were given an early anthrax vaccine (not AVA).138 The usefulness of this adult 

data is limited because the research addressed cutaneous anthrax rather than 

inhalational anthrax, and the vaccine tested was only a precursor to AVA. 

Observational data in humans also provide evidence of efficacy in adults.139

Application of Available Data

In vaccine development, whenever possible, trials are first conducted with 

adults. Pediatric trials begin only after adult safety, immunogenicity, and 

efficacy (when possible) are determined, and are often conducted using age 

de-escalation.140 The rationale and design of age de-escalation depends on 

the nature of the disease, the target population for the vaccine, and what is 

known about immune response in children. In the context of preventive HIV 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

59

vaccines, a circumstance in which vaccines would ultimately be marketed for 

both adults and children, FDA has stated that the amount and kind of adult 

data that are needed to support initiation of pediatric studies depends upon: 

(i) “the strength of the adult safety and immunogenicity data generated,” (ii) 

“what is known about the investigational vaccine in terms of its relationship 

to well characterized vaccines or novel vectors or production methods,” and 

(iii) “the relationship of documented immune response to protection.”141

Various types of information must still be gathered before pediatric AVA 

trials can proceed. Before moving from adult AVA trials to pediatric trials, 

data characterizing adverse reactions of AVA for persons 18 years of age are 

required. Researchers should begin with a thorough examination of adverse 

event data in the youngest adult AVA recipients before they can infer that 

an AVA trial with the oldest children (e.g., adolescents ages 16 and 17) poses 

a minimal level of risk. Additional dosing studies in the youngest group of 

adults must also be completed. Specifically, studies evaluating the adequacy 

of different dosing strategies in adults are required before pediatric studies 

may be conducted.142 Trials with children should begin only after all adult 

data required by FDA to scientifically and ethically justify pediatric research 

are acquired. The U.S. Centers for Disease Control and Prevention (CDC) 

and the Institute of Medicine also have recommended additional investigation into long-term side effects, alternative dosing methods, and quantitative 

determination of correlates of immunity in animal models.143

Pre-event Studies Posing No More Than a Minor Increase over Minimal 

Risk Approvable under Section 407

There will be instances in which it will be impossible to design minimal risk 

pre-event MCM research. In such cases, national-level review under section 

407 would be required, but should proceed only if researchers can demonstrate that the research poses no more than a minor increase over minimal 

risk to participants. 

A minor increase over minimal risk is only a narrow expansion of minimal 

risk; research at this risk level should not pose any significant threats to a 

child’s health or well-being.144 This risk standard is codified in section 406 

(which governs research with no prospect of direct benefit but that is likely to 

yield generalizable knowledge about the participants’ condition) and, given 
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60

the unique characteristics of pre-event pediatric MCM research discussed 

above and the fact that children cannot consent to participation, the Bioethics 

Commission concluded that this risk standard also should apply and set the 

upper limit to greater than minimal risk pre-event MCM research approvable 

under section 407.145 Pre-event MCM research offers no prospect of direct 

benefit to pediatric participants. Moreover, it is uncertain that anyone, let 

alone any children, will ever benefit from such research because the risk of a 

bioterrorism event that would require the use of any given pediatric MCM 

is thus far no more than speculative. While the Bioethics Commission did 

not rule out the possibility that other sorts of extraordinary circumstances 

might warrant exposing children to slightly more than a minor increase over 

minimal risk in research from which they do not have any reasonable expectations of benefit, the inherent uncertainty of an exposure that would affect 

children in the future strongly favors capping the permissible risk in pre-event 

MCM research at no more than a minor increase over minimal. Further, 

investigators should explore all possible strategies for conducting such research 

in a manner that would involve no more than minimal risk.

A minimal risk research design for pre-event pediatric MCM research might 

be impossible, however, for a variety of reasons. Chief among the potential 

barriers is that inferring risk between groups of children in different developmental stages during the age de-escalation process might prove impossible. 

(See Pre-event Studies Posing No More Than Minimal Risk Approvable under 

Section 404, Chapter 3.) For example, it might be impossible to infer that 

an intervention considered to be minimal risk with pubescent children will 

similarly pose only minimal risk when tested with pre-pubescent children. 

Alternatively, researchers might find that, even with comprehensive adult 

testing, potential research risks should not be considered minimal for pediatric participants due, for example, to the risks inherent in any use of the 

tested product. Other obstacles might arise if the potential MCM is designed 

to counter an agent that specifically targets some aspect of pediatric physiology (making prior testing with adults unethical or uninformative), or if 

there is no time to conduct full age de-escalation.
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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Recommendation 3: Pre-conditions to National-Level Review of Pre-event 

Pediatric Medical Countermeasure Research

Pre-event pediatric medical countermeasure research may proceed to nationallevel review under Department of Health and Human Services regulations at 

45 C.F.R. § 46.407 and/or U.S. Food and Drug Administration regulations 

at 21 C.F.R. § 50.54 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. 

In part because of the inherent uncertainty of a bioterrorism attack, preevent pediatric medical countermeasure research posing greater than a minor 

increase over minimal risk should not be approved under 45 C.F.R. § 46.407 

or 21 C.F.R. § 50.54.

When research meets these two threshold conditions—minimal risk 

research is impossible and the proposed research presents no more than a 

minor increase over minimal risk—the framework specified below provides 

the considerations necessary to approve a pediatric MCM research protocol 

under section 407. While this framework might provide useful guidance for 

other types of 407 review, the Bioethics Commission developed it specifically 

for pre-event pediatric MCM research.The term “407 review” here refers to 

review under both HHS provision 45 C.F.R. § 46.407 and FDA regulation 

21 C.F.R. § 50.54. 

Specifying a Framework

Under section 407, the Secretary of HHS, in consultation with an independent panel of experts, can review and approve pediatric research, including 

investigations with healthy children that involve greater than minimal risk 

and offer no prospect of direct benefit to participants.146 Before approving 

this type of research, however, by regulation, the Secretary must determine 

that the protocol under review meets all of the following conditions required 

under section 407:

1. The research presents a reasonable opportunity to further the understanding, 

prevention, or alleviation of a serious problem affecting the health or welfare 

of children;

2. The research will be conducted in accordance with sound ethical principles; 

and
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62

3. Adequate provisions are made for soliciting the permission of parents or 

guardians and the meaningful assent of children.147

The Bioethics Commission’s recommended framework, structured around 

the three conditions for national-level review, clarifies the circumstances in 

which proposed research presents a “reasonable opportunity” to address a 

“serious problem,” specifies a rigorous set of conditions necessary to determine 

whether the research would be conducted in accordance with “sound ethical 

principles,” and reiterates the importance of informed parental permission and 

meaningful and developmentally appropriate child assent. Decision makers 

should assess proposed pre-event pediatric MCM research that poses more 

than minimal risk using this framework in order to ensure that all the necessary aspects of a study have been evaluated and found ethically permissible 

before moving forward. 

Importantly, only after the Secretary of HHS, with the advice of an independent panel, has found it ethically permissible to proceed would parents be 

asked to decide whether to enroll their children in research. 

1. Does the Research Present a Reasonable Opportunity to Further the 

Understanding, Prevention, or Alleviation of a Serious Problem that Could 

Affect the Health or Welfare of Children?

In order to satisfy the first condition for approval under 407 review, proposed 

research must present “a reasonable opportunity to further the understanding, 

prevention, or alleviation of a serious problem affecting the health or welfare of 

children.”148 To provide more granular guidance, the Bioethics Commission 

specified the type of problem that qualifies as a sufficiently “serious problem” 

and reiterated the importance of identifying a “reasonable opportunity.” 

A. Serious Problem

At the outset of 407 review for pre-event pediatric MCM research that poses 

more than minimal risk, decision makers must confirm that the proposed 

research addresses “a serious problem affecting the health or welfare of 

children.”149 Evaluation of the seriousness of the problem is the first step of a 

407 review because if there is no serious problem or threat of a serious problem 

to address, then enrolling healthy children in greater than minimal risk 

research is clearly unwarranted. This evaluation is conducted independently of 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

63

the merits of any particular protocol. As a matter of beneficence and respect 

for persons, it would be unethical to expose child research participants who 

cannot consent to unnecessary research risks or to any risk if a problem is 

not sufficiently serious. And, when a problem is serious, beneficence calls for 

investments (e.g., through research) to protect children from potential threats. 

In the context of MCMs, a serious problem can be specified along at least 

two dimensions: (1) the consequences of exposure and (2) the likelihood of 

exposure. The panel reviewing a protocol must determine and advise the 

Secretary whether proposed research satisfies both of these criteria.

i. Seriousness Due to Consequences of Exposure

To determine the seriousness of the consequences of exposure, one must 

consider not only the magnitude of harm should an exposure occur, but also 

the vulnerability of children to exposure and the relative adequacy of any 

available therapeutic options or research alternatives.150 In this assessment, 

reviewers should consider the anticipated public health and security responses 

at the federal, state, and local levels and their ability to mitigate the consequences of any exposure, as well as the existence and availability of other 

suitable alternative MCMs. Reviewers should also consider the possibility and 

sufficiency of post-event pediatric research to mitigate both the short- and 

long-term consequences of exposure. 

Taking all of these factors into account, a serious problem is one in which 

the consequences of exposure are life threatening, permanently disabling, 

debilitating, or similarly grave. It is not enough that consequences are simply 

detrimental to the well-being of children; the detriment must be a crucial 

obstacle to the growth and development of children in order to support the 

conduct of research offering no prospect of direct benefit that poses a minor 

increase over minimal risk. Beneficence requires that, if the consequences are 

serious enough, we take measures to ameliorate the welfare of children as a class, 

including those who participate in research and future generations of children. 

ii. Seriousness Due to Likelihood (or Threat) of Exposure

A second dimension of the seriousness of a problem is the likelihood of 

exposure. This dimension adds compelling urgency to the governmental obligation to take steps to reduce or prevent future harms to the public welfare, 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

64

and to the welfare of children more specifically. Fear of exposure, however, is 

not an appropriate measure of its likelihood.

Calculating the precise probability of an attack is impossible (unless an attack 

is known to be imminent, in which case the circumstances are essentially 

similar to those of post-event rather than pre-event research).151 Rather, in 

the face of inevitable uncertainty, those considering the potential for harm 

to children as a class should use the best quantitative and qualitative evidence 

available to inform firmly grounded beliefs that estimate the likelihood 

of future events. This analysis should take into account determinations of 

the threat based on established methods for assessing risk, such as the U.S. 

Department of Homeland Security Material Threat Determination or other 

assessments that inform it. Assessments should also incorporate, to the extent 

possible, considerations of imminence, the physical properties of the agent, the 

plausibility of accessing and producing a chemical or biological agent, the ease 

with which the agent could be deployed, or the possibility that a change in 

formulation or virulence might affect the severity and incidence of exposure.152

Evidence that an attack is relatively likely, as opposed to remote, supports the 

idea that the proposed research addresses a sufficiently serious problem. 

The Bioethics Commission concluded that, as part of 407 review, the 

Secretary should provide reasons that the likelihood of exposure renders the 

problem a serious one. The Secretary’s rationale should be made publicly 

known, even if the determination is based on classified information. For 

example, the Secretary could make an unclassified rationale publicly available 

or provide a classified rationale to authorized representatives of the public 

(e.g., members of Congress). Articulating an explicit rationale helps to ensure 

a rigorous deliberative process and holds decision makers accountable to the 

public. Accountability is particularly important in cases where the threat level 

is classified because this information is often held by small groups of people 

with specific credentials and role-related priorities. 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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iii. Seriousness Due to “Vital Importance”

The Bioethics Commission drew insight in specifying what constitutes a 

serious problem from sections 404 through 406 and, in so doing, adopted 

language from section 406—a section that also regulates research offering no 

prospect of direct benefit to participants and involving more than minimal 

risk. Section 406 allows for research to be approved if the research is likely to 

generate knowledge of “vital importance for the understanding or amelioration of the subjects’ disorder or condition.”153 Although in section 406 the 

knowledge sought can relate to any condition of a research participant, 

section 407 limits research to only that which is likely to yield knowledge 

about a serious problem. In specifying what constitutes a serious problem, 

EXAMPLES OF CIRCUMSTANCES THAT MIGHT PRESENT A SERIOUS PROBLEM

Concrete examples can inform what constitutes a “serious problem.” Current regulations 

were developed in the wake of polio outbreaks, and the National Commission pointed to 

examples such as an impending epidemic in which considerable dangers to children or to 

the community at large might be avoided or prevented by enrolling children in greater than 

minimal risk research. Additional hypothetical examples might include:

1. Large quantities of weaponized sarin gas have gone missing under suspicious 

circumstances. Sarin is estimated to be five hundred times more toxic than cyanide, 

and even non-lethal exposure is likely to have unknown long-term effects on a child’s 

neurological development. A new MCM offers a promising potential intervention, but 

has not yet been tested with children.

2. Smallpox, a disease that no longer occurs naturally, is stolen from a research 

facility. The possibility of exposure poses a threat to the community at large due 

to its infectiousness and high mortality rate; pediatric populations are especially 

vulnerable. Historically, physicians have only been able to treat the symptoms rather 

than combat the virus itself. Scientists have found one new antiviral agent that is 

effective in combating the disease. This new treatment has just been approved for 

use by adults. 

3. Security sources reveal that while certain terrorist cells in unknown locations 

cannot currently deliver a “dirty” bomb—which would entail significant radiological 

exposure—they have both the intent and will to develop delivery capability within five 

years. A new form of therapy has been developed, and it has been tested and found 

safe in adults and older children. No testing on young children has yet been undertaken.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

66

the Bioethics Commission recognized that the ethical standard for 

the information to be gained from 

a protocol approved under section 

407 must also, at the very least, be as 

rigorous as the ethical standard established in section 406, and therefore 

the information to be gained must be 

of vital importance to addressing that 

serious problem as well. 

B. Reasonable Opportunity

In addition to being of vital importance to addressing a serious problem, the 

proposed MCM research must present a “reasonable opportunity” to further 

the understanding, prevention, or alleviation of that serious problem.154

Although various natural and manufactured threats can present a serious 

problem, the gravity of the problem alone is not enough to justify the research 

if the research itself does not present a reasonable opportunity to learn something significant to developing or deploying an MCM. 

To constitute a reasonable opportunity, the proposed protocol must be 

based on the current state of the science and must present an opportunity to 

learn about a specific MCM candidate that might be useful in protecting or 

treating children exposed to a serious threat. Research that can be expected to 

yield knowledge that improves the safety, availability, or feasibility of MCM 

delivery could meet this requirement. If research does not constitute a logical 

step toward ameliorating a serious problem, principles of ethical research—

including beneficence and respect for persons—require that additional risks 

not be imposed on others, particularly those who cannot consent.

2. Will the Research be Conducted in Accordance with Sound Ethical 

Principles?

Drawing on the principles of respect for persons, beneficence, justice, and 

democratic deliberation, the Bioethics Commission proposed a rigorous set of 

ethical conditions that must be employed when assessing whether pre-event 

pediatric MCM research reviewed under section 407 will be conducted in 

“[T]he criterion for judging the potential 

contribution of research must, ethically, 

be as stringent for reviews conducted 

under Section 407 as for those 

conducted under Section 406.”

IOM. (2004). Ethical Conduct of Research Involving 

Children. Washington, DC: The National Academies 

Press, p. 134.
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

67

accordance with “sound ethical principles.”155 These conditions fall into 

five general categories: 1) ethical threshold of acceptable risk and adequate 

protection from harm; 2) ethical research design; 3) post-trial requirements 

to ensure ethical treatment of children and their families; 4) community 

engagement in pre-event research; and 5) transparency and accountability.

A. Ethical Threshold of Acceptable Risk and Adequate Protection 

from Harm

Because children themselves cannot legally or ethically consent to research 

and its attendant risks, the level of research risk to which children can be 

exposed when there is no prospect of direct benefit is strictly limited—typically to the level of “minimal risk.”156 Thus, consistent with the principles of 

beneficence and respect for persons, the level of risk to which the government—and researchers—can ask parents to expose their children is limited 

and small. Although parents may reasonably permit their children to engage 

in certain higher-risk activities (e.g., contact sports), the government lacks 

comparable latitude. When children are at serious threat of future exposure, 

however, there might be reason to 

reluctantly accept testing with a 

small amount more risk if minimal 

risk research is impossible. As argued 

above, pre-event pediatric MCM 

research risk should always be limited 

to no greater than a minor increase 

over minimal risk. 

Although the level of risk permitted under section 407 is not specified or 

limited by regulation, the distinct characteristics of pre-event pediatric MCM 

research warrant strict risk limits. In particular, because this research offers 

no prospect of direct benefit and the likelihood of an exposure in which the 

research results would be required is unknown and unknowable, children 

involved in pre-event MCM research must be protected by keeping research 

risks both limited and small.

It is generally accepted that children should be protected from harm, and, in the 

context of pediatric research, limiting the research risk to which children may be 

exposed is one means of ensuring such protection. Under the current regulatory 

“[T]he question is to what extent we, as a 

society, think it’s appropriate to put that 

decision in front of a parent... .”

Nelson, S., Senior Pediatric Ethicist and Lead 

Medical Officer, Office of Pediatric Therapeutics, 

Office of the Commissioner, FDA. (2012). 

Presentation to the Presidential Commission for the 

Study of Bioethical Issues, May 17. Retrieved from 

http://bioethics.gov/cms/node/708.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

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framework, research protections can be summarized as adequately protecting 

children from harm in light of the expected results of the research—that is, 

whether the research is of possible direct benefit to individual participants, of 

potential benefit to an identifiable class of children with a disorder or condition, 

or of potential benefit to all children as a class. 

In the case of pre-event pediatric MCM research, there is no prospect of 

direct benefit to individual participants or benefit to an identifiable class 

of children because the likelihood of an attack is speculative. Rarely does a 

bioterrorism agent exist naturally in a weaponized form or in the quantity or 

virulence necessary to cause the breadth of harm expected during an attack. 

Given the particularly remote possibility that results of pre-event pediatric 

MCM research will be put to use—more so than in other types of research 

approved under section 407—and the legal and ethical incapacity of children 

to consent, when it is impossible to design a minimal risk pre-event pediatric MCM research trial, the only ethically tolerable level of risk is a minor 

increase over minimal risk. 

This “minor increase over minimal risk” threshold has been described by the 

National Commission as a narrow expansion over minimal risk, entailing “no 

significant threat to the child’s health or well-being.”157 Assessment of research 

risk should take into account the probability, magnitude, duration, and reversibility of harm.158 Risks include both potential harms from the intervention 

itself as well as those that might occur as a result of the procedures associated 

with the research. Reviewers should also take into account commonly used 

assessments of what constitutes minimal risk or a minor increase over minimal 

risk in making their determination. The level of permissible risk to which 

children may be exposed under specified circumstances includes, for example, 

risks of conditions such as redness or moderate soreness at the injection site 

(both minimal risk), or missing a few days of school due to temporary low 

fever or malaise (minor increase over minimal risk), or procedures such as 

drawing blood (minimal risk) or a skin biopsy or chest X-ray (minor increase 

over minimal risk). Procedures that entail a significant likelihood of greater 

risks than these (such as lumbar puncture or bronchoscopy) are not acceptable 

within the context of pre-event pediatric MCM research. 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

69

Risk assessment is necessarily based on empirical data, but risks cannot be 

measured directly. Judgments about risk may be based on adult human data, 

animal studies, or pediatric use of the product for different indications. If 

there are insufficient data from these sources to support the conclusion that 

the intervention poses no more than a minor increase over minimal risk 

to child research participants, more data should be obtained. Where the 

data are inconclusive or no additional data can be obtained, the remaining 

conclusion must be that the risk is more than a minor increase over minimal, 

and the research should not go forward. The assessment must be based on 

data in each case, and although empirical certainty in such matters is impossible, decision makers must strive to make the best judgment possible based 

on the available data.

B. Ethical Research Design

Pre-event pediatric MCM research should be designed and conducted under 

conditions of the greatest scientific and ethical rigor. Determining whether 

research is ethical includes evaluating the scientific necessity of the proposed 

trials, the design of the research plan, the adequacy of available data from 

prior testing conducted in adults, the benefit of the proposed study over alternatives, and the fairness of subject selection.

i. Scientific Necessity

Research with children is a matter of scientific necessity if the important 

research question cannot be answered without an ethically permissible study 

involving children. Pre-event pediatric MCM research reviewed under section 

407 should be conducted only if it poses no more than a minor increase over 

minimal risk and it is necessary to include children in order to learn how to 

protect children as a subgroup during a bioterrorism attack.159 As a matter 

of respect for persons, safeguards must be provided to ensure that children, 

as members of a vulnerable population, are not exploited through participation in unnecessary research, the results of which could be obtained by other 

means. This determination should be made using a careful, systematic evaluation of all information, including possible alternatives.160
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ii. Research Plan

To be ethical, human subjects research in general—including pediatric MCM 

research—should be both scientifically valuable and valid, and conducted 

in accordance with an ethical research plan. The research plan is a broad, 

high-level overview of the research, which can encompass multiple studies 

that collectively inform the overarching research question. In the context of 

pediatric MCM research assessed under section 407, an ethical research plan 

and each experiment contained therein must be scientifically valid, minimize 

risks to child research participants by, for example, conducting small trials 

using age de-escalation, implement appropriate monitoring, and properly plan 

for later research—all while maintaining a level of risk that is no more than a 

minor increase over minimal. Taken together, these considerations contribute 

to upholding and honoring the principles of beneficence and respect for 

persons by minimizing and managing foreseeable risks to research participants, quickly identifying and ameliorating the consequences of unforeseen 

risks, and maximizing the potential benefits by incorporating plans to acquire 

additional data.

Scientific Validity. Scientific validity is required for ethical human subjects 

research. In pediatric MCM research, each study should be well designed to 

answer a specific question of importance to the protection of children; studies 

should be adequately powered, rigorous in data collection, and feasible.161

The research plan should be peer-reviewed and approved as scientifically valid 

before moving forward with participant recruitment.

Small Trials and Age De-escalation. An ethical research plan ought to minimize 

the number of children exposed to research risks while maintaining a large 

enough group to satisfy the requirements of scientific validity. Testing an 

appropriate MCM dosage in pediatric populations should take place only 

after adult trials have been completed to determine dosing, safety, and—for 

vaccines—immunogenicity. Following adult trials, an ethical research plan 

will usually start with a very small pediatric trial with the fewest number of 

children necessary in the oldest age group (typically 10 to 20 participants) to 

evaluate the safety of the most promising dose and route of administration, 

based on adult information before expanding to later-stage studies that might 

involve many more participants.162 Larger-scale trials conducted to identify 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

71

rare adverse events from MCM interventions would not be ethically justified in a pre-event setting. However, adverse event data must be collected in 

a post-event study, closely monitoring any adverse events after an MCM is 

deployed. (See Post-event Studies, Chapter 3.) 

When appropriate, ethical MCM research with pediatric populations should 

also incorporate age de-escalation, a process by which MCMs that have 

been deemed safe in adults are tested first with older pediatric populations, 

followed by successively younger children in multiple steps, based on development-specific characteristics, as the risks are classified and minimized.163

When age de-escalation is used, trials with each new age range are informed 

by the results of the earlier trials so that trends observed in dosage (e.g., per 

body weight) or adverse events in each age group are used to determine how 

to alter the experimental design to maximize safety for the next group of 

participants. Inferring risks from young adults to older children is discussed 

in greater detail above. (See Pre-event Studies Posing No More Than Minimal 

Risk Approvable under Section 404, Chapter 3.) 

Appropriate Monitoring. Minimizing risks to participants—as required by 

beneficence, non-maleficence, and respect for persons—can be accomplished, in part, through appropriate monitoring. The safety of participants 

in certain studies should be monitored through a data safety monitoring 

board, an independent group of experts tasked with monitoring study data 

and participant safety while the research is underway. In addition, the use of 

a medical monitor—a pediatrician (or team of pediatricians) independent of 

the research team who monitors trial participants—should be included in the 

study design to monitor participants. Monitoring should include extensive 

patient follow-up, particularly when experimental interventions could carry 

lasting effects that might otherwise escape detection. Because pediatric MCM 

research reviewed under section 407 exposes children who cannot consent 

to a minor increase over minimal risk, rigorous safety monitoring—with a 

medical monitor and a data safety monitoring board—is necessary.

