The Journal of Pediatrics
Volume 150, Issue 6 , Pages 570-572, June 2007

Minimal Risk, Yet Again

  • Robert M. Nelson, MD, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: Dr. Robert M. Nelson, The Children’s Hospital of Philadelphia, Room 1513, CHOP North, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.

Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Article Outline

 

The determination that research risks are sufficiently low to justify the exposure of children to such risks absent the prospect of direct benefit is a central component of the additional protections afforded children who are to be enrolled in research.1, 2 The risks of research interventions or procedures lacking a prospect of direct benefit must be restricted to either minimal risk (for all children) or a minor increase over minimal risk (for children with a disease or condition). This restriction on research risk applies to either an entire protocol or to those components of a protocol that lack the prospect of direct benefit, such as the collection of blood for pharmacokinetic sampling or basic research involving tissue specimens. In addition, research that presents no more than minimal risk becomes eligible for such procedural efficiencies as a partial or full waiver of parental permission and/or child assent or review using an expedited process.1, 2

See related article, p 579

The interpretation and application of the concept of minimal risk has been the subject of recent debate in the research ethics literature.3, 4, 5, 6, 7, 8, 9, 10 For an intervention or procedure to be considered no more than minimal risk under US federal regulations, the “probability and magnitude of harm or discomfort” must be no greater than “those ordinarily encountered in daily life or during the performance of routine physical and psychological examinations or tests.”11, 12 The definition thus incorporates two different standards, often referred to as the “everyday risks” standard and the “routine examination” standard.3 There is general agreement that there is widespread variability in the application of this definition to different research procedures.5 The proposed solutions to this variability, however, differ dramatically. On the one hand, Kopelman3, 4 rejects the use of the “everyday risks” standard in favor of an absolute (or uniform) interpretation of the “routine examination” standard, noting with concern recent approvals at the federal level of pediatric studies that present greater than minimal risk. On the other hand, Wendler and Varma10 advocate for a “comparative analysis method” using the “everyday risks” standard, concluding that eight of nine studies reviewed at the federal level should be considered minimal risk.

In this issue of The Journal, Wendler and Glantz13 now offer arguments for and against the use of a “charitable participation standard” to determine whether the risks of nonbeneficial research interventions or procedures are “acceptably low.” In effect, this approach could be seen as a further specification of the “everyday risks” standard in an effort to address the criticism that such a standard could include inappropriately risky procedures.3 Although presented as an argument for (Wendler) and against (Glantz) using children’s participation in charitable activity as a gauge of appropriate research risk exposure, both Wendler and Glantz appear to agree that such a standard might be useful when a child is able to voluntarily assent to research participation. Even so, the “charitable participation standard” is problematic for at least three reasons: (1) an ambiguity introduced by the phrase “acceptably low risks”; (2) the failure to address the enrollment of young children in research; and (3) the continued desire for a data-driven solution to what is effectively a moral problem.

Wendler and Glantz avoid the use of the term “minimal risk” in favor of “acceptably low risks.” How, then, should we interpret the application of the “charitable participation standard” to the exposure of children with a disease or condition to nonbeneficial interventions or procedures? Absent data, it is reasonable to assume that children with asthma, for example, would be precluded from volunteering for certain outside charitable activities. If so, the use of a “charitable participation standard” might decrease the risk to which a child with a disease or condition could be exposed in nonbeneficial research. Although two of nine members of The National Commission voted against the category “minor increase over minimal risk,” based on the argument that children with a disease should be exposed to less nonbeneficial research risk than healthy children, they were in the minority.14 As a result, US federal regulations allow for the exposure of children with a disease or condition to a minor increase over minimal risk.1, 2 Wendler and Glantz shed no light on how the “charitable participation standard” should be used in this context. In fairness, it should be noted that this regulatory category appears to be unique to the United States, and ethical arguments have been made that the standard for nonbeneficial research risk exposure should be uniform among children regardless of the presence of a disease or condition.6, 15

Wendler acknowledges that the “charitable participation standard” fails to address the enrollment of young children in research and thus would require a supplemental standard. This observation also forms a large part of Glantz’s critique. The offering of a gift is not something that can be done by a surrogate, and thus the analogy to charitable giving fails absent the voluntary assent of the child. However, the role of parental permission in allowing a child to be exposed to the risks involved in charitable participation is entirely missing from both Wendler’s and Glantz’s discussion. The primary focus of ethical analysis should be on the parents’ moral responsibility, with the child’s assent serving a secondary albeit important role.6, 9

The root of the problem may be the desire to find an empirical standard for the interpretation and application of concepts such as minimal risk. As Kopelman notes, the assessment of appropriate risk exposure is inherently value laden.3 It is entirely possible, in fact, likely, that if “empirical data on the level of risks allowed in charitable activities appropriate for children” revealed an unacceptable rate of injury, parents then would decide that such risk exposure was inappropriate.13 Although data are an important part of the assessment of appropriate research risk, they are not sufficient. The fact that something is the case does not establish that it ought to be the case. This philosophical truism is supported by Wendler’s observation that the application of the “everyday risks” standard may expose children to excessive risks.7, 10

