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<v Speaker 1>Section one of Safeguarding Children Pediatric Medical Countermeasure Research. This

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<v Speaker 1>is a LibriVox recording. All LibriVox recordings are in the

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<v Speaker 1>public domain. For more information or to volunteer, please visit

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<v Speaker 1>LibriVox dot org. Recording by Patrick mccaffee, Merritt Island. Safeguarding

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<v Speaker 1>Children Pediatric Medical Countermeasure Research by Presidential Commission for the

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<v Speaker 1>Study of Bioethical Issues. Section one front Matter Executive summary

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<v Speaker 1>about the Presidential Commission for the Study of Bioethical Issues.

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<v Speaker 1>The President's Commission for the Study of Bioethical Issues. The

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<v Speaker 1>Bioethics Commission is an advisory panel of the nation's leaders

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<v Speaker 1>in medicine, science, ethics, religion, law, and engineering. The Bioethics

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<v Speaker 1>Commission advises the President on bioethical issues arising from advances

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<v Speaker 1>in biomedicine and related areas of science and technology. The

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<v Speaker 1>Bioethics Commission seeks to identify and promote policies and practices

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<v Speaker 1>that ensure scientific research, health care delivery, and technological innovation

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<v Speaker 1>are conducted in a socially and ethically responsible manner. For

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<v Speaker 1>more information about the Bioethics Commission, please see www. Dot

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<v Speaker 1>Bioethics dot gov. Executive summary, Safeguarding children is one of

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<v Speaker 1>our nation's foremost obligations. We have both a fundamental duty

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<v Speaker 1>to protect individual children from undue risk during research and

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<v Speaker 1>an obligation to protect all children during an emergency to

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<v Speaker 1>the extent ethically and practically possible by being prepared both

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<v Speaker 1>with the fruits of scientifically and ethically sound research and

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<v Speaker 1>with a full wilsome national readiness to respond. In January

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<v Speaker 1>twenty twelve, the Secretary of Health and Human Services HHS

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<v Speaker 1>asked the Presidential Commission for the Study of Bioethical Issues

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<v Speaker 1>the Bioethics Commission, to advise the U S Government in

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<v Speaker 1>its mission to be fully prepared to mitigate the impact

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<v Speaker 1>of bioterrorism attacks on ethical considerations in evaluating and conducting

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<v Speaker 1>pediatric medical countermeasure MCM research. The Secretary also asked that

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<v Speaker 1>the Bioethics Commission quote include the ethical considerations in conducting

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<v Speaker 1>a pre and post event study of anthrax vaccine absorbed

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<v Speaker 1>ava post exposure prophylaxis in children as part of its review.

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<v Speaker 1>Pediatric MCM research involves testing interventions with children that will

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<v Speaker 1>be used in response to an attack, either before an

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<v Speaker 1>attack occurs, in other words, pre event research or testing

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<v Speaker 1>such interventions following an attack. In other words, post event research,

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<v Speaker 1>pre and post event pediatric MCM research poses risks to

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<v Speaker 1>the individual children enrolled in research, who, in many cases

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<v Speaker 1>do not stand to benefit directly from the research. Research

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<v Speaker 1>with children differs from that with adults because children cannot

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<v Speaker 1>consent in the relevant sense. They are substantially lacking in

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<v Speaker 1>the developed capacities necessary for adequately informed and voluntary decision making,

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<v Speaker 1>making them a vulnerable population. Although this incapacity is most

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<v Speaker 1>often attributed to their level of cognitive development, the vulnerability

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<v Speaker 1>of children can derive from multiple sources, such as expectations

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<v Speaker 1>of deference to adult authority, lack of independent resources for

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<v Speaker 1>autonomous decision making, and long standing institutionalized relationships of adult

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<v Speaker 1>authority and power. For this reason, extra protections are warranted

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<v Speaker 1>to ensure that children are not placed at excessive risk

