ELSI Challenges with Children in Translational Medicine

Abstract

Paediatric translational research deals mainly with genomics of biological samples. It has benefitted substantially from developments in new technologies and from international collaboration to access and use large cohorts of banked biological samples and associated data. However, there are still significant ELSI (ethical, legal and societal implications) challenges that need to be addressed before we can move smoothly from the “bench” to the “bedside” to the “community”. In this chapter we shall concentrate on the intertwined ethical and legal issues regarding informed assent/consent of minors and the return of genomic results to minors and families. This leads to the societal issues faced in minor engagement and empowerment. We will then emphasise the need for healthcare integrated biobanking to maximise use of samples and data and so facilitate translational research.

1. Introduction

The European Society for Translational Medicine clearly defines Translational Medicine (TM) as:

“…an inter-disciplinary branch of the biomedical field supported by three main pillars: benchside, bedside and community. The goal of TM is to combine disciplines, resources, expertise, and techniques within these pillars to promote enhancements in prevention, diagnosis, and therapies” [1].

This definition inspires us because of its clear description of the two-way relationship between clinical practice and research and, more importantly, because it introduces the concept of community as a determining pillar. Translational medicine promises to improve health care for future populations by translating scientific knowledge from laboratory studies to clinical research to medical applications, including new treatments and preventive measures. This has now become a more realistic vision as scientists have access to biobanking facilities across the globe, facilitating and enhancing transnational collaboration.

Basic research on biological tissues has been boosted by the technological advances in omics, in particular genomic technology, and in bioinformatics handling big data, which promise to unravel the aetiology of rare and common diseases, with the vision of precision and prevention medicine, thus amplifying the necessity to regenerate risk assessment, ethical review, informed assent/consent and supervisory governance processes within a framework of Responsible Research and Innovation (RRI).

This evolution in medicine is critical for children opening new opportunities of children-tailored treatments in paediatric practice, which is not only characterised by a high percentage of rare diseases with a genetic aetiology but is also encumbered with a lack of medicines, specifically targeted for children [2].

Moreover, we cannot emphasise the importance of translational research on “outcomes and effectiveness in populations” [3], of crucial importance to the development of health policies for future generations. So, we prefer to talk about research with children, rather than limit ourselves to paediatric research, which primarily focuses on the clinical aspects.

In this chapter we will use the term child within the context referred to in the Convention on the Rights of the Child (CRC) [4], which defines a child as “every human being below the age of eighteen years unless under the law applicable to the child, majority is attained earlier”. This convention has been internationally recognised, being ratified by 196 states, with the United States (US) being just a signatory [5], making it “the most widely ratified human rights treaty in the world”. The rights it incorporates are a “set of universal standards or norms rooted in formal entitlement to their fulfilment and corresponding obligations on those providing that guarantee” [6].

Research with, and for, children is of special importance because it deals with a significantly higher proportion of genomic research, primarily on biological samples from children with rare diseases, but it is also available for epigenetic studies that may be predictive of risk for chronic disease in future adulthood. However, there is a major issue with the scarce availability of biological material to study, from a single country.

Moreover, this is coupled by the constraints of intertwined ethical, legal and societal issues (ELSI), primarily centred on two aspects:

….the ethical and legal issues of obtaining informed assent/consent for research participation by children, who are unable to provide legal consent, with ethical consideration of balancing benefits and risks to participants and to scientific progress; and.

…..the ethical and social issues associated with the return of results that might be relevant to both the current family and to future generations, compounded by legal issues of privacy and data protection.

Research with children offers the possibility of long-term study, throughout the transition into adulthood, and even beyond, to provide information on disease development and the effects of medical management, including therapy, over a long period of time. Engagement of child participants is crucial to ensure long-term contact with children and follow up into adult life.

Finally, it is important to consider the societal impact on translational research in children. A primary condition to ensure participation in research, particularly if provision of biological samples is required, is the infrastructure and openness of both an informational environment and a multi-actor inclusive research ecosystem. It is no coincidence that among the main assets (policy agendas) of RRI¹ [7] there are: scientific education, which is increasingly being implemented as scientific citizenship, public engagement, which soon turned into multi-actor engagement, open access and social justice and inclusion, especially to avoid unfair discrimination of particular groups in research.

Translational and Prevention Medicine progressively based on omics and big data [8] research, and healthcare integrated biobanking, can develop only through systemic community engagement, where young generations with their families become a pillar of the community. Raising awareness [9], making science practices and processes familiar, inclusion and engagement in scientific debates [10], transparency, participatory assenting/consenting, and governance are ELSI/RRI conditions to become scientific citizens and to collaborate in translational research. They are requirements for a responsible, quality practice in research [11].

2. Informed assent/consent and dissent

2.1 Assent and consent as an ethical-normative process

Since the Nuremberg Code, informed consent has been considered an essential condition to develop any research, the backbone of ethical and responsible research, as it should enforce and respect the willing, the autonomy of the potential participant guaranteeing sufficient knowledge and comprehension and a space of empowerment to exercise free power of choice and make an understanding, enlightened decision [12]. Moreover, the Code embodies what we now consider as the RRI horizon, particularly in the statement: “The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment”. This de facto introduced the informed consent as a process in dialogue between participant and researcher/clinician whose ethicality and consistency lie in the transparency, verifiability and accessibility of the research process that is proposed as well as in the responsible and documented verification by the research professional of the potential participant’s comprehension. If this represents a practical challenge with adults, which is concretely outlined in Article 29 of the European Clinical Trials Regulation 536/2014, particularly in the passage reiterating that the research team must during the interview first and foremost respond to the information need of the potential participant or patient populations at stake in that research [13], with minors it implies a real paradigm shift.

