Integrating Biobanks: Addressing the Practical and Ethical Issues To

Nature Reviews Cancer | AOP, published online 10 September focus 2010; doi:10.1038/nrc2913 on cancer proteomics

Nature Reviews Cancer | AOP, published online 12 August 2010; doi:10.1038/nrc2913 PerSPeCTiveS

it is now clear that much larger biobanks are Science and SocieTy required7,8. For genetic main-effect studies 2,000–5,000 samples are needed, for lifestyle Integrating biobanks: addressing the main-effect studies 2,000–20,000 samples are required and for gene–lifestyle interaction practical and ethical issues to deliver studies 20,000–50,000 samples are required8. Only when these larger resources are available can we truly understand the interactions a valuable tool for cancer research between gene, environment, lifestyle and disease and translate this knowledge into the R. William G. Watson, Elaine W. Kay and David Smith clinic through innovative diagnostics, therapeutics and preventive strategies for cancer. Abstract | Cancer is caused by complex interactions between genes, environment These larger resources can only be achieved and lifestyles. Biobanks of well-annotated human tissues are an important resource by the integration of existing biobanks that for studying the underlying mechanisms of cancer. Although such biobanks exist, already have a wealth of information and their integration to form larger biobanks is now required to provide the diversity samples. However, there are many obstacles of samples that are needed to study the complexity and heterogeneity of cancer. and challenges associated with such integration, including technical, logistical, ethical Clear guidelines and policies are also required to address the challenges of and legal ones. integrating individual institutional or national biobanks and build public trust. This Groups across both North America and Science and Society article highlights some of the main practical and ethical issues Europe have started to address these obsta- that are undergoing discussion in the integration of tissue biobanks for cancer. cles and challenges to move this process forwards. Initially, national programmes It is widely accepted that although basic The potential benefits of this personalized were established that linked previously col- scientific studies carried out using cell lines approach to the treatment of disease are lected biobank samples. These included and animal models can be informative considerable. They include the identifica- the Canadian Tumour Repository Network about the cellular and molecular aspects tion of improved biological targets using (CTRNet; see the CTRNet website; Further of cancer there is a clear requirement to validated biomarker studies, the capacity to information), which was established to link confirm this in human samples. The con- increase the likely success of clinical trials by cancer researchers with provincial tumour cept of patient-specific and disease-specific preselecting the patient population and the banks, thus creating new opportunities for (‘targeted’) therapy has expanded rapidly in fact that this will in turn reduce the time, cost translational cancer research to improve can- recent years. Many researchers believe that and the likelihood of failure of clinical trials4. cer outcomes in Canada and beyond. This this concept of personalized medicine will Information from validated biomarker stud- network gave researchers access to tissue and provide the solution to the considerable ies also allows the re-introduction of drugs clinical data. The Organisation of European challenges posed to the clinical treatment that have failed in a clinical trial setting Cancer Institutes (OECI) TuBaFrost database of cancer. The move from the traditional or that have been withdrawn from the mar- (see the TuBaFrost website; Further infor- ‘one size fits all’ approach for the treatment ket to be re-applied in a more targeted way. mation) was established in 2003 to network of cancer to targeted approaches seems to Similarly, biomarker studies might also offer European frozen tissue pathology banks for offer genuine hope for improved patient the potential to avoid adverse side effects, cancer research. In this initiative, the tis- outcomes. There are a few examples for and this would, in turn, lead to higher sue collection process was standardized, a which the concept of a highly effective compliance with various treatment regimes. code of conduct for the exchange of residual drug treatment targeted towards a specific human material for research was developed limited patient population has become The need for large integrated biobanks based on European legislation and a web- reality. The use of imatinib (Gleevec; One of the biggest limiting factors to the suc- based sample request process was developed. Norvartis) in chronic myeloid leukaemia1, cessful translation of basic scientific cellular Other examples include the Spanish tumour the use of monoclonal antibodies that tar- and molecular studies into improved patient bank, EuroBoNet (see the EuroBoNet web- get the epidermal growth factor receptor outcome has been the lack of access to large, site; Further information) and the Office of (EGFR) in patients with EGFR-expressing appropriate and well-annotated cohorts of Biorepositories and Biospecimen Research metastatic colon cancer2 and the use human tissue5,6. Focused disease-specific (OBBR; see the OBBR website; Further infor- of the ERBB2 (also known as HER2)- institutional biobanks have had some success mation) in the USA. These initial biobanks specific monoclonal antibody trastuzumab in translational and personalized medicine led to further expansions and networking (Herceptin; Genentech) in ERBB2-positive (as described above). However, owing to the to create resources across Europe and the breast cancers3 are such examples. complex and heterogeneous nature of cancer, United States. The establishment of the