Proper Planning for Post-event Research. In the context of research responsive 

to the threat of a bioterrorism attack, ethical research planning must also 

include appropriate plans for post-event testing, either through a post-event 

research arm (when pre-event testing is ethically appropriate) or through a 
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separate post-event study proposal. To plan adequately for post-event research, 

pre-event approval and plans for post-event access to funding and expertise 

should be in place. (See Post-event Studies, Chapter 3.) 

iii. Prior Adult Testing to Minimize Risk to Children

To minimize risks to potential research participants in pre-event pediatric 

MCM research, any proposed intervention should, to the extent possible, be 

thoroughly tested and found acceptably safe in adults with regard to the same 

issues that would be studied with children. Information learned from prior 

testing with adults—along with information from computer models, animal 

models, and prior comparable MCMs—can help identify proper dosing for 

initial testing in pediatric populations and characterize the risk level such 

research might impose. The condition of prior testing with adults is a matter 

both of non-maleficience—that is, not imposing unnecessary risks on more 

vulnerable individuals—and of respect for persons—which calls upon testing 

those who can consent before turning to more vulnerable populations who 

cannot. This condition applies to the extent that research with adults can 

be conducted ethically. Prior testing of an intervention with adult populations might not be possible or ethical if, for example, the intervention is only 

clinically indicated for children, is expected to cause serious adverse events in 

adults but not in children, or is otherwise not appropriate for use in adults.164

Requiring that any proposed intervention be tested in advance with adults 

when appropriate helps to ensure that child research participants who enter 

into adulthood before the tested MCM is needed will have access to an adult 

formulation of the intervention if ever necessary. 

iv. Sufficient Benefit over Alternatives

In the context of 407 review, a proposed pediatric MCM study must be 

expected to generate knowledge that would confer a sufficiently greater overall 

benefit to children as a class than would the most beneficial alternative, if any, 

that does not impose greater than minimal risk without the prospect of direct 

benefit.165 Assessing comparators is required as a matter of beneficence, which 

dictates that we strive to minimize risks while maximizing benefits in the 

present and the future. Pre-event MCM research assessed under section 407 

is only justified by beneficence if it imposes less risk of harming participants 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

73

than alternatives, including risks of other pre- and post-event research or 

current preparedness contingency plans for children.

Determining an appropriate comparator requires assessing various scenarios, 

such as the use of alternative existing therapies that have already been tested 

with children; administration of therapies that have not been tested with 

children, but are approved for use by adults; or even the prospect of a nextgeneration intervention not yet approved or in advanced development, but 

likely to be authorized at the time such an intervention might be necessary.166

v. Fair Subject Selection

Fair subject selection is a necessary condition of ethical research, and is a 

particularly important safeguard in the context of pediatric research because 

all children are vulnerable. The principles of beneficence and justice require 

that the selection of research participants is fair, minimizes risks to and 

enhances benefits for individual participants, and fairly distributes research 

risks and benefits more broadly.167 Rather than selecting subjects on the basis 

of vulnerability, privilege, or convenience, fair subject selection requires that 

a study’s particular research goals be the primary basis for determining who 

should be enrolled in research.168

In considering potential pediatric research participants for pre-event MCM 

research, the question becomes which members of this vulnerable class should 

be selected for inclusion. Certain standards provide guidance. For example, 

we should not include children who are burdened with multi-faceted vulnerabilities, such as those who are “institutionalized, cognitively or physically 

disabled, or wards of the state.”169

Children enrolled as research participants should be at least as likely to benefit 

from the results of the proposed study as children who are not participating in 

research. Determining appropriate populations to accord with this standard 

is context dependent and should include considerations such as geography, 

parents’ occupation, or other risk factors. Certain populations—for example, 

children living in urban centers—might be at greater risk of future exposure 

because they live near targets of bioterrorism and therefore might be more 

likely to benefit from the results of pediatric MCM research in the event of 

an exposure. In selecting sites for clinical trials, researchers should consider 
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locations in which participants are likely to be at elevated risk of exposure to 

the agent under investigation. Selection of particular sites could increase the 

chances that research participants would be among those likely to benefit 

from an intervention should an attack occur.170 Other populations—including 

first responders who advocate that their families be among the first to receive 

MCMs in an emergency—might have a greater potential to benefit from 

pediatric MCM research as well.171

Additionally, in research that is particularly complex, and in which children 

are expected to take on more than minimal risk for no prospect of direct 

benefit, researchers should seek to enroll research participants who are best 

equipped to understand the consequences of participation. Enrolling children 

of parents who are particularly well informed about the purpose and limits 

of pediatric MCM research, for example, could mitigate some of the heightened concerns about such research. This might include children of MCM 

researchers, policy makers, and subject matter experts. 

Some have also suggested that another group—families of military 

personnel—might be particularly well informed in situations where military 

personnel have already received the MCM being studied.172 Other factors, 

however, caution against selective enrollment of children of military personnel 

in pediatric MCM research. Military personnel work in environments with 

clear chains of command, and so might interpret encouragement to enroll 

their children in research as a tacit manifestation of duty. Military parents, 

their children, or both, might feel inappropriate pressure to participate given 

the hierarchical social structures that they inhabit. Further, while service 

members have volunteered to be exposed to higher risks than most civilians, 

their children have not. This is not to say that children of military personnel 

should be ineligible to enroll in pediatric MCM studies, just that they should 

not be singled out for participation, and it should be clear that there are no 

positive or negative repercussions in deciding whether to enroll one’s child. 

C. Post-trial Requirements to Ensure Ethical Treatment of Children and 

Their Families

Justice, which requires that the benefits and burdens of research be equitably 

distributed, gives rise to certain post-trial obligations to ensure that participants in pre-event pediatric MCM research reviewed under section 407 are 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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not disproportionately burdened as a result of their participation in research. 

First, there should be an adequate plan in place to equitably distribute interventions shown to be successful through research to all exposed children in 

the event they are needed. Second, compensation and care should be guaranteed for any child who incurs a research-related injury during participation in 

a pediatric MCM trial.

i. Distribution Protocol for All Children Tested or Assured 

Pre-event pediatric MCM research is conducted to ensure that, in the event 

of an attack, children have access to the benefit and protection of tested 

MCMs at appropriate dosages. Accordingly, children who participate in pediatric MCM research assume the risks of research that promises no prospect 

of direct benefit, but that might benefit all children as a class in the future. 

Given its ethical grounding in the potential for future benefit, pediatric MCM 

research cannot be justified unless the presumed benefit to children as a class 

is assured—that is, a documented plan must be in place for the wide and 

equitable distribution of the intervention (should research support its use) 

to children that need it in the event of an attack.173 Moreover, in order to 

respect those who agree to participate in pediatric research and to create a just 

distribution of benefits and burdens, those who participate must have access to 

the potential benefits of that research when appropriate. The assurance of an 

equitable and just distribution protocol guarantees delivery of the intervention 

to children in need, including any that participated in pre-event research.

In developing a plan that equitably and adequately accounts for the interests 

of research participants and future children, researchers and government 

officials should use successful extant distribution plans for existing MCMs as 

models to distribute the experimental intervention in the event of an emergency. To the extent possible, this plan should be proven and should include 

provision for adequate quantities of MCMs.174

Children who participate in research also should not be disadvantaged by 

such participation beyond the imposition of research risks. To the extent 

possible, the research protocol should ensure that research participants are not 

disadvantaged in an emergency situation as a result of their participation in 

pediatric MCM research. For instance, participation in a pediatric MCM trial 

for an experimental vaccine should not preclude a child from receiving the 
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eventual approved vaccine in the event of an attack, even if the vaccine supply 

is low, due to the assumption that the child might have residual immunity 

from their participation in the earlier research. Research participants should 

have the same access to the vaccine as other children who have been exposed 

to an agent; otherwise, participants would be penalized for volunteering to 

participate in the MCM research.

ii. Compensation for Research-Related Injury

Justice requires that children who participate in pediatric MCM research, 

which primarily aims to benefit other children and society more broadly, be 

treated or compensated for research-related injuries so that they do not bear a 

disproportionate share of the burdens of research. In addition, the principles of 

beneficence and respect for persons require that risks to participants be minimized; in this context, such risks include additional medical or financial harm 

resulting from research-related injuries. These ethical principles warranting 

treatment or compensation are particularly acute in the case of research-related 

injuries stemming from pre-event pediatric MCM research that is greater 

than minimal risk—children, who cannot legally or ethically consent to the 

research, are bearing greater risk than ordinarily permitted in order to potentially benefit future children in the event of a bioterrorism attack.175

The argument that compensation for research-related injuries is not required 

because participants willingly accept the risk lacks force in the case of pediatric 

research.176 Pediatric research participants are unable to provide valid informed 

consent, and therefore cannot fully accept the risks of research in the same way 

that adult research participants might. This fact weakens the argument that 

children enrolled in pre-event MCM research have waived any claim to care or 

compensation for research-related injuries by agreeing to participate. 

Before approving pre-event pediatric MCM research under section 407, 

reviewers must ensure that researchers have assured that a plan is in place 

to treat or compensate injured pediatric research participants. The strong 

ethical obligation to provide care or compensation for injuries resulting from 

participation in pre-event MCM research entails providing injured research 

participants with needed medical care, including any available medications or 

interventions. Monetary compensation might also be necessary in the event of 

severe or long-term injury. 
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Although the likelihood of severe or long-term injury from pre-event MCM 

research is, under this framework, extremely low—particularly from interventions that have already been found safe in adults—the very assurance of 

compensation is both ethically and practically important.177 (See Threshold of 

Acceptable Risk and Adequate Protection from Harm, Chapter 3.) It is important to note that compensation for research-related injuries, as discussed here, 

does not extend to incentives to participate in research. In pre-event pediatric 

MCM research, monetary reimbursement for costs outside of research-related 

injuries should be limited to reimbursement for participation costs, such as 

transportation and parking.

The Bioethics Commission reaffirmed its previous conclusion, noted in Moral 

Science: Protecting Participants in Human Subjects Research, that “subjects 

harmed in the course of human subjects research ought not individually bear 

the costs of care required to treat qualified harms resulting directly from that 

research.”178 Particularly because of their vulnerable nature, children who 

enroll in pre-event pediatric MCM research, and become injured as a result 

of their participation, should be guaranteed all necessary medical care and 

appropriate compensation for such injuries.

Because this type of research is exceptional (and rare), the cost of compensation for research-related injuries is expected to be limited and would likely 

not require any major new federal infrastructure. As articulated in Moral 

Science, there is currently no overarching federal policy to ensure that injured 

research participants receive treatment or compensation.179 However, there are 

some existing targeted federal programs, such as the National Vaccine Injury 

Compensation Program (NVICP) and the Covered Countermeasure Process 

Fund established by the PREP Act.180

NVICP is the primary mechanism through which those injured by vaccines 

receive compensation in the United States. In the context of most MCMs, the 

NVICP is inadequate because the program only provides compensation for 

injuries resulting from vaccines listed in the Vaccine Injury Table or recommended by CDC for routine administration.181 Most vaccines used as MCMs 

are not listed on the Vaccine Injury Table. Accordingly, injuries caused by these 

MCMs would not be eligible for compensation under the NVICP. Moreover, 

not all MCMs are vaccines; MCMs can be any FDA-regulated product intended 
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78

to treat or prevent harm (or diagnose a condition) from the effects of chemical, 

biological, radiological, or nuclear attacks.

Children injured as a result of participating in MCM research will, however, 

have access to, but may be insufficiently protected by, the PREP Act. The 

PREP Act—passed to limit the liability of manufacturers, distributors, and 

others who develop, prescribe, administer, test, or dispense a countermeasure—provides limited access to compensation for those injured as a result of 

receiving an MCM.182 Individuals injured as a result of receiving an MCM 

can seek compensation through the “Covered Countermeasure Process 

Fund,” a pool of funds that comes into existence once the Secretary of HHS 

declares an emergency.183 The PREP Act permits those who suffer “serious 

physical injury or death” to recover from the fund; those who suffer more 

minor injuries will be ineligible for compensation.184 The PREP Act also 

establishes a statute of limitations of one year; injuries that manifest more 

than one year after administration are not entitled to compensation.185 The 

Covered Countermeasure Process Fund is funded through congressional 

appropriations; it is unclear, however, whether Congress has ever appropriated 

funds.186 As of December 2009, 24 letters of intent requesting benefits had 

been submitted under the PREP Act.187 It is anticipated that any claims would 

be paid out of emergency appropriations.188

Regardless of whether researchers rely on an established government 

mechanism, a system particular to the research funder, or a plan specific to a 

research site, they must ensure that a treatment and compensation plan is in 

place for any particular proposed study. The costs of any resulting harm or 

injury—whether or not it is severe—should not fall on child research participants or their families.

D. Community Engagement in Pre-event Research

The principle of democratic deliberation endorses respectful and inclusive 

collaborative decision making—a process that includes community engagement.189 In the context of pre-event pediatric MCM research, engaging the 

community serves multiple ethical goals. The aims of community engagement 

include educating the public about the proposed research, providing relevant 

communities with opportunities to educate researchers about communityspecific concerns, and encouraging community members to take advantage 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

79

of research products should the need arise. Community engagement helps 

build transparent, meaningful, collaborative, and mutually beneficial relationships among those considering or conducting research and the relevant 

communities.190 Moreover, it helps to ensure that research is a joint enterprise, 

influenced by all relevant stakeholders, and that research is not directed solely 

by those who have a financial or professional interest in the results. 

The process of community engagement is the responsibility of researchers, 

and should involve the public at every stage of research; address concerns and 

prevent unnecessary misgivings about the research; and strive to preempt any 

potential underuse of MCMs by the community in which they are tested. 

In the case of pre-event pediatric MCM research, community engagement is 

particularly important to address misgivings or mistrust because individual 

children within the community are exposed to risk for the potential benefit 

of other children in the community and the broader population. Community 

engagement in post-event research is discussed in greater detail below.191

In order for community engagement to be successful, researchers must identify 

key stakeholders.192 Stakeholders are individuals or groups who can influence 

or who are “affected by the conduct or outcome” of a biomedical research 

trial.193 Examples of potential stakeholders in pediatric MCM research are 

illustrated in Figure 3.1. In the context of pediatric MCM research, relevant 

communities might be geographic—such as urban populations at potentially 

higher risk of a bioterrorism attack—or affiliated by special interests—such 

as first responders whose families might be the first to access MCMs in the 

event of an attack. 

Once key stakeholders have been identified, researchers should engage 

them early and cooperate with them throughout the entire lifecycle of preevent pediatric MCM research, from conceptualization through protocol 

development, execution, and communication of research results. Engaging 

marginalized communities along with the general public and other relevant 

stakeholders in the planning and conduct of this research will help to ensure 

ethical study design, implementation, and access to benefits should the need 

arise. The guidelines set forth in the Joint United Nations Programme on 

HIV/AIDS and the AVAC Good Participatory Practice Guidelines provide a 

useful framework for engaging relevant communities that might serve as a 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

80

Media

Opinion

leaders

Religious 

leaders

Community 

members

Communitybased 

organizations

First 

responders

Advocates 

and 

activists

Service 

providers

Nongovernmental 

organizations

Government 

bodies

National 

and local 

healthcare 

authorities

Researchers, 

funding agencies, 

and regulatory 

bodies

Trial 

implementers

Trial 

sponsors

Trial 

funders

Prospective 

trial 

participants

Pediatric MCM Trial

Trial 

participants 

and their 

families

Figure 3.1 Potential Stakeholders to Engage in Pediatric MCM Research

Adapted from: MacQueen, K.M., et al. (2012). Stakeholder Engagement Toolkit for HIV Prevention Trials. Washington, DC: 

FHI360, p. ix. Retrieved from http://www.fhi360.org/sites/default/files/media/documents/Stakeholder EngagementToolkit 

for HIV Prevention Trials.pdf; Joint United Nations Program on HIV/AIDS. (2011). Good Participatory Practices: Guidelines 

for Biomedical HIV Prevention Trials 2011, Second Edition, p.14. Retrieved from http://www.unaids.org/en/media/unaids/

contentassets/documents/unaidspublication/2011/JC1853_GPP_Guidelines_2011_en.pdf
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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model in this context.194 Alternatively, researchers might adopt the community advisory board model employed by the Framingham Heart Study or 

the HIV Vaccine Trials Network, which provides a forum for community 

member and research participant insight and input.195

E. Transparency and Accountability

The review, approval, and conduct of pre-event pediatric MCM research that 

poses more than minimal risk should be transparent in order to enhance public 

accountability. As the Bioethics Commission recognized in Moral Science, 

“[i]nsufficient access to research information allows studies and results to be 

hidden and can result in injuries to human subjects, wasted resources, and 

unethical exposure to unnecessary risk.”196 In keeping with the principles of 

democratic deliberation and beneficence, pre-event research that presents a 

minor increase over minimal risk and no prospect for direct benefit that is 

reviewed under section 407 should not be hidden from public view; rather, 

because it is fundamentally designed to benefit the public in the event of 

an unpredictable bioterrorism attack, and not to benefit directly the child 

participants, the Secretary should take special care to engage in robust and 

clear communications about pre-event pediatric MCM research projects. This 

research, which is conducted for the public good, should engage the public and 

remain transparent and accountable to them throughout the life of the project.

The Secretary should first ensure—as required by section 407—that there is 

adequate “opportunity for public review and comment” during the nationallevel review process, including the evaluation and communication of all 

anticipated risks and benefits that might be incurred in a proposed study. In 

making a decision to approve research, the Secretary should not rely solely 

on the advice of scientists, who might be predisposed to favor research, but 

should also consider the opinion of lay people, both as members of the 407 

panel and as members of the public. 

To achieve the goals of transparency and accountability, it is important to 

bear in mind that the appropriate composition of national-level review panels 

convened under section 407 will in itself provide a significantly influential 

means of community engagement and public accountability. By including 

several members of the public who do not harbor any specific bias, it is 

possible to reduce the likelihood that such panels might be compromised by 
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individuals who have conflicts of commitment or conflicts of interest, which 

include those financial, fiduciary, and other affiliations that might compromise 

the objectivity of, or public confidence in, the deliberative process. To avoid 

marginalizing community views, it is important that these panels include more 

than one community member and also recognize that not only the community 

members are expected to advocate for the interests of both research participants 

and the public good that is served by research.197 All review panel members 

should be selected based on expertise and experience, which lends them independence—that is, a lack of vested interest in skewing the deliberations either 

toward or away from approval of a particular research protocol.

Moreover, after making a determination, the Secretary should publicly 

communicate the ethical rationale for approving or rejecting any pre-event 

pediatric MCM research proposal. Before proceeding with testing, the 

Secretary must provide clear communication of expected risks and benefits 

of the research. In addition, equally clear reasons must be publicly stated that 

justify the government ethically seeking the informed permission of parents 

and the meaningful assent of children to participate in this research. 

Finally, throughout the study, the Secretary should provide periodic updates 

to and communication with the stakeholder communities and the U.S. 

public. (See Community Engagement in Pre-event Research, Chapter 3.) At 

the conclusion of the study, the study’s findings should be made available to 

the public. Those community members who belong to a community directly 

affected by the research trial should be kept abreast of research results and 

have the opportunity to benefit from the understanding gained through 

participation and engagement with the researchers throughout the process. 

* * *

All of these rigorous conditions are necessary to ensure that research approved 

under section 407 is conducted in accordance with “sound ethical principles.” 

These conditions, while necessary, are not sufficient. Informed parental 

permission and meaningful child assent also remain critical. 

3. Are Adequate Provisions Made for Soliciting the Permission of Parents or 

Guardians and the Meaningful Assent of Children?
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The third condition of section 407 requires that “adequate provisions are 

made for soliciting the assent of children and the permission of their parents 

or guardians.”198 Informed consent (or its moral equivalent) is a fundamental 

protection for research participants. Respect for persons requires that individuals be given the opportunity to make a voluntary, informed decision to 

participate in research to the extent they are able.199 Although children are 

not legally competent to give consent, whatever level of partial autonomy they 

have must be respected and they must be given the “opportunity to choose 

to the extent they are able, whether or not to participate in research.”200

Researchers must not equate parental permission and child assent with the 

legal consent of adults.201 Only competent adults have the legal authority to 

consent to participate in research or, in the context of research with children, 

to provide permission for their children to participate.202

An informed decision to permit one’s child to participate in research requires 

that parents understand specific information, including the purpose of 

the research, any risks and anticipated benefits, and alternative available 

protocols. Both parents and children should be given an opportunity to ask 

questions and should be informed that they may withdraw from the study 

at any time.203 Additionally, research participants and their parents must be 

informed of the extent to which confidentiality can be expected and should 

receive an explanation of the system in place to treat and provide compensation for any research-related injury or harm.204

Pediatric MCM research introduces additional layers of complexity to the 

informed consent process. Typical concerns about the quality of informed 

consent are magnified both by the fact that pediatric participants are not 

competent to consent, and by the heightened risks and uncertainties involved 

in MCM research. Researchers and persons independent of the research team 

whose responsibility it is to conduct the informed consent process for research 

studies must communicate these aspects of research to child participants in a 

developmentally appropriate manner. 

Meaningful Assent. By definition, pediatric research involves participants who 

are legally and ethically unable to give valid consent due to their age; but where 

meaningful assent (or dissent) can be obtained, researchers should strive to 

include children in the decision making process. Although parental permission 
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is necessary for pediatric research, respect for persons requires that children, to 

the extent that they are able, also have the opportunity to express developmentally appropriate and meaningful assent (or dissent) to participation.205 Such 

assent does not have the ethical or legal standing of informed consent, but 

nevertheless acknowledges that children are developing the capacity to make 

autonomous decisions. The capacity of children to understand and meaningfully participate in research will vary widely with age and individual maturity. 

For example, some teenagers approaching the legal age of consent might be 

able to provide assent that approaches the ethical equivalent of adult consent.206

On the other end of the spectrum, researchers should not interpret the cries 

of an infant as an instance of meaningful dissent, even though a parent might 

reasonably see her child’s distress as a reason to postpone participation or even 

to withdraw from the study. Ultimately, it falls to the informed judgment of 

parents as to whether to provide permission, but ethical research will include 

children in the process in a developmentally appropriate way.

It is essential that these differences in children’s capacity for decision making 

be taken into account through the assent process. The purpose of seeking 

meaningful assent differs from that of seeking consent. Seeking meaningful child assent or dissent is an additional way of demonstrating respect 

for children as persons and enhances the open communication efforts of 

the research team.207 In addition, obtaining child assent reflects children’s 

capacity (albeit limited) for self-determination and helps to foster the developing autonomy of children. Combined with parental permission (or denial 

of permission), meaningful assent (or dissent) can provide a substantive 

instance of the joint decision making characteristic of families.208 However, 

those evaluating a protocol also should ensure that assent procedures take into 

account empirical data reflecting differing views within families about the 

proper way to engage in shared decision making and should accommodate the 

possibility that including children in decision making can sometimes increase 

their levels of distress.209

Importantly, given the complexities involved in obtaining assent, meaningful 

assent cannot be assumed if the child fails to respond when asked. In addition, 

and consistent with current best practices, a child who meaningfully dissents, 

or does not agree to participate, should not participate. Parental permission 

cannot override a child’s sustained meaningful dissent.210
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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Practical Concerns. In order for parents and children to make a properly 

informed decision about whether to participate, the enrollment process must 

include educational materials that are appropriate for adults and children of 

various ages to ensure that both groups adequately understand the research. 

Materials should seek, for example, to inform potential pediatric participants 

about the study from the perspective of a child participant.211 Not only should 

the materials provided be developmentally appropriate, but the process of 

seeking parental permission and meaningful child assent in pre-event pediatric MCM research should be conducted by an independent person with 

expertise in developmentally appropriate child assent procedures. While an 

assent monitor is advisable in minimal risk pediatric MCM research, the 

employment of an independent person to obtain consent is imperative in pediatric MCM research that involves greater than minimal risk and no prospect 

of direct benefit. (See Pre-event Studies Posing No More Than Minimal Risk 

Approvable under Section 404, Chapter 3.)