From an ethical point of view, there has been an immense stepwise change in just a few years: from parental/guardian consent as a sine qua non for a research study, there has been a shift to positive consent of the child, a practical/ethical consent: the child is the participant, not the parents. In an ELSI horizon, this represents a significant challenge involving the child as a participant, who progressively acquires decision-making competence and legal capacity.

This means profoundly rethinking assent and consent as a dynamic, step-by-step process based on an ongoing dialogue between children, parents and researchers/biobankers, from the proposal till the reuse and secondary use and data and results access and moving toward dynamic and participatory models of regulation and interpretation. Since obtaining informed assent/consent is a process that evolves over time as children develop and mature, and will most likely extend into adulthood, we would prefer to talk about assenting/consenting for research in children to emphasise the ongoing engagement between researchers and participants.

Moreover, as children grow and gain capacity, minors highlight the direct link between consent at maturity, follow-up, and engagement, which is critical to sustainable and fair/FAIR (Findable, Accessible, Interoperable, Reusable) biobanking for our future.

It has not been an obvious process, deconstructing patterns, a long journey of inclusion and recognition of the minor as a participant, whose opinion must be considered and whose dissent must be respected. At the same time, it outlines the path of making researchers and biobankers aware of their role in increasing the risk of vulnerability and discrimination of minors involved in biobank-based research, if not acted upon responsibly, inclusive and guarantor of empowerment, and capability settings.

It took 50 years to deconstruct the paternalistic paradigm, to include the minor, the most protected subject through the regulatory framework, to respect them by providing and encouraging processes and tools of self-determination, such as agreement/assent, dissent and consent at maturity. The conception of these terms and their definition has also evolved and is addressed in the next Section 2.1.1, which follows their progressive development.

It is indicative that the regulatory framework revolves primarily around clinical trials, biomedical research in a strict sense. Only in 2006 did the Council of Europe publish the first recommendation on research on biological material of human origin [14], which served as one of the first building blocks for an ELSI framework for translational medicine and research biobanking involving children. This 50-year-long responsible bioethical evolution (revolution) has been possible thanks to soft laws that promote and recommend but do not impose good practices and fairness.

2.1.1 The ELSI evolution

Children, who are still minors, that is below the legal age for consent in a particular country, have a right to give their opinion, as laid out in article 12 of the Convention on the Rights of the Child, which states that a mature child “capable of forming his or her own views” has “the right to express those views freely in all matters…, the views of the child being given due weight in accordance with the age and maturity of the child” [4]. This agreement by the child is known as assent, and must be accompanied by the permission of the parents or guardians, to provide valid consent, as a safeguard for ethical research [15].

However, as will be discussed below, there is wide variation across countries in the practical procedures employed to obtain assent from potential child participants and legal “consent” or permission from their parents, reflecting the differences in national law regarding who is competent to provide legally valid consent. This may be problematic for international collaborative research, including biobanking. Moreover, the General Data Protection Regulation (GDPR) has added another confounding legal requirement for European research, since explicit legal consent is one of the mechanisms that make data processing lawful in Article 6(1)(a) [16].

The Declaration of Helsinki introduced assent by minors in the 2000 version, as basic principle 25: “When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorised representative” [17].

Assent was not mentioned in the 2001 Directive on Clinical Trials, where Article 4(a) states that the informed consent of the parents “must represent the minor’s presumed will” [18] but with the subsequent Regulation, assent was recognised as a national requirement in some countries. In the 2002 Council for International Organisations of Medical Sciences (CIOMS) Guidelines, prepared in collaboration with the World Health Organisation (WHO), there is mention of “knowing agreement, sometimes referred to as assent” [19] but by the next revision in 2016 [20], assent is recognised as a process.

The role of children as research participants is now widely accepted but it was through clinical trial research that the rights of children in research were highlighted. So not surprisingly, the early definitions of assent/consent for research with children are enshrined in regulations regarding clinical trials, at least in the European Union (EU).

The EU legislation regulating Clinical Trials defines minors under Article 2, as subjects “under the age of legal competence to give informed consent” and proceeds to define informed consent for minors as “an authorisation or agreement from their legally designated representative to include them in the clinical trial” [13]. Although Article 32(2) states that “a minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity”, Article 29(8) states that assent is only mandatory for “a minor who is capable of forming an opinion and assessing the information given to him or her” only when required by national law.

Meanwhile in the US, the Code of Federal Regulations, 45CFR 46 for the Protection of Human Subjects, Section 46.402, defines assent as “a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent” and defines permission as “the agreement of parent(s) or guardian to the participation of their child or ward in research” [21].

Moreover, the EU Recommendations of the Expert Group for the implementation of the Regulation define assent as “a statement of will with legal value according to national law” but proceed to recommend that even in the absence of such legal requirement, researchers should ask for an agreement from the minor, the term agreement being used “by analogy to “assent” where it is not a legal requirement” [22]. Moreover, in many countries, Research Ethics Committees (RECs) are increasingly requiring child assent for any research project on minors [23].

