Bioethical Considerations in Developing a Biorepository for the Pneumonia Etiology Research for Child Health Project

Abstract

The Pneumonia Etiology Research for Child Health (PERCH) project has the potential to provide a highly valuable resource of biospecimens that may be used to inform future studies on the causes of pneumonia. Designing a biorepository for this complex project was done in collaboration with a wide range of experts including bioethicists. In this paper, we describe the most significant ethical issues encountered related to the biorepository, focusing on its structure and informed consent. We also outline the proposed approach to the PERCH biorepository, which was designed to be sensitive to the ethical, practical, and cultural challenges inherent to the study. Through this process, we concluded that biorepository governance plans and strategies for managing informed consent should be implemented in a way to allow for careful study in order to better understand the attitudes of and impact on the stakeholders involved in the study.

Since the publication of seminal pneumonia etiology studies in the 1980s [1–3], significant technological advances, particularly in the field of molecular diagnostics, have increased the potential to identify and characterize the roles of both existing and previously unrecognized pneumonia pathogens [4, 5]. These advances in laboratory diagnostics warrant renewed examination of the causes of pneumonia in both children and adults.

The Pneumonia Etiology Research for Child Health (PERCH) project is a multi country, case-control study of children <5 years of age who are hospitalized with severe pneumonia. PERCH is funded by The Bill & Melinda Gates Foundation and is designed to determine the etiology of and risk factors for severe childhood pneumonia in vulnerable populations at 7 stand-alone sites. During project planning (2009–2010), the investigators consulted a wide range of experts to help design an efficient, effective and ethically informed study.

The Johns Hopkins Bloomberg School of Public Health (JHSPH) serves as the coordinating center for all of the PERCH sites. The study protocol was designed to incorporate expert advice while being sensitive to the on-the-ground realities of 7 resource-limited country settings. Protocol and consent templates were initially reviewed and approved by the JHSPH institutional review board (IRB). These materials were subsequently modified with site specifications and requirements and the approved by local ethics committees. The JHSPH IRB then conducted a final review and approval of the materials.

A major potential benefit of PERCH is the planned biorepository of specimens from >12 000 children across the world in order to inform future research into the causes of pneumonia. Collection and storage of biological specimens from sick children across study sites in resource-limited countries in Africa and Asia represents a particularly complex aspect of the study. Addressing the ethical challenges associated with the biorepository included development of strategies for governance of the biorepository and informed consent for specimen donation. Expert advice was sought in this regard from colleagues at the Johns Hopkins Berman Institute of Bioethics.

In this paper, we describe this collaborative approach to developing a biorepository for PERCH, which may serve as a model to others engaged in similar endeavors. First, we provide a brief overview of the most significant ethical issues encountered with biorepositories, focusing on the issues associated with their structure and informed consent. Next, we describe the cultural challenges in the proposed research, highlighted by the perspectives of participating investigators. Finally, we outline the proposed approach to the PERCH biorepository, which was designed to be sensitive to the ethical, practical, and cultural challenges inherent to this research.

BACKGROUND

Biorepositories can extend the scope of biomedical research by providing a large, accessible bank of biological specimens and data. At the same time, they can present significant and complex ethical challenges [6–9]. Issues range from those associated with informed consent, privacy protection, and returning results to individuals, to policies on access, secondary use of data, commercialization, and benefit sharing. The involvement of multiple countries, with variations in both cultural norms and levels of access to resources, can pose additional challenges. These issues are important and sometimes controversial, as evidenced by the circumstances surrounding the testing of stored specimens collected from the Havasupai tribe in Arizona under a very broadly framed informed consent document. In this case, the Havasupai understood that their biospecimens would be used to study diabetes, which was prevalent among the tribe. However, the specimens were subsequently used to conduct unrelated research, including that related to psychiatric disease. Alarmed by these uses, the Havasupai took legal action against the university that had conducted the research [10]. As this case makes clear, the issues are complex and vitally important to a broad range of stakeholders. Sound solutions need to be developed to ensure that biorepositories are developed and maintained in such a way that does not undermine their scientific value by overly limiting future access, while at the same time ensuring that specimen donors understand and are comfortable with the ways in which biospecimens and related information can be used in the future. Key stakeholders include the researchers and the participants, but they also include the participants’ communities, other researchers from both academia and industry, patients who stand to benefit from research findings, funders, and others.

