Published online September 1, 2004
PEDIATRICS Vol. 114 No. 3 September 2004, pp. 901-902 (doi:10.1542/peds.2004-1187)

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The Need for Consistency in 407 Reviews

Lainie Ross, MD, PhD
Department of Pediatrics and MacLean Center for Clinical Medical Ethics,
University of Chicago,
Chicago, IL 60637

To the Editor.—

I write to correct 1 factual error in the excellent review by Kopelman and Murphy¹ regarding the 407 panels and use this case to highlight a significant problem in pediatric research protections generally.

Kopelman and Murphy cite 10 studies involving 407 panels that are a matter of public record. Study 3 refers to a National Institute of Child Health and Human Development (NICHD) protocol that enrolled obese children and normal-weight children of obese parents in a longitudinal study of population differences in insulin sensitivity, resting-energy expenditure, and body composition using a euglycemic clamp technique. In 2000, the Office for Human Research Protections (OHRP) noted that the research offered no prospect of direct benefit and the clamp technique involved a minor increase over minimal risk. According to federal regulations, such research can only be approved if the children have a "disease or condition."^2(46.406) The OHRP stated that the researchers needed 407 review to enroll the healthy controls (normal-weight children).³ The institutional review board (IRB) of the NICHD reexamined the protocol and argued that the research could be approved under 46.406 on the grounds that the subjects were children who were either obese (a disease or condition) or normal-weight children of obese parents (who were "at risk for developing type 2 diabetes [a disease]." The OHRP accepted this interpretation,⁴ and the study did not undergo 407 review (and therefore should not have been included in the Kopelman and Murphy article).

Two other clamp studies (studies 2 and 4 as cited by Kopelman and Murphy), however, have had 407 review. Study 2 sought to induce mild hypoglycemia by using the clamp technique on children with type 1 diabetes (a disease) and healthy controls. Study 4 seeks to use the clamp technique in children of Japanese American ancestry (who are known to be at increased risk for insulin metabolic resistance syndrome [a condition]) and their white cousins as "healthy controls." Both IRBs sought 407 review for the healthy controls. Study 2 received 407 approval, and study 4 is conditionally approved.⁵

Other studies using the clamp technique with healthy controls have been approved locally.^6–8 If the study includes healthy controls, the research requires 407 review unless the researchers argue that the healthy controls are not really healthy but "at risk" (similar to the NICHD study discussed above).⁹ A recent Institute of Medicine report recommends a broad interpretation of "disease or condition."¹⁰ Even if adopted, however, clamp studies enrolling healthy children who are not at risk should be protected by 407 review as required by federal regulations. The variable approach to clamp-study research in healthy children highlights the need for greater consistency and guidance in pediatric research protections.

REFERENCES

1. Kopelman LM, Murphy TF. Ethical concerns about federal approval of risky pediatric studies. Pediatrics. 2004;113 :1783 –1789[Abstract/Free Full Text]
2. Department of Health and Human Services. Protections for children involved as subjects in research (45 CFR Part 46, Subpart D). Fed Regist. 1983;48 :9814 –9820[Medline]
3. Office for Human Research Protections. Determination letter to National Institutes of Health, November 3, 2000. Available at: http://ohrp.osophs.dhhs.gov/detrm_letrs/nov00a.pdf. Accessed July 9, 2004
4. Office for Human Research Protections. Determination letter to National Institutes of Health, August 15, 2001. Available at: http://ohrp.osophs.dhhs.gov/detrm_letrs/aug01o.pdf. Accessed July 9, 2004
5. Diekema D. Precursors to diabetes in Japanese American youth: a 3-year odyssey in the kingdom of 46.407. Presented at: Annual Meeting of the American Society of Bioethics and Humanities; October 22–26, 2003; Montreal, QC, Canada
6. Amiel SA, Simonson DC, Sherwin RS, Lauritano AA, Tamborlane WV. Exaggerated epinephrine response to hypoglycemia in normal and insulin-dependent diabetic children. J Pediatr. 1987;110 :832 –837[CrossRef][Web of Science][Medline]
7. Moran A, Jacobs DR Jr, Steinberger J, et al. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes. 1999;48 :2039 –2044[Abstract]
8. Murtaugh MA, Jacobs DR Jr, Moran A, Steinberger J, Sinaiko AR. Relation of birth weight to fasting insulin, insulin resistance, and body size in adolescence. Diabetes Care. 2003;26 :187 –192[Abstract/Free Full Text]
9. Ross LF. Convening a 407 panel for research not otherwise approvable: precursors to diabetes in Japanese American youth as a case study. Kennedy Inst Ethics J. 2004;14 :165 –187[Medline]
10. Field MJ, Behrman RE, eds, for the Committee on Clinical Research Involving Children. The Ethical Conduct of Clinical Research Involving Children. Washington, DC: National Academies Press; 2004

