Abstract
Population-based biobanks collect donors’ biological samples and associated data, following them over time to study gene–environment interactions as causes of human diseases. International biobank collaboration is envisioned as necessary for a better understanding of causes of morbidity and mortality. However, determining how to govern international biobank collaboration remains challenging due to nations’ heterogeneous ethical and legal frameworks. This article explores how China Kadoorie Biobank (CKB), a China-UK collaborative project, coped with ethical issues, such as informed consent, benefit sharing and community engagement. The CKB case study provides insights into ethical issues and governance challenges for international biobank collaboration. The transformation of biobank research from a localised endeavour to networked, internationalised projects in the context of post-genomic medical research has created a highly challenging constellation for biobank governance. The governance of global collaboration, such as between China and the UK, will depend on developing joint governance protocols based on mutual recognition and respect.
Introduction
With the development of genetics and genomics, recent years have witnessed the rise of population-based biobanks, among them DeCODE Genetics, UK biobank, and China Kadoorie Biobank (CKB). These biobanks collect large-scale blood samples, donors’ personal information, and obtain long-term access to their past and future medical and other health-related records in order to assess the complex interplay of lifestyle, environmental and genetic factors as causes of a range of diseases, such as stroke, diabetes and cancer. Although every nation has its own unique genetic resources for domestic research, maximising the full potential of biobanks requires studies of multiple populations from specific geographical areas. Thus, international networks of biobanks were envisaged as necessary in order to develop a better understanding of the causes of morbidity and mortality. Substantial money was invested worldwide in building biobank infrastructures and establishing international networks, including the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), and the Public Population Project in Genomics (P 3 G) (Asslaber and Zatloukal, 2007). Collaborations between scientific communities from the developing and the developed countries were also highly recommended for mutual benefits (Hagen and Carlstedt-Duke, 2004). However, given that national biobanks operate within ethical and legal frameworks that are heterogeneous across countries, there are roadblocks to transnational biobank collaboration, such as ethics policies, privacy laws, benefit-sharing frameworks and specimen quality (Watson et al., 2011).
Emerson, Singer and Upshur (2011) identified three interrelated ethical challenges that are central to the access and use of human tissues from the developing world—informed consent, benefit sharing and community engagement. This article explores how the CKB, an international collaborative biobank project between China and the UK, tackled these three ethical challenges, and discusses new challenges that international collaboration will create for biobank governance in the post-genomic age. It is argued that the transformation of biobank research from a localised endeavour to networked, internationalised projects in the context of post-genomic medical research has created a highly challenging constellation for biobank governance. The governance of global collaboration, such as between China and the UK, will depend greatly on developing joint governance protocols based on mutual recognition and respect.
This article is based on my empirical research on biobank governance in China from May 2010 to July 2012. I did participant observation at the biobank conferences in Taizhou and Shanghai, followed the survey teams to two villages where baseline surveys were conducted and biological materials were collected, and visited scientific laboratories where these samples were handled and stored. I interviewed scientists, bioethicists and stakeholders of various biobank projects, and also communicated further with these people at multiple sites. I also did document analysis of official documents, reports and Internet sources that I collected. In addition, six focus group studies were conducted in Hangzhou and Wenling, two cities of Zhejiang Province, Southeast China, to explore the general public’s perception of biobanks in China.
In the following, I summarise the discourse on ethical challenges of informed consent, benefit sharing and community engagement in biobanks. I then present a detailed description of the CKB project, which provides insights into the ethical issues of biobanks and governance challenges for future international biobank collaboration between China and the UK.
