Discussion

It is a foundational element of clinical practice that a patient should be informed of, or at least have ready access to, information about the circumstances and consequences of any clinical procedure they may be undergoing. Similarly, if, at the time a patient’s biospecimens are collected for clinical purposes, it is known that scientists may use the biospecimens for research purposes, the patient should also be offered information about possible future use. In this situation, informed consent should be obtained whenever feasible, even though, as in some Nordic countries, a notification process with an opportunity for the patient to opt out of research participation may be sufficient to protect the autonomy interests of participants. In planned interventional clinical research, or in research that is designed as a prospective collection of biospecimens for future research use, the research team should obtain informed consent from the research participant, with reference to anticipated future research uses of the biospecimens.

The importance of transparency and informed consent for the research use of biospecimens has been highlighted by the cases of Henrietta LacksReference Skloot⁷ and the Havasupai tribe,Reference Mello and Wolf⁸ and by several court cases in the US,Reference Weil⁹ as well as incidentsReference Hall¹⁰ and widely publicized situations in other countries.Reference Couzin-Frankel¹¹ Some studies indicate that, when asked, most participants are willing to share their health data and biospecimens with researchers if they will be used for the advancement of scientific knowledge.Reference Kim¹² However, studies have also indicated that individuals are somewhat less willing to share their biospecimens with for-profit entities or with researchers in other countries.Reference Nicol¹³ Thus, it is important to disclose this information to potential research participants as a routine matter in the informed consent process, and to provide them with information about the categories of researchers and entities with which they consent to share their biospecimens and data.

Discussion

Respect for participants’ consent is fundamental to respecting their autonomy and requires consideration of participants’ reasonable expectations for the uses of their provided biospecimens. However, it is inherently challenging to anticipate all future research questions that any single biospecimen might inform. As scientific knowledge progresses, new research areas emerge that scientists could not have reasonably foreseen. Similarly, future research purposes may arise that physicians and researchers cannot now anticipate or describe to participants in order to obtain specific consent for those future uses.

Moreover, given the potential risks that biospecimen collection imposes on patients, there is an ethical obligation to value this resource. Consents that use a broad description of future research aim to maximize the uses of these valuable resources by allowing for important future research that may not have been specifically anticipated at the time consent was given. Broad consent is intended as consent that describes the types and scopes of future uses for which specimens may be used, without returning to the participant for a specific consent for each new research study. Unlike a “blanket consent” that would allow anyone and everyone to use biospecimens for any purpose, a broad consent typically includes use restrictions and terms of oversight, such as ethics committee approval, for the future research uses of biospecimens. Many study populations and ethicists consider such broad consent to be ethically acceptable when used in conjunction with ongoing oversight of subsequent future research uses.Reference Gabriel and Mercado¹⁴ Broad consent has also been found to be acceptable by international policy documents, such as the Council for International Organization of Medical Sciences’ International Ethical Guidelines for Health-related Research Involving Humans. However, broad consents may not be acceptable to some populations or in some jurisdictions. For example, the European Union, in its General Data Protection Regulation, requires researchers to obtain specific research participant consent for use of clinical data in research.Reference Kim¹⁵ Additionally, a specific research consent may be more appropriate in some research contexts: for example, if additional uses of the biospecimens are precluded by consent terms that restrict further sharing. Nonetheless, as a normative matter, the abilities of individuals to give broad consent for future research uses is to be preferred, in that it maximizes the efficiency and opportunity for valuable scientific research, while also providing individuals an initial informed choice as to the future research uses of their biospecimens.

The concepts of this principle are also intended to apply in the case of biospecimen collection and secondary uses when the participant is a child or individual who lacks consent capacity. In those instances, consent is to be obtained from a legally authorized representative consistent with applicable laws. For new research uses of the participant’s identifiable biospecimens, some national laws or research ethics committees may require the minor to reconsent at the time they reach legal maturity. On the other hand, in some jurisdictions, an ethics review committee may find a waiver of consent acceptable in these circumstances.

In some countries, national laws or local norms may require the consent of family members (for example, the eldest male in the household) or tribal or group elders; if so, consent must be sought from the participant first, and subsequently also from these other individuals. The use of biospecimens of deceased persons in some jurisdictions may require the consent of surviving next-of-kin or of the estate administrator, if the participant did not consent before death, and those laws must also be respected when applicable.Reference Baltzan¹⁶ Consent at the population or community level is discussed in Principle 5, Safeguarding the Welfare of Specific Communities.

