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Ethical Conduct of Clinical Research Involving Children (2004)

Chapter: 8 Responsible Research Involving Children

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Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
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8
Responsible Research Involving Children

[T]hose who participate as subjects of research studies should share in the accolades usually accorded great scientists…. [They] deserve to be fully informed, treated with respect, listened to, and protected from foreseeable harm.

Institute of Medicine, 2003a, p. 29

A robust system for protecting human participants in research in general is a necessary but not sufficient foundation for protecting child research participants in particular. Meeting the special ethical and legal standards for protecting infants, children and adolescents who participate in research demands additional resources and attention beyond that required for protecting adults. Such additional commitments are particularly important given recent requirements or incentives to increase the amount of research involving children. Between 1997 and 2001, the number of industry-sponsored pediatric clinical trials and the number of child participants in such trials increased by an estimated three-fold (Dembner, 2001; Milne, 2002).

In some cases, the special ethical and regulatory protections for children may preclude potentially important clinical studies that would be approved for adult participation. This prospect can put pressure on those involved in developing or reviewing studies that include infants, children, or adolescents. A strong system of protections for adult and child partici-

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

pants in research will provide support and guidance for all involved to help them fulfill their legal and ethical responsibilities in such situations.

This chapter considers the final element in the committee’s statement of task, which relates to the unique roles and responsibilities of institutional review boards (IRBs) in reviewing research involving infants, children, and adolescents. Consistent with the report’s system perspective, the chapter also looks at the roles and responsibilities of other key parties, including investigators, research institutions, federal agencies, and public and private research sponsors. For a more comprehensive resource on ways to improve the structure and functioning of the national system for protecting human participants in research, readers may consult the analyses and recommendations in the 2003 Institute of Medicine (IOM) report Responsible Research (IOM, 2003a).

Although this chapter focuses on those who conduct, review, fund, and regulate research, the committee recognizes the important role of parents. They have a most intimate and profound duty and desire to protect and promote their child’s safety and well-being in research, as in all realms of life. Chapter 5, in particular, has discussed how investigators, IRBs, and others can effectively and compassionately support parents in fulfilling their responsibilities and, thereby, help them to feel that they have done the right thing for their child, whatever their choices about the child’s participation in research. Once parents have agreed to their child’s participation in research, they—and older children and adolescents—may sometimes have crucial responsibilities for following the research protocol (e.g., administering medicines or bringing the child in for research appointments). Investigators need to make sure that parents and older children and adolescents understand any such responsibilities before they agree to research participation and that they have appropriate support in adhering to the protocol during the course of the research.

As a general statement of concern about the responsible conduct of clinical research involving children, the committee notes that the regulations offering special protections to child participants in research do not cover all research. They apply only to clinical research that is conducted, supported, and regulated by the U.S. Department of Health and Human Services (DHHS) or that is covered by the policies of research institutions that extend these regulations to other studies conducted under their auspices. If other agencies undertake or support clinical research that includes children, they too should formally adopt these regulations, and private organizations not otherwise covered by the rules should likewise abide by them. Furthermore, institutions involved in significant innovation in clinical care for children should ensure that patients are protected by safeguards equivalent to those that federal regulations provide to research participants.

The committee believes that all research that includes infants, children,

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

and adolescents should occur under the oversight of a formal program for the protection of human research participants. In this, it follows the 2003 IOM report cited above and the 2001 report of the National Bioethics Advisory Commission (NBAC, 2001b).

Recommendation 8.1: Federal law should require that all clinical research involving infants, children, and adolescents be conducted under the oversight of a formal program for protecting human participants in research.

The committee recognizes that legitimate questions exist about the federal government’s authority to require such oversight. Thus, it also encourages state governments to exercise their authority to regulate research—but to do so in ways that are consistent with federal policies and compatible with multicenter studies.

ROLES AND RESPONSIBILITIES

Because the relationship between the investigator and the research participant is so critical to participant protection, this section begins with a summary discussion of the roles and responsibilities of investigators who conduct research involving infants, children, or adolescents. The discussion then turns to the roles and responsibilities of IRBs and research institutions. Later sections consider the roles and responsibilities of federal agencies and research sponsors.

Investigators and the Research Team

[In addition to participants’ knowledge that they are participating in research], there is the more reliable safeguard provided by the presence of an intelligent, informed, conscientious, compassionate, responsible investigator.

Henry Beecher, 1966, p. 1360

As observed by Edmund Pellegrino (1992), this statement by Henry Beecher serves as a definition of “the character traits of the morally responsible investigator” (p. 1). In clinical research, the investigator has the ultimate responsibility for ensuring the safety, rights, and welfare of individuals participating in research and for seeing that all members of the research team meet the requirements for valid, ethical research. This is the case whether the investigator has a major role in designing the research or uses a design developed by a research sponsor or others. Likewise, he or she is responsible for the safety and welfare of child participants in research, whether the study includes only children or also includes adults.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

Box 8.1 summarizes some of the major responsibilities of clinical investigators who conduct research that includes infants, children, or adolescents. To varying degrees, research institutions, sponsors of research, and regulators understand—or should understand—that investigators’ success in fulfilling their responsibilities depends significantly on supportive administrative, financial, educational, and other systems, both local and national. The infrastructure provided by these systems should extend from the initial education of investigators through the eventual dissemination of research findings and likewise should encompass all relevant settings and types of practice.

BOX 8.1
Key Responsibilities of Investigators for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents

  • Achieve and maintain appropriate training, credentials, and skills to perform or supervise all clinical and research procedures required for a study that includes children.

  • Achieve and maintain appropriate training and knowledge to meet the ethical and regulatory requirements for conducting research that includes children.

  • Ensure that research protocols involving children conform to ethical and scientific standards for such research.

  • Submit proposals and proposal amendments for scientific and ethical review and approval before beginning or modifying research and, as required, during the course of research.

  • Conduct the study in accord with the approved protocol.

  • Disclose potential conflicts of interest to appropriate parties.

  • Ensure that the processes for securing parents’ permission and children’s assent to research participation meet ethical and regulatory standards and are effective and active through the duration of the study. Provide rationale and propose appropriate protections consistent with federal and state laws if a waiver of parent permission is sought.

  • Communicate with children participating in research in developmentally appropriate ways and with guidance from their parents about what will happen to them throughout the course of the research.

  • Support appropriate safety monitoring and reporting of adverse events.

  • Report protocol violations, errors, and problems as required to research sponsors, regulators, or IRBs.

  • Disclose research results to the scientific community and the public.

  • Communicate research results, as appropriate, to research participants or participant communities.

SOURCE: Adapted from IOM, Responsible Research: A Systems Approach to Protecting Research Participants. Washington, D.C.: National Academy Press, (2003a, Box 4.1).

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

The committee commends recent efforts by research institutions, sponsors, and federal agencies to strengthen education in research ethics for investigators. Unless an educational program is narrowly tailored to investigators who will not study children, it should specifically cover ethical principles and standards for the conduct of research involving children.

