5
Understanding and Agreeing to Children’s Participation in Clinical Research

My daughter will be nine years old and she needs some kind of input in what’s going on with her… . She’s presently in a study and I need for her to be able to understand what she’s getting herself into… . She’s at the point where she asks a lot of questions … which is good.

Andrell Vaughn, parent, 2003

The quote above shows a mother’s concise, personal appreciation of the values underlying requirements that children be involved, when appropriate, in discussions and decisions about their participation in research. This mother recognizes her daughter’s growing maturity, increasing curiosity, and developing moral right to be involved in choices about “what’s going on” in the context of a close parent-child relationship.

When research involves children such as this 9-year-old, investigators and institutional review boards (IRBs) cannot rely on the conventional concept of informed consent, which applies to decisions about research participation made by those with the legal and intellectual capacity to make such choices in their own right. Children usually lack such capacity. Instead, legal authority to allow a child’s participation in research rests with parents or guardians, who must provide their permission. In addition, with respect for children’s emerging maturity and independence and consistent with federal regulations, investigators—when appropriate—seek to



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Ethical Conduct of Clinical Research Involving Children 5 Understanding and Agreeing to Children’s Participation in Clinical Research My daughter will be nine years old and she needs some kind of input in what’s going on with her… . She’s presently in a study and I need for her to be able to understand what she’s getting herself into… . She’s at the point where she asks a lot of questions … which is good. Andrell Vaughn, parent, 2003 The quote above shows a mother’s concise, personal appreciation of the values underlying requirements that children be involved, when appropriate, in discussions and decisions about their participation in research. This mother recognizes her daughter’s growing maturity, increasing curiosity, and developing moral right to be involved in choices about “what’s going on” in the context of a close parent-child relationship. When research involves children such as this 9-year-old, investigators and institutional review boards (IRBs) cannot rely on the conventional concept of informed consent, which applies to decisions about research participation made by those with the legal and intellectual capacity to make such choices in their own right. Children usually lack such capacity. Instead, legal authority to allow a child’s participation in research rests with parents or guardians, who must provide their permission. In addition, with respect for children’s emerging maturity and independence and consistent with federal regulations, investigators—when appropriate—seek to

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Ethical Conduct of Clinical Research Involving Children involve children in discussions about research and obtain their assent to participation. Although debate continues about the ethical dimensions and boundaries of parental permission and child assent, especially when adolescents are involved, much attention today focuses on more practical questions about how to interpret and implement these concepts and honor their underlying ethical principles in research practice. For example, at what age should investigators, as a general rule, begin seeking a child’s assent? What information and what role in decision making are appropriate for children at different stages of development? How should relationships between children and parents be approached? This chapter considers two elements in the charge to the committee. The first relates to the written and oral process for obtaining assent and permission for research participation from children and their parents, guardians, or other legally authorized representatives.1 The second involves an examination of children’s and parent’s expectations and comprehension of the direct benefits and risks associated with a child’s participation in research and, in particular, their understanding of the distinction between research and treatment. The discussion begins with an overview of the ethical principles and legal requirements for obtaining parents’ and children’s agreement to a child’s participation in research, including circumstances in which minors can make decisions on their own behalf. Next is a review of the literature relevant to parents’ and children’s understanding of research participation, which also covers the general research literature on the development of children’s cognitive and decisional capacities. The last sections of the chapter offer recommendations. ETHICAL PRINCIPLES AND LEGAL REQUIREMENTS The Ethics of Informed Consent, Permission, and Assent For pediatric ethics, informed consent is more properly understood as a combination of informed parental permission and (when appropriate) the assent of the child. Kodish, 2003b, p. 90 As described in Chapter 1, the ethical principle of respect for persons underlies the obligation of investigators to treat individuals as autonomous actors who must provide their informed and voluntary consent to partici- 1   For simplicity, the rest of this chapter will refer only to parents.

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Ethical Conduct of Clinical Research Involving Children pate in research. Requirements for parental permission serve the ethical obligation of investigators to respect and protect vulnerable individuals. Provisions for involving children in discussions about research participation and seeking their assent, when appropriate, attest to respect for children’s developing autonomy. Permission and assent are thus the intertwined foundations of ethical research involving children. Much of the ethical analysis that underlies the principles and processes of informed consent in research derives from or is similar to the analysis of informed consent to receive medical treatment. Nonetheless, agreement to participation in research differs from agreement to receive clinical care. As discussed in this chapter, patients—and investigators—may sometimes not clearly understand that research has purposes distinct from clinical care. Such a lack of understanding can compromise the objectives of informed agreement to participation in research. General Conditions for Informed Consent In the classic analysis by Faden and Beauchamp (1986), the conditions for autonomous decisions or actions include intentional action, understanding of the action, and voluntary or uncontrolled action. Informed consent may be viewed as one type of autonomous choice, but a choice that must also be considered within “the web of cultural and policy rules and requirements … that collectively form the social practice of informed consent in institutional contexts” (Faden and Beauchamp, 1986, p. 277). The conditions of understanding and voluntariness are central to requirements that investigators provide relevant information to prospective research participants, evaluate their understanding of this information, and assess situations for possible coercion or undue influence on the decision to participate in research. Voluntary choice extends beyond the initial, explicit agreement to participate in research to the sometimes implicit and sometimes explicit agreement to continue participation on the basis of an understanding of one’s right to withdraw. Parental permission is ethically distinct from consent, but the conditions of understanding and voluntariness and freedom from coercion or undue influence still apply to assessments of the procedures for obtaining permission. With appropriate regard for a child’s or an adolescent’s maturity, they also apply to procedures for seeking assent. Although parental permission is sometimes described as “consent” or “proxy consent” and children’s agreement is also sometimes labeled as “consent,” such labels are misleading. They do not properly reflect the ethical differences between permission or assent and informed consent. Again, as the concept has developed, only those who are held competent to make autonomous decisions on their own behalf can provide informed