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<v Speaker 1>for the benefit of others. These additional safeguards include parental permission,

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<v Speaker 1>meaningful child assent, and limits on the degree of permissible

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<v Speaker 1>research related risk. The Bioethics Commission's ethical analysis lies at

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<v Speaker 1>the intersection of the unique characteristics of MCM research and

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<v Speaker 1>pediatric research. In its nineteen seventy seven report Research Involving

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<v Speaker 1>Children the National Commission for the Protection of Human Subjects

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<v Speaker 1>of Biomedical and Behavioral Research. The National commiss preciently described

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<v Speaker 1>this type of challenge. The ethical principles at stake are

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<v Speaker 1>the moral obligation to protect the community and the moral

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<v Speaker 1>prohibition against using unconsenting persons at considerable risk to their

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<v Speaker 1>well being for the promotion of the common good. The

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<v Speaker 1>four ethical principles that guides the Bioethics Commission's discussion of

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<v Speaker 1>pediatric research protections are respect for persons, beneficence and justice

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<v Speaker 1>as outlined in the Belmont Report, and democratic deliberation, which

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<v Speaker 1>was implicit both in the way the National Commission carried

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<v Speaker 1>out its work and also in its recommendations regarding the

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<v Speaker 1>process of reviewing and approving pediatric research. HHS and later

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<v Speaker 1>the US Food and Drug Administry FDA adopted the National

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<v Speaker 1>Commission's recommendations almost verbatim, and the regulations subsequently promulgated concerning

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<v Speaker 1>research with children remain largely the same today, comprising Subpart

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<v Speaker 1>D of HHS Regulations at forty five CFR Part forty

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<v Speaker 1>six and FDA Regulations at twenty one CFR Part fifty.

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<v Speaker 1>The National Commission's most straightforward recommendations address research that poses

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<v Speaker 1>only minimal risk or that offers the prospect of direct

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<v Speaker 1>benefit to participants. These recommendations would subsequently be codified in

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<v Speaker 1>sections four to four and four to five of the

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<v Speaker 1>HHS Regulations. More complicated, but still ethically tractable was research

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<v Speaker 1>posing greater risk than minimal risk but likely to yield

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<v Speaker 1>generalizable knowledge about the participant's condition. Research that is greater

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<v Speaker 1>than minimal risk with no prospect of direct benefit to

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<v Speaker 1>subjects or benefit to others with their condition was considered

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<v Speaker 1>decidedly more controversial and ethically problematic in the regulations. This

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<v Speaker 1>last type of research was reserved for evaluation and approval

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<v Speaker 1>by a national panel of experts and the Secretary of

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<v Speaker 1>HHS for HHS supported research section four zero seven. Pre

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<v Speaker 1>event research. Pediatric research that presents no prospect of direct

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<v Speaker 1>benefit to participants or that is not likely to yield

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<v Speaker 1>generalizable knowledge about the participant's condition generally can only be

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<v Speaker 1>conducted if it presents no more than minimal risk, except

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<v Speaker 1>in extraordinary circumstances. Thus, the Bioethics Commission concluded that pre

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<v Speaker 1>event pediatric MCM research which presents no prospect of direct

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<v Speaker 1>benefit because no children are affected by the condition being studied,

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<v Speaker 1>generally cannot proceed unless it is minimal risk research. Pre

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<v Speaker 1>event research might in some cases be designed in a

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<v Speaker 1>way that would permit it to be judged minimal risk

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<v Speaker 1>through an age d escalation process in which risks are

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<v Speaker 1>assessed and evaluated at each step. Robust research with young

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<v Speaker 1>adults might support the conclusion that research with the oldest

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<v Speaker 1>children is minimal risk. Similarly, research with the oldest children

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<v Speaker 1>that further characterizes research risk might support an inference that

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<v Speaker 1>re research with the next oldest group of children is

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<v Speaker 1>minimal risk as well. Recommendation one pre event pediatric medical

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<v Speaker 1>countermeasure research risk limited to minimal, except under extraordinary circumstances.

