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In Defense of a Single Standard of Research Risk for all Children

2005; Elsevier BV; Volume: 147; Issue: 5 Linguagem: Inglês

10.1016/j.jpeds.2005.08.051

1097-6833

Robert M. Nelson, Lainie Friedman Ross,

Pharmaceutical studies and practices

The additional protections for children involved in research require the interpretation and application of 3 different levels of risk: minimal risk, minor increase over minimal risk, and more than a minor increase over minimal risk.1Department of Health and Human Services (DHHS) (45 CFR Part 46, Subpart D). Protections for children involved as subjects in research.Federal Register. 1983; 48 (March 8, 1983); revised Federal Register 1991;56:28032 (June 18, 1991): 9814-9820PubMed Google Scholar, 2Food and Drug Administration, DHHS (21 CFR Parts 50 and 56). Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products.Federal Register. 2001; 66 (April 24, 2001): 20589-20600Google Scholar There is wide variability in the categorization of various research procedures according to these levels of risk.3Janofsky J. Starfield B. Assessment of risk in research on children.J Pediatr. 1981; 98: 842-846Abstract Full Text PDF PubMed Scopus (85) Google Scholar, 4Shah 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 (238) Google Scholar Noting that the federal regulations do not define a minor increase over minimal risk, Wendler and Emanuel5Wendler 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 (27) Google Scholar in this issue of The Journal propose that this level of risk be interpreted as those socially acceptable risks that are nevertheless greater than those risks ordinarily encountered by healthy children (ie, minimal risk). However, the ethical justification for this standard appears tautological, endorsing those risks that are “acceptable” to society and rejecting those that are “unacceptable” to society without explaining why certain risks would or would not be considered socially acceptable. As an alternative, we believe that the “scrupulous parent” standard is ethically justifiable and incorporates both minimal risk and a minor increase over minimal risk within a uniform standard that should be applicable to all children. Wendler and Emanuel5Wendler 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 (27) Google Scholar present 5 possible interpretations of a minor increase over minimal risk. The “numeric” and “uncertainty” standards are defined statistically, as either a slight increase over the point estimate for “minimal risk” or the upper 95% confidence interval around this point estimate. As noted, the fact that a child is exposed to a certain level of risk does not imply that a child should be exposed to that same level of risk within research.6Ackerman T. Moral duties of parents and non-therapeutic research procedures involving children.Bioethics Q. 1980; 2: 94-111Crossref PubMed Scopus (33) Google Scholar Thus a simple statistical approach is rightly rejected. Rather, the concepts of minimal risk and a minor increase over minimal risk are both statistical and normative. The “ill-child examinations” standard is also rightly rejected because it appears to subject children with a condition or disorder to greater research risk simply because of the greater risks such children face in everyday life. In proposing the category of a minor increase over minimal risk, the National Commission rejected having a condition or disorder as a sufficient ethical justification for this category of research, but rather asserted that the inclusion of the child must be scientifically necessary.7National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Report and Recommendations: Research Involving Children. DHEW publication no. (OS) 77-0004. US Printing Office, Washington DC1977Google Scholar We will argue that this ethical principle should apply to all children regardless of disorder or condition. Wendler and Emanuel5Wendler 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 (27) Google Scholar reject the “scrupulous parent” standard absent a systematic approach by which either IRB members or parents could decide that the “risks of research procedures are “sufficiently” similar to the risks of daily life.” In rejecting this approach, Wendler and Emanuel5Wendler 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 (27) Google Scholar appear to reduce this standard to a statistical inference subject to the well-documented ambiguities of individual risk perception. However, the concept of a “scrupulous parent” is a social (not psychological) construct that reflects a considered judgment about the level of risk to which a parent should expose a child.8Freedman B. Fuks A. Weijer C. In loco parentis: minimal risk as an ethical threshold for research upon children.Hastings Center Report. 