Speaker 1: Section one of Safeguarding Children Pediatric Medical Countermeasure Research. This
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Speaker 1: LibriVox dot org. Recording by Patrick mccaffee, Merritt Island. Safeguarding
Speaker 1: Children Pediatric Medical Countermeasure Research by Presidential Commission for the
Speaker 1: Study of Bioethical Issues. Section one front Matter Executive summary
Speaker 1: about the Presidential Commission for the Study of Bioethical Issues.
Speaker 1: The President's Commission for the Study of Bioethical Issues. The
Speaker 1: Bioethics Commission is an advisory panel of the nation's leaders
Speaker 1: in medicine, science, ethics, religion, law, and engineering. The Bioethics
Speaker 1: Commission advises the President on bioethical issues arising from advances
Speaker 1: in biomedicine and related areas of science and technology. The
Speaker 1: Bioethics Commission seeks to identify and promote policies and practices
Speaker 1: that ensure scientific research, health care delivery, and technological innovation
Speaker 1: are conducted in a socially and ethically responsible manner. For
Speaker 1: more information about the Bioethics Commission, please see www. Dot
Speaker 1: Bioethics dot gov. Executive summary, Safeguarding children is one of
Speaker 1: our nation's foremost obligations. We have both a fundamental duty
Speaker 1: to protect individual children from undue risk during research and
Speaker 1: an obligation to protect all children during an emergency to
Speaker 1: the extent ethically and practically possible by being prepared both
Speaker 1: with the fruits of scientifically and ethically sound research and
Speaker 1: with a full wilsome national readiness to respond. In January
Speaker 1: twenty twelve, the Secretary of Health and Human Services HHS
Speaker 1: asked the Presidential Commission for the Study of Bioethical Issues
Speaker 1: the Bioethics Commission, to advise the U S Government in
Speaker 1: its mission to be fully prepared to mitigate the impact
Speaker 1: of bioterrorism attacks on ethical considerations in evaluating and conducting
Speaker 1: pediatric medical countermeasure MCM research. The Secretary also asked that
Speaker 1: the Bioethics Commission quote include the ethical considerations in conducting
Speaker 1: a pre and post event study of anthrax vaccine absorbed
Speaker 1: ava post exposure prophylaxis in children as part of its review.
Speaker 1: Pediatric MCM research involves testing interventions with children that will
Speaker 1: be used in response to an attack, either before an
Speaker 1: attack occurs, in other words, pre event research or testing
Speaker 1: such interventions following an attack. In other words, post event research,
Speaker 1: pre and post event pediatric MCM research poses risks to
Speaker 1: the individual children enrolled in research, who, in many cases
Speaker 1: do not stand to benefit directly from the research. Research
Speaker 1: with children differs from that with adults because children cannot
Speaker 1: consent in the relevant sense. They are substantially lacking in
Speaker 1: the developed capacities necessary for adequately informed and voluntary decision making,
Speaker 1: making them a vulnerable population. Although this incapacity is most
Speaker 1: often attributed to their level of cognitive development, the vulnerability
Speaker 1: of children can derive from multiple sources, such as expectations
Speaker 1: of deference to adult authority, lack of independent resources for
Speaker 1: autonomous decision making, and long standing institutionalized relationships of adult
Speaker 1: authority and power. For this reason, extra protections are warranted
Speaker 1: to ensure that children are not placed at excessive risk
Speaker 1: for the benefit of others. These additional safeguards include parental permission,
Speaker 1: meaningful child assent, and limits on the degree of permissible
Speaker 1: research related risk. The Bioethics Commission's ethical analysis lies at
Speaker 1: the intersection of the unique characteristics of MCM research and
Speaker 1: pediatric research. In its nineteen seventy seven report Research Involving
Speaker 1: Children the National Commission for the Protection of Human Subjects
Speaker 1: of Biomedical and Behavioral Research. The National commiss preciently described
Speaker 1: this type of challenge. The ethical principles at stake are
Speaker 1: the moral obligation to protect the community and the moral
Speaker 1: prohibition against using unconsenting persons at considerable risk to their
Speaker 1: well being for the promotion of the common good. The
Speaker 1: four ethical principles that guides the Bioethics Commission's discussion of
Speaker 1: pediatric research protections are respect for persons, beneficence and justice
Speaker 1: as outlined in the Belmont Report, and democratic deliberation, which
Speaker 1: was implicit both in the way the National Commission carried
Speaker 1: out its work and also in its recommendations regarding the
Speaker 1: process of reviewing and approving pediatric research. HHS and later
Speaker 1: the US Food and Drug Administry FDA adopted the National
Speaker 1: Commission's recommendations almost verbatim, and the regulations subsequently promulgated concerning
Speaker 1: research with children remain largely the same today, comprising Subpart
Speaker 1: D of HHS Regulations at forty five CFR Part forty
Speaker 1: six and FDA Regulations at twenty one CFR Part fifty.