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Ethical Conduct of Clinical Research Involving Children consent. Thus, parents can provide informed consent only for themselves. Minors cannot provide informed consent unless they have been judged to be able to act as adults for that purpose (see the discussion below of emancipated and mature minors). Within the limits of parental discretion described in Chapters 3 and 4, the ethical and legal provisions for parental permission assume that parents will make decisions about research participation that protect their child’s interests.2 In exceptional circumstances, for example, in certain situations involving child abuse and neglect, that assumption fails. Alternative mechanisms (e.g., appointment of a guardian) may be necessary to protect the child. In less exceptional situations, investigators who engage parents in careful discussions of research participation may still occasionally conclude that parents are not adequately considering their child’s well-being. They may then judge that the ethical standards for the child’s participation are not met, even though the parents are willing to give permission. Consent, Permission, and Assent as Processes As familiarity with the practical realities of obtaining informed consent to medical care or research participation developed, ethicists, investigators, and policymakers recognized that creating understanding is more than a simple matter of providing information or preparing clear consent forms. Rather, a careful process of communication is necessary, one that includes the opportunity for parents and children to ask questions and investigators to make assessments of the extent to which a decision about participation in research (and about continued participation, once it has started) is made freely and with understanding (Faden and Beauchamp, 1986). The inclination to concentrate on physical consent forms is, however, strong. Forms are fairly easy to review, and their use is relatively straightforward to document. Two recent reports on research ethics still found it necessary to stress in their recommendations that informed consent should be understood as a process and not merely a form (NBAC, 2001b; IOM, 2003a). A third report, which focused on social and behavioral research, concluded that IRBs focus too much on the consent form and also fail to calibrate their attention to the level of risk posed by the research (NRC, 2   Although parents are often expected to make decisions in their child’s best interests given the available alternatives, some arguments allow a role for other considerations or, at least, reasonable freedom from intrusive second-guessing by others (see, e.g., Brock, 1994 and Ross, 1998). One argument is that having assigned parents the main responsibility for raising children, society should grant them reasonable discretion in doing so according to their own values. For example, under this argument, parents may consider peripheral benefits of research participation (e.g., socialization of the child in the values of altruism).

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Ethical Conduct of Clinical Research Involving Children 2003). That is, they do not match the intensity and specificity of their review of consent documents and processes to the risk presented by the research. The recommendations at the end of this chapter suggest some ways to direct investigator and IRB attention to the process of seeking parents’ and children’s agreement to research participation. The focus on forms also reflects, in part, the concerns of research institutions and sponsors about litigation that might cite omitted information or other alleged deficiencies in consent forms. This concern is evident in the legal tone of many consent, permission, and assent forms, which include terminology that is unfamiliar and potentially intimidating to many. Such language may satisfy the “informed” aspect of consent but limit a prospective research participant’s true understanding of the proposed research. Again, the focus should be on the process, and the forms should support that process. Although failures of comprehension about any major element of research participation raise ethical concerns, a particular concern is whether prospective research participants understand that they will be participating in research and that the purpose of research differs from the purpose of normal clinical care. The purpose of research is to generate knowledge, usually for the benefit of patients or individuals in the future. The belief that the purpose of research is treatment is termed the therapeutic misconception (Appelbaum et al., 1982).3 In some cases, the description of an area of research may encourage this misconception. For example, Churchill and colleagues (1998) and Lysaught (1998) have made this argument about the labeling of gene transfer research as “gene therapy.” As discussed in Chapter 1, references to “therapeutic” and “nontherapeutic” research may likewise contribute to misperceptions that the purpose of clinical trials is individual clinical care. Referring instead to research interventions or procedures as having or not having the prospect of direct benefit may help reduce misunderstandings. King (2000) has argued that the threat that participants will misunder- 3   Research participants may also expect that being in a clinical trial may provide them benefits in the form of more information about their condition and closer monitoring than they would otherwise receive. A recent analysis of studies that compared the outcomes of patients participating or not participating in cancer clinical trials reported that “there are insufficient data to conclude” that enrollment in clinical trials leads to improved outcomes (a “trial effect”) (Peppercorn et al., 2004, p. 263). Although the results were more favorable for pediatric cancer trials than for adult cancer trials, the article emphasized the significant limitations in the quality of the data; it did not single out these trials as an exception to the general conclusion. That is, until better data are available to support a trial effect, “patients with cancer should be encouraged to enroll in clinical trials on the basis of trials’ unquestioned role in improving treatment of future patients” (p. 263).