Pellegrino and others have argued that ethical values, behavior, and character can be taught to clinicians and researchers, although this can be challenging when the surrounding environment is, in some respects, not friendly to these values and virtues (see, e.g., Pellegrino, 1992; Ludmerer, 1999; and Siegler, 2002). Again, this challenge underscores the importance of having a supportive system to stand with and behind the ethical investigator. For example, given the special ethical responsibilities of pediatric investigators and the critical need for studies that contribute to generalizeable knowledge to improve children’s health, these investigators may face a serious ethical dilemma if research sponsors seek to prevent or limit publication of their findings. Consistent with the IOM report Responsible Research (2003a), research institutions should help investigators avoid such dilemmas by approving contracts with research sponsors only if they provide for public disclosure of the findings from properly conducted research. The next section of this report suggests other ways in which IRBs and research institutions, in particular, can make it easier for researchers who study children to know and to do what is ethically and scientifically responsible.

As discussed in Chapter 2, it is also important to have sufficient numbers of pediatric investigators who have the necessary preparation to design and conduct valid and ethical research involving infants, children, and adolescents. The National Institutes of Health (NIH) and pediatric professional societies have taken steps to strengthen the education of pediatric investigators, and these efforts should be sustained.

Recommendation 8.2: To strengthen the base of qualified pediatric clinical investigators, federal and state policymakers and research institutions should support

  • education in the fundamentals of pediatric clinical research, including research ethics, in all educational programs for pediatric subspecialists and

  • additional advanced education in pediatric clinical research, including research ethics, for those who seek careers in this field of research.

Although professional societies are not normally considered to be part of the system for protecting human participants in research, they too have a role to play in developing ethical standards for human research and helping clinical investigators understand and uphold these standards in practice.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

Thus, it is important for organizations such as the American Academy of Pediatrics, the Society for Pediatric Research, and the Society for Adolescent Medicine to remain attentive not only to the need for research but to the need for continued vigilance in protecting infant, child, and adolescent participants in research.

Institutional Review Boards and Research Institutions

IRBs are the cornerstone of a system in which other entities, such as research sponsors, also have obligations to protect research participants.

Institute of Medicine, 2003a, p. 70

Much of the administrative infrastructure and activity that contribute to competent and ethical IRB and research institution performance will support equally the protection of adult and child participants in research. Beyond this foundation, however, both the research institutions that conduct research involving children and the local, central, or independent IRBs that review such research have further ethical and legal responsibilities that demand special attention. Box 8.2 summarizes these responsibilities, which begin with educating IRB members, investigators, and others about their ethical and legal responsibilities for protecting child participants in research.

The effective performance of IRB responsibilities can be threatened by the accretion of additional responsibilities for activities such as managing institutional risk related to research activities, assessing potential investigator or institutional conflicts of interest, and overseeing institutional compliance with a range of other research-related policies. Given the magnitude of the tasks involved in effectively overseeing the ethical aspects of human research, research institutions will best promote the objectives of this oversight by assigning other tasks to units other than the IRB as recommended in Responsible Research (IOM, 2003a). That report also argued for keeping IRBs (what it termed research ethics review boards) focused on the ethical dimensions of human research through the development of “distinct mechanisms” to provide separate, prior reviews of protocols for scientific merit and financial conflicts of interest. The results of these two separate reviews would then inform the final determinations made by the IRB.

Expertise in Child Health and Research

A critical obligation of IRBs is to bring appropriate expertise to the review of research involving infants, children, and adolescents. The federal regulations on children do not, however, explicitly require that IRBs in-

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

BOX 8.2
Key Ethical and Legal Responsibilities of IRBs and Research Institutions Involved with Clinical Research That Includes Infants, Children, and Adolescents

  • Educate IRB members and, as needed, IRB pediatric consultants about the ethical, legal, and scientific standards for approving research involving children and their appropriate interpretation.

  • Educate investigators who conduct research that includes infants, children, or adolescents about their special ethical, legal, and scientific responsibilities.

  • Apply ethical and regulatory standards for the initial and continuing review and approval of research protocols involving children, including careful evaluation and categorization of research risks.

  • Provide for adequate expertise in child health and research in the review of protocols that include children, including assessment of whether those conducting the studies have adequate pediatric expertise.

  • Make available reference materials and resources on research involving children, including information on research ethics, as part of IRB or research administration websites and educational programs.

  • Conduct ongoing assessments to guide improvements in IRB performance in reviewing and monitoring research involving children.

  • Develop explicit policies or guidelines on important topics for which additional guidance to IRB members or investigators is needed (see Box 8.3).

clude a member with such expertise. IRBs with publicly accessible web sites that list members of biomedical IRBs generally show at least one pediatrician member or, less often, a pediatric nurse or other child health expert. The sites usually provide little indication of any formal provisions for securing additional expertise. In the committee’s experience, these provisions are highly variable.

As more children participate in clinical trials and other research, the need is growing for both investigator and IRB expertise in the biological, medical, behavioral, and emotional dimensions of research involving infants, children, and adolescents. Given concerns cited earlier about the adequate supply of trained and experienced pediatric investigators, this can pose an additional challenge for IRBs and research institutions. In some cases, research institutions may have to reach beyond their own boundaries to fulfill their responsibilities, for example, by using outside consultants or referring protocols to IRBs that have the requisite expertise.

IRBs that review research involving children are not the only entities that need expertise in child health and research. As noted in Chapter 3, when a data safety and monitoring board or a data monitoring committee is established to monitor research that involves infants, children, or adolescents, it should include pediatric expertise appropriate for the condition

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

and population included. For certain long-term genetic studies, monitoring bodies may include individuals familiar with the impact of genetic information on the long-term psychological status of children and family members involved in such studies. In addition, as proposed in Chapter 7, agencies that accredit IRBs will require expertise in child health and research to establish standards for IRB review of research that includes children.

The following recommendation focuses specifically on IRBs. It applies to independent, central, and other IRBs as well as local IRBs affiliated with biomedical research institutions.

Recommendation 8.3: Institutional review boards (IRBs) that review protocols for clinical research involving infants, children, and adolescents should have adequate expertise in child health care and research. They should have at least three individuals with such expertise present as members or alternates during meetings in which a research protocol involving children is reviewed. Among them, these individuals—who may be generalists or specialists—should have expertise in pediatric clinical care and research, the psychosocial dimensions of child and adolescent health care and research, and the ethics of research involving children. As appropriate for specific studies, IRBs should consult with other child health experts and with parents, children, adolescents, and community members who can provide relevant family or community perspectives.

Although IRBs that review research protocols involving children can and should rely on consultants to provide additional expertise relevant to particular studies, their own membership should include core expertise in general pediatrics; child development (cognitive, emotional, and social); and the ethical, regulatory, methodologic, and psychosocial dimensions of research involving infants, children, and adolescents. The committee expects that an IRB will require at least three members or alternates with broad pediatric expertise to cover these core areas. Some IRBs may find this difficult and may choose to refer proposals for research involving to children to IRBs that do have the appropriate expertise. A referring IRB should still review proposals for issues related to local conditions and concerns.

An earlier IOM committee recommended allocating one-quarter of the membership of review boards to individuals who are not scientists, not affiliated with the research institution, and able to represent the perspectives of research participants or the community (IOM, 2003a). This committee agrees and further advises that standing pediatric advisory committees and pediatric IRBs include at least one nonscientist, unaffiliated member who can represent explicitly the perspectives of parents and children. (The presence of IRB members who also happen to be parents as well as scientists, ethicists, or clinicians does not suffice.)

