the foundations, applications and ethical dimensions of biobanks

CAE Electronic Working Papers Series

Paper No. DEG 005

The foundations, applications and ethical dimensions of biobanks

James Tansey, Michael M. Burgess1

W. Maurice Young Centre for Applied Ethics

Faculty of Graduate Studies University of British Columbia227 – 6356 Agricultural RoadVancouver, British Columbia

V6T 1Z2 604-822-8625

[email protected]

1 The authors would like to thank J. Maxwell, M. McDonald, M. Power, and A. Samarasekera for their contributions.

www.ethics.ubc.ca


James Tansey, Michael M. Burgess

Abstract Biobanks are repositories for genetic information derived either directly from patients or indirectly from stored tissue sources. In recent years, government and the private sector have invested in biobanks for a number of reasons. Population biobanks have been established to explore the relationship between genetic variation and disease in human populations. Biobanks have also been established to support criminal investigation and by the military.

Following an introduction to the science underlying the creation of biobanks, this paper describes the largest and most prominent population biobank, established in Iceland. This biobank attracted controversy largely due to the heavy involvement of private interests in its establishment. The concerns about biobanks are then set in the context of the broader literature on privacy, individual consent, collective consent and autonomy. In addition we describe the disjuncture between rhetorical accounts of the relationship between genetic information and phenotypic traits to which many ethicists have responded and the more cautious accounts of genomic scientists which stress the role of gene-environment interactions and complex non-Mendelian inheritance.

This research was supported by Genome Canada through the office of Genome British Columbia.

Please observe standard academic conventions for citation. For example: Tansey J. and M. Burgess (2004). “The foundations, applications and ethical dimensions of biobanks.” Electronic Working Papers Series. W. Maurice Young Centre for Applied Ethics, University of British Columbia at www.ethics.ubc.ca.

Table of Contents 1. Introduction................................................................................................................. 1

The mechanics of genomic research ............................................................................... 2

Genomics as “future diary”?........................................................................................... 3

Privacy and the gene ....................................................................................................... 5

2. Building biobanks ....................................................................................................... 6

Common elements ...................................................................................................... 7

Maintenance and Quality Assurance ...................................................................... 8

Purpose-built biobanks................................................................................................ 8

Biobanks derived from stored tissues ......................................................................... 9

Population biobanks...................................................................................................... 11

Iceland’s biobank ...................................................................................................... 12

Concerns with deCODE and GGPR ..................................................................... 15

3. Regulating biobanks.................................................................................................. 17

4. Ethical concerns ........................................................................................................ 20

Research ethics.............................................................................................................. 23

Assessing the risks and benefits of biobanking ........................................................ 23

Harm reduction or risk minimization........................................................................ 26

Informed consent ...................................................................................................... 27

The secondary use of data and biological material................................................... 32

The collective acceptability of research.................................................................... 34

Benefit Sharing ......................................................................................................... 37

Funding Sources............................................................................................................ 38

Protecting privacy ......................................................................................................... 39

Objections to creating biobanks................................................................................ 40

The inappropriate use of genetic information........................................................... 40

Protecting privacy within biobanks .......................................................................... 42

5. Appendix: Overview of biobanks ............................................................................. 45

Bibliography ................................................................................................................. 49

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James Tansey, Michael M. Burgess

1. Introduction In recent years, government and commercial interests have begun funding large-scale “biobanks.” The purpose of these banks is to enable researchers to explore the complex relationships between information stored in genes and variations in the phenotype of the human population. A better appreciation of these relationships offers the possibility of a clearer understanding of the genetic basis of specific medical conditions, as well as accurate screening systems and the prospect of identifying more appropriate medical interventions.

This paper begins with an overview of the science of biobanks including a more detailed review of the well-known Icelandic biobanking initiative. In the subsequent sections we describe the regulatory framework relevant to biobanking in Canada and internationally. Recognising that biobanks are often regulated by ethical frameworks established by funding agencies and research councils, the fourth section provides an overview of some of the broad debates in this field2.

Biobanks3 are composed of human tissue, from which genetic information is derived, and phenotypic information about individuals. The genetic and phenotypic information is stored on computers. Researchers can (for example) use biobanks to identify sub-populations or founder populations where the higher frequency of certain medical conditions is thought to be genetically influenced or determined. Researchers compare the DNA sequence of affected individuals with the DNA of the general population: in the

2 While there is a large literature on biobanks, the authors must acknowledge the important contribution a number of reviews made to this paper, specifically those by Cardinal, G. and M. Deschenes (2003). Surveying the Population Biobankers. Population Genetics: Legal and Socio-Ethical Perspectives. B. M. Knoppers. The Hague/New York, Kluwer Law International: 39-98, Godard, B., H. Kääriäinen, U. Kristoffersson, L. Tranebjaerg, D. Coviello and S. Aymé (2003). "Provision of genetic services in Europe: current practices and issues." European Journal of Human Genetics 11(Supplement 2 (December)): S13-S48, Godard, B., L. t. Kate, G. Evers-Kiebooms and S. Aymé (2003). "Population genetic screening programmes: principles, techniques, practices, and policies." European Journal of Human Genetics 11(Supplement 2 (December)): S49-S87, Godard, B., S. Raeburn, M. Pembrey, M. Bobrow, P. Farndon and S. Aymé (2003). "Genetic information and testing in insurance and employment: technical, social and ethical issues." European Journal of Human Genetics 11(Supplement 2 (December)): S123-S142, Godard, B., J. Schmidtke, J.-J. Cassiman and S. Aymé (2003). "Data storage and DNA banking for biomedical research: informed consent, confidentiality, quality issues, ownership, return of benefits. A professional perspective." European Journal of Human Genetics 11(Supplement 2 (December)): S8-S122, Kerr, A. (2003). The Social and Ethical Aspects of Medical Genetic Databanks, A Report Prepared for Generation Scotland Working Group.. 3 For the purposes of this paper, biobanking is defined as: The collection of genetic materials and health information for research related to human health. Such information might be used to develop personalized treatments, identify inherited risks for disease, or understand the role of genomic and environmental contributions to health in populations.

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simplest cases affected individuals share a polymorphism, a variation in the sequence of their DNA not found in the larger population.

However, only a minority of medical or genetic conditions is caused by a single gene; most appear to result from the interaction of several genes. In addition, scientists are only beginning to describe the relationship between genes and traits, as well as the relationship between the individual and the physical and social environments that individuals inhabit. This suggests that future research will necessitate larger biobanks containing much more extensive information, including information on environmental factors.

Regardless of their intended use, establishing and using biobanks raises a number of concerns. Commonly, these concerns focus on the potential use of information derived from biobanks to limit access to health care, insurance or employment. Other concerns focus on the invasion of privacy and patient confidentiality that may be necessary to establish biobanks. This “invasion” includes using biological material for purposes other than those it was collected for, or the use of information derived from biobanks by employers and the police to screen employees and citizens.

Concerns about individual autonomy are more complex. Biobanks are expensive and expenditures on this scale require strong justifications in terms of the benefits banks will deliver. The claims made as part of this argumentative rhetoric may overstate the causal link between establishing banks of genomic information and discovering the genetic origins of disease, thereby implying a kind of genetic determinism that is not supported by the science or most scientists. Nonetheless, if an individual took the rhetoric of genetic determinism literally, it could undermine a sense of autonomy, raising fears of a fated existence where the individual's life course is programmed into the individual's genes.

The mechanics of genomic research Three pieces of biological information are central to genomic research. The first is the linear information found in the DNA molecule. This information is written using four molecules or “bases.” The bases are paired across the two strands of the DNA double helix. Long stretches of these bases form genes that encode information fundamental to the nature of organisms.

Human DNA contains approximately three billion base pairs and 30,000 genes. These genes are distributed across the 46 chromosomes in a human cell, half of which come from the mother and half from the father. Each form of a gene is known as an allele and the uniqueness of a person’s genotype is determined by the specific combination of alleles.

The second type of biological information—the protein molecule—is produced via an intermediary known as messenger RNA (mRNA), which copies the necessary genes from the master DNA sequence. Proteins are built out of 20 amino acids, each described by a string of three bases known as a codon.

Proteins are responsible for much of the mechanics of biological function; the three dimensional structure of the protein, which ultimately determines its functional attributes, is determined by the sequence of amino acids. Because protein function is determined by the order of base pairs, tiny differences in their sequence within a gene can result in

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changes that affect the physical functioning of an organism when they are reproduced millions of times over in cells throughout the body.

The third type of biological information central to genomic research is the product of the complex systems and networks that arise from the interactions within and among the many types of cells that compose biological organisms.

Other than in identical twins, DNA sequences differ only slightly from one person to the next; as much as 99.9% of DNA is identical in all humans. The slight differences result in the genetic variability within humans (and other organisms). These differences—the polymorphisms—may be the product of a single variation between parents in a sequence of base pairs (Single Nucleotide Polymorphisms or SNPs). These polymorphisms are used as markers on DNA to help locate the genes that cause disease. These genes can be localized using distinct polymorphisms within human families that appear to be predisposed to a particular disease, thereby narrowing the search for a particular gene to particular sections of a DNA sequence. Other techniques then are used to localize the gene, which may be as short as several hundred bases.

Polymorphisms are not only convenient markers: in a minority of cases, when they occur within a section of DNA that codes for a gene, polymorphisms may result in disease, the most familiar model for genetic disorders being when both parents share the same polymorphism4. Other polymorphisms cause disorders that may vary depending on how many times they are repeated in a gene. For instance, the severity of Huntington’s disease appears to be related to the number of times a group of three bases is repeated within a gene: the larger the number of repeats, the more severe the condition (Hood and Rowen 1997; Baldi 2002; Cardinal and Deschenes 2003).

The more challenging disorders occur where polymorphisms are associated with a probability of getting a particular disorder. Probability appears to imply that environmental factors must combine with genetic predisposition for a disorder to appear, that other genes may also be involved, or both. The most challenging disorders are multigenic: multiple genes appear to predispose individuals to the same disease; or more than one defective gene sequence is associated with a disorder. To further complicate matters, the same gene may serve different roles in different tissues.

Genomics as “future diary”5? While genomics is a complex field communicated in a dialect that often seems impenetrable to non-geneticists, it does not take an expert to recognize that there are gaps between the rhetoric of the genomic promise and the realities of current science. While it is true that a number of significant hurdles have been crossed—technological innovations, for example, have allowed researchers to speed up the process of identifying

4 Since an individual inherits genes from both parents, a polymorphism in one chromosome can be compensated for by a normal gene sequence from the other parent. 5 Murray (1997) criticises the degree of determination implied by this phrase, which was first used in as part of an initiative to establish a model Genetic Privacy Act in the US. Annas, G. J., L. H. Glantz and P. A. Roche (1995). "Drafting the Genetic Privacy Act: Science, Policy and Practical Considerations." Journal of Law, Medicine and Ethics 23: 360, 365.

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genetic markers and sequencing DNA—it is also true that access to a “new science” that can correct for genetic disorders on a grand scale is still a long way off.

There are specific technical reasons why this is the case, including the expense of full genetic sequencing, the fact that many disorders are multigenic, and the fact that tests that indicate susceptibility are more common, less expensive and more successful than subsequent interventions. Added to this is the challenge of gene/environment interactions which suggest that genes may simply create predispositions. With so few cases where true genetic determinism has been described, it has been argued that the metaphor of DNA as a “future diary” is misleading:

It implies that the contents of that future diary reflects what is most intimate, central, and important about us—that it reveals, in some fundamental way, our social and personal identity, our loves and interests, and our actions. In fact, our genomes have little or nothing to say about any of these crucial matters. The metaphor also promotes genetic determinism. In complex disorders with many contributing factors, such as many cancers and heart disease, genetic information may indicate only a rough range of probabilities, something that falls far short of a “probabilistic future.” (Murray 1997)

The extent of the gaps in our genomic knowledge can be revealed by “inverting” a recent vision for the future of genomic research published in Nature (Collins, Green et al. 2003). The first column in Table 1 summarizes a small sample of the multitude of goals that the paper’s authors set for the genomic research community; the second column describes what these goals imply about the current state of genomic knowledge. This is not meant to belittle the tremendous advances that have been achieved, rather to suggest that the genome still contains many puzzles. To put it another way, while there was a great deal of fanfare surrounding the announcement that one person’s genome had been sequenced6, this is really only the first step in what will be a very long term research project.

Table 1: Gaps in genomic knowledge

Visionary goal Implication for the state of current knowledge

Improve understanding of current knowledge of the genome’s structure and function and of the 1-2% of bases that code for proteins.