Although there is not broad consensus about the best approach to addressing these diverse challenges, an emerging body of literature focuses on the need to adopt sound governance models for biorepositories [11–22]. A governance model describes how a biorepository is structured and functions. It describes how stakeholders relate to one another in terms of power and authority, and determines how decisions are made about use of biospecimens and related issues. The literature pertaining to biorepository governance generally reflects a preference for independent ethical oversight, robust public engagement, and access policies that promote data and materials sharing and collaboration. Proponents of these features argue that they maximize the scientific value of the biorepository, benefit the largest number of stakeholders, and encourage a sense of partnership and trust that is crucial to the success of such collaborative endeavors [18]. A full analysis of the ethical issues related to biorepositories is beyond the scope of this paper. However, some brief details about 2 key areas that needed to be addressed in designing the PERCH biorepository are provided in order to set the stage for describing the approach that will be used in this project.

BIOREPOSITORY STRUCTURE AND GOVERNANCE

One of the key decisions, particularly in the context of a multisite study involving partners with different levels of access to resources, is whether to design a centralized or decentralized biorepository. As described in Table 1, options include centralized biorepositories, semivirtual or hybrid banks, and fully virtual or distributed banks [23]. These alternative models trade off the potential for scientific benefit from any collected specimens with improving research capacity at resource-limited sites.

Table 1.

Types of Biorepositories

Type of Biorepository	Specimens	Data
Centralized biorepository	Stored centrally	Stored centrally
Semivirtual/hybrid model	Stored at multiple collecting institutions	Stored centrally
Fully virtual/distributed	Stored at multiple collecting institutions	Stored at multiple collecting institutions

A number of factors can help to guide the selection of the particular structure of a biorepository (Table 2). Although there are many practical and ethical concerns affected by the structure of a biorepository, concerns about social justice are particularly relevant in the presence of resource inequities such as those found among sites participating in PERCH. Recognizing the potential to exacerbate existing resource inequities by paying insufficient attention to social justice is echoed in The Bill & Melinda Gates Foundation global access grant agreement clause. This clause requires investigators to make “good faith efforts” to make the outputs of projects (tools, methods, and techniques) accessible to the people most in need [24]. For PERCH, this suggests the possibility of developing or ensuring capacity at local sites. Nevertheless, centralizing a biorepository may simplify logistics and increase efficient access to advanced skills and tools. Alternatively, the central repository could be placed at an institution that already offers advanced tools and highly skilled local researchers.

Table 2.

Pros and Cons of Centralized Versus Decentralized Biorepositories

	Centralized		Decentralized
Issue	Pros	Cons	Pros	Cons
Access	Clear, simple, single institution oversight for access and biorepository quality assurance; access would be easier and faster	Research sites may be reluctant to participate if they feel that their contributions are not acknowledged	Research sites may feel more vested in the biorepository and therefore be more willing to participate	Future studies and access to specimens would depend on compliance of individual investigators; decision-making may be slower and more complicated
Cost	Organizing research group or institution may be able to centralize freezer and equipment costs	Significant cost involved in setting up the equipment, staff, and long-term resource flow for an indefinite biorepository	Research sites may have some preexisting storage capacity, and costs of software that would accurately track all specimens and aliquots at sites should be minimal	A system to reimburse local investigators for continued specimen storage and for labor costs associated with future specimen retrieval would need to be developed and maintained
Logistics	Standardized methods for shipping, tracking, aliquoting, and storing specimens; request for specimens and subsequent retrieval and shipping would be more straightforward	A comprehensive setup requires not only funding but dedicated staff and a broader scope of work to maintain specimens after study completion	Research sites would maintain storage of specimens in the same manner that has been established during the participant enrollment of the parent study, but compliance will be more difficult to establish; lapses at a site could mean loss of specimens	Reliance on the research site’s capacity and expertise to maintain the specimens in a standardized way after the parent study has ended; retrieval of specimens from multiple locations could be complicated and time-consuming
Security	Resources could be devoted to centralized regulatory oversight of participant privacy, clinical data, etc for all biorepository participants	Security in a safe locale depends on money—as long as there are funds to maintain the specimens, they are safe	Research sites may be motivated to increase data and specimen security if there is no central repository or backup	Security of specimens may depend on local and national infrastructure; backup systems are not guaranteed