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

Depending on the focus of individual protocols, IRBs may also consult with parents and children affected by the condition proposed for study to obtain additional insights and guidance. These community and family perspectives are important for such tasks as comprehensively assessing a study’s potential harms and benefits (including effects on the relevant ethnic and other communities); considering the adequacy of personnel and sites for working with children; and evaluating the provisions for informing families before, during, and after the completion of research (Dresser, 2001). All members of IRBs and advisory committees should be prepared to consider relevant community interests in research that includes children, especially research involving sensitive issues such as genetic predisposition to a disease.

Given the great range of clinical studies involving infants, children, and adolescents, even IRBs that specialize in the review of such studies will need to use consultants because some protocols will present issues outside the expertise of the group’s members. Depending on a study’s focus and setting, consultants may include various kinds of pediatric medical subspecialists, child and adolescent psychologists, child life specialists, pediatric nurses and nurse researchers, and others experienced in the care and study of infants, children, and adolescents with the condition covered by the protocol. Except for certain studies involving older adolescents (e.g., some antihuman immunodeficiency virus [HIV] drug trials), adult subspecialists usually cannot provide appropriate pediatric expertise.

The rosters of pediatric consultants will need to be large enough to provide timely reviews of protocols, consistent with the IRB and institutional workload. The consultants may support multiple IRBs that review all types of biomedical research for institutions operating on that model.

Although many children’s hospitals are part of academic medical centers and have IRBs that focus almost entirely on pediatric studies, some IRBs are associated with general children’s hospitals or medical groups that are not part of academic medical centers and whose personnel have limited direct experience with the design and conduct of pediatric clinical trials or other complex studies involving children. For these IRBs, expertise in trial design and methods may need to be obtained through consultants or the referral of protocols to appropriately constituted IRBs. That is, expertise is required in pediatric research as well as in pediatric medical conditions and clinical care.

Noting the scarcity of expertise in pediatric research in their statement to the committee, the Society for Pediatric Research and American Pediatric Society recommended creating ways to pool pediatric research resources, for example, through regional pediatric advisory committees or review bodies that could assist local IRBs (SPR and APS, 2003). This could be particularly helpful for rural and other institutions that are not part of

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

academic medical centers. Such arrangements could also help institutions cooperate to increase the efficiency of reviews for multicenter studies. Moves in this direction would be assisted by the development of model affiliation or contractual arrangements that deal with liability concerns, costs, and similar practical matters.

IRB Attention to Special Protections for Children

Again, no systematic documentation exists on the extent to which IRB members understand and fulfill their responsibilities in reviewing studies that include children. In considering IRBs’ unique roles and responsibilities, the committee—beyond reference to ethical and regulatory standards—had to rely largely on its members’ judgment and experience, including their participation in such activities as regional and national meetings on human research protection, on-site or telephone consultations with IRB members and administrators, accreditation activities, and discussions of IRB reviews of multisite research projects.

The committee also checked research institution websites to see what they included about research involving children. (Some IRBs restrict access to their web sites to investigators, IRB members, and others affiliated with the institution. No comprehensive listing of relevant, publicly accessible sites is available to allow a systematic sampling.) In an informal review of publicly accessible websites of institutions that conduct research involving children, the committee found that several sites displayed little information or guidance about special requirements related to such research. In some cases, useful institutional information or guidance on research involving children was available but was not easily located or clearly identifiable, for example, in website indexes that provide links to IRB policies, guidance, and other resources. As noted in Chapter 1, the 1978 Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research is widely available on websites, but the committee could not find any site with the Commission’s 1977 report Research Involving Children. It, too, should be accessible through local IRB websites as well as through the websites of the Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA).

Website design is a topic beyond the scope of this study, but the committee encourages IRBs and research institutions to design these sites and other resources so that investigators and IRB members will find it easy to locate policies and guidance related to research involving children. For example, the table of contents of the manual of IRB policies and procedures should identify a section on children. That section either should include all relevant policies and information related to child research or should provide clear cross-references to other sections that contain relevant informa-

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

BOX 8.3
Suggested Elements of IRB and Research Institution Guidance on Clinical Research Involving Infants, Children, and Adolescents

  • Easily identified references and Internet links to DHHS and FDA regulations and guidance specific to children

  • Easily identified descriptions of state policies (including known but not written policies of administrative agencies) relevant to the conduct of research involving children and to minors’ ability to participate in research without parental permission

    • Age of majority statutes

    • Emancipated or mature minor policies and judicial decisions

    • Policies involving wards of the state and foster children

    • Other

  • Clearly labeled checklist of information and requirements for research involving children, including identification of the applicable category of research under 45 CFR 46 Subpart D and 21 CFR 50 and 56

  • Institutional policies or guidance on the qualifications of investigators or other members of the research team

    • Experience with child health care and/or research

    • Role of child health experts in the different components of research

  • Guidance for the scientific rationale sections of protocols involving children

    • Necessity for the research to include infants, children, or adolescents

    • Data from relevant laboratory, animal, and adult studies

    • Data from studies with adolescents or older children prior to studies with infants or younger children

tion. State policies on emancipated and mature minors should be cited in the sections of IRB manuals that discuss parental permission and children’s assent. To underscore the special ethical character of parents’ permission and children’s assent, policy manuals and other resources should use those terms rather than the term informed consent.

Box 8.3 lists information specific to the responsible conduct of research involving children that should be easily identifiable among the resources for investigators and IRB members provide by research institution and IRBs. More generally, institutions and IRBs may also wish to check the recently updated guidelines from the Council for International Organizations of Medical Sciences (CIOMS, 2002) discussed in Chapters 1 and 3. The guidelines include a particularly detailed appendix that lists information and explanations that should be included in a human research protocol (or associated documents). Such lists and other tools should help increase the

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×
  • Rationale for placebo-controlled trial

  • Other criteria related to federal regulations

  • Policies and guidance (national and local) for parental permission and child assent processes

    • Provisions of regulations for permission and assent

    • Role, when appropriate, of independent permission or assent monitors, taping of permission or assent discussions, avoidance of children as translators, and other steps to improve processes for seeking permission and assent

    • Criteria for the waiver of parental permission and provisions for appropriate safeguards

    • Other institutional policies or guidance related to the permission process

    • Minimum suggested age for seeking child assent

    • Provisions for adolescent consent rather than assent

    • Policies on age-appropriate methods of documenting assent

    • Sample age-appropriate assent forms or scripts

    • Other policies or guidance related to the assent process

  • Policies and guidance (national and local) on

    • Payments to children or parents related to research participation

    • Advertising of studies that include children

    • Payments to physicians for enrolling children in studies

  • Appropriate expertise on data and safety monitoring boards or data monitoring committees for studies involving children and policies on establishment of such boards or committees, even when not required, for studies involving more than minimal risk

  • Guidance on data access and publication provisions in contracts with commercial research sponsors of research that includes children

efficiency of the review process by helping investigators submit protocols that do not have be returned because they lack essential information and explanations (e.g., why a protocol providing a waiver of parental permission is justified).

Perhaps more troubling than difficulties in locating information, some institutions (including some children’s hospitals) have protocol checklists or application forms that include no items specific to protections for child research participants (and no obvious alternative document with the relevant items). Other institutions have forms that omit certain elements in the federal regulations (e.g., that research involving a minor increase over minimal risk and no direct benefit must be likely to generate vital knowledge about the child’s disorder or condition). Failure to include such elements may increase the likelihood that not only investigators but also IRB reviewers will overlook some required protections for children.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

As described in Chapter 7, federal agencies have found deficiencies in IRB practices related to research involving children, particularly in the description of the basis for IRB decisions in the meeting minutes. In addition to improving guidance for investigators, IRBs can—as recommended in Chapter 4—strengthen their own evaluations by preparing more complete written explanations of the bases for their judgments about protocols, particularly protocols that raise complex scientific and ethical questions.

