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The handle http://hdl.handle.net/1887/44738 holds various files of this Leiden University dissertation
Author: Grootens-Wiegers, P.
Title: Targeted informed consent : empowering young participants in medical-scientific research
Issue Date: 2016-12-06
General Introduction
The need for pediatric research
Scientific progress in pediatrics is urgently needed, as currently 45-60% of medication is prescribed off-label, meaning that the medication for children and adolescents is not tested in a clinical trial with the specific target group for which it is prescribed (Conroy et al., 2000; ‘t Jong et al., 2000; WHO, 2013). In pediatric practice this has several consequences (WHO, 2013):
- Drugs are prescribed to children, although a clinical trial has only been performed with adult patients;
- Medication is tested for one disease and subsequently prescribed for another;
- Prescribed dosages for children are not based on scientific evidence.
This situation is problematic, as the physiology of children’s developing bodies is different from that of adults (De Wildt, Tibboel, & Leeder, 2014). As a result, medication proven effective and safe in adults could be ineffective or even harmful in children. It is thus vital that more insight is gained in the physiology, disease pathology and treatment opportunities for children and adolescents. To this end the World Health Organization has issued a report on Priority Medicines for Children with a strong plea for more research with minors (WHO, 2013).
However, the possibilities to perform research with minors are more limited than for research with adults, as children are a protected research population. In the Netherlands it is currently only allowed to perform so-called therapeutic research with minors, meaning that the trial could be of direct benefit to the subject. Non-therapeutic research is possible only when a trial could not be conducted without the participation of the minor as a research subject, and provided that the risk associated with participation is negligible and the burden is minimal (Medical Research (Human Subjects) Act, 1998, Section 4).
These restrictions result in a limited scope of research that can be performed with minors, as research procedures that can advance scientific insights do not always directly benefit participants, or do place more than minimal risks and burden on the subject.
Attitudes towards involving minors in research
The dilemma of research needs on the one hand and protection on the other is addressed in a recent Ministry of Health-commissioned advisory report on research with children,
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presented in 2009 by the Doek Committee (Doek Committee, 2009). According to this report, changes need to be made in current regulations for research with minors.
Specifically, the age to decide upon research participation should be lowered (from 18 to 16 years old), and the limits restricting the level of risks and burden of research for minors should be loosened. According to the committee, these changes would lead to the much needed and desired increase in research possibilities with minors.
The report of the Doek Committee signifies a shift in the attitude towards research with minors. A previous commissioned report on research with children from the Meijers Committee (Meijers Committee, 1995) was based on a restrictive “no-unless” attitude;
no non-therapeutic research should be performed with minors, unless the research is absolutely necessary, cannot be performed with adults, and places negligent risks and minimal burden upon the young participants. This report was the basis for the current Dutch regulations. In contrast to the Meijers report, the report of the Doek Committee holds a “yes-if” attitude towards research with minors. Instead of the strict distinction between therapeutic and non-therapeutic research, the Doek report advises that interventional medical research may be performed with minors provided that there is at least a chance that the subject may benefit from participation, or that there is some direct benefit for the group to which the participant belongs. Observational medical research, which commonly does not provide direct benefits, may be carried out if it places ‘minimal’
(instead of ‘negligible’) risks and burden. Evaluation of the risks and burden of research participation should include the particular circumstances of the category of children and should be proportional to the importance of the research.
This change in attitude originates from a shift in the way minors are viewed. In the Meijers report, children under the age of 12 are considered incapacitated, and children older than 12 could possibly be deemed competent, but need to prove this in a competence assessment (Meijers Committee, 1995, p.32). The report recommends that consent for research participation should be sought from a representative, and the researcher should inform the child at the proper level of understanding (Meijers Committee, 1995, p.32).
It is thus clear that the Meijers report focuses on the incompetence and protection of minors and thereby they are assigned a passive role in the decision-making process.
The Doek report, however, claims that we should no longer view children as moral objects, i.e. objects in need of protection, as this does not do justice to the children.
Rather, we should view them as moral subjects, i.e. children are agents and have their own
conceptions and feelings (Doek Committee, 2009, p. 26). The child as a moral subject should be allowed to act according to its personal values, insight and will, and should thus be provided with the opportunity to participate in medical research and to be involved in the decision-making process about research participation (Doek Committee, 2009, p.33).
It is remarkable that in a timespan of only 15 years the attitude towards children has changed so significantly. Where does this change come from and what evidence do we have supporting this changing attitude? Is it indeed legitimate to view children as moral subjects instead of objects, and if so, what are the consequences for research practices?