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<v Speaker 1>Pre event pediatric medical countermeasure testing should be conducted with

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<v Speaker 1>a research design posing only a minimal level of research risk,

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<v Speaker 1>except under extraordinary circumstances. If pre event pediatric medical countermeasure

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<v Speaker 1>research cannot be conducted as a minimal risk study, research

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<v Speaker 1>that exposes children to no more than a minor increase

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<v Speaker 1>over minimal risk, a level that is still very limited

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<v Speaker 1>and poses no substantial risk to health or well being

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<v Speaker 1>should proceed to a national level review under Department of

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<v Speaker 1>Health and Human Services Regulations at forty five CFR Section

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<v Speaker 1>forty six point four zero seven and or US Food

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<v Speaker 1>and Drug Administration Regulations at twenty one CFR Section fifty

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<v Speaker 1>point five four Recommendation two risk in pre event pediatric

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<v Speaker 1>medical countermeasure research. Before beginning pre event medical countermeasure studies

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<v Speaker 1>with children, Ethically sound modeling, testing with animals, and testing

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<v Speaker 1>with the youngest adults must be completed to identify, understand,

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<v Speaker 1>and characterize research risks. If pediatric research is determined to

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<v Speaker 1>be minimal risk and is to be conducted, progressive age

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<v Speaker 1>de escalation should be employed whenever possible, from the oldest

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<v Speaker 1>age group of children to the youngest group necessary to

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<v Speaker 1>provide additional protection to the youngest, d and most vulnerable

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<v Speaker 1>children and to ensure that data from an older age

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<v Speaker 1>group can inform the research design and the estimate of

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<v Speaker 1>risk level for the next younger age group. There will

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<v Speaker 1>be instances in which it will be impossible to design

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<v Speaker 1>minimal risk pre event MCM research. In such cases, national

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<v Speaker 1>level review under section four zero seven would be required,

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<v Speaker 1>but reviews should proceed only if researchers can demonstrate that

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<v Speaker 1>the research poses no more than a minor increase over

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<v Speaker 1>minimal risk to participants. Recommendation three preconditions to national level

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<v Speaker 1>review of pre event pediatric medical countermeasure research. Pre event

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<v Speaker 1>pediatric medical countermeasure research may proceed to national level review

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<v Speaker 1>under Department of Health and Human Services Regulations at forty

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<v Speaker 1>five section forty six point four zero seven and or

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<v Speaker 1>US Food and Drug Administration Regulations at twenty one CFR

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<v Speaker 1>Section fifty point five four only when researchers have demonstrated

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<v Speaker 1>and reviewers concur that a minimal risk study is impossible

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<v Speaker 1>and the proposed study poses no more than a minor

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<v Speaker 1>increase over minimal risk to research participants. In part because

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<v Speaker 1>of the inherent uncertainty of a bioterrorism attack, pre event

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<v Speaker 1>pediatric medical countermeasure research posing greater than a minor increase

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<v Speaker 1>over minimal risk should not be approved under forty five

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<v Speaker 1>CFR section forty six point four zero seven or twenty

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<v Speaker 1>one CFR Section fifty point five four. The Bioethics Commits

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<v Speaker 1>Recommended Framework, structured around the three conditions for national level review,

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<v Speaker 1>clarifies the circumstances in which proposed research presents a quote

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<v Speaker 1>reasonable opportunity end quote to address a quote serious problem

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<v Speaker 1>specifies a rigorous set of conditions necessary to determine whether

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<v Speaker 1>the research would be conducted in accordance with quote sound

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<v Speaker 1>ethical principles endot and reiterates the importance of informed parental

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<v Speaker 1>permission and meaningful and developmentally appropriate child assent. Decision Makers

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<v Speaker 1>should assess proposed pre event pediatric MCM research that poses