To enable informed decision making, informational materials in the pediatric 

MCM context must both educate and communicate different and complex 

concepts that might not be communicated in typical biomedical research, 

including information about national security needs, the potentially unknown 

nature of the threat of an attack, and the public health requirements for the 

MCM under investigation. Particular attention must be paid to the perception of risks—both the inherent research risk borne by the participants, and 

the larger societal risk of a future attack necessitating the MCM research—

and the entire process must be conducted in a way that ensures that there is 

not an illusory perception of a prospect of direct benefit on the part of either 

parents or children. 

Reviewers are responsible for ensuring that researchers adequately describe and 

convey risk to those participating in a study. Given the complexity inherent in 

most MCM research, one means of ensuring that all the relevant information 

is clearly conveyed could be to present a video about the research to the 

participants and their parents, followed by an opportunity to ask questions.212

Research indicates that children demonstrate better understanding of study 

procedures and possible risks—and in some cases adults demonstrate better 

overall comprehension—when information is delivered in a multimedia 

format compared to the traditional written format.213 Methods of conveying 
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protocol information should take into account the various ways individuals 

assimilate knowledge. Videos and investigators who explain the protocol 

should be drawn from diverse backgrounds and should look and sound 

like Americans from all parts of the country.214 The independent person 

obtaining consent must be certain that parents and children understand 

that there will be no direct therapeutic benefit to a child participating in a 

pre-event MCM study. As appropriate, this person should ensure parent and 

participant comprehension by asking parents and children to demonstrate 

their understanding of these complex issues prior to enrollment in a study 

through simple and standardized assessments of understanding.

Various motivations affect the decision of parents to provide permission 

and children to provide meaningful assent. Motivations can include ethically reasonable influences such as altruism, developing a certain attitude in 

one’s children, or even the desire to protect one’s children by contributing to 

the development of a preventive intervention or therapeutic measure. With 

pediatric MCM research in particular, all involved should avoid using unduly 

influential rhetoric appealing to patriotism or to the responsibilities of “good 

parents” in the informed permission process. Those participating in pediatric 

MCM research should do so voluntarily, not in response to parental, social, 

or official pressure. 

* * *

Taken together, the criteria discussed above provide the ethical content of the 

three conditions for 407 review relating to pre-event pediatric MCM research 

and specify ethical standards that must all be met in order for pre-event 

pediatric MCM research to proceed when risks are determined to reach a 

minor increase over minimal risk and there is no prospect for direct benefit.215

Whether these criteria lead to approval or disapproval of proposed MCM 

research, they clarify what is at stake. 

In circumstances in which it is impossible to comply with Recommendation 

1—where possible, all pre-event pediatric MCM research be limited to 

minimal risk studies—the Bioethics Commission recommends the following:
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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Recommendation 4: Ethical Framework for National-Level Review of Pre-event 

Pediatric Medical Countermeasure Research

To ensure the thoroughness and ethical rigor of national-level review, 

reviewers should apply the Bioethics Commission’s recommended ethical 

framework for reviewing pre-event pediatric medical countermeasure research 

that poses greater than minimal risk, but no more than a minor increase over 

minimal risk, under Department of Health and Human Services regulations 

at 45 C.F.R. § 46.407 and/or U.S. Food and Drug Administration regulations 

at 21 C.F.R. § 50.54. A proposed protocol must meet the requirements of the 

framework outlined in this report to be approved.

The framework clarifies the circumstances in which proposed research 

presents a “reasonable opportunity” to address a “serious problem,” 

in particular, that 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 specifies a rigorous set of 

conditions necessary to determine whether the research would be conducted 

in accordance with the required “sound ethical principles” that fall into 

five general categories: (1) ethical threshold of acceptable risk and adequate 

protection from harm; (2) ethical research design, for example, scientific 

necessity, valid research plan using small trials and age de-escalation with 

appropriate monitoring, and planning for post-event research; (3) post-trial 

requirements to ensure ethical distribution of medical countermeasures in 

the event of an attack, as well as a plan for treatment or compensation for 

research-related injury; (4) community engagement; and (5) transparency 

and accountability. Finally, the framework reiterates the importance 

of informed parental permission and meaningful and developmentally 

appropriate child assent.

Application to Trials of AVA with Children: No More Than a Minor Increase 

over Minimal Risk Pre-event Trials of AVA with Children

In confronting the ethical questions surrounding MCM testing in pediatric populations, the Bioethics Commission concluded that before ethical 

pre-event pediatric AVA trials can be considered, further steps must be 

taken, including additional minimal risk research with adult participants 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

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to determine whether the research risks to children—who do not stand to 

benefit directly from it—pose no substantial risk to their health or well-being.

Given the amount of safety, immunogenicity, and dosing information about 

AVA in young adults aged 18 to 25 years, and given the widespread distribution 

of AVA in this population, it is possible that with additional testing in adults 

aged 18 to 20 years—testing to determine adverse effects, alternative dosing 

methods, and immunogenicity—testing of AVA with the oldest children (e.g., 

adolescents who are 16 to 17 years of age) could be considered no more than 

minimal risk. Consequently, it would be reviewed under section 404.

Informed, careful age de-escalation might allow researchers to infer minimal 

risk studies down the age scale. However, if data suggest that the use of AVA 

is affected, for example, by a child’s developmental stage (e.g., infancy or 

puberty), or if an inference of minimal risk from an older group of children 

to the next younger group is not possible, a study designed to pose a minor 

increase over minimal risk might be appropriate for national-level review. 

The National Biodefense Science Board (NBSB) stated that, given the lack 

of data about AVA use by children, pre-event AVA research with children 

currently would “present more than a minor increase over minimal risk.”216

Accordingly, pre-event AVA research with children as envisioned by NBSB 

would not be appropriate for national-level review or approvable under 

section 407 because this lack of data sets the level of risk beyond the 

acceptable threshold of a minor increase over minimal. Notably, NBSB 

considered research with children of all ages in making this determination. 

Inferring research risks from the youngest adults to children as a class (i.e., 

all persons 0 to 17 years of age), however, is considerably more difficult than 

doing so through careful age de-escalation. This is because young children 

differ developmentally in important ways from older children. Although 

extrapolation from adult data to research with children of all ages (i.e., 0 to 

17 years of age) might not support an inference that all pediatric studies are 

minimal risk—or even a minor increase over minimal risk—age de-escalation 

along the lines outlined above might permit such an inference for AVA 

research with some pediatric age groups.
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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Post-event Studies

Public health officials must be prepared to conduct post-event research when 

a bioterrorism attack occurs regardless of whether pre-event pediatric MCM 

research trials were conducted.217 In contrast to pre-event testing, in which 

ethical deliberations focus on whether any research with children would 

be ethically permissible, in post-event circumstances, research is ethically 

required to safeguard the well-being of current and future children. If a pediatric MCM research trial were completed pre-event, data should be collected 

following the administration of the tested intervention to acquire necessary 

additional safety information. In the absence of a pre-event investigation, 

an emergency situation might warrant administering an untested MCM to 

children in an effort to save lives. When children receive an untested MCM, 

it is ethically imperative that health officials collect data to learn as much as 

possible about the use of the untested MCM from the event. 

In a post-event scenario, the ethical considerations of MCM research with 

children shift markedly.218 Because of the increased likelihood that pediatric 

research participants have been exposed to an agent, and because exposed 

children will, in certain circumstances, be given an MCM under a treatment investigational new drug application (IND) (described in more detail 

below), the risks of research would be the risks of any additional observational 

procedures. Observational research might be minimal risk (approvable under 

section 404), or, given the potential to monitor and mitigate any adverse events 

related to the MCM, it might offer the prospect of direct benefit to individual 

research participants (approvable under section 405). Children exposed to a 

pathogen could also enroll in post-event research that is approvable based on 

its likelihood to yield information of vital importance to understanding or 

ameliorating the condition resulting from exposure (section 406). 

Although different types of post-event studies could be approved under 

the current regulatory and ethical framework for pediatric research, there 

are inherent complexities in designing scientifically rigorous studies and 

streamlining the logistics of MCM distribution and administration after an 

emergency event. As set forth below, community engagement is one important tool that can help ensure the success of the research and uptake of the 

intervention within the affected community.
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It is important to recognize that when the threat of an attack is imminent, 

the ethical and practical concerns surrounding proposed research track 

those of a post-event study even if technically conducted pre-event.219 The 

Bioethics Commission’s working definition of an imminent threat is that it 

is substantially certain to come about very soon and there is little to no time 

for deliberation or choice in action. These defining features of an imminent 

threat create conditions that are essentially similar, for both ethical and practical purposes, to post-event conditions. Critically, imminence should not be 

conflated with potential imminence. Imminence, by its very nature, means 

that there is no time for testing before moving to protect individuals as best as 

present knowledge permits. When an attack is imminent, research participants 

stand to benefit directly from the relevant research, or an identifiable class 

stands to benefit from the knowledge gained. In identifying the population 

affected by a determination of imminence (i.e., the bounds of the population 

that fits within the ethical review paradigm of post-event research), factors 

such as the type of attack, characteristics of the biohazardous agent, and intelligence regarding follow-up attacks should be considered. 

In sum, although technically occurring before an attack, an imminent threat 

more closely resembles a post-event than a pre-event situation for all ethical 

and practical purposes because there would be no time to test an MCM with 

children before the attack occurs and children would be imminently at risk 

of exposure resulting from a specific threat. There is therefore no need to 

map new ethical terrain for the narrowly specified circumstances that characterize an imminent threat. Rather, the ethical landscape in such cases closely 

resembles the contours of post-event research. This report’s ethical analysis 

and recommendations regarding post-event pediatric research, which follows, 

also applies to situations of imminent threat.

Ethical Issues in Post-event Research

Post-event (and imminent threat) pediatric MCM research is ethically distinct 

from pre-event research. The justification for such research no longer relies on 

a largely speculative societal benefit, but rests instead on more tangibly defined 

benefits that might accrue to children who have been exposed (or are about 

to be exposed) to an agent. Research with children who have been exposed 

could yield benefits to the identifiable class of children who are exposed to 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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the agent by producing vital knowledge about the resulting condition (section 

406). Other children who have been exposed or are at risk of exposure might 

benefit directly by participating in post-event MCM research (section 405).220

Accordingly, post-event research is necessary both as a matter of beneficence 

(i.e., offering benefit to children) and justice in fulfilling society’s obligation 

to secure the well-being of its most vulnerable citizens.

Because many children will have already received the MCM under investigation, post-event research will likely be limited to observational studies, 

involving various monitoring procedures and assessments to determine the 

function of the MCM when used by pediatric populations. Children who 

participate in a post-event MCM study approved under section 406 should be 

enrolled based on a determination that the research procedures present only 

a minor increase over minimal risk, that the intervention (in this case, monitoring procedures) presents experiences “reasonably commensurate” with what 

they would otherwise experience, and that the intervention is likely to yield 

generalizable knowledge of vital importance to understanding or ameliorating 

a condition caused by a chemical, biological, radiological, or nuclear agent 

used in a terrorism event.221

When the monitoring procedures or care involved in research is expected to 

contribute to the well-being of individual participants by monitoring and 

mitigating adverse events, or a different procedure is expected to offer the 

prospect of direct benefit, such research might be approvable under section 

405.222 While treatment for a particular bioterrorism agent will generally be 

made available to all exposed children in any event, children who participate 

in research might nevertheless benefit from their participation to the extent a 

research protocol varies in a meaningful way from the care otherwise provided.

In the case of a public health emergency, IRB review of post-event research 

protocols will need to be swift to ensure that research can be conducted in a 

timely manner, which can be facilitated by thorough advanced preparation. 

FDA regulations allow for, and even encourage, pre-approval consultations 

that allow researchers to plan post-event trials, obtain pre-approval, and 

position their work for expedited review and approval in the event of an 

emergency.223 Reviewers must bear in mind, however, that post-event research 

occurs in an emergency setting, which creates distinct ethical challenges in 
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implementing a research protocol. While the review process might need to 

be modified for post-event research to be responsive to the immediacy of 

emergency conditions, it must still ensure that any protocol reviewed is held 

to the same high standards of ethical research conduct.224

Certain ethical safeguards might be more difficult to implement in post-event 

research settings.225 For example, emergency circumstances might strain the 

process of informed parental permission and meaningful child assent.226

Nonetheless, provisions should be made to ensure that parents of potential 

child participants are adequately informed to make a reasonable decision 

regarding participation. Consent forms, for example, should be designed to 

be as simple and straightforward as possible without diminishing the essential 

information necessary to make truly informed decisions. Researchers and 

reviewers should take any potential complexities into account in advance of an 

event so that implementation of a post-event protocol is as straightforward as 

possible and research participants and their families are honored in accordance 

with respect for persons. IRBs reviewing post-event research protocols should 

ensure that an approved protocol incorporates special measures to assure that 

essential information is conveyed to parents of prospective participants and, 

when appropriate, to participants themselves. 

“I don’t think it’s ever been done to have that type of a scaled [mass casualty] event in a 

rapid response situation with all the uncertainty, confusion, fear...and then, try on top 

of that to do a...clinical research protocol, however simple that protocol may be....[The 

idea is that] when parents bring their children for access to the vaccine, if they elect to 

have their child vaccinated,...as they’re coming out [of the mass vaccination site], they’re 

offered the opportunity to enroll their child in this nested protocol for reactogenicity and 

immunogenicity. [Compare that to] how smooth that [conversation with the parent] would 

go before an event, where you have the time to really sit down with the parent, to really 

talk about the vaccine, to really answer all those questions in a one-on-one situation with 

time for the parent to sit back and reflect on that before choosing to enroll their child. 

Or, [versus] being in a situation where their child has received the vaccine because 

they’ve potentially been exposed, and I’m [the parent] trying to save their life...and having 

to have that conversation in that situation.”

Maher, C., Deputy Director, Office of Counter Terrorism and Emerging Threats, FDA. (2012). Regulatory 

Landscape for Providing MCMs to Children in an Emergency. Presentation to the Presidential Commission for the 

Study of Bioethical Issues, November 5. Retrieved from http://bioethics.gov/cms/node/788.
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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Challenges in Post-event Research Design

In an emergency, children might be offered an MCM to protect them from 

the consequences of exposure, even when the safety and proper pediatric 

dosage for that MCM are incompletely or not at all characterized. If officials 

choose to administer an untested MCM in response to an attack, they can 

either dispense the MCM and collect limited data through a passive surveillance system (e.g., the Vaccine Adverse Event Reporting System) that relies on 

self-reporting of adverse events, or conduct a more active post-event study of 

the pediatric administration of the MCM.227

Because there are strict ethical limits to the risk permitted in exposing healthy 

children to an untested MCM, a pre-event trial would necessarily involve a 

limited number of participants and therefore the resulting data would also 

be limited. Whether post-event research is conducted as active or passive 

surveillance, such research can be larger in scope than pre-event studies 

and is likely to reveal additional data, for example, about adverse events, the 

immunogenicity of vaccine interventions, and possibly even efficacy. Given 

the larger sample size, researchers might be able to enroll and collect data 

from a diverse pool of children who receive the MCM, ensuring that any 

biological differences, including environmental interactions, among populations are accounted for in the event that another widespread distribution 

becomes necessary. Conducting such analyses will help to ensure that MCMs 

are safe for all children who receive them, fulfilling the dictates of justice—

which requires that all children have equitable access to appropriate pediatric 

MCMs—and those of beneficence—which calls on those who provide the 

MCM to ensure that it is equally safe for all who receive it. 

From a purely scientific perspective, there are also disadvantages to a postevent research approach.228 While a pre-event study can be a rigorous and 

systematic investigation that provides reliable data on various aspects of the 

intervention such as dosing requirements, a post-event study necessarily 

includes uncontrolled variables and might produce a more limited range of 

data or, worse, spurious associations leading to incorrect conclusions.229

The type and amount of data that can be obtained pre-event differs from that 

which can be documented post-event. Depending on how it is conducted, a 

pre-event pediatric MCM trial could provide immunogenicity data for vaccines, 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

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dose-response curves (used to determine optimal dosing), evidence of the best 

administration method (e.g., subcutaneous or intramuscular injection, nasal 

spray, or liquid formulation), and adverse reaction data.230 Although a post-event 

study might yield useful logistical and distribution information to help shape 

future public health emergency responses, the clinical information that could 

reasonably be obtained in a post-event study likely would be general adverse 

reaction rates to the intervention, and, for vaccines, preliminary information 

about effectiveness and immunogenicity data.231 With an IND, it might be 

possible to collect efficacy data, but such research likely would require more 

controlled data collection than is possible in an emergency. Information on 

efficacy of an MCM will therefore 

always be limited, as it will be difficult 

to obtain post-event and it cannot be 

obtained pre-event because it would 

be unethical to intentionally expose 

anyone to a bioterrorism agent.232

In a post-event situation, the ability 

of researchers to control variables is 

constrained by the ethical imperative that—as a matter of justice and 

beneficence—researchers not restrict 

any child’s access to the best available care. With well-tested MCM 

distribution protocols in place, 

justice requires that all affected 

children have an equal opportunity 

to access the best available MCM 

care. Children who receive treatment in addition to the experimental 

MCM while enrolled in research 

might contribute data that would 

obscure the true effects of the MCM 

under investigation.233 For example, 

individuals might be provided with a 

long-acting measure to prevent future 

POST-EVENT RESEARCH COMPLEXITY 

In accordance with current HHS plans, in 

the event of a mass anthrax spore release, 

both AVA and long-course antibiotics 

would be made available to children. In 

this setting, it would be difficult to isolate 

adverse event data from AVA alone, since 

antibiotics also have side effects. Adverse 

reactions to the treatment regimen 

might be attributable to antibiotics or to 

the vaccine, or an interaction between 

the two. Although these data would 

be imperfect, they would still provide 

information otherwise impossible to obtain 

without putting healthy children at risk. 

Additionally, since AVA is likely to only be 

used in combination with antibiotics in 

children, understanding the adverse events 

of the combination is valuable.

Sources: NBSB. (2011). Challenges in the Use of 

Anthrax Vaccine Adsorbed (AVA) in the Pediatric 

Population as a Component of Post-Exposure 

Prophylaxis (PEP): A Report of the National 

Biodefense Science Board. Retrieved from http://

www.phe.gov/Preparedness/legal/boards/nbsb/

recommendations/Documents/avwgrpt1103.pdf;

CDC. (2010). Use of anthrax vaccine in the 

United States: Recommendations of the Advisory 

Committee on Immunization Practices (ACIP), 

2009. Morbidity and Mortality Weekly Report 

Recommendations and Reports, 59(RR-06), 1-30.
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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infection (e.g., a vaccine) as well as a short-term therapy to prevent or treat 

immediate infection (e.g., antibiotics). The data from any post-event observational studies of this short-term and long-term combination therapy might 

conflate the cause of adverse reactions or efficacy between the two interventions. Differing levels of infection or illness might also complicate research 

results, as would pre-existing conditions or opportunistic infections unrelated 

to the bioterrorism attack.234 These might result in adverse events unrelated 

to the intervention, nonetheless, being misattributed to the intervention.235

Researchers must also ensure that those injured as a result of their participation in post-event research have access to necessary medical care and 

compensation for their injury. Some people who are injured as a result of 

receiving an MCM will have access to compensation under the PREP Act. 

(See Compensation for Research-Related Injury, Chapter 3.) Those who are 

injured by observational research procedures rather than by the MCM should 

similarly be entitled to compensation. 

These design challenges underscore the need for investigators and reviewers 

to ensure that post-event research protocols are both scientifically valuable 

and valid. Such research can yield important, if limited, insights but cannot 

ethically proceed without a sound scientific design in place. By that same 

token, however, a strong post-event research framework does not obviate the 

need for appropriate and ethical pre-event research where possible.

Community Engagement in Post-event Research

To protect the population in the event of a bioterrorism attack, MCM research 

planning and implementation should include a robust system of community 

engagement (as discussed above) to keep the public apprised of research 

efforts and to enable democratic deliberation through active collaboration in 

its conduct.236 In particular, community engagement is critical to ensure that 

community members take advantage of an MCM in a post-event scenario when 

it is expected to prove beneficial. The obligation of community engagement 

falls to researchers who conduct post-event studies in collaboration with public 

health officials. The goals of community engagement—to educate the public 

about the research, allow the public to inform the researchers about its concerns 

and level of support for the research, and encourage the community to partake 

in the fruits of the research—are particularly salient in a post-event scenario. 
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Prior to an event, it will not be possible to identify all of the pertinent 

community stakeholders with an interest in post-event research. Nevertheless, 

generalized community engagement plans for the conduct of post-event 

research in a potential research community must be outlined before the 

research begins. Advance plans should include developing information 

for distribution, networking with community and faith-based organizations, and planning with local public health officials and agencies. General 

outreach strategies for disseminating information in an emergency should 

be established by researchers, as should specific measures to reach vulnerable 

populations that have difficulty engaging the health care system and groups 

that historically mistrust it. Post-event research planning should lay the 

groundwork for community engagement activities that can then be activated 

in the event of an attack.

After an event, the affected community can be defined and its specific concerns 

identified and addressed. Once an emergency occurs, or is determined to be 

imminent, location-specific post-event modifications of the more generalized 

plan, facilitated by local government, will be necessary to tailor the engagement 

effort to the affected community. Community engagement and outreach 

activities should begin immediately and must incorporate information on 

available MCMs—including both clinical details and accessibility—in 

addition to implementing research mechanisms. 

While community consultation initiatives in a post-event environment 

undoubtedly will be complicated by other primary tasks, such as the distribution of therapeutic MCMs and addressing acute medical needs, it is important 

to seek the community’s input, where possible, on the conduct of post-event 

MCM research. This can be done through public meetings or reaching out to 

local community organizations that are in regular contact with individuals 

and families. Although local community input might have only limited effect 

on the actual research design in a post-event scenario, collaboration can yield 

valuable information to guide participant recruitment, communicate with 

various groups in the community, and aid dissemination of research results. 

These measures might improve rates of use when an MCM is expected to 

prove beneficial and can encourage participation in follow-up research. A postevent scenario provides a unique opportunity to engage the community and 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

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encourage participation since the emergency itself underscores the importance 

of having tested MCMs available when needed.

Recommendation 5: Post-event Pediatric Medical Countermeasure Research

Post-event research should be planned in advance and conducted when 

untested medical countermeasures are administered to children in an emergency or when limited pre-event medical countermeasure studies have already 

occurred. Institutional review boards must be cognizant of the exigencies 

imposed upon research under emergency conditions, and when reviewing 

post-event medical countermeasure research proposals, ensure that adequate 

processes are in place for informed parental permission and meaningful child 

assent. Institutional review boards must also ensure that the research design is 

scientifically sound, children enrolled in research have access to the best available care, adequate plans are in place to treat or compensate children injured 

by research, and provisions are made to engage communities throughout the 

course of research.

Authorizing Distribution of Unapproved Drugs in an Emergency

In the event of a bioterrorism attack, the U.S government has emergency 

preparedness plans to mobilize medical interventions, drugs, vaccines, and 

supplies from the Strategic National Stockpile for distribution to affected 

portions of the population. The federal government delivers supplies to the 

states, which have individualized distribution strategies based on localized 

need and infrastructure. In the event that the MCM needed is either still 

in clinical trials or has not yet been approved for the specified application, 

there are two mechanisms available—an emergency use authorization (EUA) 

STRATEGIC NATIONAL STOCKPILE 

The Strategic National Stockpile (SNS) is a national repository of medicine and medical 

supplies that can be rapidly distributed to the American public in the case of a public 

health emergency. Established in 2003 through the Homeland Security Act of 2002, the 

SNS includes vaccinations, antibiotics, antitoxins, antivirals, life support medications, and 

other surgical and medical supplies. As an extension of the 1999 National Pharmaceuticals 

Stockpile, the SNS is directly overseen and managed by HHS and CDC. 

Source: CDC. (2012, October 15). Strategic National Stockpile (SNS) [Webpage]. Retrieved from http://www.cdc.

gov/phpr/stockpile/stockpile.htm/.
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and an IND—that allow the government to distribute an unapproved 

intervention to help people in an emergency. Underlying the motivation 

for these mechanisms are a host of ethical principles including respect for 

persons, beneficence, and justice. Together, the EUA and IND provide 

mechanisms to supply necessary MCMs with varying levels of clinical and 

research protections to ensure adequate respect for persons, as appropriate.