In any case, the Clinical Trials Regulation explicitly requires children and young people to “take part” in the assent/consent process: the minor participates while the legally designated representatives authorise their participation. Under this regard, Article 32 (1c) is critical and fully recognises the minor as the participant, stating that “the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is respected by the investigator” [13]. The Regulation also articulates how informed assent/consent is a process configured by researchers or research team members trained or experienced in working with children and shaped based on the informational need of the person who has to understand and assent/consent. This is an RRI pillar: a research proposal and the information to “assent” can only be shared with/by competent and “responsible” personnel in dialogue with the potential participant.

The 2016 updated Recommendation by the Council of Europe, firmly in dialogue with the Oviedo Convention, and its additional protocols, highlights this change of pace in Article 12(4): “If the person not able to consent is a minor, his/her opinion should be taken into consideration as an increasingly determining factor in proportion to age and degree of maturity. Any objection by the person not able to consent should be respected. Any wishes previously expressed by such a person should be taken into account” [14].

This is echoed in the 2016 CIOMS, Guideline 17, which states that children ‘who are too immature to give assent” may still communicate a “deliberate objection”, that is “an expression of disapproval or refusal of a proposed procedure”. The Regulation regarding Clinical Trials in Article 32.1(c) refers to an objection by children who have the capacity to take decisions, which implies that dissent is the “lack of assent”. The expert group states that dissent is “the expression of the minor’s will to refuse participation in a trial” and that where assent is required by national law, dissent is equated with a definite refusal to participate in a trial. The researcher should be aware that dissent may be expressed in writing or orally but also by non-verbal means of communication.

Also, consent must be obtained at the legal age of consent, to allow a clinical trial to continue into adulthood. Article 32.3 of the Clinical Trials Regulation emphasises that the “express informed consent shall be obtained before that subject can continue to participate in the clinical trial” [13]. Similarly Article 12 (5) of Rec (2016)6 states that “Where a person not able to consent, whose biological materials have been stored for future research, attains or regains the capacity to consent, reasonable efforts should be made to seek the consent of that person for continued storage and research use of his or her biological materials” [14].

In ELSI words, the consent of the young person attaining the legal age is needed for continued biobanking, and this consent is de facto the first full consent expressed after the long assenting process built on the child’s assent as well as parents/guardians’ permission to biobank.

In the last few years, this change based on the inclusion and engagement of children has become pervasive. The CIOMS together with WHO suggest not only that “Children and adolescents must be included in health-related research unless a good scientific reason justifies their exclusion…” [20] in full agreement with both the RRI [24] asset of Social Justice & Inclusion which avoids unfair exclusion of particular groups from either participation in research and/or access to benefits arising from research, and the Council of Europe’s current challenge to improve participation of children in the decision-making process on matters regarding their health [25].

Moreover, these international, global ethical guidelines for Health-related Research Involving Humans underline that before undertaking research involving children and adolescents, the researcher and the REC (and we add the biobanks/biobankers too) must ensure that: “the agreement (assent) of the child or adolescent has been obtained in keeping with the child’s or adolescent’s capacity, after having been provided with adequate information about the research tailored to the child’s or adolescent’s level of maturity” [20].

In fact, to give assent the child or adolescent is meaningfully engaged in the research discussion in accordance with their capacities. And as CIOMS guidelines underline “The process of obtaining assent must take into account not only the age of children, but also their individual circumstances, life experiences, emotional and psychological maturity, intellectual capabilities and the child’s or adolescent’s family situation” [20]. Such circumstances can play a key role in determining the child’s risk of vulnerability.

Finally, the CIOMS Guidelines stress that adolescents who reach the legal age of consent during the study are to decide if they want to continue participation or not and this decision overrides that previously given by their parents [20].

2.1.2 The child as a vulnerable in transition in research

Children are “…entitled to special care and assistance” [26] and “shall have the right to such protection and care as is necessary for their well-being” [27] because of both a risk of conditioning, due to the differential power relationships between adults (researchers, parents, guardians) and child participants, and a risk of manipulation in interaction with adults. They can be particularly exposed to an increased risk of vulnerability by:

• potential discrimination (exclusion of children with disabilities, refugees, orphans…);

• overprotection (without research specific to minors, they would suffer from the lack of development of tailored diagnosis and treatments).

But a child is a person in evolution with a vulnerability in a transition. Their vulnerability does not arise from disorders or predisposition, except in specific cases. It is a temporary vulnerability that can be increased if the adult ecosystem (researchers, parents, guardians, etc.) does not recognise children as human beings to be respected, and listened to, and valued. The participation of young people in all aspects of their personal and social development is a fundamental right; the ELSI challenge is to guarantee and provide capability/empowerment settings and inclusive environments to equip children, but also adults, to ensure children’s participation in the healthcare and research knowledge and decision making. Thus, children are counter intuitively special: they are temporarily vulnerable persons, being in a process of accelerated evolution and ethically requesting empowerment and respect for their full human development.

Biobanking with children and their engagement in TM should prove an ideal training ground for both RRI and scientific citizenship, fostering the cultural change for collaborative and participatory science. Their involvement implies the need to tackle inescapable ELSI issues that if not addressed increase vulnerability in all individuals at risk, not just children, as well as imply an irresponsibility, an unprofessionalism of the researcher, of the biobanker.

After the Nazi experiments, which exposed the human beings involved and used them as guinea pigs to the absolute vulnerability, the Nuremberg Code establishes a point of no return by recognising the free and informed consent of the potential participant as a prerequisite for research.

Here begins a long journey of inclusion and recognition of the other as a participant, still in progress, and of making researchers aware of their own role, in increasing the risk of vulnerability of individuals involved in the research, if not acted upon responsibly.

