Institutional Review Board Practices Regarding Assent in Pediatric Research
* Department of Clinical Bioethics National Institutes of Health, Bethesda, Maryland
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
Emmes Corporation, Bethesda, Maryland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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Objective. To assess how Institutional Review Boards (IRBs) implement the assent requirement for research with children.
Methods. Telephone interviews were conducted with 188 chairpersons of IRBs from a range of institutions nationwide. Respondents were queried on 4 topics: 1) which children are considered capable of assent, 2) which information investigators must provide pediatric research subjects, 3) whether IRBs favor the enrollment of children who are capable of assent, and 4) how chairpersons view payment for children’s research participation.
Results. Half of IRBs have a method that they require investigators to follow when determining which children are capable of assent, most commonly an age cutoff. Half of IRBs do not have a method, and the majority rely on investigators’ clinical judgment. IRBs largely follow the adult research regulations when determining which information should be provided to an assenting child. A total of 58% of IRBs would enroll a child who is incapable of assent in a nonbeneficial study, even if children who are capable of assent could be enrolled instead. Almost half (46%) of chairpersons believe that it sometimes or always acceptable to offer incentive payments to children, and more than one third (35%) thought it acceptable to offer payment to the parents.
Conclusion. When possible, IRBs follow the federal regulations for research with adults when implementing the assent requirement. For considerations that do not have analogs in the adult regulations, IRB practices vary widely. These data suggest that IRBs need guidance on how to implement the assent requirement in a way that provides appropriate protections for pediatric research subjects.
Key Words: child • IRB
Abbreviations: IRB, Institutional Review Board • OR, odds ratio
Enrolling children in clinical research raises special ethical concerns because they lack the legal standing to consent and often the capacity to understand the research. In most cases, the US federal regulations allow children to be enrolled in research only when their parents provide permission.1 In addition, the regulations require the assent, defined as "affirmative agreement," of children who are capable of providing it. Institutional Review Boards (IRBs) may waive the requirement to obtain children’s assent only when the research offers a "prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of research."1
Although the regulations require children’s assent, they provide almost no guidance on how the assent requirement should be satisfied, leaving this determination to the reviewing IRB. In particular, the regulations do not specify which children are capable of assent, stating only that IRBs should consider the "ages, maturity and psychological state of the children involved."1 No explanation is made of which abilities IRBs and investigators should assess to determine whether children are capable of giving assent. The regulations also do not specify what information investigators must provide children as part of the assent process or whether payment may be offered to encourage children’s assent. Despite this reliance on IRBs to ensure appropriate implementation of the assent requirement, we could find no data on how IRBs implement the assent requirement. To assess IRB practices, we conducted a study of a representative sample of IRBs that evaluate research involving children.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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Instrument
The survey aimed to address 4 aspects of IRBs’ implementation of the assent requirement for research involving children: 1) which children are considered capable of assent, 2) what information investigators must provide pediatric research subjects, 3) whether IRBs favor the enrollment of children who are capable of assent, and 4) how chairpersons view payment for children’s research participation. All questions asked the chairperson to report on the standard practice of his or her IRB, except for the 4 questions on payment, which asked for the chairperson’s personal opinion (Appendix).
The interview instrument was developed in 5 steps: 1) development of a draft instrument after a comprehensive review of the literature on children’s assent for research participation; 2) pretesting of the instrument with a pediatric researcher, a pediatric clinician, and an IRB coordinator and revision; 3) additional pretesting with 4 IRB chairs and revision; 4) review and editing by the University of Chicago’s National Opinion Research Center; and 5) review and editing by the EMMES Corporation, a private statistical analysis firm.
Participants
The study targeted 3 groups of US IRBs: 1) IRBs that primarily review pediatric research, 2) independent (proprietary) IRBs, and 3) randomly selected IRBs. The IRBs that primarily review pediatric research consisted of all institutions that belong to the Association of Medical School Pediatric Department Chairs or to the National Association of Children’s Hospitals and Related Institutions that have IRBs (N = 154). The independent IRB group consisted of all of those on the Health Industry Manufacturers Association (now called AdvaMed) list (N = 37). The randomly selected IRBs (N = 71) were chosen from a list of IRBs that have a multiple project assurance with the Office for Human Research Protection.
