Ethical Challenges for Pediatric Biobanks

Consent and assent

The informed consent process for research studies is intended to inform the participant about the study which they are invited to participate in. The BCCHB utilizes a broad consent ^* allowing specimens to be used for as-yet undetermined and future research studies. ³ Broad consents have several advantages, such as decreasing consent burden by reducing the need for several study-specific consents as well as allowing the specimens to be used until reconsent is obtained when the participant reaches the age of majority. Depending on the institution, some restrictions for future research may exist, such as the establishment of immortalized cell lines or storage of embryonic stem cells. Broad consent should include a process of oversight and approval for future research activities, details about whether or not research results will be returned to the participants, and where feasible, an ongoing process of providing information to or communicating with the donors. ⁴

The BCCHB fulfills all of the above criteria by undergoing a one-on-one informed consent “interview” with all participants using a paper-based consent form, abiding by the policy that specimens will only be released to ethically approved research projects and by producing a periodic newsletter for participants and maintaining an up-to-date website.

It should be noted that the informed consent process requirements can vary significantly, often depending on the laws applying in the specific region, but sometimes depending on the local institutional ethics boards. Broad consent informs participants and parents/guardians of potential risks related to obtaining specimens and data, such as procedures, privacy, and confidentiality, as well as potential aspects of future research, including genetic research and the associated implications, and use of specimens and data for industry to name a few.

Although this information gives rise to transparency and therefore trust, this information, which is often described in a lengthy paper form may be overwhelming for families when disclosed all at once. Short and simple consent forms are generally better received by potential participants with access to more detailed information at the discretion of the participant and at a time convenient for the participant (Vercauteren et al., white paper, unpublished).

One could argue that a strong governance structure also allows shorter and simpler consent processes, as trust in the oversight of the utilization of biobanked specimens for research eliminates lengthy explanations of how specimens and data will be used. In general, banks must balance appropriate disclosures to parents while avoiding an over-burdensome consenting process. It is crucial that banks assess parental understanding of what is meant by unspecified future use, while at the same time assuring families of privacy and confidentiality protections. The BCCHB currently has a lengthy paper-based consent form but is transitioning to a shorter and interactive electronic consent platform containing pertinent information with access to detailed information (e.g., about Research Ethics Boards [REB] and industry use) at the discretion of the participant.

The process of assent allows children the opportunity to affirm their parents' wishes to participate in the research or biobanking process, however, the age of assent varies widely among different institutions. ⁵ Unlike consent, assent is not a legally binding process and each REB is able to develop the assent process for their institution as they see fit. A study carried out by Kimberly et al. in the clinical trial setting identifies that there is a variability in age at which assent should be conducted but also the manner in which the assent should be recorded. ⁶ Of the 57 institutions surveyed, 37% required an assent signature line on the parental consent form, whereas 63% used separate assent forms. Of those institutions using separate assent forms, 30% used a single child-specific assent form, 21% used a signature line on the parental consent form plus a child-specific separate form, 10% used age specific assent forms for different age groups, and 2% used the consent form identical to the parental consent.

The Children's and Women's (C&W) REB in Vancouver, Canada requests that any child that is cognitively able and is above the age of 7 years will be asked to assent to their research participation, including BCCHB participation. Age-appropriate assent forms are developed for each research study that is approved by the C&W REB. In a previous survey by our group, high school students and adolescent hospital patients, as well as the parents of both groups were asked about the appropriate age of assent. The median-suggested age by both groups of adolescents was ∼14.5 years, whereas parents of both groups suggested 16 years as the most appropriate age of assent. ⁷

While engagement and inclusion of the child in the consent process is important, the formality of the assent process can be perceived as intimidating and may be more appropriate for adolescents than young children. More informal methods such as the utilization of verbal approval or an alternative approval mechanism, such as an assenting app may be more meaningful for younger children.

If there is a disagreement between the willingness to participate between parents and child, the general consensus is that the child will not be included in the biobank. Although from a legal perspective the parents' consent is sufficient for participation, it is disrespectful to ignore the child's wishes after specifically asking for their opinion. Alternatively, if a child would like to participate but the parents refuse consent, the child cannot be included due to the lack of legal consent. An exception is if the child is deemed to have capacity to consent (mostly adolescents, see below) in which case parental consent is not required. Input from children, adolescents, and parents such as obtained by us may inform REBs on patient preferences to assent. ⁷

While the ethical importance of assent is well accepted among pediatric biobankers, the assent process adds a significant operational and financial impact to pediatric biobanks. This factor should be considered in the budgeting and forecasting associated with pediatric biobank sustainability.