Emergency Use Authorization

There are times when the U.S. government might find that it has no 

FDA-approved drug in its arsenal to administer on a large scale to victims of a 

public health emergency. Alternatively, it might be the case that a prospectively 

safer or simpler pharmaceutical is in advanced development but has not yet 

received full FDA approval for an MCM application. In anticipation of these 

circumstances, Congress enabled FDA to authorize the use of unapproved 

products—or the unapproved use of approved products—in the event of a 

declared emergency, using an EUA. 

The EUA is a tool for providing incompletely characterized but promising 

FDA-regulated interventions to the U.S. population in the event of an emergency. It is subject to very strict limitations. An EUA can be used only when 

the Secretary of HHS has declared an emergency justifying the unapproved 

use, and only when the emergency involves an agent that can cause a serious 

or life-threatening disease.237 In order to gain approval of an EUA, there can 

be no “adequate, approved, and available alternative” to the MCM under 

consideration, and, based on the totality of the evidence (including clinical 

trials when available), the Secretary must determine that it is “reasonable to 

believe that the product may be effective” in responding to the serious or 

life-threatening disease or condition caused by the agent or pathogen specified in the emergency declaration.238 Additionally, the known and potential 

benefits of using the authorized MCM must outweigh its known and potential risks.239 In considering and issuing an EUA, FDA advises the Secretary 

based on its assessment of a range of factors in the context of the declared 

emergency, including the possible risks of not receiving the candidate intervention.240 This process can be streamlined in the event of an emergency with 

an approved pre-EUA plan. A pre-EUA is submitted to FDA for “review prior 

to the determination of an actual or potential emergency in order to reduce 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

99

the time needed during an emergency to review the submission and consider 

authorization of the product.”241

Importantly, the EUA is not a research tool. It allows for a drug or intervention 

to be given therapeutically but does not enable research on the intervention. 

The FDA Commissioner, however, can require that physicians and public 

health officials “collect and analyze safety and effectiveness data on the 

product” as a condition of the EUA.242 In order to perform research, an IND 

would need to be in place. As such, research protections do not apply to those 

who receive an MCM authorized under an EUA. Respect for persons requires 

that very specific disclosure and consent requirements, as well as detailed 

instructions for its indications, accompany every EUA. But EUAs do not 

require as detailed an informed consent for administration as would investigational drugs in a research trial.243 This streamlined consent format is essential 

for the timely provision of MCMs in an emergency and is allowed because 

there must be minimal data in place before FDA will grant authorization for 

a drug to be used under an EUA. An EUA’s streamlined consent bypasses the 

heightened protections that usually apply when an unapproved drug (or unapproved indication of an approved drug) is administered in the research context. 

FDA currently interprets the provisions of the EUA mechanism to require 

data from pediatric testing before an EUA can be issued for pediatric MCM 

use.244 The Bioethics Commission accepted the present interpretation of 

EUA requirements and agreed that it is preferable to reserve the use of the 

EUA mechanism for situations in which data are available to characterize 

the intervention in pediatric populations. Because children react to drugs 

and vaccines differently from adults, the heightened safeguards of pediatric 

research protections are appropriate for an intervention that is completely 

uncharacterized in children.

Investigational New Drug Application

Under FDA regulations, clinical investigation of a drug or biological product 

not previously approved for marketing in the United States requires submission of an IND.245

There are three types of INDs. An investigator IND (used most commonly in 

research involving interventions) is submitted by a researcher who initiates 
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and conducts an investigation of the investigational new drug. An emergency 

use IND authorizes a physician to obtain and use an experimental drug on a 

specific patient in extenuating circumstances under which there is not time to 

submit a full IND application, or to treat a patient that might not meet the 

requirements of the clinical trial protocol. The third type of IND, a treatment 

IND, allows for the use of a promising experimental drug in the treatment of 

patients not enrolled in a clinical trial while the final clinical work and FDA 

review take place.246

The IND mechanism was designed for use in planned clinical trials and may 

also be used to help individual patients in emergency situations.247 It was 

not designed for widespread distribution of a drug or intervention in the 

event of an outbreak or attack, and some have suggested that it is not well 

suited for this use. Those commentators have argued that the distribution of 

anthrax vaccine to postal workers as post-exposure treatment through an IND 

in 2001 demonstrated this inadequacy.248 However, in the case of a multistate monkeypox outbreak in 2002, the distribution of smallpox vaccine to 

children through an IND is said to have been effective, and other scholars 

have maintained that studying the effects of certain other MCMs for children 

through an IND should not present significant challenges.249

Although the IND was not designed for emergency events, an investigational 

drug or intervention can be distributed under a treatment IND in an emergency. Consistent with beneficence, a treatment IND may be granted after 

FDA determines that:

(1) The patient or patients to be treated have a serious or immediately lifethreatening disease or condition, and there is no comparable or satisfactory 

alternative therapy to diagnose, monitor, or treat the disease or condition;

(2) The potential patient benefit justifies the potential risks of the treatment 

use and those potential risks are not unreasonable in the context of the 

disease or condition to be treated; and 

(3) Providing the investigational drug for the requested use will not interfere 

with the initiation, conduct, or completion of clinical investigations that 

could support marketing approval of the expanded access use or otherwise 

compromise the potential development of the expanded access use.250
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

101

Similar to the pre-EUA mechanism, a pre-IND consultation can be arranged 

with FDA to assist in planning and expediting approval of the IND in the 

event of an emergency.251

An investigator IND requires provision of extensive information about 

preclinical testing, any clinical testing that has already been performed, and 

any additional scientific or medical information characterizing the action of 

the intervention; so too must an investigator IND include assurance that trials 

will be conducted in adherence to human subjects protections and any other 

applicable FDA regulations.252 After an IND is submitted, the investigator 

must typically wait 30 days before initiating a clinical trial while FDA reviews 

the IND for safety.253

In the event of an attack, and in the absence of pre-event pediatric MCM 

data, the appropriate MCM would be distributed, as a matter of respect for 

persons and beneficence, to children under a treatment IND with its host of 

research protections in place. An investigator IND should also be approved to 

study a small subset of those children, enrolled after they received the MCM 

through the treatment IND, in order to obtain more detailed information—

such as immunogenicity and active surveillance data—from the pediatric 

administration of the MCM.254 Beneficence and non-maleficence call for 

research with a subset of the population to better understand the intervention 

in case future use is necessary.

Recommendation 6: Regulatory Mechanisms for Post-event Pediatric Medical 

Countermeasure Research and Distribution

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. 

When a medical countermeasure is distributed broadly to children using a 

treatment IND, it is essential that the U.S. government also conduct a concurrent small-scale study under an investigator IND to obtain data that can 

potentially be used to support an emergency use authorization for pediatric 

use of the medical countermeasure in a future event. To expedite post-event 

research and ensure the availability of appropriate medical countermeasures 
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102

for children, a pre-IND consultation and approval should be put in place 

before an event.

Application to Post-event Trials of AVA with Children

In an event involving the release of weaponized anthrax, or other large-scale 

release of spores, a plan exists to provide children, like adults, treatment with a 

60-day course of antibiotics as well as AVA.255 FDA and CDC have a treatment 

IND in place to allow for broad access to AVA for children in the event of an 

emergency. Work is ongoing to clarify the informed consent process. In addition, 

FDA and CDC are collaborating to develop a nested protocol that would involve 

research and surveillance to better understand immunogenicity and reactogenicity 

to the vaccine.256 Both of these mechanisms require IRB approval.

Under the Bioethics Commission’s ethical approach, even if a pre-event study 

of AVA with children is approved, post-event research would be necessary to 

gather additional safety and immunogenicity data beyond the limited amount 

a pre-event study could produce. If a pre-event study is not approved and AVA 

is nonetheless administered to children in the event of an attack, post-event 

research would be ethically required. 

In the event of a mass release of anthrax spores, FDA has authorized administration of AVA to adults using an EUA for post-exposure prophylaxis. (AVA is 

currently approved only for pre-exposure use by adults at risk for contracting 

anthrax.257

) FDA requires pediatric data to support an EUA for pediatric 

use. In the absence of pre-event pediatric AVA research, AVA could not be 

distributed to children under an EUA. If pre-event pediatric research has 

been conducted, FDA would need to review the resulting data thoroughly and 

determine whether an EUA is warranted.

In the event of an anthrax attack, but in the absence of pre-event pediatric 

data, AVA will be available to children under a treatment IND. Beneficence 

requires that when an existing MCM can be expected to provide benefit, 

such an MCM should be made widely available. In this case, because AVA 

is expected to provide some benefit, it should be widely distributed under 

a treatment IND, allowing all parents to accept the vaccine for their child 

should they desire. This will ensure that, in accordance with respect for 

persons, the full force of pediatric research protections would govern its 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

103

distribution. In addition, any adverse event data from the administration of 

AVA to children would be collected through a passive surveillance system 

such as the Vaccine Adverse Event Reporting System.258

The nested IND (a combination of a treatment IND and an investigator IND) 

currently in place for AVA access also provides for active surveillance through 

an investigator IND of a subset of those who receive the vaccine. Because 

a treatment IND permits only limited collection of data, a proportion of 

children who receive the vaccine should also be enrolled in an active surveillance trial through an investigator IND. The subset of children and parents 

who agree to participate would do so only after a second thorough informed 

process that includes parental permission and meaningful child assent. Because 

this nested trial is an active surveillance trial rather than an intervention trial, 

the protocol would not entail any additional administration of the vaccine but 

might include procedures such as follow-up blood draws to study immunological response to the vaccine and ongoing communications to enable adverse 

reaction reporting.259 The information collected from this investigator IND 

active surveillance trial would provide baseline data about the use of AVA by 

children, and might make it possible to administer AVA more expeditiously to 

children through an EUA in the event of a future attack.260

There is an alternative structure to a nested, active surveillance trial: a 

“parallel” IND, in which a subset of exposed children would be enrolled 

through an investigator IND in a post-event trial to gather clinical data. 

These children would receive AVA through the trial rather than through the 

treatment IND, meaning that the dosage and administration of AVA could be 

varied. In addition to gathering safety and immunological response data, the 

trial would also evaluate dosing strategies. Although there are no regulatory 

barriers to such an approach, the nested IND is preferable because conducting 

dosing studies in a post-event setting risks under-immunizing children who 

have been exposed to anthrax. Moreover, conducting such studies would add 

logistical complications during an emergency situation, such as extending 

the length of time it takes to administer critical MCMs and impairing the 

adequacy of informed consent.

It is important that any post-event distribution of AVA to children, regardless of 

the specific mechanism, entail democratic deliberation in the form of extensive 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

104

community engagement. Community engagement should begin in pre-event 

research and continue through post-event activities. Children and their 

families must be made aware of the factual basis on which AVA administration 

is justified, most particularly the scientific knowledge and clinical data 

that support the decision to distribute it without full FDA approval. The 

rationale for distribution must be clearly and forthrightly communicated to 

avoid misunderstandings and potential mistrust of government, health care 

providers, and the research establishment. Moreover, it is critical that any 

post-event research protocol be scientifically sound, have adequate processes 

in place to ensure informed parental permission and meaningful child assent, 

provide for adequate treatment or compensation for research-related injuries, 

and ensure that enrolled children have access to the best available care.

Conclusion

Safeguarding children is one of our nation’s foremost obligations. The ethical 

conduct of pre- and post-event pediatric MCM research is one way to fulfill 

our duty to protect children both as individual research participants and as 

members of society to the greatest extent possible in the event of an attack.

Pediatric research that presents no prospect of direct benefit to participants 

or that is not likely to yield generalizable knowledge about the participants’ 

condition generally can only be conducted if it presents no more than 

minimal risk, except in extraordinary circumstances. Thus, the Bioethics 

Commission concluded that pre-event pediatric MCM research—which 

presents no prospect of direct benefit because no children are affected by 

the condition being studied—generally cannot proceed unless it is minimal 

risk research. Pre-event research might in some cases be designed in a way 

that would permit it to be judged minimal risk through an age de-escalation 

process in which risks are assessed and evaluated at each step. Robust research 

with young adults might support the conclusion that research with the oldest 

children is minimal risk. Similarly, research with the oldest children that 

further characterizes research risk might support an inference that research 

with the next oldest group of children is minimal risk as well. 

Only when a minimal risk research design is not possible can proposed pre-event 

MCM research proceed to national-level review under section 407. Moreover, 
ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

105

pre-event MCM research can proceed only if it presents no more than a minor 

increase over minimal risk, and is conducted in accordance with the strict guidelines offered in this report. Under no circumstances should children be exposed 

to pre-event MCM research that poses substantial risk of serious illness or injury 

when there is no prospect of direct benefit to those children.

Critically, post-event research must be conducted when untested or minimally 

tested MCMs are administered to children in an emergency. Unlike pre-event 

MCM research, post-event MCM research might present a prospect of direct 

benefit to participants or be likely to yield generalizable knowledge about the 

participants’ condition. Nevertheless, post-event studies should be minimal 

risk if possible, and incorporate robust research protections for pediatric 

participants. Emergency situations also present logistical complications, and 

responses that enable the conduct of post-event research should be prepared 

ahead of time to the extent possible with these ethical considerations in mind. 

Pediatric MCM research brings into sharp focus the fact that the health and 

security of children are paramount. It highlights the importance of both 

protecting children from unjustifiable research risks and assuring their safety 

as far as possible in the event of an emergency. Grounding its work in the 

principles of respect for persons, beneficence, justice, and democratic deliberation, the Bioethics Commission reaffirmed the ethical foundations of pediatric 

research and applied them to the particularly complex and difficult case of 

pediatric MCM research. As exemplified by the Bioethics Commission’s 

deliberations, such research warrants an ongoing national conversation in 

order to ensure the highest standards of protection for children that reflect 

an unwavering commitment to safeguard all children from unacceptable risks 

in research and through research that promotes their health and well-being.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

106
107

ENDNOTES
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1 For the purposes of this report, the Bioethics Commission defined medical countermeasures (MCMs) as U.S. 

Food and Drug Administration (FDA)-regulated products and interventions used to combat the effects of 

chemical, biological, radiological, or nuclear (CBRN) events. Given the Bioethics Commission’s definition of 

MCM, it used the term bioterrorism to refer to chemical, biological, radiological, and nuclear attacks generally.

2 Letter from Secretary Kathleen Sebelius, Health and Human Services (HHS), to Amy Gutmann, Chair, 

Presidential Commission for the Study of Bioethical Issues (PCSBI). (2012, January 6). p. 1. Retrieved from 

http://bioethics.gov/cms/sites/default/files/news/Pediatric Countermeasures Letter from the Secretary.pdf.

3 The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 

(1977). Research Involving Children (DHEW Publication OS 77-0004). Washington, DC: Department 

of Health, Education, and Welfare, p. 140. Retrieved from http://bioethics.georgetown.edu/pcbe/reports/

past_commissions/Research_involving_children.pdf.

4 The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 

(1978). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research

(DHEW Publication OS 78-0012). Washington, DC: Department of Health, Education, and Welfare. 

Retrieved from http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html.

5 The language of the two sets of regulations is substantively identical. The Bioethics Commission refers only to 

HHS regulations in the text of this report, although the discussion encompasses the provisions of Subpart D as 

codified by both HHS and FDA. See Additional Protections for Children Involved as Subjects in Research, 48 

Fed. Reg. 9,814 (March 8, 1983) (codified at 45 C.F.R. §§ 46.401 et seq.); Additional Safeguards for Children 

in Clinical Investigations of FDA-Regulated Products, 66 Fed. Reg. 20,589 (April 24, 2001) (codified at 21 

C.F.R. §§ 50.50 et seq.). 

6 In the case of FDA-regulated research, the Commissioner of Food and Drugs, in consultation with a 

national panel of experts makes the final determination (21 C.F.R. § 50.54). When research is governed 

by both FDA and HHS regulations, the Secretary of HHS makes the final determination. FDA. (2006, 

December). Guidance for Clinical Investigators, Institutional Review Boards, and Sponsors: Process for 

Handling Referrals to FDA Under 21 C.F.R. 50.54. Retrieved from http://www.fda.gov/downloads/

RegulatoryInformation/Guidances/ucm127605.pdf.

7 U.S. Centers for Disease Control and Prevention (CDC). (2010). Use of anthrax vaccine in the United States: 

Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. Morbidity and 

Mortality Weekly Report: Recommendations and Reports, 59(RR-06), p. 21. Retrieved from http://www.cdc.gov/

mmwr/preview/mmwrhtml/rr5906a1.htm; National Biodefense Science Board (NBSB). (2011). Challenges 

in the Use of Anthrax Vaccine Adsorbed (AVA) in the Pediatric Population as a Component of Post-Exposure 

Prophylaxis (PEP): A Report of the National Biodefense Science Board, p. 18. Retrieved from http://www.phe.gov/

Preparedness/legal/boards/nbsb/recommendations/Documents/avwgrpt1103.pdf.

8 Maher, C., Deputy Director, Office of Counterterrorism and Emerging Threats, FDA. (2012). Regulatory 

Landscape for Providing MCMs to Children in an Emergency. Presentation to PCSBI, November 5. Retrieved 

from http://bioethics.gov/cms/node/788.

9 Letter from Secretary Kathleen Sebelius to Amy Gutmann, op cit. 

10 The National Commission, (1978), op cit.

11 For more detail, see Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – 

Ethical Grounding, and Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research 

– Pre-event Studies Posing No More Than a Minor Increase over Minimal Risk Approvable under Section 407.

12 For more detail, see Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – 

Ethical Grounding, and Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research 

– Post-event Studies.

13 For a more detailed discussion of the definition of minimal risk (with some specific examples) see Chapter 2: 

Current Ethical and Regulatory Framework for Pediatric Research – Section 404: Minimal Risk Research, 

and Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – Ethical Threshold 

of Acceptable Risk and Adequate Protection From Harm.
ENDNOTES IV

109

14 The National Commission, (1977), op cit.

15 Protection of Human Subjects, HHS. 45 C.F.R. § 46.102; Protection of Human Subjects, FDA. 21 C.F.R. § 50.3.

16 NBSB, op cit, pp. 4-5.

17 Prescription Drug Products: Doxycycline and Penicillin G Procaine Administration for Inhalational Anthrax 

(Post-Exposure), 66 Fed. Reg. 55,679 (Nov. 2, 2002); Vietri, N.J. et al. (2006). Short-course postexposure 

antibiotic prophylaxis combined with vaccination protects against experimental inhalation anthrax. 

Proceedings of the National Academy of Sciences, 103(20), 7813-7816.

18 CDC, (2010), op cit. ACIP’s analysis takes into account AVA’s safety profile in adults and the advantages that 

vaccination can be expected to provide over long-term antibiotic use alone. Friedlander, A.M., et al. (1993). 

Postexposure prophylaxis against experimental inhalation anthrax. The Journal of Infectious Diseases, 167(5), 

1239-1242; Klinman, D.M., et al. (2009). Anthrax prevention and treatment: Utility of therapy combining 

antibiotic plus vaccine. Expert Opinions in Biological Therapies, 9(12), 1477-1486; Vietri, N.J., et al. (2006). 

Short-course postexposure antibiotic prophylaxis combined with vaccination protects against experimental 

inhalational anthrax. Proceedings of the National Academy of Sciences, 103(20), 7813-7816. 

19 CDC, (2010), op cit; NBSB, op cit. It is worth noting that the ACIP recommendation existed prior to both 

Dark Zephyr (in 2011) and the NBSB recommendation for pre-event research (also in 2011). 

20 Letter from Nicole Lurie, Assistant Secretary, Preparedness and Response, HHS, to Patricia Quinlisk, Chair, 

and Members, NBSB. (2011, April 27). p. 2. Retrieved from http://www.phe.gov/Preparedness/legal/boards/

nbsb/meetings/Documents/nbsbltr42711.pdf.

21 Ibid, pp. 1-2. 

22 NBSB, op cit, p. 40.

23 Ibid, p. 25.

24 Ibid, pp. 37-40.

25 Letter from Secretary Kathleen Sebelius to Amy Gutmann, op cit.

26 Given the Bioethics Commission’s definition of MCM, it used the term bioterrorism to refer to chemical, 

biological, radiological, and nuclear (CBRN) attacks generally. In broad terms, MCMs are pharmaceutical 

products and other products used to prevent or mitigate the health effects of a CBRN event; large-scale 

natural disaster; or naturally occurring, emerging infectious disease. This general definition can be narrowed 

either by specifying the types of responses used to prevent and mitigate harm or by limiting the types of 

events that cause the harm in question. Various governmental agencies and policy centers have taken precisely 

this approach, narrowing the definition by, for instance, limiting MCMs to products, such as vaccines and 

antibiotics, used in response to CBRN events. Project Bioshield Act of 2004. 42 U.S.C. §§ 247d-6a(a)(2)(A), 

247d-6b(c)(1)(B); Pandemic and All-Hazards Preparedness Act. 42 U.S.C. §§ 247d-7e(a)(4), (5), (7); see also 

Public Readiness and Emergency Preparedness (PREP) Act. 42 U.S.C. § 247d-6d(i)(1). The PREP Act describes 

“countermeasures” to “mean[] a drug (as that term is defined by section 201(g)(1) of the Federal Food, Drug, 

and Cosmetic Act (21 U.S.C. 321(g)(1))), biological product (as that term is defined by section 351(i) of this 

Act (42 U.S.C. 262(i))), or device (as that term is defined by section 201(h) of the Federal Food, Drug, and 

Cosmetic Act (21 U.S.C. 321(h))).” Other organizations have broadened the term to include therapeutic 

responses to natural disasters and emerging infectious diseases, such as H5N1 influenza virus and SARS. 

Biomedical Advanced Research and Development Authority (BARDA), HHS. (2011). BARDA Strategic Plan 

2011-2016. Retrieved from http://www.phe.gov/about/barda/Documents/barda-strategic-plan.pdf. Although 

some definitions of MCM include non-FDA-regulated products and/or products used in response to naturally 

occurring outbreaks, the Bioethics Commission adopted a narrow definition for the purposes of this report. 

27 Under pediatric human subjects protections adopted by HHS and FDA, research protocols involving pediatric 

subjects may be approved at the local level if they fall within the following risk-benefit profiles (and meet other 

regulatory requirements): (1) pose only minimal risk to research participants (45 C.F.R. § 46.404; 21 C.F.R. 

§ 50.51), (2) pose greater than minimal risk but offer a prospect of direct benefit to research participants (45 

C.F.R. § 46.405; 21 C.F.R. § 50.52), (3) pose no more than a minor increase over minimal risk and offer the 

prospect of generating vitally important knowledge about a participant’s condition (45 C.F.R. § 46.406; 21 

C.F.R. § 50.53).
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

110

28 This report references research regulated by 45 C.F.R. § 46.407 and/or 21 C.F.R. § 50.54 as research with 

healthy children that poses more than minimal risk with no prospect of direct benefit, but recognizes that the 

research approvable under this mechanism may include subjects with conditions and other risk classifications. 

See Chapter 2: Current Ethical and Regulatory Framework for Pediatric Research – Current Regulations for 

Conducting Pediatric Research. Importantly, there are instances in which research involving a prospective 

MCM, but not conducted for MCM purposes, can be performed in circumstances that present a prospect 

of direct benefit to participants; for example, research with broad spectrum antibiotics or interventions 

well-characterized for use in other circumstances. 

29 The National Commission recommendation of how to review such proposed research was codified in pediatric 

research protection regulations at 45 C.F.R. § 46.407 (HHS) and 21 C.F.R. § 50.54 (FDA). The National 

Commission, (1977), op cit, p. 126.

30 The evaluation of pediatric research posing greater than minimal risk but offering no prospect of direct 

benefit has been discussed to varying extents by several national bioethics commissions. The National 

Bioethics Advisory Commission (NBAC) noted that although its report on human subjects protections did 

not specifically address research with children, “special attention should be given to the ethical standards 

and regulatory requirements associated with providing adequate protections to children.” NBAC. (2001). 

Ethical and Policy Issues in Research Involving Human Participants: Volume I. Bethesda, MD: NBAC, p. 39. 