Discussion

When consent has been given for future research uses of biospecimens, researchers and research institutions, including commercial entities, have an ethical obligation to examine the content of that consent and to consider the context in which consent was given, in order to ensure that the terms of that consent allow specific intended uses. Compliance with the substance of consent is essential in safeguarding the rights and interests of participants and, at the population level, in maintaining social trust in the research enterprise.

In some cases, it may not be clear whether a specific secondary research use falls within the scope of an original consent. Importantly, resolving this is a context-specific determination that must consider the nature of the proposed secondary research; whether the secondary research could reasonably be understood to fall within the scope of the research described in the original consent; whether the secondary research includes new or significantly heightened risks, including privacy risks, that were not described in the original consent; and whether the participant population has known concerns about the specific intended secondary use.¹⁷ One approach would be to deploy a “tiered consent,” in which research participants are allowed to choose among a list of options for future research uses of their biospecimens and data. However, the use of such tiered consent carries an obligation to adhere scrupulously to the parameters of the consented uses for as long as the biospecimens and data are retained for research. Further, meeting this obligation requires appropriate IT or human infrastructure to track and respect such choices. The various types of consent for the use of biospecimens and data and their advantages and disadvantages have been discussed previously in the literature.Reference Bledsoe and Sexton¹⁸

When clinical biospecimens have been collected during clinical care and are considered for secondary research without consent for future research use, it should be required that a research ethics committee review and approve proposed uses. In that process, a research ethics committee should consider, among other factors, the nature of the proposed use, its reasonable acceptability to the participant population, and the benefits and risks to the participants, including any group harms.

Discussion

Respect for individual participants and their autonomy must also include their right to withdraw consent. Researchers should inform participants that they are free to withdraw consent at any point and for any reasons, including for future use.Reference Gabriel and Mercado¹⁹ However, in some circumstances, it may not be feasible to cease research activities already involving the biospecimensReference Yassin²⁰ or withdraw data points if the research has already been published. Also, it may not be possible to reidentify the biospecimen provided by a specific participant or retrieve biospecimens already distributed by a biobank for a research study. In addition, biospecimen-related data for research regulated by the US Food and Drug Administration, among others, may need to be maintained for study integrity, or in the interest of public health and safety, despite the withdrawn consent of a research participant.²¹ Therefore, it is critical for researchers and biobanks to communicate clearly with participants about any limitations on withdrawal of consent.²²

Discussion

In addition to respecting individual autonomy in biospecimen research, it is also important to consider the perspectives and values of the study population and associated self-defined communities in the design and conduct of the research. Specific communities may have religious or cultural norms related to biospecimen research (or research more generally) that should be respected.Reference Kowal²⁴ Some cultures prioritize communal rights with respect to decision-making and individual autonomy:Reference Mayne²⁵ for example, by requiring community consent, consent from tribal leaders or a participant’s relatives. Additionally, some communities may have requirements for burial or other disposition of unused biospecimens donated for research, such as their return to the individual or tribe.Reference Cunningham²⁶

In order to establish and maintain the trust of participants and associated self-defined communities, the religious perspectives and cultural norms and values of these communities should be considered and integrated into the research design and conduct. Historical context, community structure, and vulnerability, particularly in relation to Indigenous communities, should be considered, and, ideally, an enduring partnership formed.

Data sovereignty, or the authority and right of a population to govern data generated within a given jurisdiction, is a key consideration for biospecimen research involving indigenous communities.Reference Kukutai and Taylor²⁷ Indigenous data sovereignty should be considered before the use of specific data in research proposals, and may require further guidance from the community. Guidelines for research practices and the reporting of research on indigenous populations have been published.Reference Huria²⁸

In addition to individual risks, consideration should be given to the benefits and risks to communities of biospecimen research. Communities may benefit or be harmed by certain types of research, such as research on stigmatizing conditions, even when individually identifiable information is not released. Some types of research, such as ancestry studies, may not be acceptable to some communities.Reference Mello and Wolf²⁹ The Havasupai and San casesReference Chennells, Steenkamp and Schroeder³⁰ provide examples of dignitary harm resulting from biospecimen research in which researchers used biospecimens, without a discrete population’s prior knowledge and consent, for purposes that the population found objectionable, including studies of schizophrenia, inbreeding, population migration, dietary history, and marriage practices.

