presidential ethics panel oks anthrax vaccine testing in children

7/29/2019 Presidential Ethics Panel OKs Anthrax Vaccine Testing in Children

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March 2013

SAFEGUARDINGCHILDRENP MC R


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On the cover: Under a high magnication o12,483X, this scanning electron micrograph(SEM) depicted spores rom the Sterne straino Bacillus anthracisbacteria.

Adapted rom: CDC/Laura Rose, 2002


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Washington, D.C.

March 2013

http://www.bioethics.gov

SAFEGUARDINGCHILDRENP MC R
http://www.bioethics.gov/http://www.bioethics.gov/


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SAFEGUARDING CHILDREN Pediatric Medical Countermeasure Research

ABOU HE PR ESIDENIAL COM MISSION FOR

HE S UDY OF BIOEHICAL ISSUES

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CONENS

L P S................................................

L S B C ...............................................

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B C S C....................................................................x

A...................................................................................................................x

EXECUIVE SUMMARY ......................................................................................................

P- R...............................................................................................................

App AVA C: P- R............................6

P- R .............................................................................................................7

App AVA C: P- R ..........................

CHAP ER : I...................................................................................................

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S R b N B S B..............6

T B C C.............................................................................7

E R F P R ....................................8

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CHAPER : C E R F P R ....

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Dp C P R........................................

Respect or Persons.........................................................................................................

Benecence......................................................................................................................

Justice...............................................................................................................................Democratic Deliberation ..............................................................................................

C R C P R ........................................7

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

Pediatric Research Requiring National-Level ReviewHigher Risk and No

Prospect o Direct Benet to Healthy Participants (Section 407)..........................

C...........................................................................................................................6

CHAPER : E C P M CR .....................................................................................................................................7

E G.............................................................................................................8

P- S................................................................................................................


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Pre-event Studies Posing No More Tan Minimal Risk Approvable

under Section 404..........................................................................................................Application to rials o AVA with Children: Minimal Risk Pre-event

rials o AVA with Children........................................................................................7

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

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

Application to rials o AVA with Children: No More Tan a Minor

Increase over Minimal Risk Pre-event rials o AVA with Children....................87

P- S ..............................................................................................................8

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

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

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

Authorizing Distribution o Unapproved Drugs in an Emergency.......................7

Application to Post-event rials o AVA with Children ........................................

C.........................................................................................................................

ENDNOES...........................................................................................................................7

APPENDICES ........................................................................................................................

Appx I: S P Vb.........................................................6

Appx II: S P R P R

C.F.R. 6.7 / C.F.R. . (-) ........................................7

Appx III: C C A B A ...........................

Appx IV: A E F G N-L R

P M C R C.F.R. 6.7

/ C.F.R. ...............................................................................................8Appx V: Exp D b A P S

S.................................................................................................................................

Appx VI: G K R P M

C R .............................................................................................

Appx VII: G P B C R

P M C R ...........................................................


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Presidential Commission or the Study o Bioethical Issues

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

Phone 202-233-390 Fa 202-233-3990www.ioethics.gov


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

Phone 202-233-390 Fa 202-233-3990www.ioethics.gov

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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 signicant progress toward this goal for adults, the development of

appropriate medical countermeasures for children lags, in part due to challenges in collectingbasic dose and immunogenicity studies in pediatric populations.

On October 28, 2011, the HHSs 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 scientically valid safety and immunogenicity data about AVA PEP for

children, a complex issue with ethical, scientic, 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 NBSBalso 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

scientic communities in addition to non-prot organizations and other public constituencies. I

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

recommendations and suggestions the Commission deems appropriate.


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Amy Gutmann, Ph.D.

January 6, 2012Page 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 Commissionss recommendations on this critical component ofimproving and advancing our nations resilience, preparedness, and response efforts.

Sincerely,

Kathleen Sebelius


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x

PRESIDENIA L COMMISSION FOR HE SU DY OF BIOEHICAL ISSUES

AMY GUMANN, P.D., CHAIR

P Cp H. B

D P P S, U P

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

P, E U

YOLANDA ALI, M.B.A.

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ANIA L. ALLEN, J.D., P.D.