INFORMED CONSENT FOR DONATION OF SPECIMENS TO A BIOREPOSITORY

Although multiple models for obtaining informed consent for biorepositories have been proposed [13, 25–30], they tend to endorse the need for disclosure of some basic information:

• A reasonable assessment of risks to privacy: what they are, and how they will be minimized.

• The full range of individuals or groups with access to the samples and data stored in the bank (eg, public or restricted to certain investigators).

• Any relevant financial interests of stakeholders.

• A plan for the management of incidental information (ie, what situations, if any, will lead to the disclosure of individual results to participants or others).

• Whether samples may be used in research that leads to the development of commercial products, scientific publications, etc, and if or how participants will benefit from such developments.

• The possibility that participants may withdraw their consent at any time—information disclosed should include how to do so, and what this will mean for the donated sample (eg, will or can it be destroyed).

• That participants do not own the donated sample.

• That participants may request and be provided with (general) results of the study or studies completed.

Each of these areas presents complicated terrain. For example, although there appears to be consensus about the importance of providing general study results to participants on request, there are a range of responses that might fulfill this obligation. Careful consideration needs to be given to the extent of investigators’ responsibilities. For example, participants could be presented with prepublication findings. Alternately, “results” could be interpreted to refer only to findings in peer-reviewed academic publications. Furthermore, these results could be presented as-is, with little or no further explanation, or they could be summarized in detail to make them readily accessible and comprehensible to diverse audiences.

Models of informed consent vary and range from providing blanket consent for all potential uses of material to specific consent for a particular research study. Although the former may be desirable from a scientific and practical perspective, the hazards of doing so are exemplified in the Havasupai case described above. In contrast, specific consent comes at the cost of efficiency and utility. Locating and obtaining consent from all of the participants at a later date may be costly and/or impossible, undermining some of the reasons for having a biorepository. A variety of strategies are currently in use along the spectrum between very specific and very broad consent. Each strategy brings likely costs and benefits (Table 3).

Table 3.

Pros and Cons of Strategies for Consent and Its Withdrawal

Type of Consent	Description	Pros	Cons
Specific informed consent	Use of specimens and related data only in immediate research forbids any future study that is not included in the original consent	Adheres to a traditional view of informed consent by providing the specific information needed to decide about participation in a study; protects individual autonomy; generally less vulnerable to legal challenges	Limits potential use of samples (outside of recontacting donors); may overemphasize risk and understate the potential benefits related to research with biorepository specimens
Restricted consent	Use of specimens and related data in specific immediate research and in future investigations directly or indirectly associated with that research	Provides enough information to reassure participants that future research will not conflict with their wishes; some empirical support [25]	Limits potential use of samples and may still require recontacting participants for informed consent given unforeseen uses of data—which raises the same set of problems as above in those cases
Tiered consent	Provision of a range of detailed options to prospective research participants along spectrum from broad to specific consent	Provides individuals with more control by offering a range of options, thereby respecting autonomy; encourages participation by allowing participants to opt out of some, but not all, of the research	Complicates consent, potentially decreasing comprehension; adds significant administrative burden to biobanking
Conditional authorization	Subjects delegate autonomy to an ethics review committee to approve future proposed uses	Delegating autonomy to ethics review committee is considered an expression of autonomy; practical, efficient use of resources [26]; no need to reconsent for future studies	Sacrifices individual rights for larger research goals—the more general the consent, the less “informed” the participant; to be informed, participants need to understand the risks they are agreeing to assume by participating, and such risks cannot be known at time of consent in these cases; ethical principles should not be discarded for the sake of convenience [13, 28]
One-time broad consent	Allows the use of biological specimens and related data in immediate research and in future investigations of any kind at any time [27]	Substantial empirical support that this option is acceptable to many participants and may increase rates of participation [30]; maximizes scientific value of bank by facilitating access to samples and lowers administrative burden	Same as conditional, but more so