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<v Speaker 1>more than minimal risk using this framework in order to

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<v Speaker 1>ensure that all the necessary aspects of a study have

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<v Speaker 1>been evaluated and found ethically permissible before moving forward. Recommendation

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<v Speaker 1>four Ethical Framework for National Level Review of pre event

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<v Speaker 1>Pediatric Medical Countermeasure research. To ensure the thoroughness and ethical

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<v Speaker 1>rigor of national level review, reviewers should apply the Bioethics

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<v Speaker 1>Commissions recommended Ethical Framework for reviewing pre event pediatric medical

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<v Speaker 1>countermeasure research that poses greater than minimal risk but no

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<v Speaker 1>more than a minor increase over minimal risk under Department

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<v Speaker 1>of Health and Human Services Regulations at forty five CFR

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<v Speaker 1>Section forty six point four zero seven, and or US

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<v Speaker 1>Food and Drug Administration Regulations at twenty one CFR Section

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<v Speaker 1>fifty point five four. A proposed protocol must meet the

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<v Speaker 1>requirements of the framework outlined in this report to be approved.

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<v Speaker 1>The framework clarifies the circumstance dances in which proposed research

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<v Speaker 1>presents a reasonable opportunity to address a serious problem, in

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<v Speaker 1>particular that seriousness must be judged by the consequences of exposure,

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<v Speaker 1>likelihood or threat of exposure, and the vital importance of

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<v Speaker 1>the information to be gained. The framework also specifies a

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<v Speaker 1>rigorous set of conditions necessary to determine whether the research

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<v Speaker 1>would be conducted in accordance with the required sound ethical

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<v Speaker 1>principles that fall into five general categories. One ethical threshold

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<v Speaker 1>of acceptable risk and adequate protection from harm. Two ethical

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<v Speaker 1>research design, for example, scientific necessity, valid research plan using

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<v Speaker 1>small trials and age d escalation with appropriate monitoring and

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<v Speaker 1>planning for post EVAs research. Three post trial requirements to

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<v Speaker 1>ensure ethical distribution of medical countermeasures in the event of

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<v Speaker 1>an attack, as well as a plan for treatment or

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<v Speaker 1>compensation for research related injury, for community engagement, and five

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<v Speaker 1>transparency and accountability. Finally, the framework reiterates the importance of

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<v Speaker 1>informed parental permission and meaningful and developmentally appropriate child assent

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<v Speaker 1>application to trials of AVA with children pre event research.

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<v Speaker 1>In confronting the ethical questions surrounding MCM testing in pediatric populations,

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<v Speaker 1>the Bioethics Commission concluded that before ethical pre event pediatric

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<v Speaker 1>AVA trials can be considered, further steps must be taken,

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<v Speaker 1>including additional minimal risk research with adult participants to determine

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<v Speaker 1>whether the research risks to children who do not stand

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<v Speaker 1>to benefit directly from it, pose no substantial risk to

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<v Speaker 1>their health or well being. Given the amount of safety,

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<v Speaker 1>immunogenicity and dosing information about AVA in young adults aged

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<v Speaker 1>eighteen to twenty five years, and given the widespread distribution

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<v Speaker 1>of AVA in this population, it is possible that with

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<v Speaker 1>additional testing in adults aged eighteen to twenty years, testing

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<v Speaker 1>to determine adverse effects, alternative dosing methods, and immunogenicity testing

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<v Speaker 1>of AVA with the oldest children, for example, adolescents who

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<v Speaker 1>are sixteen to seventeen years of age, could be considered

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<v Speaker 1>no more than minimal risk. Consequently, it would be reviewed

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<v Speaker 1>under section four zero four. Informed Careful age d escalation

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<v Speaker 1>might allow researchers to infer minimal risk studies down the

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<v Speaker 1>age scale. However, if data suggests that the use of

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<v Speaker 1>AVA is affected, for example, by a child's developmental stage,