Little research evidence exists concerning the role that children can and want to play in decision-making about medical-scientific research. Increased insights are necessary in order to justify the changing attitude towards children, and to understand how children can truly be involved to support best practices.
Background of this thesis
An amendment of the Dutch law based on the Doek report would facilitate an increase in medical-scientific research with children in the Netherlands, and indeed the Dutch Parliament seems to be willing to grant substantial changes in the Dutch law1. However, a number of issues arise concerning this new attitude towards children. These concern (1) informed consent as a prerequisite for research participation, and (2) the claim that children should be considered as moral subjects.
1. Informed Consent as a prerequisite for research participation
With regard to involvement in the decision about research participation, there is a rather unique situation in the Netherlands (Lepola et al., 2016). Next to the internationally recognized distinction between adults who have the right for self-determination, and minors (and other incapacitated groups) for whom decisions need to be executed by representatives, there is a third situation when it comes to medical decision-making.
1 An amendment is at the time of writing under discussion by the Dutch Senate, to be retrieved at:
https://www.eerstekamer.nl/wetsvoorstel/33508_verrichten_van_medisch
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Children from the age of 12 until 182 are assigned a role in shared decision-making about research participation together with their parents or legal guardians3. This means that they have an official role in the so-called informed consent process, a necessary require- ment for research participation in order to protect research participants from unethical practices. The requirements for informed consent stem from various guidelines, among which the Nuremberg Code (1949) and the Helsinki Code (originating from 1964, revised multiple times: World Medical Association, 2013). The core value of these guidelines is the protection of research participants and the ethical consideration that the interest of the research participants supersedes the interest of the research itself. All research guidelines have in common that they state that research with humans is only allowed if (1) the research setup is scientifically sound and approved by an Institutional Review Board; (2) participation is voluntary; and (3) informed consent is provided.
In the Netherlands, research participation is regulated by the Dutch law on medical research with humans (Medical Research (Human Subjects) Act, 1998), which in accor- dance with the previous advice from the Meijers Committee, holds a “no-unless” attitude towards research participation of minors: research with persons younger than 18 years old is prohibited, unless it can benefit them. Non-therapeutic research is only possible when the research cannot be conducted without minors and there is negligible risk and minimal burden (Art. 4). If research is performed with children from the age of 12, then they should provide written consent, together with their parents. In Article 6, it is specified that before asking consent for participation, information should be provided on the purpose, nature and duration of the research and the risks for the participant (Art. 6.5), and that it should be ensured that the participant can understand this information (Art 6.6). It thus follows that adequately informing young research participants is an essential requirement for obtaining informed consent, and thus for research participation. Without proper understanding of what it is that someone signs up for, we can neither speak of informed consent, nor of actual voluntary research participation.
2 At the time of writing an amendment to change the age limits for shared consent to 12-16 has been approved by the Dutch House of Representatives (Tweede Kamer) and is under discussion in the Senate (Eerste Kamer; file 33.508).
3 In the remainder of the text, whenever there is mention of ‘parents’ one can also read ‘parents or legal guardians’.
In practice, this informed consent procedure translates into the provision of an ‘informed consent form’ consisting of several pages of written text concerning the specifics on the research, sometimes accompanied by additional oral explanation. For children in the age range of 12-18, a special form is provided next to the form that the parents receive. This special form is supposed to be directed at the level of understanding of the minors.
However, it is questionable whether the special forms indeed create comprehension, as studies on children participating in research demonstrate a lack of understanding of essential research concepts. For example, in one study, 76% of the children did not understand the risks related to participation (O'Lonergan & Forster-Harwood, 2011), 86%
reported not to understand what the doctor told them about the research (Unguru, Sill,
& Kamani, 2010) and 51% of the children was even unaware that the treatment they underwent was in fact part of clinical research (Unguru et al., 2010). Other studies have reported that children often feel excluded from doctor-patient conversations, because doctors tend to direct their explanations to the parents, and because the language is too complex and too technical (Broome, Richards, & Hall, 2001; Chappuy, Doz, Blanche, Gentet, & Tréluyer, 2008; Kodish et al., 2004; Tates, Meeuwesen, Bensing, & Elbers, 2002).
These results indicate a fundamental problem with the informed consent procedure among minors: it appears that current practice is not up to standards with the ethical intent to inform research participants at the proper level of understanding and stimulate an informed and voluntary decision.