Interrelated Ethical Challenges
Any discussions about the ethics of biomedical research inevitably target informed consent. Following the Nuremberg Code and the Declaration of Helsinki to protect the autonomy of research subjects, informed consent ensures individuals their fundamental rights to participate in or withdraw from any biomedical research. In the context of post-genomic biobanks, consent issues become more complicated because of ethical dilemmas in the application of informed consent in the case of large-scale biobanks. There are concerns about secondary uses of samples (Cambon-Thomsen, 2004; Cambon-Thomsen, Rial-Sebbag and Knoppers, 2007; Haga and Beskow, 2008; Hansson, 2009); preferences for broad consent or narrow consent for future biobank research (Caulfield and Kaye, 2009; Hansson, Dillner, Bartram, Carlson and Helgesson, 2006; Wendler, 2006); and the harmonisation of ethical guidelines and regulations in international collaborations (Kaye, 2011; Yuille et al., 2008). Although the necessity of informed consent has been highlighted in biomedical research settings, there is also evidence that participants have difficulty understanding the role and impact of informed consent in epidemiological and biobanking studies. For example, several studies have shown that most participants in Western countries did not understand the consent forms they had signed for biobank research (D.T. Chen et al., 2005; Critchley, Nicol, Otlowski and Stranger, 2012). A quantitative study on informed consent in China indicates that conveying information to participants and obtaining informed consent in the Chinese study setting is difficult: although about average 90 per cent of the participants in China perceived the information concerning the objective of the epidemiological project to be adequate, an average of 76 per cent still incorrectly viewed their participation to be part of routine health check-up, rather than as part of a research project (Lynoe, Sandlund, Jacobsson, Nordberg and Jin, 2004). Under these circumstances, Dixon-Woods et al. (2007) suggest that we not treat ‘misunderstandings’ merely as a technical problem to be solved through improving the written information given to research participants; instead, attention needs to be paid to people’s real expectations and motivations for participation. This touches upon another important biobanking issue—benefit sharing.
Benefit sharing is a two-edged sword: it can either hurt the researcher–participant relationship, or it can balance the conflicts of interest and public trust in biobanks. UNESCO’s International Declaration on Human Genetic Data provides that ‘benefits resulting from the use of human genetic data, human proteomic data or biological samples collected for medical and scientific research should be shared with the society as a whole and the international community’. 1 The Human Genome Organisation (HUGO) Ethics Committee’s Statement on Benefit Sharing provides a more specific interpretation that a benefit should be determined based on needs, values, priorities and cultural expectations of an individual and/or a given community. 2 Despite emerging domestic and international principles on benefit sharing, benefit sharing between research participants and researchers remains controversial and complex because it involves various ethical concerns, such as ownership, compensatory justice, and solidarity (Simm, 2007). A fair distribution of research benefits in international health research among sponsors, researchers and participants in developing countries, and the translation of fair-benefit framework into practice are even more complex. If fairness among interacting parties is not achieved properly, there are risks of data and tissue abuse and exploitation (Schulz-Baldes, Vayena and Biller-Andorno, 2007). In the last decade, a series of cases were reported that tissue exportation from the developing world, for example, Uganda, India and Tonga, to the developed world involved possible exploitation of the Third World populations in the commercialisation of these tissues, and thereby, the erosion of public trust in biomedical research (Upshur, Lavery and Tindana, 2007). Therefore, it is essential to allocate and share benefits equitably among the interest groups so as to promote public trust.
Community engagement and public participation based on this kind of trust in biobank studies are crucial for the life of any biobank. The cases of DeCODE Genetics’ and UK Biobank’s engagement with the public have been studied extensively in order to identify the success or failure of biobank governance (Gottweis and Petersen, 2008). In Iceland, the public was initially supportive about the Icelandic Health Sector Database and the Databases for Genetic and Genealogic Information, a joint project of the Icelandic government and the private company DeCODE Genetics. Later, the public became unsatisfied with issues of consent and privacy, which created a gap between the Icelandic society and DeCODE Genetics, and finally undermined the biobank project (Pálsson, 2008). In the UK, the proposal of UK Biobank has proven to be highly controversial. Scientific communities and the public expressed concerns about its scientific validity and benefit to public health. Learning from the DeCODE experience, UK Biobank was, therefore, carefully launched. Consultation with the public and other stakeholders was considered necessary to gain the public support, and consent for the biobank was discursively framed to engender the public’s trust (Petersen, 2005). The Ethics and Governance Council was set up as an independent body to monitor the operation of UK Biobank and to make sure the biobank acts in the interest of the public according to the Ethics and Governance Framework (Tutton, 2007). More broadly, studies in various countries investigated donors’ attitudes to informed consent (Barr, 2006; Ducournau, 2007; Hoeyer, 2003; Kettis-Lindblad, Ring, Viberth and Hansson, 2007; Skolbekken, Ursin, Solberg, Christensen and Ytterhus, 2005); community concerns about benefit sharing and commercialisation issues in biobanks (Haddow, Laurie, Cunningham-Burley and Hunter, 2007; Otlowski, 2007); and the public’s perception of the internationalisation of biobanks (Gottweis, Chen and Starkbaum, 2011). All efforts were made to understand donors’ attitudes and perceptions towards biobanks, and to guarantee that enough community members would participate in biobank projects.