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<v Speaker 1>for example infancy or puberty, or if an inference of

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<v Speaker 1>minimal risk from an older group of children to the

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<v Speaker 1>next younger group is not possible, a study designed to

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<v Speaker 1>pose a minor increase over minimal risk might be appropriate

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<v Speaker 1>for national level review. Post event research. Public health officials

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<v Speaker 1>must be prepared to conduct post event research when a

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<v Speaker 1>bioterrorism attack occurs, regardless of whether pre event pediatric MCM

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<v Speaker 1>research trials were conducted. In contrast to pre event testing,

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<v Speaker 1>in which ethical deliberations focus on whether any research with

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<v Speaker 1>children would be ethically permissible. In post event circumstances, research

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<v Speaker 1>is ethically required to safeguard the well being of current

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<v Speaker 1>and future children. If a pediatric MCM research trial were completed,

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<v Speaker 1>pre event data should be collected following the administration of

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<v Speaker 1>the tested intervention to acquire necessary additional safety information. In

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<v Speaker 1>the absence of a pre event investigation, an emergency situation

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<v Speaker 1>might warrant administering an untested MCM to children in an

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<v Speaker 1>effort to save lives. When children receive an untested MCM,

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<v Speaker 1>it is ethically imperative that health officials collect data to

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<v Speaker 1>learn as much as possible about the use of the

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<v Speaker 1>untested na M from the event Recommendation five Post event

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<v Speaker 1>pediatric medical countermeasure research. Post event research should be planned

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<v Speaker 1>in advance and conducted when untested medical countermeasures are administered

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<v Speaker 1>to children in an emergency, or when limited pre event

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<v Speaker 1>medical countermeasure studies have already occurred. Institutional review boards must

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<v Speaker 1>be cognizant of the exigencies imposed upon research under emergency conditions,

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<v Speaker 1>and when reviewing post event medical countermeasure research proposals, ensure

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<v Speaker 1>that adequate processes are in place for informed parental permission

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<v Speaker 1>and meaningful child assent. Institutional review boards must also ensure

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<v Speaker 1>that the research design is scientifically sound. Children enrolled in

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<v Speaker 1>research have access to the best available care equip Plans

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<v Speaker 1>are in place to treat or compensate children injured by research,

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<v Speaker 1>and provisions are made to engage communities throughout the course

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<v Speaker 1>of research. In the event of a bioterrorism attack, the

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<v Speaker 1>US government has emergency preparedness plans to mobilize medical interventions, drugs, vaccines,

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<v Speaker 1>and supplies from the Strategic National Stockpile for distribution to

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<v Speaker 1>affected portions of the population. The federal government delivers supplies

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<v Speaker 1>to the states which have individualized distribution strategies based on

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<v Speaker 1>localized need and infrastructure. In the event that the MCM

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<v Speaker 1>needed is either still in clinical trials or has not

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<v Speaker 1>yet been approved for the specified application, there are two

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<v Speaker 1>mechanisms available in Emergency Use Authorization EUA and an Investigational

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<v Speaker 1>New Drug Application i in D that allow the government

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<v Speaker 1>to distribute an unapproved intervention to help people in an emergency.

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<v Speaker 1>Underlying the motivation for these mechanisms are a host of

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<v Speaker 1>ethical principles, including respect for persons, beneficence, and justice. Together,

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<v Speaker 1>the EUA and i in D provide mechanisms to supply

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<v Speaker 1>necessary MCMs with varying levels of clinical and research protections

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<v Speaker 1>to ensure adequate respect for persons as appropriate. Recommendation six

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<v Speaker 1>regulatory Mechanisms for post event pediatric medical countermeasure research and distribution.

