An ethical inquiry into the storage and use of bodily material of minors for genetic research

Introduction In history, children were often regarded as second-rate citizens, both in society in general and in medical research specifically. They were considered expendable and used as preferred research subjects, for example to test new vaccines. Much has changed duringthe last century, as clinical research on children became the subject of ethical reflections resulting in guidelines that try to define a balance between participation in research and protection against abuse.Recently there has been a rise in genetic research in general. Such research is supported by the availability of tissue collections, often referred to as biobanks. The establishment of such biobanks has been associatedwith certain ethical issues, which are discussed in some depth in the literature. Also research on stored tissue samples from children can yield valuable information. This raises specific ethical issues which are not completely analogous to the issues raised by the use of adult biological materials. Although much has been written about both the ethical issues related to pediatric clinical trials and those related to adult biobanks, much less has been written about the ethical issues related to pediatric biobanks. These include the scope of parental consent, the balancebetween risks and benefits and the return of individual research results. In this doctoral thesis we have investigated and assessed these themes in order to provide guidance and recommendations.Study Design and ResultsOur ethical inquiry and subsequent recommendationsare based on four steps. First, we performed a state-of-the-art of the concepts and themes in current literature and guidelines. Second, we investigated the current ethos and checked it against the theoretical state-of-the-art. Our investigation of the ethos is done through empirical research of opinions of lay people and professionals. Third, concepts and themes that arose from the first and second part are elaborated, investigated and checked for consistency in in-depth theoretical reflections. Finally, based on the cumulative experiences from the previous parts, we have formulated recommendations. Part 1: State-of-the-art of the ethical aspects of genetic research on pediatric stored tissue samplesWe performed two reviews. With the first review we investigated guidelines and position papers on the topic of biobanks and biological sample collections to check what they recommend for pediatric participants. This review had the form of a systematic review. We found 18 documents that dealt with the issue of stored tissue samples of minors separately. The content of these documents was categorized according to four themes: consent, principles of non-therapeutic research on vulnerablepopulations, ethics committee approval and difference between anonymousand identifiable samples. With the second review we investigated the existing ethical literature on the topic of research on stored tissuesamples from minors. We found 20 theoretical and empirical documents dealing with the issue. After review, we distilled five clusters of themes: consent, risks, benefits, return of results and ownership. We did not find a consistent covering of the ethical themes in either the guidelines or the ethical literature. Part 2: Ethos: Empirical inquiries into the storage and use of pediatric tissue samples for genetic researchIn this part, we studied the opinions of lay people and professionals on the topic of using stored tissue samples from minors for genetic research.To query the opinion of lay people we performed ten focus group discussions (qualitative method), five with adults and five with young people (aged 15-19). After analysis of the discussions, we found the following recurrent categories: the requirement that research should not pose any burden on children and that it should benefit other children, the trust people had in the role of parents, the need for information and the growth towards autonomy. Both the adults and the teenagers we interviewed thought that the inclusion of tissue samples from minors in research had ethical implications. A major concern was that non-therapeutic research would pose no extra burden on children, which would assume the use of non-intrusive methods of gathering samples and the use of samples that were gathered in a diagnostic context. The overall impression was that parents would be the best persons to make decisions on behalfof a small child, and that the same parents would engage their childrenin the decision making when they grew older.To query the opinion ofprofessionals, we took a two step approach. We performed ten semi-structured interviews (qualitative method) with professionals from Belgium, UK and Saudi Arabia involved in genetic research on stored tissue samplesfrom minors. After analysis, we found that researchers were concerned about too bureaucratic consent procedures. But we also found the need forguidance from ethics committees with regard to the scope of consent. Interviewees thought that children should not be burdened with research and should be told, in their own language, about the research. Secondly, we also did a survey among Belgian geneticists. We found that the vast majority of the respondents (92 %) thought that research on stored tissue samples is useful. A majority of respondents stated that parental consent is valid (82,5 %) and 76,5 % thought that children should also be given the right to assent when they understood the implications of storage of biological samples and of genetic research. A small majority put the age at which