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Background, Discussion Questions and References

Pediatric Ethics Subcommittee of the Pediatric Advisory Committee Meeting
September 9-10, 2013

Draft

The Pediatric Ethics Subcommittee of the Pediatric Advisory Committee is meeting on Monday, September 9 and Tuesday, September 10, 2013, to discuss ethical issues in pediatric product development, including medical countermeasures, focusing on the concepts of minimal risk, disorder or condition, and exposure of pediatric subjects to risks under 21 CFR 50.54.  Over the past 2 years, ethical issues in pediatric medical countermeasure development have been a focus of attention, culminating in the March 2013 report of the Presidential Commission for the Study of Bioethical Issues  (available at http://bioethics.gov/sites/default/files/PCSBI_Pediatric-MCM508.pdf, accessed August 29, 2013). While the specific recommendations in that report are not the subject of this Subcommittee meeting, the discussion and report provide the context and opportunity for the Subcommittee to discuss three topics that will inform draft guidance on the additional protections for children enrolled in FDA-regulated clinical investigations (21 CFR 50 subpart D). This document serves as an introduction to the meeting, outlines the three topics for Subcommittee discussion, and provides a brief overview of the agenda and a list of the readings that have been distributed to the Subcommittee members.

FDA has convened the Pediatric Ethics Subcommittee to address pediatric ethical issues, including research involving children as subjects as specified under 21 CFR 50.54.  Similar to the June 2008 Subcommittee meeting at which the concept of prospect of direct benefit (found in 21 CFR 50.52) was discussed, this meeting is also structured as a non-voting discussion given the complexity of these topics. The subcommittee is not being asked to assess the specific recommendations of the Presidential Commission for the Study of Bioethical Issues, nor to opine on whether a particular pediatric clinical trial, such as a trial of anthrax vaccine in the absence of an exposure to anthrax, should or should not proceed, and under what circumstances. If a subcommittee member chooses to express an opinion on whether such a trial should or should not proceed, he or she risks exclusion from a future panel that may consider that question if such a protocol is submitted for review under 21 CFR 50.54.  Although a stated opinion on a matter is not prima facie evidence that a subcommittee member would have a closed mind on a particular issue, an appearance of intellectual bias may exist when statements of record that have been made by that member draw conclusions or strongly appear to draw conclusions to a degree that would appear to preclude an impartial and objective evaluation of information on that matter when presented to the subcommittee (see 21 CFR 14.80(f)). That being said, Subcommittee members may wish to illustrate general points using case examples drawn from their experience with the development of pediatric products or, more specifically, pediatric medical countermeasures. However, the focus of discussion should remain on the general ethical concept being illustrated by the case rather than on the case itself. Subcommittee members are also reminded that they have only been screened for any conflicts of interest concerning FDA-regulated products for the prevention and/or treatment of anthrax, including raxibacumab to treat inhalational anthrax. As such, discussion of these products does not raise any additional concerns about potential undeclared conflicts of interest. However, subcommittee members have not been screened for any other pediatric products. Subcommittee members must declare whether they may have any conflicts of interest when using a non-anthrax case example to illustrate a general point.

Topics to be Discussed:

The Additional Safeguards for Children in Clinical Investigations (21 CFR 50 subpart D) provide an ethical and regulatory framework for assessing whether a proposed clinical investigation involving children ought to proceed. Provided that the necessary criteria are met, an Institutional Review Board (IRB) may approve the enrollment of children in a clinical investigation under one of 3 categories: minimal risk (50.51), greater than minimal risk but presenting the prospect of direct benefit to individual subjects (50.52) and greater than minimal risk and no prospect of direct benefit to individual subjects but likely to yield generalizable knowledge about the subjects disorder or condition (50.53). If an IRB does not believe that a clinical investigation involving children meets the requirements of 50.51, 50.52 or 50.53, but finds that the clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, the IRB may refer the clinical investigation for review by a federal panel under 21 CFR 50.54. The federal panel can recommend that the clinical investigation satisfies the conditions of either 50.51, 50.52, or 50.53, or can recommend that the clinical investigation proceed under 50.54 if additional conditions are met. The Subcommittee will discuss three concepts that play an important role in this assessment: minimal risk, disorder or condition, and the allowable risks under 50.54.

Topic for discussion: "minimal risk"

A clinical investigation may enroll children if the interventions or procedures included in the protocol present no greater than minimal risk and there are adequate provisions for soliciting the assent of the children and the permission of their parents or guardians (21 CFR 50.51). Note that there is no requirement that the children enrolled in such trial have a disorder or condition.  Thus, children without any health conditions could be exposed to any interventions or procedures approved under this category.

