'Biobank Governance: The Cautionary Tale of Taiwan Biobank' by Shawn H.E. Harmon, Shang-Yung Yen and Shu-Mei Tang in (2018) 15(1)
SCRIPTed 103 comments
The importance of biobanks has long been mooted, and multiple models of development and operation can be found as a result of many actors founding biobanks (from institutions starting disease-specific banks to governments starting national population biobanks). Many countries began developing biobanks in the absence of national policies to aid in that formation. Taiwan was one such country. Believing that the unique genetic makeup, distinctive lifestyles, and disease-causing factors of the Taiwanese people deserved study, Taiwan took steps to create Taiwan Biobank. This paper examines Taiwan Biobank’s development and governance and focuses on two matters in particular which generated consternation during the development of Taiwan Biobank: the position adopted in relation to autonomy and ethnicity; and the approach toward transparency and internal governance. It concludes that Taiwan Biobank’s conflict-ridden evolution represents a cautionary tale, an example of how not to develop a flagship resource.
The authors state
Shortly after the sequencing of the human genome, it was claimed that medical knowledge would be accelerated by the formation of ‘biobanks’, here defined as new repositories of human tissue and generated data (genetic, phenotypic, lifestyle, environmental, and demographic) together with associated health data (occupation, lifestyle, diet, and medical), which repositories are collective, inclusive, prospective, and purposively indeterminate. It was felt that large-scale longitudinal investigations into the interaction between common disease genes and environmental factors would be an optimal way to overcome common diseases and improve health.
Therefore, many countries began developing national policies to aid in the formation of biobanks, or began developing biobanks in the absence of policies. Taiwan fell into the latter category. Believing that the unique genetic makeup, distinctive lifestyles, and disease-causing factors of the Taiwanese people deserved specific study, Taiwan took steps to create a national biobank. Proponents considered that, if the genes involved in common diseases could be defined and their risk quantified, new and improved treatments could be developed for Taiwan. Like many such banks, then, Taiwan Biobank’s conception was an exercise in promise; a leap into the scientific and policy unknown supported by claims that risks would be offset by advances in health and by valuable collaborations and commercial returns, the latter of which was not always clearly conveyed to or understood by the public.
This paper examines the establishment, development, and governance of Taiwan Biobank. First, it reviews the historical evolution of Taiwan Biobank. Secondly, it examines two areas that generated significant controversy in this evolution, namely, positions adopted in relation to autonomy and ethnicity, and approaches in relation to transparency and internal governance. We propose that Taiwan Biobank’s problematic evolution represents a cautionary tale, highlighting pitfalls to avoid in developing a national flagship resource.
2 The Development of Taiwan Biobank
... Like many countries, Taiwan adopted a policy of sci-tech innovation as a means of achieving sustainable development and international competitiveness. Health technology innovation and the establishment of biobank infrastructure resources featured heavily in this policy:
1997: The Science and Technology Advisory Group (STAG) of the Executive Yuan held its first strategic review meeting on biotech policy, intending to promote national projects in genetic medicine and public health technology. Consequent projects included the National Genetic Medicine and the National Pharmacy and Biotech Projects.
1998: A second strategic review meeting resulted in the National Development Fund investing NT$20 billion to support the development of the biotech industry, the emphasis being on technology innovation projects, strategic alliances, and enterprise creation, including the investment by state-owned enterprises in the biotech industry.
1999: The Luchu Science Park was redeveloped with a Biomedicine District.
2001: Multiple regional ‘Biotech Hallways’ were created.
2002: The Academia Sinica established the Taiwan Han Chinese Cell and Genome Bank Project, which relied on data collected randomly through the computerised household registration system.
2004: The STAG argued that Taiwan should become an ‘island of biomedical technology’, and made a number of related recommendations.
In response to the STAG, the Taiwanese Government launched the Biomedical Technology Island Plan 2005, which comprised three main projects: the National Health Information Infrastructure Project; the Taiwan Clinical Services Project; and Taiwan Biobank. With respect to the latter, the National Science Council (NSC), predecessor to the Ministry of Science and Technology, asked Academia Sinica’s Institute of Biomedical Sciences (IBS) to plan a large-scale population biobank that would support biotechnology development and medical research in Taiwan.