European Biobanking and Biomolecular Box 1 | The Biobanking and Biomolecular Resources Research infrastructure Resources Research Infrastructure (BBMRI) programme (see the BBMRI website; Further The European project Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) was established in 2008 to network European biobanks with the aim of improving resources for information) illustrates moves to coordi- biomedical research and therefore contributing to the improved prevention, diagnosis and nate existing biobanking activities across treatment of disease. The resource includes 261 biobanks across 23 countries with a total of more 9,10 Europe (BOX 1). The development of the than 16 million samples. It is only possible to achieve this using a federated network of centres in Cancer Bioinformatics Grid (caBIG®) infra- European countries, which is best described as a distributed hub structure of existing biobanks. structure (see the Cancer Bioinformatics This will provide the flexibility to facilitate expansion and multiple uses (see the BBMRI website; Grid website; Further information) is Further information). connecting research organizations across The mission of the BBMRI is: the United States11 (BOX 2). The National • To benefit European health care, medical research and, ultimately, the health of the citizens of Comprehensive Cancer Network (NCCN; the European Union see the NCCN website; Further information) • To have a sustainable legal and financial conceptual framework for a pan-European Biobank has collected patient data outcomes for infrastructure breast cancer, non-small-cell lung cancer, • To increase scientific excellence and efficacy of European research in the life sciences, especially colorectal cancer, non-Hodgkin’s lymphoma in biomedical research and ovarian cancer. The data, along with • To expand and secure the competitiveness of European research and industry in a global records of patient treatments and patient out- context, especially in the fields of medicine and biology comes, have allowed retrospective comparative studies to be conducted. The analysis of subpopulations in these databases has already However, providing a clear definition of the Epidemiological Research (dataSHaPER; led to changes in clinical practice12,13. scope of a biobank is a problem when inte- see the dataSHaPER website; Further There are many reports outlining the grating biobanks that have been collected information) has been developed through complexity of biobanking that provide across different institutions or countries for the Public Population Project in Genomics strong recommendations and the identifica- different reasons. There is a clear need for (P3G) and Promoting Harmonisation tion of best practice for all aspects of the such flexibility, owing to the ever-expanding of Epidemiological Biobanks in Europe process14 (see the National Cancer Institute development of technology and under- (PHOEBE) and involves 25 international Best Practices for Biospecimen Resources standing of the complexity of cancer, but biobanks. These international collabora- website; Further information). FIGURE 1 out- this flexibility has effects on patient consent, tions have defined several core high priori- lines the steps involved in biobanks. As the standard operating procedures, information ties for improved study integration, such as requirements for complex multi-institutional technology management systems, and the sample collection, preliminary processing and international collections to study cancer use and distribution of samples. and storage, as well as the importance of processes have been established, this article documenting key aspects of the standard focuses on some of the important practical Standard operating procedures. The operating procedure, such as the time of and ethical issues related to the integration of careful and well-documented process- collection and processing so that this vari- biobanks. ing and annotation of samples is essential able is recorded and linked with the sample. to provide a useful resource for scientific These networks have all identified the need Practical implementations to integration interrogation. valid data are defined as for quality assurance systems that operate Definition and use of biobanks. There those that are reproducible, but variation across the sites and that can address com- are many types (BOX 3) and definitions is an enemy to such reproducibility. The pliance with, and the implementation of, of biobanks, which are informed by the importance of standard operating proce- standard operating procedures, but their goals, objectives or statements of purpose, dures has been well established to prevent implementation has not yet been agreed. and so differ from institution to institu- variation in the patient consent, collection. defined in the most general terms, a tion, processing, storage and distribution Information technology management systems. biobank is a collection of biological speci- of samples. Several important documents A central component of any biobank is mens and corresponding participant data. have been produced that clearly define the bioinformatics and data management The goals of the biobank will therefore the best practices for biobanks14,15 (see the system. It is clear that to harness the full determine the types of material collected, National Cancer Institute Best Practices for potential of any biological sample, informa- the scope of the research and the consent Biospecimen Resources website; Further tion needs to be collected not only about used to collect the samples. A clear defini- information). However, balancing the the standard operating procedures and tion of the scope of a biobank is essential to standardization and flexibility of biobanks pathological status, but also the demo- define informed consent for its participants, is of considerable