Non-coding portions dominate the genome sequence; little is known about non-coding portions under active selection. Genomics lacks a holistic understanding of gene function and the full range of functions it performs.

Develop a detailed understanding of the heritable variation in the human genome, particularly the interplay between multiple genetic factors and the environment: “[c]omputational and experimental methods to detect gene-to-gene and gene-environment interactions … are also required.” (p840)

Current advances have largely been achieved through identifying what may turn out to be the exceptions to the rule: phenotypes coded by a single gene

6 See the Human Genome Project at http://www.genome.gov/10001772.

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The need to translate genome-based knowledge into viable health interventions

Completing the human genome sequence is the starting point; translation to health benefits “has been less clearly articulate” (p840)

Investigate the relationship between genes and social behaviour including sexual orientation and intelligence to provide a firm scientific foundation.

The relationship between genes and a range of social behaviours is poorly understood and is likely highly complex.

Privacy and the gene The immense promise of genomic research—rhetorical or not—has often seemed to place a high public and corporate value on genetic information. At the same time, the fact that many people consider genetic information to be the most intimate information that can be revealed by an individual has placed the gene in a highly sensitive category of information that includes such things as health and credit information. While many policies and regulations have evolved in the past century to protect individual privacy in a variety of circumstances, issues around privacy and the gene are often considered to challenge the efficacy of these mechanisms.

This may, in part, be a result of the newness of genetic technologies, an increased awareness or understanding of the technologies, or a combination of these and other factors. Regardless, practices that have provoked scandals in recent years, such as retaining human tissue for research, raised little concern even twenty years ago (Kerr 2003).

Allen (1997) describes the devices that have emerged in the last one hundred years to place the force of law behind what had for centuries only been a philosophical ideal, distinguishing between the informational, decisional, physical and proprietary dimensions of privacy relevant to the genetics debate.

• Informational privacy is defined as “the claim of an individual to determine what information about himself or herself should be known by others” (in Allen 1997); it is the dimension of privacy most commonly addressed by bioethicists. Typically, informational privacy in medical settings has been protected by asking patients to actively provide informed rather than presumed or tacit consent, both of which could be secured simply through an individual’s decision to interact with the medical system.

Informational privacy is based on norms that define modernity, in particular the relationship between the individual and society and the tension between the “right to know” and “right not to know” (Edwards 2002: 14).

• Physical privacy concerns the right of the individual to choose whether he or she wishes to be subject to observation, testing or screening. The fact that DNA can be extracted from very small amounts of tissue has led to concerns about covert DNA sampling and prompted the United Kingdom’s Human Genetics Commission to recommend making it illegal to deceitfully gather genetic information for non-

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medical purposes (Casci 2002)7. Current regulations in that country and some American states allow for mandatory testing of some or all categories of prisoners on the basis that it is in the collective interest to violate the physical privacy of criminals8.

• Decisional privacy concerns the right of the individual and families to make specific choices about information arising from their persons or personal affairs. An example of decisional privacy is an individual’s right to tell or not tell others about the results of predictive testing done on a foetus.

Decisional privacy issues reveal the challenge of trying to regulate collecting genetic information in isolation from other social norms and practices. Funding and supporting pre-natal genetic testing while limiting the range of possible interventions draws the state into an area that was previously in the realm of fate. The mere existence of the capacity to use knowledge to intervene between parents and the fate of their child may well alter current notions of rights and responsibilities.

• Proprietary privacy is related to the ownership of personal information, in this case, genetic information9. Proprietary privacy raises the question of the individual’s right to compensation for commercial products derived from the commodification of their genes, whether and when the individual retains property rights, and to what extent.

“Commodification” is a rhetorically laden term (typically) used to refer to the process of assigning a range of ownership rights to some “thing.” These rights include, for example, the right to manage, exclude others, sell or lease, and receive compensation for trespass or loss, as well as a corresponding set of ownership duties to, for example, maintain so that others are not injured. Private ownership of genetic materials and/or information resulting from the analysis of the materials creates the possibility of profit and incentives for distribution, as well as access and investment in research. Commodification is seen by many as problematic, primarily because it may remove respect for things such as humans, gametes, foetuses, human organs or genetic sequences by inappropriately assigning these monetary value and control mechanisms (e.g., patents).

2. Building biobanks Human tissue banks have existed at least since the medical establishment began using tissues and cadavers for research and training purposes (Nelkin and Andrews 1998).

7 This recommendation was released at the same time as a case was reported of a covert paternity test completed using a DNA sample extracted from dental floss (Kennedy, H. (2002). Bing's genes concern us all. The Guardian. London.). 8 There seems to be an emerging position against covert testing, although presumably court sanctioned testing under sufficiently pressing conditions is a possibility. Under the current Canadian criminal code, it is possible to apply for a warrant to collect a DNA sample as part of a criminal investigation. 9 The defining case in US law is Moore vs. University of California. The case sets a possible precedent that biological materials collected in the course of routine surgery, where consent has been given, may be available for research purposes and using genetic information derived from them. From the perspective of public and private research institutions, the tissue itself has little value; it is the knowledge and testing that they bring to bear on the tissue that gives it commercial potential.

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Small-scale biobanks for specific genetic diseases, that is repositories that store information in a digital format, have existed for decades.

The majority of biobanking initiatives reflect emerging not established standards of practice. Biobanks may be identified, identifiable (coded), anonymized (unlinked), or anonymous (unidentifiable) (European Society of Human Genetics 2003; Godard, Raeburn et al. 2003; Godard, Schmidtke et al. 2003): • In identified biobanks, information stored with samples includes identifiers such as

patient name or number. • In identifiable biobanks, unidentified samples can be linked back to identifiers

through a coding system. • In anonymized biobanks, samples are irreversibly stripped of all identifiers and

cannot be re-linked with those identifiers. • In anonymous biobanks, samples are collected without identifiers, therefore the

source is impossible to identify.

The purpose of the research and the source of the genetic material affects the nature of the identification used in a given research project (European Society of Human Genetics 2003; Godard, Raeburn et al. 2003; Godard, Schmidtke et al. 2003). The Public and Professional Policy Committee of the European Society of Human Genetics (PPPC) recommends: different approaches to ownership of samples based on the character of the collection (European Society of Human Genetics 2003); and that the various approaches to ownership should be subjected to multiparty contracts rather than defined in legislation. According to the Committee, only anonymous data should be regarded as “abandoned,” in which case “…the processor and/or Principal investigator should be considered as the custodian of these data…” (European Society of Human Genetics, 2003a, recommendation 27(b)). Otherwise:

…the subject should always be considered as a primary controller of its DNA and clinical information directly derived from it. Once the information has been processed, it becomes research data (ie data) unless there is agreed private ownership. The processor and/or principle investigator of DNA sample[s] and genetic data should be considered as the custodian of the DNA/genetic data. (European Society of Human Genetics, 2003a, recommendation 27(a))

Common elements

Biobanks may vary significantly in design and purpose, but generally they share the following elements: • Biological source material: DNA can be extracted from very small amounts of

human tissue. In some cases, such as population biobanks in the United Kingdom and Iceland, DNA sampling is part of a specific research program. In other cases, DNA is extracted from archival tissue banks held by pathologists or within a medical organization. For example, researchers in the United States have proposed using the blood samples on “Guthrie cards” used to test infants for phenylketonuria, a gene-based metabolic disorder, as a source of genetic material for other studies.

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• Genetic information systems: DNA is extracted from an individual’s biological material and information describing the unique characteristics of the person’s genotype is stored in an electronic database.

• Phenotypic information: information derived through physical examination, from questionnaires, or from an individual’s health records. Since DNA does not provide an easily accessible blueprint for constructing biological organisms, researchers need to compare an individual’s DNA with his or her phenotype. Phenotypic information allows biobank researchers to explore associations between polymorphisms and phenotypes without necessarily fully understanding the intervening biological mechanisms.

Socio-environmental information derived through surveys to characterize key aspects of an individual’s physical environment and behaviour is increasingly recorded and stored in biobanks as researchers begin to examine gene-environment interactions.

Maintenance and Quality Assurance

The long-term utility of all biobanks is heavily influenced by how a bank maintains its samples. For example, in some cases a DNA sample is exhaustible (Godard, Raeburn et al. 2003); consequently, a biobank must ensure proper conservation. In fact, it has been argued that “quality assurance… should be a sine qua non condition of banking” (Godard, Schmidtke et al. 2003: 6).

Mechanisms to enhance quality assurance include explicit procedures for storage, registration, and coding of samples (Godard, Schmidtke et al. 2003), guidelines for the actual storage facilities, and the participation of qualified, experienced personnel.

Purpose-built biobanks Until recently, some of the most extensive biobanks were held by the military (for a detailed review, see (McEwen 1997)). For example, the United States military holds DNA information for approximately three million service personnel. Banks have also been developed to aid civil/criminal investigations. By 1996, 40 American states had enacted legislation to collect DNA samples from criminals convicted of certain violent or sexual crimes, while in the United Kingdom, police are authorized to take “non-intimate samples” including hair and saliva from anyone convicted of a crime10. Currently the British police DNA bank holds 2 million records and the British government claims that the bank has enabled them to match 1,000 samples from crime scenes with records in the bank (Travis 2003).

The Canadian National DNA Data Bank (NDDB), established in 2000, contains two indexes. The Crime Scene Index (CSI) contains data collected from crime scenes and processed by RCMP laboratories across the country. This index relies on investigating officers to submit evidence from crime scenes. The Convicted Offender Index (COI) contains genetic information from specific classes of convicted offenders described in Section 487.04 of the Criminal Code of Canada11. The list of designated offences is

10 In a controversial move, British police have added DNA from voluntary samples taken during investigations when investigators have been trying to exclude suspects. 11 For a list of offender classes see section 487.04 at http://www.canlii.org/ca/sta/c-46/

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extensive, covering all sexual or violent crimes, including breaking and entering. In addition, investigators can apply for a warrant to take DNA samples from persons convicted of sexual offences (listed in section 487.055) prior to the enactment of the DNA Identification Act (1998).

In the case of COI data, a number of measures are taken to ensure that material held by authorities cannot be misused in the course of further criminal investigations. The laboratory processes samples then updates offenders’ criminal records to show that a valid sample has been recorded. Each sample is identified by a unique code once the identity of the individual has been confirmed through fingerprint analysis. The DNA material can only be identified using the unique code, ensuring that those involved in the analysis of DNA taken from convicts do not know the individual’s identity. The original sample card is retained and all other intermediate materials destroyed. The system is set up so that investigators must make a direct match between data held in the CSI and COI indexes, thereby reducing the likelihood of inappropriate convictions.

The NDDB can only be used to aid criminal investigation; it is not available for research. By late 2003 investigators looking for matches across the two indices had 452 matches from crime scene and convicted offender samples and 29 matches between crime scene samples12.

A recent press release posted on the NDDB website includes a plea for greater use to be made of the database. The release suggests that only 50% of designated primary offences and 10% of secondary offences are recorded in the CSI. Drawing on evidence from the United States, the NDDB proposes that expanding the number of designated offences to include a larger number of minor offences would increase the efficacy of the data bank, although there is no evidence that specific amendments to the legislation are being proposed.

The DNA Identification Act allows for collecting and disclosing genetic information for specific offences. However, the purposes for which it can be used have been limited in subsequent amendments to those related to forensic matters. Under the Act, Canadian authorities can share information internationally through Interpol, while “respecting the privacy and security of such data.”

Biobanks derived from stored tissues An important source of material for establishing new biobanks or extending existing banks is previously stored tissue samples. As mentioned above, the United States holds a large archive of Guthrie cards13. In some jurisdictions, these cards, which were originally used to screen infant blood for phenylketonuria, are now used for additional genetic screening, and may be subject to more DNA testing in the future as methods improve and the cost of testing falls (McEwen 1997: 245). Also in the United States, the military biobank constructed for the purpose of identifying soldiers killed in action has already

12 Specific cases of where genetic information has been used in criminal investigations are described in detail on the NDDB website (www.nddb-dnbg.org). 13 See http://www.smccd.net/accounts/skyline/NCBC/bioethics/bioethics5.html.

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been used in criminal investigations by military police. The genetic information captured in Britain’s is currently only used to match data records and crime scene samples. It is not yet clear whether the mechanisms in place are sufficient to ensure that the database will not be used for research on genes for violent or criminal behaviour (Adams 2002).