Speaker 1: The National Commission's most straightforward recommendations address research that poses
Speaker 1: only minimal risk or that offers the prospect of direct
Speaker 1: benefit to participants. These recommendations would subsequently be codified in
Speaker 1: sections four to four and four to five of the
Speaker 1: HHS Regulations. More complicated, but still ethically tractable was research
Speaker 1: posing greater risk than minimal risk but likely to yield
Speaker 1: generalizable knowledge about the participant's condition. Research that is greater
Speaker 1: than minimal risk with no prospect of direct benefit to
Speaker 1: subjects or benefit to others with their condition was considered
Speaker 1: decidedly more controversial and ethically problematic in the regulations. This
Speaker 1: last type of research was reserved for evaluation and approval
Speaker 1: by a national panel of experts and the Secretary of
Speaker 1: HHS for HHS supported research section four zero seven. Pre
Speaker 1: event research. Pediatric research that presents no prospect of direct
Speaker 1: benefit to participants or that is not likely to yield
Speaker 1: generalizable knowledge about the participant's condition generally can only be
Speaker 1: conducted if it presents no more than minimal risk, except
Speaker 1: in extraordinary circumstances. Thus, the Bioethics Commission concluded that pre
Speaker 1: event pediatric MCM research which presents no prospect of direct
Speaker 1: benefit because no children are affected by the condition being studied,
Speaker 1: generally cannot proceed unless it is minimal risk research. Pre
Speaker 1: event research might in some cases be designed in a
Speaker 1: way that would permit it to be judged minimal risk
Speaker 1: through an age d escalation process in which risks are
Speaker 1: assessed and evaluated at each step. Robust research with young
Speaker 1: adults might support the conclusion that research with the oldest
Speaker 1: children is minimal risk. Similarly, research with the oldest children
Speaker 1: that further characterizes research risk might support an inference that
Speaker 1: re research with the next oldest group of children is
Speaker 1: minimal risk as well. Recommendation one pre event pediatric medical
Speaker 1: countermeasure research risk limited to minimal, except under extraordinary circumstances.
Speaker 1: Pre event pediatric medical countermeasure testing should be conducted with
Speaker 1: a research design posing only a minimal level of research risk,
Speaker 1: except under extraordinary circumstances. If pre event pediatric medical countermeasure
Speaker 1: research cannot be conducted as a minimal risk study, research
Speaker 1: that exposes children to no more than a minor increase
Speaker 1: over minimal risk, a level that is still very limited
Speaker 1: and poses no substantial risk to health or well being
Speaker 1: should proceed to a national level review under Department of
Speaker 1: Health and Human Services Regulations at forty five CFR Section
Speaker 1: forty six point four zero seven and or US Food
Speaker 1: and Drug Administration Regulations at twenty one CFR Section fifty
Speaker 1: point five four Recommendation two risk in pre event pediatric
Speaker 1: medical countermeasure research. Before beginning pre event medical countermeasure studies
Speaker 1: with children, Ethically sound modeling, testing with animals, and testing
Speaker 1: with the youngest adults must be completed to identify, understand,
Speaker 1: and characterize research risks. If pediatric research is determined to
Speaker 1: be minimal risk and is to be conducted, progressive age
Speaker 1: de escalation should be employed whenever possible, from the oldest
Speaker 1: age group of children to the youngest group necessary to
Speaker 1: provide additional protection to the youngest, d and most vulnerable
Speaker 1: children and to ensure that data from an older age
Speaker 1: group can inform the research design and the estimate of
Speaker 1: risk level for the next younger age group. There will
Speaker 1: be instances in which it will be impossible to design
Speaker 1: minimal risk pre event MCM research. In such cases, national
Speaker 1: level review under section four zero seven would be required,
Speaker 1: but reviews should proceed only if researchers can demonstrate that