In 1974, the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research highlighted that “Respect for persons incorporates at least two ethical convictions: i. first, that individuals should be treated as autonomous agents, ii. and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy” [28].

However, the Belmont Report declines respect for persons not yet capable of full autonomy, for instance for minors, beyond mere protection, envisaging to give them the opportunity to choose what shall or shall not happen to them, and whether, or not, to participate in research to the degree that they are capable.

The Report introduces a key concept in terms of RRI and participatory biobanking with both children and vulnerables, highlighting that to respect persons one must give consideration and substantial weight to all the actors at stake, including the potential participants, balancing their right to be especially protected and at the same time empowered and enabled to participate in research.

The Report is also a pioneer in introducing the role of third parties to acknowledge vulnerables’ wishes and to protect them from harm. RECs as well as biobanks can be considered as the third party for excellence within the research biobanking and TM horizon: as shared before, their role in recognising and including minors as participants, as well as guaranteeing their rights and promoting their capabilities, is central.

Twenty years later the Barcelona Declaration [29] strengthens this RRI principle balancing protection and capacity-building guarantee. In fact, the care, and the protection for the vulnerable, for those whose autonomy or dignity or integrity are capable of being threatened, are core principles. But the principle also specifically requires not merely non-interference with the autonomy, dignity or integrity of beings, but also that they receive assistance to enable them to realise their potential.

Subsequent research ethics guidelines follow The Belmont Report in linking vulnerability to consent, exploitation and special protections. For example, the Declaration on Bioethics and Human Rights stipulated in Article 8 that “In applying and advancing scientific knowledge, medical practice and associated technologies, human vulnerability should be taken into account. Individuals and groups of special vulnerability should be protected, and the personal integrity of such individuals respected” [30].

Meanwhile, CIOMS in its Guideline 15 invokes “special protections” and reaffirms the role of third parties: “When vulnerable individuals and groups are considered for recruitment in research, researchers and research ethics committees must ensure that specific protections are in place to safeguard the rights and welfare of these individuals and groups in the conduct of the research” [31]. They should “promote voluntary decision-making, limit the potential for confidentiality breaches, and …protect the interests” of the vulnerable [31]. Recommended safeguards include the request for an intermediary to obtain assent/consent, the use of consent materials appropriate for the participant and adequate data protection measures, such as pseudonymisation and secure data storage systems.

The notion of universal vulnerability (fragility or susceptibility to suffering, linked to human embodiment) underpins ethical concern for all research participants. But universal vulnerability is not explicitly identified in research ethics guidelines. Instead, there is an assumed “normal” research participant for whom standard ethical protections are adequate. This baseline normal research participant is characterised by Luna as “mature, moderately well-educated, clear thinking, literate, [and] self-supporting” [32]. Vulnerable participants are identified against this implicit norm and their vulnerability is essentially specific and relational: they are vulnerable to agents regarding particular threats, and individuals are vulnerable because they are especially susceptible to harm or exploitation by others. Only 3 Guidelines define special vulnerability from CIOMS [31], Canadian Tri-Council [33] and International Conference on Harmonisation (ICH), in its glossary [34].

CIOMS and the Canadian Tri-Council Policy Statement define vulnerability in terms of decreased ability to protect one’s own interests, secondary to intra-personal factors (e.g., reduced capacity to give informed consent) or contextual factors (e.g., limited access to social goods including rights, opportunities and power).

RECs and biobanks are charged with ensuring that additional safeguards to protect the rights and welfare of subjects who are likely to be vulnerable are included (directly or just by providing their samples and data) in the research under review. To make this determination, they might be advised to consider questions such as: (1) is inclusion necessary? and (2) if so, are safeguards adequate?

In parallel, they play, together with the Research Infrastructures, a central role within the research ecosystem to empower and engage children and families as well as researchers and clinicians as a team, to support an inclusive scientific community based on transparency, inclusion, mutual recognition and openness. Biobanking and TM with children grow and we need an ethically healthy balance between the protection of vulnerable persons, a risk/mitigation assessment competence, and the development of a fair/FAIR research in the age of omics medicine: it is critical to support researchers/clinicians in rethinking the assenting/consenting process with minors to fully recognise and include them, stepping forward the risk of vulnerability via participation.

2.2 Not just information but tailored dialogue

2.2.1 Comprehension and informational tools

Full informed consent from adult research participants can only be provided when they have “competence or decisional capacity… to understand material information, appreciate the situation and its consequences… and communicate a choice” [35]. The same requirements can and should be considered for capacity to provide informed assent.

According to McGregor and Ott [36], capacity to consent can be considered as having four elements: “(1) understanding the information relevant to make a decision, (2) appreciating how the decision will impact them personally, (3) manipulating the information rationally and reasoning, and (4) communicating a voluntary choice”.

For research with children, information is provided not only to the legally designated representatives but also to the minor, when it must be “tailored to the child’s or adolescent’s level of maturity” [20] or as the Clinical Trials Regulation, Article 32(1)(b) requires, “adapted to their age and mental maturity” [13]. However, “age only partly correlates with maturity” [22]. Increased maturity is related to age since the skills to understand the information provided develop as the child grows, but more importantly competence depends on mental development, with cognitive capabilities and decisional capacity increasing and evolving with age. In the US, Institutional Review Boards (IRBs) are empowered to ascertain if “children are capable of assenting” by considering the ages, maturity, and psychological state of the children involved” [21].