A recent case involving the Nuu-chah-nulth First Nation (Vancouver Island, British Columbia) drew attention to some of the challenges of regulating the vast number of tissue banks gathered by scientists, pathologists and other researchers around the world. In this case, 883 samples were originally gathered as part of a genetic study of arthritis by a biological anthropologist employed at the University of British Columbia in the early 1980s (Kleiner 2000; Dalton 2002). On leaving the university, the researcher took the samples first to the University of Utah and then to Oxford, subsequently using the samples—without the consent of the Nuu-chah-nulth—to analyse genetic diversity in tribe members as part of a study of how North America had been populated by First Nations peoples.

Based on current ethical guidelines, reconsent is not required for fully anonymized samples where there is no possibility of linking the sample back to the individual14. However, it is clear from the first of two papers published on the latter study that the authors made explicit use of genealogical information in order to select a subsample of maternally unrelated individuals for detailed analysis (Ward, Frazier et al. 1991; Ward, Redd et al. 1993). This suggests that individual identifiers may not have been removed from the samples.

The Nuu-chah-nulth experience highlights some of the very real concerns over using stored material. For example, the researchers were able to move across jurisdictions with both tissue samples and the genetic information derived from them, making it difficult to regulate their activities15. In addition, the stored materials were used subsequent to the first study for research far removed from the original intent. This was done without the donors’ consent. These facts are further complicated in the case of the Nuu-chah-nulth—and for other “New World” First Nations—by the historical experience of theft by westerners of aboriginal bodies and body parts: the inappropriate use of tissue may be seen as extension of these practices into the modern era. Using the samples for anthropological studies on the migration of aboriginal peoples throughout North America has been seen by some First Nations as an attack on aboriginal rights, including land claims.

And the experience of the Nuu-chah-nulth is by no means unique. According to the American Journal of Bioethics (http://www.aztrib.com/index.php?sty=18824 captured

14 Ethics approval processes have evolved significantly since the early eighties when consent for the Nuu-chah-nulth study was secured. Ward himself recognizes this in a comment to Nature: “The way people operated at the time ...it didn’t cross anyone’s mind [that consent was not renewed]” (Dalton, 2002). Kleiner (2000) contacted UBC and established that based on the original consent form, Ward was required to get further permission before proceeding with the analysis of genetic diversity. 15 In a case known as the “Texas Vampires” incident, scientists from Newfoundland working in Texas returned to the province with blood samples from a family with a rare heart condition, then returned to the US. The participants wanted to know whether they had the genetic marker the researchers were looking for, but it proved impossible to find out. The most credible account of this story can be found at: http://ottawa.cbc.ca/regional/servlet/View?filename=ot_keon20031219

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March 04), “The Havasupai Tribe has filed a $50 million lawsuit against Arizona State University, the Arizona Board of Regents and three researchers alleging that blood samples taken from tribal members under the pretext of diabetes research were destroyed, lost or used in studies of schizophrenia, inbreeding and population migration without the donors' consent.”

The Tri-Council16 Policy Statement, Ethical Conduct for Research Involving Humans, (Medical Research Council of Canada, Natural Sciences and Engineering Council of Canada et al. 2003: i.4) suggests that research involving aboriginal peoples requires special attention, particularly since human tissue and samples may have special status in some cultures. The Tri-Council argues that more consultation is required before firm guidelines can be established and proposes that more general guidelines (reviewed below) regarding biobanks should prevail. Notably, in lieu of these consultations, the Tri-Council Policy Statement does not appear to preclude working with First Nations. In Section 10 on the use of tissues in research, the Tri-Council states:

The status accorded the human body and its parts varies among individuals and cultures. It varies in part due to how people perceive, identify with or relate to their bodies. Some people or cultures take little interest in tissue removed from their bodies. Other cultures regard certain parts of the body (e.g., the placenta) as sacred. Other parts of the body may be regarded as appropriate for gift-giving, provided that the use for research does not compromise medical diagnosis or care. What some regard as an invasive method to acquire tissue samples, other individuals or cultures will not. These examples illustrate the continuing importance of assessing the ethics of research involving human subjects through a subject-centred perspective. (http://www.pre.ethics.gc.ca/english/policystatement/section10.cfm)

Population biobanks In order to understand the relationship between polymorphisms and disease in humans, genetic researchers need data for large populations of individuals. By using population biobanks to examine both the DNA and the medical records of populations, researchers hope to identify polymorphisms, intra-genomic relationships and genome/environment relationships related to disease.

Population biobanks have been proposed or started in many countries, including the United Kingdom, Iceland, Italy, Israel and Sweden (Potts, 2002: 32). In a number of these countries, governments have made significant investments in very large databases. Broadly speaking, the goal is to develop banks that allow researchers to explore the relationship between genotype, as revealed by DNA mapping and sequencing, and phenotype, as expressed in health records.

In addition, genetic researchers have started to target sub-populations within countries, as well as relatively homogeneous ethnic groups that for one reason or another have been

16 The Social Science and Humanities Research Council (SSHRC); The National Sciences and Engineering Research Council (NSERC); and The Canadian Institutes of Health Research (CIHR), formerly The Medical Research Council (MRC).

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genetically isolated. Populations that are more homogeneous are considered more attractive to researchers since they may have a higher incidence of a particular genetic disorder that can more easily be traced to a specific polymorphism. Consequently, cultural isolation (e.g., as found in certain Jewish populations), or physical isolation (e.g., as found in certain island populations, such as on Tonga (Cardinal and Deschenes 2003)) represent a fortuitous accident from which researchers hope to reap benefits.

The advantage of constructing a biobank from a more homogeneous population is that, since more polymorphisms are shared in common by the population, it may be easier to isolate the gene causing a particular disease (Potts 2002). In addition, in the case of diseases with a gene-environment interaction, social, cultural and environmental homogeneity may help isolate the causal pathways. Whereas Mendelian inheritance patterns can be studied by simply collecting samples from families affected by the genetic disorder, large-scale biobanks are considered especially effective for studying more complex and more common non-Mendelian inheritance patterns17. Because of the complex nature of non-Mendelian characteristics, traits are much less likely to be seen in familial clusters; in this case, “genetic” is not the same as “familial”18.

Biobanking initiatives are starting to attract the kind of significant capital investment necessary to establish the information base required for genetic research. For example, the British government recently approved a US$70 million biobank to explore the relationship between genetic variation and environmental influences in the pathology of human disease. Five hundred thousand Britons between the ages of 45 and 69 will be asked to donate blood, from which DNA will be extracted, complete a survey describing their lifestyle characteristics, and subject themselves to a medical examination. The volunteers will then be tracked for a decade and their health monitored through their interactions with the National Health Service (Rose 2003: 325).

Countries that have a national health system have a head start in establishing biobanks, since at the very least, billing and contact information is available centrally and can be used to track diagnoses and service utilization. However, even in national health systems, health care records are variously organized and are often held locally; commonly, they are not integrated unless there has been a special effort to do so for quality of care, public health, or research purposes. Nonetheless, Sweden and Denmark in particular have robust databases that have supported a multitude of population health studies19.

Iceland’s biobank The high-profile Icelandic biobank is perhaps both the most advanced and extensive population biobank initiative to date; it is also the most widely known. Kari Stefansson, an Icelandic genetic researcher who had been working in the United States, first proposed

17 Non-Mendelian disorders include those involving multiple alleles, traits that only appear on the X chromosome, conditions characterized by multiple traits and multiple alleles, that produce a continuum of phenotypes (polygenic traits) and allele’s that produce a single defective gene product that results in a wide range of functional defects (pleiotropic traits). 18 We are grateful to Dr. Angela Brooks-Wilkinson for her invaluable insights on this issue. As we discuss below, the complex nature of non-Mendialian inheritance has important implications for issues such as collective consent. 19 The province of British Columbia has a sophisticated centralized digital database that records health care use and classifies the incidence of disease using the International Classification of Disease protocol, but does not include genetic information.

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the biobank in 1997. Stefansson personally lobbied the Icelandic government and investors to support the biobank in order to capitalize on Iceland’s unique geographic and cultural attributes. The company he founded, deCODE, is now listed on NASDAQ.

Three critical factors make Iceland’s population ideal for a large-scale biobank (Jonatansson 2000): • Relative geographic isolation: Iceland was the last European nation to be settled.

Colonized in the 9th and 10th centuries, it is primarily populated by the descendents of early Norse and Celtic settlers who arrived 1,100 years ago and who prevented subsequent colonization attempts. Even in the twentieth century, when Iceland has become less isolated, restrictive immigration policies have retained a population that deCODE has argued is more genetically homogenous than other European populations. (It should be noted that evidence supporting the contention that Iceland’s population is relatively homogenous (Gulcher, Helgason et al. 2000) has been contested on the basis that the data used contained errors (Abbott 2003; Arnason 2003).)

• A widespread interest in genealogy: Icelanders are far more likely to research and maintain genealogies than other populations. These genealogical resources should help researchers trace the genetic lineage of diseases and disorders through generations.

• An extensive national health care system: Iceland has a centralized national health care system that is governed through a parliamentary democracy that tends towards centralization and the concentration of power. The result is that once parliament decided to support the database, construction could begin rapidly and efficiently (Jonatansson 2000: 36).

The Icelandic biobank, labelled the Genealogy Genotype Phenotype Resource (GGPR), is composed of three electronically linked databases (Merz, McGee et al. 2004). The Database Act (1998) licenses deCODE to construct a national computerized record database from the health records—the Health Services Database (HSD)—for the entire population (285,000 people) in a form that maintains the confidentiality of individuals. deCODE is responsible for the cost of developing HSD, but the company does not have direct access to its data.

deCODE also approaches volunteers to donate a blood sample to the initiative. The company receives informed consent from the donor and enters the data into a database. The process of linking the DNA sample to health records is managed by the Icelandic government, which ensures that confidentiality is maintained. By 2002, 50,000 Icelanders had donated blood to GGPR (Potts 2002). According to deCODE’s website, that number had doubled by 200420

The third data source used by deCODE is the island nation’s genealogical records documenting the lineage of Iceland’s inhabitants. It has been calculated that between 625,000 and 750,000 people have lived in Iceland since its settlement; by 2002, 560,000 names and relationships had been entered into the database (Potts 2002: 8).

20 http://www.decodegenetics.com/

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The importance of these extensive genealogical records has been understated in the debate surrounding GGPR. Through these records, deCODE can construct very large familial clusters, which helps to narrow the search for a target gene by: • comparing healthy and unhealthy individuals from within the same cluster to see the

extent to which genotypes differ; and • comparing distantly related sufferers of the same condition to find areas of genetic

similarity.

Using this type of genealogical evidence to support identifying family clusters—even if the evidence can be somewhat unreliable21—can simplify the task of isolating genetic effects from random polymorphisms.

Figure 1 describes the various steps involved in constructing GGPR. Records kept in medical clinics are typically in paper form, and deCODE has established a team of encoders to transfer the data to digital form. The final step of integrating the data from each of the three sources is completed by the Personal Data Protection Authority (a government department), which is responsible for encrypting and linking the three data bases within GGPR.

Figure 1: Flow diagram describing the GGPR

(Source: Merz et al, 2004)

Iceland’s Database Act specifies the allocation of costs and benefits between deCODE, the Icelandic government and the Icelandic population. The goal is to ensure that, in addition to the benefits expected to accrue to the health care system from research, the Icelandic government and people benefit from GGPR. Under the Act, deCODE is responsible for raising the funds required to build the biobank (US$10.5-19.3 million)—including the cost of digitizing the health records—and must pay the government an annual license fee of approximately US$700,000. deCODE must also share profits from its commercial activities with the government (up to US$1.4 million per annum). Other financial benefits are distributed indirectly to the Icelandic population through share

21 Genealogical records may be unreliable due to high rates of “false paternity,” meaning that the father documented in the record is not a biological parent.

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ownership; deCODE is a publicly traded company and a large number of Icelanders are shareholders22.

While deCODE is free to negotiate agreements with other parties, data storage and all processing and research activities must occur within Iceland. This “tethering” clause ensures the maximum benefit to Iceland in terms of employment, as well as ensuring that the biobank will always be governed according to Iceland’s sovereign laws.

To date, deCODE has successfully applied for a number of patents for gene sequences derived from the biobank. The company claims to have identified genes linked to a number of conditions including schizophrenia, stroke, Alzheimer’s disease and osteoporosis (Potts 2002). The company has also come to a financial arrangement with the Swiss pharmaceutical company, Hoffman-La Roche, worth US$200m. As part of that agreement the company will make any medicines derived from research using the biobank available free-of-charge to the Icelandic population.

