Human tissue biobanks: the balance between consent and the common good

Abstract

Biobanks are currently archiving human materials for medical research at a hitherto unprecedented rate. These valuable resources will be essential for developing ‘personalized’ medicines and for a better understanding of disease susceptibilities. However, for such scientific advances to benefit everyone, it is crucial that biobanks recruit donations from all sections of the community. Unfortunately, other initiatives, such as transplant programmes, have clearly demonstrated that ethnic minorities are under-represented. Here we suggest that this issue deserves serious consideration to avoid biobanks evolving into ethnically biased archives which unwittingly promote race-specific research. Specifically, this necessitates research ethics committees engaging in a re-assessment of the relative merits of individual personal sovereignty and the common good.

Introduction

Biobanks are archives of biological materials, collected for a variety of purposes including: preservation of plant seeds (e.g. the Svalbard Global Seed Vault); storage of human materials for transplants (e.g. corneal biobanks); artificial insemination; forensic investigations; and to aid conservation of endangered species (Leon-Quinto et al., 2009). Some biobanks collect a single sample type (e.g. DNA in a ‘genebank’), whilst others preserve a variety of materials to enable comprehensive cellular, genomic and proteomic studies of the same individual. Biobanks can also be subdivided into those which aim to answer one specific question and others which have no specific research problem in mind (‘systematic’ biobanks, such as the Infectious Diseases Biobank [IDB] at King’s College London [KCL]: Williams et al., 2009).

Until recently the modus operandi of most medical researchers was to use fresh clinical materials to test a hypothesis. The premise was either proven, or not, and then the process repeated to answer subsequent questions. This approach is highly wasteful since those tissues not directly needed to examine each argument are usually discarded (often as a condition of the research ethics permissions). In contrast, clinical biobanks can archive and distribute material to multiple researchers, hence maximizing the usage of every donation. Biobanks can also facilitate the understanding of rare diseases by either gradually accumulating sufficient amounts of materials or, by networking with other biobanks.

The potential of biobanks for advancing medicine were recognized in 2009 by Time magazine, which considered them to be ‘one of the ten ideas that are changing the world right now’ (Park, 2009). As an example, one study that the IDB is assisting is KCL’s investigation of the human immune response dynamics stimulated by vaccination against the H1N1 influenza virus. This project has characterized changes in the expression of each (of ~36,000 per individual) human gene in lymphocytes from 75 subjects before and after vaccination and compared these results to the concentrations of some plasma proteins (HIRD, 2010).

Large-scale population-based clinical archives such as the Biobank UK will also allow extensive genome-wide association studies to identify genetic markers for susceptibility to individual diseases, for example, by the UK Biobank’s donations from over 500,000 volunteers (UK Biobank, 2011). Similarly, the characterization of other host polymorphisms which predict the efficacy of specific drug regimens for individual patients will become more widespread, leading to personalized treatments. This revolution in prescribing is already happening. Amongst patients with human immunodeficiency virus (HIV) infections, abacavir™ is not given to those with the genotype HLA-B*5701, since this drug can cause life-threatening hypersensitivity reactions in such individuals (Mallal et al., 2002). Similarly, there is increasing evidence that patients infected with hepatitis C virus with specific polymorphisms around the IL28β gene do not benefit from interferon and ribavirin therapy (Holmes et al. 2011; Ge et al., 2009).

The identification of such genetic markers is critically dependent upon the demographic characteristics of the populations studied, and this in turn makes the recruitment strategies of clinical archives critical. In addition, the establishment of biobanks has raised old and new ethical challenges. Indeed, blood collection contravenes the first dictum of medical ethics, Hippocrates’s call to ‘first do no harm’, since this invasive procedure carries a 0.6% risk of an adverse event (Garozzo et al., 2010). To make this risk acceptable, there are important moral issues concerning consent, usage, ownership of samples, as well as patient confidentiality. Biobanks, and their regulators, can draw on historic ethical precedents to provide guidance to develop appropriate moral operational strategies. For example, the German Ethics Council has proposed that biobanks should be established on the basis of: confidentiality; informed consent; ethics review; sample quality-control; and transparency (Deutscher Ethikrat, 2010). One of the most fundamental, yet neglected, ethical problems revolves around the practical requirement for biobanks to collect samples which are a representative selection of the community. How this is achieved in practice has re-ignited the classical ethical debate regarding the balance between respecting the autonomy of individuals and pursuing the common good. Research ethics committees (REC) need to be actively engaged in developing novel ethical policies and influencing legislators, so as to avoid future treatment disparities.

