Children and adolescents who participate in clinical research may have vastly different experiences and perceptions of their experiences depending on the nature of the research and their own medical, psychological, and social circumstances. Some may not really understand that they are participating in research or may be reluctant participants. Others—like Suzanne Pattee—may find it to be a positive experience that gives them a greater sense of control over their situation. Although the literature is not extensive, the committee identified some research that is relevant to assessments of what children and adolescents understand about research participation and when and how their agreement to participate in research should be sought. A more extensive literature on children's general cognitive or decision-making capacities also has implications for these assessments. Studies continue to expand understanding of the patterns of cognitive development and variation in children and adults. Many psychologists agree, in general, that children's cognitive development follows a fairly regular course, although they disagree about many specifics. In a highly simplified account, as described by followers of Piaget,6 children first develop sensory and motor skills (from approximately birth to age 2 years) and then begin to use language and images (to approximately ages 6 or 7 years), develop certain concrete reasoning and problem-solving abilities (to approximately age 11 or 12 years), and, lastly, acquire more advanced capacities to think and reason about complex, abstract concepts, relationships, and processes (adolescence). Other psychologists put more emphasis than Piaget and his followers on the role of cultural and social factors in children's development, in particular, children's interactions with parents, other adults, and peers (see, e.g., Vygotsky, 1978; and Doolittle, 1997). Still others take an information-processing approach that focuses on maturation of the sensory capacities, encoding abilities (attentiveness to and retention of information relevant to a task), and information retrieval skills (Siegler, 1991). Particularly for more abstract concepts and reasoning capacities, research suggests that both adolescents and adults vary considerably in their capacities. It also suggests that culture, context, experience and training affect both the pace and the eventual adult level of cognitive development and performance (see, e.g., Capon and Kuhn, 1982; Chi and Ceci, 1987; Nisbett et al., 1987; Chien et al., 1996; Morris and Sloutsky, 1998; Segall et al., 1999; and Klaczynski and Robinson, 2000; etc.). These findings reinforce the argument for viewing informed consent (as well as permission and, as appropriate, assent) as a process that should stress careful explanation; provide opportunities for questions; and take into account the language, cultural, and other characteristics of prospective research participants. Although IRB policies and other sources often require assent starting at age 7 years, investigators should treat children as individuals and consider when it may be reasonable and respectful to provide children under that age with simple information about what will happen. Table 5.1 depicts Broome's summary of how the general theoretical and research literature on children's development relates to the more specific question of children's developing capacity to understand and make decisions about research participation. It refers to social and emotional as well as cognitive factors.
Recent years have seen an increasing interest in determining what children and adolescents comprehend about research participation and using that knowledge to guide decisions about when and how to seek children's agreement to participate in research. The findings are not entirely consistent, and each study has limitations in terms of the methods and the populations studied that affect generalizations. For example, most of the studies involved healthy middle-class children, although some included children with different kinds of medical problems. The focus was usually on children's intellectual or cognitive capacities rather than their emotional state or development. One exception involves studies of gravely ill children (Bluebond-Langner, 1978; Bluebond-Langner et al., in press). The possible effects of mental disorders (e.g., depression) on children's involvement in discussions and decisions about research participation have received little attention. Some studies that the committee reviewed presented children with hypothetical research situations; others took place in the context of actual clinical research or other psychosocial research (i.e., research not involving the study of research understanding as such). Studies varied in the complexity of the hypothetical or real situations facing children and also in the way in which information was presented (e.g., in writing or orally). Few studies have included children as young as age 7 years, the age at which many IRBs and others advise that assent first be sought (see, e.g., AAP, 1995). Some of the research reviewed below examined children's understanding of or agreement to medical care rather than research participation. Findings from these studies are relevant to the extent that they relate to children's and adolescent's knowledge of their medical condition (if any) and their understanding of medical procedures or other dimensions of clinical care (e.g., the potential harms and benefits of different treatments) that are identical or similar to those used for clinical research. Very little research has investigated the actual process of obtaining children's assent to research participation. One study, already discussed above in the section on parents, analyzed 85 informed-consent conferences that concerned research participation by children with cancer (Olechnowicz et al., 2002). (Under federal regulations, assent was not a necessary condition for this research to proceed.) Of the 34 conferences that concerned children over age 7 years, the child was present during 14. The mean age of these children was 14 years (range, 10 to 18 years); the 20 children not included were younger (but their average age was not reported). The study authors reported that the investigators conducting the conferences differed in how they approached the discussion; for example, whether they indicated that the decision should be a family decision, the parents' decision, or “up to” the child (p. 808). During the conferences, older children asked more questions than younger children. Most children, however, talked very little and real discussion was uncommon. The majority of the questions from children focused on the disease and the treatment. Although it did not assess child or adolescent understanding directly and did not observe the process of assent, another study examined 70 informed-consent documents that were used with adolescents being recruited for genetic research (Weir and Horton, 1995). The investigators concluded that the documents were often confusing and unclear. This is consistent with the findings from evaluations of informed-consent documents for adults. The investigators also concluded that the documents did not reflect “developing ethical and legal standards” for research involving adolescents (p. 347).