Speaker 1: the research poses no more than a minor increase over
Speaker 1: minimal risk to participants. Recommendation three preconditions to national level
Speaker 1: review of pre event pediatric medical countermeasure research. Pre event
Speaker 1: pediatric medical countermeasure research may proceed to national level review
Speaker 1: under Department of Health and Human Services Regulations at forty
Speaker 1: five section forty six point four zero seven and or
Speaker 1: US Food and Drug Administration Regulations at twenty one CFR
Speaker 1: Section fifty point five four only when researchers have demonstrated
Speaker 1: and reviewers concur that a minimal risk study is impossible
Speaker 1: and the proposed study poses no more than a minor
Speaker 1: increase over minimal risk to research participants. In part because
Speaker 1: of the inherent uncertainty of a bioterrorism attack, pre event
Speaker 1: pediatric medical countermeasure research posing greater than a minor increase
Speaker 1: over minimal risk should not be approved under forty five
Speaker 1: CFR section forty six point four zero seven or twenty
Speaker 1: one CFR Section fifty point five four. The Bioethics Commits
Speaker 1: Recommended Framework, structured around the three conditions for national level review,
Speaker 1: clarifies the circumstances in which proposed research presents a quote
Speaker 1: reasonable opportunity end quote to address a quote serious problem
Speaker 1: specifies a rigorous set of conditions necessary to determine whether
Speaker 1: the research would be conducted in accordance with quote sound
Speaker 1: ethical principles endot and reiterates the importance of informed parental
Speaker 1: permission and meaningful and developmentally appropriate child assent. Decision Makers
Speaker 1: should assess proposed pre event pediatric MCM research that poses
Speaker 1: more than minimal risk using this framework in order to
Speaker 1: ensure that all the necessary aspects of a study have
Speaker 1: been evaluated and found ethically permissible before moving forward. Recommendation
Speaker 1: four Ethical Framework for National Level Review of pre event
Speaker 1: Pediatric Medical Countermeasure research. To ensure the thoroughness and ethical
Speaker 1: rigor of national level review, reviewers should apply the Bioethics
Speaker 1: Commissions recommended Ethical Framework for reviewing pre event pediatric medical
Speaker 1: countermeasure research that poses greater than minimal risk but no
Speaker 1: more than a minor increase over minimal risk under Department
Speaker 1: of Health and Human Services Regulations at forty five CFR
Speaker 1: Section forty six point four zero seven, and or US
Speaker 1: Food and Drug Administration Regulations at twenty one CFR Section
Speaker 1: fifty point five four. A proposed protocol must meet the
Speaker 1: requirements of the framework outlined in this report to be approved.
Speaker 1: The framework clarifies the circumstance dances in which proposed research
Speaker 1: presents a reasonable opportunity to address a serious problem, in
Speaker 1: particular that seriousness must be judged by the consequences of exposure,
Speaker 1: likelihood or threat of exposure, and the vital importance of
Speaker 1: the information to be gained. The framework also specifies a
Speaker 1: rigorous set of conditions necessary to determine whether the research
Speaker 1: would be conducted in accordance with the required sound ethical
Speaker 1: principles that fall into five general categories. One ethical threshold
Speaker 1: of acceptable risk and adequate protection from harm. Two ethical
Speaker 1: research design, for example, scientific necessity, valid research plan using
Speaker 1: small trials and age d escalation with appropriate monitoring and
Speaker 1: planning for post EVAs research. Three post trial requirements to
Speaker 1: ensure ethical distribution of medical countermeasures in the event of
Speaker 1: an attack, as well as a plan for treatment or
Speaker 1: compensation for research related injury, for community engagement, and five
Speaker 1: transparency and accountability. Finally, the framework reiterates the importance of
Speaker 1: informed parental permission and meaningful and developmentally appropriate child assent
Speaker 1: application to trials of AVA with children pre event research.