Genetic representation

One fundamental aspect of biobanking is the concept of ensuring adequate genetic representation. This is a crucial issue for clinical archives as large influential research studies will become increasingly dependent upon such resources. Consequently, if samples held by such archives are unrepresentative of society as a whole, future treatments for those not initially represented are likely to become increasingly compromised as the era of personalized medicine comes to the fore.

Unfortunately, there are well-acknowledged problems in recruiting organ and tissue donations from ethnic minorities (Bratton et al., 2011; Salim et al., 2010), and in the USA educational schemes have been introduced to address this specific issue (Callender and Miles, 2010). Whilst there is little available data regarding the demographics of biobank volunteers, one US study suggested that 60% would be willing to donate to bio-repositories, though ethnic minorities, women and those without a degree expressed concerns that the government would have access to their information (Kaufman et al., 2009). Explanations for the reticence of ethnic minorities to participate in transplant programmes, and possibly also biobanks, probably include multiple factors. Undoubtedly the history of ‘scientific imperialism’/‘bio-colonialism’ by western medicine has alienated many in developing nations from conventional medicine (Emerson et al., 2011). Even within contemporary western democracies there have been examples of scientific racism, notably the 42-year-long Tuskegee syphilis study of impoverished African-Americans (Crenner, 2011; Roy, 1995).

This antipathy to western medicine may explain the reluctance of the Indonesian government to share samples of H5N1 influenza virus with the international scientific community (Gelling, 2007). Unfortunately, some politicians have exacerbated these tensions. The past president of South Africa, T. Mbeki, gave undue credence to those who refute the evidence that HIV causes acquired immunodeficiency syndrome (AIDS) (Mbeki, 2000) and, in the USA, L. Farrakhan has claimed that the influenza virus vaccination programme is a genocidal governmental conspiracy (UPI, 2009). Inevitably such comments negatively impact upon public confidence in medical initiatives. Indeed, one study of gay and bisexual ethnic-minority men in the USA indicated that 45% of respondents approved the statement that ‘HIV does not cause AIDS’ (Hutchinson et al., 2007). One suggestion to restore public faith in biobanks includes the formation of ‘tissue-trusts’ to serve the interests of the common good (Emerson et al., 2011), which would involve donors and community members being actively engaged in the process of research governance.

The issue of genetic representation in biobanks is critical to ensuring that personalized medicine does not end up being a two-tier system of ‘haves’ and ‘have nots’. Sadly this is already the case for white as opposed to black children needing bone marrow transplants in the UK (John, 2004). This moral dilemma needs to be addressed by ethics regulators with immediacy to avoid a similar trend amongst biobank donations. The IDB is located in a highly ethnically diverse region of London UK. Encouragingly, an early audit of HIV-infected donors to the IDB revealed that the demographics of the volunteers and the local multi-ethnic community matched census-derived demographic data acceptably (Kozlakidis et al., 2011). However, in this instance it was not possible to establish whether this represented either self-interest or the true altruism necessary to sustain large clinical archives.

The underlying ethical issues can be condensed down to the conflict between: the current rights of an individual not to contribute samples to medical research versus the future rights to enjoy probable future equality of medical treatment for his/her sons, daughters and their descendants. Indeed, the question arises whether any individuals have the exclusive and absolute moral right to exclude their entire gene-line from future medical advances? If we uphold such a ‘right’, how do we equitably balance this moral argument against the ‘rights’ of the as yet unborn progeny? In most ethical, legal and religious traditions, unborn children have few, if any, rights, and none exist for future ‘potential-humans’ – the gene line.

