Introduction

Biobanks enable the high-quality, long-term, mass storage of human biological samples for translational, interdisciplinary research. Samples include tissue, blood, urine, and genetic data derived from such sources that come from clinical research participants or as by-products with consent from patients receiving treatment. While the exact numbers of biobanks that exist globally are unknown, interest in the establishment and ethical governance of such entities grows, as evidenced by increased weight given to relevant accreditation, training, and scholarly discourse [1, 2]. While only a proportion of existing biobanks hold material derived from children, pediatric biobanking is arguably the most efficient means for advancing critical clinical research given the limited availability of pediatric samples [2]. Only pediatric samples can assist researchers to understand and treat childhood diseases, human development, and the gene-environment interaction [2, 3]. Despite this, international regulation governing pediatric biobanking is generally inconsistent and unclear owing to the varying laws, policies, and guidance documents that regulate biological sample removal, biobank facilities, access to and privacy of genetic data, and the issues associated with lack of capacity to consent by most pediatric participants [4, 5]. There are estimated to be approximately 90 guidelines for biobanks published by national and international bodies generally [6]. However, few provide specific guidance on pediatric biobanking and these are not always binding and enforceable, nor are they consistent or comprehensive. There is a critical need for regulation and guidance on pediatric biobanking to be consolidated and clarified at an international level so that research—which will often be transnational—can more quickly, efficiently, and ethically be translated to useful information and treatment in pediatric care.

Background

Pediatric biobanking has nuanced ethical, social, and legal implications above those associated with biobanking generally. Many of these issues relate to the lack of capacity or vulnerability of child participants when their tissue enters a biobank, what role parents play in authorizing such participation, and how biobanks should deal with a child participant’s transition into adulthood.

For example, pediatric biobanking is complicated by a child’s generally assumed lack of legal capacity to consent to the collection and ongoing storage of their samples, particularly prior to the teenage years [7]. Furthermore, given the varying ages and maturity of children involved, questions arise as to whether, and to what extent, child participants should be involved in the original consent process and their assent or refusal respected [8,9,10]. Ethics committees may require both assent from the child after a certain age (e.g., 12 years and older) and consent from a legal guardian; however, this requirement can vary, and decisions still need to be made on the capacity of the child to assent. Given the ongoing nature of biobank storage, children also reach maturity and adulthood while the original research is ongoing or have reached maturity when new uses of the samples are proposed. Disagreement exists about gaining consent from a participant upon reaching adulthood due to the feasibility and costs of this process and whether human research ethics committees can waive this requirement [7, 11].

While it is accepted that parents (sometimes called “legal representatives/guardian” in documents) can consent on behalf of a child, the scope of this consent is contested [12]. Biobank samples are stored and can be used for extended periods of time, long after individual research projects end. Therefore, so long as a proposed project is approved by an ethics committee and the request respects the access governance requirements, samples can be used for new research projects, including ones that were unforeseeable at the time of consent [11, 13]. The quality of parental consent is also questionable. Research shows parents are often poorly informed about the biobanking process, including falsely believing in a therapeutic benefit to the child, not understanding that DNA can be obtained from biological samples, and falsely expecting the return of genetic information [14,15,16,17].

There are also pediatric specific concerns above the general privacy and confidentiality risks of biobanking. For example, while all biobanks are susceptible to data breaches, the limited availability of pediatric data and comparative lack of information about pediatric specific diseases create a critical need for translational and interdisciplinary sharing of biobank data [3, 10, 18]. Questions arise as to whether, and the extent to which, information derived about the child from the research should be shared with that child or their family. Arguments in favor reason that given the systematic lack of benefit for the participating child [19], particularly following the Declaration of Helsinki’s broadening of pediatric participation to include children who would not be directly benefited but from whom research would benefit other children of the same age or with the same condition [32], the child ought to reap any therapeutic or informational benefit from participating in a biobank [3]. Yet children are vulnerable as dependents and are therefore more susceptible to harms arising from genetic discrimination, such as familial or public stigma due to undesirable traits or unknown genetic relations and false beliefs about genetic determinism [11, 19, 20]. It is also arguable that children have a right to an “open future” and should have the opportunity to consent themselves to being given any information upon maturity [21]. This is further complicated given research outcomes have varying levels of validity and actionability, such as information relating to adult-onset diseases [3, 22].