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Loretta M. Kopelman, PhD
Department of Medical Humanities,
Brody School of Medicine,
East Carolina University,
Greenville, NC 27858-4354

Timothy F. Murphy, PhD
Department of Medical Education,
University of Illinois College of Medicine,
Chicago, IL 60612-7309

In Reply.—

We appreciate Dr Ross’s¹ close attention to our analysis of 407 review panels and wish to clarify certain facts at issue. To understand the evolution of 407 policies, we listed all studies for which institutional review boards (IRBs) sought 407 reviews as well as 2 pivotal National Institute of Child Health and Human Development (NICHD) studies.² First, in 1993, as a result of public criticism, the National Institutes of Health (NIH) convened an ad hoc panel to review growth hormone studies.³ We were able to mention its procedures because one of us (L.M.K.) served as co-chair of the panel, the deliberations and reports of which remain confidential. Second, we included the NICHD study regarding obesity, which was approved by an IRB at the NIH in 1996. In November 2000, the Office for Human Research Protections (OHRP) suspended the study, invoking 407 regulations and posting its determination letter publicly.⁴ Dr Ross is correct that no 407 panel ultimately reviewed the study, but the study is relevant because the OHRP notified researchers that they should have done so: "OHRP finds that this study may only be conducted by HHS [US Department of Health and Human Services] if the requirements of HHS regulations at 45 CFR 46.407 are satisfied."⁴ As we indicated, the OHRP found that aspects of this research involved greater than minimal risk with healthy children (pp.1784–1785). The most controversial portions of the study involved children who were not obese (although they had 1 obese parent) undergoing insulin clamp studies (which had been completed in 1999). The OHRP required certain actions to be taken by December 8, 2000, including modifying the study and devising a plan about whether to contact "the parents or guardians of the subjects who participated in the above referenced research and inform them of their child’s inappropriate enrollment in this research."⁴ The NICHD obesity study was pivotal because of the public way in which researchers were notified about 407 compliance. The OHRP’s actions showed a new era in oversight and compliance, contributing to the subsequent wave of IRB requests for 407 review and approval.

The OHRP also asked for "a list of active research protocols being conducted by the NIH intramural research program that involves normal, healthy children."⁴ The OHRP was particularly concerned about an "insulin tolerance test designed to induce hypoglycemia (a blood sugar less than 50 mg/dL) in normal children." OHRP specifically stated that otherwise normal children having at least 1 obese parent should not have been viewed as having a "condition," a classification necessary to conduct research involving a "minor increase over minimal risk." The OHRP was critical of the IRB deliberations that lead to the 1996 approval of this study and requested information about the "hundreds" of children investigators claimed had been involved in this sort of research. Dr Ross¹ is therefore in error that the OHRP regarded having 1 obese parent as "a condition" that would justify exposure to a minor increase over minimal risk if children were otherwise healthy; the OHRP explicitly rejected this view.⁴

It is also incorrect that the Institute of Medicine encouraged a "wide interpretation" of "disorder or condition" that would allow having 1 obese parent to be viewed as itself a condition of the child.⁵ One of us (L.M.K.) was a member of the Committee on Clinical Research With Children, and the Institute of Medicine report reflects our concern with and rejection of broad interpretations (see ref 5, recommendation 4.3).

In our analysis we used only publicly available sources and thus cannot comment on the private communications available to Dr Ross.

REFERENCES

1. Ross L. The need for consistency in 407 reviews [letter]. Pediatrics. 2004;114 :901[Free Full Text]
2. Kopelman LM, Murphy TF. Ethical concerns about federal approval of risky pediatric studies. Pediatrics. 2004;113 :1783 –1789
3. National Institutes of Health, Human Growth Hormone Protocol Review Committee. Report of the NIH Human Growth Hormone Protocol Review Committee. Bethesda, MD: National Institutes of Health; 1992.
4. US Department of Health and Human Services, Office of Human Research Protection. November 3, 2000. Re: Human Research Subject Protections Under Multiple ProjectAssurance (MPA). Available at: http://ohrp.osophs.dhhs.gov/detrm_letrs/nov00a.pdf. Accessed July 12, 2004
5. Institute of Medicine, Committee on Clinical Research Involving Children. The Ethical Conduct of Clinical Research Involving Children. Washington DC: National Academies Press; 2004

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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				L. Ross, L. M. Kopelman, and T. F. Murphy The Need for Consistency in 407 Reviews Pediatrics, September 1, 2004; 114(3): 901 - 902. [Full Text] [PDF]

This Article Extract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Ross, L. Articles by Murphy, T. F. Search for Related Content PubMed PubMed Citation Articles by Ross, L. Articles by Murphy, T. F. Related Collections Office Practice Social Bookmarking                         What's this?