2. The child as moral subject
According to the Doek Committee, children should be granted influence in decision- making about medical-scientific research participation and should be allowed to act according to their personal values, based on the notion that they should be considered a moral subject. In the Doek report, however, there is hardly any justification for the fundamental shift from viewing the child as an object of protection to viewing the child as a moral subject. The main evidence that is provided for this shift is a research study of Sokol et al. (Sokol, Chandler, & Jones, 2004). In this research an analysis is presented of children’s moral judgements, demonstrating that children initially have an objective view of moral responsibility (i.e. actions are either ‘good’ or ‘bad’ in itself), which then during development changes into a subjective notion of responsibility (i.e. the intention of an action is also considered when judging an action as ‘good’ or ‘bad’). Sokol does not mention the concept of a ‘moral subject’ or ‘moral object’, but discusses the type
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of morality that children possess. It is remarkable that such a big shift in thinking as proposed by the Doek report (that is even responsible for an amendment in the law) is not supported by a body of sound scientific evidence. It appears as if the Doek Committee has based her recommendations mostly on intuitive expert opinion.
Aims
If we are to involve more children in research, and especially if we are to involve children more in research decision-making, we need to make sure that the informed consent process is ethically sound. Given the lack of understanding among young participants in other countries, as mentioned before, it is likely that a similar problem exists in the Netherlands.
In order to guarantee an adequate informed consent process as prescribed by the Dutch law, we need to gain more insight in the quality of the current informed consent process and materials for minors in the Netherlands. In addition, the currently used information format for minors is similar to that of adults (i.e. several pages of plain text), whereas information needs and preferred communication formats differ between children and adults (Broome, 1999). Therefore, new informed consent material should be developed specifically targeted at children and adolescents, in order to achieve optimal understanding in minors and empower them to make an informed and voluntary decision about research participation.
The legitimacy of the claim that ‘children should be viewed as moral subjects’ should be investigated. Is there evidence supporting this claim? And are children indeed capable of decision-making in a research context? Moreover, what can we learn from children’s experiences during the informed consent process, and what are their preferences for involvement? In other words: what is the role that children can play, should play and want to play in decision-making on participation in medical-scientific research. These issues will be addressed in this thesis from a theoretical and empirical angle, in order to lead to recommendations on involvement of minors in the informed consent process.
Research Questions
Following the above, three central research questions were formulated:
1. How can research information material be targeted to minors in order to empower them to participate in decision-making?
2. What is the role that children can, should and want to play in decision-making concerning participation in medical-scientific research?
3. Is the change in view on the status of the child in medical-scientific research (from moral object to moral subject) legitimate?
In order to answer these questions, the following subquestions will be addressed:
1. Is there scientific evidence on the quality of research information for minors?
(Chapter 2)
2. What is the quality of currently used research information material in the Netherlands? (Chapter 3)
3. What are children’s preferences and needs concerning text and supporting visuals in research information? (Chapter 3)
4. How can novel information material be adapted to optimally connect to the preferences of the end-users (i.e. children, adolescents, parents, research nurses, pediatricians)? (Chapter 4 and 5)
5. What are the perspectives of minors themselves on their role in decision-making about medical-scientific research? (Chapter 6)
6. At what age can minors be expected to be competent for medical decision-making?
(Chapter 7)
7. What view on children should we adopt in the context of participation in medical decision-making? (Chapter 8)
Target group
The study target group is “minors”, in this thesis loosely defined as children and adolescents younger than 18 years old, in the Netherlands. In our evaluation of the competence of minors in medical decision-making, we have looked beyond the juridical boundaries of involving children from the age of 12, in order to focus on the (developing) capacities
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and possibilities of children (Hein, Troost, & Lindeboom, 2014). For the development of novel research information material, we have focused on children in the age category from 10-14 years old, as research has indicated that this is a distinct target group in terms of understanding research information. Children younger than 10 years old seem to be incapable of understanding certain essential research concepts, whereas children older than 14 seem to have a similar understanding to that of adults (Hein, Troost & Lindeboom, 2014; Ondrusek, Abramovitch, Pencharz, & Koren, 1998; Weithorn & Campbell, 1982).
Methods
In order to gain more insight in the quality of patient information forms for minors (sub- question 1), a systematic literature search was performed. Two aspects of quality were analyzed: the effect of format on understanding and the optimal readability of text in the documents.
To address the quality of research information for children in the Netherlands (subquestion 2), text readability and the role of visuals in the forms were assessed.
In order to increase our understanding of how to optimally connect research information to children (subquestion 4 and 5), we used a process of consultation of the target group and subsequent participatory development. This participatory method was chosen based on the notion that children are the experts on their own information needs and preferences and perspectives (Dedding, Reis, Wolf, & Hardon, 2015; Lansdown, 2001).