Despite the international ethical discussions on issues such as informed consent, benefit sharing and community engagement, Zhang (2009) found that Chinese scientists and regulators knew little about these discussions; they did not consider ethical issues seriously in the creation of biobanks, neither did they have a clear approach to benefit sharing in international collaboration. For those who increasingly realise the importance of international collaboration in biomedical research, they tended to adapt international ethical guidelines and regulations for their research in China (Petryna, 2005, 2009; Sleeboom-Faulkner, 2013).
‘For the purpose of efficiently protecting and rationally utilising human genetic resources in the PRC, strengthening genetic research and improving our understanding of genetics, and promoting international cooperation and exchange on the basis of equality and mutual benefits’ (Ministry of Science and Technology and the Ministry of Public Health, 1998) 3 ,the Interim Measures for the Administration of Human Genetic Resources (Interim Measures), promulgated by the General Office of the State Council, was issued by the Ministry of Science and Technology and the Ministry of Public Health, PRC, on 10 June 1998. The Human Genetic Resources Administration of China (HGRAC) was established to review and examine international collaborative projects involving human genetic resources in China. Therefore, the CKB case needs to be understood within Chinese institutional arrangements.
China Kadoorie Biobank
Building International Collaboration
Kadoorie Study of Chronic Disease in China (KSCDC), which was renamed China Kadoorie Biobank (CKB), was established in 2004 as a collaborative project among the University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), the Chinese Centre for Disease Control and Prevention (Chinese CDC) and the Chinese Academy of Medical Sciences (CAMS). The initial funding for the KSCDC came from the Kadoorie Charitable Foundation, a Hong Kong-based trust established in 1997 by the Kadoorie family. Originally Baghdadi Jews, the family became one of the wealthiest families in Hong Kong through finance, real estate and utilities. Their philanthropy extends to a variety of programmes across Southeast Asia, in particular China and Nepal, which are designed to provide long-term sustainability in the realms of health care, community development, poverty alleviation, education and the environment. 4 To acknowledge the crucial financial support from Kadoorie Charitable Foundation, the name ‘Kadoorie’ was retained in the organisation’s current name, ‘China Kadoorie Biobank’ (personal communication with a CKB manager, 18 March 2012). The follow-up of the project during 2009–2014 was supported by the Wellcome Trust in the UK with 2.5 million pounds (Wellcome Trust, 2009). The CTSU of Oxford University also received core funding for the CKB from the UK Medical Research Council, the British Heart Foundation and Cancer Research UK.
This collaborative project was based on decades of collaboration and trust between researchers from China and the UK (Li, Guo, Z. Chen, J. Chen and Peto, 2012). Sir Richard Peto, professor of medical statistics and epidemiology at the University of Oxford, has carried out many epidemiological studies in China since the 1980s and is well known for his finding on causal links between tobacco smoking and lung cancer in China. 5 In 1985, Sir Rory Collins, the current principal investigator and chief executive officer of UK Biobank, became co-director, with Sir Richard Peto, of the University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU). Researchers from CTSU primarily conduct large-scale clinical trials and epidemiological studies of chronic diseases. They were actively involved in planning the UK Biobank, a national health resource of 0.5 million people aged 40–69 years that has the aim of improving the prevention, diagnosis and treatment of various diseases. However, this project did not progress smoothly because of debates over its scientific value, ethical concerns and political legitimacy (Barbour, 2003). Given the difficulties in the negotiations of UK Biobank, the CTSU refocused its efforts on a similar biobank project in China instead. To that end, they contacted Li Liming, who was then president of the Chinese CDC and the current vice-president of CAMS, for collaboration.