The timing of the consent discussion is important and can be more critical for the inclusion of children and young adults in biobanks as illness of a child is often more stressful to parents than being sick themselves. Seeking biobanking consent and assent before surgery takes great sensitivity. The ethical obligation of informing the patient about research and biobanking, especially if full consent and assent has to be obtained before the procedure, can create added stress and concern to both parents, guardians, and the children themselves. Allowing a protocol where verbal permission for obtaining specimens for pediatric biobanks followed by formal consent after the acute event results in better patient satisfaction, better understanding of the consent itself, and an increased participation rate. ⁸ However, this approach can only be considered if the method to obtain the specimens would not increase the risk of the procedure. Note that verbal permission is still controversial in the biobanking community as some feel strongly that formal consent is necessary before any specimen is obtained. The argument is that consent should precede gathering and/or processing any specimens that would not normally be obtained/processed for that person's clinical care.

Verbal permission before obtaining full consent is also more labor intensive as it requires increased administrative work and additional contact with families. The BCCHB has REB approval to obtain verbal permission for specimen collection if there is no additional risk to the patient with regard to the collection, and the procedure to obtain the specimen is planned within 24 hours of contact with the formal consent process happening after the specimens are obtained (usually between 1 and 4 weeks after verbal permission was obtained). Striking the right balance between informing participants and avoiding harm (such as stress) takes skill and training.

Reconsent

As pediatric biobank participants could have their specimens and clinical data used for research after they reach the age of majority, it is necessary to develop policies and procedures with regard to reconsent. Reconsent is defined as an “action in which a research participant makes the decision to participate in a study once again or consent to new elements of the study.” ⁸ There is currently no gold standard with regard to the need for reconsent. Issues to consider include whether all specimens and data need to be destroyed or whether they can still be used for future research, a significant operational and financial consideration.

Some pediatric biobanks argue there is no need for reconsent if there is no further collection of specimens and data on the patients (personal communication, International Society of Biological and Environmental Repositories [ISBER] Pediatric Special Interest Group). However, others argue that any patient who has reached the age of majority needs reconsenting if the specimens and data are still held by the biobank, regardless of whether further biospecimens and data are collected and that specimens and data need to be anonymized or removed if reconsent cannot be obtained.

Furthermore, the term reconsent may not be appropriate here, given that the reconsenting process would not involve new decisions on the part of parents, but would rather ask the child to make a choice about the continued use of their specimen once they reach adulthood. This is a crucial difference given that a new consenting process is not meant to simply capture a change in choice for an already consented individual, but rather represents an entirely new consenting adult who may or may not understand the original intent of the bank or its inherent risks and benefits.

Over the last few decades, there have been a number of studies to address these complex ethical issues from the perspectives of parents and donors. A study of 1186 patients at five major medical centers in the United States found that while half of their participants would want to be recontacted to obtain consent for the future use of a specimen collected from them in childhood, a large majority would be willing to give consent for continued use if asked and was in favor of continued use if the biobank could not contact them to obtain consent. ⁹

Our group asked adolescents and parents about the importance of reconsent. ⁷ More than half of participants in all groups felt that reconsent was important. However, approximately half of the adolescent groups as well as the hospital parents felt that in the absence of reconsent (e.g. due to inability to recontact) they would still wish for their specimens to be used in research.

Other factors to consider include the possibility that an individual may not be aware of their participation in a biobank, causing confusion and potential tensions within a family unit. Moreover, specimens and data already released to researchers cannot be retracted and this should be made clear to the consenting party. It is clear that pediatric biobanks have to develop a policy for reconsent and develop procedures for means to recontact a participant and a subsequent process if a participant cannot be contacted.

The BCCHB's policy allows specimens and data to be used in the absence of reconsent if the patient cannot be reached for reconsent, but in these instances the identifying data will be transferred to a third party that will only reidentify the participant for unexpected clinical reasons. No further specimens or data can be collected on these participants in the absence of reconsent. Other pediatric biobanks opt to fully anonymize specimens and data with no possibility of reidentification. Recontacting participants for the purpose of reconsent at the age of majority can be time consuming, costly, and sometimes impractical as participants may be difficult to contact due to change of contact information as well as disinterest in accepting and returning contact efforts from the biobank. However, in the era of new technologies and electronic consent some of these impracticalities may be overcome.