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JOHN D. ARR AS, P.D.

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BAR BAR A F. AK INSON, M.D.

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ALEXANDER G. GARZA, M.D., M.P.H.A S, Of H

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

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PRESIDENIA L COMMISSION FOR HE SU DY OF BIOEHICAL ISSUES

SAFF* AND CONSULANS

Executive Director

L M. L, P.D., M.S.

Associate Directors

M G, J.D.

K Sp-B, J.D., M. B

Communications Director

H W V, M.S.J.

Senior Advisors

D DGz, P.D.

P A. Lb, P.D., J.D.

J D. M, P.D.

Research Sta

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K M. B, P.D.

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K M, P.D.O N, M.P.H.

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ACKNOWLEDGEMENS

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x


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EXECUIVE SUMMARY


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EXECUTIVE SUMMARY

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Pre-event Research

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Recommendation 1: Pre-event Pediatric Medical Countermeasure ResearchRisk 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 o research risk except under

extraordinary circumstances. I 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 riska 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 o 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

Beore beginning pre-event medical countermeasure studies with children,

ethically sound modeling, testing with animals, and testing with theyoungest adults must be completed to identiy, understand, and characterize

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

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


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EXECUTIVE SUMMARY

possible rom the oldest age group o children to the youngest group necessary

to provide additional protection to the youngest and most vulnerable children,and to ensure that data rom an older age group can inorm the research design

and the estimate o risk level or the next younger age group.

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

Pediatric Medical Countermeasure Research

Pre-event pediatric medical countermeasure research may proceed to national-

level review under Department o 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 posesno more than a minor increase over minimal risk to research participants.

In part because o the inherent uncertainty o a bioterrorism attack, pre-

event 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.

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6

Recommendation 4: Ethical Framework or National-Level Review o

Pre-event Pediatric Medical Countermeasure Research

o ensure the thoroughness and ethical rigor o national-level review,

reviewers should apply the Bioethics Commissions recommended ethical

ramework or 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 o 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 require-ments o the ramework outlined in this report to be approved.

Te ramework clarifes 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 o exposure, likelihood (or

threat) o exposure, and the vital importance o the inormation to be

gained. Te ramework also specifes a rigorous set o conditions necessary to

determine whether the research would be conducted in accordance with therequired sound ethical principles that all into fve general categories: (1)

ethical threshold o acceptable risk and adequate protection rom harm; (2)

ethical research design, or example, scientifc necessity, valid research plan

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

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

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

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

engagement; and (5) transparency and accountability. Finally, the rameworkreiterates the importance o inormed parental permission and meaningul and

developmentally appropriate child assent.

Application to rials o AVA with Children: Pre-event Research

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EXECUTIVE SUMMARY

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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 emer-gency or when limited pre-event medical countermeasure studies have already

occurred. Institutional review boards must be cognizant o the exigencies

imposed upon research under emergency conditions, and when reviewing


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8

post-event medical countermeasure research proposals, ensure that adequate

processes are in place or inormed parental permission and meaningul childassent. Institutional review boards must also ensure that the research design is

scientifcally sound, children enrolled in research have access to the best avail-

able care, adequate plans are in place to treat or compensate children injured

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

course o research.

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Recommendation 6: Regulatory Mechanisms or Post-event Pediatric Medical

Countermeasure Research and Distribution

When there are no data on the administration o 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 saeguard 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 concur-

rent small-scale study under an investigator IND to obtain data that canpotentially be used to support an emergency use authorization or pediatric

use o the medical countermeasure in a uture event. o expedite post-event

research and ensure the availability o appropriate medical countermeasures


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EXECUTIVE SUMMARY

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

beore an event.

Application to rials o AVA with Children: Post-event Research

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CHAPER

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27/162

INTRODUCTION

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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 o advances in

biomedicine and related areas o

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 o the United

States

Scope: identiy the basic ethical

principles that should underlie the

conduct o 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 o1974, Pub. L. No. 93-348, 88 Stat. 342.


29/162

INTRODUCTION

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Ethical issues about the involvement

o children arise because o

competing answers to the ollowing

question: Under what conditions (i

any) are these various types

o research justiied?