To promote trust and avoid harm to communities, researchers should make a good faith effort to engage with self-defined communities as early as possible in the study design stage. The research should be relevant to the study population and their communities, and research without meaningful engagement should be avoided.Reference Huria³¹ To the extent feasible, research benefits to the community should be maximized. Research co-design maximizes study value and participation while minimizing potential harms to the community. Engagement can demonstrate respect for a community’s values, culture, and traditions. By building trust, researchers may also be better able to perform long-term studies and conduct follow-ups when necessary. However, in some circumstances, researchers may struggle to determine which self-defined groups are part of a study population, who speaks for the community, or which community engagement approaches are feasible and appropriate for the proposed work. Guidelines related to these issues have been published by H3Africa.³²

The need for and type of community consultation will depend on the study population, the type of research and downstream assays and research questions, and cultural sensitivities regarding the research. In addition, feasibility and available resources need to be considered. Possible strategies may include engagement with community leaders, surveys, focus groups, and deliberative democracy approaches involving the study population and associated communities. Community representatives may serve, as appropriate, on biobank governance/advisory boards such biospecimen utilization access committees and ethics review boards. In addition, in certain circumstances, it may be appropriate to establish community advisory boards to provide ongoing advice on issues related to community perspectives regarding the design and operation of a biobank and/or associated research.Reference Olson³³

Discussion

Research uses of biospecimens and associated data that have been primarily or largely gathered from one defined population have the potential to result in published findings that may be perceived as adversely characterizing that population. In this context, one should be cognizant of the risk of populations being characterized in research findings as possessing inherited genetic traits suggesting suboptimal health outcomes, experiencing heightened incidence or prevalence of specific illnesses, or adversely affected by dietary habits or environment. The historical example previously mentioned, of the use of biospecimens and health information from members of the Havasupai tribe to study incidence of mental illness, is cautionary in this regard.

In considering possible adverse impacts of research findings on a specific participant population, one must balance the need for scientific impartiality and objectivity with predictable negative impacts on that participant population. This principle is not intended to discourage publication of research findings for fear of offending a participant population, but is intended to caution scientists who are downstream users of previously collected biospecimens and data, and the ethics committees that review proposed research, to be aware of these possible effects and to seek to design and publish their studies, not by disguising results, but by carefully qualifying findings and suggesting consideration of any alternate explanations.

Discussion

Biospecimen research on important scientific and health issues frequently benefits from significant amounts of linked data, such as clinical, phenotypic, and genotypic data. As more information is collected, the risks of reidentification and possible discrimination against research participants and associated groups, such as their geographic, racial, or ethnic communities, also arise. It is therefore important to remove identifying information not needed for anticipated downstream uses to protect the privacy of participants and the confidentiality of their data.

Protecting the privacy interests of participants and maintaining the confidentiality of their associated health data is not only ethically appropriate and legally required; it also promotes participation in research if individuals feel confident that their privacy is safeguarded throughout the research process.

Internationally, the regulatory landscape regarding biospecimen use, data protection, and individual privacy is fragmented. Many countries and jurisdictions have implemented legislation on the collection of data, and, in particular, the international sharing of data. Currently, 172 countries have enacted data privacy laws, and others are considering bills or draft laws. While these are not specific to participant privacy in research, they do encompass such uses and have a resounding effect on research.Reference Greenleaf³⁴

Considerable variation exists in terminologies related to identifiability. These terms include identified, de-identified, tokenized,Reference Nunes³⁵ coded, pseudonymized, anonymized, and anonymous biospecimens and data, all of which have implications on the levels of privacy and protection afforded. The US Food & Drug Administration and European Medicines Agency have adopted International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E15 definitions to define these categories for genomic data.³⁶ The European Data Protection Board has also issued guidelines on pseudonymization for data used in research.³⁷

Researchers should develop and institute explicit policies and procedures to protect the privacy of participants and the confidentiality of their data. These policies and procedures should include specific data encryption methods, coding practices, access controls, agreements not to release code keys or attempt reidentification of individuals from de-identified data, and the use of nondisclosure agreements when appropriate. The risks of reidentification and associated harms to participants and implemented mitigation processes should be discussed during the informed consent process.