Minimal risk is currently defined as “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”  Please discuss the application of the concept of minimal risk to the assessment of the appropriateness of exposing children to the risks of interventions and procedures within clinical investigations.  Please consider the following issues in your discussion:

  • The "daily life" standard is qualified by the phrase “ordinarily encountered.”  Ordinary can be understood to mean common, usual, or normal. Should any activity of daily life (regardless of the associated risk) be considered when judging whether a research risk is minimal? Should activities of daily life with especially high or low associated risk be excluded? How should one decide which activities of daily life should be considered appropriate comparators when assessing whether research risks should be considered no more than minimal?
  • Does adding the qualifier "of average, healthy, normal children" to the application of the definition of minimal risk further narrow the range of daily life activities that would be considered appropriate comparators?  Please comment on the ethical arguments (e.g., considerations of justice) used to support the use of this qualifier.
  • Is the purpose for which children are exposed to risks morally relevant? In other words, is it equally appropriate to expose children to the risks inherent in a "research" activity versus a "daily life" activity if the activities have comparable risks? For example, many daily life activities, like playing team sports, are enjoyable for the child (and may teach discipline, teamwork, promote fitness, etc) in contrast to most research activities. Are there factors other than risk that ought to be considered when deciding whether daily life risks and research risks are appropriate comparators?
  • There have been a number of proposals that try to capture the "normative" or "value laden" aspect of applying the definition of minimal risk. Two such proposals are the "charitable participation" and "scrupulous parent" standards. In your discussion of the application of minimal risk, please identify whenever possible your key assumptions about the usefulness of such standards.
  • Should the application of minimal risk be dependent on a child’s age and/or developmental stage?  For example, if an intervention is minimal risk for an adolescent, would the same intervention necessarily be considered minimal risk for a younger child? If not, why not? If yes, what is the justification for such an approach? For example, would such variation reflect the empirical differences in risk exposure at different ages, or the moral significance of child assent and/or adolescent "consent"?

Topic for discussion: "disorder or condition"

To be approvable under 21 CFR 50.53, clinical investigations involving interventions or procedures that present no more than a minor increase over minimal risk and do not offer a prospect of direct benefit to the enrolled children must be likely to yield generalizable knowledge about their disorder or condition that is of vital importance for the understanding or amelioration of that disorder or condition. In addition, the intervention or procedure must present experiences to the enrolled children that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations. Finally, adequate provisions must be made for soliciting the assent of the children and permission of their parents or guardians.

Consistent with the recommendations of the Institute of Medicine (2004), the Secretary's Advisory Committee on Human Research Protections (SACHRP) recommended that “the term condition should be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific or clinical evidence has shown to negatively affect children's health and well-being or to increase their risk of developing a health problem in the future” (July 28, 2005, letter to the Secretary of Health and Human Services; available at http://www.hhs.gov/ohrp/sachrp/sachrpltrtohhssec.html, accessed August 29, 2013).
Please discuss the application of the concepts of “disorder” and “condition” to the assessment of clinical research protocols under 21 CFR 50.53. In your discussion, please consider the following:

  • If the phrase "disorder or condition" should not be limited to children with a disease, by what criteria and/or characteristics should a suitable population of children who would be eligible for enrollment be identified?
  • Some argue that certain group characteristics (e.g., exposure to violence) should not be used by themselves to justify exposure to more than minimal risk absent a prospect of direct benefit, unless an established link exists between that characteristic and a negative effect (i.e., deficit) on that group’s health or well-being.  This claim is grounded on considerations of justice. Others argue that research presenting more than minimal risk may be necessary to establish such a link, and thus this approach may be too restrictive. Please comment.
  • In addition to group characteristics that identify children who currently suffer from a deficit in health or well-being, the concept of "condition" also has been understood as referring to characteristics that define a group of children as being "at risk" for developing deficits in the future.  Please discuss the factors that should be considered when assessing whether a group of children is "at risk." To what extent should the magnitude of the harm that may result be considered independent of the probability of that harm? How does our ability to monitor for or mitigate the potential harms impact on our risk assessment?
  • The qualifier that the knowledge to be gained is of vital importance for the "understanding or amelioration" of the enrolled children’s disorder or condition suggests that both "pure" (i.e., understanding alone without any practical application) and "applied" (i.e., developing knowledge to improve or make better) research may be approvable under this category. Does this qualifier influence your understanding and/or application of the "disorder or condition" requirement?

Topic for Discussion: "Exposure of pediatric subjects to risks under 21 CFR 50.54":

Clinical investigations that are not otherwise approvable under 21 CFR 50.51, 50.52 or 50.53 may proceed, after consultation with a panel of experts and following opportunity for public review and comment,  if the FDA Commissioner determines that the clinical investigation:

  • presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and
  • will be conducted in accordance with sound ethical principles; and
  • adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.

The level of risk to which a child may be exposed when participating in research approved under 21 CFR 50.54 is not specified by the regulations.