National Commission or the Protection oHuman Subjects o Biomedical and BehavioralResearch. (1977). Research Involving Children(DHEW Publication OS 77-0004). Washington,

DC: Department o Health, Education, andWelare, p. 91. Retrieved rom http://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pd.
http://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pdfhttp://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pdfhttp://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pdfhttp://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pdfhttp://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pdfhttp://bioethics.georgetown.edu/pcbe/reports/past_commissions/Research_involving_children.pdf


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6

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INTRODUCTION

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Te Bioethics Commissions Charge

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THE NATIONAL BIODEFENSE SCIENCEBOARD

The Pandemic and All-Hazards

Preparedness Act established NBSB in

2006. The 13-member board advises

the Secretary o HHS on scientic,

technical, and other matters o special

interest to HHS regarding activities

to prevent, prepare or, and respond

to adverse health eects o publichealth emergencies resulting rom

chemical, biological, nuclear, and

radiological events, whether naturally

occurring, accidental, or deliberate.

NBSB members come rom diverse

backgrounds and a range o experience

in both medicine and public health. The

members are required to meet at least

twice a year in a public orum.

NBSB has advised the Secretary on many

issues, including: H1N1 immunization,

home stockpiling o MCMs, mental

health issues during a disaster, and

prioritization in MCM development.

Source: Kathleen Sebelius, Secretary, HHS.(2012, July 3). National Biodeense Science BoardCharter, p. 1. Retrieved rom http://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-

renewed-charter.pd.
http://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-renewed-charter.pdfhttp://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-renewed-charter.pdfhttp://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-renewed-charter.pdfhttp://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-renewed-charter.pdfhttp://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-renewed-charter.pdfhttp://www.phe.gov/Preparedness/legal/boards/nbsb/Documents/2012-renewed-charter.pdf


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8

A B C

NBSB,

b

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q, B C

p-

MCM;

,

p p (

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b .

B C

MCM p FDA- p p ,

b, , .26

Ethical and Regulatory Framework or Pediatric Research

P ,

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z , pb, p b pp

b pp. U , b pb

pp b, pp

p p b b

pp. A

p -b p,

p -, p

xp. T p b p-

p p p, b ( -),j, b.

Because o the sensitivity o the

involvement o children in research,

[NBSBs] recommendation voiced [its]

desire to have other ocused experts,

like [the Presidential Commission or

the Study o Bioethical Issues], ormally

review and address these issues

rom an ethical perspective. The

[NBSB] is condent that the [Bioethics]

Commission will help us and our nation

deliberate this very complex issue,

ensuring sae medical countermeasures

or our children.

Parker, J.S., Chair, NBSB. (2012). The NationalBiodeense Science Board Report. Presentationto the Presidential Commission or the Study oBioethical Issues, May 17. Retrieved rom http://bioethics.gov/cms/node/715 .
http://bioethics.gov/cms/node/715http://bioethics.gov/cms/node/715http://bioethics.gov/cms/node/715http://bioethics.gov/cms/node/715


33/162

INTRODUCTION

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CHAPER

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CURRENT ETHICAL AND REGULATORY FRAMEWORK FOR PEDIATRIC RESEARCH II

p pb p

p : p

q . M

(MCM) , , p

q x

.

p p

p . I b

pp

p

pp p p p-

p.

Ethical Underpinnings: GuidingPrinciples

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p

p. R

bj

, pp

N C

P H Sbj

B B R

( N C) Belmont Report, b

b, N C bq p , B C xp

pp pb b .41

HISTORICAL RESEARCH ABUSESA convergence o research abuses

infuenced the move toward

regulatory human subjects research

protections developed in part by the

National Commission in the 1970s

and enacted by the Department

o Health, Education, and Welare

(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 Beechers publication o an

article in the New England Journal of

Medicine, which exposed 22 cases

o human experimentation abuses,

also motivated human subjectsresearch regulation. Among the cases

included in Beechers publication was

the Willowbrook studyresearch

conducted with institutionalized and

mentally handicapped children.