As reviewed below, most studies of children's understanding of the purposes and procedures of research suggest that children under age 9 or 10 years have a limited ability to understand the purposes, risks, and potential benefits of research, especially more complex research. These younger children are better able to grasp the more practical aspects of research (e.g., what they are expected to do) than they are to understand the more abstract dimensions (e.g., expectations of confidentiality). Most studies and summaries conclude that by the age of 14 or 15 adolescents differ little from adults on measures of research comprehension, but some suggest caution about other dimensions of adolescents' understanding and judgment.7 Children Compared to Adolescents A few studies suggest that children as young as age 6 or 7 years can comprehend some aspects of research. One study that included 6- to 9-year-olds (studied in groups not individually) concluded that although older children comprehended more about a vaccine study, children as young as 6 years could ask what the investigators viewed as reasonable questions about the research (Lewis et al., 1978). They could comprehend certain basic information about what might happen to them in medical treatment or research and what they were expected to do. A study by Susman and colleagues (1992) of hospitalized young people ages 7 to 20 years did not find important differences between children ages 7 to 13 years and young people ages 14 to 20 years. Both groups did better in understanding concrete features of research (e.g., what they were to do) than in comprehending more abstract features (e.g., alternatives and the right to withdraw). The investigators concluded that emotional factors (e.g., anxiety and a sense of control) were more important than age or cognitive development in affecting the participants' understanding of research participation (Dorn et al., 1995). Most studies, however, have reported differences in comprehension between younger and older children. For example, in assessing the results of a study of 102 children 7 to 18 years of age, Tait and colleagues (2003b) concluded that children under age 11 years had particularly limited understanding of the study protocol (which involved an anesthesia or a surgery study), the potential benefits, and their right to withdraw from the study. Another study (Nannis, 1991) reported that more than 84 percent of the fifth graders (approximately 11 years old) in the study correctly understood what research was, whereas only 35 percent of the third graders (approximately 9 years old) answered the question correctly. In a study that included only second, fourth, and sixth graders, Hurley and Underwood (2002) reported that few of the participants in their psychological study understood its primary goals, even after a debriefing. They speculate that their results may have reflected the complexity of both the study (which investigated how children coped with peer provocation) and the debriefing. Broome and colleagues (2001) found that children younger than age 10 years could describe overall goals and potential benefits but did less well in describing research risks. (This study, which also involved a parent component, as discussed earlier, included 24 children and young people with leukemia and 10 children and young people with diabetes; participants were 8 to 22 years of age and were involved in various studies related to their condition.) The investigators also reported that both children and adolescents who could discuss the purpose of the research could not always “translate [that understanding] into an acknowledgement that they themselves were involved in a clinical trial” (Broome et al., 2001, p. 41). In a study of 18 children ages 5 to 18 years who were involved in nutrition research that did not offer the prospect of direct benefit, Ondrusek and colleagues (1998) concluded that compared with older children and adolescents, children under age 9 years showed deficient understanding of the purpose of the study, its potential harms and benefits, and their right to withdraw. (Children under age 13 years were read information about the study; older participants received a written form with the same information. This difference in presentation might have affected the results.) Younger children were, for example, more likely than older children to relate the research to checking their own health rather than to gaining information that would help sick children. The authors concluded that “the current age of 7 years for initiating assent (in addition to parental consent) is possibly not appropriate and should be reconsidered” (Ondrusek et al., 1998, p. 158). Based on a study of student understanding of research and research rights (which included 4th, 7th, and 10th graders and college students), Bruzzese and Fisher (2003) reported that a majority of students at each level answered the questions correctly. A sizeable minority of the fourth graders, however, appeared to be confused about the purpose of the research (which was to compare the ability of children in different age groups for their abilities to comprehend the meaning of research). Overall, the study reported a steady increase by age in student's comprehension of the purpose and nature of the study as well as the risks and potential benefits of the study. In sum, most research indicates that children between ages 6 or 7 years and ages 9 or 10 years can understand the more practical features of research but show a lesser appreciation than older children of the more abstract features of research (e.g., understanding of risks). The