Speaker 1: Section two of Safeguarding Children Pediatric Medical Countermeasure Research by
Speaker 1: Presidential Commission for the Study of Bioethical Issues. This LIVERVOK
Speaker 1: recording is in the public domain. Recording by Patrick mccaffee,
Speaker 1: Merritt Island. Chapter one introduction. Our sense of justice, beneficence
Speaker 1: and respect for human dignity calls upon the country to
Speaker 1: do what it reasonably can to safeguard all children in
Speaker 1: the event of a public health emergency. This protection includes,
Speaker 1: for example, providing medicine, vaccines, and other interventions as needed.
Speaker 1: Our same sense of justice, beneficence, and respect for human
Speaker 1: dignity calls on us to safeguard individual children who participate
Speaker 1: in scientifically and ethically sound clinical research to develop these interventions,
Speaker 1: and to protect individual children from participating in research that
Speaker 1: could impose undue risks on them. In other words, as
Speaker 1: a country, we have both a fundamental duty to protect
Speaker 1: individual children from undue risk during research and an obligation
Speaker 1: to protect all children during an emergency to the extent
Speaker 1: ethically and practically possible by being prepared both with the
Speaker 1: fruits of scientifically and ethically sound research and with a
Speaker 1: fulsome national readiness to respond. In January twenty twelve, the
Speaker 1: Secretary of Health and Human Services HHS asked the Presidential
Speaker 1: Commission for the Study of Bioethical Issues, the Bioethics Commission,
Speaker 1: to advise the U S Government in its mission to
Speaker 1: be fully prepared to mitigate the impact of biol terrorism
Speaker 1: attacks on ethical considerations in evaluating and conducting pediatric medical
Speaker 1: countermeasure MCM research. Pediatric MCM research involves testing interventions with
Speaker 1: children that will be used in response to an attack,
Speaker 1: either before it occurs in other words, pre event research,
Speaker 1: or testing such interventions following an attack in other words,
Speaker 1: post event research. Pre and post event pediatric MCM research
Speaker 1: pose risks to the individual children enrolled in research, who,
Speaker 1: in many cases do not stand to benefit directly from
Speaker 1: the research. The tension between the need to conduct pediatric
Speaker 1: MCM research to protect children in the event of a
Speaker 1: future attack and the risks of this research to individual
Speaker 1: children who do not stand to directly benefit from it
Speaker 1: creates the central ethical challenge of pediatric MCM research. As
Speaker 1: noted in the Belmont Report, the ethical dilemma facing the
Speaker 1: Bioethics Commission derives in part from the principle of beneficence,
Speaker 1: which quote requires that we protect against risk of harm
Speaker 1: to subjects, and also that we be concerned about the
Speaker 1: loss of the substantial benefits that might be gained from
Speaker 1: research end The Bioethics Commission addresses this tension in this report.
Speaker 1: A major bioterrorism attack could require deployment of pediatric MCMs
Speaker 1: to safeguard children. In the event of a bioterrorism attack,
Speaker 1: m cms should be ready and available for pediatric use
Speaker 1: under current federal plans. In the event of an emergency,
Speaker 1: children would be provided with at least some MCMs that
Speaker 1: have been approved for adults, even though many of these
Speaker 1: treatments have not been tested with children. Extrapolating from data
Speaker 1: in adult populations may be insufficient to determine safety and
Speaker 1: proper doses of MCMs for children. Pediatric research might therefore
Speaker 1: be necessary to determine the safest doses and formulations of
Speaker 1: MCMs for children pre event. MCM research presents challenges that
Speaker 1: are distinct from other types of research, as it involves
Speaker 1: research on a hypothetical condition with an undefined and perhaps
Speaker 1: unknowable likelihood of occurring, and while the knowledge gained could
Speaker 1: be profoundly useful, we may never have and hope never
Speaker 1: to have occasion to use it. The ramifications of these
Speaker 1: characteristics are discussed in greater detail below. Post event research
Speaker 1: poses its own challenges because this research generally will be
Speaker 1: conducted in very stressful circumstances. In post event MCM research,
Speaker 1: the experimental intervention will often be provided in concert with
Speaker 1: additional tested treatments that could confound data collected regarding the MCM. Moreover,
Speaker 1: the stressful circumstances in which post event research likely will
Speaker 1: be conducted might make safeguards such as obtaining adequate, informed
Speaker 1: parental permission and meaningful child assent particularly difficult. In this report,
Speaker 1: the Bioethics Commission also addresses research conducted when the threat
Speaker 1: of an attack is imminent, because, as discussed in greater
Speaker 1: detail below, in these cases, the ethical and practical concerns
Speaker 1: track those of a post event study, even if technically
Speaker 1: conducted pre event pediatric research itself presents particular ethical complications.