Although deficiencies in IRB minutes may reflect poor documentation rather than inadequate analysis, it may also signal inattention by the IRB and research institution both to their responsibilities for assessing research involving children and to the specific regulatory requirements for the approval of such research.1 Protocol checklists or approval application forms that include items or attachments specific to research involving children help highlight—for reviewers as well as investigators—the ethical and regulatory standards for approving and conducting such research.

Recommendation 8.4: For their policy manuals, websites, and other resources, institutional review boards (IRBs) and research institutions should provide easily understood and easily located information that directs investigator and IRB member attention to the ethical principles and special regulatory requirements that apply to the conduct and review of research that includes infants, children, and adolescents.

Box 8.4 provides an example of the items related specifically to children that might be included in a protocol checklist or application form or provided as an easily identified attachment. Depending on the other information and support readily available to investigators, an IRB and research institution might opt for a shorter form that emphasizes the risk categories.

Development of Supplementary Institutional Policies and Guidance

IRBs, research institutions, and research sponsors must pay meticulous attention to federal regulatory requirements relating to research involving children, provide information and education about these requirements, and establish administrative systems that support adherence to the requirements. Beyond these fundamentals, however, IRBs, research institutions, and re-

1  

One study that investigated IRB requirements for consent forms concluded that the inclusion by an IRB of recommended provisions for the use of biological samples was associated with higher volume of protocols reviewed by the IRB and with reliance by the IRB on the 1999 National Bioethics Advisory Commission report on biological samples and the 1993 DHHS manual for IRBs (White and Gamm, 2002).

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

BOX 8.4
Example of Protocol Checklist for Investigators That Highlights Requirements for IRB Approval of Research Involving Children

Purpose: To direct the attention of investigators and IRB members to the ethical and regulatory standards for research involving children, this checklist asks investigators to answer the following questions about their research. The items in this checklist supplement those included in the general protocol checklist. The text of protocols should include appropriate explanations.

Level of Risk: Please check the level of risk presented by the research and note the associated conditions and the requirements for additional information and for parental permission and child assent. See additional requirements and guidance on permission and assent in Section x. See also requirements and guidance related to minimization of risk and other investigator responsibilities at Section y.

___Minimal Risk research that does not involve risk (potential for physical, emotional, social, or similar harm) greater than that encountered by average, normal, healthy children during daily life or during the performance of routine physical or psychological examinations or tests.

Only one parent or the legal guardian needs to give permission.

Child’s affirmative assent is required for children capable of providing it.

Please describe:

What are the processes for obtaining parental permission and children’s assent?

___Greater than Minimal Risk research that holds out the prospect of direct benefit to the child.

Only one parent or the legal guardian needs to give permission.

The child’s assent is not a requirement if the prospect of direct benefit is important to the child’s health or well-being and is available only in the context of the research.

Please explain:

What is the evidence or other basis for proposing that this research has the prospect of direct benefit?

How is the risk presented by the research justified by the anticipated benefit to the children?

How is the relation of the anticipated benefit to the risk at least as favorable to the subjects as that presented by available alternative approaches?

What earlier studies (e.g., involving adults) support the initiation of research with children?

What are the processes for obtaining parental permission and children’s assent?

What is the process if the child dissents?

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

___Minor Increase over Minimal Risk research that does not hold out a reasonable prospect of direct benefit to the child but is likely to yield generalizeable knowledge about the child’s disorder or condition.

Both parents or legal guardians (if there is more than one guardian) must give permission unless one parent or guardian is deceased, unknown, incompetent, or not reasonably available or does not have legal responsibility for the custody of the minor.

The child’s affirmative assent is required for children capable of providing it.

Please explain:

In what ways does the research involve a minor increase over minimal risk but not more than that?

In what ways do the procedures involved in the research involve experiences commensurate or similar to experiences inherent in the child’s actual or expected medical, dental, psychological, social, or educational situations?

In what ways is the research likely to yield generalizeable knowledge about the children’s disorder or condition that is of vital importance for understanding or ameliorating the disorder or condition?

What are the processes for obtaining parental permission and children’s assent?

___Other research that does not fit the categories above and is therefore not otherwise approvable but that presents a reasonable opportunity to understand, prevent, or alleviate serious problems affecting the health or welfare of children.

Both parents and legal guardians (if there is more than one guardian) must provide permission.

The Secretary of the U.S. Department of Health and Health Services or the Commissioner of the Food and Drug Administration must approve the research.

Please explain:

Why does this research not fit the categories listed above? In what ways is this research likely to generate knowledge that is vitally important to understanding, preventing, or alleviating a serious problem affecting children’s health or welfare? (Note: This IRB considers protocols in this category using the same standard for potential contribution to knowledge as it applies to research involving a minor increase over minimal risk.)

Other special considerations or requirements in research involving children.

Please check as appropriate. The research involves

___Foster children or wards of the state

___Waiver of parental [one or both] permission for some or all of the participants

___Research sites suitable for age groups included in the study

___Research team with pediatric experts appropriate for the age groups included in the study

SOURCE: Adapted from forms used by Children’s Hospital Boston, and Vanderbilt University.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

search sponsors can support responsible research by developing supplementary policies and guidance that further define or clarify ethical research practices. Box 8.3 above suggested several topics for such policy development, including policies on payment related to research participation and processes for seeking permission and assent.

Although it should be brought up to date in some areas, the 1993 IRB manual developed by the Office for Protection from Research Risk, the predecessor of OHRP, provides useful starting points for consideration by IRBs and research institutions (OPRR, 1993). Earlier chapters of this report have also suggested or recommended topics for supplementary IRB policies or guidance.

Review of Multicenter Protocols

As discussed in Chapter 2, multicenter clinical trials have a particularly important role in pediatric studies given the low prevalence of many serious medical conditions in children. Investigators and research sponsors involved in such studies have expressed considerable frustration with the time required to secure approval from IRBs at each study site, especially in view of the considerable variation among IRBs in the time from submission of a protocol to the time of approval of that protocol. For example, in a statement to the committee, the Children’s Oncology Group noted that the time to IRB approval for trials under their auspices varies from 4 weeks to more than a year (COG, 2003). Another source of frustration is the variability among IRBs in their decisions or directions about such matters as study design, assent and permission forms and procedures, and assessment of research risks.

Particularly for clinical trials, frustration may be multiplied because research protocols often have already been reviewed by an NIH study section and one or more scientific committees of a cooperative trials group or other research network.2 A protocol may also be reviewed following IRB approval by committees at institutional General Clinical Research Centers. All may consider ethical and legal issues in their reviews, although that is not the central purpose of these reviews. The IRB is the entity distinctively accountable for reviewing a proposed study’s compatibility with ethical standards and federal regulations on the protection of child participants in research.