importance. The main graphic, diagnostic, medical and family determine standard operating procedures challenge related to biobank integration history and clinical outcome data of the for sample collection and storage, define the is the consistency of standard operating participant. For such data, the patient must data management system and determine procedures across multiple sites, so that be identifiable to a member of the biobank the use of the samples. All of these char- differences observed across patient popula- so that the information can be updated over acteristics are not only required for a high tions are not affected by where and how the time. Issues associated with such informa- quality resource but also for building public samples were processed. There are ongo- tion extend beyond the storage of data and trust, avoiding the misuse of the resource ing international collaborations address- linking it to a specific participant and also and setting clear expectations for the ing these issues; for example, the data include data reporting, data searching and contributors to and users of the biobank. Schema and Harmonisation Platform for mining, data accessibility and network

security, and require personnel to enter, definitions that are underpinned by common Medical or surgical Acquisition manage and maintain the data in the future. standard operating procedures for data col- procedure There are a large number of commercially lection, uploading, management and audit. and institutionally available data manage- Unfortunately, there is no such agreement; Patient Processing ment systems but there is no common con- however, the world wide Biobank Summit sensus on which system delivers an overall has indicated that biobanks should agree on Restocking Biobanks are Storage solution. Biobank information management minimum data sets that are interchangeable a continuum systems (BIMS) are emerging as a proposed between biobanks and identify the complete solution that allow the storing, tracking ontology and multi-lingual definitions of Study evaluation Distribution and most importantly the searching of sev- the data set. In addition, access policies and eral sources of data at the same time. The levels of security to protect the identity and Patient feedback Scientific analysis Karolinska Institute has developed such a confidentiality of patients must be agreed. system, and it has been proposed that this This can be achieved using network security Publication BIMS model could be used to manage the and access control that limit different users data from the planned lifeGene project, to different aspects of the data. For example, Figure 1 | The steps involvedNature in Re establishingviews | Cancer which will include 500,000 Swedish par- data managers would be able to see patient- a biobank. The steps involved in biobanks are a continuum, starting with participant consent, ticipants and will follow them for decades identifiable information that is applicable to leading to the collection, processing, storage using both questionnaires and testing of their institution only, so that they can update and distribution of samples. The process fin- individuals. Another such project is the UK the appropriate information, and researchers ishes with the publishing of data and informing Biobank, which will gather samples from or external collaborators would see the de- participants of how their samples have been 500,000 participants with extensive medical identified codes of participants as well as the used, which then supports the continuation of and family histories and follow them for relevant clinical and scientific data that are recruitment to biobanks. 30 years. This project is expected to col- applicable only to their level of access and lect 15 million aliquots of blood and dNA. requirements. This approach would help to However, it is clear that a strong and close address issues of confidentiality and reassure participants to make an informed decision interaction between the information tech- participants of privacy, which is central to regarding their involvement in a study. A nology development team, data managers, building public trust. However, it is clear that clearly defined biobank makes it easier to biobank managers, clinicians and research- an important requirement for these informa- inform participants about the process and ers is required to build a system that is tion technology systems is that they are built the use of their samples; however, with fit for purpose and that also contains the in a flexible way to accommodate the ever- increasing pressure for flexibility in the appropriate security features to protect par- evolving requirements of participants and use and sharing of samples, the consent ticipant confidentiality and so foster public users of biobanks. process has become more complicated. In trust. Individual biobanks need to agree to addition, biobanks are typically established use standard identification schemata, data ethical issues associated with integration for long-term use, therefore the details of formats, data quality assurance and con- Patient consent. Informed consent is a future research projects cannot be known. trol processes, database architectures and fundamental and key mechanism put in Obtaining new informed consent for each common security processes when building place to protect the interests, welfare and new project is in most cases difficult, if their systems. rights of research participants and it is gen- not practically impossible. However, it The integration of databases is one of erally accepted as an absolute imperative has been argued that general consent to the most challenging issues for establishing for the collection of human samples16,17. future research projects is not sufficient. biobank networks. Ideally, data should be Central to the consent process is informa- To what extent can such consent about