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<v Speaker 1>When there are no data on the administration of a

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<v Speaker 1>medical countermeasure to children and it will be provided to

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<v Speaker 1>children in an emergency, the medical countermeasure should be provided

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<v Speaker 1>under a treatment Investigational New Drug Application n D to

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<v Speaker 1>ensure that rigorous pediatric research protections apply to safeguard those

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<v Speaker 1>children who receive the medical countermeasure When a medical countermeasure

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<v Speaker 1>is distributed broadly to children using a treatment n D,

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<v Speaker 1>it is essential that the US government also conduct a concurrent,

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<v Speaker 1>small scale study under an investigator n D to obtain

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<v Speaker 1>data that can potentially be used to support an emergency

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<v Speaker 1>use authorization for pediatric use of the medical countermeasure in

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<v Speaker 1>a future event. To expedite post event research and ensure

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<v Speaker 1>the availability of appropriate medical countermeasures for children, a pren

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<v Speaker 1>D consultation and approval should be put in place before

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<v Speaker 1>an event application to trials of AVA with children post

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<v Speaker 1>event research. In an event involving the release of weaponized

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<v Speaker 1>anthrax or other large scale release of spores, a plan

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<v Speaker 1>exists to provide children, like adults, treatment with a sixty

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<v Speaker 1>day course of antibiotics as well as AVA. FDA and

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<v Speaker 1>the US Centers for Disease Control and Prevention CDC have

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<v Speaker 1>a treatment ind in place to allow for broad access

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<v Speaker 1>to AVA for children in the event of an emergency.

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<v Speaker 1>Work is ongoing to clarify the informed consent process. In addition,

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<v Speaker 1>FDA and CDC are collaborated to develop a nested protocol

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<v Speaker 1>that would involve research and surveillance to better understand immunogenicity

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<v Speaker 1>and reactogenicity to the vaccine. Both of these mechanisms require

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<v Speaker 1>IRB approval under the Bioethics Commission's ethical approach. Even if

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<v Speaker 1>a pre event study of AVA with children is approved,

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<v Speaker 1>post event research would be necessary to gather additional safety

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<v Speaker 1>and immunogenicity data beyond the limited amount a pre event

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<v Speaker 1>study could produce. If a pre event study is not

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<v Speaker 1>approved and AVA is nonetheless administered to children in the

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<v Speaker 1>event of an attack, post event research would be ethically required.

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<v Speaker 1>It is important that any post event distribution of AVA

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<v Speaker 1>to children, regardless of the specific mechanism, entail democratic deliberation

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<v Speaker 1>in the form of extensive community engagement. Community engagement should

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<v Speaker 1>begin in pre event research and continue through post event activities. Moreover,

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<v Speaker 1>it is critical that any post event research protocol be

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<v Speaker 1>scientifically sound, have adequate processes in place to ensure informed

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<v Speaker 1>parental permission and meaningful child assent, provide for adequate treatment

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<v Speaker 1>or compensation for research related injuries, and ensure that enrolled

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<v Speaker 1>children have access to the best available care. Pediatric MCM

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<v Speaker 1>research brings into sharp focus the fact that the health

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<v Speaker 1>and security of children are paramount. It highlights the importance

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<v Speaker 1>of both protecting children from unjustifiable research risks and assuring

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<v Speaker 1>their safety as far as possible in the event of

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<v Speaker 1>an emergency. Grounding its work in the principles of respect

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<v Speaker 1>for persons, beneficence, justice, and democratic deliberation, the Bioethics Commission

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<v Speaker 1>reaffirmed the ethical foundations of pediatric research and applied them

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<v Speaker 1>to the particularly complex and difficult case of pediatric MCM research.

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<v Speaker 1>As exemplified by the Bioethics Commission's deliberations, such research warrants

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<v Speaker 1>an ongoing national conversation in order to ensure the highest

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<v Speaker 1>standards of protection for children that reflect an unwavering commitment

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<v Speaker 1>to safeguard all children from unacceptable risks in research and

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<v Speaker 1>through research that promotes their health and well being. End

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<v Speaker 1>of section one. Recording by Patrick mccaffee, Merritt, Islands