The chairpersons of all identified IRBs were invited to participate. Chairpersons were excluded when 1) their IRB had not reviewed any pediatric research protocols in 2000, 2) their IRB reviewed <10 total (adult and pediatric) research protocols in 2000, or 3) they had <1 year of total IRB experience. At least 1 of the exclusion criteria was met by 34 chairpersons, and 4 IRBs were no longer in existence. Of the remaining 224 potential participants, 188 chairpersons agreed to be interviewed, 24 were unreachable, and 12 declined to respond (response rate: 84%).
Process
The telephone interview took 
30 minutes. Most questions were multiple-choice, although some allowed for open-ended responses. Interviewers aimed to record the respondents’ comments as close to verbatim as possible. Open-ended responses were coded independently by 2 authors, who were blinded to the identities of the respondents. All discrepancies were discussed until consensus was reached; therefore, no test of interrater reliability was performed.
Analysis
The data collected were key-entered and analyzed by the EMMES Corporation, a private statistical analysis firm. Entered data were validated by a subset of the authors. Univariate associations between respondent characteristics and both enrollment and payment policies were calculated using the SAS procedure LOGISTIC. All analyses were conducted using SAS version 8.2. This study was approved by the IRB for the National Institute of Child Health and Human Development.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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Of the 188 IRB chairpersons surveyed, 119 (63%) are affiliated with academic medical centers, 27 of which are exclusively pediatric institutions (Table 1). The same percentage of chairpersons (11%) are affiliated with independent IRBs, nonmedical university IRBs, and community medical center IRBs. Sociodemographic and professional characteristics of respondents are listed in Table 2. Women represent 22% of respondents, and 53% of respondents had been a member of an IRB for >10 years.
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Regarding how investigators determine which children are capable of assent, 91 IRBs require that investigators use a particular method (Table 3). Most (89%) cited an age cutoff as the required method. The age cutoff of 7 was most common (46%), with 16% of IRBs using a lower limit and 35% using a higher limit. For IRBs that do not mandate a particular method (N = 91), most chairpersons reported that investigators rely on their clinical judgment (68%) and/or on an age cutoff (40%) to determine whether a child is capable of assent.
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We found that IRBs require children who are capable of assent to receive information about the study in writing (68%), orally (23%), or either, depending on the circumstances (6%). Chairpersons were asked whether their IRBs require investigators to provide children each of the elements of informed consent that the federal regulations require investigators to provide adults who make an autonomous decision to enroll in research. The vast majority (99%) of IRBs require children to be informed that they can refuse to participate, of the purpose of the study (97%), of a description of common risks (97%), and whether they will benefit (94%). Fewer IRBs (73%) require investigators to inform children of serious but rare risks.
A slight majority (58%) of chairpersons reported that their IRB would allow investigators to enroll children who are incapable of assent in a nonbeneficial study involving a single 10-mL blood draw, even when the research could be conducted with children who are capable of assent. IRBs that are affiliated with pediatric institutions are more likely than IRBs that are affiliated with other institutions to allow enrollment of children who are unable to give assent when their participation is not necessary (odds ratio [OR]: 4.6; P = .0009). IRBs that review >100 pediatric protocols a year are more likely to allow enrollment of children who are unable to give assent when their participation is not necessary compared with IRBs that review few pediatric protocols (1–5/year; OR: 3.7; P = .03).