Retrieved from http://bioethics.georgetown.edu/nbac/human/overvol1.pdf. The Advisory Committee for 

Human Radiation Experiments (ACHRE) called for work to resolve the “controversial, unresolved issues” in 

“research with patients in the midst of a potential medical emergency” and “research involving children that 

may offer them no prospect of direct benefit but that may put them at greater than minimal risk, depending 

on how minimal risk is understood.” ACHRE also called for regulations to address the conduct of research 

involving institutionalized children, the variation in IRB performance, and clarification of the meaning of 

minimal risk in research with children. (Finding 22, Recommendation 11). ACHRE. (1995). Final Report of 

the Advisory Committee on Human Radiation Experiments. New York, NY: Oxford University Press. Retrieved 

from http://www.hss.doe.gov/healthsafety/ohre/roadmap/achre/report.html; See also National Human 

Research Protections Advisory Committee. (2001). Children’s Workgroup Report. Retrieved from http://www.

hhs.gov/ohrp/archive/nhrpac/mtg04-01/child-workgroup4-5-01.pdf; Secretary’s Advisory Committee on 

Human Research Protections (SACHRP). (2005, April 18). Subcommittee on Research Involving Children: 

Recommendations Related to 45 C.F.R. § 46.404. Retrieved from http://www.hhs.gov/ohrp/sachrp/

sachrpltrtohhssec.html.

31 For more detail, see Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – 

Pre-event Studies.

32 Klassen, T.P., et al. (2008). Children are not just small adults: The urgent need for high-quality trial evidence 

in children. PLoS Medicine, 5(8), 1180. 

33 Ibid, pp. 1180-1182; Stephenson, T. (2005). How children’s responses to drugs differ from adults. British 

Journal of Clinical Pharmacology, 59(6), 670-673.

34 Environmental Protection Agency (EPA). (2005). Guidance on Selecting Age Groups for Monitoring and 

Assessing Childhood Exposures to Environmental Contaminants 2005. Retrieved from http://www.epa.gov/

raf/publications/pdfs/AGEGROUPS.PDF. 

35 Bleicher, E.W.B. (2009). Encouraging research and development of pediatric medical devices through 

legislative and regulatory action: The Pediatric Medical Device Safety and Improvement Act of 2007 in 

context. Food and Drug Law Journal, 64(3), 531-564.

36 Ibid.

37 Anderson, M., Member and Fellow, American Academy of Pediatrics. (2012). Practical Challenges Posed by 

Pediatric Research. Presentation to PCSBI, May 17. Retrieved from http://bioethics.gov/cms/node/709; Thaul, 

S. (2007). FDA’s Authority to Ensure that Drugs Prescribed to Children are Safe and Effective (CRS Publication 

no. RL33986). Washington, DC: Congressional Research Service, p. 4. Retrieved from http://www.fas.org/

sgp/crs/misc/RL33986.pdf. 
ENDNOTES IV

111

38 Best Pharmaceuticals for Children Act. 21 U.S.C. § 355a; Pediatric Research Equity Act. 21 U.S.C. § 355c. Both 

laws were reauthorized in the U.S. Food and Drug Administration Amendments Act of 2007. Pub. L. No. 

110-85, 121 Stat. 823 (2007). They were amended in 2012 by the FDA Safety and Innovation Act. Pub. L. No. 

112-144, 126 Stat. 993 (2012).

39 Anderson, op cit. Over 425 labels were changed to include pediatric information as of October 2011. Institute 

of Medicine (IOM). (2012). Safe and Effective Medicines for Children: Pediatric Studies Conducted Under 

the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: National 

Academies Press, p. 34. Retrieved from http://www.iom.edu/Reports/2012/Safe-and-Effective-Medicines-forChildren.aspx.

40 Ibid.

41 The National Commission, (1978), op cit; The National Commission, (1977), op cit; PCSBI. (2010, 

December). New Directions: The Ethics of Synthetic Biology and Emerging Technologies. Washington, DC: 

PCSBI, pp. 24-31; PCSBI. (2011, December). Moral Science Protecting Participants in Human Subjects Research. 

Washington, DC: PCSBI, pp. 96-101; PCSBI. (2012, October). Privacy and Progress in Whole Genome 

Sequencing. Washington, DC: PCSBI, pp. 27-31; NBAC. (1999). Ethical Issues in Human Stem Cell Research. 

Rockville, MD: NBAC. Retrieved from http://bioethics.georgetown.edu/nbac/stemcell.pdf; NBAC. (1997). 

Cloning Human Beings. Rockville, MD: NBAC. Retrieved from http://bioethics.georgetown.edu/pcbe/

reports/past_commissions/nbac_cloning.pdf; ACHRE. (n.d.) About the information contained in this gopher. 

Retrieved from http://www.gwu.edu/~nsarchiv/radiation/dir/mstreet/about/intro.txt.

42 Protection of Human Subjects, HHS. 45 C.F.R. § 46.102; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.3; IOM. (2004). The Ethical Conduct of Clinical Research Involving Children. Washington, DC: National 

Academies Press.

43 The National Commission, (1977), op cit.

44 Council for International Organizations and Medical Sciences (CIOMS) and World Health Organization 

(WHO). (2002). International Ethical Guidelines for Biomedical Research Involving Human Subjects, Guideline 

8, 14. Geneva: WHO; International Conference on Harmonisation. (1996, June). Guideline for Good Clinical 

Practice E6(R1). Retrieved from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/

Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf; Protection of Human Subjects, HHS. 45 C.F.R. §§ 46.401 et 

seq; Protection of Human Subjects, FDA. 21 C.F.R. §§ 50.50 et seq; World Medical Association. (2008). Code 

of Ethics of the World Medical Association: Declaration of Helsinki. Ferney-Voltaire, France: World Medical 

Association. 

45 The National Commission, (1978), op cit.

46 Beauchamp, T.L. (2005). The Origins and Evolution of the Belmont Report. In J.F. Childress, E.M. Meslin, 

and H.T. Shapiro. (Eds.). Belmont Revisited: Ethical Principles for Research with Human Subjects (pp. 12-25). 

Washington, DC: Georgetown University Press, pp. 15-16. For a similar debate on the conflation of autonomy 

and beneficence regarding pediatric research, see Miller, R.B. (2003). Ethical Issues in Pediatric Research.In 

Children, Ethics, and Modern Medicine. Bloomington, IN: Indiana University Press; Ramsey, P. (1970). The 

Patient as Person. New Haven, CT: Yale University Press.

47 Mellanby, K. (1947). Medical experiments on human beings in concentration camps in Nazi Germany. British 

Medical Journal, 1(4490), 148-150.

48 For more detail, see Appendix I: Sources of Pediatric Vulnerability.

49 The phrase “essential interests” prescribes an analysis that focuses on those interests that are vital to an 

individual. It is distinct from a “best interests” assessment, which broadly encompasses all of an individual’s 

interests, regardless of gravity. Essential interests include one’s interests in life, health, bodily integrity, freedom 

from undue coercion, and freedom of expression. DeGrazia, D., Professor of Philosophy, George Washington 

University. (2012). Special Considerations for Research with Children. Presentation to PCSBI, May 17. 

Retrieved from http://bioethics.gov/cms/node/708.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

112

50 Redmon, R.B. (1986). How children can be respected as ‘ends’ yet still be used as subjects in non-therapeutic 

research. Journal of Medical Ethics, 12(2), 77-82. Redmon argues that the higher the risks and the less likely 

prospect for future societal benefit, the less plausible it is that the child would endorse participation in 

retrospect. Ibid.

51 Protection of Human Subjects, HHS. 45 C.F.R. § 46.408; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.55; Emanuel, E.J., Wendler, D., and C. Grady. (2008). An ethical framework for biomedical research. In 

E.J. Emanuel, et al. (Eds.). The Oxford Textbook of Clinical Research Ethics. New York, NY: Oxford University 

Press, p. 126.

52 Of course, this is true of all decisions parents make on behalf of their children, such as how they are dressed 

or what schools they attend. This is part of how parents build the character of children—form them into 

members of families, cultures, religions, and societies—and help to make them, in part, who they are as 

persons.

53 Grady, C. (2004). Ethics of vaccine research. Nature Immunology, 5(5), 465-468.

54 Ramsey, P. (1970). Consent as a canon of loyalty with special reference to children in medical investigation. 

In P. Ramsey. (Ed.). The Patient as a Person (pp. 1-58). New Haven, CT: Yale University Press, pp. 11-12. 

Elsewhere, Ramsey acknowledges that research with children may be the lesser of two evils, that is when 

failing to do the research is also immoral. See Ramsey, P. (1976). The enforcement of morals: Nontherapeutic 

research on children. The Hastings Center Report, 6(4), 21-30; Marshall, M.F., Director, Program in Biomedical 

Ethics, Center for Biomedical Ethics and Humanities, Professor, Public Health Sciences, School of Medicine, 

and Professor, School of Nursing, University of Virginia. (2011). Anthrax Vaccine Trials in Children: Research 

and Risk in Mass Casualty Medicine. Presentation to PCSBI, November 5. Retrieved from http://bioethics.

gov/cms/node/781.

55 The National Commission, (1977), op cit; Dickert, N.W. (2009). Re-examining Respect for Human Research 

Participants. Kennedy Institute of Ethics Journal, 19(4), 311-338; Lysaught, M.T. (2004). Respect: Or, how 

respect for persons became respect for autonomy. Journal of Medicine and Philosophy, 29(6), 665-680; 

Lebacqz, K. (2005). We Sure Are Older But Are We Wiser? In J.F. Childress, E.M. Meslin, and H.T. Shapiro. 

(Eds.). Belmont Revisited: Ethical Principles for Research with Human Subjects (pp. 99-110). Washington, DC: 

Georgetown University Press.

56 The National Commission, (1978), op cit; Miller, P.B., and N.P. Kenny. (2002). Walking the moral tightrope: 

Respecting and protecting children in health-related research. Cambridge Quarterly of Healthcare Ethics, 11(3), 

217-229.

57 The National Commission, (1978), op cit.

58 Ibid.

59 Ibid.

60 PCSBI, (2010, December), op cit, p. 4.

61 The National Commission, (1978), op cit.

62 Ibid.

63 Ibid. As stated in the Belmont Report, there are widely held justifications for unequal, but equitable distribution 

of research burdens and benefits.

64 Emanuel, et al., (2008), op cit, p. 126.

65 The National Commission, (1977), op cit, p. 132. 

66 PCSBI. (2010). Commission Deliberations and Public Comment. Meeting 3, Session 4, November 16. 

Retrieved from http://bioethics.gov/cms/node/183; Gutmann, A., and D. Thompson. (2004). Why Deliberative 

Democracy? Princeton, NJ: Princeton University Press; The National Commission, (1978), op cit; The National 

Commission, (1977), op cit; PCSBI, (2010, December), op cit, pp. 24-31; PCSBI, (2011, December), op cit. 

67 The National Commission, (1977), op cit. 

68 Ibid, p. xviii. 
ENDNOTES IV

113

69 Ibid. 

70 Ibid, pp. 127-128. 

71 Ibid, pp. 140-141. 

72 For more detail, see Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – 

Community Engagement in Post-event Research, Pre-event Studies Posing No More Than a Minor increase 

over Minimal Risk Approvable under Section 407.

73 The National Commission, (1977), op cit, p. 136. 

74 See Additional Protections for Children Involved as Subjects in Research, 48 Fed. Reg. 9,814 (March 8, 

1983) (codified at 45 C.F.R. §§ 46.401 et seq.); Additional Safeguards for Children in Clinical Investigations 

of FDA-Regulated Products, 66 Fed. Reg. 20,589 (April 24, 2001) (codified at 21 C.F.R. §§ 50.50 et seq.) 

In 1979, FDA published proposed regulations and solicited comments in the Federal Register, but these 

regulations were never finalized and eventually FDA withdrew them in 1991. See Protection of Human 

Subjects; Proposed Establishment of Regulations, 44 Fed. Reg. 24,106 (Apr. 24, 1979) (to be codified at 

21 C.F.R. pt. 50); Withdrawal of Certain Pre-1986 Proposed Rules, 56 Fed. Reg. 67,440 (Dec. 30, 1991). 

Although FDA formally adopted Subpart D in 2001, it had provided a number of safeguards to children 

even in the absence of special regulations: defining children as a vulnerable population for IRB review, 

providing information sheets with special provisions for parental permission and child assent, and encouraging 

investigators and IRBs to use HHS Subpart D as guidance for all research with children (see Additional 

Safeguards for Children, 66 Fed. Reg. 20,589). With congressional passage of the Pediatric Rule in 1998, 

which established a presumption of research with children and allowed FDA to require pediatric studies in 

certain products, and the FDA Modernization Act of 1997, which created economic incentives for pediatric 

product drug trials, the number of pediatric trials within FDA’s purview increased dramatically. FDA 

recognized a growing need for additional safeguards, which was reinforced by the Children’s Health Act, in 

which Congress mandated that “all research involving children that is conducted, supported, or regulated by 

HHS to be in compliance with 45 C.F.R. part 46, Subpart D” within six months of enactment (see Additional 

Safeguards for Children, 66 Fed. Reg. 20,589); Children’s Health Act of 2000. 42 U.S.C. § 289. In compliance 

with the Children’s Health Act, FDA adopted the language of HHS Subpart D as an interim rule with only 

minor modifications in language to tailor them to FDA’s regulatory authority.

75 Protection of Human Subjects, HHS. 45 C.F.R. §§ 46.40 et seq; Protection of Human Subjects, FDA. 21 C.F.R. 

§§ 50.1-3.

76 Although other agencies might conduct pediatric clinical research, this report focuses on FDA and HHS 

regulations, which govern most of the clinical research conducted in the United States.

77 Protection of Human Subjects, HHS. 45 C.F.R. §§ 46.401 et seq; Protection of Human Subjects, FDA. 21 C.F.R. 

§§ 50.50 et seq. 

78 Ibid.

79 Ibid. Of note, when this responsibility falls to FDA alone, the determination is made by the Commissioner 

of Food and Drugs rather than by the Secretary of HHS. Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54. For concurrent review under §§ 46.407 and 50.54, the Secretary makes the final determination. FDA. 

(2006, December). Guidance for Clinical Investigators, Institutional Review Boards, and Sponsors: Process 

for Handling Referrals to FDA Under 21 C.F.R. 50.54. Retrieved from http://www.fda.gov/downloads/

RegulatoryInformation/Guidances/ucm127605.pdf.

80 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54.

81 This report uses HHS citations in text, recognizing that the discussion applies to both HHS and FDA 

regulations.

82 The National Commission, (1977), op cit.

83 Ibid.

84 Ibid, p. 137.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

114

85 Ibid.

86 Ibid, pp. 2-3.

87 Ibid, p. xx. 

88 IOM, (2004), op cit; Letter from Secretary’s Advisory Committee on Human Research Protections 

(SACHRP) to Michael O. Leavitt, Former Secretary, HHS. (2005, July 28). SACHRP Chair Letter to HHS 

Secretary Regarding Recommendations. Retrieved from http://www.hhs.gov/ohrp/sachrp/sachrpltrtohhssec.

html; The National Commission, (1977), op cit; National Human Research Protections Advisory Committee 

(NHRPAC). (2001). Final Report to NHRPAC from Children’s Workgroup. Retrieved from http://www.hhs.

gov/ohrp/archive/nhrpac/documents/nhrpac16.pdf; Marshall, E. (2000). Enforcers halt NIH study called less 

risky than outdoor play. Science, 290(5495), 1281; Wendler, D., et al. (2005). Quantifying the federal minimal 

risk standard. Journal of the American Medical Association, 294(7), 826-832; see generally, Ross, L.F. (2003). 

Do healthy children deserve greater protection in medical research? Journal of Pediatrics, 142(2), 108-112; see 

also Rossi, J., and R.M. Nelson. (2012). Is there an objective way to compare research risks? Journal of Medical 

Ethics, 38(7), 423-427; Fisher, C.B, Kornetsky, S.Z., and E.D. Prentice. (2007). Determining risk in pediatric 

research with no prospect of direct benefit: Time for a national consensus on the interpretation of federal 

regulations. American Journal of Bioethics, 7(3), 5-10.

89 The National Commission concluded “[t]he acceptability of the risk presented by such an intervention should 

be determined in the same way that the acceptability of risk is determined for interventions that are applied in 

standard [medical] practice.” The National Commission, (1977), op cit, p. 125.

90 Ibid, pp. 125-126.

91 Protection of Human Subjects, HHS. 45 C.F.R. § 46.405; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.52; The National Commission, (1977), op cit, pp. 5-6.

92 Protection of Human Subjects, HHS. 45 C.F.R. § 46.405; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.52.

93 Although the National Commission never directly defined the term, it generally referred to it as a benefit 

to the individual’s “health or welfare.” The National Commission, (1977), op cit; More recently, NBAC 

specifically defined the range of benefits an IRB could consider, including within the category of direct 

benefit, “clinically significant information that could be used to influence the care provided,” “standard 

treatments or interventions as part of the research,” and “access to experimental therapies that may improve 

the participant’s health status.” NBAC explicitly distinguished these benefits from what it termed “indirect 

benefits,” (encompassing benefits such as social contact, sharing information with others, and personal 

satisfaction) and from “incentives and payments,” which it explained were not benefits. NBAC, (2001), op cit, 

p. 73. Other scholars have written extensively on the use of altruism or contribution to an important project as 

a benefit justifying some degree of risk over minimal. King, N.M.P. (2000). Defining and describing benefit 

appropriately in clinical trials. Journal of Law, Medicine, and Ethics, 28(4), 332-343; Litton, P. (2012). A more 

persuasive justification for pediatric research. American Journal of Bioethics, 12(1), 44-46; Simon, C., et al. 

(2006). Altruistic discourse in the informed consent process for childhood cancer clinical trials. American 

Journal of Bioethics, 6(5), 40-47; Spriggs, M. (2006). Can children be altruistic research subjects? American 

Journal of Bioethics, 6(5), 49-50; Wendler, D. (2012). A new justification for pediatric research without the 

potential for clinical benefit. American Journal of Bioethics, 12(1), 23-31. 

94 The National Commission, (1977), op cit, p. 127.

95 Ibid, pp. 126-127.

96 Ibid, p. 127.

97 Ibid.

98 Ibid, p. 139.
ENDNOTES IV

115

99 Human Subjects Protection, HHS. 45 C.F.R. § 46.406; Human Subjects Protection, FDA. 21 C.F.R. § 50.53. 

The appropriateness of research posing more than minimal risk without the prospect of direct benefit involving 

children who have a disease or condition remains a contested issue. Fisher, et al. (2007), op cit; Martin, 

R.A., and J.S. Robert. (2007). Is risky pediatric research without prospect of direct benefit ever justified? 

American Journal of Bioethics, 7(3), 12-15. There is ongoing uncertainty over the precise definition of “disease 

or condition,” including whether it should be broadly or narrowly interpreted and whether being “at risk” for 

an illness constitutes a “condition.” Some have argued that “disease or condition” may be interpreted narrowly, 

as only a fully expressed disease or disability, or broadly, to include anything associated with illness. Problems 

with narrow interpretations arise because they do not take into account the fact that “the boundaries between 

being ‘healthy,’ ‘at risk,’ and ‘having a disease’ often blur,” and a narrow vision may shut out vital research 

for preventive therapies. At the same time, broad interpretations create the possibility of considering race, 

ethnicity, age, economic status, or other factors as “conditions” that justify risky research when the scientific 

evidence for causality among these factors may be questionable; Kopelman, L.M. (2004). What conditions 

justify risky nontherapeutic or “no benefit” pediatric studies: A sliding scale analysis. The Journal of Law, 

Medicine, and Ethics, 32(4), 749-758. Although debate over the scope of “disease or condition” continues, most 

IRBs are able to administer the provision adequately, and have roundly rejected its application to particular 

children who, due to clinical factors, can be classified as “at risk” for a disease or condition. See, e.g., Grimes 

v. Kennedy Krieger Institute, Inc., 782 A.2d 807 (Md. 29, 2001); Letter from Michael A. Carome, Director, 

Division of Compliance Oversight, HHS, to Michael M. Gottesman, Deputy Director for Intramural 

Research, National Institutes of Health (NIH). (2000, November 3). RE: Human Research Subject 

Protections Under Multiple Project Assurance (MPA) M-1000 Research Project: Population Differences in 

the Insulin Sensitivity, Resting Energy Expenditure, and Body Composition of Overweight Children and 

Children of Overweight Parents. Retrieved from http://www.hhs.gov/ohrp/detrm_letrs/nov00a.pdf.

100 For example, “[c]hildren with major chronic conditions, such as cystic fibrosis, diabetes, and sickle cell disease, 

used to die before reaching the age of majority. Now many live well into adulthood.” Oberman, M., and J. 

Frader. (2003). Dying children and medical research: Access to clinical trials as benefit and burden. American 

Journal of Law and Medicine, 29(2-3), 301-317. 

101 The National Commission, (1977), p. 140. 

102 Ibid, pp. 140-141.

103 Ibid, pp. 127-128, 140.

104 Ibid, p. 11. 

105 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54. [Emphasis added].

106 Proposed Regulations on Research Involving Children, 43 Fed. Reg. 31,786, 31,786 (July 21, 1978).

107 Ibid.

108 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54.

109 Botkin, J.R., Consultant, Pediatric Advisory Committee, FDA. (2005). Presentation to the Pediatric Ethics 

Subcommittee, Pediatric Advisory Committee, FDA, November 15. Retrieved from http://www.fda.gov/

ohrms/dockets/ac/05/transcripts/2005-4178t1.pdf.

110 “Healthy” in this context refers to individuals without the condition under investigation. While many children 

may have chronic conditions or transient infections, these illnesses do not necessarily interfere with their 

ability to act as controls in research. Unless a protocol involves no more than minimal risk, the inclusion of 

healthy individuals as controls cannot be approved under section 406 by a local IRB. Likewise, few of these 

protocols offer the prospect of direct benefit to healthy participants and thus cannot be approved under 

section 405. Protocols involving healthy controls have been the source of significant tension because, while the 

condition at issue might be very “serious,” it is rarely the type of exceptional situation for which the National 

Commission envisioned a need for nationwide public input and a justification for higher risk.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

116

111 See Appendix II: Summary of Pediatric Research Protocols Reviewed under 45 C.F.R. § 46.407 and/or 21 

C.F.R. § 50.54 (1991-2012); see also e.g., Kopelman, L.M., and T.F. Murphy. (2004). Ethical concerns about 

federal approval of risky pediatric studies. Pediatrics, 113(6), 1783-1789; Ross, L.F. (2005). Lessons to be 

learned from the 407 process. Health Matrix: Journal of Law-Medicine, 15(2), 401-421. One reason for this low 

number of protocols undergoing 407 review is the fact that the FDA did not fully adopt the language of HHS 

Subpart D, with minor modifications, until the year 2000. Additional Safeguards for Children in Clinical 

Investigations of FDA-Regulated Products, 66 Fed. Reg. 20,589, 20,591 (Dec. 2, 1998). The number of cases 

reviewed and approved is still remarkably small, even if the time period considered is the past 12 years after the 

language was fully adopted.

112 The National Commission, (1978), op cit; The National Commission, (1977), op cit, p. 140.

113 For more detail, see Chapter 1: Introduction – About this Report, and Chapter 3: Ethical Considerations for 

Pediatric Medical Countermeasure Research – Pre-event Studies Posing No More Than a Minor Increase over 

Minimal Risk Approvable under Section 407.

114 The benefit referred to in section 405 is not limited to the benefits of an intervention, but includes as well 

the benefits of a “monitoring procedure likely to contribute to the subject’s well-being.” Protection of Human 

Subjects, HHS. 45 C.F.R. § 46.405; Protection of Human Subjects, FDA. 21 C.F.R. § 50.52.

115 The Bioethics Commission recognized that in certain instances, when a threat is imminent, research carried 

out prior to the actual event might nevertheless be carried out more like post-event research (e.g., observational 

trials that are potentially approvable under section 405 because the imminence of the threat presents a 

situation where research participants stand to directly benefit). 