2  

NIH no longer requires IRB approval before peer review, although a grant cannot be awarded without such approval (NIH, 2000b). Individual NIH institutes may decide that certain categories of research require IRB approval before submission of an application. Peer reviewers are to consider protections for human research participants in their reviews.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

Several studies have reported considerable variability in IRB decisions about research protocols (see, e.g., Burman et al., 2001, 2003; Silverman et al., 2001; Stair et al., 2001; Hirshon et al., 2002; and McWilliams et al., 2003). As additional examples of variability, Tables 8.1 and 8.2 report selected results of IRB reviews of two protocols for multicenter clinical trials conducted through the Cystic Fibrosis Therapeutics Development Network (Ramsey, 2003). Both trials included adults as well as children. For one protocol involving an early-phase study of the safety and tolerability of an oral pancreatic enzyme product, the time to IRB approval for nine IRBs ranged from 3 to 18 weeks with a median of 5 weeks. Six IRBs gave full approval for the enrollment of children as planned; three IRBs approved the study for adult participants only, although one gave approval to include children following appeal. For a second protocol for a randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetics of an anti-inflammatory agent in adult and child patients, four of seven IRBs gave full approval whereas three approved the research for adult participants only. Of the IRBs giving full approval, three categorized the research as involving a minor increase over minimal risk and no direct benefit, but one categorized it as involving more than minimal risk with the prospect of direct benefit.

To cite another example, the REACH (Reaching for Excellence in Adolescent Care and Health) project of the Adolescent Medicine HIV/AIDS Research Network published its experience with IRB determination of risk among 11 investigational sites as reported by site investigators (Rogers et al., 1999). The study involved adolescent subjects between 12 and 18 years of age who were either HIV positive through either sexual activity or drug use or who were HIV negative but engaged in high-risk activity. The objective was to examine the progression of HIV while controlling for the comorbidity of other sexually transmitted diseases. The study procedures included face-to-face interviews, a computerized interview (site blinded), laboratory analysis of clinical samples (blood, urine, blinded drug screen), physical examinations (including gynecological and urogenital examinations), and a wrist radiograph to determine bone age. All REACH sites had a certificate of confidentiality (see Appendix C) from the federal government. The blood volume to be drawn was 100 milliliters (ml) at baseline and annually, 60 ml at 3 and 6 months, and 80 ml at 6 months for HIV-positive subjects and approximately 60 ml at baseline and annually and 50 ml at 6 months for HIV-negative subjects. Four IRBs considered the protocol to present no greater than minimal risk, while one considered it greater than minimal risk. One judged it to present greater than minimal risk for HIV-negative subjects only, and two additional IRBs required changes in order to consider the protocol to be minimal risk. One imposed a screen for anemia prior to blood draws, and the other required that the wrist x-rays

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

TABLE 8.1 Example 1—Variability in IRB Approval of a Multicenter Research Protocol That Includes Children

Site

IRB Approval Time (wks)

Full Approval

Modified Approval

Comments or Issues

A

7

X

 

 

B

3

X

 

Approval under Section 406

C

3

X

 

 

D

9

 

≥ 18 yrs onlya

The IRB was unable to determine if this research fit into any of the required categories because information about the study drug was not sufficient to determine the risk to the subjects. The research was not approved for children.

E

4

X

 

 

F

16

X

 

Approval under Section 406.

G

3

X

 

 

H

10

 

≥ 18 yrs only

1. Lack of available data from studies with healthy volunteers; approved only for individuals ≥18 years of age.

2. Individuals 13 to 18 years will be approved in the future, pending a safety review.

3. Clarify how financial reimbursement is distributed between child and parents.

I

18

 

≥ 18 yrs only

The proposed research activity involves patients between the ages of 13 and 45 years. The IRB cannot approve the research for patients younger than age 18 years because of the level of risk for this group.

aThe application to the IRB was withdrawn because the pediatric cohort was filled.

SOURCE: Ramsey (2003).

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

TABLE 8.2 Example 2—Variability in IRB Approval of a Multicenter Research Protocol That Includes Children

Site

Full Approval

Modified Approval

Comments/Issues

A

 

≥18 yrs only

Greater than minimal risk without direct benefit; not approvable for children

B

 

≥18 yrs only

Pediatric approval under 45 CFR 46.406 only after review of safety data from studies with adults

C

X

 

Approved under 45 CFR 46.406, but blood draws must be <5% of total blood volume

D

X

 

Minor increase over minimal risk; both parents must sign (under 45 CFR 46.406)

E

X

 

Minor increase over minimal risk; information gained would contribute to generalizable knowledge

G

 

≥18 yrs onlya

Board deferred approval of the participation of pediatric patients (ages 6 to 17 years) until more information about the effects of the study drug on children becomes available.

I

X

 

Greater than minimal risk but direct benefit (under 45 CFR 46.405); both parents must provide permission

aThe IRB application was withdrawn because the pediatric cohort was filled.

SOURCE: Ramsey (2003).

for bone age be deleted for HIV-negative controls (as a condition for waiver of parental permission).

In addition to being frustrating and sometimes costly, inconsistency in IRB judgments may raise ethical concerns. For example, when different IRBs reach different conclusions about research risks or potential benefits and place different conditions on studies, might some children be exposed to higher than acceptable levels of risk? Alternatively, might some children be denied participation in potentially beneficial research?

To some extent, the variability in IRB judgments reflects the uncertainties inherent in (and the reason for) much clinical research. It may also reflect, as discussed in Chapter 2 and 4, the limited data on the less-than-

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

mortal but possibly more-than-minimal harms and discomforts that children may experience from common procedures used in research.

In addition, reasonable people may disagree about how much risk a protocol presents. Chapter 4 made clear that many of the key concepts applied in reviews of research have a substantial subjective component that will lead to variations in decisions, although clearer definitions and education may reduce some of these variations. Furthermore, some variability can be traced to the lack of precision in the regulations themselves (as reviewed in Chapter 4) and the lack of reviewer education about special standards for research involving children. Differences in local culture and institutional policies sometimes play a role. Variability may also be a function of reviewers’ lack of expertise in child health care and research. Efforts to improve efficiency should not neglect the need for reviewer education and appropriate pediatric expertise (as recommended above), whether reviews are local, regional, or central.

In some cases, quick IRB approval with no questions asked may be the outcome of an efficient, expert review process. Alternatively, quick approval may sometimes result from a cursory review that does not adequately consider the criteria for approving research involving children, including the risks posed to children. Such an approval may be a relief to investigators and research sponsors but represents a departure from ethical and regulatory standards.

Several groups have proposed steps to change the review of multicenter studies. For example, another IOM committee recently recommended that “[o]ne primary scientific review committee and one primary Research Ethics Review Board should assume the lead review functions [for multicenter studies], with their determinations subject to acceptance by the local committees and boards at participating sites” (IOM, 2003a, p. 102). As described by the earlier committee, acceptance could be refused for serious safety concerns or unique local circumstances.

The National Cancer Institute (NCI) and OHRP are testing a central review model for oncology clinical trials. The central IRB (CIRB) reviews all protocols and then posts the results of each review on its web site along with other relevant information. As described by NCI, “local IRBs have the option to accept the CIRB approval ‘as is,’ accept it with de minimus modifications3 … or they may decide not to accept the CIRB review and require that the investigator submit the protocol for full Board review at their site” (NCI, 2003).