young people can understand storage or research rather high: 16-18 years (51 % and 53,1 % respectively). Although there is some consensus in the literature that donors should be allowed to give broad consent for future research on their biological samples, only 47,6 % thought that parents should be allowed to consentto any future research on their children s samples.Our empirical inquiry has demonstrated that there is a support for and a beliefin the usefulness of genetic research on stored tissue samples from children and that the right of parents to consent to such research is not questioned.However, there is a strong emphasis on the fact that research should not burden children. Also, children should be involved in the decision making process as they grow older, but it is acknowledged that the capacityof a child to understand what is at stake does not correspond to fixed age thresholds and should preferably be assessed on a case-by-case basis. Part 3: Normative and theoretical reflections In this part, we provided in-depth normative and theoretical reflections on three important topics with regard to the ethical use of storedtissue samples for genetic research (risk and benefit/consent/return ofindividual results), based on the findings from part one and two and supplemented by theoretical foundations. In a first reflection we questionwhether and how the idea of minimal risk is applicable to pediatric research on stored tissue samples. The duty to solidarity, which is oftenquoted in the context of biobank participation, is limited when participants are minors. We argue that the main issues at stake are the fact that research should not burden children and that their values are respected. Also, the prerequisite of group benefit as it is often used in thecontext of clinical trials is hard to maintain when genetic research isat stake, as future benefits of such research are hard to define at theonset. The requirement that research on children s tissue can be done if the same research cannot be done on adults is more straightforward.A second reflection deals with the scope of parental consent for non-therapeutic genetic research. This scope has two dimensions, a temporal one and one related to the content of what is consented to. The temporal scope of parental consent is limited. Young adults have the right to decide autonomously on the faith of their samples once they reach the age ofunderstanding or competence. With regard to the content of what is consented to, there is a growing tendency to ask for broad consent to any future genetic research when participants are adults. We argue that this tendency cannot be directly transferred to parental consent. As children have the right to develop and exercise their own autonomy and have theirown values, and as research and science are not completely value-free, they should be given the opportunity to revise the consent given by their parents for research on their samples.A third reflection deals with the question of the return of individual results in pediatric biobanks. Biobanks with adult participants may have different policies with regard to the return of such research. They can decide not to return any results, return results that are clinically relevant and can be acted upon or leave the choice to the participants whether or not to receive specific results. The situation is different when participants are children. As they have not autonomously decided to participate in the research and are a vulnerable population the duty to return information that may be relevant to their health is higher. Also, parents do not have the right to opt out of receiving such information. However, parents should not be given access to genetic information about their children that has no direct relevance to their health or important clinical significance.Conclusion and RecommendationsBased on the inquiries in parts one and two and the in-depth reflections of the third part, we have formulated recommendations with regard to the use of stored tissue samplesfrom minors. These recommendations can be used and further elaborated by professional organizations. With regard to risks and benefits we statethat research on stored tissue samples should not burden children physically or emotionally and that genetic research on stored tissue samples from children can only be done if the same research cannot be done on samples from adults. With regard to consent, we state that consent by a legal guardian or parent is needed, and that the focus of the right to have a say shifts from the parent(s) to the children as the latter grow older. All children should receive information on their level and a child sassent or dissent should be taken into account. Mature minors should berecontacted and given the opportunity formally to withdraw their samples when they reach the age of understanding or the age of majority. Parents and young people should be notified of new research done on samples and given the possibility to refuse to participate to research if they object to it. With regard to the return of individual results, we state that parents should not be allowed to opt out of receiving information about preventable or treatable early-onset diseases. Also, they should not be given access to any and all genetic data that research may produce. Biobanks should consider returning information about preventable or treatable early onset conditions when participants are minors. Finally, the ethics committee supervising research on stored tissue samples from minors should contain specialists in pediatric research, pediatric genetics and child psychology.nrpages: 234status: publishe