Since maturity is also related to socio-economic factors, such as “educational level and belief system” [37], health status, culture and family dynamics [38], using age as an indicator for capacity to assent is not sufficient. But using age groups to produce guidelines for procedures to engage child participants acts as “a practical instrument” [22].

Various studies have tried to determine the level of understanding at different ages, so as to establish an age of assent, but there is no agreed decision. The American Academy of Paediatrics and the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research recommend assent for children above 7 years of age [39]. It is generally agreed that adolescents are competent to make decisions regarding research participation. However even here the age groups used vary markedly from 10 to 19 years by WHO [40] to 10–18 years by the Expert Group on Clinical trials [21] to 11–21-year-olds by the American Academy of Paediatrics [41].

Hein argues that children aged 12 and above are able to provide informed consent rather than assent [42]. This is based on her previous studies using the modified MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) to assess children’s decision-making capacity, where it was established that children aged 11.2 years and above were competent to agree to research participation while those below 9.6 years were not, with those in between being ‘in transition’ with increasing capacities [43].

However, in the EU, there is no agreement on specified ages for consent and assent in research with children, as evidenced by the survey led by the Working Group on Ethics at the European Network of Paediatric Research at the European Medicines Agency (EnprEMA) [44], with age for assent starting at 4 years old, while the legal age for informed consent varies between 14 and 18 years [45].

Even legal maturity is arbitrarily assigned a specific age by a country or by individual states in the US, generally the age of 18 years. In the States, this has led to the legal recognition of “emancipated” or “mature” minors who are legally allowed to provide informed consent without the need for their parents’ consent, or even without the parents’ awareness about their involvement in research. Minors who are married or join the US Armed Forces obtain automatic emancipation. In some US states, other minors, such as those who are pregnant, or parents themselves or living independently, can be emancipated through a declaration by the Courts. In the United Kingdom [46], children over 16 are legally able to give consent for participation in clinical trials but there is no legal statute governing other types of research. Some have therefore argued that Gillick competence should also apply [47].

Finally, there are no specific guidelines as to how the researcher should ensure that the potential participant has really understood the information provided. Although Article 31(1)b of the Clinical Trials Regulation requires the potential child participant to be provided with information that is “adequate in view of their capacity to understand it”, it does not make comprehension mandatory for the child as required for the parent by Article 29(5), which states that “it shall be verified that the subject has understood the information” [13].

The Recommendations of the Expert Group on Clinical Trials with children recommend that the information provided should be ethically approved and the material provided to children checked “for sufficient understanding in the relevant” group of children, but there is no specific guideline for the research team.

Researchers are now developing tools to check understanding, such as the modified Quality of Informed Consent [48, 49]. A recent review [50] only identified 19 studies that used tools to assess comprehension of children during the assenting process, of which only seven studies were from real research studies. The tools used were mainly questionnaires with either multiple choice questions or open-ended questions but there were also interviews and observations. The review did suggest that the use of “enhanced paper forms (e.g., by simplified text or illustrations)” was useful. The paucity of the literature underlies the importance of research on this topic and the need to develop assent models for children.

Children as potential participants must be provided with relevant information that allows a free decision about participation in a proposed study. This should include information about the aims, methods, benefits and risks of the study, as well as details related to the rights of the participant, such as the right to withdraw from research at any time and the right to confidentiality. Children’s concerns may be different from those of their parents [51], so the information has to be tailored to their needs, which will become more obvious depending on how strong an engagement there is between the research team and the children/adolescents. However, the information should be targeted to the capacity of the child [52] and be in “a language or another form of communication that the individual can understand” [53].

Another practical aspect that determines understanding is how the information is communicated. The Clinical Trials Regulation, Article 32(1)(b) states that only “investigators or members of the investigating team who are trained or experienced in working with children” [13] should provide information. The researcher should use patience and sensitivity in communication [37] and provide sufficient time to be asked questions to clarify any issues, maybe alone rather than in the presence of parents. The research team must remain aware of the family dynamics, which may indirectly affect the child’s decision to participate or not.

One has to consider the amount of information provided as well as the type of material used for facilitating comprehension. Article 29(4) of the Clinical Trials Regulation recommends “special attention shall be paid to the information needs of specific patient populations and of individual subjects, as well as to the methods used to give the information” [13]. The Expert Recommendations for Clinical Trials recommend that initially there should be provision of two separate sheets “one with a summary, and the other with more detailed information” [22] [to both children and their parents, so as not to overload them. Detailed information is to be provided only once they show an interest in learning more. This is good practice for a dynamic and tailored assenting process that evolves over time.

2.3 The role of research ethics committees

Research Ethics Committees (RECs), because of their third-party role, guarantee special protection and empowerment for children participating in research as highlighted in the section on vulnerability. They provide an independent review of the research proposal, ensuring that not only are ethical principles being addressed but there is definite feasibility of the outlined procedures being fulfilled by the research team. This provides an additional safeguard for responsible translational research with children, in particular with regard to ensuring informed assent from children below the legal age of consent. Ideally RECs should ensure that the children and parents were involved in the study design [54]. RECs evaluate and can require modifications to the proposed format of information being provided, methodology applied during the dialogue with participants and the tools supporting the assenting process such as information Sheets and Assent forms [55].

RECs are an important safeguard for clinical research where the clinician is the researcher, as they generally require intermediaries to communicate with potential participants and obtain their assent/consent. This is particularly important when the clinician is also the principal investigator and who may therefore be the cause of therapeutic misconception and/or who may have a conflict of interest in relation to research funding.