Sources: Beecher, H.K. (1966). Ethics in clinicalresearch. 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: PediatricExperimentation. In Grodin, M.A. and L.H. Glantz.(Eds.). Children as Research Subjects(pp. 1-25).New York, NY: Oxord University Press, pp.15-19; Mellanby, K. (1947). Medical experimentson human beings in concentration camps inNazi Germany. British Medical Journal, 1(4490),148-150.


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6

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p q ,

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b p, b

p ( xp

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z p p).48

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b, p-

b

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pp

pp

b p b -

pp p

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p b-

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b, p p -

b. F p,

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APPLIED ETHICS IN PEDIATRIC RESEARCH

Paternalism constitutes those actions that

restrict the reedom o others on the grounds

that those actions are the best way to promote

or protect their interests. In the case o children,

such restrictions are not only justied because

children cannot identiy and pursue their own

interests, but because such restrictions on

a childs reedom guarantee his autonomyin

either or both o two ways: these restrictions

protect the child rom harm that would limit his

reedom in the uture (being seriously injured,

or a lack o education), or these restrictions are

what we think the child will lateragree to, what

he will later see as something he would do in

his own interest.

Source: Redmon, R.B. (1986). How children can berespected as ends yet still be used as subjects in non-therapeutic research. Journal of Medical Ethics, 12(2),80. [Original emphasis].


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7

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8

Table 2.1Regulations Governing Review of Pediatric Human Subjects Research Protocols

Local IRB Review Mechanisms

45 C.F.R. 46.404

Refected by FDA at:21 C.F.R. 50.51

Minimal risk

HHS will conduct or und research in which the IRB nds that no greater than minimal risk to children ispresented, only i the IRB nds that adequate provisions are made or soliciting assent o the children and

the permission o their parents or guardians as set orth in 46.408.

45 C.F.R. 46.405


Prospect of direct benefit to the individual participant

HHS will conduct or und research in which the IRB nds that more than minimal risk to children is presentedby an intervention or procedure that holds out the prospect o direct benet or the individual subject, or by a

monitoring procedure that is likely to contribute to the subjects well-being, only i the IRB nds that:

a. The risk is justied by the anticipated benet to the subjects;b. The relation o the anticipated benet to the risk is at least as avorable to the subjects as that presented

by available alternative approaches; andc. Adequate provisions are made or soliciting the assent o the children and permission o their parents or

guardians, as set orth in 46.408.

45 C.F.R. 46.406


Likely to yield generalizable knowledge about participants condition and only minor increase over

minimal risk

HHS will conduct or und research in which the IRB nds that more than minimal risk to children is presented

by an intervention or procedure that does not hold out the prospect o direct benet or the individualsubject, or by a monitoring procedure which is not likely to contribute to the well-being o the subject, only i

the IRB nds that:

a. The risk represents a minor increase over minimal risk;

b. The intervention or procedure presents experiences to subjects that are reasonably commensurate withthose 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 orcondition which is o vital importance or the understanding or amelioration o the subjects disorder or

condition; andd. Adequate provisions are made or soliciting assent o the children and permission o their parents or

guardians, as set orth in 46.408.

National-Level Review Mechanisms

45 C.F.R. 46.407


Greater than minimal risk with no prospect of direct benefit to individual participantsor those participants condition

HHS will conduct or und research that the IRB does not believe meets the requirements o 46.404,

46.405, or 46.406 only i:

a. The IRB nds that the research presents a reasonable opportuni ty to urther the understanding,prevention, or alleviation o a serious problem aecting the health or welare o children; and

b. The Secretary,* ater consultat ion with a panel o experts in pertinent disciplines (or example: science,

medicine, education, ethics, law) and ollowing opportunity or public review and comment, hasdetermined either:

1. That the research in act satises the conditions o 46.404, 46.405, or 46.406, as applicable, or2. The ollowing:

i. The research presents a reasonable opportunit y to urther the understanding, prevention, or

alleviation o a serious problem aecting the health or welare o children;ii. The research will be conducted in accordance with sound ethical principles; andiii. Adequate provisions are made or soliciting the assent o children and the permission o their

parents or guardians, as set orth in 46.408.

* Note: In the case o review by FDA under 50.54, the Commissioner o Food and Drugs convenes the expert panel and makes the naldetermination, which is orwarded to the HHS Secretary. For concurrent review under 46.407 and 50.54, the Secretary makes thenal determination.