3  

As part of a “facilitated review,” the local IRB may not delete or contradict elements in a protocol approved by the CIRB, although safety related “stipulations” may be added. Also, certain kinds of local “boilerplate” changes may be considered for inclusion in consent documents to accommodate state or local laws and in certain other cases.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

Regardless of the model, central or regional review could be counter-productive for research involving infants, children, or adolescents unless the review organization possesses expertise sufficient to its responsibilities in assessing such research. A critical goal of any streamlined review process should be not only to reduce inefficiency and unproductive redundancy but also to reduce the inexpert review of research involving children and, thereby, improve the quality of reviews.

A different strategy for improving consistency and efficiency in IRB review was taken in an NIH grant-funded project to establish a voluntary national IRB database and information system by use of a secure Internet site (IRBnet, 2003). The primary goals were to (1) support communication among IRBs and investigators and (2) provide standardized guidance for investigators in developing protocols, including protocols involving children. The project will allow the centralized distribution and review of protocols and consent, assent, and permission forms from multiple centers. It will also support the sharing and updating of information about IRB decisions and other developments.

Recommendation 8.5: The federal government, research institutions, research sponsors, and groups of institutional review boards should continue to test and evaluate means to improve the efficiency as well as the quality and consistency of reviews of multicenter studies, including those involving infants, children, and adolescents.

Again, any streamlining strategy that extends to research involving children should be attentive to the special ethical and regulatory requirements for such research. It should provide for expertise in child health and research that is consistent with Recommendation 8.3 and the accompanying discussion. It should also be attentive to the qualifications and characteristics of local investigators and research sites as discussed in Chapter 4. One argument for retaining a meaningful role in protocol review for local IRBs is that a local process seems more likely to engage and educate investigators in the ethical conduct of clinical research, for example, through service as an IRB member or presentation of protocols at an IRB meeting.

Furthermore, the process for reviewing multicenter protocols should become more efficient if, as suggested earlier in this chapter, research institutions and IRBs provide investigators with more specific and easily located guidance on the standards for research involving children. As an anonymous reviewer of this report wrote, “[i]f the local [investigator] is not provided with the tools to make a good and thoughtful IRB application, he will only do so if he’s extremely process-savvy. It’s not the least bit surprising that IRB responses are all over the proverbial map [for multicenter studies], if the quality of applications [for IRB review] is all over the map.”

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×
Sharing Information About IRB Decisions

Although reports are mainly anecdotal, research sponsors are said on some occasions to engage in IRB “shopping.” This practice may involve choosing research sites on the basis of expectations about the rigor of IRB review. It may also mean submission of a protocol disapproved by one IRB to another IRB without disclosure of the previous decision. A 1998 study by the DHHS Office of the Inspector General raised concerns about this practice based on interviews involving six university-based IRBs (OIG, 1998b). Citing similar concerns, the FDA issued an advance notice of proposed rulemaking in 2002 to obtain information on IRB practices for the purposes of determining whether investigators and research sponsors should be responsible for disclosing to an IRB the results of any IRB decisions made previously (FDA, 2002b). It also asked for information to help it assess how extensive the problem of IRB shopping was. As of the end of 2003, no final rule had been issued.

This committee believes that the sharing of information about IRB decisions—especially the specific rationales for decisions—would be helpful to IRBs involved in the review of multisite protocols. The NIH project to create a national IRB database (cited earlier) has information sharing as one feature. A narrower approach would involve the posting of information on a sponsor’s website listing IRBs that had reviewed or would be reviewing a protocol, the results of the review, the decision outcome, the date, and a contact person at each IRB (Nelson, 2002). IRBs reviewing the same protocol could then query other IRBs to learn, for example, their rationales for negative decisions or modifications. The committee encourages a test of this strategy with a set of NIH-supported or FDA-regulated studies that include children. In addition, the committee encourages the FDA to share the results of its audits of investigators and research sites with the relevant IRBs.

Federal Agencies

For approximately a half century, the federal agencies responsible for conducting and sponsoring biomedical research and for regulating medical products have—sometimes directed by the U.S. Congress—played a major role in developing policies to protect human participants in research. In recent years, they have paid increasing attention to the application of those policies by investigators, IRBs, and research institutions and to the education of these parties about their responsibilities. Federal agencies have also taken some steps to collect better information to guide the evaluation and improvement of system performance.

Box 8.5 summarizes some of the key responsibilities of federal agencies. Although this report has focused primarily on the activities of OHRP and

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

BOX 8.5
Key Responsibilities of Federal Agencies for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents

  • Provide and promote educational programs for investigators, IRBs, research institutions, and research sponsors on regulations related to research involving children

  • Develop additional policy guidance for investigators, IRBs, research institutions, and research sponsors about the application of regulations related to research involving children

  • Monitor and enforce compliance with regulations

  • Define and collect the data needed to oversee, evaluate, and improve performance nationally and locally and to develop or revise policies

  • Report on system goals and performance to policymakers and the public

  • Support innovative projects to improve efficiency, reduce inappropriate variability in practices and decisions, and evaluate the effectiveness of policies to protect child participants in research

  • Promote cooperation among the government agencies responsible for conducting, funding, and overseeing human research to provide consistent incentives for ethical research conduct and reduce duplicate or conflicting requirements or policies related to research involving children

FDA, other agencies, notably NIH, also have roles to play in promoting the protection of human research participant. NIH, for example, has funded research on decision making about children’s participation in research. Furthermore, NIH and other agencies also have important responsibilities for other aspects of ethical research conduct related to research participant safety, privacy, and conflict of interest.

Education and Guidance for IRBs and Investigators

Beyond the regulations themselves, the resources made available by OHRP and FDA strongly shape if not dominate local IRB policy manuals and resource links. Although the 1993 IRB Manual and other resources provide some information and guidance about research involving children, the OHRP website does not make it easy to locate resources related to research involving children. For example, under the heading “Policy Guidance,” the list of topics does not specifically mention children. The OHRP home page recently added a link to the regulations governing children’s participation in research (http://ohrp.osophs.dhhs.gov). OHRP’s list of guidance materials includes neither the 1977 report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

Research on research involving children nor any other identifiable document on this topic. The agency’s website should include links to both that report and the reports of the National Human Research Protection Advisory Committee. It should make all resources related to research involving children easy to identify and locate.

In contrast to the dearth of easily located OHRP resources related to research involving children, the FDA provides considerable information and guidance through the website for its Division of Pediatric Drug Development (http://www.fda.gov/cder/pediatric).4 The site lists and has links to the FDA’s interim regulations on safeguards for children in clinical investigations. It likewise lists and has links to the agency’s official guidance on pediatric drug research (i.e., the ethical and scientific guidelines for pediatric research developed by the International Conference on Harmonisation [FDA, 2000b; ICH, 2000b]).5

In addition to OHRP and FDA, other agencies that fund or oversee research that includes children should examine their guidance for the ease with which special considerations in the design, conduct, and oversight of such research can be identified. These other agencies include, for example, the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health. For requirements and topics that they have in common, agencies should also cooperate to provide guidance that is consistent in content.

Recommendation 8.6: The Office for Human Research Protections, the Food and Drug Administration, the National Institutes of Health, and other agencies with relevant responsibilities that include research involving children should each provide—in an easily identifiable document or set of linked documents—comprehensive, consistent, periodically updated guidance to investigators, institutional review boards, and others on the interpretation and application of federal regulations for the protection of child participants in research.