the exchangeable across multiple national and tion that educates the participant about the unknown future be accurately described international sites using a web-based system, research and how samples will be collected as informed consent?18–20 One proposed and facilitated by agreed consent, ontolo- and used, along with details of potential solution to this problem is to accept gen- gies, naming conventions, data formats and benefits and risks. This information allows eral consent for future research if the participants have the option to withdraw their data and if future research projects Box 2 | The cancer Bioinformatics Grid (caBiG®) are approved by an Institution Review Board (IRB) or Research Ethics Committee The Cancer Bioinformatics Grid (caBIG®) was launched in 2004 by the US National Cancer Institute and is already enabling many research organizations to move their clinical and basic (REC). It can be argued that adopting a research programmes forwards. The caBIG® programme aims to create a virtual web of somewhat lower standard than that of clas- interconnected data, individuals and organizations, with the ultimate goal of improving the sic informed consent could be justified interaction of those involved in treatment-focused research, leading to improved patient because the risks to individuals resulting outcome. It is essentially an infrastructure for connecting research organizations that allows for a from research on their human biological systems approach to biomedical research. It relies on the widespread use of sophisticated and material do not involve physical harm, as powerful information technology, which offers improved data management and data exchange is the case with clinical trials21 (BOX 4). In and sharing. This will facilitate a move from the traditional self-contained or isolated model of addition, it has been proposed that owing research organizations to the concept of large networks that allow faster, larger and standardized to the benefits that are associated with the collaborative research. The CaTissue suite developed by caBIG® is a biobanking managing system knowledge generated through these poten- designed to collect, manage, process, annotate, request and distribute biospecimens and associated information (see the Cancer Bioinformatics Grid website; Further information). tial future studies, and the fact that this information could accrue to all individuals

as well as future generations, it may be transferred to third parties, thus putting the original institution in charge of the biobank. possible to justify an expansive use of privacy of donors at risk. If recipients use Transfers of existing biobanks to third participants’ samples for future studies22. samples for their own purposes, the invest- parties with the inclusion of personalized In recent research conducted in the ments and efforts of the original biobank donor data should be possible only with the United States on stored biological materi- holder could be threatened. Biobank mate- approval of a REC or IRB28. als, it was found that biobanks used consent rial is a valuable resource and the ethical forms that offered individuals the option of issues of allocating such material emerge if Patient access. An individual’s right to designating how their biological materials the samples and data are misused. However, access their genetic data is linked to control could be used with varying degrees, includ- if the transfer of samples is too restrictive over their own identity. This varies across ing whether the materials could be stored; because of transfer agreements that include biobanks, as do the ethical justifications for whether participants could be contacted complex and costly control mechanisms, the the differences. In Estonia, personal genetic again in the future; whether the materi- resulting inaccessibility of biobank material data is available to participating individuals als could be used for genetic testing; and does not allow a large number of researchers on request or the participants can decide whether the materials could be shared with to use this resource in the interests of science that the information should be withheld researchers who were not part of the original and for the good of the public21. from them. likewise, in Iceland, patients are research team. In addition, a few biobanks However, except in circumstances entitled to information about their health offered options for participants to designate prescribed by law, it has been strongly (for example, condition, prognosis, risks how their biological materials could be used argued that the transfer of samples or and benefits of treatment) on request. The in future research — for example, by specify- information must take place in a simple UK Biobank takes a different and less open ing whether identifiers could be retained, or coded or double-coded way, with the approach. Although the Biobank Protocol specifying the research topics for which the recipient of double-coded samples having acknowledges that individuals will have materials could be used23. no access to the code. Should the recipi- the legal right to access their personal data In support of Elger and Caplan’s17 sugges- ents’ research require an association with if required, it also makes it clear that they tion that general consent should be the inter- personalized data, this may be provided will not routinely receive any individual national standard, the European Council has only by an official of the biobank to which information that relates to their blood sam- taken the view that broad consent to future the donors originally entrusted their samples ples (including biochemistry and genetic research use is acceptable24. This implies and data. The rationale for this is that an findings). The assumption that participants that individual donors renounce any ongo- alternative anonymization strategy, which should only be