53/162


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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 o age. Because smallpox was eradicated in 1979, no manuacturer still

produced the vaccine and only a limited supply o stockpiled vaccine doses remained.

Motivated by concerns about a possible bioterrorism attack using smallpox virus, the

study was intended to demonstrate the saety o 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

inections 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 oresee the likelihood o a bioterrorism attack, many ound it dicult to

quantiy the possibility o uture benet to children as a class. Further complicating the

reviewers considerations was news o a potentially saer, 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 i 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 or children in an emergency.

Source: Quigley, R. (2004). Uncertain benet: The public policy o approving smallpox vaccine research. AmericanJournal of Public Health, 94(6), 943-946.


60/162


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7 p. N, - b

q , . F ,

b , pp.111

Conclusion

T

ppp p, b (

-), j, b

b b N C 77

. I ,

, p

q p . A

xp , p .

B pp, j pp

b, p p

bp B C b

MCM . I x p, B C

x MCM

pp p q p p MCM p

MCM p.


61/162

7

CHAPER

E C

P M C R


62/162


8

S H H S (HHS) q

B C z (MCM) ,

b p- p- x b

(AVA). I p, B C, pp b -

pp Cp ,

q , f,

b xp b . T , b

p xp

p, q MCM .

Ethical Grounding

E b b pp

Belmont Report b b N C

P H Sbj B B R

( N C)p p, b (

-), j, b. A N C

p Research Involving Children C.F.R. P 6, Sbp

D C.F.R. P , Sbp D. (I p, Cp ,

B C p , HHS

x, p p Sbp D

b b HHS U.S. F D A (FDA).)

C p

b . Rp

p x p q

b b p p pp.

A ( ) , -

p p p p. Y

p,

b ( ) pp. C

b p pp MCM pp b,

, p,

p p. T


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ETHICAL CONSIDERATIONS FOR PEDIATRIC MEDICAL COUNTERMEASURE RESEARCH III

b . F xp, , b p ,

xp j xp .

I j p p, b b -

z b p. A

Cp p, b -b

. R pb

b pb

Belmont Reportq x

pb p , , ( ) b z

b .112 B

q x,

p -b ,

pb pp, p p ,

MCM. J, qb b

b, b p p, b, -

, q b .

pp pp

p p-

p pp b ( C.F.R. 6.

( )) p b

pp ( C.F.R. 6.6 ( 6)). I x

p- p MCM xp pp, p b , ,

z b

b (ppb C.F.R. 6. (

)); p

x pb.

I pb p- p

MCM , p , pp -

, C.F.R. 6.7 ( 7) p

p. T 7 p pp


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p ,

B C pb MCM x. C p

MCM x

b N C. P MCM q

b p xp p

p 7, , b

p Cp

p b.113 M, b

z p

b b b p

b B C

pp p- MCM b

b pp.

I x p- p MCM ,

b z. Y p- MCM

b p pp b xp , b

( 6), pp

MCM ,

( ) p b

pp ( ).114 W MCM,

p pb

p b

. R p

b p p p, x

b pp. A p p,

xp b p

p p b

x.

A p MCM b b b-

p- b p- , p- p- p

. I p- , pp

b xp ,


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pp b pp pp

b b pp . Pp p- b xp

b xp

MCM . P- , , -

p pp

MCM. B p

, p- p- p

. F pp p,

(.., pb q

b) p p

p- p-.115

T b b.116

Pre-event Studies

P- p MCM b

pp b pp. Fp , p- MCM p

, () p -

b b b b

xp p ; () -

b ; ()

p xp p . G

, p- b pp b pp, b pp

. P- MCM b pp

6 b pp b

p zb b b. A p- p-

MCM b pp ,

q b , xp -

, b 7.

x f

p- p MCM b ,

b pp . I p


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pb b b

, b b pp , p- p MCM pp

- . N- 7

b p , N C p

, xp b

b p b xp

b .117

Pre-event Studies Posing No More Tan Minimal Risk Approvable underSection 404

W pb, p- p MCM

b xp . S

b ppb .118 D

MCM q x

p. S b b

, , b , b p b

. P p , , -

z . O pp ,

x pb

(.., 8 ), b pb

b

p b b

(.., 6 7 ). M, 6 7 p pp

, p p, p.