Adopting UK Biobank as its model, the IBS conceived of Taiwan Biobank, which would collect biological samples (blood, plasma, urine, and tissue) from some 200,000 healthy participants aged 30-70, and link those samples/data with their lifestyle, family history, and health information in an effort to determine the effects of genetic and environmental factors and interactions on common diseases, and to develop personalised medicine. Objectives included: determining the prevalence of specific genes and variations in the population; simplifying the procedure for searching for biological marker molecules; improving research into new curative medicines (especially for Taiwan-prevalent diseases); and simplifying disease-prevention and improving public health and hygiene decisions. Importantly, both Taiwan Biobank and its Pilot Study was structured around ethnicity; it aimed to build the resource by collecting samples from four target groups – the Hakka, the Minnan, the Han, and Aboriginals.
2.2 Controversy and ethnicity during the Pilot Study (2003-2007)
Prior to commencement, Academia Sinica was tasked with performing a Pilot Study to test the scientific/technical feasibility of Taiwan Biobank. It had a target of 1,000 participants from three geographic regions: Miaoli (primarily Hakka); Chiayi (primarily Minnan); and Hualien (primarily Aboriginal). The ethnic foundation for the Pilot Study was not accompanied by any detailed or openly-discussed or accepted definition of each group, nor indeed by any explanation as to what or who counted as Aboriginal. Nonetheless, the Pilot Study Protocol was approved by Academia Sinica’s Institutional Review Board (IRB) in 2005.
The process leading up to (and beyond) this approval has been described as a ‘development-first’ approach with decisions being made almost exclusively by policy and science elites in closed processes. Moreover, these decisions were sometimes based on misinterpretations of the course adopted in other countries, and they persistently exemplified either simplistic understandings of risk, or a complete disregard for the associated risks. And while there was some effort to encourage scientific discourses, there was no effort to be transparent or to undertake any public engagement. Indeed, it has been argued that the complexity of the project together with the exclusivity of its development hindered both public understanding and public debate. In short, there was no interest in social supervision.
Eventually, and primarily after the academic community began to complain, the Pilot Study met with a maelstrom of public criticism, exemplified by a commentary in the China Times which raised questions about consent, confidentiality, and benefit-sharing, and which demanded that the plans for Taiwan Biobank be made public. One of the issues that was persistently raised was that of ethnicity. Given the poor record of Aboriginal treatment, the fragility of human subject protections, the circulation of stories about failures to meet consent standards, and the general absence of benefit-sharing models in Taiwan, the Taiwan Association for Human Rights made a formal request (in July 2006) that Academia Sinica publish its project processes online so as to improve transparency. That request was refused, and the Pilot Study continued unabated.
2.3 Law-making, further controversy and recruitment (2007-2023)
By 2007, and despite social outcry and non-engagement with social and ethical matters, the Pilot Study was viewed as having demonstrated feasibility. Thus, the Ministry of Health and Welfare (MOHW) directed the IBS to commence a Preparatory Study which would recruit 15,000 participants aged 30-70. The Preparatory Study dropped the overt emphasis on ethnic groups, but focused on Hakka, Minnan, and Aboriginal regions for its recruitment. As the study progressed, the number of participants was reduced to 8,000. During this time, the Executive Yuan took steps to legislate in the biobank setting so as to bring its regulatory environment more in line with international standards, adopting the Human Biobank Management Act 2010 (HBMA 2010), amending the Personal Information Protection Act 2010, and adopting the Human Subjects Research Act 2011 (HSRA 2011), more on which infra.