For a single nonbeneficial blood draw study, 98% of chairpersons would allow reimbursement to parents for their expenses (Table 4) and 53% would allow reimbursement to children for the time and inconvenience related to the study. An additional 28% of chairpersons would allow reimbursement to the children under certain conditions, the most common being that the payment does not constitute an undue inducement. Chairpersons of IRBs that review large volumes of pediatric studies (>100/year) are more likely to allow compensation to the child for time and inconvenience than chairpersons that are affiliated with IRBs that review few pediatric protocols (1–5/year; OR: 8.3; P = .04). Regarding a $10 incentive payment to the child for participation in the nonbeneficial, blood draw study, 28% of chairpersons would allow it and 18% would consider allowing it depending on the circumstances. Again, chairpersons of IRBs that review a larger volume of pediatric studies (51–100/year) were more likely to allow this $10 payment than those that review a smaller number of pediatric studies (1–5/year; OR: 3.7; P = .04). Regarding a $10 incentive payment to parents, 27% of IRB chairpersons would allow it and 8% would do so in some circumstances. There were no significant correlations between whether the IRB would allow a $10 incentive payment to parent or child and the gender of the IRB chairperson, whether the chairperson had children, or the type of institution with which the IRB chairperson was affiliated.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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In reviewing and approving pediatric research, IRBs must strike a balance between protecting individual children and allowing valuable scientific research to go forward. The assent requirement is intended to ensure respect for pediatric subjects, giving them a voice in whether they participate in research. Given the absence of regulatory specificity, we assessed how IRBs across the country implement the assent requirement. Our data reveal that, when available, IRBs rely on analogs in the federal regulations regarding consent for adults to implement the assent requirement for children. In contrast, there is wide variation across the United States in implementation of those aspects of the assent process that do not have clear analogs in the regulations for adults. In particular, there is wide variation in which children are considered able to give assent, how ability to give assent is determined, whether children who are unable to give assent are enrolled in nonbeneficial research when their participation is unnecessary, and whether payment is allowed. This level of variation in IRB practices suggests that many IRBs may not be striking the appropriate balance between protecting individual children and allowing important research.
The National Commission2 and the American Academy of Pediatrics3 recommend that assent be obtained from children aged 7 and older. Our data suggest that only 20% of IRBs follow this recommendation. Other IRBs use a higher age cutoff, some use a lower age cutoff, and 47% leave it to the judgment of the investigator. This disagreement is not surprising given that the regulations do not specify an age cutoff or which abilities a child needs to be capable of assent.
Asking for assent from children who are not capable may upset them and hinder important research. For example, Schwartz4 found that telling children that they are participating in research makes them anxious. In contrast, failing to obtain the assent of children who are capable represents a failure to respect pediatric research subjects. If appropriate respect entails that all children who can indicate a choice should be required to give assent, then IRBs that require assent of older children only are failing to respect younger children. Conversely, if assent should be required only for children who can understand all of the elements of informed consent, then IRBs that require investigators to obtain the assent of younger children may be inappropriately hindering research. To address this concern, it will be important to provide IRBs guidance on the reason for requiring the assent of children and guidelines for which children are capable of assent.
The adult informed consent guidelines were written to ensure that adults can make an autonomous decision whether to enroll in research, yet the vast majority of IRBs provide children, even those who are not autonomous, with the same information that must be provided to adults. The lone exception that we found is that slightly more than one quarter (27%) of IRBs do not require investigators to inform children of the serious but rare risks of research participation. These findings highlight the need for explicit guidance on which information children should be provided to give assent. If children should receive the same information that is provided to adults, then 1 in 4 IRBs is failing to respect children by failing to provide crucial data on serious risks. If IRBs should provide different information as part of the assent process, then these differences may need to be specified, because many IRBs simply follow the guidelines for adults. The regulations may need to tailor which information children must receive to their ages and abilities.
One notable finding was the proportion of IRBs (58%) that would allow the enrollment of a child who is not capable of assent in a nonbeneficial study, even when the research could be conducted with children who can give assent. This practice contradicts the National Commission’s recommendation that "where appropriate, studies have been conducted on animals and adult humans, then older children, before involving infants."2
IRBs that review a large volume of pediatric studies or are affiliated with a pediatric institution are significantly more likely to allow the enrollment of children who are incapable of assent when their participation is not necessary. Although these institutions may be faced with greater demand for research participants, this reason alone does not justify enrolling young children who are incapable of assent in nonbeneficial research when children who are capable of assent may be enrolled instead. The federal regulations may need to be modified to reflect the principle of favoring the enrollment of older children who are capable of assent unless there are scientific or safety reasons to enroll younger children who cannot give assent.
IRBs that enroll children who cannot give assent when their participation is unnecessary may be influenced by the 1998 National Institutes of Health policy that "children must be included in all human subject research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them."5 This policy has the laudable aim of rectifying the dearth of research on many children’s conditions and drug reactions; however, this policy is consistent with the principle of enrolling children who are capable of assent when possible.