Discussion

The issue of privacy is particularly pertinent to genetic/genomic research data derived from biospecimens. Genetic and genomic data are unique to an individual and can have downstream implications for the individual, their family, and community members. There are possible negative consequences of the intended or unintended release of genetic/genomic data, including discrimination for life and health insurance or employment due to certain genetic characteristics that may be perceived as undesirable.Reference Godard³⁸ There are also concerns regarding potential uses of these data by law enforcement agencies.Reference Schmid³⁹ By the very nature of genetic and genomic data, de-identification of these data cannot completely guarantee sustained privacy. This situation is further exacerbated by increasing requirements to make such research data available through genetic and genomic databases and supplemental data to scientific publications.Reference Gymrek⁴⁰

Some jurisdictions may have regulations with specific requirements to protect genetic and genomic data. For example, the European General Data Protection Regulation considers genomic and genetic data a special, protected category of data, requiring rules regarding the processing and sharing of this data, particularly with entities outside of the regulatory jurisdiction.Reference Shabani and Borry⁴¹

Studies indicate that participants surveyed are concerned about the possibility of identification and, while willing to share their data, require assurance that it will be shared with reputable entities in a secure and protected mannerReference Husedzinovic⁴² and governed by a trustworthy body with the power to enforce regulations of processing and sharing.Reference Lynch⁴³ Therefore, participants should be informed about potential uses of their biospecimens in genomic and genetic research. This information should be included in the informed consent process, along with details about any future sharing of these data and a discussion of risks and measures being taken to ensure the privacy and confidentiality of the participant at each phase of biospecimen and data use and sharing.

Finally, there are situations in which researchers seek to perform genetic or genomic analysis on biospecimens originally collected without explicit participant consent for such future genetic or genomic research. In these cases, researchers should first make reasonable efforts to select biospecimens that were originally collected with consent for future genetic and genomic research. If such resources are not practicably available, it is essential that the researcher gain ethics committee approval for the proposed research uses, and that the review process include particularly rigorous consideration of the factors embedded in these Principles, including privacy and respect for human and community welfare. Further, any approvals should be specific to the study presented and not generic in nature, so as to permit repetitive reuse of biospecimens.

All reuse ideally should be approved by the authorized research ethics committee most closely affiliated with the origin of the biospecimens and, where appropriate, through consultation with the communities from which the biospecimens were collected. This would avoid situations like that of the Havasupai, in which de-identified biospecimens were repeatedly shared downstream without reference to the initial representations made to participants and their communities when the biospecimens were first gathered.

Discussion

Despite cultural and socioeconomic factors influencing expectations and the value placed on accessing results,Reference Canedo⁴⁴ there is a notable societal trend toward expecting access to individual results.Reference Wong⁴⁵ Returning individual results is increasingly viewed as a manifestation of respect for study participants, grounded in the principle of reciprocity. Participants contribute valuable information to research for societal benefit and thus have an implied right to access their personal health information, which should be honored whenever possible.

Generally, the demand for returning individual results is highest for validated research methods from certified laboratories and for results that are clinically urgent and actionable. Conversely, concerns about returning results arise when results are not fully validated, their health implications are unclear, their value in clinical decision-making is limited, or the information is complex. In such cases, questions about the data’s meaning and usability for participants should be considered to avoid confusion and anxiety in participants.

The legal and regulatory frameworks governing the return of individual results from biospecimen research to research participants vary significantly across jurisdictions and types of research results.Reference Lang, Zawati and Sobel⁴⁶ These frameworks vary from mandates to return individual results under certain conditions to provisions that address conditions for participant access to such data.

Returning individual results is not always possible, particularly in secondary research, where personal identifiers are typically removed and participants’ identities are encoded or anonymized. This is further complicated with the passage of time. In secondary research conducted years after biospecimen collection, contact information may be lost or outdated.

Respecting participants requires that results be returned in an ethically appropriate manner that accommodates the diverse needs and preferences of specific communities and type of information.⁴⁷ Depending on the results’ implications, a trusted individual able to interpret the results should be identified, ideally a known health care professional or counselor who can discuss the findings in a contextually and culturally appropriate way. This necessitates careful planning and allocation of costs.