So where does this leave us? There appear to be several areas of agreement on the interpretation of minimal risk that are worth noting. First, most commentators believe that minimal risk should be a uniform standard. In other words, whether an intervention or procedure is minimal risk should not depend on the particular research population but rather be assessed relative to the experiences of an “average, healthy, normal” child. Second, the fact that some children live in risky environments should not be used as an argument in favor of increased research risk exposure. However, the US federal regulations create an ambiguity if living in a risky environment creates a condition sufficient to warrant exposure to a minor increase over minimal risk. Third, as most research procedures are not normally experienced by children, the assessment of risk must involve a comparison of the risks in one context (everyday life or routine examinations) to another context (nonbeneficial research). As such, we must consider the equivalence of risks. Fourth, the assessment of the risks of interventions or procedures that do not offer the prospect of direct benefit must be independent of the inclusion of other interventions that offer the prospect of direct benefit in the same research protocol.16 These recommendations have been endorsed by more than one federal panel and have recently been forwarded to the Secretary of Health and Human Services for incorporation into guidance and/or policy.16, 17

The implementation of the above guidelines would be a reasonable first step toward a uniform interpretation of the definition of minimal risk. It is unlikely, and perhaps unnecessary, that these guidelines eliminate the documented variability in applying the definition to specific research procedures.5 On the assumption that the federal definition of minimal risk will not change, we are left with the ambiguity introduced by the juxtaposition of the two different standards, that is, the “routine examination” and “everyday risks” standards. The concept of minimal risk was introduced by The National Commission to reflect the boundaries of appropriate parental decision-making about children’s exposure to research risk.14 We may gain some moral insight into parental decision-making by reflecting on the appropriateness of a child participating in different charitable activities. This insight, however, will reflect the degree to which such parental decisions are value-laden and not the degree to which we can use data about the risks of charitable participation to decide about the appropriateness of nonbeneficial research risks. Finally, the value-laden nature of this risk assessment will not be eliminated by simplifying the definition of minimal risk to include either the “routine examination” standard or the “everyday risks” standard, but not both.

Back to Article Outline

References 

  1. Department of Health and Human Services. 45 CFR Part 46: Additional Protections for Children Involved as Subjects in Research. Federal Register. 1983;48:9814
  2. Food and Drug Administration. 21 CFR Parts 50 and 56: Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products. Federal Register. 2001;66:20589–20600
  3. Kopelman LM. Minimal risk as an international ethical standard in research. J Med Philosophy. 2004;29:351–378
  4. Kopelman LM, Murphy TF. Ethical concerns about federal approval of risky pediatric studies. Pediatrics. 2004;113:1783–1789
  5. Shah S, Whittle A, Wilfond B, Gensler G, Wendler D. How do institutional review boards apply the federal risk and benefit standards for pediatric research?. JAMA. 2004;291:476–482
  6. Nelson RM, Ross LF. In defense of a single standard of research risk for all children. J Pediatr. 2005;147:565–566
  7. Wendler D, Belsky L, Thompson KM, Emanuel EJ. Quantifying the federal minimal risk standard: implications for pediatric research without a prospect of direct benefit. JAMA. 2005;294:826–832
  8. Wendler D, Emanuel EJ. What is a ‘minor’ increase over minimal risk?. J Pediatr. 2005;147:575–578
  9. Ross LF, Nelson RM. Pediatric research and the federal minimal risk standard. JAMA. 2006;295:759
  10. Wendler D, Varma S. Minimal risk in pediatric research. J Pediatr. 2006;149:855–861
  11. Department of Health and Human Services. 45 CFR Part 46: Federal Policy for the Protection of Human Services. Federal Register. 1991;56:28003–28023
  12. Food and Drug Administration. 21 CFR Parts 50 and 56. Federal Register. 1991;56:28025–28029
  13. Wendler D, Glantz L. A Standard for assessing the risks of pediatric research: pro and con. J Pediatr. 2007;150:579–582
  14. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Research Involving Children: Report and Recommendations. Washington, DC: US Government Printing Office; 1977;
  15. Ross LF. Do healthy children deserve greater protection in medical research?. J Pediatr. 2003;142:108–112
  16. In:  Field MJ,  Behrman RE editor. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press; 2004;
  17. SACHRP Chair Letter to HHS Secretary Regarding Recommendations. 2005;Dated July 21. Accessed March 4, 2007. Available from: http://www.hhs.gov/ohrp/sachrp/sachrpltrtohhssec.html

PII: S0022-3476(07)00264-8

doi:10.1016/j.jpeds.2007.03.040

Refers to article:

  • A Standard for Assessing the Risks of Pediatric Research: Pro and Con

    David Wendler, Leonard Glantz
    The Journal of Pediatrics June 2007 (Vol. 150, Issue 6, Pages 579-582)

The Journal of Pediatrics
Volume 150, Issue 6 , Pages 570-572, June 2007

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