1993; 23: 13-19Crossref PubMed Scopus (113) Google Scholar As such, the concept of a “scrupulous parent” provides a richer moral context with which to judge “socially acceptable risk” than that provided by Wendler and Emanuel.5Wendler 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 (27) Google Scholar The argument presented by Wendler and Emanuel5Wendler 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 (27) Google Scholar in favor of the “socially acceptable risk” standard operates on the well-documented ambiguity in the interpretation of minimal risk. In effect, they define minimal risk as those “risks ordinarily encountered by healthy children” and a minor increase over minimal risk as those socially acceptable risks ordinary children encounter. As Kopelman9Kopelman L.M. When is the risk minimal enough for children to be research subjects?.in: Kopelman L.M. Moskop J.C. Children and health care: moral and social issues. Kluwer Academic Publishers, Dordrecht, The Netherlands1989: 89-99Crossref Google Scholar points out, the phrase “daily life” contained in the definition of minimal risk is open to either interpretation. The proposed process by which an IRB should apply the “socially acceptable standard” fails to provide any real clarification. The IRB should gather all “available data” and assess whether the level of research risk is “sufficiently similar” to “the risks of daily life and routine examinations for average, healthy children.” This process is precisely the one that Wendler and Emanuel5Wendler 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 (27) Google Scholar reject under the “scrupulous parent” standard. If the research risk is judged not to be comparable, the IRB can then decide whether the risks remain “socially acceptable.” This standard seems to be reduced to the collection of data about risks that parents may expose ordinary children to in the course of everyday life (such as working on a family farm), and the admonition that an IRB must then decide whether this level of risk is socially acceptable. In contrast, the standard of a “scrupulous parent” provides greater moral content by indexing “socially acceptable” risks to the level of risks to which parents ought to expose their children rather than to what parents ordinarily do. The moral justifications provided by the National Commission to expose children with a disorder or condition to a minor increase over minimal risk absent any prospect of direct benefit were 2-fold. First, the definition of minimal risk was conservative, indexed to the risks encountered by an average, normal, healthy child during routine examinations or tests, or during everyday life. Second, exposing a child with a disorder or condition to only a “slight” increase over this minimal level of risk required scientific justification because The National Commission embraced the fundamental principle that no child, regardless of whether they have a condition or disorder, should be enrolled in research unless it is absolutely necessary to answer an important scientific question about the health and welfare of children.7National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Report and Recommendations: Research Involving Children. DHEW publication no. (OS) 77-0004. US Printing Office, Washington DC1977Google Scholar The current federal regulations allow a local IRB to approve research presenting a minor increase over minimal risk and no direct benefit only if it involves children with a disorder or condition (assuming the research may provide information of vital importance for understanding or ameliorating that disorder or condition).1Department of Health and Human Services (DHHS) (45 CFR Part 46, Subpart D). Protections for children involved as subjects in research.Federal Register. 1983; 48 (March 8, 1983); revised Federal Register 1991;56:28032 (June 18, 1991): 9814-9820PubMed Google Scholar, 2Food and Drug Administration, DHHS (21 CFR Parts 50 and 56). Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products.Federal Register. 2001; 66 (April 24, 2001): 20589-20600Google Scholar At times, the inclusion of a control group exposed to this same level of research risk (ie, children lacking the disorder or condition under study) is scientifically necessary. Currently, such research can only be approved after a process of federal review.10Nelson R.M. The newly established process for federal review of pediatric research protocols.Medical Res Law Policy. 2004; 3: 965Google Scholar Whether a child ought to be exposed in research to a minor increase over minimal risk, assuming scientific necessity, should not depend on whether he or she has a condition or disorder. Rather, the “scrupulous parent” standard should be interpreted to incorporate both minimal risk and a minor increase over minimal risk within a single ethically justified standard.8Freedman B. Fuks A. Weijer C. In loco parentis: minimal risk as an ethical threshold for research upon children.Hastings Center Report. 1993; 23: 13-19Crossref PubMed Scopus (113) Google Scholar, 11Ross 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 To accomplish this, Subpart D should be amended to include a child-specific definition of minimal risk rather than rely on the general definition found in the Common Rule.12Department of Health and Human Services (DHHS) (45 CFR 46 Subpart A). Final regulations amending basic HHS policy for the protection of human research subjects.Federal Register. 1981; 46 (January 26, 1981); revised Federal Register 1991;56:28003-18 (June 18, 1991): 8366-8391Google Scholar We offer for consideration a modification of the definition of minimal risk proposed by Ackerman:11Ross 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 “the probability [and magnitude] of physical [or] psychological harm is no more than that to which it is appropriate [for a scrupulous parent] to intentionally expose a child for educational purposes in family life situations.”6Ackerman T. Moral duties of parents and non-therapeutic research procedures involving children.Bioethics Q. 1980; 2: 94-111Crossref PubMed Scopus (33) Google Scholar This definition would obviate the need to distinguish between minimal risk and a minor increase over minimal risk. It would apply to healthy children and children with a disorder or condition and thereby eliminate the current double standard that allows for disproportionate research burdens to be placed on children with a disorder or condition.