O ,

b b p p

b x p .

x pb p

, -, p p p ,

p p p .119


67/162


I p z p

b . A , xp,

. I

( b

),

p (.., b , p ).

M, B C z , ,

p p - .120 T

- p p , , q

p ,

pb, x p. I b

, xp, b pb

b .

N (.., 7 ) p b . B

p ( ) ,

xp b ( 7 ) q

f . W

b p , - pp,

b b p

x p. B C -, b

p , p

b p b .121 A

b -

j , , -

b (

p pp) p xp

j p b p.

p - p

b ,


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. A -

b b pp : p- b . W p

p b b b ,

bp, b,

.122 S, p

b b , ,

, b MCM

p . R p p

- b p

b b ppp b

p (.., p-pb, pb, p-pb,

, , , , ). F

xp, b b

b, , , b p

pb p , pb,

- b b .

A - p p z

p- p MCM . T , , x

p . Sp -

-, p

b z x p

q IRB pp. I U.S.

b p p

p p bp, b q

p f - p. T

-

p.

A, - b

ppp b p p

p , pb b p . C, ,

b z b , b

b p.123 C bz


69/162


p . A px b, xp,

pp

z U S 7. C b b

(.., ) ,

b . G b

ppx ,

p .124 W b

b , MCM b

, x b

b b p .125

A p b

p p MCM , ,

, b . F xp, p-

p MCM p ppp,

p p pp,

j p p b p p.126F p p p

p MCM . A p p

p b p

.

b p , -

.

E p- p j j pp

.

p j MCM b

Pb R E Pp (PREP) A -

. (S Cp R-R Ij, Cp .)

W pb, p- p p -

p p b b p ( ) b b

b ( ). I p b

b ,


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6

, z, b , b, p . I

- pb , xp, b xp-

b

, f b MCM

b 7, p

. (S P- S P N M T

M I M R Appb S 7, Cp

.) I , p p,

, p -

j b p.

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 o research risk except underextraordinary circumstances. I 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 riska 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 o 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

Beore beginning pre-event medical countermeasure studies with children,

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

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

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

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

possible rom the oldest age group o children to the youngest group necessaryto provide additional protection to the youngest and most vulnerable

children, and to ensure that data rom an older age group can inorm the

research design and the estimate o risk level or the next younger age group.


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7

Application to rials o AVA with Children: Minimal Risk Pre-event rials

o AVA with Children

A AVA ppb p

pp. P

p AVA b ,

pb p-

(.., 8 ), b pb

p-

(.., 6 7 ). M AVA p

, f

b

.

Available Data

T , ( pb p

p), AVA b b . B b , AVA pp

b FDA z p

bBacillus anthracis, p 8 6 p-

p xp.127 AVA b

b , ppx .

AVA b b b .128

AVA b b p , pb

pp.129 D

AVA

.130 A AVA

AVA p (..,

).131 A , (b p )

(b 7 ) j .132 L

(b ), p p

(b 6 6 ), b (b


72/162


8

) j . S

, , p AVA, j , b

p b p

.133 A, b pb

AVA b pbb

p

p p x .134

AVA b , b

p z . W -

b q b,

q p, p b

p x, .135

D f AVA

p , , x, bb.136 T AVA -

x b b b

.137 Ab

p p p

b b p. I

f AVA ,

6 xp x xp

x ( AVA).138 T b x

x, p AVA.

Ob p f .139

Application o Available Data

I p, pb,

. P b , ,

f ( pb) , -.140 T - p

, pp ,

b p . I x p HIV


73/162


, b

b , FDA pp p p p:

() , ()

b p

z p ,

() p p p.141

V p b b p AVA

p. B AVA p , z AVA p 8

q. R b x

AVA p b

AVA (.., 6 7) p

. A p

b p. Sp, q

q b p

b .142 b q b FDA j p

q. T U.S. C D C P (CDC)

I M -

- , , q

.143

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

Risk Approvable under Section 407

T b b pb

p- MCM . I , -

7 b q, b p -

p

pp.