Speaker 1: Competent adults can generally consent to accept risks for the
Speaker 1: benefit of others during research through the informed consent process.
Speaker 1: Agreeing to place oneself at risk for the good of
Speaker 1: others is often viewed as admirable, generous, and honorable. Children,
Speaker 1: on the other hand, are ethically and legally incompetent to
Speaker 1: consent on their own behalf, and therefore cannot agree to
Speaker 1: assume research risks for the benefit of others. A child's
Speaker 1: reduced autonomy and increased vulnerability, along with the inability to
Speaker 1: provide informed consent, necessitates additional protections during research. These protections
Speaker 1: include limits on the level and types of research risks
Speaker 1: a child can be asked to assume, and generally require
Speaker 1: some prospect of direct benefit to the participant if research
Speaker 1: risks exceed the minimal ones that a healthy child living
Speaker 1: in a safe environment routinely encounters in daily life or
Speaker 1: during a routine medical examination. The Bioethics Commission's ethical analysis
Speaker 1: lies at the intersection of the unique characteristics of MCM
Speaker 1: research and pediatric research. In its nineteen seventy seven report
Speaker 1: Research Involving Children, the National Commission for the Protection of
Speaker 1: Human Subjects of Biomedical and Behavioral Research, the National Commission
Speaker 1: presently described this type of challenge. The ethical principles at
Speaker 1: stake are the moral obligation to protect the community and
Speaker 1: the moral prohibition against using unconsenting persons at considerable risk
Speaker 1: to their well being for the promotion of the common
Speaker 1: good end. Although the National Commission did not address pediatric
Speaker 1: MCM research specifically, the principles it articulated respect for persons,
Speaker 1: beneficence and its corollary non maleficence and justice offer a
Speaker 1: way to frame the complexities of MCM research involving children.
Speaker 1: An additional principle implicit in the National Commission's work, democratic deliberation,
Speaker 1: further informs this analysis. For this report, the Bioethics Commission
Speaker 1: examined these existing, well established ethical principles that guide pediatric
Speaker 1: research to enumerate considerations for the ethical conduct of pre
Speaker 1: event and post event MCM studies with children. The Bioethics
Speaker 1: Commission first considered pre event studies those posing minimal risk
Speaker 1: in other words, no greater risk than that faced by
Speaker 1: a healthy child in daily life or at a routine
Speaker 1: medical examination, as well as those posing greater than minimal
Speaker 1: risk while offering no direct prospect of benefit to the
Speaker 1: individual child participants, but that are important to the potential
Speaker 1: future benefit of many or all children. The Bioethics Commission
Speaker 1: then considered post event studies those posing minimal risk as
Speaker 1: well as those posing some additional risk but also offering
Speaker 1: the prospect of direct benefit to the individual children who participate,
Speaker 1: or offering the prospect of generalizable knowledge about the participant's
Speaker 1: condition both pre and post event. MCM research studies with
Speaker 1: children are ethically challenging for each of these categories, and
Speaker 1: consistent with its charge, the Bioethics Commission also existed the
Speaker 1: specific ethical issues raised in the context of proposed research
Speaker 1: on anthrax vaccine absorbed AVA with children anthrax vaccine absorbed.
Speaker 1: The complexities of pediatric MCM research were highlighted by government
Speaker 1: actions surrounding AVA, a particular MCM for anthrax. In early
Speaker 1: twenty eleven, the US government conducted an exercise called dark
Speaker 1: Zephyr to test local, state, and federal government responses to
Speaker 1: a large scale anthrax release in a major metropolitan area.