By the time scientists from CTSU, Oxford, and the Chinese CDC prepared this project, the Interim Measures had been in place, which state that only through collaboration with domestic scientists can foreign researchers gain access to the genetic resources of the Chinese population. Adhering to the requirements of the Interim Measures, the British and Chinese scientists made a joint application. The Chinese collaborative party duly went through the formalities of application for approval from local administrative departments to HGRAC. The CKB study was finally approved in 2004, with Li Liming as the principal investigator and Chen Zhengming, professor of epidemiology at Oxford and the director of the China Programme in CTSU, as the co-principal investigator in the UK.
Engagement with Local Community
The establishment of population-based biobanks relies on the recruitment of a large number of participants, who then undergo a baseline survey with follow-up over the long term to study gene–environment interactions in human diseases. The baseline survey usually takes more than one hour to complete and includes a questionnaire, physical examinations and the collection of biological materials. Re-survey of randomly chosen surviving participants is necessary for unbiased prospective assessments of disease/gene associations. The follow-up studies must be connected with participants’ past and future medical records (Ollier, Sprosen and Peakman, 2005).
Unlike the UK Biobank, the CKB study is not designed to be representative of the general population of the nation. Its baseline survey was conducted in ten geographically defined regions (five rural counties in the provinces of Sichuan, Gansu, Henan, Zhejiang and Hunan; and five urban districts, Harbin, Qingdao, Suzhou, Liuzhou and Haikou) across China. These study sites were carefully selected based on
patterns of major chronic disease rates and risk exposures, levels of economic development, relative stability of the population and local infrastructures (including quality of existing death reporting systems, access to broadband internet, and availability of a reliable courier service for shipment of blood samples by air), and long-term local commitment to the project. (Z. Chen et al., 2005, p. 1245)
All study participants are monitored by China’s Disease Surveillance Points System, as well as by the regional CDCs. The follow-up study is electronically linked with the new national health insurance claim databases that are now established in all ten study regions (Z. Chen et al., 2005; Z. Chen et al., 2011).
The organising structure of the CKB is a top-down process with various administrative institutions between the superior and the subordinate levels. The CKB has two central study coordinating centres, with an international coordinating centre located at the University of Oxford and a national coordinating centre in Beijing. The central centres collaborated with ten regional coordinating centres in the selected regions. The Chinese CDC invited its subordinate units, provincial CDCs, to cooperate in this project, and similar invitations were passed down from regional to local CDCs, and finally reached grassroots administrative units—village or street committees. Health departments at various levels were also involved in this network. All men and women aged 30–79 who are permanent residents in each administrative unit and without major disabilities were identified and invited to participate. 6
To recruit enough participants into the CKB, mass propaganda and mobilisation activities were organised at different administrative levels. Incentivised by competition among ten centres, the regional coordinating centres were actively involved in the CKB project. As one centre reported:
With high degree of attention and support from Department of Health of our province, local governments and administrative departments of public health at various levels in [name deleted] city, the baseline survey of KSCDC in our province was implemented strictly according to the requirements of national programme, and made an outstanding achievement in organisation and coordination, propaganda and mobilisation, project management and quality control…the amount of samples and survey quality ranked among the best…Both CDCs of province and [name deleted] city won ‘Advanced Group Prize’ awarded by the Chinese CDC and CTSU, Oxford.
7
Local meetings were organised to introduce the project and call on residents to participate. Street or village committee members and doctors at street or village health clinics visited each household, handing out invitation letters and study information leaflets. CKB recruitment began in 2004. By the end of 2008, the recruitment goal of half-a-million Chinese participants had been met.
Informed Consent and Benefit Sharing
As mentioned above, informed consent, benefit sharing and community engagement are interrelated issues in biobanks. Before the CKB study began recruiting participants, its central coordinating centres underwent ethics reviews by CTSU, Oxford, the Chinese CDC and CAMS. In addition, ethics approval was also gained from Institutional Review Boards (IRBs) at the local CDCs in the ten regions. Chen Zhengming prepared documentation with standard operating procedures (SOPs) in Chinese. 8 In the SOPs, detailed procedures for informed consent specified that survey staff should use the local dialect to introduce briefly research aims, contents and procedures. To preclude participants’ doubts and to increase the degree of their adaptability, staff were also required to explain clearly to participants why their blood samples would not be analysed immediately, and to emphasise that all participants would receive a detailed physical examination report along with computer-generated, personalised health care advice and a health-education brochure at the end of survey.