Concerns with deCODE and GGPR

Iceland has maintained health records since 1915 and the decision to make these records accessible to deCODE was made following public and legislative debate. A large majority in parliament made the decision on the condition that the database cannot be used to identify individuals. However, it is this transfer of publicly held information to a corporation that has raised the greatest concerns among opponents of the initiative. Critics argue that individuals did not consent to have their health records transferred to a private entity for analysis: GGPR is not constructed on the basis of informed consent.

Regulators counter that since the database is anonymous, informed consent is unnecessary, a position they argue is consistent with international regulations on biobanking (Jonatansson 2000). In addition, the Database Act allows individuals to withdraw their health records from the GGPR database—7% of the population had done so by March 2003 (Editorial 2003)—and the company will be prosecuted if it seeks to indirectly identify individuals, who, for instance, inhabit a remote community, or have a rare and visible condition and therefore could be relatively easily located. [See Informed consent below for a discussion of this issue.]

Regardless of these provisions, there is a vigorous and ongoing debate in the Icelandic and international press primarily about whether a private company should in any way be able to extract commercial gain from a public good. This debate is similar in character to more general debates about the role of private interests in providing health care, a practice which is often characterized as the violation of a sacred trust. Apparently, many doctors have quietly obstructed the assembly of the central health database by refusing to transfer records of their patients and the Icelandic medical association has expressed concern about the initiative as a whole (Abbott 2000) (for more recent commentary see Potts, 2002: 18). Add to this mix the unproven allegation that deCODE financially

22 The fact that many citizens invested savings in deCODE stock, which subsequently crashed, is rarely mentioned. The company raised US$173m in capital through an initial IPO in 2000 when stocks sold for around US$25 per share. The subsequent crash in biotechnology and information technology stocks drove the stock price below US $2 per share.

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supported the Independent Party, Iceland’s ruling conservative party (Fortun 2001), and the conditions are ripe for an ongoing controversy.

In a recent article, Merz et al. (2004) sought to summarize the major concerns related to GGPR and recent regulatory changes. The authors recognize that the data resources available in Iceland have been extremely useful in past epidemiological research, but suggest that GGPR is a distinctly different initiative, primarily because it involves a private interest.

Merz et al. summarize five broad areas of concern: • Because of the unique nature of genetic data, individuals who contribute to the

database will be inherently identifiable. • An “opt-out” clause available to Icelanders excludes children and those lacking

capacity, unless a guardian acts on their behalf. • Granting deCODE unique access to the data amounts to creating a monopoly, which

violates the provisions of the European Economic Area and may also limit academic and other commercial research interests.

• In its original form, it was not clear that GGPR was subject to independent oversight. Although a new committee, appointed by the Director General of Public Health, was established following a restructuring, it is still not clear whether there is independent oversight.

• Regardless of the current regulatory mechanisms, many critics feel that the initiative commodifies Icelandic people by creating a market for information derived from their bodies.

These authors suggest that there are a number of other problems with the Iceland biobank. For example: • Although the transfer of data from HSD to GGPR is through a securely encrypted

link, the transfer of paper-based health data to digital media is done manually. The authors suggest that in a country as small as Iceland, those hired to do the transcription may recognize the health records of specific individuals.

• Exercising the opt-out option is only possible once the data has been digitized, which does not offer strong protection for private health information.

• deCODE has admitted that it has the technical ability to identify patients—even though the data is encrypted—but would not do so since such an act would be illegal.

• Although it has become common practice for epidemiologists to conduct research with health records, in this case, deCODE, which is responsible for constructing HSD, can choose which data to include based on commercial rather than public health criteria. This could reduce the utility of the database for providing health care services.

In addition, Merz et al. suggest that HSD and GGPR have been conflated and that this may have been an intentional strategy to reduce the number of opt-outs since citizens might think they were withdrawing their records from the health service in general rather than just the genetic database. The authors also argue that earlier attempts to aggregate health records have encountered difficulties when opting-out is biased towards a particular sub-population, for instance, the mentally ill.

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The authors argue that while the genealogical information is public, if an individual chooses to opt out of HSD, they should, by default also be removed from the genealogical source. According to the deCODE website23, genealogical data has been collected for the nearly 750,000 people who have ever lived in Iceland. The critics suggest that the decision to opt out should be applied to the use of all deCODE data, including that which is publicly held and accessible.

Merz et al. have also identified a number of emergent issues. For example, it is not clear whether the government will continue to add data from opt-outs to HSD or will block the transfer of this data to GGPR. Merz et al. also note that a recent amendment to the law allows deCODE to access, without express consent, clinical tissue samples collected and stored at various institutions in order to extract DNA samples. According to the authors, the University of Iceland hospital alone holds nearly half a million samples dating back 70 years (ibid: 6).

Merz et al. reaffirm that their central concern is that health data from HSD has been added to GGPR without securing informed consent. In response, it has been argued that ethicists ask too much of the informed consent mechanism, which can become a “merely ritualized routine” (Hoeyer and Lynoe 2004). The commentators ask Merz and his colleagues what information a consent form should include for it to make a difference to an issue that has been so widely and publicly debated. They also question whether it is appropriate to use informed consent as a general solution to any type of ethical problem.

3. Regulating biobanks The United Nations Educational, Scientific and Cultural Organization recently agreed to an International Declaration on Human Genetic Data (United Nations Educational Scientific and Cultural Organization 2003), which aims to:

…ensure the respect of human dignity and protection of human rights and fundamental freedoms in the collection, processing, use and storage of human genetic data, human proteomic data and of the biological samples from which they are derived… (United Nations Educational Scientific and Cultural Organization 2003, Article 1(a))

and to ensure that:

[a]ny collection, processing, use and storage of human genetic data, human proteomic data and biological samples shall be consistent with the international law of human rights. (United Nations Educational Scientific and Cultural Organization 2003, Article 1(b))

In many countries, collecting genetic information is regulated within existing health and privacy statues. Legislators have found it difficult to keep up with the pace of innovation in this sector and much of the work of regulating the frontiers of genetic research has to-date been left to the courts (Allen 1997). Legislators have found it difficult to develop

23 www.decodegenetics.com

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guidelines that are general enough to cover most eventualities, but specific enough to be limited in their application to collecting genetic information24.

As a result, collecting and storing genetic information in Canada and in other countries is typically regulated through a patchwork of legislation (Edwards 2002). In Canada, this regulation is particularly fragmented, due to the constitutional division of powers between the federal and provincial governments. This division allocates significant legislative power to both bodies, creating potential inconsistencies in the application of regulations from province to province. Excepting forensic DNA analysis, legislation that explicitly protects genetic privacy is lacking in Canada (Burgess, Lewis et al. 2002; Edwards 2002).

Edwards (2002, p. 6) argues that, despite the lack of legislation explicitly protecting genetic privacy, the Canadian Charter of Rights and Freedoms and federal and provincial human rights acts, such as the Canadian Privacy Act25, offer some protection. That said, the author describes this legislation as a “cumbersome” tool for this purpose. The lack of clear legislative direction means that regulatory guidelines relevant to biobanks must, at best, be derived from more general legal principles.

This legislative vacuum has not gone unnoticed. Included among 22 recommendations presented in the Canadian Privacy Commissioner’s 1992 report, Genetic Testing and Privacy, were recommendations to develop and implement specific legislation to protect genetic privacy and to prevent discrimination based on refusal to submit to genetic testing (Edwards 2002, citing the 1999-2000 Annual Report of the Privacy Commissioner, p. 3). The commissioner’s 1999-2000 Annual Report indicates that these recommendations, along with “virtually all” of the others, had “…fallen on deaf ears.… we still have no legal framework for this intrusive technology” (Edwards 2002, citing the 1999-2000 Annual Report of the Privacy Commissioner, p. 3). According to the commissioner, the Privacy Act, which only applies to federal government institutions, was “not up to the job” of protecting informational privacy. Since the commissioner’s 1999-2000 report, genetic technologies have continued to develop. According to Edwards:

The significance of these advances, and their possible implications for genetic privacy, cannot be overestimated. (Edwards 2002, p. 4)

The commissioner’s subsequent Annual Report further noted the need for complete protection of privacy of personal health information (Edwards 2002, P. 11). However, in a report commissioned by Industry Canada, Burgess, Lewis et al. (2002, p. 22) argue for the need for measures to specifically protect genetic privacy, stating that “Health information privacy may not fully cover concerns raised by genetic privacy.”

24 One effort in the US to draft legislation on the basis that genetic information is different from other health-related information collapsed (Murray, T. (1997). Genetic Exceptionalism and "Future Diaries": Is Genetic Information Different from Other Medical Information? Genetic Privacy (op. cit). M. A. Rothstein: 60-73.). Writing specifically about European biobanks, Goddard, Schitdke et al. (2003) noted that most laboratories with DNA banks have no written policies or agreements regarding the use of their collections beyond establishing consent guidelines. 25 According to the federal Department of Justice, “[t]he purpose of this Act is to extend the present laws of Canada that protect the privacy of individuals with respect to personal information about themselves held by a government institution and that provide individuals with a right of access to that information.”

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One relevant piece of legislation in Canada is the Personal Information Protection and Electronic Documents Act (PIPEDA), which covers all personal information:

…including personal health information collected, used or disclosed in the course of commercial activity by a federal work, undertakings or business. (in Edwards 2002)

This legislation, first implemented in January 1, 2001, was adopted in phases, the final phase coming into force on January 1, 2004. Focussing on the federal government’s jurisdiction over key aspects of commercial activity, PIPEDA is now in force throughout Canada, with the exception of the province of Quebec, which exercised the provincial right to implement substantially equivalent legislation26. However, due to (among other things) the constitutional division of power:

…the vast majority of employees in most industries will not be protected unless and until the relevant province passes substantially similar legislation. (Edwards 2002, p. 11)

The Canadian Standards Association Model Code, which includes ten “Principles of Fair Information Practices” recognized by the Organization for Economic Co-operation and Development, was partially incorporated into Canada’s Privacy Act (Burgess, Lewis et al. 2002; Edwards 2002) Governments and the public sector are under statutory obligation to comply with these guidelines; however, the private sector, while encouraged to voluntarily adopt the principles, is under no obligation to do so. Similarly, respect for privacy or confidentiality is among the guiding principles of the Tri-Council Policy Statement Ethical Conduct for Research Involving Humans (Tri-Council Policy Statement 2003: i.4).

Although not carrying the force of law, compliance with the Tri-Council Policy Statement can be enforced through sanctions, including the withdrawal of research funds. While public research institutions such as universities are compelled (in law or through sanctions) to comply with the Tri-Council Policy Statement and the principles of the Model Code; private research institutions are not. This means that biobanks supported with Tri-Council funds or established within institutions receiving Tri-Council support are subjected to at least two levels of guidelines and/or legislation protecting privacy, while private biobanks, unless they fall under the scope of PIPEDA or are based within Québec, are not necessarily subjected to such external scrutiny or controls.

Edwards concludes her paper by highlighting a number of concerns rising from her review of Canadian legislation, including the potential for discrimination in the workplace, or on the part of insurance companies, as well as concerns about whether the “culture of high ethical standards” that reportedly pervades clinical research is sufficient to protect individual privacy.

26 Québec was the only Canadian province to have passed substantially similar legislation at the time of Edwards’ paper (Edwards, J. (2002). Genetic Privacy: Patchwork Protection. Edmonton, Industry Canada Genetic Privacy Project: 23.). Contrast this with the situation in the United States where many states have adopted legislation which explicitly regulates the collection, use and disclosure of health information – including genetic information (Burgess, M. M., P. Lewis, P. Bromley, B. Kneen and V. McCaffrey (2002). Above and Beyond: Industry Innovation Related to Genetic Privacy. Vancouver, Industry Canada: 27.).

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A recent review of cross-national differences in approaches to governing population biobanks (Cardinal and Deschenes 2003), summarized and examined a wide range of issues related to their governance and operation. The authors examined governance in Canada, Estonia, Iceland, Tonga, the United Kingdom and in HAPMAP, an international consortium (Canada, Nigeria, Japan, USA, China, United Kingdom and the SNP Consortium) gathering donor samples from countries in Africa, Asia and the United States. The review examined eight critical issues in detail: • approaches to public consultation, including general considerations, types of

consultation and population level input; • recruitment of participants, including the distribution of risks and benefits,

differences in values among participants and differences in cultural perceptions; • consent, including the dilemmas associated with individual and collective

responsibilities, form of consent, rights of withdrawal; • population support, including specific consideration of group interests; • the normative framework guiding research, including the extent to which ethical

principles are reflected in the legislation; • oversight and surveillance, including mechanisms for ensuring accountability and

mechanisms to regulate access to biobanks; • benefit sharing, including diffusion of research results, distribution of financial

benefits from patents and consideration of in-kind contributions to the research process; and

• privacy, including storage of, and access to genetic information.

