Minimal Risk, Yet Again
2007; Elsevier BV; Volume: 150; Issue: 6 Linguagem: Inglês
10.1016/j.jpeds.2007.03.040
ISSN1097-6833
Autores Tópico(s)Ethics in medical practice
ResumoThe 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.1Department of Health and Human Services45 CFR Part 46: Additional Protections for Children Involved as Subjects in Research.Federal Register. 1983; 48: 9814PubMed Google Scholar, 2Food and Drug Administration21 CFR Parts 50 and 56: Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products.Federal Register. 2001; 66: 20589-20600Google Scholar 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.1Department of Health and Human Services45 CFR Part 46: Additional Protections for Children Involved as Subjects in Research.Federal Register. 1983; 48: 9814PubMed Google Scholar, 2Food and Drug Administration21 CFR Parts 50 and 56: Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products.Federal Register. 2001; 66: 20589-20600Google ScholarSee related article, p 579 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.3Kopelman L.M. Minimal risk as an international ethical standard in research.J Med Philosophy. 2004; 29: 351-378Crossref PubMed Scopus (84) Google Scholar, 4Kopelman L.M. Murphy T.F. Ethical concerns about federal approval of risky pediatric studies.Pediatrics. 2004; 113: 1783-1789Crossref PubMed Scopus (32) Google Scholar, 5Shah 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: 476-482Crossref PubMed Scopus (233) Google Scholar, 6Nelson R.M. Ross L.F. In defense of a single standard of research risk for all children.J Pediatr. 2005; 147: 565-566Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 7Wendler D. Belsky L. Thompson K.M. Emanuel E.J. Quantifying the federal minimal risk standard: implications for pediatric research without a prospect of direct benefit.JAMA. 2005; 294: 826-832Crossref PubMed Scopus (115) Google Scholar, 8Wendler D. Emanuel E.J. What is a ‘minor’ increase over minimal risk?.J Pediatr. 2005; 147: 575-578Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 9Ross L.F. Nelson R.M. Pediatric research and the federal minimal risk standard.JAMA. 2006; 295: 759PubMed Google Scholar, 10Wendler D. Varma S. Minimal risk in pediatric research.J Pediatr. 2006; 149: 855-861Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar 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.”11Department of Health and Human Services45 CFR Part 46: Federal Policy for the Protection of Human Services.Federal Register. 1991; 56: 28003-28023PubMed Google Scholar, 12Food and Drug Administration21 CFR Parts 50 and 56.Federal Register. 1991; 56: 28025-28029PubMed Google Scholar The definition thus incorporates two different standards, often referred to as the “everyday risks” standard and the “routine examination” standard.3Kopelman L.M. Minimal risk as an international ethical standard in research.J Med Philosophy. 2004; 29: 351-378Crossref PubMed Scopus (84) Google Scholar There is general agreement that there is widespread variability in the application of this definition to different research procedures.5Shah 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: 476-482Crossref PubMed Scopus (233) Google Scholar The proposed solutions to this variability, however, differ dramatically. On the one hand, Kopelman3Kopelman L.M. Minimal risk as an international ethical standard in research.J Med Philosophy. 2004; 29: 351-378Crossref PubMed Scopus (84) Google Scholar, 4Kopelman L.M. Murphy T.F. Ethical concerns about federal approval of risky pediatric studies.Pediatrics. 2004; 113: 1783-1789Crossref PubMed Scopus (32) Google Scholar 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 Varma10Wendler D. Varma S. Minimal risk in pediatric research.J Pediatr. 2006; 149: 855-861Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar 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 Glantz13Wendler D. Glantz L. A Standard for assessing the risks of pediatric research: pro and con.J Pediatr. 2007; 150: 579-582Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar 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.3Kopelman L.M. Minimal risk as an international ethical standard in research.J Med Philosophy. 2004; 29: 351-378Crossref PubMed Scopus (84) Google Scholar 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.14National Commission for the Protection of Human Subjects of Biomedical and Behavioral ResearchResearch Involving Children: Report and Recommendations. US Government Printing Office, Washington, DC1977Google Scholar As a result, US federal regulations allow for the exposure of children with a disease or condition to a minor increase over minimal risk.1Department of Health and Human Services45 CFR Part 46: Additional Protections for Children Involved as Subjects in Research.Federal Register. 1983; 48: 9814PubMed Google Scholar, 2Food and Drug Administration21 CFR Parts 50 and 56: Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products.Federal Register. 2001; 66: 20589-20600Google Scholar 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.6Nelson R.M. Ross L.F. In defense of a single standard of research risk for all children.J Pediatr. 2005; 147: 565-566Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 15Ross L.F. Do healthy children deserve greater protection in medical research?.J Pediatr. 2003; 142: 108-112Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar 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.6Nelson R.M. Ross L.F. In defense of a single standard of research risk for all children.J Pediatr. 2005; 147: 565-566Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 9Ross L.F. Nelson R.M. Pediatric research and the federal minimal risk standard.JAMA. 2006; 295: 759PubMed Google Scholar 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.3Kopelman L.M. Minimal risk as an international ethical standard in research.J Med Philosophy. 2004; 29: 351-378Crossref PubMed Scopus (84) Google Scholar 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.13Wendler D. Glantz L. A Standard for assessing the risks of pediatric research: pro and con.J Pediatr. 2007; 150: 579-582Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar 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.7Wendler D. Belsky L. Thompson K.M. Emanuel E.J. Quantifying the federal minimal risk standard: implications for pediatric research without a prospect of direct benefit.JAMA. 2005; 294: 826-832Crossref PubMed Scopus (115) Google Scholar, 10Wendler D. Varma S. Minimal risk in pediatric research.J Pediatr. 2006; 149: 855-861Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar 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.16Field M.J. Behrman R.E. Ethical Conduct of Clinical Research Involving Children. The National Academies Press, Washington, DC2004Google Scholar 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.16Field M.J. Behrman R.E. Ethical Conduct of Clinical Research Involving Children. The National Academies Press, Washington, DC2004Google Scholar, 17SACHRP Chair Letter to HHS Secretary Regarding Recommendations. 2005Google Scholar 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.5Shah 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: 476-482Crossref PubMed Scopus (233) Google Scholar 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.14National Commission for the Protection of Human Subjects of Biomedical and Behavioral ResearchResearch Involving Children: Report and Recommendations. US Government Printing Office, Washington, DC1977Google Scholar 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. A Standard for Assessing the Risks of Pediatric Research: Pro and ConThe Journal of PediatricsVol. 150Issue 6PreviewTo evaluate the safety and efficacy of medical interventions for children, investigators often must conduct research with children, including research that does not offer the children a compensating potential for clinical benefit.1,2 For example, when evaluating lopinavir/ritonavir therapy in children with human immunodeficiency virus, investigators first gave single doses to a few children to determine what dose levels they could tolerate.3 These tests, necessary preludes to future efficacy studies, posed some risks to the participating children but did not offer them any potential for clinical benefit. Full-Text PDF
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