In October 2012, Taiwan Biobank was formally approved by Academia Sinica’s IRB with the aims of preventing, diagnosing and treating a wide range of serious and life-threatening common complex diseases suffered by the Taiwanese people. Country-wide recruitment commenced in late 2012, and over 77,000 participants have thus far provided 30ml of blood, 20ml of urine, specified physical measures, detailed information about themselves, and have agreed to have their health followed. In accordance with Article 5 of the HBMA 2010, Taiwan Biobank established an Ethics and Governance Council (EGC) to act as an independent guardian of Taiwan Biobank’s Ethics and Governance Framework, and to advise the Competent Authority (the MOHW) on its revision from time to time. Very early in the EGC’s existence, however, Taiwan Biobank took steps to amend its Protocol so that, in addition to the 200,000 participants originally envisioned, it could collect 100,000 patient samples and data from Taiwan’s major hospitals, and it could focus on some specifically identified conditions (e.g., breast, lung, liver, colon, and rectum cancers, strokes, chronic kidney diseases, and Alzheimer’s Disease). This amendment was approved post facto by the EGC (in 2012). In early 2015, the MOHW recommended that hospitals share their banked resources with Taiwan Biobank. However, on 30 September 2016, Academia Sinica’s IRB, which has authority to suspend or terminate any research that is not conducted in accordance with its requirements, or that has been associated with unexpected serious harm to subjects, held that it must approve any amendment to the Taiwan Biobank Protocol prior to its implementation. It therefore suspended Taiwan Biobank activities in response to this self-initiated inclusion of hospitals, holding that Taiwan Biobank should be governed by the EGC and the IRB jointly, with the EGC responsible for ‘management’ and the IRB responsible for ‘research’.
Taiwan Biobank responded that the EGC, not the IRB, is the main ethical governance structure for Taiwan Biobank. The MOHW countered that the Protocol should be submitted to and confirmed by the MOHW, which is the Competent Authority under the HBMA 2010.This dispute re-ignited criticism from a range of stakeholders, including the Taiwan Association for Human Rights, and led to delays in operations. While the jurisdictional conflict has not been resolved, the IRB did issue a Certificate of Approval on 2 March 2017, which states that (1) annual progress reports should be submitted to the IRB for review, (2) progress reports submitted to the MOHW should be copied to the IRB, and (3) all adverse events must be reported promptly to the IRB. This Certificate also seems to have approved the amendments to the Protocol, opening the way for hospitals to transfer their holdings to Taiwan Biobank.
This rather tortured history highlights two matters which appear to have undermined the good governance of Taiwan Biobank in its early phases, and the general satisfaction with its development (though they cannot be said to have derailed its development). The first relates to its handling of ethnicity, including the special requirements that it imposes with respect to obtaining participant consent, and the second relates to the transparency (and accountability) around the undertaking’s governance.
'23andMe: a new two-sided data-banking market model' by Henri-Corto Stoeklé, Marie-France Mamzer-Bruneel, Guillaume Vogt† and Christian Hervé in (2016) 17(19)
BMC Medical Ethics comments
Since 2006, the genetic testing company 23andMe has collected biological samples, self-reported information, and consent documents for biobanking and research from more than 1,000,000 individuals (90 % participating in research), through a direct-to-consumer (DTC) online genetic-testing service providing a genetic ancestry report and a genetic health report. However, on November 22, 2013, the Food and Drug Administration (FDA) halted the sale of genetic health testing, on the grounds that 23andMe was not acting in accordance with federal law, by selling tests of undemonstrated reliability as predictive tests for medical risk factors. Consumers could still obtain the genetic ancestry report, but they no longer had access to the genetic health report in the United States (US). However, this did not prevent the company from continuing its health research, with previously obtained and future samples, provided that consent had been obtained from the consumers concerned, or with health reports for individuals from other countries. Furthermore, 23andMe was granted FDA authorization on February 19, 2015, first to provide reports about Bloom syndrome carrier status, and, more recently, to provide consumers with “carrier status” information for 35 genes known (with high levels of confidence) to cause disease.
In this Debate, we highlight the likelihood that the primary objective of the company was probably two-fold: promoting itself within the market for predictive testing for human genetic diseases and ancestry at a low cost to consumers, and establishing a high-value database/biobank for research (one of the largest biobanks of human deoxyribonucleic acid (DNA) and personal information).