REPORTS FROM PERCH STUDY SITES

In addition to reviewing relevant information about biorepository practices in the academic literature, we also elicited information from the principal investigators from each of the 7 PERCH study sites in order to get a better sense about important contextual details. This included information about capacities, resources, and any culturally rooted issues that would be likely to affect the proposed plans to establish a biorepository. We also elicited strategies that have been employed for community engagement. Responses that were especially useful in better understanding some the ethical challenges in establishing a biorepository for PERCH are summarized below.

Cultural Barriers to Research Involving the Collection of Blood or Other Tissue Specimens

Some of the sites experienced resistance to blood specimen collection during past research. In one study, stories spread through the community that “Draculas” (blood suckers) and “Satanists” had infiltrated the study clinics and hospitals. These stories nearly brought the previous research to a complete halt. Some less dramatic examples of resistance to the collection of biological tissues followed a similar theme: fears of exploitation at the hands of foreign entities. At 2 sites, study personnel were accused of selling blood to foreigners from children enrolled in a study. At a third site, staff members were accused of shipping breast milk overseas for commercial purposes. Concerns arose in another study site community about the amount of blood being collected due to the appearance of large bottles that would be used to place blood samples into culture. In all of these cases, study personnel were able to successfully respond by engaging with their local communities and addressing the concerns. Strategies for public engagement included meeting with community leaders such as traditional healers (who were thought to be the source of some of the rumors in at least one instance), inviting community leaders to observe study procedures in order to address their concerns, and broader engagement through community-wide meetings and appearances on radio talk shows.

Community and Public Engagement

PERCH sites provided information about their approach to community engagement in past research. Some of these methods include the following:

• Community advisory boards.

• Community sensitization in advance of study enrollment (meetings, questions and answer sessions, etc).

• Employing community agents as part of the study as field workers, etc.

• Dissemination of study results through local media outlets.

• Obtaining “community consent” from local leaders (eg, tribal chiefs and traditional healers).

In aggregate, the importance of utilizing a range of strategies to engage with the local community is apparent. This can build trust and enhance accountability via open communication and transparency.

FINAL PERCH BIOREPOSITORY GOVERNANCE STRUCTURE

The final PERCH biorepository was developed on the basis of the scientific needs of the study and the relevant ethical and cultural issues. The PERCH biorepository will include independent ethical oversight, public engagement, and access policies built into a governance structure.

With respect to structure, the preference would be to store some volume of each specimen that is collected at the local study site to enhance local capacity, and aliquots at a centralized storage site to increase the safety and security of specimens. Unfortunately, this is infeasible for PERCH on logistical and ethical grounds. In particular, only small volumes of some specimens will be collected from each child. Therefore, in order not to compromise PERCH study, volume-limited specimens will only be stored at each individual site. Data about each specimen, however, will be maintained in a central PERCH biorepository database. Specimens that are not volume-limited (eg, liquid medium from nasopharyngeal and oropharyngeal swabs and postmortem specimens) or those that are renewable (eg, extracted DNA and isolates) will also be stored at individual sites, although eventually some of these specimens may be contributed to a central biorepository. PERCH will therefore be developing a semivirtual biorepository, with the possibility of eventually developing a centralized biorepository with a subset of samples that are also available at local sites. However, since sites may have concerns about shipping materials, the details of such an approach will need to be worked out in the future.

The agreed upon governance principles of the semivirtual biorepository will do the following:

1. Facilitate future discovery by allowing stakeholders access to study specimens. The executive committee will review and approve requests for access. (The executive committee is composed of all 7 PERCH project site principal investigators [PIs], and 3 PERCH core team members, including the overall PI, a co-PI, and the laboratory director.)

2. Encourage the transfer of future technological advances, including vaccines and diagnostic tools developed from biospecimens, to the most affected communities.

3. Consistently and purposefully consider the ethical principles of beneficence, justice, and respect for persons in all research requests.

