Ethical Conduct of Clinical Research Involving Children (2004) / Chapter Skim
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5 Understanding and Agreeing to Children's Participation in Clinical Research
5 Understanding and Agreeing to Children's Participation in Clinical Research
Pages 146-210
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From page 146... ...
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.
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From page 147... ...
ETHICAL PRINCIPLES AND LEGAL REQUIREMENTS The Ethics of Informed Consent, Permission, and Assent For pediatric ethics, informed consent is more properly under stood as a combination of informed parental permission and (when appropriate) the assent of the child.
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From page 148... ...
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.
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From page 149... ...
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)
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From page 150... ...
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.
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From page 151... ...
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.
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From page 152... ...
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)
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From page 153... ...
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.
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From page 154... ...
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)
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From page 155... ...
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)
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From page 156... ...
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.
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From page 157... ...
Although the terminology or label used in different states varies, emancipated minors can make decisions as if they had reached the age of majority. They thus can provide informed consent to medical treatment in their own right.
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From page 158... ...
Again, as Appendix B explains, statutes and case law rarely refer specifically to decisions by minors about participation in research. Because state laws are so variable and often vague, investigators and IRBs must be knowledgeable about federal, state, and local laws related to consent, confidentiality, and related matters when they consider research that involves waiver of parental permission.
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From page 159... ...
. Some research findings about informed consent for clinical care are also relevant to the research context, although the ethical and informational requirements are usually more stringent for informed consent in the context of research.
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From page 160... ...
It also supports a recognition that decision making about research participation -- whether on one's own behalf or that of another -- is an imperfect process. General Reading Levels, Readability, and Informed Consent and Permission Forms Consent and permission forms are only one element of a meaningful process of parental decision making about a child's participation in research.
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From page 161... ...
In reality, little is known about these conversations, including whether they can compensate for deficient consent forms. Although forms should not be the main focus of the consent and permission process, the exercise of developing a clear, readable, and informative consent document can contribute to the design and implementation of a clear, understandable, and constructive process for seeking informed consent or permission.
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From page 162... ...
(The authors noted that participants in their study tested at an average literacy level at or above ninth grade, higher than might be found in many research contexts.) Evaluations of consent forms often focus on quantitative "grade-level" measures of readability, but other aspects of written forms should also be considered.4 These include the logical flow of ideas, the organization of headings and subheadings, type style and size, page layout, the helpful use of graphics, and cultural and linguistic appropriateness or adaptations.
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From page 163... ...
Presentation of Quantitative Information Just as the readability of research consent and permission forms may affect parent's comprehension, so may the way in which information about the probability of potential harms and potential benefits of research participation is presented. The committee found no studies that assessed the quantitative information provided to prospective research participants or to the parents of prospective research participants.
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From page 164... ...
They also cited three studies from the 1990s that reported a near majority or majority of physicians believed that research participants did not understand the information given them or realize that they were participating in research. Several studies suggest that research participants frequently have expectations of benefit, even in clinical trials that test safety but not efficacy (see, e.g., Daugherty et al., 1995; Schutta and Burnett, 2000; Meropol et al., 2003; and Weinfurt et al., 2003)
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From page 165... ...
Although patients in medical research were viewed as being at greater risk and more likely to get unproven treatments than those in clinical investigations or clinical trials, they were thought to be more likely to benefit medically. The term medical study was viewed more positively than medical research, perhaps because it seemed to suggest research involving records and not patients.
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From page 166... ...
A number of research institutions and IRBs set an eighth-grade reading level as the target for written materials, but as discussed earlier, a target of a sixth-grade reading level may benefit many parents and other adults as long as essential information can still be accurately presented. Research about the comprehension of quantitative information suggests that investigators should present estimates of potential harms and benefits using frequencies rather than (or in addition to)
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From page 167... ...
to enroll their child in a physiological study (without a prospect of direct benefit) related to sudden infant death syndrome.
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From page 168... ...
or declined (n = 37) to have their newborn infant included in one of three randomized, controlled clinical trials in a neonatal intensive care unit (Zupancic et al., 1997)
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From page 169... ...
Joseph Lilly, parent, 2003 The circumstances under which parents face making a decision about a child's participation in research may have a profound effect on their ability to evaluate information, ask questions, and make reasoned assessment of the potential harms and potential benefits presented by the proposed research. In particular, the conditions for informed and reasoned choice are threatened when parents are confronting a new diagnosis of a life-threatening medical condition and a crisis situation in which immediate decisions are sought.
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From page 170... ...
studied 33 Australian parents whose children's health status ranged from healthy to seriously ill. The investigators reported that parents of ill children, some of whom were or had been involved in clinical trials, saw the greatest potential for direct or personal benefit from the trial.
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From page 171... ...
As described above, parents who agreed were more likely than parents who did not agree to believe that the trials would probably benefit their child and were less likely to believe that the trials were risky. Overall, these studies point to the need for particular care in the design and review of processes for seeking parental permission for research that will involve seriously ill children and high-stress situations.
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From page 172... ...
Olechnowicz and colleagues (2002) evaluated 85 "informed consent" conferences, comparing those with the child present versus those with the child not present.
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From page 173... ...