The recent efforts by the federal government to strengthen education in research ethics are an important positive step. These efforts include some workshops and programs devoted specifically to research involving children. OHRP, the FDA, and other agencies should cooperate in the contin-

4  

The division is part of the Office of Counter-terrorism and Pediatric Drug Development within the Center for Drug Evaluation and Research. The FDA also has an Office of Pediatric Therapeutics within the Office of the Commissioner.

5  

Guidance from other FDA centers is not so easy to locate. For example, the draft guidance on premarket approval of pediatric medical devices from the Center for Devices and Radiologic Health can be found using the “A to Z Index” for the Center’s website, but the agency’s home page and links do not mention children.

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

ued development of such educational programs at the national level for use at all levels by government agencies, research institutions, pediatric academic societies, and other groups. For example, in its statement to the committee, the Society for Pediatric Research noted its eagerness to play a role in disseminating such educational programs (SPR and APS, 2003).

In addition to formal educational programs for investigators and IRBs and the development of up-to-date and easily located guidance for investigators, the committee encourages OHRP to continue to invest in its quality improvement initiative, with attention to the special requirements and challenges of research involving children. For IRBs and research institutions seeking to improve their programs for protecting child research participants, the availability of consultation and other support from OHRP can be valuable both to the local institution and to agency staff in enlarging their appreciation of the various environments in which these programs operate.

Protocols Referred to the Secretary of DHHS

As described in Chapters 3 and 4, under Section 407 of 45 CFR 46, IRBs can refer research proposals to the Secretary of DHHS for review and approval when they find that the proposals are ineligible for approval under other sections of the regulations (Sections 404, 405, and 406) and also appear to offer a “reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.” Section 54 of 21 CFR 50 similarly provides for the referral of protocols for review by the Commissioner of the FDA.

In Chapter 4, the committee recommended that those reviewing protocols referred to the Secretary or the Commissioner for review should apply the criterion of “vital importance” in judging the potential contribution to knowledge that could result from the proposed research. It argued that the standard for approving these otherwise-not-approvable protocols should not be weaker than the standard applied to protocols that present more than a minor increase over minimal risk, offer no prospect of direct benefit, and involve children with a disorder or condition.

Box 8.6 lists examples of protocols that have been referred for Section 407 reviews (and, in one case involving a smallpox vaccine, for joint DHHS and FDA review under 21 CFR 50.54). OHRP has returned some protocols on the basis of staff determinations that they clearly do not fit the criteria for referral under Section 407. Issues related to at least two protocols referred to the FDA were resolved before the protocols proceeded to a review panel (David Lepay, M.D., Ph.D., Food and Drug Administration, personal communication, December 15, 2003).

Recently, DHHS has moved to improve significantly the process for reviewing research proposals that IRBs have referred to the Secretary under

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

BOX 8.6
Examples of Protocols Referred for Review by the Secretary of DHHS Under 45 CFR 46.407, by Year of Referral and Institution

1991

The New England Medical Center Hospital: Study of myoblast transfer in Duchenne muscular dystrophy. Not approved but few details are publicly available. (56 FR 49189)

1993

Children’s Hospital of Pittsburgh: Proposed study of cognitive function and hypoglycemia (generated through the use of an insulin clamp) in children with insulindependent diabetes mellitus. Approved. (58 FR 40819)

2001

University of Washington: Study of precursors to diabetes in Japanese-American youth. Public comment on departmental recommendation for approval initially requested August 7, 2002 (67 FR 51283-51284). Reopened for public comment in December, 2002 (67 FR 77495). No final decision from the Secretary of DHHS. (http://ohrp.osophs.dhhs.gov/pdjay/pdjayindex.htm)

2002

Harbor-UCLA Medical Center: Test of dilute smallpox vaccine in children ages 2 to 5. Disapproved by the Secretary of DHHS and the Commissioner of FDA for reasons related to expected lack of availability of the vaccine and not to Subpart D requirements.

(67 FR 66403; http://ohrp.osophs.dhhs.gov/dpanel/dpindex.htm)

2003

University of California, Los Angles: Longitudinal study of prolonged HIV infection, antiretroviral therapy, and thymus performance involving comparisons between infected and noninfected children. No final decision from the Secretary of DHHS.

(68 FR 42061; http://ohrp.osophs.dhhs.gov/panels/407-04pnl/pindex.htm)

University of North Carolina: Longitudinal study of newborn infants with cystic fibrosis involving flexible fiber-optic bronchoscopy and procedural sedation. No final decision from the Secretary of DHHS.

(68 FR 35414; http://ohrp.osophs.dhhs.gov/panels/407-02pnl/pindex.htm)

Albert Einstein College of Medicine: Study of the role of metabolism in sleep mechanisms in adolescents. No final decision from the Secretary of DHHS.

(68 FR 35415; http://ohrp.osophs.dhhs.gov/panels/407-03pnl/pindex.htm)

Rhode Island Hospital: Study of the effects of small to moderate amounts of alcohol on sleep, waking performance, and circadian phase. No final decision from the Secretary of DHHS.

(68 FR 17950; http://ohrp.osophs.dhhs.gov/panels/407-01pnl/pindex.htm)

SOURCE: Kopelman and Murphy, (in press) and Office for Human Research Protections (through January 2004).

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

the Section 407 process. By using its website (as well as publication in the Federal Register) to post information and solicit comments about protocols that are under review, the agency has made the process more open to the public and to interested investigators, IRBs, and others. The names and comments of expert reviewers can be read as can other key documents, which may include the initial application for IRB review of the protocol, excerpts from the minutes of the reviewing IRB(s), and relevant correspondence. Previously, it was very difficult to get information even with a Freedom of Information Act request.

The committee commends OHRP for the steps that it has taken to improve the efficiency, effectiveness, and openness of the Section 407 process. It also encourages further reforms. The current process solicits comments from experts but does not provide for the experts to discuss and refine their views, consider and perhaps resolve disagreements, or present their views coherently as a group. A better alternative would be to create a standing Section 407 panel that would meet as needed to consider referred proposals (using topic-specific consultants as appropriate). Although ad hoc panels can provide expert reviews, they do not accumulate experience and insight in the way that a continuing panel would be able to do.

The committee was encouraged that the new Secretary’s Advisory Committee on Human Research Protections has identified as one of its priorities the development of recommendations for improving the Section 407 process. The group will consider whether it should constitute a subgroup of the full committee to serve as a standing Section 407 advisory panel.

Recommendation 8.7: The Office for Human Research Protections and the Food and Drug Administration should

  • continue their activities to establish an open and publicly accessible review process for considering research protocols referred by institutional review boards for review under 45 CFR 46.407 and 21 CFR 50.54;

  • create a standing panel that would meet as needed to consider such proposals; and

  • provide detailed guidance on the interpretation of the federal regulations governing research involving children to reduce unnecessary referrals of protocols.

A further concern about the current process is that it is unclear to what extent and for what reasons the agency is declining to consider referred protocols and sending them back to the originating IRB. Committee members are aware of instances of this practice, but the lack of public information deprives IRBs of important insights into agency views and deprives the larger community of interest of the opportunity to evaluate agency deci-

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

sions. The committee urges OHRP to provide more information about returned proposals and its criteria or reasons for returning them.

An open process for reviews under Section 407 combined with more guidance about the interpretation of the regulations, as recommended in Chapter 4, should help reduce referrals by IRBs of protocols that do not fit the criteria for such review. It should also encourage IRBs to refer protocols when truly appropriately rather than avoid referrals by using overly broad interpretations of the terms such as direct benefit, condition, minimal risk, or minor increase over minimal risk.