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Ethical Conduct of Clinical Research Involving Children stand the purpose of research is large enough that IRBs should devote more attention to the description of potential benefits in the consent process. King argues, for example, that IRBs should require a statement in consent forms that benefit is not expected in early-stage studies, unless the investigators can make a good case for a reasonable prospect of direct benefit. King also argues that in consent forms the introductory discussion of what a study hopes to prove may mislead participants who are eager to receive treatment that will improve their lives. In addition, one of the anonymous reviewers of this report observed that in his long experience, protocols for clinical trials do not always clearly distinguish between the potential benefits or harms generally associated for treatment of a disease and the potential benefits and harms specific to the intervention being tested. In an analysis of the therapeutic misconception, Dresser observed that patient advocacy groups “often portray study participation as the way to obtain cutting-edge therapy” (Dresser, 2003, p. 240; see also, Dresser, 2001). Dresser suggested that exaggerated expectations about research benefits not only can undermine informed decision making by individuals but also can diminish social activism that promotes better access to existing beneficial care (also see, more generally, Callahan, 2003). When research includes medical procedures or interventions, clinical investigators have the obligation to provide them as carefully and as competently as they would in usual care situations. Nonetheless, to protect the validity of the research and its potential to create knowledge that will benefit future patients, certain elements in a research protocol (e.g., random assignment to an experimental or control group and blinding of investigators to the experimental or control group) typically limit how much a particular patient’s care may be individualized to better meet that patient’s best interest. “The opportunities for [clinical] choice disappear when neither the health care professional nor the subject plays a role in deciding on treatment” (Lidz and Appelbaum, 2002, p. V-57). This underscores the importance of helping prospective research participants understand what participation in the research will and will not involve and what limitations the research protocol will impose on practitioner and participant decisions about treatment. Legal Requirements for Permission and Assent General The concept and practice of informed consent have evolved as much through the judicial route as through the ethical route. For the most part, however, courts have focused on informed consent to clinical care, not research participation. The term informed consent itself gained currency

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Ethical Conduct of Clinical Research Involving Children BOX 5.1 Selected Regulatory Provisions for Informed Consent That Also Apply Generally to Parental Permission for a Child’s Participation in Research Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. (a) Basic elements of informed consent. Except as provided in paragraph (c) or (d) of this section, in seeking informed consent the following information shall be provided to each subject: a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental; a description of any reasonably foreseeable risks or discomforts to the subject; a description of any benefits to the subject or to others which may reasonably be expected from the research; a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; following a 1957 court case in which the court held that physicians had the duty to disclose “any facts which are necessary to form the basis of an intelligent consent by the patient to proposed treatment” (Salgo v. Stanford Jr., 1957). Aside from the direction provided by the Nuremberg tribunal, legislators and regulators, rather than judges, have been the major source of requirements for consent to research participation. As described in Chapter 1, the 1962 amendments to the Federal Food, Drug, and Cosmetic Act (P.L. 87-781) included requirements for informed consent from those participating in research involving investigational new drugs “except where it is not feasible or it is contrary to the best interests of such human beings” (21 USC 355(i)(4)). In 1966, the U.S. Surgeon General significantly expanded

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Ethical Conduct of Clinical Research Involving Children a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained; for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained; an explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject; and a statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (b) Additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject: a statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable; anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent; any additional costs to the subject that may result from participation in the research; the consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject; statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject; and the approximate number of subjects involved in the study. SOURCES: 45 CFR 46.116 and 46.408. FDA regulations are at 21 CFR 50.25 and 50.55 requirements for informed consent in clinical research funded by U.S. Public Health Service grants. Government officials provided more explicit guidance and direction in subsequent years, notably, in 1981 U.S. Department of Health and Human Services (DHHS) regulations that remain in place today. The regulatory language concerning informed consent is fairly detailed. Box 5.1 includes the main provisions that apply by reference to parental permission for a child’s participation in research. Statements from the regulations often appear verbatim in instructions to clinical investigators and in consent forms (see, e.g., NIH, 2000a). Some studies have, however, documented discrepancies between the elements required and the elements actually found in consent forms (White et al., 1996; Silverman et al., 2001).

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Ethical Conduct of Clinical Research Involving Children Parental Permission Federal regulations usually require that parents provide permission for a child’s participation in research (45 CFR 46.408; 21 CFR 50.55). (Consistent with earlier chapters, the text refers to the regulations that apply to federally conducted or supported research as DHHS regulations to distinguish them from the similar but not identical FDA regulations.) As discussed further below, the regulations define children with reference to state laws establishing the legal age for consent to the treatments or procedures involved in the research. In general, the rules for informed consent listed in Box 5.1 also apply to permission. That is, parents or guardians are to be provided the same kinds of information and disclosures that would be provided to adults consenting to research in their own right. The regulations define parents as biological or adoptive. A guardian is someone who is appointed by a court and who can authorize medical care for a child. Both parents must provide permission for the child to be included in research when research involves greater than minimal risk and does not hold out the prospect of direct benefit to the child. The regulations allow exceptions when one parent is dead, incompetent, not reasonably available, or not legally responsible for the child’s care. In these situations, permission from one parent will suffice. Waiver of Parental Permission Under certain circumstances when parental permission is not a reasonable requirement to protect a child, the DHHS regulations allow an IRB to waive parental permission—provided that an appropriate mechanism for protecting the child is substituted and the action is consistent with federal, state, and local laws (45 CFR 46.408(c)). As an example of a situation in which a waiver might be appropriate, the regulations cite only situations involving neglected or abused children. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (hereafter, the National Commission) mentioned several other circumstances in which parental or guardian permission might be waived, including when parents are incompetent to provide permission, when the research involves conditions for which state laws allow adolescents to be treated without parental consent, or when the research involves mature adolescents and only minimal risk (National Commission, 1977). The DHHS regulations do not describe what additional protective procedures might be appropriate if parental permission is waived but only state that the choice will “depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition” (45 CFR 26.408(c)). One option is to appoint an independent research monitor or participant