Speaker 1: Dark Zephyr revealed that about seven point six million individuals
Speaker 1: would be exposed to anthrax during such an event, including
Speaker 1: as many as one point seven million children, all of
Speaker 1: whom would require treatment. Although the government had plans in
Speaker 1: place to treat adults, officials involved in the exercise quickly
Speaker 1: realized that there was no evidence supporting a clear course
Speaker 1: of action for the treatment of children. The planned response
Speaker 1: during the exercise involved administering AVA for post exposure prophylaxis
Speaker 1: to both adults and children in combination with antibiotics. The
Speaker 1: US Food and Drug Administration FDA has approved AVA for
Speaker 1: use by adults before an anthrax exposure, but has not
Speaker 1: approved AVA for post exposure prophylaxis by adults or for
Speaker 1: any use by children, and there are no data on
Speaker 1: the use of AVA by children. While antibiotics help prevent
Speaker 1: or treat immediate infection with anthrax and are the only
Speaker 1: current approved post exposure treatment for children, they cannot provide
Speaker 1: the long term protection that vaccination confers against the persistence
Speaker 1: of dormant spores. Long term use of antibiotics is also
Speaker 1: associated with side effects, including gastrointestinal discomfort, which can result
Speaker 1: in intolerance and poor adherents. In addition, evidence from animal
Speaker 1: models suggests that even the initial response to combined antibiotic
Speaker 1: and vaccine treatment is superior to antibiotics alone. In the
Speaker 1: absence of data on the use of AVA by children
Speaker 1: and the corresponding lack of FDA approval for its post
Speaker 1: exposure use in pediatric populations, current HHS plans based on
Speaker 1: recommendations by the Advisory Committee on Immunization Practices ACIP include
Speaker 1: making available a three dose course of AVA in combination
Speaker 1: with antibiotics to children who have been exposed to anthrax,
Speaker 1: and conducting post event observational research with a subgroup of
Speaker 1: those children who received it to better understand the effects
Speaker 1: of AVA. Research protections would be in place for all
Speaker 1: children receiving AVA, whether as treatment or as part of
Speaker 1: a research study. See Authorizing Distribution of NA approved Drugs
Speaker 1: in an emergency Chapter three scientific recommendation by the National
Speaker 1: Biodefense Science Board in response to the findings of dark Zephyr,
Speaker 1: in particular the nation's lack of preparedness to treat children
Speaker 1: in the event of an anthrax attack, Doctor Nicole Lurie,
Speaker 1: HHS Assistant Secretary for Preparedness and Response, asked the National
Speaker 1: Biodefense Science Board NBSB to recommend the best course of
Speaker 1: action to prepare for a potential use of AVA vaccine
Speaker 1: in a pediatric population end quote. In addition, doctor Lewie
Speaker 1: requested that NBSB consider the risk involved in conducting a
Speaker 1: study of AVA with children before or after an attack,
Speaker 1: and the logistical challenges of administering AVA to children during
Speaker 1: an attack. The National Biodefense Science Board. The Pandemic and
Speaker 1: All Hazards Preparedness Act established NBSB in two thousand and six.
Speaker 1: The thirteen member board advises the Secretary of HHS on quote, scientific, technical,
Speaker 1: and other matters of special interest to HHS regarding activities
Speaker 1: to prevent, prepare for, and respond to adverse health effects
Speaker 1: of public health emergencies resulting from quote, chemical, biological, nuclear,
Speaker 1: and radiological events, whether naturally occurring, accidental, or deliberate. NBSB
Speaker 1: members come from diverse backgrounds and a range of experience
Speaker 1: in both medicine and public health. The members are required
Speaker 1: to meet at least twice a year in a public forum.
