How Do Institutional Review Boards Apply the Federal Risk and Benefit Standards for Pediatric Research?

Abstract

EDIATRICIANS OFTEN MUSTtreat children in the absence of sufficient data. 1 For example, approximately 70% of all medications do not include sufficient data for use in children. 2,3 To provide the necessary data and to ensure medical interventions are safe and effective for children, it is necessary to conduct clinical research with children. 4,5 Currently, more than 1900 clinical trials are approved for children in the United States. 6 Food and Drug Administration (FDA) requests have led to proposals to enroll another 38 000 children in clinical research. 7 One FDA request led to a series of studies, enrolling thousands of children, to establish a safe and effective dose of ibuprofen for infants. 8 Another FDA request led to studies assessing whether the combination of lopinavir and ritonavir, proven effective in adults, is safe and effective in children with human immunodeficiency virus infection. 8 Ethical guidelines for pediatric research must balance the protection of individual children with the importance of allowing research needed to improve pediatric medicine. 9-13 Federal regulations 14,15 attempt to achieve this balance by empowering institutional review boards (IRBs) to approve pediatric research in 3 risk and benefit cat-e g o r i e s : ( 1 ) s t u d i e s t h a t o f f e r participating children a prospect of direct benefit 16 ; (2) studies that do not of-Context Federal regulations allow children in the United States to be enrolled in clinical research only when the institutional review board (IRB) determines that the risks are minimal or a minor increase over minimal, or that the research offers a prospect of direct benefit. Despite this reliance on IRBs, no data exist on how IRBs apply the risk and benefit categories for pediatric research.Objective To determine how IRB chairpersons apply the federal risk and benefit categories for pediatric research. Design, Setting, and Participants Telephone survey, conducted between May and August 2002 of 188 randomly selected chairpersons of IRBs in the Unites States. The survey consisted of 21 questions to assess the application of federal risk standards to research procedures, whether certain interventions offer a prospect of direct benefit to participating children, and the extent to which IRBs use the federal definition of minimal risk when categorizing the risks of research procedures in children. Main Outcome MeasuresResponses regarding categorization of the risk level and direct benefits of pediatric research procedures. ResultsA single blood draw was the only procedure categorized as minimal risk by a majority (152 or 81%) of the 188 respondents. An electromyogram was categorized as minimal or a minor increase over minimal risk by 100 (53%) and as more than a minor increase over minimal risk by 77 (41%). Allergy skin testing was categorized as minimal risk by 43 IRB chairpersons (23%), a minor increase over minimal risk by 81 (43%), and more than a minor increase over minimal risk by 51 (27%). Regarding benefits, 113 chairpersons (60%) considered ad...

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“…For all these reasons, proposed research may or may not proceed on the basis of what might be considered subjective determinations of minimal risk by REBs. The literature clearly substantiates difficulties with the use of a nebulous standard for minimal risk and although other standards have been proposed for use, they have yet to be adopted 35,36,37,38,39,40,41,42,43,44 .…”

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“…36 My approach is to determine the level of risk associated with both treatment arms, ascertain whether the potential risks associated with the 2 treatment arms are identical (unlikely) or different, and then confirm that the risks and benefits are equivalent to those of care outside of the research.…”

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“…In addition, the risks of routine clinical examinations and daily life activities are dissimilar to net research risks because people mostly incur them for their own benefit rather than for the benefit of others. For these reasons, the minimal risk threshold, although widely endorsed, has been notoriously difficult to define and implement (Shah et al 2004;Lenk et al 2004).…”

“…Indeed, empirical studies have found significant variation in how IRBs/RECs evaluate research risks and potential benefits (van Luijn et al 2006;Shah et al 2004;Lenk et al 2004). These data raise concern that some participants are not being protected from excessive risks and that valuable studies involving acceptable risk are being rejected-or not even submitted given the uncertain outcomes of ethical review.…”