The CKB study adopted the broad consent with opt-out approach to informed consent. That is, participants allowed researchers access to their medical records and allowed the long-term storage of blood for anonymised and non-specified medical research purposes, and they had the right to refuse to participate or to withdraw from the study after participation. For practical convenience, only the key points of informed consent were written on the consent form that participants signed. Other comprehensive information was introduced through meetings and study information leaflets. The central coordinating centres repeatedly stressed the need for informed consent in guiding the work performed by the regional staff (personal communication with a CKB manager, 18 March 2012).
Despite the CKB’s efforts regarding informed consent, misunderstandings still arose between the CKB and the local communities. As a CKB manager said:
Because participants’ levels of education were different, the degrees of their understanding of informed consent were also not the same. People from urban areas understood better. They knew these blood samples need to be kept for a long term for scientific research. But rural people had different understandings. For example, Tongxiang in Zhejiang Province represents rich rural areas in China. As their knowledge is limited, they had many doubts about biobanks. They were worried that it was a human trial; that very serious things would happen, so they didn’t trust biobanks enough. (Interview, 31 March 2012)
During my participant observation at the baseline survey sites in rural regions of a population-based biobank project in China, 9 I was interested in whether Chinese participants in biobank studies understood the concept of informed consent. When I asked more than ten research participants randomly throughout one baseline survey whether they read the informed consent, it was apparent that they really didn’t understand what informed consent was and that they had barely read the form. When I asked participants why they came for the biobank study, all replied that it was for the free physical examinations, which had also been promoted by their community leaders and doctors in their door-to-door visit to local residents. In our focus group study on the general public’s perception of biobanks in China, we explored the public’s reasons for participating or not participating in biobank studies. The focus group study identified two main reasons for the public’s participation in biobanks—to improve scientific research and to receive free physical examinations, therefore, their motivation for participation in biobanks is not only for the common good, but also for benefit sharing. Local community leaders encouraged their community members to participate in the CKB project mainly because they considered participation in research to benefit many subjects: ‘This activity brought common people real benefits, making them gain free physical examinations and health care advice.’ 10 This appeal resonated with the needs of the local people.
What benefits then would the Chinese and British researchers share in the CKB case? After the successful recruitment of a half-million participants in China, British researchers receive access to plenty of resources for collaborative research and scientific publications. As one CKB manager pointed out, the establishment of CKB was cost effective and can complement the work of the UK Biobank. For the Chinese parties, the Chinese CDC and CAMS enhanced their research-capacity building through international collaboration; for example, collaboration with a strong overseas partner has helped them gain adequate funding, advanced IT and data management support, training opportunities from Oxford, more and better publications and the improvement of biomedical research and public health (Interview, 31 March 2012). It seems that, so far, both researchers and research participants in the CKB case have received their expected benefits.
Discussion and Conclusion
In this section, I will discuss the strengths and weaknesses of CKB and its implication for the governance of international biobank collaboration. The project gained access to the local communities through the assistance of local and provincial government officials. Needless to say, without massive propaganda and mobilisation for community engagement through these officials in both cases, the foreign research parties would not have succeeded in convincing the public to donate blood samples. The project used free physical examinations and feedback from medical check-up as incentives for the local communities’ participation in the biomedical research. The CKB researchers know Chinese people’s needs, expectations and priorities. Despite recent multiple reforms of the Chinese health care systems, a huge inequality in access to health care remains, and the Chinese people who do have access to care are still responsible for paying the bulk of their health care expenses out of pocket (Hougaard, Østerdal and Yu, 2011). Therefore, it is entirely understandable that free physical examinations became the incentive and priority for participation in biobank studies for the Chinese people, with those from poor rural areas served by the worst health care conditions being particularly motivated to participate.