Policy Development, Guidance, Data Collection, and Research

The most comprehensive policy recommendation in this report calls for all research involving children to be conducted under the oversight of a formal human research participant protection program. A uniform federal policy is preferable but in the absence of federal action, corresponding state action is encouraged. As encouraged earlier in this chapter, all federal agencies that support or conduct research involving children should adopt the provisions in Subpart D of 45 CFR 46.

Most committee recommendations do not call for new or revised regulations. One that does is the recommendation that FDA make its regulations on the waiver of parental permission for a child’s participation in research consistent with those of DHHS.

In general, the recommendations for federal agencies focus on the development of additional guidance for investigators, IRBs, research sponsors, and agency personnel and the collection of additional information to guide the further improvement of policies and programs. In addition to the recommendations in this chapter, the report includes recommendations or suggestions that OHRP, FDA, and NIH—as appropriate given their respective roles and responsibilities—

  • develop procedures for identifying, collecting, and reporting basic data on research involving children to provide one foundation for designing further guidance or education for investigators and IRBs;

  • create a centralized national registry of research trials involving children (including healthy children);

  • provide official guidance for investigators and IRBs based on this committee’s interpretation of minimal risk and other key concepts in the regulations on research involving children;

  • continue work through the Secretary’s Advisory Committee on Human Research Protections to develop consensus assessments of the risk presented by procedures or interventions commonly used in clinical research involving children;

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×
  • cooperate to provide more explicit guidance on both the factors that should be considered in decisions about waiver of parent permission and the safeguards that are appropriate for different situations when parental permission is waived;

  • join with private foundations and advocacy groups to support research on permission and assent processes and information materials;

  • solicit ideas for research that could illuminate the ethical and practical implications of different kinds of payments related to children’s participation in research;

  • harmonize guidance on safety monitoring for research organizations, including the standardization of requirements and practices for reporting adverse events;

  • require that safety monitoring reports be shared with the relevant IRBs to alert them to potential problems with a study under their jurisdictions;

  • prepare additional guidance about the elements that should be included in data and safety monitoring plans and provide that all clinical trials—including those supported by NIH—be monitored with the same degree of rigor and scrutiny; and

  • require that protocols that include children and that involve more than minimal risk have a plan (not necessarily a board or committee) for monitoring the safety of child research participants and also provide that reports based on this plan be made available to relevant IRBs on a timely basis.

Research Sponsors

Research sponsors—both public and private—have crucial ethical and legal responsibilities for the protection of adult and child participants in research. The conditions that they impose or attempt to impose on the recipients of research funding can either support or undermine the ethical conduct of research and the safety of research participants.

Large commercial sponsors of clinical research typically have well-developed policies and programs for designing, implementing, and monitoring human research consistent with federal regulations and, often, international standards. In fact, in the committee’s experience, their monitoring typically exceeds that required or undertaken by government sponsors of research and can serve, in some respects, as a guide to extending oversight by public funders of high-risk clinical studies.

Earlier in this chapter, the committee advised research institutions to approve contracts with research sponsors only if they provide for public disclosure of findings. Research sponsors should likewise refrain from entering into contracts that limit such disclosure. In addition, the committee

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
×

suggested ways in which the sharing of information about IRB decisions and concerns could be improved, for example, by the posting of information about IRB reviews on sponsors’ websites. The results of the FDA investigation of “IRB shopping” by research sponsors may suggest the need for new steps to safeguard the integrity of the system for protecting human research participants.

An important, continuing question about the system for protecting human participants in research involves the costs associated with developing, reviewing, implementing, and monitoring protocols to meet ethical and regulatory standards. As described in another IOM report, “no satisfactory agreement has been reached regarding how the increasing costs of protecting participants should be distributed” (IOM, 2003a, p. 57). That report also notes that recent tragedies and administrative penalties for noncompliance with regulations have prompted significant increases in the resources that research institutions devote to their programs for protecting human research participants. The report commended NIH for providing one-time grants to fund information system and infrastructure improvements. It argued, however, that government agencies should—like private research sponsors—pay directly for initial and continuing IRB review. This committee agrees.

One concern mentioned in Chapter 3 involved monitoring for long-term problems (e.g., the late effects of cancer chemotherapy or irradiation) that arise after research studies are completed. The discussion mentioned the limitations of FDA’s postmarket surveillance strategies, which, in any case, apply only to products approved for marketing by the agency. Research sponsors as well as investigators, IRBs, and relevant government agencies should consider potential late adverse effects of investigational therapies and assess what monitoring, end points, and evaluation plans might be advisable for studies with the potential for such harm.

Reflecting a different concern about research-related harms, the committee recommended in Chapter 6 that research organizations and sponsors should pay medical and rehabilitation costs for children injured as a direct result of research participation, without regard to fault. On another point, the committee recommended that research sponsors not cover finder’s fees to physicians based on the referral of a child for enrollment in a study.

CONCLUSION

Policies and procedures for protecting adult and child participants in research have evolved over several decades, often prompted by public reports of unethical or questionable research practices. That evolution continues as policymakers, IRBs, research institutions, and investigators find shortfalls in their performance and devise strategies to improve the

Suggested Citation:"8 Responsible Research Involving Children." Institute of Medicine. 2004. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press. doi: 10.17226/10958.
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effectiveness and efficiency of the system for protecting human research participants.

Investigators play a central role in the system for protecting child participants in research. Ensuring that they understand their obligations is a high priority as is further work to build an administrative, financial, and information infrastructure that makes it easier for investigators to know and fulfill their responsibilities. IRBs and research institutions can clearly improve their guidance and tools to help investigators design and implement ethically and scientifically sound clinical studies. Similar improvements by government agencies will, in turn, assist IRBs and research institutions as well as investigators.

Government policymakers can also fund research and demonstration projects to expand the knowledge base for strengthening the performance of the system for protecting child participants in research, for example, by testing strategies to improve the quality and consistency of reviews for multisite research projects and reduce unnecessary burdens and frustrations for their investigators and sponsors. Such improvements will not eliminate tensions between the goal of protecting today’s children from research harms and the goal of advancing research that improves the health and well-being of tomorrow’s children. They can, however, help all parties feel more confident that the system for protecting child research participants is trying to identify and remove needless burdens on those who undertake these critical investigations.

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In recent decades, advances in biomedical research have helped save or lengthen the lives of children around the world. With improved therapies, child and adolescent mortality rates have decreased significantly in the last half century. Despite these advances, pediatricians and others argue that children have not shared equally with adults in biomedical advances. Even though we want children to benefit from the dramatic and accelerating rate of progress in medical care that has been fueled by scientific research, we do not want to place children at risk of being harmed by participating in clinical studies.

Ethical Conduct of Clinical Research Involving Children considers the necessities and challenges of this type of research and reviews the ethical and legal standards for conducting it. It also considers problems with the interpretation and application of these standards and conduct, concluding that while children should not be excluded from potentially beneficial clinical studies, some research that is ethically permissible for adults is not acceptable for children, who usually do not have the legal capacity or maturity to make informed decisions about research participation. The book looks at the need for appropriate pediatric expertise at all stages of the design, review, and conduct of a research project to effectively implement policies to protect children. It argues persuasively that a robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular.

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