Cardinal and Deschenes’ study is summarized in Table 2. Most of the cases described depend on an alliance that centrally involves government agencies in funding and establishing biobanks. The exceptions are Iceland and Tonga (an initiative that ultimately failed). This extensive review suggests that the standard for governance and consent is relatively high.

4. Ethical concerns An ethical review of the issues associated with biobanking is not a simple matter. Sherwin (2001) suggests that both substantive and procedural approaches should be practiced simultaneously in attempting to define the “public interest.” She has suggested that:

…when approaching complex policy matters, we should actively seek out moral perspectives that help to identify and explore as many moral dimensions of the problem as possible. (Sherwin, 2001)

Three components comprise the public interest: the natural rights of individuals; common interests that benefit all members of society; and, collective interests that can only be pursued through collective action. Adjudicating between these components and, in some cases, determining what is a “common” or “collective” interest will often require fair procedures that are in turn justified through reference to substantive values (i.e., natural rights) (Sherwin, 2001).

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In as much as the goal of adjudication is to determine appropriate behaviour, the exercise of determining a common or collective interest is a form of normative ethics27. Yet the contribution of normative ethics to policy depends on describing and justifying the many different moral perspectives that make up the complexity of a particular policy issue.

Biobanks enable research that cannot be wholly anticipated at the time the bank is created28. Any defence of the benefits of biobanks must, therefore, be based in large part on a belief in the value of subsequent research. While there are highly visible and optimistic accounts of the products of the yet-to-be-completed research (Collins, et al., 2003), actual benefits are likely distant in time and difficult to articulate in detail (c.f. Harper 1995; Nelkin and Lindee 1995; Caulfield 2000).

The list of anticipated benefits derived from biobanks generally include: • new knowledge of:

o disease aetiology, and natural history; o genomic contributors to health; o pathogenic and environmental contributors to disease; and o the genomic-organism-environment interaction;

• new treatments in the areas of: o pharmacology; and o genetic therapies;

• new tests to: o reduce harm from pharmacological treatments with genetic risks; o detect pathologies earlier; o personalize risk assessment and preventive strategies; and o support population-based risk assessment and preventive strategies;

• new preventive strategies to: o personalize risk assessments and dietary/environmental advice; o identify high risk populations most likely to benefit from closer follow-up; o develop medications or other treatments to supplement missing genetic functions

associated with increased risk; and o and stronger arguments for environmental policies.

It should be noted that biobanks do not constitute the research that might produce these benefits; banks are an intermediate step in a process that produces a collection of data and materials that facilitate further research29.

27 Normative ethics is distinct from descriptive ethics (accounts of how ethical issues are managed) and theoretical ethics (justifications of moral positions) (McDonald, 2000). 28 Biobanks and their purposes have previously been defined as a “facility that stores DNA for future analysis” for the purpose of providing “for the future requirements of families affected by serious single gene disorders and who require DNA analysis for the purpose of: (1) confirmation of diagnosis at the molecular level; (2) presymptomatic diagnosis; and (3) carrier detection” (Godard, B., J. Schmidtke, J.-J. Cassiman and S. Aymé (2003). "Data storage and DNA banking for biomedical research: informed consent, confidentiality, quality issues, ownership, return of benefits. A professional perspective." European Journal of Human Genetics 11(Supplement 2 (December)): S8-S122.). More recently, a DNA bank has been defined as “a facility that stores extracted DNA, transformed cell lines, frozen blood or other tissue, or biological materials, for future DNA analysis,” while a DNA database is “a repository of genetic information obtained from the analysis of DNA, sometimes referred to as ‘DNA profiles’.” 29 Under the Tri-Council Policy Statement it is unclear whether biobanking is itself a research activity: “First, the undertaking must involve “research,” which involves a systematic investigation to establish facts, principles or

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There are a number of mechanisms described as able to evaluate whether the “good” that might come from biobanks (and other databank-based research tools) is a “common good,” and whether it can overcome objections based on social risks and lost opportunities. The primary mechanisms are: • reviews by independent ethics committees; • collective and/or individual informed consent; • public funding decisions; and • privacy protection legislation.

However, underlying many of the debates about common good (or public interest) is a lack of trust in the ability of social institutions to fairly determine and assess common and collective interests to, in essence, act as moral “gatekeepers.” Many members of the public are suspect of the familiar rhetoric which claims that all members of society will benefit from this technology while neglecting to mention that some individuals, or companies, will benefit disproportionately. This lack of trust in the fairness of relevant social institutions often inhibits separating dependable descriptions of the effects of biotechnology on institutions and society from the technology itself. For instance, it is hard to make sense of the strong reaction against transgenic crops in the United Kingdom without considering what effect the British government’s handling of the occurrence of bovine spongiform encephalopathy in cattle destined for human consumption had on public trust in government institutions in that country.

Primary critiques of biobanks typically focus on social risks and lost opportunity costs that cannot be assessed or managed through individual informed consent or privacy protection. In the case of social risk, concerns about such things as genetic discrimination (e.g., denial of health insurance or employment) are tied to the fact that inherited disease risks identified through biobanks—regardless of whether the banks are identified, identifiable, anonymized or anonymous—may be associated with families or founder mutations. Concerns about lost opportunity costs typically focus on a perceived overemphasis on the genetic components of health and disease to the detriment of other factors (e.g., environmental) and approaches30.

To paraphrase distinctions described by Thompson (2000), moral concerns related to biobanking can be understood as objections to the formation of biobanks per se, concerns about the risks of the use of biobanks to donors, society, and social institutions, and concerns about the social institutions that will develop, use, and manage biobanks31.

generalizable knowledge.” (Tri-Council Policy Statement, 2003, Article 1.1a) (emphasis added). The inclusion of an article specific to biobanking suggests the rejection of this simple exclusion. 30 Lippman provided early conceptualization of “geneticization” that remains a core definition in current literature (1989, 1991). Excellent subsequent accounts of the problems and even exaggerations of the benefits of genetic and genomic research include Caulfield (2000), Nelkin & Lindee (1995), and Harper (1995). 31 Another schema would be whether genetic testing or biobanking and research is: inherently wrong; neutral but not good enough to displace more important goods; offends individual rights in its use, or has unjust consequences within current social institutions (Burgess, M. (2001a). "Wither morality in genetic tests?" University of Alberta Health Law Review 9(3): 3-9.).

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Research ethics32

According to McDonald, the evolution of the ethics of research involving humans has been driven by a history of tragic examples. These examples have led to considerable, although by no means complete, consensus (Pence 1990; Rothman 1991: 13; McDonald 2000). For example, while the ethical review of research differs in Canada from that found in the United States (e.g., Canadian policy is not legislated) (McDonald and Meslin 2003), in these and many other western countries, ethical review is based primarily on principles articulated in such documents as the 1947 Nuremberg Code, the 1979 Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, and subsequent documents (see Brody 1998).

In Canada, the Tri-Council will “consider funding (or continued funding) only to individuals and institutions which certify compliance with” the Tri-Council Policy Statement, Ethical Conduct for Research Involving Humans (Tri-Council Policy Statement 2003). Moreover, Tri-Council funding is provided to a researcher on the condition that all applicable research at the researcher’s institution is conducted in compliance with the Tri-Councils policy (McDonald 2000, p. 80). Hence any biobank established at any research institution which receives any funding from the Canadian federal research councils represented by the Tri-Council must be in accord with the policy. Similarly, since the 1998 adoption of the Tri-Council’s Policy Statement, research institutions have made compliance with the policy a condition of employment for its researchers (McDonald 2000, p. 81).

Assessing the risks and benefits of biobanking The first requirement of research ethics is utilitarian: the anticipated benefits of specific research must be equal to, or greater than the risks associated with the research (McDonald 2000, p. 33). In fact, this requirement to balance harms and benefits is one of the guiding principles behind the Tri-Council Policy Statement (Tri-Council Policy Statement 2003: 3).

That said, this requirement is far from a simple calculation. At the most fundamental level, characterizing what is a “benefit” or a “harm,” and the relative weight assigned to each of these, can be highly subjective (Burgess, Lewis et al. 2002, p. 19). Moreover, the benefits of research may be very broad in scope—including social, economic, personal, and educational goods (McDonald 2000, pp. 33-36)—and may touch on a complexity of values. Consequently:

[a]ll too often relevant parties – sponsors, research competition adjudicators or REBs – fail to address the overall value question in ways

32 For a detailed account of the practical and regulatory aspects of how research ethics in Canada is governed, see McDonald, 2000. Although reviews of research review systems found similar problems in the US, Australia and Quebec, McDonald’s report challenges whether ethics committee review is an appropriate “system.” (Office of the Inspector General (1998). Review Boards: Their Role in Continuing Review. Boston, Department of Health and Human Services (US). Review of the Role and Functioning of Institutional Ethics Committees IECS (1996). Report of the Review of the Role and Functioning of Institutional Ethics Committees. Canberra, Government of Australia. Parizeau, M.-H. (1998). Rapport d’enquete concernant des committes de la recherche au Quebec, Quebec : Ministere de la Sante et des Services Sociauz.).

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that are credible and transparent to the many stakeholders in research. (McDonald 2000, p. 36)

Building on an earlier recognition of special considerations related to genetic research (cf Glass, Weijer et al. 1996; Glass KC, Weijer C et al. 1997), the Tri-Council Policy Statement dedicates a section to banking genetic materials. The preamble identifies the ethical concerns that must be addressed by anyone proposing a biobank:

Though the banking of genetic material is expected to yield benefits, it may also pose potential harms to individuals, their families and the groups to which they may belong. Accordingly, researchers who propose research involving the banking of genetic material have a duty to satisfy the REB and prospective research subjects that they have addressed the associated ethical issues, including confidentiality, privacy, storage, use of the data and results, withdrawal by the subject, and future contact of subjects, families and groups. (Tri-Council Policy Statement, F. Banking of Genetic Material, Article 8.6)

The focus here is on establishing a factual account of risks and controls that can support individual informed consent to the biobank and the research’s “expected” benefits. That said, the Tri-Council’s Banking of Genetic Material stipulates that it “should be read particularly in the context of other Sections of this Policy” (Tri-Council Policy Statement, 2003), making it consistent with the model of the Tri-Council’s “proportionate approach to ethics assessment”:

The concept of proportionate review gives practical expression to the general principle that, especially in the context of limited resources, the more potentially invasive or harmful is the proposed and ongoing research, the greater should be the care in its review. While all research must be reviewed adequately, proportionate review is intended to reserve most intensive scrutiny, and correspondingly more protection, for the most ethically challenging research. (Tri-Council Policy Statement, 2003, Section D.1; Article 1.6)

The text explains that this approach:

…starts with an assessment, primarily from the viewpoint of the potential subjects, of the character, magnitude and probability of potential harms inherent in the research. (Tri-Council Policy Statement, 2003, Section D.1; Article 1.6)

There is considerable critique of the Canadian (and United States) ethical review system(s), including inadequate resources for such review (cf. McDonald, 2000). In that context, “proportionate review” is clearly an attempt to garner and focus the most attention and resources on the most harmful research, permitting expedited review for research with only “minimal risk.”

The standard of minimal risk is commonly defined as follows: if potential subjects can reasonably be expected to regard the probability and magnitude of possible harms implied by participation in the research to be no greater than those encountered by the subject in those aspects of his or

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her everyday life that relate to the research then the research can be regarded as within the range of minimal risk. (Tri-Council Policy Statement, 2003, Section C1)

This definition of minimal risk focuses exclusively on harms to individuals posed by clinical research; there is no recognition that it is conceptually feasible that social harms (i.e., discrimination and risks born by groups rather than individuals) could exceed minimal risk. Since social risks distributed across populations are difficult to assess, most ethical reviews are limited to describing the risks in informed consent forms, encouraging honest communication with the group (Article 8.1), and making specific reference to the conditions to be considered for research involving aboriginal populations (Section 6)33.