These issues require specific and practical guidance to enable the safe, efficient, and ethical storage and sharing of pediatric samples and data. While regulation should be clear, comprehensive, and consistent, it can take a variety of forms with different levels of enforceability and influence over practice. Legal and non-legal measures can combine to regulate an area of practice and while both types can be influential, a hierarchy does exist which assumes specific laws hold greater influence compared with non-legal guidelines, mainly because stronger forms of compliance are available (e.g., breaches can result in offenses being committed). It should be noted that international conventions (sometimes referred to as “international law”) may be influential but are generally only enforceable if implemented in domestic law. Non-legal guidelines also sit in a regulatory hierarchy depending on the strength of recommendations made and the pressure to adopt them. While general laws exist in every country that can impact on the operation of pediatric biobanks, the lack of specificity of these laws and how they apply in the context of child participants mean that tailored regulation which forms a more specific framework to guide practice is necessary. For example, it is accepted that parents must consent on a child’s behalf; however, given the longitudinal nature of research and biobank storage, there may be uncertainty about the legal duration of that parental consent. With this in mind, this paper seeks to map the current state of international regulation relevant to pediatric biobanking to identify the extent to which it considers and consistently addresses these nuanced issues.

Methods

Regulatory mapping was undertaken of international pediatric biobanking documents to find documents governing pediatric biobanks. Searches of Google Scholar was conducted to find international guidance documents on pediatric biobanking and children in clinical research or biobanking generally. Articles discussing the ethical, legal, and social issues of pediatric biobanking were also reviewed for references to regulatory documents until saturation. Located documents fell into four categories listed below from the most influential to the least influential.

  • Enforceable: requires compliance enforced via domestic law, conditions of funding, or through compulsory membership

  • Voluntarily binding: by requiring voluntary members to abide by guidelines

  • Recommends: recommending specific guidelines for biobanks

  • Information only: with bodies explicitly identifying relevant information or implicitly refraining from suggesting any particular solutions or advice

International guidance documents that specifically address biobanking are found in Table 1. International guidance documents that address pediatrics in research are in Table 2. National guidance documents addressing either pediatrics or biobanking are in Table 3.

Table 1 International guidelines on biobanking with specific mention or discussion of pediatrics
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Table 2 International guidelines that are generally about clinical or medical research and discuss minors in relation to consent
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Table 3 National guidelines on biobanking with specific mention or discussion of pediatrics
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Results

While there are many international and national guidance documents on pediatric biobanking, Table 1, 2, and 3 show that most of these documents lack regulatory force, often fail to address specific issues of concern raised in the literature, and, when they do, can be inconsistent in the approach suggested. This can lead to confusion for researchers and those administering biobanks with pediatric material, as well as for participants and families.

The nature of guidelines

Tables 1 and 3 show that the most specific pediatric biobanking guidelines are for information only or make recommendations that fall short of being voluntarily binding or enforceable. For example, the European Society of Human Genetics (ESHG) [23], International Society for Biological and Environmental Repositories (ISBER) [24], and Organisation for Economic Co-Operation and Development (OECD) [25] all have guidelines which are not binding. In contrast, the Ethical guidelines for analytical research on the human genome published by the Japanese Government are enforceable, but apply only nationally [26]. Some bodies have had their guidelines integrated into domestic regulation; for example, the Australian National Health and Medical Research Council (NHMRC) guidelines must be followed as a condition to accessing NHMRC funding [27]; ISBER’s guidelines are voluntarily binding on biobanks that seek accreditation using the American-based international biobank program “A2LA” which use the ISO 20387:2018 guidelines. The latter has been used to accredit biobanks in the USA, China, France, Italy, India, Poland, and South Africa [6]. The integration of these guidelines into regulation in a way that make compliance to some extent mandatory is, however, the exception rather than the norm.

Table 2 identifies the United Nations Convention on the Rights of the Child as part of the voluntarily binding backdrop in which biobanks conduct research, which pose several rights relevant to the conduct of pediatric research, the key one being the principle of a child’s “best interests” [28]. While all countries have signed and ratified, apart from the United States of America, enforceability only arises through ongoing monitoring and integration in domestic law. While some guidelines may be sufficiently recognized or respected either domestically or internationally to influence practice without such formal integration, this influence can be difficult to gauge.

