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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 >12000 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.
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 . 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 . 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.
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 . These alternative models trade off the potential for scientific benefit from any collected specimens with improving research capacity at resource-limited sites.
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 . 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.
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).
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.
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.
PERCH sites provided information about their approach to community engagement in past research. Some of these methods include the following:
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.
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:
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.
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.
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.
We gratefully acknowledge the work of Alison Boyce in reviewing the literature used to develop this paper.
This article and its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or the National Institutes of Health.
This work was supported by grant 48968 from The Bill & Melinda Gates Foundation to the International Vaccine Access Center, Department of International Health, Johns Hopkins Bloomberg School of Public Health; the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research (grant UL1 RR 025005); and the Niarchos Foundation (Bioethics Rapid Response Initiative).
This article was published as part of a supplement entitled “Pneumonia Etiology Research for Child Health,” sponsored by a grant from The Bill & Melinda Gates Foundation to the PERCH Project of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.