116 For more detail, see Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – Postevent Studies.

117 The National Commission, (1977), op cit, p. 140.

118 Protection of Human Subjects, HHS. 45 C.F.R. § 46.404; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.51.

119 Regules, J.A., Cummings, J.F., and C.F. Ockenhouse. (2011). The RTS,S vaccine candidate for malaria. Expert 

Review of Vaccines, 10(5), 589-599; WHO. (2002). Considerations Arising from Vaccine Trials Conducted in 

Paediatric Populations with High Disease Burden in Developing Countries: WHO/IVR Ethics Meeting, 26-28 

November 2002, Accra, Ghana. Geneva: WHO Department of Vaccines and Biologicals. Retrieved from 

http://whqlibdoc.who.int/hq/2004/WHO_V&B_04.04.pdf.

120 Such has been the case for AVA, for example. Given the lack of pediatric data, the NBSB stated “the absence 

of data about the safety and immunogenicity of AVA in children does not support the conclusion that AVA 

administration presents no more than a minor increase over minimal risk.” NBSB, op cit, p. 24. The American 

Academy of Pediatrics made a similar finding, noting that, “given the possible risks,” any pre-event pediatric 

AVA study would fall under the ambit of 21 C.F.R. § 50.54/45 C.F.R. § 46.407. Anderson, op cit.

121 “Zero data and limited data are very different.” Berkelman, R. (2012). Medical Countermeasure Roundtable. 

Presentation to PCSBI, August 2. Retrieved from http://bioethics.gov/cms/node/747.

122 Berlin, C.M. (2009). Pharmacokinetics in Children [Webpage]. Retrieved from http://www.merckmanuals.

com/professional/pediatrics/principles_of_drug_treatment_in_children/pharmacokinetics_in_children.html.

123 Cieslak, T.J., and F.M. Henretig. (2003). Ring-a-ring-a-roses: Bioterrorism and its peculiar relevance to 

pediatrics. Current Opinion in Pediatrics, 15(1), 107-111.

124 Sebastian, R.S., et al. (2010, September). What We Eat in America, NHANES 2005-2006: Fluid Milk 

Consumption in the United States. Food Research Group Dietary Data Brief No. 3. Retrieved from http://www.

ars.usda.gov/SP2UserFiles/Place/12355000/pdf/DBrief/3_milk_consumption_0506.pdf.

125 American Academy of Pediatrics. (2006). Chemical-biological terrorism and its impact on children. Pediatrics, 

118(3), 1267-1278; Benavides, S., and M.C. Nahata. (2002). Anthrax: Safe treatment for children. Annals of 

Pharmacotherapy, 36(2), 334-337; Cieslak and Henretig, op cit.
ENDNOTES IV

117

126 Protection of Human Subjects, HHS. 45 C.F.R. §§ 46.401 et seq.; Protection of Human Subjects, FDA. 21 C.F.R. 

§§ 50.50 et seq.

127 FDA. (2012, May). BioThrax® (Anthrax Vaccine Adsorbed), p. 2. Retrieved from http://www.fda.gov/

downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/

UCM074923.pdf.

128 IOM. (2002). The Anthrax Vaccine: Is it Safe? Does it Work? Washington, DC: National Academies Press.

129 Department of Defense. (n.d.). Anthrax Vaccine Immunization Program. Retrieved from http://www.anthrax.

osd.mil/vaccine/safe.asp; IOM noted that, similar to other vaccines, there are sex differences in adverse 

reaction rates following administration of AVA and they recommended monitoring these differences in future 

studies. IOM, (2002), op cit; Niu, M.T., et al. (2009). VAERS Working Group: Adverse events after anthrax 

vaccination reported to the Vaccine Adverse Event Reporting System (VAERS), 1990-2007. Vaccine, 27(2), 

290-297; Sever, J.L., et al. (2004). Safety of anthrax vaccine: An expanded review and evaluation of adverse 

events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiology and Drug 

Safety, 13(12), 825-840.

130 CDC, (2010), op cit. See generally CDC. (2012). Vaccine Information Statements: Anthrax. Retrieved from 

http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-anthrax.pdf.

131 CDC. (2012). Vaccine Information Statements. Retrieved from http://www.cdc.gov/vaccines/pubs/vis/; CDC. 

(2012). Vaccine Information Statements: Anthrax. Retrieved from http://www.cdc.gov/vaccines/pubs/vis/

downloads/vis-anthrax.pdf; CDC. (2012). Vaccine Information Statements: Yellow Fever. Retrieved from 

http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-yf.pdf; CDC. (2012). Vaccine Information Statements: 

MMR. Retrieved from http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-mmr.pdf.

132 CDC. (2012). Vaccine Information Statements: Anthrax. Retrieved from http://www.cdc.gov/vaccines/pubs/

vis/downloads/vis-anthrax.pdf.

133 CDC. (2012). Vaccine Information Statements. Retrieved from http://www.cdc.gov/vaccines/pubs/vis/; CDC, 

(2010), op cit.

134 Protection of Human Subjects, HHS. 45 C.F.R. § 46.102; Protection of Human Subjects, HHS. 45 C.F.R. § 

46.404.

135 CDC, (2010), op cit, p. 8; IOM, (2002), op cit; Marano, N., et al. (2008). Effects of a reduced dose schedule 

and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: A 

randomized trial. Journal of the American Medical Association, 300(13), 1532-1543.

136 Ivins, B.E., et al. (1996). Efficacy of a standard human anthrax vaccine against Bacillus anthracis aerosol spore 

challenge in rhesus monkeys. Salisbury Medical Bulletin, 87(Suppl), 125-126; Fellows, P.F., et al. (2001). 

Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus 

anthracis isolates of diverse geographical origin. Vaccine, 19(23–24), 3241-3247; Pitt, M.L., et al. (2001). In 

vitro correlate of immunity in a rabbit model of inhalational anthrax. Vaccine, 19(32), 4768-4773.

137 Vietri, et al., (2006), op cit; Friedlander, et al., (1993), op cit.

138 Brachman, P.S., et al. (1962). Field evaluation of a human anthrax vaccine. American Journal of Public Health, 

52(4), 632-645; CDC, (2010), op cit, p. 9; Friedlander, A.M., Grabenstein, J.D., and P.S. Brachman. (2012). 

Anthrax Vaccines. In S.A. Plotkin, et al. (Eds.). Vaccines, 6th Edition, Edinburgh: Elsevier/Sanders, p. 136.

139 CDC, (2010), op cit.

140 FDA. (2006). Guidance for Industry: Development of Preventive HIV Vaccines for Use in Pediatric 

Populations. Retrieved from http://www.fda.gov/BiologicsBloodVaccines/GuidanceCompliance

RegulatoryInformation/Guidances/Vaccines/ucm074819.htm; Guinovart, C., and P.L. Alonso. (2007). 

Methods for determining vaccine efficacy and effectiveness and the main barriers to developing a fully 

deployable malaria vaccine. Defining and Defeating the Intolerable Burden of Malaria III: Progress and 

Perspectives: Supplement to American Journal of Tropical Medicine and Hygiene, 77(6), 278-281; Lell, B., et al. 

(2009). A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

118

malaria vaccine candidates in children in Gabon. PLoS ONE, 4(10), e7611; Pediatric Research Equity Act. 21 

U.S.C. § 355c; WHO, (2002), op cit.

141 FDA, (2006), op cit.

142 Nelson, S., Senior Pediatric Ethicist and Lead Medical Officer, Office of Pediatric Therapeutics, Office of 

the Commissioner, FDA. (2012). Presentation to PCSBI. May 17. Retrieved from http://bioethics.gov/cms/

node/708.

143 CDC, (2010), op cit.

144 The National Commission, (1977), op cit, p. 139. 

145 For more detail, see Chapter 1: Introduction – About This Report, and Chapter 3: Ethical Considerations for 

Pediatric Medical Countermeasure Research – Ethical Grounding.

146 If the research is solely under FDA purview, the Commissioner of Food and Drugs will make this 

determination, rather than the Secretary of Health and Human Services. If the research is subject to both FDA 

and HHS regulation (i.e., because it is funded by HHS and regulated by FDA), then the review is conducted 

jointly by the agencies and the Secretary of HHS makes the final decision. Protection of Human Subjects 

Research, FDA. 21 C.F.R. § 50.54; Protection of Human Subjects Research, HHS. 45 C.F.R. § 46.407. 

147 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54.

148 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407 [Emphasis added]; see also Protection of Human 

Subjects, FDA. 21 C.F.R. § 50.54.

149 Ibid.

150 Much of this assessment will prove pathogen-specific. For additional details on the specific vulnerabilities of 

children to various threat agents, see Appendix III: Characteristics of Category A Biological Agents.

151 For further discussion of the implications of imminence, see Chapter 3: Current Ethical and Regulatory 

Framework for Pediatric Research – Post-event Studies.

152 Changes in formulation or virulence of an agent will also significantly and independently affect the value of 

proposed MCM research.

153 Protection of Human Subjects, HHS. 45 C.F.R. § 46.406; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.53.

154 To avoid improper optimism or research bias, the determination that research is likely to yield important 

knowledge should be determined not just by scientists, but by lay members of the reviewing panel as well.

155 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54. Although the regulations present no further guidance as to what constitutes “sound ethical principles,” 

the National Commission pointed to the Belmont principles of respect for persons, beneficence, and justice 

in its original recommendation, and specified additional principles that ought to apply. “The Commission 

believes that only research of major significance, in the presence of a serious health problem, would justify the 

approval of research under Recommendation (6)(B). The problem addressed must be a grave one, the expected 

benefit should be significant, the hypothesis regarding the expected benefit must be scientifically sound, and an 

equitable method should be used for selecting subjects who will be invited to participate. Finally, appropriate 

provisions should be made for assent of the subjects and permission and participation of parents or guardians.” 

The National Commission, (1977), op cit, p. 12.

156 Protection of Human Subjects, HHS. 45 C.F.R. § 46.404; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.51.

157 The National Commission, (1977), op cit, p. 139. 
ENDNOTES IV

119

158 Fleischman, A., Clinical Professor, Department of Pediatrics, Department of Epidemiology and Population 

Health, Albert Einstein College of Medicine, Yeshiva University. (2012). Ethical and Practical Considerations 

in 407 Review of Pediatric Research. Presentation to PCSBI, November 5. Retrieved from http://bioethics.

gov/cms/node/781.

159 Anderson, op cit; The National Commission, (1978), op cit.

160 The National Commission, (1978), op cit.

161 Emanuel, E.J., Abdoler, E., and L. Stunkel. (n.d.). Research Ethics: How to Treat People Who Participate 

in Research, National Institutes of Health (NIH). Retrieved from http://www.bioethics.nih.gov/education/

FNIH_BioethicsBrochure_WEB.PDF; Emanuel, E.J., Wendler, D., and C. Grady. (2000). What makes 

clinical research ethical? Journal of the American Medical Association, 283(20), 2701-2711; Shevell, M. (2002). 

Ethics of clinical research in children. Seminars in Pediatric Neurology, 9(1), 46-52.

162 FDA. (2011). Ensuring the Safety of Vaccines in the United States [Webpage]. Retrieved from http://www.

fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM298181.pdf; Michael, 

N., Director, U.S. Military HIV Research Program. (2013). Presentation to PCSBI, January 15. Retrieved 

from http://bioethics.gov/cms/node/816; IOM. (1993). The Children’s Vaccine Initiative: Achieving the Vision. 

Washington, DC: National Academies Press, p. 109-127. Retrieved from http://www.nap.edu/openbook.

php?record_id=2224&page=114; WHO, (2002), op cit.

163 WHO, (2002), op cit.

164 CIOMS and WHO, (2002), op cit; The National Commission, (1977), op cit.

165 Strictly speaking, the concept of “overall benefit to children as a class” here considers not only expected benefit 

but also any relevant risks such as risks of adverse reactions to the use of MCMs. 

166 In the event of an emergency, MCMs that are unapproved can be distributed in accordance with mechanisms 

that will be considered in detail in Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure 

Research – Post-event Studies.

167 Emanuel, et al., (2000), op cit.

168 Ibid.

169 Shevell, (2002), op cit.

170 PCSBI, (2011, December), op cit, p. 82.

171 Lockwood, B., 1st Vice President, USA Council of International Association of Emergency Managers. (2012). 

Medical Countermeasure (MCM) Distribution. Presentation to PCSBI, November 5. Retrieved from http://

bioethics.gov/cms/node/782 (“The single most frequently cited reason for [first responders] hesitating to 

report is lack of family protection.”); See also Walker, K., Program Manager, Emergency Services Coalition 

for Medical Preparedness. (2012). Comments submitted to PCSBI, September 11, 2012 (“Biological and 

chemical threats pose an universal, existential danger to all Americans, [and] the emergency services sector as 

the frontline require[s] special measures....Any plan to confront these threats cannot be considered complete 

without a strategy to ‘protect the protectors.’”).

172 Moore, T.A., Chairman, Department of Infectious Diseases, Ochsner Health System. (2012). Medical 

Countermeasure Roundtable Discussion. Presentation to PCSBI, July 9. Retrieved from http://bioethics.gov/

cms/node/747.

173 This plan might draw on extant distribution strategies and should include acquisition to the Strategic National 

Stockpile (SNS), like other products the U.S. government plans to use for pediatric populations in an 

emergency. 

174 To ensure an adequate supply, systems must be in place for rapid scale-up procedures and preparation for 

production and storage of the MCM in the event research concludes the MCM is appropriate for pediatric 

use. Hodge, J., Lincoln Professor of Health Law and Ethics, Sandra Day O’Connor College of Law, Arizona 

State University. (2012). Special Considerations for Medical Countermeasure Research and Use. Presentation 

to PCSBI, May 17. Retrieved from http://bioethics.gov/cms/node/710; Kaplowitz, L.J., Deputy Assistant 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

120

Secretary for Policy, Director, Office of Policy and Planning, Office of the Assistant Secretary for Preparedness 

and Response, HHS. (2012). Special Considerations for Medical Countermeasure Research and Use. 

Presentation to PCSBI, May 17. Retrieved from http://bioethics.gov/cms/node/710. 

175 This is not to say, however, that other contexts do not warrant treatment or compensation for research-related 

injuries. The Bioethics Commission reaffirms its endorsement of treatment and compensation for qualified 

harms resulting directly from research, as first set forth in Moral Science. PCSBI, (2011, December), op cit, pp. 

62-70.

176 Hope, T. (1997). Compensating subjects of medical research. Journal of Medical Ethics, 23(3), 131-32 

(arguing that compensation is not justified when research participants consent to risks). However, this view 

is overbroad, and does not apply in case of pediatric research. Fleischman, A.R., and L. K. Collogan. (2008). 

Research with children. In E.J. Emanuel, et al. (Eds.). The Oxford Textbook of Clinical Research Ethics. New 

York, NY: Oxford University Press. 

177 As a practical matter, individuals might be less willing to enroll children in pre-event pediatric MCM research 

conducted under section 407 if they are left unprotected in the event of injury, but, practical considerations 

aside, the ethical considerations provide sufficient reason to mandate compensation.

178 PCSBI, (2011, December), op cit, p. 62. 

179 Ibid, p. 64.

180 Health Resources and Services Administrations, HHS. (n.d.). National Vaccine Injury Compensation 

Program. [Webpage]. Retrieved from http://www.hrsa.gov/vaccinecompensation/index.html; PREP Act. 42 

U.S.C. §§ 247d-6d(i)(1).

181 The Office of Special Masters, U.S. Court Of Federal Claims. (2004). Guidelines for Practice Under The 

National Vaccine Injury Compensation Program. Retrieved from http://www.uscfc.uscourts.gov/sites/default/

files/OSM.Guidelines.pdf.

182 PREP Act. 42 U.S.C. §§ 247d-6d(i)(1); Targeted Liability Protections for Pandemic and Epidemic Products and 

Security Countermeasures. 42 U.S.C. §§ 247d-6d; Liu, E.C. (2010). Pandemic Flu and Medical Biodefense 

Countermeasure Liability Limitation. Washington, DC: Congressional Research Service, p. 4. Retrieved from 

http://www.fas.org/sgp/crs/misc/RS22327.pdf.

183 Covered Countermeasures Process. 42 U.S.C. §§ 247d-6e; Targeted Liability Protections for Pandemic and 

Epidemic Products and Security Countermeasures. 42 U.S.C. §§ 247d-6d; Liu, (2010), op cit, p. 4. (A declaration 

for anthrax has been in effect since October 1, 2008); Targeted Liability Protections for Pandemic and Epidemic 

Products and Security Countermeasures. 42 U.S.C. §§ 247d-6d.

184 PREP Act. 42 U.S.C. §§ 247d-6d(i)(1).

185 Ibid.

186 Countermeasures Injury Compensation Program (CICP): Administrative Implementation, HHS. 42 C.F.R. pt. 

110. 

187 HHS. (2010). Justification of Estimates for Appropriations Committees, p. 394. Retrieved from http://www.

hrsa.gov/about/pdf/budgetjustification2011.pdf.

188 Ibid.

189 For more detail, see Chapter 2: Current Ethical and Regulatory Framework for Pediatric Research – 

Development of the Central Tenet of Pediatric Research, Democratic Deliberation. See also The National 

Commission, (1978), op cit; The National Commission, (1977), op cit; PCSBI, (2010, December), op cit, pp. 

24-31; PCSBI, (2011, December), op cit, pp. 96-101; PCSBI, (2012, October), op cit, pp. 27-31. 

190 Joint United Nations Program on HIV/AIDS. (2011). Good Participatory Practices, Guidelines for Biomedical 

HIV Prevention Trials 2011, Second Edition. Retrieved from http://www.unaids.org/en/media/unaids/

contentassets/documents/unaidspublication/2011/JC1853_GPP_Guidelines_2011_en.pdf.
ENDNOTES IV

121

191 For more detail, see Chapter 3: Ethical Considerations for Pediatric Medical Countermeasure Research – Postevent Studies, Community Engagement in Post-event Research.

192 Joint United Nations Program on HIV/AIDS, op cit.

193 Ibid, p. 14; Horowitz, C.R., Robinson, R.M., and S. Seifer. (2009). Community-based participatory research 

from the margin to the mainstream: Are researchers prepared? Circulation, 119(19), 2633-2642. 

194 Joint United Nations Program on HIV/AIDS, op cit.

195 Community advisory boards, when used, are generally stipulated for every site at which a study is conducted 

and provide a means for community members and research participants to provide insight and feedback on 

the proposed research design and methods. For further information on the Framingham Heart Study Ethics 

Advisory Board, see The Framingham Heart Study. (2013). About the Framingham Heart Study [Webpage].

Retrieved from http://www.framinghamheartstudy.org/about/index.html. For further information on the 

community advisory boards of the HIV Vaccine Trials Network, see the HIV Vaccine Trials Network. 

(n.d.). Community Advisory Board (CAB). Retrieved from http://www.hvtn.org/community/cab.html. 

See also Community Recommendations Working Group of Community Partners and NIAID. (2009). 

Recommendations for Community Involvement in National Institute of Allergy and Infectious Diseases HIV/

AIDS Clinical Trials Research. Retrieved from http://www.hvtn.org/community/CAB_Recommendations_

Certified.pdf (describing the requirements for community advisory boards in certain NIH-funded trials); 

Woodsong, C., and Q. A. Karim. (2005). A model designed to enhance informed consent: Experiences from 

the HIV Prevention Trials Network. American Journal of Public Health, 95(3), 412-419. 

196 PCSBI, (2011, December), op cit, pp. 47-48.

197 IRB membership criteria might also inform 407 panel composition. The membership requirements of IRBs 

are established by Institutional Review Boards, FDA. 21 C.F.R. § 56.107 and IRB membership, HHS. 45 

C.F.R. § 46.107; See also Recommendations 3.9 and 3.10 of the NBAC’s 2001 report. NBAC, (2001), op cit; 

DeVries, R., and C.P. Forsberg. (2002). Who decides? A look at ethics committee membership. HEC Forum, 

14(3), 252-258; Schuppli, C.A., and D. Fraser. (2007). Factors influencing the effectiveness of research ethics 

committees. Journal of Medical Ethics, 33(5), 294-301; Speers, M.A., and S. Rose. (2012). Commentary: 

Labeling institutional review board members does not lead to better protections for research participants. 

Academic Medicine, 87(7), 842-844.

198 Protection of Human Subjects, HHS. 45 C.F.R. § 46.407; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.54.

199 The National Commission, (1978), op cit.

200 Ibid; See also Young, W.F., President, The Endocrine Society. (2012). Comments submitted to PCSBI, 

August 23, 2012 (“IRBs [should] avoid viewing children of all ages as equal in cognition and critical 

thinking capabilities. Older children and adolescents should be viewed with the potential for higher levels of 

understanding and self-determination.”).

201 For the purposes of this report, the Bioethics Commission refers both to parents and legal guardians when it 

used the word “parent.”

202 Protection of Human Subjects, HHS. 45 C.F.R. § 46.116; Protection of Human Subjects, HHS. 45 C.F.R. 46 

§ 46.408; Diekema, D.S. (2006). Conducting ethical research in pediatrics: A brief historical overview and 

review of pediatric regulations. The Journal of Pediatrics, 149(Suppl.1), S3-11; Kodish, E. (2003). Informed 

consent for pediatric research: Is it really possible? The Journal of Pediatrics, 142(2), 89-90.

203 Protection of Human Subjects, HHS. 45 C.F.R. § 46.116; The National Commission, (1978), op cit.

204 Protection of Human Subjects, HHS. 45 C.F.R. § 46.116.

205 The National Commission, (1977), op cit, p. 129; The National Commission, (1978), op cit.

206 Even where not recognized by law, mature adolescents may generally be perceived as at least as capable of 

understanding the ramifications of their choices, and of exercising self-determination, as their less wise 

counterparts who happen to be 18 years of age. 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

122

207 Joffe, S. (2003). Rethink “affirmative agreement,” but abandon “assent.” The American Journal of Bioethics, 3(4), 

9-11; Wendler, D., and S. Shah. (2003). Should children decide whether they are enrolled in nonbeneficial 

research? The American Journal of Bioethics, 3(4), 1-7; Wilfond, B.S., and D.S. Diekema. (2012). Engaging 

children in genomics research: Decoding the meaning of assent in research. Genetics in Medicine, 14(4), 

437-443.

208 Miller, V.A., and R.M. Nelson. (2006). A developmental approach to child assent for nontherapeutic research. 

The Journal of Pediatrics, 149(1Suppl), S25-S30.

209 Brody, J.L., et al. (2003). Voluntary assent in biomedical research with adolescents: A comparison of parent 

and adolescent views. Ethics and Behavior, 13(1), 79-95; Snethen, J.A., et al. (2006). Family patterns of 

decision-making in pediatric clinical trials. Research in Nursing and Health, 29(3), 223-232; Varma, S., Jenkins, 

T., and D. Wendler. (2008). How do children and parents make decisions about pediatric clinical research? 

Journal of Pediatric Hematology/Oncology, 30(11), 823-828; Wendler and Shah, op cit, p. 4.

210 Protection of Human Subjects, HHS. 45 C.F.R. § 46.402(b). There are two possible exceptions to requiring 

participant assent: First, when the research offers a prospect of direct benefit to participants that is otherwise 

unattainable with existing alternatives. This exception does not apply in the case of research reviewed under 

section 407. Second, taking into account the age, maturity, and psychological state of potential participants, an 

IRB determines that participants are not competent to reasonably be consulted. Protection of Human Subjects, 

HHS. 45 C.F.R. § 46.408(a). On the differing standards for dissent and assent, see Murphy, T.F. (2003). 

Assent and dissent in 407 research with children. The American Journal of Bioethics, 3(4), 18-19; Wendler, D.S. 

(2006). Assent in paediatric research: Theoretical and practical considerations. Journal of Medical Ethics, 32(4), 

229-234; Wendler and Shah, op cit, p. 6.

211 Fleischman, op cit.

212 Ibid.

213 O’Lonergan, T.A., and J.E. Forster-Harwood. (2011). Novel approach to parental permission and child assent 

for research: Improving comprehension. Pediatrics, 127(5), 917-924.

214 Fleischman, op cit.

215 See Appendix IV: An Ethical Framework to Guide National-Level Review of Pediatric Medical 

Countermeasure Research under 45 C.F.R. § 46.407 and/or 21 C.F.R. § 50.54.