Protecting informed consent and addressing health inequalities

A cornerstone of contemporary medical ethics is the act of obtaining informed consent (IC) prior to the commencement of a study. Traditionally, IC is considered to be specific to a particular research study (Greely, 2007). This highly prescriptive view of IC can be counterproductive, since it inadvertently promotes wastage of samples not needed in the original study in a way which the donors might not have supported given the choice (Johnsson et al., 2008). Moreover, this strict interpretation of IC effectively destroys the future potential of biobanks, as it requires researchers to contact each donor again and again for consent to each and every new research project, however similar it is to the last one. Indeed, the real advantage of clinical archives is that their samples can be used in multiple future experiments which have not yet been planned, using technologies which have not been developed, to answer questions which have not yet been formulated. This dialectic between (the presumed) absolute requirement for specificity of sample usage in ICs and the functioning of biobanks have led many to question whether IC should be viewed as a moral absolute (Laurie, 2008; Hoeyer et al., 2005).

An alternate suggestion is that altruism, solidarity and reciprocity should be considered as having an equivalent moral basis to that of IC (Knoppers and Chadwick, 2005). This problem was addressed in the Council of Europe’s biobanking recommendations, which state: ‘consent need not be specific, but it must be as specific as possible with regard to unforeseen uses’ (Council of Europe, 2006). Such ‘broad consent’ (BC: also referred to as ‘open’ consent) has been proposed as best practice for biobanks (Hansson et al., 2006; NRES, 2011; Cambon-Thomsen et al., 2007; Haga and Beskow, 2008; Wendler, 2006) and normally involves specific prohibitions which preclude samples from being used for trivial or controversial studies. In the UK, such exclusions include studies involving cosmetics, investigations into reproduction, contraception or stem cells, as well as use in animal models. Those who favour BC over IC are not without opponents, who view BC as a ‘dilution’ of ethics which could destroy public trust (Hofmann, 2009; Caulfield, 2007). In practice, this criticism does not seem to be borne out by experience (Lipworth et al., 2009), and supporters of BC consider it to be morally equivalent to IC provided it is combined with robust systems of research governance (Elger and Caplan, 2006).

For many, the argument has now moved on to more controversial fields such as whether consent – in any form – should be abandoned altogether for biobanks, genebanks and population databases (Kaye, 2004). Indeed, there was an attempt by deCODE Genetics Ltd. to establish the Health Sector Database (HSD) comprising the medical records, genealogical and genetic data of all Icelanders on a basis of ‘presumed consent’ (Wright, 2011). The HSD project proved to be controversial and was criticized over their policies on privacy and consent and the scheme was prevented from starting by a 2003 legal ruling by the Icelandic Supreme Court.

In countries such as the UK, which provide free healthcare, there is also debate as to whether there should be a moral obligation for patients to automatically permit any residual clinical material (taken for diagnostic tests) to be used in medical research: i.e. an ‘opt-out’ as opposed to the current ‘opt-in’ system. Such ‘opt-out’ archives are already operating (e.g. the Vanderbilt DNA genebank) and have stimulated new approaches to governance as well as innovative public education strategies (Pulley et al., 2010).

We suggest that should biobanks fail to capture samples that are truly representative of society, then the issue of consent may need to be significantly re-addressed and replaced by an ‘opt-out’ system for patients attending NHS appointments. This is not an issue of minimizing tissue wastage but one of the inclusion of all members of society. The introduction of an opt-out consent process might have certain drawbacks, i.e. that it would disadvantage those who are less educated or robust enough to ‘complain’ or opt-out of the accepted system. In addition, there is a cognitive bias towards accepting the default situation, so donors are more likely to accept passively that their samples are used than actively to object. Whilst on face value these appear to be powerful moral arguments against an ‘opt-out’ system, in extremis the failure to adopt such a system may adversely affect the healthcare of their descendants, thereby further exacerbating pre-existing inequalities. We would suggest that concerns regarding the latter situation significantly outweigh an individual’s ‘rights’ and that donation of samples to biobanks should be considered an altruistic societal obligation.