Speaker 1: NBSB has advised the Secretary on many issues, including H
Speaker 1: one one, immunization, home stockpiling of MCMs, mental health issues
Speaker 1: during a disaster, and prioritization in MCM development. In its
Speaker 1: October twenty eleven report, NBSB considered whether to conduct pre
Speaker 1: event research to gather safety and immunogenicity degree of immune
Speaker 1: response data about AVA with children, or whether instead to
Speaker 1: gather such data post event. In conducting its analysis, NBSB
Speaker 1: accepted quote the US government's threat analysis and recognized that
Speaker 1: the dissemination of basilis and thrasis spores is a threat
Speaker 1: to the US population, including its large proportion of children
Speaker 1: end quote. NBSB also explicitly stated that quote administering AVA
Speaker 1: to children would present more than a minor increase over
Speaker 1: minimal risk end quote, due specifically to the lack of
Speaker 1: data about AVA with children. NBSB ultimately recommended that the
Speaker 1: US government conduct a pre event study to test the
Speaker 1: safety and immunogenicity of AVA with children before an anthrax
Speaker 1: attack occurs, but noted that any pre event AVA study
Speaker 1: should proceed only following a thorough review of the ethical
Speaker 1: considerations involved. This ethical review became part of the Bioethics
Speaker 1: Commission's task outlined here, and nbsb's scientific and technical assessment
Speaker 1: informed this ethical review. The Bioethics Commission's charge catalyzed by
Speaker 1: nbsb's recommendation, HHS Secretary Kathleen Sabelius asked the Bioethics Commission
Speaker 1: in January twenty twelve to quote conduct a thorough review
Speaker 1: of the ethical considerations of conducting clinical trials of medical
Speaker 1: countermeasures in children, and to include the ethical considerations in
Speaker 1: conducting a pre and post event study of AVA post
Speaker 1: exposure prophylaxis in children as part of its review end
Speaker 1: Because of the sensitivity of the involvement of children in research,
Speaker 1: nbsb's recommendation voiced its desire to have other focused experts,
Speaker 1: like the Presidential Commission for the Study of Bioethical Issues
Speaker 1: formerly review and address these issues from an ethical perspective.
Speaker 1: The NBSB is confident that the Bioethics Commission will help
Speaker 1: us and our nation deliberate this very complex issue ensuring
Speaker 1: safe medical countermeasures for our children. Although the Bioethics Commission's
Speaker 1: charge stemmed from nbsb's recommendation, the charge was significantly broader
Speaker 1: than a review of the ethical considerations associated with a
Speaker 1: pre event pediatric study of AVA. As stated in Secretary
Speaker 1: Sabilius's request, the Bioethics Commission was charged with considering the
Speaker 1: ethical issues associated with pediatric research for all MCMs, that is,
Speaker 1: drugs and vaccines intended to treat or prevent physical harm
Speaker 1: or to diagnose a condition resulting from a bioterrorism attack.
Speaker 1: The Bioethics Commission considered the terms to encompass all FDA
Speaker 1: regulated products and intervisions used in response to chemical, biological, radiological,
Speaker 1: and nuclear attacks. Ethical and regulatory framework for pediatric research.
Speaker 1: Pediatric research is critical for identifying safe and effective ways
Speaker 1: to diagnose, prevent, and treat disease and injury in children.
Speaker 1: Ethical pediatric research should minimize risks and, when possible, provide
Speaker 1: a reasonable prospect of direct benefit to individual participants. Unlike
Speaker 1: research with freely consenting adults, in which greater levels of
Speaker 1: risk might be permissible even without the prospect of direct benefit,
Speaker 1: children who participate in research are afforded special protections due
Speaker 1: to their vulvulnerability and inability to legally consent to participate.
Speaker 1: Any research conducted with children must therefore respect children's well
Speaker 1: being and dignity as persons, as well as their current
Speaker 1: and future capacities for self determination, and must protect children
Speaker 1: from exploitation. These ethical imperatives are dictated by the foundational
Speaker 1: principles of respect for persons, beneficence and its corollary non maleficence, justice,
Speaker 1: and democratic deliberation. The current regulatory framework adopts an approach
Speaker 1: recommended by the National Commission that is categorizing pediatric research
Speaker 1: based on both the level of research risk and the
Speaker 1: prospect of direct benefit. To participants, research that proposes only
Speaker 1: minimal risk to participants, research that offers the prospect of
Speaker 1: direct benefit to participants, or research that provides the opportunity
Speaker 1: to gain generalizable knowledge about the participant's condition. Each fits
Speaker 1: neatly into one of the regulatory categories of research approvable
Speaker 1: at the local level, which are intended to govern the
Speaker 1: majority of pediatric research. Some proposed MCM research, however, might
Speaker 1: involve exposing healthy children to greater than minimal risk while
Speaker 1: offering no prospect of direct benefit, and therefore does not
Speaker 1: fit into one of these categories. In its report Research
Speaker 1: Involving Children, the National Commission recognized the ethical challenge inherent
Speaker 1: in considering whether research that poses more than minimal risk
Speaker 1: and offers no prospect of direct benefit to participants nevertheless
Speaker 1: might be justified by the quote promise of substantial long
Speaker 1: term benefit to children in general end quote. The National
Speaker 1: Commission did not reach a conclusion about the permissibility of
Speaker 1: any such research with healthy children, instead recommending that decisions
Speaker 1: taking into account quote sound ethical principles end quote, along
Speaker 1: with other important considerations, be made at the national level
Speaker 1: on a case by case basis. It intended this type
Speaker 1: of review only for rare and exceptional cases about this report.