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Ethical Conduct of Clinical Research Involving Children advocate. His or her role would be to verify the adolescent’s understanding of the research and the assent process, determine that the agreement to participate is voluntary, and document the basis for the waiver of parental permission. If another adult (e.g., a grandparent) is knowledgeable and involved with the minor, the advocate might also seek that person’s views. Other protective strategies are described later in this chapter. In a departure from DHHS regulations, the regulations of the Food and Drug Administration (FDA) do not allow the waiver of parental permission, even when it is not a reasonable requirement to protect the child (FDA, 2001b). FDA has argued that its statute does not permit such a waiver. As noted earlier, the statute governing FDA requires the consent of those to whom investigational drugs are being administered (or their representatives) except when it is not feasible or is contrary an individual’s best interests. In the committee’s view, this language allows for waivers consistent with DHHS regulations. A recommendation presented later in this chapter urges that FDA bring its policies on waiver of parental permission into agreement with those governing research conducted or supported by DHHS. It also urges FDA, the National Institutes of Health (NIH), and the Office for Human Research Protections (OHRP) to cooperate to define more explicitly the factors that should be considered in waiver decisions and the safeguards that are appropriate for different situations when parental permission is waived. Although not limited to research involving children, OHRP (then called the Office for Protection from Research Risks) and FDA have since 1996 provided for waivers of consent or permission when research involves certain emergency situations (Ellis and Lin, 1996; 45 CFR 46.116(c) and (d); FDA, 1996b; 21 CFR 50.24). A detailed set of requirements must be met and documented before a waiver can be approved. For example, “the subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions” (21 CFR 50.24(a)(1)); “[t]here is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation” (21 CFR 50.24(a)(2)(iii)); and “participation in the research holds out the prospect of direct benefit to the subjects” (21 CFR 50.24(a)(3)). In addition to IRB review, draft regulatory guidance from FDA specifies a process of community consultation and public disclosure (FDA, 2000a). The committee learned that at least one proposal for FDA approval of research under these regulations was being prepared under the auspices of the Pediatric Emergency Care Applied Research Network (James Chamberlain, M.D., Children’s National Medical Center, personal communication, October 13, 2003).

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Ethical Conduct of Clinical Research Involving Children Children’s Assent Although decisional capacity develops through childhood and even into adulthood, practical and policy considerations have led policymakers to require, in most cases, that individuals achieve a specified age (the “age of majority”) before they can enter into contracts, consent to medical care, and make other crucial decisions in their own right. State policies are important for clinical research because federal regulations on human research protections define children as “persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted” (45 CFR 46.402; 21 CFR 50.3(o)). As described below, minors (those who have not achieved the age of majority) can still be held competent to consent to medical treatments under certain circumstances. Consistent with recommendations in the National Commission’s 1977 report, federal regulations generally require assent to research participation from children judged capable of providing it. They define assent as “a child’s affirmative agreement to participate in research” and also state that “[m]ere failure to object should not, absent affirmative agreement, be construed as assent” (45 CFR 46.402(b); 21 CFR 50.3(n)). Assent is not, however, required if an IRB concludes that the research has the prospect of directly benefiting the child and that potential benefit is available only in the research context (45 CFR 46.405; 21 CFR 50.52). Assent may also be waived under the same conditions in which adult’s informed consent may be waived. The federal regulations do not specify an age at which IRBs should expect investigators to begin to seek assent from children. Rather, IRBs are to consider the ages, maturity, and psychological state of the prospective research participants. In the committee’s experience, most IRBs require investigators to seek assent from children over the age of 6 or 7 years. The judgment about assent may apply to all the children who are to participate in a study or to each child individually. As discussed later in this chapter, the assent process for older adolescents may differ little from the process for seeking informed consent if that consent process is suitably structured. Thus, investigators would provide the same kinds of information as is required for adults. The regulations permit oral presentation of assent information and allow discretion on the part of the IRB about the way assent is documented (45 CFR 46.117 (c)(2) and 45 CFR 46.408 (e); 21 CFR 50.55(g)). FDA guidance on pediatric drug research (developed by the International Conference on Harmonisation [ICH]) provides that “[p]articipants of appropriate intellectual maturity should personally sign and date either a separately designed, written assent form or the written informed consent” (FDA, 2000b, p. 19781, emphasis added). Although the ICH guidance puts more