provided with health informa- ing rights to exercise control over the uses permanently destroys the information that tion about themselves in a clinical situation of their donated materials and the source links a sample and donor identity, risks the in which a trained professional can provide itself 25. This point has been emphasized by loss of information of scientific value, as appropriate interpretation and guidance lies Shickle26 who states that “providing that there is no way to prevent multiple inclusions behind this prohibition. The justification for there is proper disclosure and so on, then of the same participant, and this approach this position is that it would not be construc- the choice for the individual is to participate does not allow retroactive validation and tive and might even be harmful to provide on the terms offered or not. There is a ‘nega- demonstration of reproducibility. To facilitate health information but no interpretation, tive right’ not to be included in the research clear autonomy, transfers of samples and data counselling and support. The UK Biobank without consent. There is no ‘positive right’ to third parties must be fully documented cannot provide such counselling and support for a biobank to be run in such a way just for future reference according to standard because it is purely a research initiative29. because an individual would like it to be so.” operating procedures27. The German Ethics Council recommends Subject to the consent of donors, the that if individual communication of research Investigator access. The scientific potential transfer of samples should be permissible pro- results to the donor is agreed, then they must of biobank samples and data can often be vided that the recipient is subject to standards also be told as part of the information to be fully exploited only if their use is not con- of donor protection and quality assurance given that they must divulge these details in fined to individual research projects speci- equivalent to those that are applicable to the certain circumstances — for example, when fied in advance. donors should be able to give generalized consent to the use of their samples and data for the purposes of medi- Box 3 | Types of cancer biobanks cal, including genetic, research. For this rea- A population-based biobank is defined as a large repository of donated human DNA and/or its son, donors should also be able to consent information, collected from volunteers with and without cancer, which is used to identify the to the transfer of samples and data from genes that contribute to human disease. This is an essential resource if we are to understand the biobanks to third parties for the purposes genetic risk factors that are associated with cancer development and the genetic profile of the of medical research. Most biobanks provide patient that is associated with the development of cancer. These resources also need to include samples and data to various researchers high-quality lifestyle data. who are often not directly affiliated with the Disease-based biobanks are defined as a collection of biological material from patients with biobank holders. The transfer of samples cancer, and are essential to understand the molecular and cellular development of cancer at a and sharing of data raises several ethical specific stage. questions. If samples and data are physi- These types of biobanks can be collected for clinical purposes; for example, they could be cally transferred outside the biobank, the established for medical purposes, such as a blood bank. Specimens can also be collected as a by-product of diagnostic or curative procedures; for example, from hospital pathology recipient might use the material for purposes departments. Biobanks can also be collected for specific research investigations; for example, other than those to which the sample donors clinical trials. have consented or the samples might be

Box 4 | donor information required for consent time. It should not be possible to waive this right. However, there should be a provision In light of ethical controversies, informing participants about the details of storage and research for donors to allow samples and data to con- involving their samples is crucial. It is widely agreed that sample donors must be informed about: tinue to be used in the case of withdrawal • The voluntary nature of participation if they are anonymized — that is, if the link • The type of consent used (informed consent for the primary clinical or research purpose, or a to the participant’s identity has been elimi- general consent for future research) nated28. This is particularly important if the • The circumstances of sampling, including the risks and benefits of the procedure biobank has been integrated into a larger • The aims of storage (clinical purpose or research purpose) and the nature, extent and duration of network and samples are shared across the proposed use, including the possibility of genetic analysis that network. • The extent of and conditions for the possible future transfer of samples and data Participants need to be made aware of the • The measures taken to protect confidentiality (who will have access to the samples and fact that it will not be possible for samples information and the risks for individual donors and groups) and data that are included in completed • The form of data storage and combination research to be extricated from the research • The anonymization or pseudonymization of samples and data and other ancillary donor results and destroyed. The right to withdraw protection measures and any provision for state access to samples and data from a biobank does not include the right to • The right to withdraw consent withdraw research results that have already been accumulated. Rather, it means a pro- • The limits of withdrawal and the fate of samples and data in this instance and if the biobank closes