216 NBSB, op cit, p. 25.

217 Given the Bioethics Commission’s definition of MCM, as FDA-regulated products and interventions used 

to combat the effects of CBRN events, the post-event research discussion is focused on MCMs employed in 

response to a CBRN event. Much of what is discussed, however, can be applied more broadly to interventions 

used in response to any public health emergency.

218 This section primarily addresses the ethical considerations of post-event MCM research with children. 

However, ethical concerns can emerge in other aspects of bioterrorism planning and response as well, 

especially in the clinical realm, involving, for example, triage, the distribution and allocation of supplies, and 

informed consent to treatment. See, e.g., Berg, J., and N. King. (2006). Strange bedfellows? Reflections on 

bioethics’ role in disaster response planning. The American Journal of Bioethics, 6(5), 3-5; Holloway, H.C., et al. 

(1997). The threat of biological weapons: Prophylaxis and mitigation of psychological and social consequences. 

Journal of the American Medical Association, 278(5), 425-427; Moreno, J. (2002). Bioethics After the Terror. 

American Journal of Bioethics, 2(1), 60-64; Pesik, N., Keim, M.E., and K.V. Iserson. (2001). Terrorism and 

the ethics of emergency medical care. Annals of Emergency Medicine, 37(6), 642-645; Sutton, V. (2005). A 

multidisciplinary approach to an ethic of biodefense and bioterrorism. The Journal of Law, Medicine, and 

Ethics, 33(2), 310-322; Thewes, J., Fitzgerald, D., and D.P. Sulmasy. (1996). Informed consent in emergency 

medicine: Ethics under fire. Emergency Medicine Clinics of North America, 14(1), 245-254. To the extent that 

these complexities constrain the conduct of researchers, they ought to inform the design and implementation 

of post-event research. They are also deserving of distinct ethical consideration for those developing guidelines 

for disaster preparedness and emergency clinical practice—topics that lie outside the purview of this report.

219 For more detail, see Chapter 1: Introduction, and see Chapter 3: Ethical Considerations for Pediatric Medical 

Countermeasure Research – Ethical Grounding.
ENDNOTES IV

123

220 It is also possible that post-event research could be minimal risk (approvable under 45 C.F.R. § 46.404) where 

the only intervention is observational research.

221 Protection of Human Subjects, HHS. 45 C.F.R. § 46.406; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.33.

222 Protection of Human Subjects, HHS. 45 C.F.R. § 46.405; Protection of Human Subjects, FDA. 21 C.F.R. § 

50.52.

223 Investigational New Drug Application, Early Application, FDA. 21 C.F.R. § 312.82.

224 Maher, op cit.

225 Chong, S., et al. (2010). Clinical research in times of pandemics. Public Health Ethics, 3(1), 35-38; IOM. 

(2011). Advancing Regulatory Science for Medical Countermeasure Development: Workshop Summary. 

Washington, DC: National Academies Press, pp. 69-70.

226 Biros, M.H., et al. (1995). Informed consent in emergency research: Consensus statement from the Coalition 

Conference of Acute Resuscitation and Critical Care Researchers. Journal of the American Medical Association, 

273(16), 1283-1287; Quinn, S.C., Thomas, T., and S. Kumar. (2008). The anthrax vaccine and research: 

Reactions from postal workers and public health professionals. Biosecurity and Bioterrorism: Biodefense Strategy, 

Practice, and Science, 6(4), 321-333.

227 HHS. (2013, February 8). Vaccine Adverse Event Reporting System (VAERS) [Webpage]. Retrieved from 

http://vaers.hhs.gov/index; Postmarketing Reporting of Adverse Experiences, FDA. 21 C.F.R. § 600.80; 

Investigational New Drug Application, FDA. 21 C.F.R. pt. 312. For an illustration of the differences 

between active and passive surveillance, see Appendix V: Example of Difference between Passive and Active 

Surveillance Study.

228 NBSB, op cit.

229 Ibid.

230 Ibid.

231 Bales, M.E., et al. (2002). Epidemiologic response to anthrax outbreaks: Field investigations, 1950–2001. 

Emerging Infectious Diseases, 8(10), 1163-1174; NBSB, op cit. 

232 This may not be the case if pathogens are naturally occurring in certain regions, which might make efficacy 

testing in those regions ethically possible.

233 NBSB, op cit.

234 Halsey, N.A., et al. (2012). Algorithm to assess causality after individual adverse events following 

immunizations. Vaccine, 30(39), 5791-5798.

235 Ibid.

236 For more detail, see Chapter 2: Current Ethical and Regulatory Framework for Pediatric Research – 

Development of the Central Tenet of Pediatric Research, Democratic Deliberation, and see Chapter 3: Ethical 

Considerations for Pediatric Medical Countermeasure Research – Pre-event Studies Posing No More Than a 

Minor Increase over Minimal Risk Approvable under Section 407, Community Engagement.

237 Expanded Access to Unapproved Therapies and Diagnostics. 21 U.S.C. § 360bbb-3.

238 Ibid.

239 Ibid.

240 Ibid.

241 FDA. (2005, August 3). SOPP 8010: Administrative Procedures for Emergency Use Authorization of Medical 

Products. Retrieved from http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatory

Information/ProceduresSOPPs/ucm061226.htm. 
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

124

242 FDA. (2007, July). Guidance-Emergency Use Authorization of Medical Products. Retrieved from http://www.

fda.gov/RegulatoryInformation/Guidances/ucm125127.htm.

243 Nightingale, S.L., Prasher, J.M., and S. Simonson. (2007). Emergency Use Authorization (EUA) to enable 

use of needed products in civilian and military emergencies, United States. Emerging Infectious Diseases, 13(7), 

1046-1051.

244 Maher, op cit.

245 Investigational New Drug Application, FDA. 21 C.F.R. § 312.20. Although the IND process is the same for 

drugs and biologics, the process of approval for drugs and biologics is different. Drugs are approved by FDA 

through the New Drug Application, Abbreviated New Drug Application, and Over the Counter processes 

and biologics are approved through the Biologic Licensing Application process. FDA. (2010, September 21). 

Types of Applications [Webpage]. Retrieved from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/

HowDrugsareDevelopedandApproved/ApprovalApplications/default.htm.

246 FDA. (2011, June 6). Investigational New Drug (IND) Application [Webpage]. Retrieved from http://www.

fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/

InvestigationalNewDrugINDApplication/default.htm. 

247 Investigational New Drug Application, FDA. 21 C.F.R. pt. 312.

248 Nightingale et al., op cit. 

249 Halsey, N., Professor of International Health, Johns Hopkins Bloomberg School of Public Health and 

Professor and Pediatric Infectious Disease Physician, Department of Pediatrics, Johns Hopkins School 

of Medicine. (2012). Assessing Pediatric Research: Considering Individual Risk and Societal Benefit. 

Presentation to PCSBI, August 2. Retrieved from http://bioethics.gov/cms/node/744; Nelson, op cit.

250 Investigational New Drug Application, FDA. 21 C.F.R. § 312.305.

251 Investigational New Drug Application, FDA. 21 C.F.R. § 312.82; FDA. (2011, June 6). Investigational 

New Drug (IND) Application [Webpage]. Retrieved from http://www.fda.gov/Drugs/

DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/

InvestigationalNewDrugINDApplication/default.htm. 

252 Investigational New Drug Application, FDA. 21 C.F.R. pt. 312.

253 FDA. (2011, June 6). Investigational New Drug (IND) Application [Webpage]. Retrieved from http://www.

fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/

InvestigationalNewDrugINDApplication/default.htm. 

254 Memorandum from Jason Gerson, Senior Officer, Innovate FDA, and Skip Nelson, Senior Pediatric Ethics, 

Office of Pediatric Therapeutics, FDA, to PCSBI. (2012, May 15). FDA Medical Countermeasures-Related 

Documents and Information.

255 CDC, (2010), op cit, p. 21; NBSB, op cit, p. 18.

256 Maher, op cit. 

257 CDC, (2010), op cit; Maher, op cit.

258 HHS. (2013, February 8). Vaccine Adverse Event Reporting System (VAERS) [Webpage]. Retrieved from 

http://vaers.hhs.gov/index.

259 The 2002 IOM Report on AVA safety and efficacy distinguishes between active and passive surveillance trials, 

and describes the methods of several active surveillance trials. Those studies include blood draws to determine 

immunogenicity, as well as close communication between health care personnel and vaccine recipients to 

determine the presence of both local and systemic adverse events. IOM, (2002), op cit.

260 See Maher, op cit; Nelson, op cit.
125

APPENDICES
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

126

Appendix I: Sources of Pediatric Vulnerability

Although children might exhibit a range of vulnerabilities, the one most 

commonly associated with children is cognitive vulnerability. The chart below 

summarizes the much broader range of potential vulnerabilities that a child 

might experience.

TYPE OF VULNERABILITY DESCRIPTION OF SOURCE OF VULNERABILITY

Incapacitational Limits on the capacity to deliberate about and decide to participate in a 

study due to cognitive development and deliberative ability.

Juridic Formal relationships of authority or power, often hierarchical, built into 

social structures. Especially noteworthy for children are the legal and 

parental authority of parents or guardians.

Deferential Social and cultural pressures that socialize some into a willingness to 

comply with the desires of others, despite an inner reluctance. This may 

coincide with the relationships characteristic of juridic vulnerability.

Social Entrenched prejudice and stereotypical thinking that compromises care 

and consideration due to children. Membership in a group whose rights and 

interests have been socially disvalued.

Situational Medical urgency or other forms of exigency create circumstances that 

remove or create obstacles to eliciting the education, deliberation, and 

decision making characteristic of informed consent and child assent.

Medical Medical diagnoses or prognoses that alter a prospective participant’s costbenefit calculations to skew them toward taking risks they otherwise would 

think foolish.

Allocational Social and accidental distribution of benefits and burdens that participation 

in research might exacerbate or exploit.

Adapted from: Kipnis, K. (2003). Seven vulnerabilities in the pediatric research subject. Theoretical Medicine, 24(2), 107-120.
APPENDICES V

127

Appendix II: Summary of Pediatric Research Protocols Reviewed under 

45 C.F.R. § 46.407 and/or 21 C.F.R. § 50.54 (1991-2012) 

Since 1991, 14 expert panels have been convened pursuant to 45 C.F.R. 

§ 46.407 (and/or 21 C.F.R. § 50.54) to review pediatric research protocols. 

Of these protocols, 10 were approved, including 2 approved under 45 C.F.R. 

§ 46.406 and another approved under 45 C.F.R. § 46.405 for the affected 

children involved and under 45 C.F.R. § 46.407 for the healthy child 

participants. Four research protocols were denied approval by national-level 

reviewers. One protocol was denied on the grounds that it lacked sufficient 

scientific justification and contained serious shortcomings with respect to 

informed consent, and because the in vitro and animal data were insufficient to 

justify the research in younger children prior to testing with older children. Two 

protocols were denied because there were insufficient data from adult trials to 

justify the work with children. Another protocol, a review of Dryvax (smallpox 

vaccine) research, was not approved because bioterrorism preparedness plans 

had evolved and the government no longer planned to use Dryvax for children.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

128

PRIOR NATIONAL-LEVEL REVIEWS (1991-2012)

TITLE, YEAR RESEARCH GOAL 

Myoblast Transfer in Duchenne Muscular 

Dystrophy, 1991*

Characterize the effects of myoblast transfer in young children. 

NIH Human Growth Hormone Protocol, 

1992†

Test synthetic human growth hormone to determine whether it increases 

ultimate adult height.

Cognitive Function and Hypoglycemia in 

Children with Insulin-Dependent Diabetes 

Mellitus, 1993‡

Collect data on differences in children related to blood sugar. Proposal 

would test healthy children and children with Type I diabetes. Testing 

would involve infusing through two intravenous lines glucose and insulin 

at varying infusion rates to attain a specific blood glucose level.

Hyperglycemic and EuglycemicHyperinsulinemic Clamp Procedure 

(Subset of Larger Obesity Study halted 

by OHRP for review), 2000§

Monitoring obese or at risk for obesity children to understand genetic 

factors that affect body weight. Included in the protocol were blood 

draws, X-ray imaging, MRI abdomen scans, and the “clamp” procedure, 

involving an overnight hospital stay while intravenous catheters were 

inserted and used to infuse sugar and insulin.

Precursors to Diabetes in JapaneseAmerican Youth, 2002¶Study would enroll 300 healthy, non-diabetic children with some degree 

of Japanese descent and 150 healthy, non-diabetic children of Caucasian 

descent between the ages of 8 and 10 years and follow them for two years 

to observe factors that could contribute to diabetes development. Protocol 

involved physical examination, blood draw, intravenous glucose tolerance 

test, dual energy X-ray absorptiometry, and MRI to measure abdominal fat.

Alcohol, Sleep, and Circadian Rhythms in 

Young Humans, Study 2–Effects of Evening 

Ingestion of Alcohol on Sleep, Circadian 

Phase, and Performance as a Function 

of Parental History of Alcohol Abuse/

Dependence, 2003#

Protocol would study the effects of a small or moderate evening 

dose of alcohol on sleep, waking performance, and circadian phase 

in adolescents and young adults, and examine how the effects may 

differ between individuals who have a parent with a history of alcohol 

dependence and those who do not. Study would give participants 

alcohol.

Characterizations of Mucus and Mucins in 

Bronchoalveolar Lavage Fluids from Infants 

with Cystic Fibrosis, 2003**

Proposed longitudinal study of the changes in bronchoalveolar lavage 

fluid of infants diagnosed with cystic fibrosis in the neonatal period. 

Researchers would perform bronchoscopies in infants diagnosed with 

cystic fibrosis in the first six weeks of life, at six months, and at one 

year. Control data would be obtained from children without cystic 

fibrosis who were undergoing bronchoalveolar lavage for other clinical 

indications.

* Proposed Protocol Entitled Myoblast Transfer in Duchenne Muscular Dystrophy; Recommendations, 56 Fed. Reg. 49189 

(Sept. 27, 1991). † NIH Human Growth Hormone Protocol Review Committee. (1992). Report of the NIH Human Growth Hormone Protocol 

Review Committee. Bethesda, MD: NIH. ‡ Cognitive Function and Hypoglycemia in Children with IDDM, 58 Fed. Reg. 40819 (July 30, 1993). § Marshall, (2000), op cit. ¶ Ross, L.F. (2004). Convening a 407 panel for research not otherwise approvable: “Precursors to diabetes in 

Japanese American youth” as a case study. Kennedy Institute of Ethics Journal, 14(2), 165-186.
APPENDICES V

129

REASON REFERRED TO 407 REVIEW PANEL PANEL DECISION

Research involved risks “significantly greater 

than minimal” and offered no prospect of direct 

benefit to the individual children who were to be 

participants. 

Not approved. The panel concluded that the proposed protocol lacked 

sufficient scientific justification and contained serious shortcomings 

with respect to informed consent. The panel found the protocol 

to be based on insufficient in vitro and animal data, and to lack 

justification for initiation in younger rather than older children. 

Concerns raised by various nonprofit oversight 

groups and IRBs that use of placebo controls 

in these trials exposed children to unnecessary 

discomfort and psychosocial risks. Panel 

convened mid-study.

Approved. The panel concluded that the risks posed were no greater 

than a minor increase over minimal and with adequate disclosure 

about placebo and ongoing monitoring of the placebo group, 

including annual re-assent, the study complied with section 406.

Research involved greater than minimal risk 

and offered no prospect of direct benefit to the 

individual children who were to be the healthy 

control participants. 

Approved. The panel concluded the protocol presented reasonable 

opportunity to further understanding of a serious condition 

affecting the health or welfare of children.

Research involved greater than minimal 

risk, offered no prospect of direct benefit, 

and proposed to enroll healthy children as 

participants. 

Approved. The protocol was originally approved by the IRB as 

involving minimal risk, based on their assessment that the study 

was no more dangerous than “playing actively on sidewalks and 

streets.” The HHS Office for Human Research Protections (OHRP) 

halted the study, finding the IRB application of minimal risk outside 

the proper scope of the term. OHRP later permitted the study to 

proceed under a reinterpretation of the participants as having a 

condition by being at risk for developing Type 2 diabetes, and a 

finding that the research was no more than a minor increase over 

minimal risk (section 406).

Research involved greater than minimal 

risk, offered no prospect of direct benefit, 

and proposed to enroll healthy children as 

participants. 

Approved. The panel concluded that it was an opportunity to 

further understanding of a serious condition affecting the health 

or welfare of children. One panel member dissented, arguing that 

design defects made the trial unlikely to yield useful information. It 

is unclear whether the protocol was ever employed.

Research involved greater than minimal 

risk, offered no prospect of direct benefit, 

and proposed to enroll healthy children as 

participants. 

Not approved. The panel concluded that insufficient data existed 

for similar research in adult populations from which a decision 

about the risks and safety of the protocol could be made. OHRP 

allowed research to move forward in the population of individuals 

21 to 22 years of age, noting that the resulting information could be 

used when the adolescent protocol was re-reviewed.

Research involved greater than a minor increase 

over minimal risk and offered no prospect of 

direct benefit to participants.

Approved. The panel concluded that it was an opportunity to 

further understanding of a serious condition affecting the health 

or welfare of children, but conditioned approval on certain protocol 

modifications to ensure that the protocol complied with sound 

ethical principles.

# Solicitation of Public Review and Comment on Research Protocol: Alcohol, Sleep, and Circadian Rhythms in Young 

Humans, Study 2—Effects of Evening Ingestion of Alcohol on Sleep, Circadian Phase, and Performance as a Function of 

Parental History of Alcohol Abuse/Dependence, 68 Fed. Reg. 17950 (April 14, 2003).

**Solicitation of Public Review and Comment on Research Protocol: Characterization of Mucus and Mucins in 

Bronchoalveolar Lavage Fluids from Infants with Cystic Fibrosis, 68 Fed. Reg. 35414, 35415 (June 13, 2003).

General Sources: Kopelman, L.M., and T.F. Murphy. (2004). Ethical concerns about federal approval of risky pediatric 

studies. Pediatrics, 113(6), 1783-1789; Ross, L.F. (2005). Lessons to be learned from the 407 process. Health Matrix: 

Journal of Law-Medicine, 15(2), 401-421.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

130

PRIOR NATIONAL-LEVEL REVIEWS (1991-2012)

TITLE, YEAR RESEARCH GOAL

HIV Replication and Thymopoiesis in 

Adolescents, 2003*

Study to understand the premature aging of the immune system for 

individuals infected with HIV. Study proposed using healthy, HIV negative 

controls as well as individuals with HIV. Study would enroll individuals 

between the ages of 13 and 24 years and the protocol involved medical 

histories, physical exams, and computed tomography (CT) scans of the 

thymus. A subset of the study populations would receive glucose either 

intravenously or by the mouth and be monitored through blood draws.

Sleep Mechanisms in Children: Role of 

Metabolism, 2003†

In order to better understand the interaction of sleep and metabolism 

in children, the study would track glycogen content, glutamate turnover 

rate, and glutamate-glutamine cycling in wakefulness and sleep in 

children aged 13-17 years. 

Multicenter Randomized Dose Response 

Study of the Safety, Clinical, and Immune 

Responses of Dryvax Administered to 

Children 2 to 5 years of Age, 2003‡

Study would test a diluted form of Dryvax, a smallpox vaccine, in children 

between the ages of 2 and 5 years. The goal of the study was to determine 

whether the limited remaining supply of Dryvax, which was no longer being 

produced, could be stretched to protect more people by diluting the vaccine.

Effects of a Single Dose of 

Dextroamphetamine in Attention 

Deficit Disorder: A Functional Magnetic 

Resonance Study, 2004§

Protocol would administer a single 10 milligram dose of 

dextroamphetamine with concurrent functional magnetic resonance 

imaging (fMRI) to children between the ages of 9 and 18 years 

with attention deficit hyperactivity (ADHD) and normal controls. In 

addition to the fMRI, subjects would also submit to a screening MRI, 

neuropsychological testing, and basic health exam and medical history 

review, including pregnancy testing. 

Gonadotropin Releasing Hormone (GnRH) 

Agonist Test in Disorders of Puberty, 2005¶

Study would investigate the quality of a new diagnostic procedure 

intended to better distinguish among causes of precocious puberty and 

delayed puberty in children and young adults. Investigators planned to 

administer in healthy children and children with disorders of puberty 

a single dose of leuprolide acetate and measure hormonal response in 

serial blood samples over a 24-hour period. 

Precursor Preferences in Surfactant 

Synthesis of Newborns, 2005#

Study designed to better understand the potential differences in 

precursor preferences in surfactant synthesis between preterm infants 

with immature lungs and full-term infants with normal lung function. 

Protocol involved administration of labeled palmitate and acetate to both 

subject groups and, subsequently, measuring the incorporation of each 

infusion into surfactant collected by tracheal aspiration.

A Phase III Randomized Trial of Granulocyte 

Colony Stimulating Factor Stimulated Bone 

Marrow vs. Conventional Bone Marrow 

as a Stem Cell Source in Matched Sibling 

Donor Transplantation, 2008**

Protocol would compare granulocyte colony stimulating factor stimulated 

bone marrow with conventional bone marrow as a stem cell source in 

matched sibling donor transplantation. Study would be conducted in 

sibling pairs, one sibling acting as the bone marrow donor and the other 

receiving the bone marrow. 

* Ross, (2005), op cit.

†

 Solicitation of Public Review and Comment on a Research Protocol: Sleep Mechanism in Children: Role of Metabolism, 68 Fed. 

Reg. 35415 (June 13, 2003). ‡

 Solicitation of Public Review and Comment on Research Protocol: A MultiCenter Randomized Dose Response Study of the 

Safety, Clinical, and Immune Response of Dryvax® Administered to Children 2 to 5 Years of Age, 67 Fed. Reg. 66403, 66404 

(Oct. 31, 2002); Irene Stith-Coleman and David A. LePay, HHS, to Stewart Laidlaw. (2003, January 24). Determination Letter. 

Retrieved from http://www.hhs.gov/ohrp/archive/dpanel/determ.pdf. §

 Solicitation of Public Review and Comment on Research Protocol: Effects of a Single Dose of Dextroamphetamine in Attention 

Deficit Hyperactivity Disorder; a Functional Magnetic Resonance Study, 69 Fed. Reg. 47158, 47159 (Aug. 4, 2004); Pediatric 

Ethics Subcommittee of the Pediatric Advisory Committee, HHS, FDA, Center for Drug Evaluation and Research. (2004, 

September 10). Transcript of Pediatric Ethics Subcommittee of the Pediatric Advisory Committee. Retrieved from http://www.

fda.gov/ohrms/dockets/ac/04/transcripts/2004-4066T1.htm. ¶

 Office of Human Research Protections. (2007, February 23). Gonadotropin Releasing Hormone (GnRH) Agonist Test in 

Disorders of Puberty [Webpage]. Retrieved from http://www.hhs.gov/ohrp/archive/children/gnrh.html; Letter from Bernard 
APPENDICES V

131

REASON REFERRED TO 407 REVIEW PANEL PANEL DECISION

Research involved greater than minimal risk 

and offered no prospect of direct benefit to the 

individual children who were to be the healthy 

control participants. 

Approved. The panel concluded that this protocol presented an 

opportunity to further the understanding of a serious condition 

affecting the health or welfare of children. Panelist concerns 

focused on radiation exposure during CT scans but the panel 

ultimately decided the protocol was approvable.

Research involved greater than minimal risk, 

offered no prospect of direct benefit, and proposed 

to enroll healthy children as participants. 

Not approved. The panel concluded that there were not yet any 

data in adults.

Research involved greater than minimal risk, 

offered no prospect of direct benefit, and proposed 

to enroll healthy children as participants. 

Not approved. The protocol was rejected because bioterrorism 

preparedness plans had evolved and the government no longer 

planned to use Dryvax for children.

Research involved greater than minimal risk 

and offered no prospect of direct benefit to the 

individual children who were to be the healthy 

control participants. 

Approved. The panel concluded the protocol presented was a 

reasonable opportunity to further understanding of a serious 

condition affecting the health or welfare of children. Approval was 

conditioned on return of neuropsychological testing results to 

children and parents. 

Research involved greater than minimal risk 

and offered no prospect of direct benefit to the 

individual children who were to be the healthy 

control participants. 