committee notes the shortfalls in younger children's understanding of research but believes that evidence does, on balance, support their involvement in age-appropriate discussions of participation in research and their ability to dissent (as provided for by federal regulations) from participation in research that does not present the prospect of a direct benefit. Such participation respects children's developing maturity and emerging autonomy. This is consistent with the moral purpose of assent. Younger and Older Adolescents Consistent with a continuing maturation of cognitive capacities, most research shows differences between younger and older adolescents in their comprehension of providing informed consent to participate in research. Research on differences between adolescents and adults is more mixed. A 1981 study by Lewis (involving 108 adolescents in the 7th, 8th, 10th, and 12th grades) looked at adolescents' recognition of risks and future consequences in a hypothetical situation involving peer counseling about cosmetic surgery or a trial of acne medication. She found sizeable differences by age, with the older adolescents showing greater awareness of risk and future consequences. Older adolescents were also more likely to suggest the need for independent professional opinion about the situations presented to them. When Halpern-Felsher and Cauffman (2001) replicated the study, however, they did not find important differences by age in the ability to recognize of risks and future consequences. Their findings are consistent with the findings of studies by Kaser-Boyd and colleagues (1985) and Ambuel and Rappaport (1992). In their study of competency to consent to medical treatment, which involved 98 participants at ages 9, 14, 18, and 21 years, Weithorn and Campbell (1982, p. 1589) reported that the 14-year-olds in their study did not differ from adults on four standards of competency: understanding, choice, reasoned outcome, and rational reasons. A number of summaries of the literature also suggest that by the age of 14 years, most adolescents possess the “psychological elements of ‘intelligent' consent” (Grisso and Vierling, 1978, p. 420; see also Weithorn and Campbell, 1982; Leiken, 1993; Weir and Peters, 1997; Thompson, 2000b). Others are more cautious about the capacity of adolescents to evaluate participation in research. For example, after reviewing the few studies of age-related differences in judgments of risk, Millstein and Halpern-Felsher (2001) state that, depending on one's perspective, these studies could point either to a “heightened sense of vulnerability [among young people] compared to that among adults” or to a picture of adolescents being less accurate in their judgments than adults (p. 30). After noting the limitations of the available research (e.g., a lack of longitudinal studies that differentiate cohort from developmental influences), they conclude that “the finding of age-related increases in risk identification does call into question the degree to which we should consider adolescents, particularly younger adolescents, competent” (p. 24). Based on their review of the literature on the development of judgmental maturity, Steinberg and Cauffman (1996) concluded that evidence points to greater differences between early adolescents and mid- and later adolescents than between the two older groups. The authors suggested that more research is needed on the cognitive and noncognitive factors associated with mature decision making as needed. In presenting initial results from an Australian study of 234 participants ages 12, 15, 18, and 21 years who were asked about several medical treatment vignettes, Bartholomew (1996) reported that 12-year-olds showed less evidence of decisional capacity than older participants. In contrast, 15-year-olds did not show significant differences from 18-year olds on measures related to comprehension and the amount of information sought. On other measures that related to reasoning capacities, however, 15-year-olds were more like 12-year-olds than they were like older participants. A study by Bernhardt and colleagues (2003) of children's views of participation in a genetic susceptibility study suggested that the children (ages 10 to 17 years) did not initially appreciate the study's risks and potential benefits. When conversation encouraged them to “personalize” the possible consequences of genetic testing, they developed a fuller appreciation of the possible risks. This supports the emphasis on discussion in the design of the assent process. Other research suggests that the development of decision-making capacities continues into adulthood, although “not all of these developmental changes point to increased rationality” (Millstein and Halpern-Felsher, 2001, p. 37). For example, certain biases in decision making may increase with age, including the tendency to reject evidence inconsistent with one's views and accept evidence that supports them (Stanovich and West, 2000; Millstein and Halpern-Felsher, 2001; but see also, Klaczynski and Gordon, 1996 and Klaczynski and Narasimham, 1998). Although a number of studies indicate that adolescents differ little from adults in certain elements of competent decision making, research overall suggests that abilities to comprehend important dimensions of research participation continue to evolve during adolescence. As the research reviewed earlier in this chapter made clear, adults are not always well informed and often show deficits in understanding related to research participation, especially when they are under stress. Overall, the committee concludes that it is usually advisable