Different laws across Europe

An additional complication in the regulation of biobanks is the apparent lack of a standardized legal framework between, as well as within, individual states. The historical necessity for studying different diseases affecting each member state of the European Union (EU), for example endemic malaria in areas of Spain and Greece and inflammatory bowel disease and breast cancer in northern Europe, meant that in each case different set of rules and regulations were implemented. As a result there are currently slightly different consent forms in each country and for each type of material collected (Zika et al., 2010). The necessity for the harmonization and standardization of ethics and law has been led to recommendations by the EU (BBMRI, 2009) and the suggestion that if all countries simply abide by a tight interpretation of the Helsinki Declaration further regulation would be counterproductive (Hansson, 2011).

In the UK there are circumstances whereby legislation permits research on tissues (from the living) to proceed without the consent of the donors. However, such samples are usually anonymized residual diagnostic materials and are frequently not stored under ideal conditions for subsequent research studies. For example, the provenance of these materials is unknown (e.g. the number of freeze−thaw cycles they have undergone) and consequently not suitable for transcriptome analyses (due to inappropriate storage conditions). Consequently, such samples are often of limited value since they could result in the generation of misleading research data.

Role of ethics committees to strike the balance

Human biobanks are facilitating medical research, which will have profound implications for the way patients are treated. Whilst there has been debate regarding the introduction of BC instead of IC, in Europe the former has been accepted as a ‘gold-standard’ for clinical archives. In many countries the primary responsibility of RECs is: ‘to ensure that the research respects the dignity, rights, safety and well-being of individual research participants’ (Tinker and Coomber, 2004). However, there is usually no requirement for such committees to make judgements on the broader ethical implications of their decisions in a societal context and over the longer term for research generally. The issue of genetic inclusion into biobanks is particularly pertinent and deserves serious consideration given the development of the first race-specific drug (BIDIL; see http://www.bidil.com/).

We suggest that this issue should be addressed by RECs considering applications by biobanks, which should also take a lead in suggesting (and approving) steps to avoid demographic imbalances in such collections. These could involve the ‘opt-out’ and ‘presumed consent’ approaches to obtain donations from hospital patients. Another, approach might be to re-brand biobanks as a necessary public health measure (akin to historic actions such as the: mandatory confinement of tuberculosis patients; iodinization of salt; water fluoridation; and vaccination programmes). Such public health initiatives are generally widely accepted without significant disquiet. Alternatively, or additionally, the potential benefits of biobanks should be publicized more vigorously and combined with educational programmes directed towards those communities who are found to be under-represented.

RECs are central to these debates and may involve them re-assessing their role. Should they restrict their moral remit solely upon the duty of care to the research participant? Or, should this be widened to include their moral responsibilities to society as a whole? Indeed it would be unfortunate if future generations came to regard early 21st century medicine as complicit in discriminating along racial lines through neglecting policies which could redress any longer term disadvantage. We therefore suggest that RECs should carefully consider the following points when assessing applications for biobanks and population-based studies:

1. Ensure that such projects have a clear policy, and plan, to recruit volunteers who are representative of local and national demographics.

2. Place greater emphasis on the long-term and broader societal impact of the research studies.

3. Consider alternative ethical models to IC for obtaining tissue donations for medical research.

Whether minority ethnic groups later choose to take part in the clinical research from which the biobanks are built remains to be seen. However, without engaging in the first scientific step, no further benefits can follow.

Furthermore, ethics committees are not usually set up to provide a legal opinion but are there to strike a moral balance between the individual and society. We would thus like them to seriously reconsider this balance in the case of specific consent and opt-in policies when collecting samples for biobanks.

Conclusions

The issues raised in this article are not restricted to RECs, but also need to be considered at the level of legislators and national regulatory agencies. However, ethics committees are in an excellent position to lead the moral debate on this topic and are relatively free from different legal rules to make independent judgements. How should research help balance the need to respect autonomy against the requirements of justice to address health inequalities?