Speaker 1: In confronting the ethical questions surrounding MCM testing in pediatric populations,
Speaker 1: the Bioethics Commission concluded that before ethical pre event pediatric
Speaker 1: AVA trials can be considered, further steps must be taken,
Speaker 1: including additional minimal risk research with adult participants to determine
Speaker 1: whether the research risks to children who do not stand
Speaker 1: to benefit directly from it, pose no substantial risk to
Speaker 1: their health or well being. Given the amount of safety,
Speaker 1: immunogenicity and dosing information about AVA in young adults aged
Speaker 1: eighteen to twenty five years, and given the widespread distribution
Speaker 1: of AVA in this population, it is possible that with
Speaker 1: additional testing in adults aged eighteen to twenty years, testing
Speaker 1: to determine adverse effects, alternative dosing methods, and immunogenicity testing
Speaker 1: of AVA with the oldest children, for example, adolescents who
Speaker 1: are sixteen to seventeen years of age, could be considered
Speaker 1: no more than minimal risk. Consequently, it would be reviewed
Speaker 1: under section four zero four. Informed Careful age d escalation
Speaker 1: might allow researchers to infer minimal risk studies down the
Speaker 1: age scale. However, if data suggests that the use of
Speaker 1: AVA is affected, for example, by a child's developmental stage,
Speaker 1: for example infancy or puberty, or if an inference of
Speaker 1: minimal risk from an older group of children to the
Speaker 1: next younger group is not possible, a study designed to
Speaker 1: pose a minor increase over minimal risk might be appropriate
Speaker 1: for national level review. Post event research. Public health officials
Speaker 1: must be prepared to conduct post event research when a
Speaker 1: bioterrorism attack occurs, regardless of whether pre event pediatric MCM
Speaker 1: research trials were conducted. In contrast to pre event testing,
Speaker 1: in which ethical deliberations focus on whether any research with
Speaker 1: children would be ethically permissible. In post event circumstances, research
Speaker 1: is ethically required to safeguard the well being of current
Speaker 1: and future children. If a pediatric MCM research trial were completed,
Speaker 1: pre event data should be collected following the administration of
Speaker 1: the tested intervention to acquire necessary additional safety information. In
Speaker 1: the absence of a pre event investigation, an emergency situation
Speaker 1: might warrant administering an untested MCM to children in an
Speaker 1: effort to save lives. When children receive an untested MCM,
Speaker 1: it is ethically imperative that health officials collect data to
Speaker 1: learn as much as possible about the use of the
Speaker 1: untested na M from the event Recommendation five Post event
Speaker 1: pediatric medical countermeasure research. Post event research should be planned
Speaker 1: in advance and conducted when untested medical countermeasures are administered
Speaker 1: to children in an emergency, or when limited pre event
Speaker 1: medical countermeasure studies have already occurred. Institutional review boards must
Speaker 1: be cognizant of the exigencies imposed upon research under emergency conditions,
Speaker 1: and when reviewing post event medical countermeasure research proposals, ensure
Speaker 1: that adequate processes are in place for informed parental permission
Speaker 1: and meaningful child assent. Institutional review boards must also ensure
Speaker 1: that the research design is scientifically sound. Children enrolled in
Speaker 1: research have access to the best available care equip Plans
Speaker 1: are in place to treat or compensate children injured by research,
Speaker 1: and provisions are made to engage communities throughout the course
Speaker 1: of research. In the event of a bioterrorism attack, the
Speaker 1: US government has emergency preparedness plans to mobilize medical interventions, drugs, vaccines,
Speaker 1: and supplies from the Strategic National Stockpile for distribution to
Speaker 1: affected portions of the population. The federal government delivers supplies
Speaker 1: to the states which have individualized distribution strategies based on
Speaker 1: localized need and infrastructure. In the event that the MCM
Speaker 1: needed is either still in clinical trials or has not
Speaker 1: yet been approved for the specified application, there are two
Speaker 1: mechanisms available in Emergency Use Authorization EUA and an Investigational
Speaker 1: New Drug Application i in D that allow the government
Speaker 1: to distribute an unapproved intervention to help people in an emergency.