Absence of specific consideration of pediatric participants in biobanking guidance

Tables 1 and 3 show that there is insufficient pediatric specific guidance for biobanks. For example, ESGH and ISBER guidelines acknowledge that pediatric genetic data generally pose additional ethical concerns but do not expressly state the specific concerns nor provide ways in which to address those concerns [23, 24]. The OECD, ISBER, and World Medical Association’s (WMA) Declaration of Taipei guidelines simply note that biobanks can store genetic data and that biobanks should make efforts to protect the privacy of participant data [24, 25, 29]. While it is important to acknowledge that guidelines must be sufficiently broad so as to allow for flexibility and nuance of the specific contexts of biobanks and the research, apart from the ESGH guidelines, the common nuances of protecting pediatric privacy and confidentiality are also generally missing from those guidelines [23]. For example, while biobanks are generally required to protect the privacy and confidentiality of all participants equally, there is a lack of detail about whether it is permissible or desirable to return research information and results about the child to the parents who provided legal consent, rather than waiting for the child to mature and consent themselves, particularly children in middle adolescence who may be fully capable of making such decisions. This is also important given genetic data can reveal important information about familial relations or family members that may impact the child and their relatives if found out. There is also a lack of detail about whether and in what conditions pediatric information stored in biobanks can be shared with other biobanks or other researchers with only the Italian National Bioethics Committee (NBC) considering this and calling for a prohibition on third parties accessing pediatric biobank data [30].

Most biobank guidelines do acknowledge the need for someone to consent on behalf of the child [25, 31,32,33,34,35]. Some documents were broad, referring to a legal representative, but some were narrower, assuming parental authority was required. The scope of either authority was only defined by the NBC [30]; however, all others failed to identify whether parents could consent to all research, similar research, or just the research project or whether the child’s information could be shared to other biobanks and research teams.

Many documents failed to identify whether the child’s assent was required and whether consent was required upon reaching maturity. There was general acceptance that minors’ opinions should be increasingly considered as they mature, but no guidance as to whether this requires staying in contact with minors, especially given the one-off nature of biobank sample donations [23, 29, 30, 34, 36,37,38,39]. There was also little guidance on whether and what information should be relayed in the future to the child or their family in the consent process.

There was also a lack of explicit recommendations as to whether re-consent for subsequent research was required from the child (or who at the time of consequent research was now an adult) rather than the parent. For example, the WMA’s Declaration of Taipei requires consent for new research from persons who were not able to consent but have since gained capacity, but this is not raised in the context of minors [29]. Furthermore, the ESGH suggests that participants and their parents may be notified of new research, but only requires researchers to consult ethics committees before research changes “considerably” [23]. The Swiss Academy of Medical Sciences states that minors should be able to exercise their rights “as soon as they become capable of discernment” [39].

Absence of specific guidance on pediatric biobanking in general pediatric research guidelines

Tables 2 and 3 show that there were many international research guidelines dealing with children that failed to provide guidance for pediatric biobanking. For example, the WMA’s Declaration of Helsinki [33] and the NHMRC documents identify the need for age-appropriate assent for children in clinical research but do not identify the biobank-specific need for consent when the minor matures due to the ongoing nature of biobank storage of samples [27, 38, 40]. While the Council for International Organizations of Medical Science & World Health Organization [34] guidelines on children in research require assent, respecting deliberate objections, and the need for re-consent generally in pediatric research, the nuances of biobanking are not identified, for example, the difficulty in re-consenting due to the nature of one-off donations, ongoing long-term research resulting in difficulties of re-contacting for consent, and the return of information unforeseeably known due to a lack of technology at the time of consent.

Discussion: Divergence and contradictions

The most significant issue across these guidance documents was the conflicting standards and expectations in the following areas.