Speaker 1: This report by the Bioethics Commission enumerates the ethical conceit
Speaker 1: iterations associated with conducting pre and post event MCM research
Speaker 1: with children. The Bioethics Commission examined the current ethical and
Speaker 1: regulatory framework to assess the types of ethically permissible pre
Speaker 1: and post event research. It built on the work of
Speaker 1: the National Commission to provide decision makers with necessary ethical
Speaker 1: tools to assess whether research posing greater than minimal risk
Speaker 1: with no prospect of direct benefit to healthy child participants,
Speaker 1: the most ethically complex pre event pediatric MCM research can
Speaker 1: proceed fulfilling its charge. The Bioethics Commission applied its analysis
Speaker 1: to the particular case of AVA as well. Due to
Speaker 1: the unique characteristics of pre event MCM research in US,
Speaker 1: including uncertainty that the research results will ever be used
Speaker 1: and the fact that children are not legally or ethically
Speaker 1: competent to consent to participate in research. The Bioethics Commission
Speaker 1: concluded that greater than minimal risk pre event research is
Speaker 1: ethically unacceptable if valuable information about an MCM could be
Speaker 1: obtained using a study designed involving only minimal risk. If
Speaker 1: pre event pediatric MCM research cannot be designed as minimal risk,
Speaker 1: the proposed research should pose no more than a minor
Speaker 1: increase over minimal risk and proceed to national level review.
Speaker 1: Although the regulations might allow pediatric research that poses greater
Speaker 1: than a minor increase over minimal risks to be approved
Speaker 1: if it also meets ethical standards, the Bioethics Commission concluded
Speaker 1: that higher risk is unacceptable in the context of pre
Speaker 1: event MCM research. Such research does not directly benefit the
Speaker 1: child participants, and the likelihood that the results of such
Speaker 1: research would benefit other children is unknown or unknowable. In
Speaker 1: accordance with its commitment to democratic deliberation and transparency, the
Speaker 1: Bioethics Commission held four public meetings to address the Secretary's request.
Speaker 1: Experts addressed a range of ethical, public health, scientific, medical, security,
Speaker 1: and regulatory issues associated with this report, providing a wide
Speaker 1: array of professional and institutional perspectives, including those from scientific
Speaker 1: and medical communities, nonprofit organizations, and other individuals and groups.
Speaker 1: The Bioethics Commission published a request for information in the
Speaker 1: Federal Register and received almost one hundred written responses. In
Speaker 1: the course of its work, the Bioethics Commission performed an
Speaker 1: in depth review of relevant literature and in its deliberations,
Speaker 1: took into account the relevant work of prior commissions, in
Speaker 1: particular the National Commission's path breaking work in establishing pediatric
Speaker 1: research protections. Based on the Bioethic Commission's detailed examination, Chapter
Speaker 1: two of this report provides an overview of the ethical
Speaker 1: foundations for pediatric research protections and the current regulatory structure
Speaker 1: governingaf Patrick research. Chapter three sets forth and analyzes the
Speaker 1: ethical issues associated with conducting pre event and post event
Speaker 1: MCM research with children, and applies this ethical analysis to
Speaker 1: the particular case of AVA. End of Chapter one. Introduction
Speaker 1: recording by Patrick mccaffee, Merritt, Island,