Stoeklé et al argue
Two major problems relating to autonomy are immediately apparent here: the problem of scientific literacy [30] and the lack of training of physicians in genetics [31, 32]. Indeed, it has been shown that more than half the individuals buying genetic tests online subsequently consult a physician to discuss the result [33]. It might therefore be a good idea to create a “direct-to-physician genetic reporting service”, or at least an optional service of this kind, effective before and after the purchase of the kit. Such a service would ensure that physicians were better trained in the interpretation and explanation of genetic tests and would ensure better counseling and follow-up for users, while providing users with greater autonomy. It would also make it possible for the test of- fered by 23andMe to be considered a real medical diag- nosis test rather than as simply providing information. This vision of autonomy differs from those prevailing in the UK and the US, in which all individuals wishing to have access to their genetic and medical data are free to do so, provided an agreement has been reached with the family in cases of clinical analysis, regardless of their level of genetic knowledge and the conditions of the service on offer [29, 34].
The press has reported incidents in which families requesting genetic tests via the Internet have learned, from the results obtained, that the presumed father was not the real biological father or in which the biological father has found that he has children that he didn’t know existed [35, 36]. 23andMe warns its clients in ad- vance of the possibility of such discoveries being made through its tests (see the website and blog of 23andMe) and seems to have resolved this problem. It nevertheless remains legitimate for civil society to pose the question as to whether private companies should be able to reveal such information through so-called “phylogeny” or “health report” genetic testing rather than through (offi- cial) paternity tests, particularly if they do not ensure, other than virtually, that this choice was consented to by all of the people concerned by the results and not just by the principal person concerned [34]. For preventive surgery, the best known case is undoubtedly that of an American actress who underwent a prophylactic double mastectomy following positive results in a genetic test for the breast cancer 1 (BRCA1) mutation [37]. In the wake of her decision, an increase was observed in the numbers of BRCA1 and 2 tests and of prophylactic double mastectomies carried out [38]. Over and above the principle of not doing harm, which is called into question by major, potentially traumatic surgery, this approach also raises questions about the principle of autonomy, because there may be a risk of abuse in the long term. Indeed, if such practices were to become systematic, insurers might have the right to oblige their clients to undergo testing if they have a family history of disease, particularly for genetic predispositions to cancer, due to the costly and debilitating nature of targeted treatments if the disease is diagnosed late.
Ethical issues also arise within the testing company. These issues include the dematerialization and digitization of data, the anonymization of genetic data, the confidenti- ality of self-reported information and the storage of data and samples (Fig. 5) [39, 40]. Indeed, when informed consent forms and the commercial contract are signed digitally, the consumers provide the company with their names, together with a set of personal information about themselves and their families relating to health and ethni- city. The company states on its website that names, addresses, e-mail addresses and bank data will not be disclosed or used. Nevertheless, such information (Fig. 2) significantly increases the medical, scientific and financial value of the data. It is therefore unsurprising that the contract stipulates that data, DNA and biological samples will be kept and may be re-used in other research if the consumer consents. With the multiplication of this transaction by hundreds of thousands of individuals, the company is well aware that its consumers have not only paid a few hundred dollars each, on average, for genetic testing services, but have actually sold their samples and information for inclusion in a major biobank and database for use by scientists and doctors. But what are the conse- quences for the consumer? Can separate pieces of infor- mation about an individual be brought together? Particularly as concerns the consumer’s name and import- ant items of personal information? These issues have not been sufficiently explored by the company, which seems to safeguard its own interests more strongly than those of its consumers, although 23andMe received institutional review board approval for its research protocol and a revised consent document in 2010 (23andMe blog). Indeed, Genentech has paid $60 million (in total) for the WGS data of 3,000 23andMe consumers with Parkinson’s disease, with the aim of generating new therapeutic target leads [41]. However, despite large amounts of clear, illustrated information about the phenotypes and/or diseases revealed by their analyses, the robustness and accuracy of the chip used for testing are not perfect at individual level and not all of the mutations detected have been validated by Sanger sequencing (thereby potentially mixing false and true positives and negatives). A client may therefore unknowingly carry a deleterious mutation that may be reported in the information delivered by the company or may knowingly carry such a mutation that is not identified in the results delivered by the company. The risk of false- positive or false-negative results for these tests is the prin- cipal concern of the FDA and its approval process [42]. However, in the context of a study of several thousand people (carried out by GWA), missing a single SNP in an individual is not a problem because there are thousands of others. At an individual level, missing a SNP may have much greater consequences. The previous economic model was based on low prices to attract more consumers, providing more data and biological samples to be valorized and sold. The four rounds of investment in this company (Fig. 4) may have been designed to address the problem of the probable lack of benefit from this side of the market until the second market had been established (Fig. 3) [43]. This second market has now been established through the collaboration between 23andMe and Genentech.