Child and parental involvement

While many documents acknowledged the need for child involvement during the decision-making process, there was lack of consistency as to what “assent” meant, at what age assent must be sought, and whether assent was sufficient or just necessary in addition to parental consent. For example, the NBC guidelines only required biobanks to provide the minor with age-appropriate information, the United Nations’ Convention on the Rights of the Child only states that a child’s views must be given “due weight in accordance with their age and maturity” in matters that affect them [28], and the ESGH and ISBER guidelines required researchers to obtain assent from the child [23, 24, 30]. If biobanks were required to get consent from the child, there was conflict as to whether this must be a legal standard of capacity (i.e.. “Gillick” competency as required by the Medical Research Council (MRC) guidelines [41]) or because the child was “sufficiently mature” (i.e., required by the Council of Europe (1997) [35] and NHMRC guidelines [27]). The European Parliament and the Council of the European Union [37] state that parental consent is not necessary so long as the child has been offered preventative or counseling services in the context of processing personal data. Other guidelines only require dissent or “deliberate objections” to be respected rather than requiring formal assent [30, 34, 35] and many are silent on this issue altogether [29, 31, 36, 42].

Tables 1, 2, and 3 show that while minors should have the right to withdraw their consent upon maturity, there was divergence as to whether this was a requirement or an ideal. The NHMRC information paper [38] suggests that research should not continue without such consent whereas the ISBER guidance leaves this to biobanks to determine for themselves [24]. ISBER and OECD suggest consent “may” be required from mature minors but do not clarify the circumstances or criteria that may constitute conditions requiring consent [24, 25]. Many diverse exemptions are provided from the requirement to obtain consent. For example: the ESGH exempts gaining consent where it is unreasonable or disproportionate to the benefits [23]; the WMA’s Declaration of Taipei exempts gaining consent to protect the health of the population from identified, serious, and immediate threats [29]; and the European Parliament and Council of Europe permit exemption where it is against the public interest, to comply with law, or for scientific or historical research purposes [37]. The OECD simply notes that research ethics committees can waiver consent without identifying any reasons [25].

Governance of biobanks

Guidance in relation to governance of biobanks is also varied.Footnote 1 Some connote protective powers to ethics committees. For example, the ESGH requires the committee to review new research on the same sample or when the research changes significantly from the original description in the consent [23], and the NHMRC grants wide powers to ethics committees, such as to approve the plan for researchers to disclose or not disclose information in certain conditions to the donor, their relatives, or community [27]. However, the P3G international pediatrics platform guidance document notes that the capacity of clinical oversight committees to act as the gatekeepers on decisions to return information to patients is complicated by parental authority [43]. The WMA’s Declaration of Helsinki, although not specifically relating to pediatric biobanking, grants broad power to research ethics committees to waive the need for consent for collection, storage, or re-use generally.

Return of information

Privacy and confidentiality issues in pediatric biobanking were inconsistent across the guidelines. Regarding the return of information to the child or their family, the ESGH, for example, states that the parents’ right to not know information is overridden by the child’s right to access any benefit from involvement in pediatric biobanking [23]. The MRC states that information should only be shared to prevent actual or threatened suffering to the child and, namely, to inform and update general practitioners [41]. The NBC, NHMRC, and P3G platform state that only information that is scientifically valid and reliable, clinically useful, and relating to childhood conditions should be returned [27, 30, 38, 43]. Japan’s guidelines state that information can be returned directly to minors over 16 so long as due consideration has been given to the effect of the information on the minor [26]. For minors under 16, their representative must be consulted regarding returning information to the minor, and the representative can also make a request for information disclosure from the ethics review committee.

Only three bodies consider a solution to this problem. The MRC sought to clarify this in consent forms to include circumstances of disclosure to pediatrics [41]. The Italian Society of Human Genetics & Telethon Foundation asks participants to identify in their consent forms whether they wish to be informed of results; however, these are not specific to pediatric participants [44]. The Government of South Australia requires all results pertaining to genetic information be returned through a genetic counselor, but is also not specific to pediatric participants [45].

Conclusion

While there are some guidelines about pediatric biobanking, and others consider specific issues relating to pediatric research, the web of international documents relating to pediatric biobanking often conflicts between guidelines and is not comprehensive in its guidance. There is no universal consensus on the nuanced issues arising from pediatric biobanking, and given the translational nature of biobanking and their limited availability of samples, enforceable and cohesive regulation should be established to better facilitate this growing area of research. Better guidance is needed for researchers, biobank administrators, ethics committees, and child participants as they mature.