Participation of the target group is a means to obtain a better understanding of the target group and to ensure that the final product will reach the intended audience (C. Hart & Chesson, 1998). Participation is not an on-or-off phenomenon; it can be reached at various levels of intensity. According to Hart (R.A. Hart, 1992), there are eight levels of participatory involvement, described by the so-called Ladder of Hart. The levels vary from manipulation (i.e. pretend involvement, without real implications) to shared decision-making (see box 1).
In our study, we developed research information material that is of legal status and there- fore we adopted an initial top-down approach (i.e. without involving the target group) in order to ensure that all the required information would be present. Subsequently, children were involved at level 5: children were consulted about their perspective and experiences
and their input was implemented. Due to the nature of the legally mandatory content for the new information material, level 5 was the highest participatory involvement possible in this study.
Levels of participation (R.A. Hart, 1992) 8. Child-initiated; shared decisions with adults 7. Child-initiated and directed
6. Adult-initiated; shared decisions with children 5. Children are consulted and informed 4. Children are assigned but informed 3. Tokenism
2. Decoration 1. Manipulation
Box 1. The Ladder of Hart (R.A. Hart, 1992). Level 1-3 are assigned as ‘non-participation’
Children were consulted in focus groups to identify their preferences and needs for text and supporting visuals (subquestion 3). This group form of interviewing was chosen, because it reduces the influence of the interviewer and thereby increases the influence of the children on the discussion outcome (Kitzinger, 1995). In addition, in a focus group the children can respond to each other, leading to a more in-depth discussion of the topics that they themselves consider important. Based on the results, new information material was developed in co-creation: feedback from end-users on the information material was collected by surveys, interviews and focus groups (subquestion 4).
The new information material was designed in the format of a comic book. Comic books combine written text with pictures and a story-line, which makes them ideally suited for education of young patients (M. J. Green & Myers, 2010). Pictures supporting written information are a powerful tool to increase comprehension (Mayer, 2001). Considering the story-line, Barnett observed that the use of a story-format for children significantly improves comprehension when compared to a standard text-format (Barnett, Harrison, Newman, Bentley, & Cummins, 2005). Comics have already shown their potential as a useful medium in school education and can improve patient education as well (M. J.
Green & Myers, 2010; Tjiam et al., 2013).
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A draft of the comic strip was developed by a science communicator in collaboration with pediatricians. The draft was presented to children participating in a clinical trial and to two school classes. Children were consulted for further development in surveys and interviews. Subsequently, the material was revised and re-evaluated in four school classes with children of varying ages and educational levels. Next, the new material was evaluated in focus groups with research nurses of 8 Dutch medical centers and children participating in a clinical trial and their parents. Based on their recommendations, a final revision was executed in order to optimize the material for use in research practice.
An empirical study using semi-structured interviews was set up to gain insight in the perspectives of minors on their role in the decision-making process (subquestion 5). In order to discuss the role that children can play in decision-making, a multidisciplinary review was drafted, combining insights from neuroscience, psychology, ethics, decision- making science and medical practice (subquestion 6). Evidence on the developing brain in children and adolescents was reviewed and related to the capacities required for medical- decision making; (1) communicating a choice, (2) understanding, (3) reasoning, and (4) appreciation (Appelbaum & Grisso, 2001), in order to assess at what age minors can be expected to be competent to be involved in the informed consent process. In addition, an ethical background review was written, discussing the way we view children in the context of medical decision-making, and to identify how the debate can be advanced by recognizing the potential of children (subquestion 7).
Outline
The body of this thesis is divided into three parts.
Part I: If we are to involve more children in research, we need to make sure that informed consent as the prerequisite for ethical research practice is performed adequately. There- fore, in Part I the quality of the current informed consent for children and adolescents is examined based on a systematic literature review (Chapter 2), the analysis of Dutch information forms for minors, and focus groups with minors on their information needs and preferences (Chapter 3).
Part II: We will discuss how to improve informed consent practice in Part II, in which the participatory development of innovative research information material for minors is presented (Chapter 4 and 5).
Part III: Finally, the change in attitude towards children in research as described by the Doek Committee will be evaluated. In Part III the role children can, should and want to play in decision-making about medical-scientific research is discussed from the perspectives of minors themselves (Chapter 6) and from a theoretical standpoint (Chapter 7 and 8).
In the discussion (Chapter 9), the insights from this research project will be combined and recommendations will be given on how to empower minors in decision-making about research participation.
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