A review of data from Center Watch, a clinical trials listing service, suggests that almost one quarter of pediatric trials offer payment, with amounts ranging from $25 to $1500.7 A survey of 128 IRBs that review pediatric research found that 66% had approved payment of some form (reimbursement or incentive) to either child or parent, ranging from $1 to $1000.8 Specific recommendations on paying children or parents for participation in pediatric research are absent from the federal guidelines. The American Academy of Pediatrics recommends that children be given no more than a token of appreciation that is revealed only after completion of the study.6
Chairpersons in our study for the most part agreed that investigators may compensate parents for out-of-pocket expenses and children for time and inconvenience, with some citing stipulations for the latter such as the compensation being in the form of a toy or gift certificate. Agreement between chairpersons dropped, however, when they were questioned about allowing a $10 incentive payment to children or parents. Many cited "coercion" as the reason not to offer incentive payments.
Coercion involves the use of a threat or negative force to influence another’s actions. Payment, in contrast, involves a positive offer. It is likely that the chairpersons meant to critique incentive payments not as coercion but as "undue" inducements, or excessively positive offers. Undue inducement involves an offer whose immediate appeal leads individuals to make decisions that conflict with their best interests. It has been argued that small incentives are unlikely to have this impact and may encourage important research.7 Financial reward has been shown to be a significant motivator for normal, healthy volunteers to participate in research, especially among young adult volunteers.9,10
Offering incentives in pediatric research requires particular caution because the parent has a potential to benefit without facing risks themselves. A study of 44 parents who enrolled their children in different asthma studies, with a mean reimbursement of $570 per study, found that the financial benefit was a positive influence on the parent to enroll the child. However, the parents reported this reason as less important than learning more about their child’s disease and helping medical science.11 More research, especially empirical research, is needed to assess the impact of small incentives on the choices of subjects and their parents.
Guidelines for payment in pediatric research have been described to minimize the risk of undue inducement.7 For example, incentives should be justified explicitly to the IRB and should be listed apart from the benefits section in the assent and consent forms. Incentives should be structured to minimize undue inducement and to ensure that the incentive goes to the child, such as a savings bond in the child’s name or a certificate to a children’s store. Many chairpersons in this survey stipulated conditions such as these when asked about the $10 incentive to the child.
Limitations
One possible limitation of our study is that only chairpersons were interviewed, and their views may not accurately reflect the practices of the IRBs that they represent. Multiple-choice questions may have limited the extent to which chairpersons could communicate the subtleties of their practices, although for all questions, respondents were able to answer "other" or "it depends" and provide additional information that was later coded and included in analysis.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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The federal regulations do not specify how the assent requirement for pediatric research should be satisfied, leaving this determination to the reviewing IRB. Implementing the assent requirement correctly is important to ensure that IRBs achieve a proper balance of protecting children while allowing important research to proceed. The purpose of this study was to develop empirical data on how IRBs implement the assent requirement. We found that IRBs rely on the analogous regulations for adults when available. For aspects of the assent process that are unique to research with children, there is wide variation in IRBs’ practices across the United States. These findings suggest that IRBs need guidance to ensure that the assent requirement is implemented in a way that appropriately respects pediatric research subjects. Specifically, IRBs may need guidance on which children are capable of assent, which information they should be provided, whether older children who are capable of assent should be favored over those who are younger and incapable, and whether it is appropriate to offer payment to parents or children.
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APPENDIX: QUESTIONS ON INTERVIEW INSTRUMENT REGARDING ASSENT AND PAYMENT |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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Next, I would like to ask you about a specific example of research with children.
Imagine that your IRB is asked to review a study of blood clotting in healthy children. The study involves 1 clinic visit with a single 10-mL blood draw.
13. To be enrolled in this clotting study, would you require that children give their assent if they are capable of doing so?
1 = Yes 2 = No 
Why not? 3 = Don’t know 4 = It depends please specify
14. Imagine that there is no scientific need to enroll children of a particular age in this clotting study. Therefore, the researcher plans to enroll children of all ages. In your view, should children who are unable to assent, such as 3-year-olds, be excluded from this study, or should the investigator be able to enroll these children without their assent?
[QxQ: The mention of 3-year-olds is intended solely as an example of children who clearly cannot give assent. For this question, assume that the investigator will enroll only children for whom the procedure is deemed appropriate.]
1 = Exclude them
2 = Allow enrollment without assent, with parents’ permission
3 = Don’t know
4 = Other Please specify
15. Does your IRB require investigators to use a particular method to determine which children are capable of giving assent?