In addition, under special circumstances (like during the Covid epidemic) RECs are able to consider waivers of consent and assent when it would otherwise be impractical to carry out the research, which is deemed to be of minimal risk and of significant social benefit [54]. In practice, RECs may waive parental consent if it is considered to be detrimental to the child [56], due to conflict between the children and their parents, or even harm by the parents, for example, for research on drug use, domestic abuse, child abuse and reproductive and sexuality issues [20].

In the US, recommendations to introduce assent and involve IRBs were introduced in the late 1970s [57] and there is federal legislation [21] requiring assent from children (below the legal age for consent) participating in research and permission from the parent(s) or guardian, unless assent is waived by an IRB [21]. IRBs also are empowered to waive parental permission in such cases [1]. Furthermore, a waiver to child assent can be applied by IRBs if the children are deemed to be of such limited capacity to assent that they cannot be engaged in decision making, or if the proposed research is of absolute benefit to that group of children and can only be obtained through that specific research even if there is greater than minimal risk [21]. In cases of waiver, the IRB will require further protection of the child, e.g., by appointing an advocate or guardian to accompany the child in the research process. The IRB can also authorise waivers for parental permission for emancipated minors, who are able to provide legal consent.

3. Return of results

Technological developments in genomic research with the production of large amounts of data and the exploratory analysis of gene variants, mirroring the trend in healthcare, have led to a growing problem with respect to an increased potential for findings unrelated to the aims of the study. These can be incidental findings that are totally unexpected or less commonly secondary findings that are actively searched for during the study but unrelated to the research aims. So current literature is discussing individual research results to include all types of results. What is uniformly accepted is that all research results have to be validated [58, 59] by confirming the result in an accredited laboratory before being returned.

It is always recommended to discuss and decide on return (or not) of results at the time of dialogue in the assenting/consenting process [60]. Dynamic consent would allow participants to change their preferences.

Moreover, in the translational context [61], with the new omics technology [62], it has become crucial to consider the effect all results would have on the participants, right from the start of developing the study protocol. Genomic counsellors should be part of the research team to evaluate risks versus benefits to participants during the study and to offer their services beyond the study, to the participant’s when their healthcare is affected and extended family if appropriate.

3.1 Which result?

In Europe, the Additional Protocol to the Convention on Human Rights and Biomedicine is clear that results relevant to the “current or future health or quality of life of research participants” must be offered together with “health care or counselling” [63], reiterated also in Rec (2016)6 [14]. Although in the United States there is no federal law mandating return of research results, changes to the Common Rule in 2017 [64] require researchers to inform participants during the consent process whether “clinically relevant research results, including individual research results” will be returned [65].

It is now generally accepted that research participants should receive all research results [65], including genomic research results [66, 67, 68] not just if these are of benefit to the participant. The public, patients and participants support and want to receive results [65], although research also shows that the more knowledge made available to the participant, including counselling, the less strong was the desire for results [68, 69, 70, 71]. On the other hand, the scientific and health professionals are more restrained about disclosing information [68, 70], mirroring the ethical and legal challenges related to disclosure. This is even more relevant in research with children because it is often genomic research and moreover children have a long future ahead, so any possible healthcare intervention should be as early as possible.

So, any results that warrant an action should be returned. “Actionable” has been defined as follows: “if there are available preventive and/or treatment measures and the disorder has either (i) childhood onset and such measures are therefore initiated in childhood, or (ii) adult onset, but such measures have been demonstrated to be effective when started in childhood” [72]. As of 2021, the Clinical Genome Resource Paediatric Actionability Working Group was able to provide guidelines regarding return of results related to 143 genes, on the basis of actionability [73].

The American College of Medical Genetics and Genomics (ACMG) guidelines to assist in return of secondary findings following clinical gene sequencing [74] recommend not to return results related to adult-onset non-treatable disease but to report findings related to adult-onset conditions that are treatable only in adult life, because of potential benefit to the parents or other family members [75], also labelled as “personal utility” to the health or reproductive decisions of the relatives [76].

These ACMG guidelines have been used to develop guidelines for research practice. A particular set of guidelines that concentrate on the preferences of children and their parents [76] decided that results for adult-onset diseases, non-treatable diseases and carrier status would not be disclosed to children below 18 years; adolescents in these guidelines are 13–17-year-olds.

3.2 To whom?

Parents believe they have a right to be given results from genomic research on their children [71, 77] even for results unrelated to the main aims of the study [58] and also irrespective of actionability [78]. However, this practice threatens the child’s right to an “open future”, that is the parents receiving all the information can undermine the right of the children to decide for themselves in future.

Research participants may opt not to receive results, and this should be certainly respected for mature adults [79] to respect their “right not to know” information about their health [14, 63] but if parents opt not to receive their children’s actionable results, it may be necessary to obtain an ethical opinion. The European Society of Human Genetics (ESHG) and EuroGentest recommend that the final decision on return of serious and actionable incidental findings should be made by professionals [59]. The researcher may have a duty to override the parents’ right not to know [80].

Ideally parents should share the results with their children, according to their age and maturity. Adolescents should be involved together with their parents in deciding what results they want to receive [81]. Adolescents do take different independent decisions from their parents and may want less information than their parents [81]. In the case of disagreement between parents and participating children, there should be return of results if immediate action is necessary, with such decision being taken by a multidisciplinary team of geneticists, ethicists and counsellors [76].

For adult-onset disorders actionable only in adulthood, results should not be disclosed to safeguard the child’s autonomy and right to decide on disclosure once they attain the legal age of consent. This view has also been supported by the public [71]. However, for genomic results, the likelihood is that the result is important for the family, including the parents, in which case benefit to the parents will also be of benefit to the child [80].