Speaker 1: Underlying the motivation for these mechanisms are a host of
Speaker 1: ethical principles, including respect for persons, beneficence, and justice. Together,
Speaker 1: the EUA and i in D provide mechanisms to supply
Speaker 1: necessary MCMs with varying levels of clinical and research protections
Speaker 1: to ensure adequate respect for persons as appropriate. Recommendation six
Speaker 1: regulatory Mechanisms for post event pediatric medical countermeasure research and distribution.
Speaker 1: When there are no data on the administration of a
Speaker 1: medical countermeasure to children and it will be provided to
Speaker 1: children in an emergency, the medical countermeasure should be provided
Speaker 1: under a treatment Investigational New Drug Application n D to
Speaker 1: ensure that rigorous pediatric research protections apply to safeguard those
Speaker 1: children who receive the medical countermeasure When a medical countermeasure
Speaker 1: is distributed broadly to children using a treatment n D,
Speaker 1: it is essential that the US government also conduct a concurrent,
Speaker 1: small scale study under an investigator n D to obtain
Speaker 1: data that can potentially be used to support an emergency
Speaker 1: use authorization for pediatric use of the medical countermeasure in
Speaker 1: a future event. To expedite post event research and ensure
Speaker 1: the availability of appropriate medical countermeasures for children, a pren
Speaker 1: D consultation and approval should be put in place before
Speaker 1: an event application to trials of AVA with children post
Speaker 1: event research. In an event involving the release of weaponized
Speaker 1: anthrax or other large scale release of spores, a plan
Speaker 1: exists to provide children, like adults, treatment with a sixty
Speaker 1: day course of antibiotics as well as AVA. FDA and
Speaker 1: the US Centers for Disease Control and Prevention CDC have
Speaker 1: a treatment ind in place to allow for broad access
Speaker 1: to AVA for children in the event of an emergency.
Speaker 1: Work is ongoing to clarify the informed consent process. In addition,
Speaker 1: FDA and CDC are collaborated to develop a nested protocol
Speaker 1: that would involve research and surveillance to better understand immunogenicity
Speaker 1: and reactogenicity to the vaccine. Both of these mechanisms require
Speaker 1: IRB approval under the Bioethics Commission's ethical approach. Even if
Speaker 1: a pre event study of AVA with children is approved,
Speaker 1: post event research would be necessary to gather additional safety
Speaker 1: and immunogenicity data beyond the limited amount a pre event
Speaker 1: study could produce. If a pre event study is not
Speaker 1: approved and AVA is nonetheless administered to children in the
Speaker 1: event of an attack, post event research would be ethically required.
Speaker 1: It is important that any post event distribution of AVA
Speaker 1: to children, regardless of the specific mechanism, entail democratic deliberation
Speaker 1: in the form of extensive community engagement. Community engagement should
Speaker 1: begin in pre event research and continue through post event activities. Moreover,
Speaker 1: it is critical that any post event research protocol be
Speaker 1: scientifically sound, have adequate processes in place to ensure informed
Speaker 1: parental permission and meaningful child assent, provide for adequate treatment
Speaker 1: or compensation for research related injuries, and ensure that enrolled
Speaker 1: children have access to the best available care. Pediatric MCM
Speaker 1: research brings into sharp focus the fact that the health
Speaker 1: and security of children are paramount. It highlights the importance
Speaker 1: of both protecting children from unjustifiable research risks and assuring
Speaker 1: their safety as far as possible in the event of
Speaker 1: an emergency. Grounding its work in the principles of respect
Speaker 1: for persons, beneficence, justice, and democratic deliberation, the Bioethics Commission
Speaker 1: reaffirmed the ethical foundations of pediatric research and applied them
Speaker 1: to the particularly complex and difficult case of pediatric MCM research.
Speaker 1: As exemplified by the Bioethics Commission's deliberations, such research warrants
Speaker 1: an ongoing national conversation in order to ensure the highest
Speaker 1: standards of protection for children that reflect an unwavering commitment
Speaker 1: to safeguard all children from unacceptable risks in research and
Speaker 1: through research that promotes their health and well being. End
Speaker 1: of section one. Recording by Patrick mccaffee, Merritt, Islands