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Ethical Conduct of Clinical Research Involving Children situations, investigators still have an obligation to discuss the expected or possible burdens that research participation may impose on the child, to offer their best assessment of the prospect of benefit, and to explain what relevant options for palliative care may be available within or outside the research setting. Waiver of Parental Permission As described earlier and consistent with the recommendation of the National Commission, DHHS regulations permit IRBs to waive parental or guardian permission for a child’s participation in research when such permission (1) is not a reasonable requirement to protect the child and (2) is not inconsistent with federal or state laws. The regulations also require the substitution of an appropriate protective mechanism when a parental waiver is approved. The FDA regulations do not allow such waivers, even when the research involves, for example, abused or neglected children who would thereby be denied the potential benefits of research participation. For a variety of reasons, it is generally desirable to seek parental involvement in decisions about children’s and adolescents’ participation in research, especially when the research involves a clinical trial or presents more than minimal risk. In some situations, however, requiring parental permission could put a child or an adolescent at risk of violence, expulsion from the home, or other harm. This could impede some important research. For example, researchers trying to identify risk factors for HIV infection among different groups of adolescents might be successful in encouraging some teens to involve their parents but be unable to recruit those teens who are most fearful of violent parental reactions. Such reactions may be part of a family dynamic that is, itself, a risk factor. In addition, some adolescents have no parents or guardians and are not wards of the state, and others are runaways or “throw-aways” (adolescents who are evicted from or asked to leave the home by their parents) (Blustein et al., 1999). Research to understand the circumstances of these adolescents—including their health status—is unlikely to be feasible if parental permission is required. Likewise, it may not be possible to enroll these adolescents in clinical studies that have the prospect of direct benefit. In some cases, an adolescent for whom parental permission is not feasible may be able to receive an investigational product outside a trial if the product (e.g., an antidepressant) is approved for other uses or age groups. (Such use will still require either parental consent or a judgment that such consent is not required under applicable laws.) Although this approach may, on balance, be prudent and may potentially benefit the individual adolescent, it will not advance knowledge to benefit future adolescents.

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Ethical Conduct of Clinical Research Involving Children Committee experience and some research suggest that many IRBs are reluctant to consider waivers of parental permission for adolescent’s participation in research even though the proposed waivers are consistent with DHHS regulations and relevant state laws. Restrictive IRB policies and practices can be just as constraining as current FDA policies, thereby limiting research that can benefit adolescents. Again, parental involvement and permission is usually advisable, especially for research involving more than minimal risk. IRBs should not, however, employ a blanket policy of denying protocols that provide for waivers of parental permission. Rather, they should consider protocols on their merits taking into account their purposes and rationales (e.g., parental neglect, fear of parental violence), the basis for assessing the adolescent’s capabilities to make decisions, proposed safeguards, and applicable federal and state policies. Recommendation 5.4: Institutional review boards should consider granting waivers of parental permission for adolescent participation in research when the research is important to the health and well-being of adolescents and it cannot reasonably or practically be carried out without the waiver (consistent with 45 CFR 46.116(d) and 45 CFR 408(c)) or the research involves treatments that state laws permit adolescents to receive without parental permission (consistent with the definition of children at 46 CFR 402(a)) and when the investigator has presented evidence that the adolescents are capable of understanding the research and their rights as research participants and the research protocol includes appropriate safeguards to protect the interests of the adolescent consistent with the risk presented by the research. The committee agrees with the National Human Research Protections Advisory Committee (NHRPAC) (Marshall, 2001) and the Society for Adolescent Medicine (SAM, 1995) that FDA’s restrictive policy hampers important research involving adolescents. As discussed earlier in this chapter, the committee believes that FDA’s statute provides discretion when parental permission is not feasible or it is contrary to the child’s best interests. Furthermore, as NHRPAC has noted, the FDA regulations define children with reference to state laws that apply in the locale where the research takes place, which reasonably means that the age of consent (i.e., when parental permission is not required) depends on the law of that state. States also permit minors to consent to treatment in their own right under a range of circumstances, although these provisions do not explicitly mention research.

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Ethical Conduct of Clinical Research Involving Children Recommendation 5.5: The Food and Drug Administration should adopt policies consistent with federal regulations at 45 CFR 46.408(c) that allow institutional review boards with appropriate expertise to waive requirements for parental permission in research, provided that additional, appropriate safeguards are in place to protect the child’s or the adolescent’s welfare. OHRP, FDA, and NIH should cooperate to develop guidance for investigators and IRBs on the additional safeguards that should be in place when a waiver of parental permission is sought and obtained. The safeguards should fit the risks associated with specific studies. In making recommendations about health research with adolescents that involves only minimal risk, the Society for Adolescent Medicine advises that IRBs should find that the research meets several conditions (SAM, 1995). Box 5.3 provides an example of questions devised by one IRB based on this advice. Beyond these questions, IRBs and investigators should be familiar with state policies relevant to the medical treatment of minors without parental permission. In some cases, safeguards might involve a research ombudsman or independent advocate who would review the adolescent’s situation, identify relevant state laws, observe or participate in the consent discussion (including, unless inappropriate in the circumstances, discussion of the desirability of parental involvement), perhaps hear the views of a nonparent relative or other adult who is providing support and guidance, and document the BOX 5.3 Questions and Information for Investigators Seeking Waiver of Parental Permission for Adolescent’s Participation in Research Please specify why the research could not be practically conducted without a waiver and why parental permission is not a reasonable requirement. Are the risks associated with this protocol minimal? Please specify why. The IRB requires assurance that the waiver of parental permission will not adversely affect the rights and welfare of the subjects. How will you ensure the privacy and confidentiality of the study subjects? Investigators must encourage each adolescent to seek the support of a parent or another adult prior to participation. How will this be accomplished? The informed consent must also address this issue. Investigators must establish procedures to allow adolescents to seek assistance on a confidential basis after completing surveys containing questionnaires that may raise issues for which adolescents may desire further information or assistance. Please specify how this will be accomplished. SOURCE: Children’s Hospital Boston, no date