Discussion

The responsible use of biospecimens is critical to maintain the trust of research participants, research sponsors, and the public. Individuals who donate their biospecimens for research often contribute their biospecimens for altruistic purposes, and they expect them to be well utilized to advance scientific discovery and improvements in health care. Also, while risks to participants from biospecimen research are generally low, participants may undergo invasive procedures for the collection of those biospecimens, and biospecimen use may pose risks to particpants’ privacy. Consequently, those who collect or use biospecimens for research have an obligation to ensure the responsible use of biospecimens and data, including ensuring biospecimen quality and fitness for intended purposes and sharing biospecimens to facilitate research that may potentially benefit research participants and society.

Underutilization of biospecimens collected in research has been identified as a significant ethical issue.Reference Cadigan⁴⁸ Studies have shown that those who collect and store biospecimens for research have concerns about underutilization of biospecimens in their collections.Reference Henderson⁴⁹ Factors affecting utilization include findability, the availability of other sources of biospecimens, the choice of collection model, strategic planning, and other important factors, such as the availability and nature of informed consents.Reference Bledsoe and Sexton⁵⁰ Using informed consents with broadly stated permissible future research uses (see Principle 2) and minimizing restrictions in the consents can help maximize the use of biospecimens.

Appropriate stewardship of the biospecimen is a critical component in the effort to enable responsible use. Responsible stewardship must also include protection of the privacy of research participants (see Principle 7), the confidentiality of their data, and appropriate uses of their biospecimens, including good governance (see Principle 11).

Ensuring responsible use of biospecimens also includes the ethical disposal of biospecimens when they are no longer useful. There may be local, legal, or biosafety rules for the disposal of human biospecimens. Additionally, as noted previously, certain populations may require return of any unused biospecimens for burial and/or religious ceremonies (see Principle 5).

Research data sharing is an ethical obligation that allows other scientists to verify the study’s results, reanalyze the data, reach new conclusions, or explore new research questions. Such sharing is required by funding agencies or research sponsors, for example by the National Institutes of Health.⁵¹

To facilitate transparency (see Principle 1), researchers may also consider sharing general information about the research uses of biospecimens in their collections by sending newsletters to participants or creating a publicly available website.

Discussion

Governance and oversight of the collection, storage, distribution, and use of human biospecimens is critical for ensuring that biospecimens are collected and used in ways that are ethically and scientifically sound. It is also important to earn and maintain the trust of participants and the public.Reference Dive⁵² The importance and components of good governance in the use of human biospecimens have been addressed in a number of international ethical guidelines.⁵³

As noted in these guidelines, good governance includes transparency, accountability and stewardship of biospecimens (see Principle 10). Governance and oversight are especially important where no consents are available, or consents are used that are broad in their nature with regard to future research uses.

To provide appropriate oversight, a competent research ethics committee should review protocols for the collection, storage, distribution, use, and disposal of human biospecimens in compliance with relevant national and local regulations and policies. The research ethics committee should have knowledge of regulatory and ethical standards relevant to the proposed biobanking protocol. Any proposed specific research uses of the biospecimens should be evaluated by the research ethics committee to determine whether their intended use is ethically appropriate, whether the samples are suitable, and whether the researchers are able to undertake the proposed work. Furthermore, the ethics committee must consider the protections in place for the privacy of participants and the confidentiality of their data, whether the use is consistent with the expectations of participants expressed through consent, and whether any potential group harms have been considered and addressed, particularly for international sharing where regulations and cultural norms may differ.

Good governance is particularly important for biobanks, because biobanks can serve as surrogate decision-makers/caretakers for biospecimens and data, particularly when a broad consent is used for future research uses. Biobanks may establish a governance plan consisting of the set of authorities, processes, and procedures guiding key operational decisions made within the resource. Such governance plans should also include legacy or contingency plans to mitigate the risks to biospecimens in cases of management change, funding termination, or completion or discontinuation of research participation. In addition to oversight by research ethics committees, biobanks may use a variety of other governance and oversight committees to provide guidance and oversee operations. Finally, as previously mentioned, good governance and oversight should also involve community engagement when feasible and appropriate (see Principle 5).