Generally, parents are prepared to share genetic results with extended family [58] but they should respect the child’s autonomy by considering their preferences and assess possible risks to privacy by sharing the information; this should be balanced with the potential benefit to relatives [82]. It may be necessary to involve an ethics committee to assist in this decision, to ensure the confidentiality of genomic information is protected. They should consider this issue at the time of writing the research protocol.

Genomic technologies are used for diagnosing genetic disorders and for research, but it can be difficult to distinguish between the two [59] though it is clearly reasonable to do so [68]. However translational research encompasses both aspects and therefore, the distinction may not be necessary and guidelines for clinical care could reasonably be applied also to research.

4. Data protection issues

With the introduction of the GDPR, consent has taken on a legal connotation since consent is one of the mechanisms in Article 6(1)(a) that make data processing lawful [16]. Article 4(1)(11) states that this legal consent should be “freely given, specific, informed and unambiguous indication of the data subject’s … agreement to the processing of personal data concerning him or her” [16] and according to Article 9(2)(a) it should be explicit for sensitive data. However, this has to be understood as separate from the ethical need for informed assent/consent.

As mentioned by the European Data Protection Supervisor, there is “clear overlap between informed consent of human participants in research projects involving humans and consent under data protection law” [83]. Should another legal basis be applied for data protection, informed assent/consent “could still serve as an ‘appropriate safeguard’ of the rights of the data subject’ [83].

Recital 161 of the GDPR states that for participation in clinical trials, the provisions of the Clinical Trials Regulation [13] apply, implying the age of consent to personal data processing is the same age as the age to consent for trial participation [45].

Article 8 of the GDPR introduces age limits for the child’s consent to data processing, but only in relation to information society services. This is set at 16 years, below which parental legal consent is required, unless the state opts for a lower age, but with a minimum of 13 years. However, it appears that this has not been generally used as a guideline for setting legally valid consent for data processing in research. In particular, for clinical trial research in Europe, the legal age for consent is known to vary between 14 and 18 years [45], with the proviso that children below that age are also, as regulated by Article 32(2), involved in the informed consent procedure, thus in the assenting procedure, “in a way adapted to his or her age and mental maturity” [13].

The GDPR does not mention scientific research with minors, although Article 12 requires that information provided to children is in a “concise, transparent, intelligible and easily accessible form, using clear and plain language, in particular for any information addressed specifically to a child” and Recital 38 highlights the need for “specific protection” of children’s “personal data, as they may be less aware of the risks, consequences and safeguards concerned and their rights in relation to the processing of personal data”.

The GDPR also safeguards the right to withdraw consent to data processing, implying withdrawal as a research participant, at any time without suffering any repercussions. Children also have a right to withdraw their assent at any time.

Although the right to access to data processed in scientific research may be waived through derogations under Article 89(2) if “such rights are likely to render impossible or seriously impair the achievement of the specific purposes” [16], this may lead to different practices in European member states, thus complicating multinational research collaboration.

5. Healthcare integrated biobanking and engagement

Since rare diseases affect only a few individuals in a population, and most rare conditions are paediatric in onset, the rare disease community has been pioneering to ensure paediatric transnational and international collaboration to obtain large cohorts to study and to create ante litteram a constant translational dialogue between clinics, research and Patient/Parent Associations [84] through research biobanks and registries.

Currently it is widely recognised as a crucial requirement for Precision and Prevention Medicine to have the availability of an extensive collection of human samples (both diseased and healthy) with well-documented phenotypic data [85]. Getting timely diagnoses and treatments requires the identification of biomarkers that would be useful for early detection, prevention and treatment of diseases associated with specific medical conditions such as cancer, cardiovascular disease and many other disorders. The ability to determine specific biomarkers for disease diagnosis and prognosis of therapeutic response will have a meaningful impact on healthcare for everybody.

The European challenge to infrastructure research to support and increase collaborative, responsible quality research, has been central to infrastructure biobanking thanks to the dedicated Biobanking & Biomolecular Resources Research Infrastructure – BBMRI-ERIC [86] and its inclusive community of practices. The BBMRI-ERIC Directory, for instance, provides an aggregated overview of global biobanks and collections of samples and data that are available for research.

Omics, artificial intelligence-driven process automation, data analytics, robotics and other emerging technological advances are driving the revolution of biospecimen science, both providing new insights into the genetic component of human disease and developing an automated and more personalised approach to healthcare. This means a paradigm moving toward dynamic and participatory models of regulation, governance and interpretation within an RRI horizon as well as a translational, healthcare integrated evolution of biobanking with a direct impact for any citizen, regardless of disease or health condition.

Translational, healthcare integrated biobanking, like TM, requires the construction of a conscious community, an extended scientific community, which proactively recognises and includes as partners both the patient-citizen and the clinician, and fully regenerates and concretises research as a responsible process, precisely because it is participatory.

In conclusion: I can only be accountable for an act, for a process (be responsible for it) if I understand it, I’m conscious and both trained and engaged; just as I act responsibly for a process because I am understood by it, I am recognised as a part of it, a partner in it. As shared by the participatory community of the Italian National Node (BBMRI.it): “To contribute to, and to participate in, the biobanking process, and to take advantage of results, it is essential to be informed, and aware of the scientific process that arises from biobanking, and to understand how this innovative scientific model is set up; an innovative model, above all, because it defines personalised diagnoses and treatments and requires a re-thinking of rights, responsibilities, and choices” [87].