for parents to be involved in decision making about research participation for adolescents. Adolescents' capacity to make informed decisions should not, however, be dismissed out of hand, especially when requiring parental permission would endanger adolescents or preclude their participation in research with important potential to benefit them or other adolescents in the future. Several studies suggest that younger children have less understanding than adolescents of their rights in research, including rights related to confidentiality and their choice to participate in a study (or withdraw from a study once it has started). For example, Bruzzese and Fisher (2003) asked children in the 4th, 7th and 10th grades to identify violations of research rights in several hypothetical vignettes. The youngest children were least able to identify such situations. In a study of 9-, 15-, and 21-year-old males, Belter and Grisso (1984) concluded that the 9-year-olds were less able to recognize violations of patient rights and less able to protect against such violations than the 15- and 21-year-olds. With respect to confidentiality specifically, Hurley and Underwood (2002) found that sizeable minorities of second graders in their study did not understand the “fine points of confidentiality,” despite repeated explanations in different contexts that information from their study would not be shared with family or school personnel (p. 140). Fourth and sixth graders did better. In their study of children ages 5 to 12 years, Abramovitch and colleagues (1991) likewise found younger children to be more uncertain about confidentiality. In contrast, Bruzzese and Fisher (2003) reported that a large majority of the students at each grade level (4th, 7th, and 10th grades) in their study understood confidentiality. In discussing the difference between their findings and those of Abramovitch and colleagues (1991), Bruzzese and Fisher (2003) suggested that their repeated explanations of rights—before students took the permission form home to parents and again before the testing began—may have contributed to their better results among the younger children. Hurley and Underwood (2002) also provided repeated explanations, without the expected effects, but the youngest children in the study by Bruzzese and Fisher were older than the youngest children in the two other studies. On the question of what would happen if they wanted to stop participating in the study, the children in the different age groups studied by Hurley and Underwood (2002) had similar, high levels of accurate responses. In contrast, the study by Ondrusek and colleagues (1998) cited earlier found that children under age 10 years had a low level of understanding that they could withdraw from the study. Even the older children believed that their parents would not like them to withdraw. Abramovitch and colleagues (1991) also found that few children ages 5 to 12 years believed that they had the right to withdraw from the study. In the study by Brusseze and Fisher (2003), fourth and seventh graders were less likely than older adolescents to understand that they had the right to withdraw from the study, although the majority in both groups did indicate accurately that they had that right. The investigators noted that they had, on the basis of findings from previous research, made particular efforts to provide explicit explanations of voluntary participation and how to withdraw from participation. Bruzzese and Fisher (2003) concluded that providing a brief lesson in the rights of research participants improved understanding of these rights for individuals in each of the grade levels studied as well as for college students. (The investigators compared the responses of the students receiving the research rights lesson with students receiving education about an unrelated topic.) Their findings suggest, however, that even young adults may not be aware of their right to ask questions of investigators. They may also be uncomfortable asking questions in some research situations. Overall, Hurley and Underwood (2002) also concluded that processes for obtaining assent and debriefing children after research participation were “moderately effective” in helping children understand their rights as research participants (p. 139). Younger children understood less than older children. The authors cautioned that debriefing might “do more harm than good” for younger children who do not understand the information provided (p. 139). Although her opinions were focused on medical care rather than research, the views of a 7-year-old on how hospitals could make children more comfortable suggest that some very young children do have concepts of responsible action by health professionals. As expressed to her mother (a newspaper columnist), the child set forth several rules (McIntyre, 2002; used with permission; excerpts not in original order):