A xp

; p -b.144 T 6

( pp b b

zb b pp ) ,


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6

q p- p MCM

b pp, BC pp

pp p- MCM ppb

7.145 P- MCM pp

b p pp. M, ,

, b b

b q p MCM

p. W B C

pb x

xp

b xp-

b, xp

pp pb p-

MCM . F,

xp pb

.A p- p MCM

b pb, , . C p

b b p -

p - p p pb.

(S P- S P N M T M R Appb

S , Cp .) F xp, b pb

b pb

p p-pb .

A, , p

, p b p-

pp , xp,

p. O b p MCM

p p p p-

( p ),

-.


75/162


6

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

Pediatric Medical Countermeasure Research

Pre-event pediatric medical countermeasure research may proceed to national-

level review under Department o 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 o the inherent uncertainty o a bioterrorism attack, pre-event 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.

W

pb pp p

p b p

pp p MCM p 7. W p

p 7 , B C p p

p- p MCM .T 7

b HHS p C.F.R. 6.7 FDA

C.F.R. ..

Speciying a Framework

U 7, S HHS, p- p xp, pp p ,

pp b pp.146 B pp

p , , b , S

p all q

7:

. T p b pp ,p, pb

;

. T b pp;


76/162


6

. Aq p p p

.147

T B C ,

- ,

pp p b pp

pb, p

b

pp, p p p

p ppp . D pp p- p MCM p

-

p b pb

b .

Ip, S HHS, p-

p, pb p p b

.1. Does the Research Present a Reasonable Opportunity to Further the

Understanding, Prevention, or Alleviation o a Serious Problem that Could

Aect the Health or Welare o Children?

I pp 7 , pp

p reasonable opportunity ,

p, serious problem

.148 p , B Cp p pb q f pb

p b pp.

A. Serious Problem

A 7 p- p MCM p

, pp

pb

.149 E pb p 7 b pb pb

,

. T p


77/162


6

p p. A b p

p, b xp pp pb

f . A, pb , b

(.., ) p p .

I x MCM, pb b p

: () q xp ()

xp. p p

S pp b .

i. Seriousness Due to Consequences o Exposure

q xp,

xp , b

b xp q

b p p .150 I ,

p pb p

, , b -q xp, x b

b MCM. R pb

f p- p b -

- q xp.

, pb

q xp , p b,

b, . I q p -b ; b

b p pp

pp b p

. B q , q

, ,

pp .

ii. Seriousness Due to Likelihood (or Treat) o ExposureA pb

xp. T p b-

p p pb ,


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6

p. F xp, ,

ppp .

C p pbb pb (

b ,

p- p- ).151 R,

b , p

b q q

b b

. b b , U.S.

Dp H S M T D

. A p, x

pb, , p pp ,

pb p b ,

b p, pb

xp.152

E , pp , pp pp f pb.

B C , p 7 ,

S p xp

pb . S b pb

, b . F

xp, S pb b

p z p pb(.., b C). A xp p

b p b

pb. Ab p p

b b p pp

p - p.


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6

iii. Seriousness Due to Vital Importance

B C p

pb 6 , , p

6

pp b pp

. S 6 b pp

p -

bj .153 A 6 pp,

7

b pb. I p pb,

EXAMPLES OF CIRCUMSTANCES THAT MIGHT PRESENT A SERIOUS PROBLEM

Concrete examples can inorm what constitutes a serious problem. Current regulations

were developed in the wake o 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 o weaponized sarin gas have gone missing under suspicious

circumstances. Sarin is estimated to be ve hundred times more toxic than cyanide,

and even non-lethal exposure is likely to have unknown long-term eects on a childsneurological development. A new MCM oers a promising potential intervention, but

has not yet been tested with children.

2. Smallpox, a disease that no longer occurs naturally, is stolen rom a research

acility. The possibility o exposure poses a threat to the community at large due

to its inectiousness and high mortality rate; pediatric populations are especially

vulnerable. Historically, physicians have only been able to treat the symptoms rather

than combat the virus itsel. Scientists have ound one new antiviral agent that is

eective in combating the disease. This new treatment has just been approved or

use by adults.

3. Security sources revea