From proactive participation of citizenship to state-of-the-art infrastructure and global standards, to necessary regulatory controls, various issues need to be overcome to benefit from the revolutionary potential of biobanking. Patients-citizens, clinicians, researchers, and institutions altogether should rethink and regenerate the clinical practice in a horizon of scientific development through systematic, extensive data and sample collection, based on compliance with the correct (ELSI, qualitative, “institutional-organisational”) and congruous requirements for potential research use.

Translational biobanking is ethical, sustainable and fair as a collaborative process and a participatory pact between all the players involved. This participatory pact represents a pact of responsibility between all the various actors involved. Giving custody and taking care of samples (being custodians and responsible for the care, but not being the owners) is the cornerstone of this participatory process. The biobank as a third party, a custodian, ensures patient/participant’s participation, rights and data security, guaranteeing samples and data use and distribution consistent with the assent/consent expressed, transparent procedures, participatory governance and returning of results.

Ideally paediatric biobanks should be an integral part of healthcare services for children. This is not the prevalent scenario, except for certain countries, such as Italy [88]. This situation maximises collection and use of biological material, which is important for any childhood condition. There should also be population-based biobanks with a paediatric focus, to collect biospecimens from unselected healthy children, to study genetic variants and their interaction with the socio-economic environment in health and disease, which can lead to disease prevention measures to maintain a healthy population.

6. Vision for the future

Research with children is most fruitful when there is sustained interaction with the child, supporting them throughout the entire research. This is real engagement, encompassing much more than provision of information, answering research queries and obtaining assent. It is the basis for dynamic assent and will hopefully lead to research involvement throughout adulthood. On a basic level engagement shows respect for the developing maturity of the child and increases confidence in decision making and so empowers the child. Furthermore, engagement with family is crucial to joint decision making with child participants and their parents/guardians and creates ongoing dialogue and being part of the team with researchers and clinicians in scientific development.

The advances in genomic technology and bioinformatics have opened up the field of translational research with children, now facilitated by access to substantial numbers of biological samples from children, stored in a number of worldwide paediatric biobanks, together with associated clinical data. This allows studies to be conducted on diseases that affect children, but also offers an opening to the future co-created healthcare and science horizon and practice.

Healthcare integrated biobanking, omics based and AI/machine learning-supported big data research, are core in Translational and Prevention Medicine and one of the new forms of research that impacts everyone. The younger generations, both as future citizens and as potential scientists, are at the forefront of the development, sustainability, and equity of sample-based and data-driven science, of TM. Children can eventually be paediatric patients or “next generation” patients; they may be asked to give their blood, saliva or tissues for research, as well as benefit from TM in the future. Furthermore, children are also potential “next generation” scientists, researchers and healthcare professionals. This is the world that concerns them first and foremost; the RRI shift is for them and with them.

However, multiple ELSI challenges remain. The ethical issues of obtaining informed assent highlight the need to improve the assent process, to provide adequate informational tools and to have clear policies about shared decision-making with the family. This will only be possible if we take into consideration the views of the children and their families/guardians and recognise them as partners of the research ecosystem.

It is worth mentioning the need to carry out more research on the views of adolescents and their parents to participate in research and to return of individual research results. A recent review of laws and policies regulating return of results identified the differences between 20 countries, thus proving not only a great problem to a harmonised policy but also a deterrent to international collaboration [89]. This mirrors similar discrepancies in interpretation and implementation of the same law, as is happening in Europe with the GDPR, where some countries are opting to introduce national derogations for scientific research, which again differ from country to country.

Nevertheless, sample-and-data-based translational research can be envisioned as a living lab, to empower children to be conscious of their scientific rights (to science, to enjoy the benefits, to participate in the scientific progress…), to take part proactively in research processes and make informed decisions about their own health. Moreover, providing children with opportunities to engage in science and become familiar with health and life science topics, handing on biobanking, can also help bridge the gap between the scientific, expert community, families and citizenship. Our aspiration is to empower and train the adult research ecosystem to include children and to recognise them as the participants while engaging and empowering the next generation in Responsible Research and Innovation.

Acknowledgments

The authors are members of the BBMRI-ERIC ELSI experts’ network that brings together experts on ethical, legal and societal implications from across the National Nodes.

Dr. Sara Casati is part of the ELSI Services and Research Unit of BBMRI-ERIC as a bioethicist. This article was conceived with her BBMRI-ERIC affiliation.

Dr. Bridget Ellul, from the University of Malta, is an ELSI adviser to DwarnaBio, the national biobank in Malta and is a National Node expert from BBMRI.mt, the Malta node.

The open access fees are covered by BBMRI-ERIC.

Conflict of interest

The authors declare no conflict of interest.

BBMRI-ERIC disclaimer: Where authors are identified as personnel of the Biobanking and BioMolecular resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC), the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of BBMRI-ERIC.

Notes/thanks/other declarations

This article is not the product of a specific project, rather it was inspired by several collegial exchanges over the years. Dr. Sara Casati thanks especially the BBMRI ERIC Stakeholder Forum Patient and Citizen Pillar and the CY-Biobank team for inspiration and open dialogue during various professional encounters. She also thanks colleagues and friends participating at the Paediatric Stage: Paediatric Biobanking and Minor Engagement at the EBW22 Roadshow in Rome, October 2022.

The authors also thank Michaela Th. Mayrhofer for reviewing and commenting on this proposal.