Please focus your discussion of 21 CFR 50.54 on the circumstances, if any, in which a child could be exposed to more than a minor increase over minimal risk absent a prospect of direct benefit.  A minor increase over minimal risk is not defined in 21 CFR 50 subpart D.  Descriptions of this level of risk by The National Commission range from "slightly" more than minimal risk to no "substantial" risk of illness or injury.  SACHRP recommended that the harms associated with a minor increase over minimal risk be "transient and reversible" (July 28, 2005, letter to the Secretary of Health and Human Services).  In your discussion, please consider the following:

  • Should the degree of uncertainty about the need for the future use of a product influence the level of allowable research risk? If yes, what types of uncertainty would be relevant to the determination (for example, uncertainties regarding the risk of a future event involving the intentional release of a weaponized agent, the future benefit for the enrolled children, and the future benefit of the results for all children)? Pediatric medical countermeasures can also refer to preventive or treatment interventions that are necessary in response to natural events, such as nuclear accidents secondary to earthquakes or the emergence of novel strains of influenza. How does uncertainty about the occurrence of these types of events influence the level of allowable research risk?
  • Should the magnitude of the harm to be prevented and/or treated be an independent factor influencing the level of allowable research risk? In other words, if the harm to be prevented is severe (i.e., significant morbidity and/or mortality), should we tolerate a greater degree of uncertainty about the probability of that harm occurring when establishing the level of allowable research risk? Further, how should the potential extent of the harm influence the level of allowable risk?  Is it relevant whether a potential harm might be experienced by a relatively small number of children versus hundreds or thousands of children?

Finally, research under 21 CFR 50.54 can only proceed after an opportunity for public review and comment. For some threats, information that may be pertinent to establish the probability of the event occurring may be classified (especially for intentional threats). 

  • Please discuss the extent or process by which sufficient sensitive information that is relevant to establish the probability of an event should be made available in order to fulfill the ethical requirement for public review and comment.

Overview of the Agenda and Background Readings:

Following the welcome and introductory remarks by Drs. Botkin and Ellenberg, Dr. Nelson (FDA) will provide an overview of the goals for the meeting including a presentation of the questions for discussion. The perspective provided by Dr. Amy Gutman on the Presidential Commission for the Study of Bioethical Issues, published in the New England Journal of Medicine, provides an overview of the context for the subcommittee discussion. Dr. Michelle Roth-Cline (FDA) will then provide an overview of the ethical framework of 21 CFR 50 subpart D, and review the past recommendations of the Pediatric Ethics Subcommittee on protocols referred for review under 21 CFR 50.54. Chapter 4 of the Institute of Medicine report on the Ethical Conduct of Clinical Research Involving Children (2004) serves as a general introduction to the topics that will be discussed today, especially with respect to the application of minimal risk and the understanding of disorder or condition.

The next 3 talks will provide an overview of the available tools for making medical countermeasures available to the American public. Ms. Cynthia Kelley (FDA) will review the various pathways available to FDA for making medical countermeasures available, including the use of an emergency use authorization and distribution under an IND. Dr. John Alexander (FDA) will review the process of labeling products for use as pediatric medical countermeasures, highlighting the recent experience with the approval of Raxibacumab for the treatment of anthrax disease. Dr. Susan Gorman (CDC) will then outline current plans for responding to a public health emergency, including the operational challenges of distributing medical countermeasures under these various mechanisms.

Following these introductory presentations, the agenda then includes 5 talks that set up the topics for discussion. The first 2 talks by Drs. Wendler (NIH) and Rossi (Drexel University) will cover the topic of minimal risk. There are 5 articles included in the background packet which cover the range of issues raised in the interpretation and application of minimal risk. The JAMA (2010) article by Annette Rid and colleagues presents an approach to evaluating the risks of clinical research. Rossi and Nelson (2012) provide a critical commentary on that approach. Wendler and Glantz (2007) debate the pros and cons of a proposed standard for assessing the risks of pediatric research, along with a commentary on the debate by Nelson (2007).  Wendler (2009) also presents a proposal for varying the application of minimal risk as a function of the child’s age. Two articles provide background on the discussion of the concept of disorder or condition.  The 2004 IOM report includes a section that proposes a recommended definition. To supplement this discussion, Shah and Wendler (2010) offer a legal interpretation of the condition requirement. The final topic on the exposure of children to risk under 21 CFR 50.54 does not have any specific readings associated with it, but is raised by the Presidential Commission report as summarized by Dr. Gutmann.

List of Background Readings:

  1. Gutmann, A. Safeguarding Children — Pediatric Research on Medical Countermeasures. NEJM, 2013.
  2. Institute of Medicine, Chapter 4: Defining, Interpreting, and Applying Concepts of Risk and Benefit in Clinical Research Involving Children. In: Ethical Conduct of Clinical Research Involving Children (Washington, D.C.: National Academies Press, 2004): 113-145.
  3. Nelson, R. M. (2007). "Minimal risk, yet again." J Pediatr 150(6): 570-572.
  4. Rid, A., et al. (2010). "Evaluating the risks of clinical research." JAMA 304(13): 1472-1479.
  5. Rossi, J. and R. M. Nelson (2012). "Is there an objective way to compare research risks?" J Med Ethics 38(7): 423-427.
  6. Shah, S. and D. Wendler (2010). "Interpretation of the subjects' condition requirement: a legal perspective." J Law Med Ethics 38(2): 365-373.
  7. Wendler, D. (2009). "Minimal risk in pediatric research as a function of age." Arch Pediatr Adolesc Med 163(2): 115-118.
  8. Wendler, D. and L. Glantz (2007). "A standard for assessing the risks of pediatric research: pro and con." J Pediatr 150(6): 579-582.