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Ethical Conduct of Clinical Research Involving Children reason for waiving parental permission. IRBs should consider the guidelines from the Society for Adolescent Medicine. For research involving more than minimal risk, they advise (among other protections) that IRBs determine that someone other than the investigator will assist the adolescent by identifying an adult familiar with his or her situation, committed to his or her well-being, and willing to offer appropriate emotional support. Further, the Society recommends that an appropriately trained professional (e.g., psychologist or masters level social worker), who is not involved in the study should confirm the capacity of the adolescent as a mature minor to give informed consent by finding evidence of: (a) cognitive ability to comprehend the objectives and requirements of the research and other important considerations (e.g., the voluntary nature of participation, the potential of risks and benefits) as would be required for a competent adult; (b) reasonable judgment as evidenced by the ability to address problems, to foresee the long-term consequences of action or inaction, and to evaluate the validity of information; and (c) personal responsibility to be able to comply with the requirements of the research protocol, especially those designed to ensure individual safety. (SAM, 1995, p. 266.) Finally, it is important for regulators and institutions to develop appropriate policies and procedures for waiving parental permission and child assent to permit research involving children who have acute, unanticipated health problems (e.g., extreme prematurity or head trauma) when parents are not immediately available or not medically competent to provide permission and when the child is incapacitated. Consistent with OHRP and FDA policies and regulations on emergency research, IRBs should develop policies and procedures for simultaneously protecting the well-being of the affected children and the rights of the parents while still permitting the acquisition of new knowledge concerning the most frequent causes of child morbidity and mortality in the United States, which are—for children beyond infancy—intentional and unintentional injuries. The committee recognizes that many institutions have been unwilling to consider such research out of concern about adverse outcomes and the concurrent legal liability associated with these outcomes. Children’s Assent or Dissent in the Context of the Family Rather than viewing the process of requesting a child’s agreement to participation in clinical research as an independent event, investigators and IRB members should adopt a family systems perspective. In the committee’s experience and as indicated in some of the research reviewed above, parents often want to decide whether their child will be approached about research participation. Children are usually not approached unless parents are willing to consider the child’s participation.

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Ethical Conduct of Clinical Research Involving Children In some cases, parents may agree to a child’s participation in research with the expectation that the child, once approached, may not want to participate and that the child’s wishes will be accepted. In other situations, parents and children may negotiate decisions about research participation, with the views of adolescents tending to have more weight. Sometimes, parents may expect their wishes for the child to participate in research to prevail over a child’s wish not to participate in research, especially when the research has the prospect of benefiting an ill child. Federal regulations governing research involving children appropriately do not require the child’s assent when research offers the prospect of an important direct benefit that is available only in the context of the research” (45 CFR 46.408(a); 21 CFR 50.55 (c)(2)). Investigators should avoid suggesting to children that they can make the participation decision when their parents can override their wishes. Nonetheless, even when it can be overridden, a child’s dissent should not be regarded as simply inferior to the parents’ views and decisions but, rather, should be viewed as reflecting a different and still important point of view. Investigators or others involved in the assent process should work with parents to help them understand children’s views and treat them respectfully. It will usually be better for all involved if agreement between parent and child—especially an older child or adolescent—can be achieved. This may involve a developmentally variable process of negotiation. As discussed earlier, it may sometimes be reasonable—as part of a respectful and noncoercive assent process with parental agreement—for investigators to come back to a child who says “no” to see whether he or she may feel differently later. In rare instances, understanding and respect may lead an investigator or clinician involved with the child’s care to advocate—with great sensitivity to the family’s wishes and values—on behalf of a dissenting older child or adolescent when the assent process reveals compelling reasons for encouraging parents to consider accepting rather than overriding the dissent. One such situation may arise when a mature adolescent who has a grave medical problem that has been unresponsive to treatment asks not to be subjected to a burdensome investigative procedure that offers at most a remote prospect of meaningful benefit. When parents are desperate to do something or fear feeling guilty in the future if they refuse proposed interventions, they may find it difficult to fully consider the burdens that research participation is likely to impose on their child. When research does not have the prospect of direct benefit to the child, the committee interprets the regulatory requirements that “adequate provisions are made to solicit the child’s assent” to mean that the child’s dissent overrides parental permission. Investigators should be alert to nonverbal indications of children’s wishes about research participation, particularly