Capacity to consent

Many pediatric biobanks endorse “capacity to consent.” This is a process in which biobank personnel obtaining participant consent, often of an adolescent, determines whether the patient is mature and knowledgeable enough to consent for themselves even if they have not reached the age of majority. Currently, standardized criteria for determining capacity to consent are lacking and there is no set minimum age for capacity to consent, although most institutions determine capacity to consent only in adolescents and some limit this to specific subgroups such as emancipated minors or married minors.

The practice at BCCHB is that adolescents (age 14 years and over) should be given the opportunity to consent for themselves if deemed to have capacity, using a set of criteria (Table 1) to determine capacity to consent. Criteria include the initiative the child undertakes and the questions the child asks about biobank participation and all criteria in Table 1 need to be met before an adolescent is deemed to have capacity to consent. Since inception of the BCCHB, we have determined capacity to consent 75 times in children ranging from age of 14 to 18 years, which constitutes 5% of adolescents in our biobank. In all cases, the parent/legal guardians were required to be present and there has to be consensus that the patient can consent for themselves.

Barriers to determine capacity to consent includes major parental involvement, concerns about absence of parental consent for legal reasons and REB audits, discomfort with determining capacity in children that have not reached adolescence, and additional work to do the assessment for biobank personnel. Currently, the BCCHB policy states that a minor can only consent for themselves if: (1) there is consensus with patient and parent/legal guardian on capacity to consent or (2) this is an emancipated minor. An advantage of obtaining capacity to consent includes the elimination of the need to reconsent at the age of majority, although this does remove an opportunity to reconnect with participants and maintain an ongoing relationship.

Potential loss of privacy

One of the perceived risks associated with biobanking is a breach of patient confidentiality and subsequent loss of privacy. Loss of privacy may have additional consequences in pediatric participants. Although in both adult and pediatric biobanking they may have negative effects on insurance policies and job opportunities now or in the future, pediatric participants may also suffer from interference with childhood development, such as bullying, negative impact on school performance, as well as school/career opportunities. ¹⁰

In addition, some of these consequences may also affect (minor) siblings, future siblings, and parents in a more significant way compared to adult biobank participants, as minor siblings may go to the same school or have the same social circles as the participant and parents may worry not only about themselves but also what the loss of privacy means for the family as a whole. Therefore, great care should be taken to protect privacy of participants. The BCCHB has completed a Privacy Impact Assessment and, like many other biobanks, has confidentiality agreements with all biobank staff.

Research findings

Another consequence associated with biobank participation is the effect of primary and secondary findings as well as whether and when results should be returned to the participant. Most REBs agree that participants have the right to have research results returned to them that are clinically actionable (this is often based on current standards of care and may include treatment options, genetic counseling, and screening/preventative measures). Whether or not to return research findings should be clearly discussed with the participant during the consent process and included in the consent form.

Adult biobank participants can often decide for themselves whether they want research results returned to them. For pediatric participants these decisions are made by parents/guardians and the timing of the return of results can be complicated. There has been some general consensus within the bioethics and genetics communities to not return predicative genetic testing results to children for adult-onset conditions until they reach adulthood. This has been referred to as the child's “right to an open future.” However, recently there have been calls to rethink this concept given evidence that families can cope well with complex genetic information and when retuning genetic results that may be in the child and family's best interest. ¹¹ Nevertheless, there are still concerns about the potential consequences of returning results that may not have effect until adulthood (e.g., Huntington's disease), including potential psychosocial harm to the child and family. ¹²

Note that delaying the return of clinically actionable findings may be risky due to loss of contact. Therefore, if it is considered beneficial to the participant and family to delay return of results, a strong connection between the patient and doctor should be in place to prevent the inadvertent inability to recontact the participant at a time that the findings should be disclosed. Inevitably, genetic information returned to research participants may tell parents or siblings something about their genetics. While some parents may want this information (e.g., for prenatal counseling), they are not typically seen as research participants themselves and have not consented to receiving results. Decisions about return of results to parents that may affect minor siblings, which is more common in pediatric biobanking, should be carefully considered as they are neither research participants nor can they consent for themselves.

The BCCHB has a standard operating procedure to address return of research results that is based on initial consultation with REB, clinician, and researcher.