The committee agrees that more research would be helpful to understand parent and child views about children's participation in discussions and decisions about participation in research. It also encourages more research on the effects on communication of including children in initial discussions of research participation and, more generally, the effects of different ways of structuring the permission and assent process.
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From page 174... ...
This is possible in a well-designed consent and permission process. In another study that examined parents' preferences for clinician involvement in decisions about clinical care (not research)
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From page 175... ...
In another article from their study of parents' agreement to children's participation in a clinical anesthesia or surgery study, Tait and colleagues (2002) asked 184 parents and 38 investigators to rank elements of informed consent by importance.
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From page 176... ...
Physicians had explained randomization in 83 percent of the discussions. As the researchers observed, "to make informed consent more effective, future research must seek to improve communication" (Kodish et al., 2004, p.
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From page 177... ...
Particular care needs to be taken when seeking permission from parents who are just beginning to cope with a child's serious illness or injury and its treatment. In these circumstances, investigators and IRBs should consider structuring parental permission as a continuing process that is sensitive to parents' developing knowledge of their child's diagnosis and prognosis, as well as the treatment options.
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From page 178... ...
178 ETHICAL CONDUCT OF CLINICAL RESEARCH INVOLVING CHILDREN BOX 5.2 Questions Parents May Want to Ask When Considering Their Child's Participation in Clinical Research · What is the purpose of the research? Who is paying for it?
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From page 179... ...
. These findings reinforce the argument for viewing informed consent (as well as permission 6The basics of Piaget's conceptualization of development are covered in Inhelder and Piaget, 1958; Piaget and Inhelder, 1969; and Grisso and Vierling, 1978.
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From page 180... ...
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.
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From page 181... ...
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)
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From page 182... ...
. Comprehension of Research Purposes, Characteristics, and Possible Consequences I would like to see consent forms be presented in [a clearer]
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From page 183... ...
. They could comprehend certain basic information about what might happen to them in medical treatment or research and what they were expected to do.
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From page 184... ...
. 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)
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From page 185... ...
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.
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From page 186... ...
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.
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From page 187... ...
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.
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From page 188... ...
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.
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From page 189... ...
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.
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From page 190... ...
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.
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From page 191... ...
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.
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From page 192... ...
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.
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From page 193... ...
Of the 21 centers obtaining assent, 10 used a separate assent form with an explanation of the study, whereas the rest provided for initials or a signature on an adult consent form. Some centers used distinct parental permission forms.
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From page 194... ...
. Approximately one-third of the respondents said that their IRB would waive parental permission for a study that involved anonymous testing of adolescents for HIV infection.
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From page 195... ...
. In its summary of common findings of noncompliance after investigation of complaints, OHRP listed several topics under the heading of informed consent, including failure to obtain legally effective consent and various deficiencies in consent documents (OHRP, 2002d)
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From page 196... ...
Focus on Permission and Assent as Processes We have to make sure that in our attempts to protect children we aren't making the consent process so onerous and paper heavy that we're actually prohibiting or inhibiting new studies from open ing, or conversely scaring families away. Lise Yasui, parent, 2003 As discussed earlier, informed consent -- and, by extension, permission and assent -- should be viewed as a process, not a form.
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From page 197... ...
In addition, if the research changes in ways that could affect the parents' and children's assessment of the risks in relation to the potential benefits, permission and assent should also be sought again. For children with serious medical conditions, the initiation of permission and assent procedures for clinical research is often inextricably intertwined with decisions about basic clinical care.
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From page 198... ...
Regardless of the study population, consent and permission forms and processes should avoid language that creates or reinforces confusion about the difference between research and clinical care. In designing and reviewing procedures and related written materials for seeking parental permission, investigators and IRBs should consider what is known or expected about the educational, language, cultural, and other relevant characteristics of the populations to be involved in particular studies.
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From page 199... ...
To support investigators in meeting their ethical obligations as part of the permission and assent process, research sponsors should recognize these costs. Recommendation 5.3: Investigators -- with assistance and oversight from institutional review boards, research institutions, and research sponsors -- should design procedures for seeking parental permission for a child's participation in research that are sensitive to educational, cultural, and other differences among families and include provisions for · educating -- not merely presenting information to -- parents about issues critical to informed decision making and, as appropriate, assess ing the degree to which these critical issues are understood; · writing consent and permission materials in the simplest language that still conveys essential information about the study; and · providing competent, trained translators and interpreters, when needed, and otherwise assisting parents with limited English-language proficiency with making informed decisions.
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From page 200... ...
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.
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From page 201... ...
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.
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From page 202... ...
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)
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From page 203... ...
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)
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From page 204... ...
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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From page 205... ...
Recommendation 5.6: In designing and reviewing procedures for seek ing a child's assent to participation in research, investigators and insti tutional review boards should aim to create assent processes that con sider 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 charac teristics 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)
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From page 206... ...
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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From page 207... ...
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 matu rity -- about the way in which information is presented to children and the manner in which assent is documented. Investigators and institu tional review board members should apply that knowledge in deter mining what procedures will best serve the goals of assent for particular research protocols and populations.
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From page 208... ...
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.
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From page 209... ...
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.
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From page 210... ...
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.
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