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Ethical Conduct of Clinical Research Involving Children when children may be reluctant to distress their parents by voicing disagreement. The federal regulations specify that failure to object to participation should not, by itself, be construed as assent. Again, in the committee’s view, a child’s dissent does not preclude investigators seeking the child’s assent at another time, as long as such practices are respectful and not coercive and parents are involved and supportive. Some research has the potential to reveal sensitive information about a child or, more often, an adolescent that might provoke negative, even punitive, parental reactions. Investigators should be sensitive to this potential and should determine when adolescents and possibly younger children should be told about the kinds of information that may be shared with their parents if they agree to participate in research. Researchers studying adolescents have been concerned that the federal privacy regulations (see Appendix C) may allow parents to have access to information about adolescents that would otherwise be held confidential. The regulations defer to state laws on parental access to the health records of minors, which means that research-related personal information may be protected in some states and not in others. Recommendation 5.6: In designing and reviewing procedures for seeking a child’s assent to participation in research, investigators and institutional review boards should aim to create assent processes that consider and respect the child and the family as a unit as well as individually. The process for requesting assent should be developmentally appropriate given the ages and other characteristics of the children to be approached; provide opportunities for children to express and discuss their willingness or unwillingness to participate; clarify for parents and children (as appropriate) the degree of control that each will have over the participation decision; and when appropriate, describe to children and parents the kinds of information about the child that will or will not be shared with the parents. Age-Appropriate Assent Processes The construction of age-appropriate assent materials and procedures should be informed by the literature on cognitive development in general and on child and adolescent capacities for assent in particular. For children and adolescents at all ages, the assent process should be designed to be an empowering and respectful experience. The research on children’s cognitive, intellectual, social, and emotional development and their understanding of research participation provides

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Ethical Conduct of Clinical Research Involving Children somewhat mixed directions on the question of a minimum age for seeking affirmative assent. As long as investigators and IRB members recognize that the assent process for young children should be age appropriate and quite simple, it is not unreasonable for investigators to be asked to seek assent for children as young as age 7 years. (Such an age-defined policy may be useful for practical reasons, but investigators should also be encouraged to provide simple explanations for children younger than that age who seem to be capable of understanding basic information.) For younger children (to age 9 or 10), assent information and procedures can be limited and can focus on a subset of the information required for adults. For example, the discussion and, if appropriate, written material or assent form for younger children should explain in simple language what the study is about and whether it might help (e.g., “We want to see whether a new medicine will or won’t help children like you who have earaches.” or “We want to understand your illness better.”); what will happen and when (e.g., “You will have to come to the clinic once a week for 8 weeks to have a shot, you will not be allowed to eat for 12 hours, and then the following things will happen: …”); what discomfort there might be and what will be done to minimize it (e.g., “Your head may hurt after the test and you may need to stay in bed for a day.” “You will get a cream on your skin that will keep you from feeling the shot.” or “You will have someone to whom you can talk about your feelings.”); who will answer the child’s questions during the study; and whether an option to say “no” exists (e.g., “You do not have to be in this study and no one will be mad at you.” or “If you say “yes” and then change your mind, that is okay.”). With the increasing age of the child, assent information should become correspondingly more substantive and specific and should use language appropriate to the cognitive and emotional maturity of the child or adolescent. The nearer an adolescent is to the age of majority, the more the assent process should resemble a well-designed informed-consent process for adults. Most research suggests that by age 14 or 15 years adolescents are similar to adults in their ability to comprehend the meaning of participation in research, although they may still be maturing in other areas of understanding and decision making. If consent forms for adults are written to be easily read by those with reading skills at less than a high school level, they may be appropriate to use as the assent form for middle to older adolescents. As for adults, in designing assent processes and written information for children and adolescents, investigators should take into account the

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Ethical Conduct of Clinical Research Involving Children expected language competencies and preferences of the groups to be included in the research. For emancipated and mature minors who are making decisions in their own right, the process for seeking assent should still be sensitive to the level of maturity of these adolescents (e.g., their attitudes about risk taking) and appropriate safeguards should be provided. Discretion in Documenting Assent As described above, federal regulations permit oral presentation of assent information and allow the IRB to use discretion about the way in which assent is documented. Although the guidelines on pediatric drug research adopted by ICH (and issued as FDA guidance) are more specific (requiring signatures on assent forms for participants of “appropriate intellectual maturity” [FDA, 2000b, p. 13]), they, too, allow some discretion and should not be rigidly interpreted. On the basis of the literature reviewed in this chapter, the committee suggests that requiring a child’s signature on an assent form may be developmentally inappropriate for younger children (e.g., those under age 9 or 10 years). A signature requirement may confuse rather than inform a child, and a child may even experience this situation as intimidating or coercive. Recommendation 5.7: Guidance and education for investigators and members of institutional review boards should make clear that federal regulations allow discretion—based on children’s developmental maturity—about the way in which information is presented to children and the manner in which assent is documented. Investigators and institutional review board members should apply that knowledge in determining what procedures will best serve the goals of assent for particular research protocols and populations. While allowing for discretion with individual children or adolescents, IRBs and institutions can provide guidance about age-appropriate options for documenting assent. For example, in addition to developing sample age-appropriate information and assent materials for younger children, institutions can suggest that investigators use their judgment in determining when it is appropriate and respectful to ask younger children to sign simple assent forms. If investigators have developed an adult consent or permission form that is suitable for use with adolescents, the form could be used to document adolescent assent. Alternatively, then adolescents could sign a simpler assent form that includes age-appropriate information beyond that included on the form for younger children.