4. Engage the communities at study sites.

5. Maintain a degree of independent ethical oversight through the executive committee.

The PERCH executive committee will be primarily responsible for implementing a biorepository structure based on these governance principles. The executive committee is charged with ensuring that the structure includes plans for the ethical oversight of all specimens and isolates that are procured for study purposes. Table 4 outlines the involvement of all key stakeholders, including study funders, teams, PIs, participants and affected communities, and commercial enterprises, in the proposed PERCH biorepository governance structure.

Table 4.

Stakeholder Concerns and Responsibilities

Stakeholder	Key Concerns	Involvement in Governance Structure
Study funder	Intended outputs of project (including tools, methods, and techniques) to be made accessible (with respect to cost, quantity, and applicability) to the people most in need within the developing countries of the world	Global access plan serves as basis for governance structure
PERCH investigators	Completion of project aims; fairness in access to specimens and future research opportunities; maintenance of the biorepository	Responsible for oversight by way of the executive committee; responsible for securing biorepository funding
Study teams	Fair access to study specimens from all sites; equity in future research opportunities; ownership of the biorepository	Responsible for oversight by way of the executive committee; responsible for research requests of specimens stored at study sites; responsible for alerting and involving all PERCH principal investigators
Study participants and affected communities	Protection of privacy; fair benefits from future technological developments	Key role in determining allocation of profits from tiered pricing scheme if one is developed; responsible for notifying advocacy networks of findings
PERCH executive committee	High-quality review of research requests; key developments made accessible through research and policy networks	Responsible for oversight by way of sample and isolate sharing; responsible for notifying colleagues of findings
Commercial enterprises	Access to specimen; ownership of research results and technologies arising from research	No role in oversight; key pricing tiers to fund maintenance of specimens

FINAL PERCH BIOREPOSITORY INFORMED CONSENT LANGUAGE

For informed consent, the PERCH team will employ a hybrid model, primarily using a restricted consent strategy supplemented by conditional authorization (Table 3). Future research can only include studies designed to better understand the causes of childhood diseases. The draft consent document templates, subject to local IRB approval, also include specific requests for permission to ship samples and data outside of the country, as needed. In addition, the consent template discloses that future testing may include genetic assays the results of which will not be returned to the participants. Finally, potential participants are told that future studies will be approved by a committee charged with ensuring that the “children’s safety and rights are respected.” The requests for permissions to store specimens for future research are separated from the request for permission for participation in PERCH so that both cases and controls can be enrolled in the study while still opting out of participation in the biorepository.

This consent format was created because of the need to incorporate permission from parents for storage and future testing without knowing exactly where or when study specimens would be tested. After consulting the sites, PERCH investigators decided that the “childhood diseases” clause mentioned above was appropriate to allow for future pathogen discovery. Most of the sites agreed with this language, with a handful of local adaptations.

CONCLUSIONS

The PERCH project is uniquely positioned to inform future research on causes of childhood pneumonia. Establishing a biorepository infrastructure at the outset that allows for this future research was a critical component during project design. By working with the 7 diverse study sites and their respective ethics committees, a semivirtual biorepository was ultimately adopted as the most feasible and best suited approach for the project, given both the lack of long-term support for a centralized repository and the opportunities involved for local site investigators in establishing a biorepository on site.

The PERCH team’s planning for biorepository governance and management of informed consent illustrates the benefits of funding mechanisms that promote careful preparation of study design with the added benefit of expert consultation. In this case, consultation with bioethicists facilitated the navigation of the practical and ethical terrain surrounding the development and governance of promising biorepositories. Merely having an enhanced understanding of this terrain is helpful, even in the absence of consensus about the best methods for addressing concerns, and should lead to better processes and outcomes in the long term. Furthermore, the absence of strong consensus and a dearth of available data suggest that biorepository governance plans and strategies for managing informed consent should be implemented in a way to allow for careful evaluation in order to better understand the attitudes of and impact on key stakeholders. Careful approaches to capturing the perspectives of key stakeholders will allow future efforts to be even better tailored to their preferences, needs and concerns.