Approved. The panel found that there was more than a minor 

increase over minimal risk for healthy children but that the study 

presented an opportunity to understand, prevent, or alleviate a 

serious problem affecting the health or welfare of children.

Research involved greater than minimal risk 

and offered no prospect of direct benefit to the 

individual children who were to be the healthy 

control participants. 

Approved. The panel concluded that the study presented an 

opportunity to further understanding of a serious condition 

affecting the health or welfare of children.

Research involved more than a minor increase 

over minimal risk and offered no prospect of 

direct benefit to the healthy sibling donors.

Approved. The panel concluded that the study presented an 

opportunity to further understanding of a serious condition 

affecting the health or welfare of children.

A. Schwetz, Director, Office of Human Research Protections, Office of Public Health and Science, and Diane Murphy, 

Director, Office of Pediatric Therapeutics, FDA, to Mary Ellen Sheridan, Associate Vice President for Research, The University 

of Chicago. (2006, May 16). Retrieved from http://www.hhs.gov/ohrp/archive/children/stipulat.pdf; Pediatric Ethics 

Subcommittee of the Pediatric Advisory Committee, HHS, FDA, Center for Drug Evaluation and Research. (2005, November 

15). Transcript of Pediatric Ethics Subcommittee of the Pediatric Advisory Committee, pp. 158-165. Retrieved from http://

www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4178t1.pdf. # Solicitation of Public Review and Comment on Research Protocol: Precursor Preference in Surfactant Synthesis in Newborns, 

70 Fed. Reg. 30128 (May 25, 2005); Pediatric Ethics Subcommittee of the Pediatric Advisory Committee, HHS, FDA, Center 

for Drug Evaluation and Research. (2005, June 28). Transcript of Pediatric Ethics Subcommittee of the Pediatric Advisory 

Committee, pp. 202-222. Retrieved from http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4151t1.pdf. **Botkin, J.R., Professor, Pediatrics, University of Utah. (2008). Pediatric Ethics Subcommittee Meeting Summary: Presentation 

to Pediatric Ethics Subcommittee, December 9. [Slide Presentation]. Retrieved from http://www.fda.gov/ohrms/dockets/

ac/08/slides/2008-4406s1-01.pdf; Pediatric Ethics Subcommittee of the Pediatric Advisory Committee, HHS, FDA, Center 

for Drug Evaluation and Research. (2008, December 9). Transcript of Pediatric Ethics Subcommittee of the Pediatric Advisory 

Committee, pp. 23-24. Retrieved from http://www.fda.gov/ohrms/dockets/ac/08/transcripts/2008-4406t-01.pdf.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

132
APPENDICES V

133

Appendix III: Characteristics of Pathogens Classified by the National 

Institute of Allergy and Infectious Diseases, U.S. Department of 

Homeland Security, and U.S. Centers for Disease Control and 

Prevention as Posing the Greatest Risk to National Security and 

Public Health (Category A Biological Agents)*

Listed in the table below are the characteristics of various pathogens, determined by the National Institute of Allergy and Infectious Diseases at the 

National Institutes of Health, the U.S. Department of Homeland Security, 

and the U.S. Centers for Disease Control and Prevention to pose the greatest 

threat to U.S. security and public health. This class of pathogens is generally referred to as “Category A Biological Agents.” Pathogens designated as 

Category A Biological Agents are generally defined as follows: they (1) can be 

easily disseminated or transmitted between people, (2) cause high mortality 

rates with a potential for major impact on the public health, (3) carry the 

prospect of mass panic and social disruption, and (4) require special action 

for public health preparedness.†

* Adapted from: Email Correspondence from Richard Gorman, National Institute of Allergies and Infectious Diseases, NIH, 

to Kavita Berger, PCSBI. (2012, July 30). † National Institute of Allergy and Infectious Disease (NIAID). (2012, February 27). Category A, B, and C Priority 

Pathogens, National Institutes of Health [Webpage]. Retrieved from http://www.niaid.nih.gov/topics/biodefenserelated/

biodefense/pages/cata.aspx#.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

134

CATEGORY A BIOLOGICAL AGENTS

Name Organism type Transmission Estimated 

Mortality: 

Untreated

Estimated 

Mortality: Treated

Anthrax* 

(inhalational)

Bacillus anthracis

Bacteria Inhalation of 

aerosolized spores

90% 75%

Botulism†

Clostridium botulinum

Bacteria Spore toxin 

transmitted through 

food sources

25% 6%

Plague‡ Yersinia pestis

Bubonic Plague Bacteria Bite from infected flea 

or rodent

50-60% 5-14%

Pneumonic Plague Bacteria Inhalation of plague 

bacteria

Secondary infection 

due to untreated 

bubonic or septicemic 

plague

~100% 36-57%

Septicemic Plague Bacteria Bite from infected flea 

or rodent

Secondary infection 

due to untreated 

bubonic or pneumonic 

plague

~100% 22-28%

* For additional anthrax references, see: Inglesby, T.V., et al. (1999). Anthrax as a biological weapon: Medical and public 

health management. Journal of the American Medical Association, 281(18), 1735-1745; CDC. (2012). Questions and

answers about anthrax [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/anthrax/faq/; CDC. (2006). Anthrax: 

What you need to know [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/anthrax/needtoknow.asp; NIAID. 

(2010). Anthrax [Webpage]. Retrieved from http://www.niaid.nih.gov/topics/anthrax/Pages/default.aspx. †

 For additional botulinum toxin references, see: Arnon, S.S., et al. (2001). Botulinum toxin as a biological weapon: 

Medical and public health management. Journal of the American Medical Association, 285(8), 1059-1070; CDC. (2001). 

Facts about botulism [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/botulism/factsheet.asp; NIAID. (2010). 

Botulism [Webpage]. Retrieved from http://www.niaid.nih.gov/topics/botulism/Pages/default.aspx.
APPENDICES V

135

Medical 

Countermeasures

Cause of Death Unique Pediatric 

Vulnerability

Why a Potential Threat

Vaccines and antibiotics 

are available

Antitoxins are in 

development

Pneumonia Close to ground

Higher respiratory rate

Bacteria is found worldwide

Capability exists to produce 

and aerosolize large 

amounts of spores

Antitoxins are available Suffocation, muscle 

paralysis

Smaller size

Hand to mouth behavior

Extreme lethality 

and potency (a single gram 

could kill 1 million people)

Ease of production, 

transportation, and misuse

Need for prolonged 

intensive care for infected 

patients

Antibiotics are available Pneumonia, shock, sepsis Higher respiratory rate

Curiosity

Less fluid reserve

sBacteria exist in many labs

Long history of use as 

biological weapon

Person-to-person spread

‡

 For additional plague references, see: Inglesby, T.V., et al. (2000). Plague as a biological weapon: Medical and public 

health management. Journal of the American Medical Association, 283(17), 2281-2290; CDC. (1997). Fatal human 

plague: Arizona and Colorado 1996. Morbidity and Mortality Weekly Report, 46(27), 617-620; CDC. (2012). Plague: 

Frequently asked questions [Webpage]. Retrieved from http://www.cdc.gov/plague/faq/; CDC. (2012). Plague: Maps 

and statistics [Webpage]. Retrieved from http://www.cdc.gov/plague/maps/index.html; CDC. (2005). Frequently asked 

questions about plague [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/plague/faq.asp; CDC. (2001). Facts 

about plague [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/plague/factsheet.asp; NIAID. (2007). Plague 

[Webpage]. Retrieved from http://www.niaid.nih.gov/topics/plague/Pages/default.aspx.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

136

CATEGORY A BIOLOGICAL AGENTS

Name Organism type Transmission Estimated 

Mortality: 

Untreated

Estimated 

Mortality: Treated

Small Pox*

Variola major

Virus Inhalation of infected 

respiratory drops

Contact with infected 

individual

30% No treatment available

Tularemia†

Francisella tularensis

Bacteria Bites from fleas, ticks, 

or infected animals

5-60%‡ 2%

Viral Hemorrhagic Fevers§

Arenavirus (Lassa 

Fever)

Virus Inhalation or ingestion 

of virus via rat fecal 

particles

Contact with infected 

fluids

75-78% 15-20%

Filovirus (Ebola & 

Marburg)

Virus Contact with infected 

bodily fluids

Ebola: 50-90%

Marburg: 23-90%

No treatment available

* For additional smallpox references, see: Henderson, D.A., et al. (1999). Smallpox as a biological weapon: Medical 

and public health management. Journal of the American Medical Association, 281(22), 2127-2137; CDC. (2009).

Questions and answers about smallpox disease [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/smallpox/faq/

smallpox_disease.asp; CDC. (2004). Smallpox disease overview [Webpage]. Retrieved from http://www.bt.cdc.gov/

agent/smallpox/overview/disease-facts.asp; NIAID. (2008). Smallpox [Webpage] Retrieved from http://www.niaid.nih.

gov/topics/smallpox/Pages/default.aspx. †

 For additional tularemia references, see: Dennis, D.T., et al. (2001). Tularemia as a biological weapon: Medical and 

public health management. Journal of the American Medical Association, 285(21), 2763-2773; CDC. (2011). Tularemia 

[Webpage]. Retrieved from http://www.cdc.gov/tularemia/; CDC. (2003). Key facts about tularemia [Webpage]. 

Retrieved from http://www.bt.cdc.gov/agent/tularemia/facts.asp; CDC. (2003). Frequently asked questions about 

tularemia [Webpage]. Retrieved from http://www.bt.cdc.gov/agent/tularemia/faq.asp; NIAID. (2012). Tularemia 

[Webpage]. Retrieved from http://www.niaid.nih.gov/topics/tularemia/Pages/default.aspx. ‡

 Variations depend on the strain and severity of infection.

§ A few examples of viral hemorrhagic fevers are provided in the table above. This list is not exhaustive. For additional 

hemorrhagic fever references, see: Borio, L., et al. (2002). Hemorrhagic fever viruses as a biological weapon: Medical 

and public health management. Journal of the American Medical Association, 287(18), 2391-2405; McCormick, J.B., 

et al. (1986) Lassa fever: Effective therapy with Ribavirin. The New England Journal of Medicine, 314(1), 20-26; CDC. 

(2012). Questions and answers about Marburg hemorrhagic fever [Webpage]. Retrieved from http://www.cdc.gov/

ncidod/dvrd/spb/mnpages/dispages/marburg/qa.htm; CDC. (2012). Lassa fever [Webpage]. Retrieved from http://www.

cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm; CDC. (2012). Questions and answers about Ebola hemorrhagic 

fever [Webpage]. Retrieved from http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola/qa.htm; CDC. (2012). 

Arenaviruses [Webpage]. Retrieved from http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/arena.htm; CDC. 

(2011). Viral hemorrhagic fevers [Webpage]. Retrieved from http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/

vhf.htm; NIAID. (2013). Ebola/Marburg [Webpage]. Retrieved from http://www.niaid.nih.gov/topics/ebolaMarburg/

Pages/default.aspx.
APPENDICES V

137

Medical 

Countermeasures

Cause of Death Unique Pediatric 

Vulnerability

Why a Potential Threat

Vaccine is available

Antivirals are in 

development

Pneumonia, secondary skin 

infections

Higher respiratory rate

Hand to mouth behavior

Virus exists in few labs

Person-to-person spread

Specific therapy is lacking

Antibiotics are available Pneumonia Curiosity Infects over 100 animal 

species

Ability to be aerosolized

As few as 10 bacteria can 

cause infection

Can survive at low 

temperatures

Ribavirin therapy

Hemorrhagic diathesis, 

shock, multi-organ system 

failure

Curiosity

Close to ground

Could have a high case 

fatality rate

Some are endemic in 

central Asia and southern 

Africa

Can be aerosolized

Only supportive treatments
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138

Appendix IV: An Ethical Framework to Guide National-Level Review of 

Pediatric Medical Countermeasure Research under 45 C.F.R. § 46.407 

and/or 21 C.F.R. § 50.54

The following ethical framework is intended to guide the review of any pre-event 

pediatric medical countermeasure research protocol that cannot be designed to 

pose only minimal risk and therefore rises to the level of national-level review 

under 45 C.F.R. § 46.407 and/or 21 C.F.R. § 50.54. Importantly, any such 

protocol should pose no more than a minor increase over minimal risk.

1. Does the research present a reasonable opportunity to further the understanding, 

prevention, or alleviation of a serious problem that could affect the health or welfare 

of children?

A. Serious problem, as judged by: 

i. Consequences of exposure

ii. Likelihood (or threat) of exposure

iii. “Vital importance”

B. Reasonable opportunity

2. Will the research be conducted in accordance with sound ethical principles?

A. Ethical threshold of acceptable risk and adequate protection from harm 

B. Ethical research design

i. Scientific necessity

ii. Research plan

a. Scientific validity

b. Small trials and age de-escalation

c. Appropriate monitoring

d. Proper planning for post-event research

iii. Prior adult testing to minimize risk to children

iv. Sufficient benefit over alternatives

v. Fair subject selection

C. Post-trial requirements to ensure ethical treatment of children and their families 

i. Distribution protocol for all children tested or assured 

ii. Compensation for research-related injury

D. Community engagement in pre-event research

E. Transparency and accountability 

3. Are adequate provisions made for soliciting the permission of parents or guardians 

and the meaningful assent of children?
APPENDICES V

139

Appendix V: Example of Differences between Active and Passive 

Surveillance Studies

This chart demonstrates visually the stark differences between active and 

passive surveillance studies. During active surveillance, the patient is actively 

followed and asked pointed and specific questions about the reactions they 

might be experiencing. The healthcare provider or researcher can evaluate 

directly the severity of those reactions because there is direct communica

tion. Passive surveillance, however, involves individuals self-reporting and can 

occur at any time post-administration. As a result, the data are less precise 

and are self-selected based on those patients who are more apt to report an 

adverse event. In addition, the data might be less specific and follow-up data 

on the patient’s overall health status might not be as readily available as they 

are in active surveillance.

-

TIME FROM VACCINE 

ADMINISTRATION

ACTIVE SURVEILLANCE PASSIVE SURVEILLANCE

0 Vaccine administration Vaccine administration

Participant leaves health care facility

At any time, participant may call in to the 

Vaccine Adverse Event Reporting System 

and report a possible adverse event; the 

patient may be contacted for follow-up, 

such as release of medical records for 

data analysis

30 minutes Participant completes reaction 

questionnaire

1 day Repeat questionnaire

2 days Repeat questionnaire

3 days Repeat questionnaire

4 days Repeat questionnaire

5 days Repeat questionnaire

1 week Repeat questionnaire 

Participant’s blood is drawn for 

immunogenicity study

2 weeks Repeat blood draw

4 weeks Repeat blood draw

Adapted from: IOM. (2002). The Anthrax Vaccine: Is it Safe? Does it Work? Washington, DC: National Academies Press.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

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Appendix VI: Glossary of Key Terms Related to Pediatric Medical 

Countermeasure Research

Adverse event: An undesired medical occurrence that presents itself during 

treatment with a medical product, which may or may not have been caused 

by the treatment. 

Adverse reaction: An undesired side effect of a medical treatment or drug.

Age de-escalation: Conducting trials first in adults, then with older children, 

and then with progressively younger children as appropriate in order to 

prevent undue risk to young children.

Agent (chemical or biological): A biological substance or chemical compound 

that can be used purposefully as a weapon to cause sickness or death.

Anthrax: An infectious disease caused by B. anthracis spores, which can be 

contracted in humans either by inhalation, skin contact, or ingestion.

Antibiotics: Medicines that are used for the treatment or prevention of bacterial infections.

Antibody: Protein that is used by the immune system to recognize and fight 

bacteria, viruses, and other substrates that appear foreign or harmful.

Anthrax vaccine adsorbed (AVA): An FDA-licensed human anthrax vaccine 

approved for use in those 18-65 years of age who are at high risk of exposure.

Biohazard: A biological agent that is a hazard to humans or the environment.

Clinical trial: A research study designed to answer a specific question 

regarding the effectiveness and safety of drugs, biologics, or medical devices.

Common Rule: Federal regulations that govern human subjects research; also 

known as the Federal Policy for the Protection of Human Subjects, adopted 

by 18 federal departments and agencies.

Cutaneous anthrax: An infection caused by B. anthracis that is limited to the 

skin.

Dark Zephyr: An exercise conducted by the U.S. government in early 2011 

to test local, state, and federal government responses to a large-scale anthrax 

release in a major metropolitan area. 
APPENDICES V

141

Dosage: The prescribed frequency, quantity, and size of doses of a therapeutic 

agent to be administered to a patient.

Dose: The amount of a medication to be administered.

Efficacy: The ability of a medical product or treatment to produce the desired 

therapeutic effect.

Emergency use authorization (EUA): An authorization issued by FDA to 

allow either the use of an unapproved medical product or an unapproved use 

of an approved medical product during a declared emergency.

Immune response: The process through which the body recognizes and 

defends itself against bacteria, viruses, and substances that appear foreign 

and harmful. 

Immunization: The process by which a person is made immune or resistant to 

an infectious disease, typically by the administration of a vaccine. 

Immunogenicity: The ability or degree to which a substance can produce an 

immune response. 

Inhalational anthrax: An infectious disease caused by breathing in the spores 

of the bacteria B. anthracis.

Investigational new drug application (IND): An application submitted to 

FDA before studying a drug or biologic in humans.

Medical countermeasure (MCM): FDA-regulated products and interventions 

used in response to chemical, biological, radiological, and nuclear attacks.

Metabolic: Having to do with the chemical reactions involved in the body’s 

use of energy.

Off-label use: The practice of prescribing a medical product for use not in 

accordance with that approved by FDA. 

Pathogen: A microorganism that causes disease; for example, B. anthracis is 

the pathogen that causes anthrax.

Pharmaceutical: A medicinal drug.
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

142

Prophylaxis: Measures taken to prevent disease before the onset of signs or 

symptoms of infection.

Reactogenicity: The ability of a vaccine to cause expected negative or adverse 

reactions.

Research protocol: A plan detailing the methods of a research study as well 

as the detailed plan for collecting and analyzing data, and ensuring quality 

and safety.

Spores: Small, usually one-celled organisms that can give rise to other organisms without interacting with one another under favorable conditions.

Strategic National Stockpile (SNS): The United States’ national repository of 

antibiotics, chemical antidotes, vaccines, antitoxins, life-support medications, 

intravenous administration and airway maintenance supplies, and medical/

surgical items to be used in the case of a public health emergency.

Subpart D: A stringent set of additional research protections for children that 

supplement those protections provided for federally supported or regulated 

human subjects research more broadly.

Systemic: Relating to or affecting multiple organ systems or the entire human 

body.

Vaccine: A product that improves immunity to a particular disease.

Vaccine Adverse Event Reporting System (VAERS): The United States’ 

national vaccine safety surveillance program that collects information about 

adverse events that occur after the administration of vaccines. Data submitted 

to VAERS are analyzed and made available to the public. 

Vector: An organism that carries disease-causing microorganisms from one 

host to another.
APPENDICES V

143

Appendix VII: Guest Presenters to the Bioethics Commission 

Regarding Pediatric Medical Countermeasure Research

Michael R. Anderson, M.D., F.A.A.P.

Vice President and Chief Medical Officer, 

UH Case Medical Center; Associate 

Professor of Pediatric Critical Care, 

Case Western Reserve University; Chief 

Medical Officer, UH Rainbow Babies and 

Children’s Hospital; Member and Fellow, 

American Academy of Pediatrics

Tom L. Beauchamp, Ph.D.

Professor of Philosophy, 

Senior Research Scholar, 

Kennedy Institute of Ethics,

Georgetown University

Georges Benjamin, M.D.

Executive Director, 

American Public Health Association

Ruth Berkelman, M.D.

Rollins Professor and Director, 

Center for Public Health Preparedness 

and Research, Emory University

David DeGrazia, Ph.D.

Professor of Philosophy, 

George Washington University

Alan R. Fleischman, M.D.

Clinical Professor, Department of 

Pediatrics, Department of Epidemiology 

and Population Health, Albert Einstein 

College of Medicine, Yeshiva University

Richard Gorman, M.D.

Head, Pediatric and Obstetrics Integrated 

Program Team, HHS Office of the 

Assistant Secretary for Preparedness and 

Response; Associate Director for Clinical 

Research, Division of Microbiology and 

Infectious Disease, National Institute of 

Allergy and Infectious Diseases, National 

Institutes of Health

Neal Halsey, M.D.

Professor of International Health, 

Johns Hopkins Bloomberg School of 

Public Health; Professor and Pediatric 

Infectious Disease Physician, 

Department of Pediatrics, 

Johns Hopkins School of Medicine

James G. Hodge, Jr., J.D., LL.M.

Lincoln Professor of Health Law 

and Ethics, Sandra Day O’Connor College 

of Law, Arizona State University; 

Director, Public Health Law and Policy 

Program; Director, Network for Public 

Health Law – Western Region

Lisa Kaplowitz, M.D., M.S.H.A.

Deputy Assistant Secretary for Policy, 

Director, Office of Policy and Planning, 

Office of the Assistant Secretary for 

Preparedness and Response, 

U.S. Department of Health and 

Human Services
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Nicola P. Klein, M.D., Ph.D.

Research Scientist II, Kaiser Permanente 

Northern California Division of Research; 

Co-Director, Kaiser Permanente Vaccine 

Study Center

Bruce Lockwood, C.E.M.

1st Vice President, USA Council of 

International Association of Emergency 

Managers; Deputy Director, Emergency 

Management, Town of Hartford, CT

CAPT Carmen Maher, B.S.N., 

M.A., R.N., R.A.C.

Deputy Director, Office of Counter 

Terrorism and Emerging Threats, 

U.S. Food and Drug Administration

Mary Faith Marshall, Ph.D., F.C.C.M.

Director, Program in Biomedical Ethics, 

Center for Biomedical Ethics and 

Humanities; Professor, Public Health 

Sciences, School of Medicine, Professor, 

School of Nursing, University of Virginia

Suzet M. McKinney, Dr.P.H., M.P.H.

Deputy Commissioner, Bureau of 

Public Health Preparedness and 

Emergency Response, Chicago 

Department of Public Health; Adjunct 

Assistant Professor, Community Health 

Sciences, School of Public Health, 

University of Illinois at Chicago 

Thomas A. Moore, M.D., F.A.C.P.

Chairman, Department of Infectious 

Diseases, Ochsner Health System 

Chair, FDA Anti-Infective 

Drug Advisory Committee

Robert “Skip” Nelson, M.D., Ph.D.

Senior Pediatric Ethicist, Office of 

Pediatric Therapeutics, Office of the 

Commissioner, U.S. Food and Drug 

Administration

John S. Parker, M.D., Major General 

(Retired)

Chair, National Biodefense Science 

Board; Senior Vice President, Science 

Applications International Corporation

Sonja Rasmussen, M.D., M.S.

Deputy Director, Influenza Coordination 

Unit, Office of Infectious Diseases, 

U.S. Centers for Disease Control and 

Prevention

David Resnik, J.D., Ph.D.

Bioethicist and IRB Chair, National 

Institute for Environmental Health 

Sciences, National Institutes of Health

Holly A. Taylor, M.P.H., Ph.D.

Associate Professor, Department of Health 

Policy and Management, Bloomberg 

School of Public Health; Core Faculty, 

Berman Institute of Bioethics, Johns 

Hopkins University
APPENDICES V

145

Dennis F. Thompson, Ph.D.

Alfred North Whitehead Professor 

of Political Philosophy,

Faculty of Arts and Sciences,

Professor of Public Policy,

Kennedy School of Government

Harvard University

Paul B. Thompson, Ph.D.

W.K. Kellogg Professor of Agricultural, 

Food and Community Ethics, 

Professor of Philosophy, Professor 

of Agricultural, Food and Resource 

Economics; Professor of Community, 

Agriculture, Recreation and Resource 

Studies, Michigan State University

David Wendler, M.A., Ph.D.

Head, Unit on Vulnerable Populations, 

Department of Bioethics, NIH Clinical 

Center, National Institutes of Health
SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

146

Presidential Commission for the Study of Bioethical Issues

1425 New York Avenue NW, Suite C-100

Washington, D.C. 20005

(202) 233-3960

http://www.bioethics.gov