Given that building biobank research infrastructures and tools, and keeping it for basic and applied research, are costly, it is crucial to have solid funding models for the initial set up and long-term operation of any biobank. Gottweis and Lauss (2012) present three funding models in the biobanking field:
(a) the entrepreneurial biobank model that is often carried out in a public-private partnership between a commercially oriented entity and different state institutions; (b) the biosocial model in which patient activist groups promote fund, and facilitate the creation and operation of a biobank; and (c) the public biobank model in which biobank networks are supported mostly through taxpayers money and non-profit research funding organizations.
The CKB represents the public biobank model, with its main funding from charitable foundations such as Kadoorie Charitable Foundation and the Wellcome Trust. The CKB is a conventional cohort study in its management and has not been opened yet for data sharing and commercial uses. The commercialisation of biobanks, on one hand, can be a solution to financial support and the possible translation of basic research to clinical application; on the other hand, it involves the sensitivity of ownership, property rights and benefit sharing.
In the CKB case, more attention has been paid to informed consent and benefit sharing in the creation of the biobank. However, fundamental ethical issues still remain due to the lack of robust national governance mechanisms of biomedical research in China. China and the UK have similar governance frameworks for many areas of medical research, such as uses of human embryonic stem cells. 11 Their distinct differences are the formal system for implementation, oversight mechanisms and the institutional structures for ethical review. China’s IRBs are largely composed of professionals associated with the research institutions, while their counterparts in the UK are required to be independent from the institutions that they review (CURE Committee, 2009). In this sense, the IRBs of Chinese collaborative institutions in CKB are not independent bodies that monitor ethical aspects of the biobank. Although the Interim Measures ruling outlines the basic principles of equality and mutual benefit sharing in international collaborative research on genetic resources, it does not provide the specifications of benefit-sharing frameworks in the implementation of international biobank collaboration. Moreover, there are no guidelines and laws in China to govern the ownership, intellectual property, and privacy issues in the creation and operation of biobanks. 12 Given these ethical and legal uncertainties in national systems of governance, the CKB has to cope with various challenges in its future development.
To conclude, this article explores the CKB case in its institutional contexts to understand the ethical issues and governance challenges of international collaborative biobanks. To protect national genetic resources and promote international research collaboration, the central government instituted Interim Measures for the Administration of Human Genetic Resources in 1998. At that point, HGRAC became the watchdog agency that controlled the export permit of human genetics. International collaboration between Chinese and foreign researchers on genetic research needs to conform to mutual fair benefit sharing. The CKB was fully aware of the sensitivity of the ethics of biobanks in international collaborative projects. Great efforts have been made to handle informed consent, benefit sharing and community engagement in the establishment of the CKB. Although participants harboured misunderstandings of informed consent, as in some other cases, it seems that informed consent in the CKB can also be interpreted as a solution to accommodate a number of biobanking concerns, such as benefit sharing, trust, fairness, and dignity (Hoeyer, 2008). However, the CKB still needs to tackle the governance challenges of international biobank collaboration. Given the complexities of biobanks and the need for long-term support and trust from the public, the Chinese authorities must follow closely the broader ethical and legal issues of biobanks in international discussions, such as the protection of participants’ privacy and interests, public understanding of biobanks, rather than confine its regulation to the protection of national genetic resources. Furthermore, it is essential to develop joint governance protocols based on mutual recognition and respect for international collaboration, such as between China and the UK.
Footnotes
APPENDIX 1
Interim Measures for the Administration of Human Genetic Resources
Promulgated by the General Office of the State Council upon the approval of the State Council on 10 June 1998
The Ministry of Science and Technology
and
The Ministry of Public Health
The People’s Republic of China
Acknowledgements
The research for this article was conducted as part of the ‘Biobank Governance’ project funded by the Humanities and Social Sciences Research Programme of the Ministry of Education, PRC (10YJCZH010) and the ‘Asian Biopoleis: Biotechnology and Biomedicine as Emergent Forms of Life and Practice’ Project, funded by the Ministry of Education, Singapore, and the Humanities and Social Sciences (HSS) Division in the Office of the Deputy President (Research and Technology) at the National University of Singapore (NUS). I would like to thank Philip Andrews-Speed and Michael M.J. Fischer for their comments on earlier drafts of this article. I am also grateful to all the people who have offered their support and assistance in my fieldwork.