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Ethical Conduct of Clinical Research Involving Children Investigator Knowledge and Skills Developmentally appropriate and family-sensitive procedures for obtaining children’s assent and parents’ permission for a child’s participation in research require communication skills and knowledge of child psychology and family dynamics. Education in these skills may not be part of the standard training for clinical researchers, including some investigators who conduct studies that include children. Investigators and other team members who are experienced in communicating with children and families will usually be better prepared to undertake these procedures than those who work entirely or mainly with adults. Even experienced pediatric researchers may, however, benefit from formal training in both the regulations related to permission and assent and the means of implementing permission and assent as “a process, not a form.” Recommendation 5.8: To increase investigator competence in communicating with children and parents about research participation, educational programs for investigators and research staff who expect to do research involving children should include training and evaluation in developmentally appropriate and family-sensitive processes for seeking permission and assent. Directions for Research Although the committee was encouraged to find some research on parental permission and child assent, much of that research involves very small numbers of participants and other limitations. The range of pediatric conditions and research experiences covered by studies of permission and assent is also fairly limited. Better evidence about how parents and children of different ages comprehend various dimensions of research and research participation is needed to help investigators and IRBs devise ethical and effective processes for explaining research and seeking permission and assent. To the same end, more research is needed to describe how permission and assent are actually sought in different contexts, how processes vary, and what processes appear to better serve the goals underlying the requirements for permission and assent, given the variations in research purposes and populations. Recommendation 5.9: Federal agencies, private foundations, and advocacy groups should encourage and support research on existing and innovative permission and assent processes and information materials to support improvements in these processes and guide the education of investigators and institutional review board members.

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Ethical Conduct of Clinical Research Involving Children One template or model for permission and assent clearly will not fit all parents and children, and certain research contexts (e.g., acute serious illness) will make reasoned reflection and decision making more difficult. Some topics that should be considered for investigation include: current practices for seeking permission and assent for different types of research and for children of different ages and with different conditions (e.g., mild chronic conditions or life-threatening diseases); the effect on the flow of information of different processes for seeking permission and assent (e.g., approaching the parent first, involving both the parent and the child in the first meeting, or including a facilitator or research advocate for certain kinds of research); the consequences for communication, comprehension, and decision making of parents and children with different characteristics (e.g., education level, language, and cultural background) and different research purposes or contexts; and the opportunities that children actually are given to dissent, the way in which they express a reluctance or an unwillingness to participate in research, and the reactions of parents and investigators. In addition, the committee encourages public and private support for research on innovative ways to improve permission and assent processes generally. One starting point would be research on shared decision making between clinicians and patients and methods for improving patient understanding of and decision making about clinical services (see, e.g., O’Connor et al., 1999; Deyo et al., 2000; and Volk et al., 2003). Depending on the research and the circumstances, strategies might include interactive videos, computer programs, and Internet resources. As described in Appendix B, policies on research participation by wards of the state are poorly documented. The committee encourages a systematic effort to document state policies, their rationales, and their application as a basis for further discussion of the appropriateness of these policies and practices. Some state policies and practices that were an understandable reaction to historical abuses and controversies may now go beyond the provisions and protection of federal regulations in ways that unduly restrict research participation that could benefit the population of children and adolescents who are wards of the state. CONCLUSION Both ethical principles and legal requirements place strong emphasis on having competent adults provide informed consent for their participation in research. Because children are usually not legally or intellectually compe-

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Ethical Conduct of Clinical Research Involving Children tent to provide consent, an alternative approach has been devised that relies on parental permission and, when appropriate, children’s assent to participation in research. For adults agreeing to clinical research in their own right and for parents agreeing to a child’s participation in clinical research, studies suggest that truly informed consent or permission is unlikely to be completely achieved for all individuals in all research situations. Parents who are asked to provide permission for their child’s participation in clinical trials are, in particular, often making decisions under great stress and time pressure. Some prefer to trust the physician’s assessment rather than make their own, and investigators must be acutely sensitive to the influence that they wield in discussions with parents of ill or injured children. A significant minority of parents may misunderstand the purpose of research, especially when the research tests an intervention for a medical condition. Nonetheless, the goal of having parents provide informed permission remains an important protection for children, both when participation in research is initially sought and throughout the course of a study. The capacity to make voluntary, informed decisions clearly evolves from birth through adolescence and into adulthood. It also clearly varies among individuals of the same age. The goal should be to involve children in discussions and decisions about research participation as appropriate, given their cognitive and emotional maturity and psychological state. Involving children in discussions and decision making respects their emerging maturity, helps them prepare for participation in research, and gives them an opportunity to express their concerns and objections—and, possibly, influence what happens to them. This chapter has discussed some circumstances that may raise concerns about undue or even coercive influences on family decision making, for example, when a child’s physician is also the investigator seeking agreement to the child’s participation in research. Payments to parents or children related to research participation have also raised questions about the potential for undue influence. The next chapter examines these questions.