Nor is there recognition of the weakness of primarily considering the ethical treatment of research subjects at the ethical review stage. McDonald is critical of this limited focus, writing that:

…for most researchers, REB members and in [sic] research administrators, [the ethical review stage] is the sum and substance of the ethics process. (McDonald 2000, p. 59)

In the United States, federal funding agencies conduct audits and enforce compliance with ethical requirements, with the result that, rather than being limited to a one-time review in advance of the main research effort, the ethical treatment of research subjects is an ongoing process. It should also be noted that while the United States is now moving to accrediting “systems of protection” at federally funded research institutions, including Institutional Review Boards (IRBs), Data Safety Monitoring Boards (DSMBs), and other parts of human research protection, Canada has established no system of accreditation for federally funded Canadian institutions. That said, neither the United States nor Canada has adequate protection for private sector research endeavours (McDonald and Meslin 2003).

The fact that the Tri-Council and other Canadian research sponsors “do not use such measures” (McDonald 2000, p. 64) is particularly relevant in any discussion of the ethical review of biobanks. Biobanks are specifically designed to persist and provide information for many years; without a means of testing for and enforcing ongoing compliance with ethical requirements, ethical standards may decline with time and the potential for harms may increase.

In practice, the primary assessment of benefits focus on whether research proposals have scientific validity, or are able to justify the conclusions based on the proposed methods. For example, the Tri-Council states that:

[t]he REB shall satisfy itself that the design of a research project that poses more than minimal risk is capable of addressing the questions being

33 This limitation of concern for collective well-being to aboriginal peoples was a deliberate decision on the part of Tri-

Council which rejected the recommendation of the Tri-Council Working Group on Ethics to make concern for collectivities, particularly vulnerable groups, part of ethical review (unpublished manuscript: McDonald, M., Cross-Cultural Issues in Canadian Policies for Ethical Research Notes for the CIHR Workshop on a Tribal Controlled DNA Bank. 2001: Vancouver, BC.)

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asked in the research. (Tri-Council Policy Statement, C2. Scholarly Review as Part of Ethics Review. Article 1.5)

This is later clarified by the statement, “The primary tests to be used by REBs should be ethical probity and high scientific and scholarly standards.”

Because biobanks are intended from the outset to allow research that cannot be wholly anticipated at the time the bank is created, evaluating the benefits of a proposed bank focuses on whether the bank will enable ethical and scientifically valid research. However, once the potential usefulness of the biobank for future research is established, there is rarely further ethical review of the merit or importance of the bank or its effect on other research (i.e., lost opportunity costs). As McDonald has noted, the current system of ethical review is based on front-end review with an almost complete lack of monitoring of on-going research and no provision for the retrospective assessment of whether the benefits of completed projects outweighed the net social costs of such projects.

Moreover, there is often an explicit assumption that peer review or competitive funding will help establish both scientific validity and merit34. This is especially problematic for research that is approved on a programmatic as opposed to a project basis, for the peer review committee will not be able to consider the costs and benefits of specific parts of the research program. [See Funding Sources below for a discussion of the role of funding decisions in assessing merit].

It is difficult for ethical review boards to challenge the merit or worth of research without stimulating disciplinary battles or charges of failing to recognize the incremental and uncertain nature of knowledge development. McDonald has criticized the evaluation of the benefits of research in ethics review by “sponsors, peer review adjudicators or REBs” as based on an ideology of the “free market” of research that is both generally supportive of the expected benefits of research and lacking in concrete assessments with sufficient breadth of stakeholders (McDonald, 2000)35.

It is also a system that is expert driven and controlled by the very parties whose conduct should be regulated – researchers, research institutions, and research sponsors – with little or no participation in governance on the part of research subjects. Moreover, McDonald has emphasized that the failure to establish routine retrospective assessment of completed research allows no means of learning from past successes and failures or, even more importantly, assessing the quality of ethical review.

Harm reduction or risk minimization A significant component of the ethical review of research is an evaluation of whether there is a way to answer the research question with less risk than the proposed method. In some cases research-related risks, pain or inconvenience can be reduced by alternative procedures (i.e., drawing blood from children as part of clinical tests rather than on a separate occasion).

34 Projects not submitted for competitive research funding are sometimes sent for peer review as part of ethical review. 35 We are grateful to an independent reviewer for pointing out that it is often very difficult to identify “expected benefits” in advance in scientific research and that it may even be counter-productive to hold researchers to this standard.

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In the area of biobanking, likely harm reduction strategies raise a number of issues. For example, the design of a biobank might be challenged for gathering information not relevant to answering anticipated research questions, or for not having an amount of software design “noise” sufficient to prevent identifying individuals. In addition, the continued usefulness of a biobank often depends on the successive addition of information linked to the data and the stored samples. Consequently, it is always reasonable to ask researchers and management whether the bank is designed for the optimal protection of privacy balanced against its utility for research, or whether the provisions could reasonably be required to be stronger, recognizing that protecting privacy might ultimately undermine the bank’s future usefulness.

The Tri-Council’s Ethical Conduct for Research Involving Humans specifically identifies individuals, their families, and biological relatives as bearing risks related to genetic research. The list of risks includes privacy, confidentiality, loss of benefits and “other harms.” (Tri-Council Policy Statement, 2003, Section 8). Basically, the Tri-Council requires that no third party have access to information on the risk or diagnosis of an individual without the individual’s informed consent36.

Due to the complexities of explaining the genetic contributions to risk and disease, as well as the familial implications and possible duty to warn other family members, the Tri-Council recommends genetic counselling be provided where appropriate, echoing a long list of similar recommendations (Tri-Council Policy Statement, 2003, page 8.4; NIH-DOE Working Group on the Ethical Legal and Social Implications of Human Genome Research, 1993; American Society of Human Genetics Social Issues Committee, 1998; Burgess, Knoppers et al., 1998). This means that while it is consistent with standards and practices of informed consent to suggest harm reduction in how research is conducted, or how a biobank is constructed, most of the current focus is on accurately describing risk and supporting individuals to understand the risk prior to providing informed consent.

Informed consent Biobanks rely on research for the prospective collection of material. Consequently, in most cases biobanking requires research subjects to voluntary give informed consent to the collection and use of their material (Tri-Council Policy Statement 2003Section 10, p. 10.1 and Section 10.2).

Free and informed consent is a guiding principle of the Ethical Conduct for Research Involving Humans. Described as being “…at the heart of ethical research involving human subjects” (Tri-Council Policy Statement 2003Article 2.1), informed consent—along with Research Ethics Boards37—is intended to act as a barrier that protects research subjects from abuse (McDonald 2000, p. 38)38. Under the notion of informed consent that has developed in Canada even competent and un-influenced research participants cannot

36 Informed consent to biobanking by an individual cannot authorize the accumulation of research related to family members (cf. Burgess and Brunger, 2000, Weijer 1999; Weijer et al, 1999). 37 In providing ethical oversight, REBs “ensure an acceptable balance between risks and benefits” (Godard et al., 2003d, p. S93). 38 Informed consent is explicitly described in Articles 8 through 12 of the UNESCO Declaration (United Nations Educational Scientific and Cultural Organization (2003). International Declaration of Human Genetic Data. Paris, United Nations Educational, Scientific and Cultural Organization,: 11.).

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authorize a particular use of data or material if it is not described to them39 (Etchells E, Sharpe G et al. 1996 cf ; Burgess, Claude M. Laberge et al. 1998)40.

The value of free and informed consent has also been recognized by the Public and Professional Policy Committee of the European Society of Human Genetics (PPPC), which insists on the need for informed consent as well as oversight by an ethical review committee in the case of biobanks (European Society of Human Genetics, 2003a; Godard et al., 2003d). Research participants must voluntarily authorize participation based on an informed understanding of the risks and benefits of the research, including options to participating41.

Presuming the review of the research determines that the research is reasonable to offer to individuals for consent, and that the consent forms and disclosures are likely to provide sufficient support for a reasoned and voluntary decision by the participants, informed consent from individuals is acceptable moral authorization because it depends on the moral authority of an individual’s right to determine what personal risks are justified. While the determination might be uncertain to the individual or irrational to observers, the strong notion of individual autonomy permits the individual to authorize or refuse participation.

Recommended elements to be disclosed to potential study subjects include not only the risks and benefits of the research, as well as the limitations and outcomes, they also cover how results will be communicated and how confidentiality will be protected (Godard, Schmidtke et al. 2003). According to the PPPC, consent must be freely given, provided in writing, and based on information regarding the use of the samples, including access to and sharing of the samples, and the timeline for storage of the samples (European Society of Human Genetics, 2003a; see also Godard and Schmidtke et al 2003)42.

Due, at least in part, to bureaucratic structures and the current scarcity of resources needed to conduct ethical review, informed consent is now the primary focus of what has become a superficial review of ethical issues in research (Burgess and Brunger 2000, p. 145). McDonald has suggested that an analysis of what actually takes place in an ethics

39 While informed consent is becoming the norm even for anonymous biobanks, there are still strong power relationships at play. For example, the patient-doctor relationship could create a sense of obligation on the part of a potential subject to participate (Rothstein, M. (2002). "The Role of IRBs in Research Involving Commercial Biobanks." Journal of Law, Medicine and Ethics 30: 105-8., or not participate (see above—Iceland’s biobank—Abbott, A. (2000). "Iceland's doctors rebuffed in health data row." Nature 24 August: 819.). 40 Key legal precedents include Reibl v. Hughes; II(R) v. Hunter, 1966; Arndt v. Smith, 1997. 41 There is a very large literature related to informed consent in general, and its relevance in genetic practice and research. Probably the most comprehensive historical and theoretical account of informed consent is Faden and Beauchamp (Faden and Beauchamp (199_). A History and Theory of Informed Consent.). Empirical accounts critiquing the practicality and scope of informed consent began in the mid-1980s Burgess, M. (1986). An empirically grounded approach to ethical analysis and social change. Discourse and Institutional Authority: Medicine, Education, and Law. S. Fisher and A. Todd. Ablex, Norwood, New Jersey: 49-77. with a growing literature of recent accounts specific to genetic testing (cf., Burgess, M. and L. d'Agincourt-Canning (2002). "Genetic Testing for Hereditary Disease: Attending to Relational Responsibility." Journal of Clinical Ethics 12(4): 361-372.; Rapp, R. (1988). "Chromosomes and Communication: the discourse of genetic counselling." Medical Anthropology Quarterly 2: 143-157.). 42 An important reference is Buchanan A. An Ethical Framework for Biological Samples Policy. In: NBAC, ed. Research Involving Human Biological Materials: Ethical Issues and Policy Guidance. Vol. 2. Washington DC: National Bioethics Advisory Commission, 1998. His recommendations on ethics were adopted by NBAC in volume 1.

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review reveals an “ethical tunnel vision” in which approval is “functionally an approval of consent forms.” Consequently:

… the REB approval process and informed consent bear far more moral weight than they can possible sustain. (McDonald, 2000)

This burden has resulted in a process effectively comprised of tangible items such as consent forms, which Godard, Schmidtke et al. (2003) critique as insufficient to fulfill ethical requirements, and adverse incident reports (McDonald 2000, p. 299). This risks reducing harms “to simple measures of pain, morbidity and mortality” with the result that a range of other impacts related to a patient’s sense of control, privacy, relationship with expertise and sense of autonomy are neglected (McDonald 2000, p. 299) and the potential effects on affected collectives are not evaluated (Burgess and Brunger 2000, p. 145). As much as the historical connection between current genetics and earlier eugenics43 is distinguished on the basis of reproductive choice and informed consent (Kerr and Cunningham-Burley 2000), the emphasis on consent is challenged as inadequate (Burgess 2000): the practical application of free and informed consent to the research environment remains problematic.

Some commentators have even suggested that the expectation of personal benefit—even in the face of explicit warnings that no personal benefits were likely—is a strong motivator for all forms of research participation, and these expectations must be addressed in the process of counselling research participants (Kass, Sugarman et al. 1996). Kass et al. attribute such presumptively irrational behaviour (believing there will be benefits when warned none are likely to be forthcoming) on the trust that research subjects place in researchers and research institutions. This casts some doubt on the standard view that research subjects are generally able to calculate and adequately protect their own best interests.

Informed consent is often taken as general consent for research applications well beyond those envisaged when the research subject signed the form (Kerr 2003). Insofar as informed consent can be reduced to a simple signature on a consent form, monitoring consent becomes rather simple. However, according to McDonald (2000) consent “…is a process of willing and knowing participation over time” that should be considered an extended process within the period of research participation. The general reliance on consent forms and the lack of follow-up to ensure compliance can lead to the conclusion that the ethics review process is primarily intended to protect research institutions, researchers and sponsors and not the research subject. This apparent emphasis on accountability for, rather than to subjects (McDonald, (2000, pp. 304-305) is particularly concerning in the case of biobanks, due to the sensitivity of the information they hold and the potentially lengthy time that they might hold it.