down hibition of obtaining new data and analysis from the samples. Even if biobanks decide • Whether individual or aggregated research results will be disclosed to sample donors to retain existing data in an impersonalized • The possible consequences of the communication of results of genetic analyses for the donor form, questions arise as to whether com- and their relatives, including possible obligations to divulge (for example, to insurance plete and irreversible anonymization can institutions) be considered as a solution to the problem. • The use of biobank samples for commercial purposes (patients planned, benefit sharing planned, when can withdrawal take place? One obvi- and if so, in which form) ous point in time when withdrawal will be • Issues of payment of expenses, remuneration or benefit sharing impossible is when samples and data have been analysed and are part of a publicised concluding new employment or insurance according to the Nuremberg Code and the research result. Also, at this point, the par- contracts in the future. In addition, when declaration of Helsinki. However, exercising ticipant’s data will have been merged with such individual communication to the this right conflicts with the interest of sci- the other data of that particular study and donor has been agreed, the findings must be ence and industry to maintain the statistical integrated into the result to create new data imparted by a person with the appropriate integrity of population-based databases, sets. However, participants could potentially counselling skills, especially when commu- particularly given the aims of using these withdraw at any point before this occurs31. nicating the results of genetic diagnosis28. databases for longitudinal studies. There are The comparative analysis of practices in However, most biobanks take a different two important problems to withdrawing: Europe and the United States has shown that, position regarding the right of donors’ access namely, what can be withdrawn and when although the exact details may be different, to data. Participants are kept informed it can be withdrawn31. Although all studies all biobanks examined deem the provision about research that is currently in progress discuss the right to withdraw from research of a withdrawal option to be important. The or completed. These findings are usually generally, almost one-third failed to discuss fact that informed consent is requested and made available through regular information this right specifically with respect to research that information is provided about the mech- sheets, newsletters or a dedicated website. It involving biological materials. Therefore, anisms of withdrawal also plays a decisive is clear that continuing public engagement specific discussion of the right to withdraw part in ensuring that participant autonomy and the feedback of findings is necessary for biological materials may be necessary to pre- is maintained23. However, the withdrawal of an acceptable public profile of biobanks30. serve this basic right regarding participation samples that have been shared with network It is recommended that such an approach in research23. partners has not yet been resolved and so is a should be taken following the integration of The UK Biobank offers a set of graded challenge to the integration of biobanks. biobanks, as the ability to identify individual options for withdrawal (complete with- samples shared across resources would not be drawal, discontinued participation and no The roles of IRBs and RECs. As can be possible owing to anonyomization. However, further contact requested), which attempts observed, the role of IRBs and RECs if participants are informed at the time of to balance the interests of the participant for seems to be crucial for the management of donating samples of their ability to access data removal with the interests of the sci- biobanks. Therefore, before conducting a research data, then new mechanisms need to entific community. In Estonia, there seems research project involving the use of biobank be identified to relay information from future little room for negotiation, as donors have samples and data, the consent of an IRB or studies to participants from the collaborating the right to have their data deleted from the REC should be necessary for studies in users of the biobank. database on request, and any violation of which bodily substances are to be collected this right, including coercion to participate, from a donor’s body for research purposes; Withdrawing samples or data from is punishable as a criminal offence29. The the project calls for identified samples (that biobanks. The right of participants to German Ethics Council argues that donors are linked to the individual in a way that withdraw their personal data reflects the must have the right to withdraw their consent makes them immediately identifiable) to basic principles regulating medical research to the use of their samples and data at any be transferred to external researchers, and

entire existing biobanks are to be transferred facilitate the smooth sharing and integration 15. The German Ethics Council Biobanks for Research, Opinion. Deutscher Ethikrat [online] (2004). to third parties with identified samples of biobanks. If such issues are not dealt 16. Sheikh, A. A. Genetic research and human biological included. with, the public will withdraw its trust and samples: some legal and ethical considerations. Med. Law 23, 897–912 (2004). The involvement of an IRB or REC, individuals will start to revoke their con- 17. Elger, B. S. & Caplan, A. L. Consent and anonymization and the need for its favourable opinion, is sent, which would fundamentally affect the in research involving biobanks. EMBO J. 7, 661–666 (2006). intended to ensure that a narrowly worded quality and completeness of such resources, 18. Annas, G. 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