According to a French Agence de Biomédecine report on genetic tests published in 2014 [44], there is currently no consensus definition of a genetic test and very few countries have adopted specific legislation relating to genetic testing, the principal countries to have done so being Austria, Switzerland, Germany and Portugal. In the United States, genetic tests for medical purposes are accessible without a medical prescription and are billed by the laboratories concerned. However, 24 American states have prohibited divulgation of the results of genetic tests in the absence of a physician. Nevertheless, companies selling genetic tests via the Internet, such as 23andMe, at least before they were prevented from doing so by the FDA, report the results of their tests dir- ectly to their clients. According to an Institut National de la Santé et de la Recherche Médicale (INSERM) report on genetic tests dating from 2008 [45], this is per- mitted because genetic information is not considered to be particularly sensitive in the US. Instead, it is seen as ordinary personal information, unless supplied by a genetic test governed by the FDA. Nevertheless, increasing numbers of “genetic privacy” laws have been passed in the US in recent years, by contrast to Europe, which now seems to be moving in the opposite direction [44]. Indeed, the European Union (EU) is increasingly moving towards the broader and freer circulation of data for research purposes [44]. According to the French Agence de Biomédicine report published in 2014 [44], the UK has recently gone further, because the Human Genetics Commission responsible for providing the British government with expert advice now considers that it would not be desirable to ban tests bought over the Internet, simply because it would be impossible to police such a ban given the freedom of access to the Internet available today. However, it did recommend the estab- lishment of a certain number of guidelines concerning test quality, the information transmitted and the qualifi- cations of those carrying out the test. The proof of this shift in position is that 23andMe entered the British market in December 2014, about a year after it was banned by the FDA in the US [41, 46]. Ireland, Denmark, Finland, the Netherlands and Sweden have all accepted the sale of the 23andMe test in their territories (23andMe Europe). It might be possible for France to follow the same course of action. Most countries are currently facing a change in the definition of health data much more complex than any previously observed, which has been neglected for far too long. It is now possible to generate health data with non-certified medical technolo- gies as simple as a smartphone or any kind of connected object [47]. Is it really the fault of 23andMe for having understood this issue or that of the health authorities for not having thought sufficiently deeply about it?
The data and samples that 23andMe “lend” to different research teams also raise two other ethical problems: the inequality of access to data and samples between research teams due to differences in financial resources or nationality, as the laws of some countries are not compatible with the patentability of human genes (Fig. 5.). One direct consequence is a significant bias in the race for publication and international tenders [39]. The issue of the patenting of human genes is far from resolved, particularly in the US and in European coun- tries, such as France. In the emerging world of targeted molecular therapies and genetic tests for diagnosis and prognosis, these questions will need to be addressed [39, 48]. There are already inequalities between research teams in terms of the production and use of scientific knowledge, through access to high-quality scientific pub- lications or various new technologies, probably due to significant qualitative and quantitative differences in resources between countries and between research teams in the same country. Should access to and use of knowledge be based on the financial clout of a team or its scientific intuition, particularly if society hopes for new ideas to emerge from science [49]?
Another link that would merit closer scrutiny is that connecting 23andMe to Google. Google was one of the principal investors in all four rounds of financial invest- ment in this company. Google may be interested in the web behavior information for its search engine activity, and in the self-reported information and genetic infor- mation, which may be of use to subsidiary companies, (e.g., X, originally Google X lab) (Fig. 5). This idea raises other ethical issues due to the transhumanist vision of Google, with its growing monopoly on the emergence of new technologies, ultimately resulting in a lack of competition and, in some instances, a possible threat to democracy. Indeed, after five years of investigation, the European Commission accused Google of abusing its dominance of the market in April 2015 [50]. This example illustrates the difficulties inherent to companies attempting both to provide services and to relay information. 23andMe should therefore carefully consider the risks they face, because, in this instance, the products are biological materials and health data.