This time component is, in fact, a crucial part of any discussion concerning informed consent and biobanks. Since the objective of biobanks is to establish a database for future research questions that are either unanticipated or questions that cannot be framed in any

43 Goddard, Kääriäinen et al. (2003a, p. S15) notes that genetics in the first half of the twentieth century was focussed on eugenics.

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detail without first conducting research based on the data held in the biobank (Godard, Schmidtke et al., 2003), consent to participate in research conducted with data from a biobank cannot be simply “informed.” This is further complicated by the fact that the social risks of particular research results and any potential duty to disclose to family and blood relatives cannot be described (cf. (Knoppers and Laberge 1989; Knoppers and Laberge 1995); Tri-Council Policy Statement, 2003: pp. 8.3-8.7).

Typically, there are two responses to this problem: “re-consenting” and “blanket consent.”

• Re-consenting explicitly rejects the presumption that it is possible to authorize future research, stating that informed consent is only valid if participants understand the specific nature, risks and benefits of particular research. This necessitates each research project using biobanks to seek and receive newly informed consent specific to each project.

A compromise is sometimes struck where consent to be included in the biobank is sufficient for the use of data or materials in any research where identifying characteristics can be separated from the data through aggregation or other processes. In this case only identifiable or additional participant contacts require additional consent.

• Blanket consent suggests that the challenge presented by future research to informed consent can be described to research participants who can then decide whether or not to authorize that research. Variations include options to authorize only certain kinds of research—such as research on a familial disease—or only under certain conditions (Tri-Council Policy Statement 2003 p8.7)—such as when data is anonymous44 (Rothstein, 2002). This permits people who require more specific information before giving consent to decline participation, while enabling others to authorize future research. Adopting blanket consent addresses the concern of some research groups that re-consent could “bring to a halt all research on existing, archived material” (Godard, Schmitkde et al., 2003). One persistent ethical issue with this approach is the presumption that future research will not be objectionable to those who provide blanket consent45. However, possibly more pressing a challenge is the fact that there is good reason to think that blanket consent is not consistent with accepted ethical guidelines in Canada. Moreover, research where the benefits cannot be sufficiently described to a participant to justify its authorization creates real challenges for the process of securing consent (Greely 1999; Caulfield, Upshur et al. 2003).

Buchanan (1998) points out a possible third response in his discussion of dignatory harms, which is to inform people that their tissues will be used in research subject to certain constraints. This is “informing without consent.”

44 The American Society for Human Genetics has stated explicitly that blanket consent is inappropriate if samples are identifiable (Godard, Scmitkde et al., 2003, citing ASHG, 1988). 45 “Evidence-based ethics” would be an appropriate activity here, in which data about the actual acceptability of subsequent research could be collected and serve as a basis to evaluate the standard of blanket or open-ended consent. (cf, McDonald, 2001) Additionally, individual consent might reasonably be supplemented with widespread dissemination of subsequent research based on the biobank, whether directly to participants, a wider public, or both.

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Even using anonymized or exclusively aggregated data and materials can create problems. Not only is there debate over whether research using aggregate data that does not identify individuals can be conducted without informed consent specific to the research, but participants in biobanks often want to be contacted if research reveals even potentially relevant information about them. And although many genetic tests46 lack definitive clinical relevance, which may be a good reason for refusing to fund access (Caulfield, Burgess et al. 2001), when data exists as a result of research there is probably a fair presumption in favour of disclosure with careful explanation (Burgess and Hayden 1996). According to Edwards (2002:16), in the case of aggregate, anonymous data, “…many data protection statutes…” permit its collection, use, and disclosure. Burgess, Lewis et al. (2002, p. 7) recommend as an industry standard that, among other things, “Genetic information that is not linked to identifying information and is derived from repositories of previously gathered materials may, under some circumstances, be used without consent…,” subject to REB approval.

A fourth possible form of consent, described by Burgess, Lewis et al. (2002, pp. 12-13), is “dynamic informed consent.” Appearing to be a form of re-consent, dynamic informed consent allows study participants to be included or excluded in research as they feel appropriate in response to updated information on the goals, risks, and benefits of ongoing studies, follow-up research, or wholly new research projects.

First Genetic Trust47, an American company that provides a web-based infrastructure for dynamic informed consent, explains on its website that blanket consent:

…for unspecified future use of biological samples and data generated from clinical trials, is no longer adequate for genetic research… Research subjects cannot provide truly informed consent for unspecified future research that he/she does not and will not know about. (Burgess, Lewis et al. 2002, p. 12)

However, according to the PPPC:

As it is difficult to foresee all the potential research applications that a collection may be used for, individuals may be asked to consent for a broader use. In that case, there is no need to recontact individuals although the subjects should be able to communicate should they wish to withdraw. (European Society of Human Genetics, 2003a, recommendation 8; see also Godard, Schmidtke et al., 2003)

46 While there may be a duty to inform patients of information that might make a difference to their health or direct their clinical care, it is often misleading to think that such strong inferences can be drawn from research: the relevance of research conclusions to the clinical status of patients is often ambiguous. Initial research may be looking for a basis to direct more thorough data collection and focused analysis, and the results are preliminary and insufficient to direct clinical care. 47 Burgess and Lewis et al. indicate that they were unable to confirm companies that use dynamic informed consent, nor, presumably, the mechanisms by which it is applied. Nonetheless, such an approach “…could enable continued use of well-characterized patient samples as new technologies and hypotheses are developed,” making its application particularly well-suited to biobanks. (Burgess, M. M., P. Lewis, P. Bromley, B. Kneen and V. McCaffrey (2002). Above and Beyond: Industry Innovation Related to Genetic Privacy. Vancouver, Industry Canada: 27.).

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The committee also allows for the use of pre-existing collections of anonymous and anonymized samples (recommendations 9 and 11; Godard, Schmidtke et al., 2003), but recommends recontact of subjects when feasible, or review by an ethics oversight committee.

It should be noted that informed consent generally does not require that the reason someone refuses to participate in certain research be disclosed, or rational according to some standard. Since there is no obligation for someone to participate in any particular research project, refusing to participate is usually accepted unconditionally and efforts to clarify reasons are sometimes considered a form of harassment48. Foregoing the requirement to seek specific informed consent to genetic research precludes individuals’ ability to refuse to have their data or materials used in genetic research.

Finally, it should be pointed out that much of the literature on informed consent and biobanking focuses on protecting privacy through safeguarding access to identifying information. But as indicated above in regard to the Tri-Council provisions for using human tissues in research, there are ethical sensitivities around tissue that are non-informational. For example, for some people, certain tissues have symbolic meaning and are regarded as sacred, some even requiring ritual and special storage. Indeed one of the objections to retaining the Nuu-chah-nulth samples has been the violation of cultural norms for the disposal of tissue.

The secondary use of data and biological material Data collected for a particular project, or biological materials stored for research or other purposes—for example by pathology laboratories or tumour banks that routinely collect biological samples—are sometimes used for additional research49 without requiring either re-consent or the blanket consent of the persons who are the source of the information or materials. This may be permissible for two reasons: • the sample is useful without the patient’s identity being known; or • the separation of the data from identifiers is accomplished by people with legitimate

access to the full record in the discharge of their responsibilities to patients and the health care system.

However, Buchanan (1998) adds a very important qualification to this, namely that people should at least be informed that their de-linked or anonymized tissues are going to be used in research.

A strong case can be made that current practices concerning biological samples often fail to treat people with due respect because they systematically mislead regarding why samples are being taken and their uses…. The main point to be appreciated here, however, is that we should not simply assume that informed consent is the only means for protecting

48 There are stronger arguments for the obligation to participate in some research, or research where an individual’s unique circumstances make their contribution necessary and possibly sufficient to provide considerable benefit. This is beyond the scope of the current discussion, and seems to require justifying the special status of health research over other ways to fulfill duties of beneficence. 49 Edwards (Edwards, J. (2002). Genetic Privacy: Patchwork Protection. Edmonton, Industry Canada Genetic Privacy Project: 23.) refers to “function creep,” in which the data is used for secondary purposes other than those for which the original consent was obtained.

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individuals against the dignatory harm of being deceived or mislead. The alternative of disclosure ought to be considered. (Buchanan, 1998)

For example, in epidemiological research, information about a group who has a particular disease is interesting due to the group’s service utilization patterns or its association with a particular risk factor. If appropriately stored, this information could be accessed without identifying the individuals who are the source of the information (or tissue). (Health care records are accessed regularly for reasonable non-patient benefit purposes, such as for billing purposes and quality control audits of health records.)

In some cases, authorization for storage in the first place is based on benefit to others. This could occur under conditions of informed consent to a specific research project, through the legally mandated retention of tissues during an autopsy, or through donation of tissues or a cadaver for medical research or education. Human tissue gift acts are legal doctrines created to provide a category for biological materials to be responsibly managed without assigning the legal status of “property” to tissue or fluids. Basically, the doctrine permits people to donate tissues, blood, organs or their cadavers for scientific research or transplantation. If tissues and fluids were property, then it would be a simple matter to designate proprietary rights, but that would permit undesired activities such as the sale of human biological materials50.

Similarly, legal doctrines intended to permit pathologists to take and retain tissues and fluids during autopsy and to retain them in pathology departments help establish entitlements and responsibilities regarding how these should be managed. The discretion permitted by those entrusted with the gifted tissues and fluids is similar to that of ownership, but limited by what is considered socially appropriate (See European Society of Human Genetics 2003; Godard, Schmidtke et al. 2003, especially pages S97-S98 and S102). The result is that many researchers and pathology departments have collections of biological materials and some data that they have been able to use for some forms of basic research. It is the customs and practices that have become common around these “banks” that are the starting point for many researchers and institutions when they consider the possibility of genetic research on secondary banks, or consider establishing a biobank through the prospective collection of materials and data.

It is difficult to maintain the argument when making secondary use of data or materials that the duty to inform about research results that are possibly relevant to participants can be ignored. That said, variables such as the size of the collections used, the fact that many of the individuals will be deceased, and the expense of re-consenting, could make further research expensive and difficult, and in some cases impossible. Maintaining such a requirement would encourage researchers to prefer anonymized data and material for secondary genetic research: if the data and materials are truly unlinked and cannot be reconnected to identifying data, then the duty to disclose is suspended and no duty to re-consent prior to research is implied. It may, in fact, be that there has been a trend to encourage unlinked or anonymous testing for secondary research because it simplifies the ethics and reduces the costs (see Godard, Schmidtke et al., 2003).

50 There are provisions in the Tri-Council Policy Statement and various provincial human tissue gift acts in Canada that permit tissues to be used for research without consent if the tissues are unlinkable to the donors, or with informed consent if donors can be identified (Tri-Council Policy Statement, 2003, Article 10.3).

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The nature of genomic or genetic research might make a difference to the permissibility of the secondary use of data. For example, genetic testing may be considered to be a more sensitive type of research than the routine (and accepted) use of health records or banked tissue for epidemiologic studies (Edwards 2002). Individuals may have a general, if perhaps indescribable discomfort, about the use of sensitive information. If this is the case, permission for secondary genetic use cannot be presumed or authorized under initial conditions because some persons may object to genetic testing of their materials on the grounds that they believe this type of testing is in some way different from other kinds of research. That said, Canada’s Privacy Commissioner has interpreted the federal Privacy Act as protecting genetic information, but not the actual genetic material (Edwards 2002, p. 17), such that materials collected for one purpose may lack protection against additional testing or research.

The Tri-Council Policy Statement notes that the secondary use of data;

…becomes of concern only when data can be linked to individuals, and becomes critical when the possibility exists that individuals can be identified in the published reports… Individuals should be protected from harm caused by unauthorized use of personal information in which they believed they had an expectation of privacy and the benefit of confidentiality. (Tri-Council Policy Statement 2003)

There are at least two reasons why the secondary use of data and materials for genetic or genomic research might be considered more sensitive than in the case of other types of epidemiologic research. Both reasons centre on genetically related “others”: • genetic information about inherited characteristics (as opposed to genome changes

associated with, for example, cancer pathology) is relevant to genetically related family members (Tri-Council Policy Statement 2003); and

• some genotypes are associated with founder mutations that have significance for whole groups or communities.

These reasons may combine with a sense of genetic tests being more “intimate,” thereby requiring the permission of all affected parties and/or those with concerns about stigmatization or discrimination that may result from characterization as a member of an at-risk family or community. Some researchers suggest that non-Mendelian genetics with their complex relation to traits likely will not be a basis for discrimination since they do not run strongly in family groups; other commentators think that social attitudes and institutions are not sufficiently fine-grained to distinguish between Mendelian and non-Mendelian characteristics.