1 = Yes 2 = No 15a. How do you think investigators determine which children are capable of giving assent? CODE ALL
1 = Age cutoff
2 = Investigators’ clinical judgment
3 = Don’t know
4 = Other Please specify
16. What method does your IRB require investigators to use to determine which children are capable of giving assent? CODE ALL
1 = Investigator’s clinical judgment
2 = Children’s age What is the minimum age?
3 = Cognitive tests Please specify which tests
4 = Other please specify
5 = It depends please specify
17. Would your IRB require that children who are capable of assent receive information in writing about this clotting study?
1 = Yes 2 = No 3 = Don’t know 4 = It depends please specify
18. Would your IRB require that children who are capable of assent be provided with information orally about this study?
1 = Yes
2 = No skip to 24
3 = Don’t know
4 = It depends please specify
Now, I would like to ask what information your IRB would require that children receive about this clotting protocol
19. First, would your IRB require that children be informed that this clotting study does not offer them a chance of direct medical benefit?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
20. Would your IRB require that children be informed of the purpose of this study?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
21. Would your IRB require that children be informed of the common risks and discomforts of venipuncture, such as bruising?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
22. Would your IRB require that children be informed of the serious but rare risks of venipuncture, such as blood clots or infection?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
23. Would your IRB require that children be informed that they can refuse to participate in this clotting study?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
The next section concerns the ethics of payment with respect to this study.
24. First, do you think that it would be acceptable for the investigator of this clotting study to reimburse parents for their out-of-pocket research-related expenses, such as the costs of transportation to the clinic?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
25. Do you think that it would be acceptable for the investigator to compensate children for the time and inconvenience related to this study, such as the time that the children spend undergoing research procedures?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
26. Next, if the investigator had trouble recruiting subjects for this study, do you think it would be acceptable to offer children a $10 incentive payment, in addition to any payments for out-of-pocket expenses and time and inconvenience?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
27. Finally, would it be acceptable to offer a $10 incentive payment to the children’s parents?
1 = Yes 2 = No Why not? 3 = Don’t know 4 = It depends please specify
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ACKNOWLEDGMENTS |
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The opinions expressed are the authors’ own. They do not reflect any position or policy of the National Institutes of Health, Public Health Service, or Department of Health and Human Services.
We thank Dr Joseph Fins, Director of Medical Ethics at the Cornell campus of New York Presbyterian Hospital, for his editorial assistance.
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FOOTNOTES |
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Received for publication Oct 6, 2003; Accepted Feb 10, 2004.
Reprint requests to (D.W.) National Institutes of Health, Bldg 10, Rm 1C118, Bethesda, MD 20892-1156. E-mail: dwendler{at}cc.nih.gov
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONAPPENDIX: QUESTIONS ON INTERVIEW...REFERENCES |
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1. Department of Health and Human Services. United States Federal Regulations, 45 CFR 46, Subpart D (1991)
2. National Institutes of Health. NIH policy and guidelines on the inclusion of children as participants in research involving human subjects. Available at: www.nih.gov/grants/guide/notice-files/not98-024.html. Accessed April 21, 2004
3. American Academy of Pediatrics. Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. Washington, DC: The Academy; 1995:286–294
4. Schwartz AH. Children’s concepts of research hospitalization. N Engl J Med.1972; 287 :589 –592
5. Policy on the inclusion of children as subjects in clinical research. NIH Guide.1997; 26 (3)
6. American Academy of Pediatrics, Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics.1995; 95
:286
–294
7. Wendler D, Rackoff JE, Emanuel EJ, Grady C. The ethics of paying for children’s participation in research. J Pediar.2002; 141 :166 –171[CrossRef][Web of Science][Medline]
8. Weise K, Smith ML, Maschke KJ, Copeland HL. National practices regarding payment to research subjects for participating in pediatric research. Pediatrics.2002; 110
:577
–582
9. Van Gelderen CE, Savelkoul TJ, van Dokkum W, Meulenbelt J. Motives and perception of healthy volunteers who participate in experiments. Eur J Clin Pharmacol.1993; 45 :15 –21[CrossRef][Web of Science][Medline]
10. Tishler CL, Bartholomae S. The recruitment of normal healthy volunteers: a review of the literature on the use of financial incentives. J Clin Pharmacol.2002; 42 :365 –375[Abstract]
11. Rothmier JD, Lasley MV, Shapiro GG. Factors influencing parental consent in pediatric clinical research. Pediatrics.2003; 111
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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