To summarize, findings about children's and adolescents' understanding of their rights in research are generally consistent with findings about their comprehension of research purposes and characteristics. Older children and adolescents understand more than younger children. Some studies indicate that careful explanations of research rights can help both younger and older children have an improved understanding of their rights as research participants. Few studies have directly examined the influence of children's or adolescents' experience with illness on their understanding of research participation. The literature cited above in the general discussion of children's cognitive development suggests that culture, context, and experience as well as age can influence children's cognitive skills and understanding of the world. In their research on children's experience of grave illness (e.g., cancer recurrence), Bluebond-Langner and colleagues (in press) found “evidence for children's ability to hold several, sometimes contradictory views of their illness and what a particular treatment, drug or trial would offer.” The children—and their parents—could recognize that their condition was not curable but still express belief or hope in the possibility of a cure. In the context of grave illness, the views of many children about participation in a clinical trial may be captured in one child's statement: “What choice is there? It is this or nothing.” The investigators reported that children's experiences with grave illnesses are more predictive of their understanding of their illness and prognosis than is their age. Earlier qualitative studies suggest that children who have serious chronic illnesses may develop an earlier conceptual understanding of death than healthy children (see, e.g., Bluebond-Langner, 1978; and Sourkes, 1995). In the study by Broome and colleagues (2001) cited earlier, the investigators found that half of the 24 children with cancer indicated awareness that they were in research, whereas all 10 diabetic children knew they were involved in research and could more clearly differentiate between clinical care for their condition and the treatment-related aspects of the clinical trials in which they were participating. The authors link the differences in understanding to differences in experiences. The children with diabetes had lived with their condition for a longer period, were on a stable treatment regimen, and had been involved in multiple studies since the diagnosis of their condition. As an incentive for their participation in research, these children also received a gift certificate or payment at the end of the studies. In contrast, the children with cancer had more recently received the diagnosis, had little or no previous experience with research, were presented with the option to participate in research soon after receiving the diagnosis under highly stressful circumstances, and were never offered financial incentives to participate in the research. These children were often involved in several studies, and the studies were typically simultaneous and related to each other and their clinical care. Some of the children with cancer were in data collection studies that did not involve an experimental intervention, and some of them may not have understood that this data collection was research. In addition, several of the children with cancer “were removed from the discussions” surrounding their enrollment in research because of pain or the severity of their illness (p. 44). As children develop, one mark of increasing maturity is an increasing desire for autonomy in decision making. Voluntary choice and independence in thinking are important dimensions of informed consent. The influence of parents appears to be strongest for younger children but parents influence adolescents as well. In a study with individuals ages 9 to 10, 14 to 15, and 21 to 25 years that used hypothetical vignettes about medical treatment, investigators reported that considerable deference to parents' preferences was evident at all ages (Scherer, 1991). The youngest children, however, were the most deferential, particularly for vignettes involving more severe and complicated situations. The children gave various reasons for their deference, including respect for parental judgment and knowledge, need for parental support, desire to avoid conflict, and a belief that they had no choice. Based on responses of just the 14- and 15-year-olds in this study, Scherer and Reppucci (1988) reported that deference varied depending on the degree of parental pressure depicted. Abramovitch and colleagues (1991), in their study of participation in psychological research by children ages 5 to 12 years, found children across this age spectrum were concerned about withdrawing from research for fear of disappointing their parents and health care professionals. Based on their interviews with children with cancer and children with diabetes, Broome and Richards (2003) reported that nearly all the children had faith that their parents would protect them. Responses were more mixed on whether parents would support children's choices about research participation, although most thought their parents would take their views into account. In their study cited earlier, Geller and colleagues (2003) suggested that the older and more mature the child the greater the likelihood that decisions would be made jointly rather than by the parents alone. The children and adolescents that they interviewed generally believed that the decision to participate should be the child's, “unless they're like babies” (p. 264). All, however, wanted to know what their parents thought. A minority (all younger girls) said that they would defer to their parents. Reporting on a study with 37 adolescents and their parents, Brody and colleagues (2003) found that the two groups agreed approximately three-quarters of the time on decisions involving an asthma research vignette. Both, however, claimed that they had “ultimate responsibility for the participation decision” (p. 79). Bluebond-Langner and colleagues (in press) have stressed that one complication in determining what gravely ill children understand or want with respect to treatment or participation in research is that these children, in particular, may not express their concerns, wishes, or fears to their parents, clinicians, or investigators. This reticence may reflect not only the children's deference to their parents but also the children's desire to protect their parents from the additional distress of knowing their child's fears or facing the mutual acknowledgment of the prospect of death. The investigators refer to a process of “mutual pretense” that constrains free discussion and questions about treatment or research in the context of grave illness. Children's dissent or unwillingness to agree to research participation is not well studied. Citing the work of Abramovitch and colleagues (1991), Thompson (2000b) notes that children may find meaningful dissent difficult “not only because of limitations in judgment, but also because their invitation to participate typically occurs in a context of prior parental permission, institutional support (whether the institution is a school, childcare center, hospital, or other setting), and adults' interests in furthering the research enterprise” (pp. 164-165). When a parent believes that the child should participate in research for altruistic or other reasons and the child does not want to participate, the actual decision about research may involve sensitive discussions with the parent and child. As long as the child is not coerced into assenting, it is reasonable for parents to engage in persuasive discussion, for example, about the importance of helping others. Even young children know what it means to “help” someone, although the ability of children to reason abstractly about altruism develops with age. Children also show empathy, sympathy, and other traits associated with the moral motives for adult altruism (Hoffman, 1990; Eisenberg et al., 2002; Bernhardt et al., 2003). Nonetheless, consistent with the regulations, the child's dissent should override parental assent when the research does not promise direct benefit to the child.
Although research is limited and findings are not entirely consistent, they support a gradual expansion of the involvement of children in discussions and decisions about research participation. For younger children, the emphasis should be on providing basic information about what will happen, responding to their questions and concerns (including those not explicitly expressed), and—particularly when the research does not offer the prospect of direct benefit—recognizing when children do not want to participate. Even when federal guidelines do not require the child's assent, investigators should still inform children (as appropriate given the circumstances) about what will happen and answer any questions that the child may have. As children mature, they can participate more fully in discussions and decisions about their participation in research, although the involvement of parents is still required and prudent in most situations. Older adolescents may not have the legal capacity to make decisions in their own right, but the research reviewed here generally suggests that their level of comprehension of research approaches that of adults. Many aspects of the assent process can be similar to the consent process for adults if that process has been designed to accommodate people of various educational, social, and cultural backgrounds. For children and adolescents as well as adults, physical incapacity or distress related to serious illness may limit the extent to which they are involved. Fisher (2003) has described a general approach to assent that aims for a “goodness-of-fit” between children's maturing skills and the assent processes. Because children have limited experience exercising their rights in response to requests from adults (especially in educational, medical, or unfamiliar settings), the assent process should be designed to demonstrate that participation is voluntary and dissent will not be penalized. In some cases, tutorials on research procedures and protections may be an appropriate element of the assent process. Opportunities for supported decision making that involves a parent-child discussion can also be created; a facilitator may be helpful in such a discussion. The broad objective is to create assent contexts and processes that minimize stress, encourage children's involvement in decisions about their participation in research, and ensure that their wishes and concerns are adequately communicated and considered. Based on their analysis of findings related to both parents and children, Broome and colleagues (2003) similarly argue for variations in the permission and assent process to fit the circumstances, particularly in studies involving adolescents. They conclude that the explanations of research should be provided separately to adolescents and their parents and that parents and adolescents should, when feasible, be provided more time (hours to days) to consider participation in clinical trials related to serious illness. For adolescents and their parents, agreement to research participated should be regarded as a “shared endeavor … based on implicit, developmentally based negotiations” (Broome et al., 2003, p. S23). Among the sensitive issues related to research participation is when adolescents should be free to consent to research participation without parental permission. As noted above, although the DHHS regulations make provisions for the waiver of parental consent when appropriate, the FDA regulations do not. The research reviewed here suggests that the DHHS regulations reasonably provide for waivers, as long as safeguards are provided that are appropriate for the individual adolescent being considered for research participation. |
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