The collective acceptability of research That the nature of the effects of genetic testing challenges the moral adequacy of individual informed consent for genetic research (Foster, Berensten et al. 1998; O'Neill 1998; Fox 1999; Weijer, Goldsand et al. 1999; Burgess and Brunger 2000) is perhaps no more clearly seen than in the case of the collective acceptability of research. Since the risks and benefits presented by genetic research and biobanks accrue to non-participants—i.e., information about a participant may be relevant to the risks and

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benefits of non-participants, including descendants—individual consent should not by itself authorize the acceptability of risks and benefits.

The ethical assessment of research begins by considering whether the benefits of research have been maximized, and the risks minimized and whether net benefits outweigh net risks. The next primary limit to the research is whether participants authorize their participation through informed consent. However, if the harms or risks those refusing to participate seek to avoid are social responses to genetic characterizations, then simple individual refusal may not be an effective deterrent if other family or community members consent to research. Whenever a health risk is associated with a visible or identifying characteristic, then the stigma does not require that an individual be tested to be subjected to harm. As many Ashkenazi woman can attest, stigma still attaches to them after being tested and found not to have the BRCA 1 or 2 mutations associated with breast cancer risk from the related founder mutations, because they are still members of a high-risk community. This stigmatization may be most likely where strong racial stereotype already exists or where socio-economic marginalization occurs along racial or ethnic lines.

Biobanks also create the possibility of the potential for stigmatization by disease category or genetic susceptibility. In this case, a new form of predictive genetic testing can create a new social group that may be subject to discrimination because of suspect genes or related conditions.

Creating a biobank enables the characterization of numerous genomically-related risk factors that are potentially stigmatizing of people identifiable by their ethnic community membership or familial relations to other affected people. Consequently, while informed consent may be necessary for biobanking and genetic testing, it is not sufficiently protective of families and communities (Tri-Council Policy Statement, 2003). Even more challenging are the issues raised by community consent (Cardinal and Deschenes 2003; Kerr 2003; Weijer and Miller 2004). For instance, if research with individuals from a sub-population reveals that they have a significantly higher risk for a genetic disorder for which there is no treatment, it will be hard to avoid violating the “right not to know.” This complex area of research ethics is sometimes characterized in terms of the notion of “collective consent”51 (Weijer 1999; Weijer, Goldsand et al. 1999).

The fact that the risks and benefits of biobanking are borne collectively suggests that the individual can be replaced by the entire group: with sufficient information, the group (e.g., a family, an ethnic community or a disease-based collective) likely to be affected could come to a decision about whether to participate52. Where consensus is not possible, the local political and social structure of the group could be depended on for the ultimate decision. This approach has been suggested by discussions and through the establishment

51 In collective consent, consent by the community’s leadership is both sufficient and necessary for the research to proceed. Collective acceptability involves meaningful discussions between researchers and members and leaders of the community, and relies on the participation of the broader community (Burgess, M. M. and F. Brunger (2000). Negotiating Collective Acceptability of Health Research. The Governance of Health Research Involving Human Subjects (HRIHS). M. McDonald. Ottawa, Law Commission of Canada: 117-151.). 52 Burgess and Brunger (Ibid.) identify three theoretical approaches with regard to research and communities or collectives: research on the group, in which the participants are not involved except as research subjects; collaborative research, involving a joint effort by researchers and the community; and research consulting, in which the researcher is hired by the community.

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of databases and biobanks controlled by groups at risk (Foster, Berensten et al. 1998; Weijer, Goldsand et al. 1999; Davis 2001). In fact, the recommendations of the Public and Professional Policy Committee of the European Society of Human Genetics (PPPC) note that “…additional consent may be required at a group level through its cultural [sic] appropriate authorities” (European Society of Human Genetics 2003a).

However, the notion of collective consent is problematic for several reasons (Burgess and Brunger 2000). For example, it is not necessarily true that a political process will provide the same moral authority to a group decision as autonomy does in the case of individual informed consent. While collective consent seems to authorize investigators or biobanks to proceed without individual consent, individuals may agree to the group’s participation but decline participation themselves for a variety of reasons, including that they do not wish to be inconvenienced, or that they do not trust the researcher or research institution. And while they may not want to use those reasons to block the group’s participation, their individual consent cannot be implied from the group consent. Similarly, an individual’s right to participate may also be overridden by a group’s decision to not participate (Godard, Schmitdke et al., 2003).

Collective consent then agrees to accept risks on behalf of dissenters whose individual informed consent is insufficient to protect them from the risks to which they are exposed by the participation of other members of the group. However, collective consent based on any political process short of consensus must devalue dissent to the group decision. In many cases the dissenters are likely to include those who are routinely disenfranchised within the group. While “…the notion of informed consent requires that no individual can be required to accept a group’s assessment of the acceptability of research” (Burgess and Brunger 2000, p. 125), collective consent as a process establishes a socially sanctioned position from which dissent may be difficult. Informed consent is an individual’s decision to accept or reject participation in research or biobanks based on their personal evaluation of the research, and is intended to counter the power or momentum that tends toward complacent compliance in health care settings where research recruitment is often conducted. Research ethics typically tries to identify and provide additional protection to “vulnerable populations.” Dissent from a group-based decision is a good indication that the dissenters need to be considered from this perspective53.

A major tenet of informed consent is that it is a relationship or a process that is sustained throughout research, and that participants may re-evaluate their decision at any time and change their mind54. Aside from the practical problems of actually withdrawing from participating in research or removing materials from collections, this relational aspect of informed consent is difficult to preserve in the case of collective consent for groups that do not have explicit processes of representation and delegated decision-making. Of course, once clearly critical information is available, a group can reconvene to reassess their decisions and consent.

53 Sometimes dissenters are quite empowered and may claim to protect the vulnerable by actions that serve the dissenter’s interests as much or more than those in whose behalf they claim to speak. 54 Within the context of collectives, consultation between researchers and the subjects may be encouraged to take the form of a partnership (Burgess, M. M. and F. Brunger (2000). Negotiating Collective Acceptability of Health Research. The Governance of Health Research Involving Human Subjects (HRIHS). M. McDonald. Ottawa, Law Commission of Canada: 117-151.).

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However, even this can be difficult. As is seen in the case of deCODE and GGPR, collective consent can play a role in securing funds or other forms of support for a community. This type of relationship might suggest that the initial consent by the group implies a collectively negotiated contract of a political nature. In these cases it is unclear whether there is still room for individual consent or refusal.

Benefit Sharing Where there is no option to participate or not participate in a biobanking project, negotiating with collectives usually involves changes or additions to privacy protection, provisions for individual informed consent, and benefit sharing. In the latter case, independent of the benefits arising from research, researchers, public funding agencies, or private industry may provide benefits in exchange for permission to create a biobank, and/or in exchange for services provided to create, sustain, and administer the biobank, or merely for access to an existing biobank.

Accepting risks to a population in exchange for population-based benefits is a political decision: it must be fairly negotiated according to the norms of the population55. It is therefore important to distinguish the benefits of research—described in a consent form as benefits from the biobank—from negotiated benefits given in exchange for recruitment and for donating the data and materials necessary for the biobank.

Benefits for the group and its members can include56: • research on conditions or issues important to the group and its members. This might

result in changes to clinical care or environmental remediation; • funding for the biobank and related data collection; • access to the biobank by researchers from within the study population; • outright financial compensation or a percentage of the access fees charged by the

bank; • training in activities related to biobanking and research for local researchers; • providing access to research generated information related to clinical care or health

planning; • free or reduced price access to tests or treatments arising from the research; • providing health care services that may or may not be related to genetic disease; and • creating local facilities and employment opportunities.

It is important to note that an exchange of benefits is a way of justifying to the population contributing to the biobank that the risks to privacy, as well as administrative and financial costs, or other effects of the biobank on the collective are justified (Godard, Schmidtke et al. 2003, citing HUGO, 1996, Martin and Kaye, 1999, and HUGO, 2000). While they enhance the overall benefits the population derives from the bank, their role in the bank’s moral justification is complex. For example, the more widely negotiated benefits provided by a biobank are acknowledged, the more attractive they are to

55 The collective may need to negotiate agreement within the group, in particular with dissenting sub-groups. 56 These benefits are not necessarily present for all biobanks; they are contingent on the situation and specific negotiations. In addition, in light of the fact that some of these social benefits can be achieved independent of the biobank and the associated risks, it is reasonable to ask whether there is a more economical means to achieve them.

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empowered segments of a population, the greater the pressure may be on individuals to authorize participation.

It is important to understand that benefits are offered in exchange for setting up the biobank to the group of people necessary to establish it, not to individuals who give informed consent. The validity of informed consent can be questionable if an offer of benefits in exchange for an individual’s promise to participate is sufficient inducement to compromise voluntariness. Although the success of a biobank will depend on good participation rates, the potential benefits of a biobank cannot be used as incentives to recruit individuals.

However, if benefits are available to all members of the population, individuals can decide whether to participate without being influenced by offers of otherwise unavailable benefits. This is relevant to the negotiation of the collective acceptability of research, where the risks to the population are related to developing the biobank and research, and cannot be authorized or effectively controlled through individual informed consent.

Funding Sources Typically, biobanks are expensive57. Creating and maintaining biobanks can require substantial amounts of both private and public funds and may involve researchers from both public and private research sectors (European Society of Human Genetics 2003; Godard, Schmidtke et al. 2003). Any significant commitment of funds will be based on a careful review of expected benefits and an assessment of where investments and benefits might be undermined. Benefits, such as population health care information, are the result of research enabled by a biobank, so a proposed bank is likely to be evaluated for whether its design will facilitate further research that may, in turn, lead to other benefits.

This is the most active assessment of the merits of biobanks; however, while private and public funds have already been committed to establishing large biobanks, it has been surprisingly difficult to establish the anticipated benefits. Identifying the potential benefits of biobanks and justifying the expenditure of public and private funds depends on the knowledge and expertise of those persons most likely to use and/or be employed by biobanks. This vested interest, when combined with the need to compete with other research ventures for funds, establishes a strong bias in those tasked with assessing the benefits of biobanks in favour of the banks. This bias may also support a tendency among funders58 to avoid assessing whether the benefits likely to follow from basic research are of sufficient magnitude and likelihood to justify risks and lost opportunity costs.

Evaluating whether a biobank can facilitate research is likely to be an easy threshold to pass in the context of research ethics, peer reviewed research, and funding to promote research. Whether future research intended to deliver health benefits could be

57 This is not true for all biobanks—tissue banks are often small and relatively inexpensive—nor is it necessarily true for all time—the cost of even large biobanks could drop rapidly, driven by further developments in research and technology. 58 McDonald (McDonald, M. (2000). HRIHS: Process and Context. The Governance of Health Research Involving Human Subjects (HRIHS). M. McDonald. Ottawa, Law Commission of Canada: 43-76.) identifies research sponsors as one of five groups with particular influence regarding the direction of research. The five groups include: research funders; the scholarly community; research institutions; government (through regulatory and policy tools); and interest groups and the public.

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accomplished more efficiently or more effectively than through a biobank, or whether lost opportunity costs or the harms from a biobank and research arising from it might challenge the overall benefit ratio, are unlikely to be issues raised in any regulatory context. Claims of what kind of research can be based on biobanks are contested, and depend in part on the kind of information gathered, the construction of the databases, and to a very large extent on the state of bioinformatics. However, although academic and media discussions may raise these issues (SIBI 2000), political discourse and activity are the primary locations for debates about whether the benefits of biobanks are worthy of investment and merit the associated risks in light of cultural and ethical norms within a given society (NESCO-International Bioethics Committee-Subcommittee on Bioethics and Population Genetics 1995).

There is always a role for “public” representation in the proposing and structuring of a biobank. Public funders and gatekeepers of access to patients and health records may be the instigators of biobanks, or may negotiate on behalf of the public with private parties seeking to establish biobanks. For example, deCODE had to negotiate with the Icelandic government and health care sector, while the United Kingdom’s Biobank was jointly launched by the Wellcome Trust and the Medical Research Council with support from the Department of Health (The UK Biobank 2003; The UK Biobank 2004). Public agency participation in the formation of a biobank is predicated on the assessment that some benefit is likely to be derived, that the benefit would be in the public interest, and would represent a good investment of resources. Just how these assessments are made, on what criteria, and with whose participation is often unclear and varied. This means that objections to the formation of biobanks as poor investments are rarely met with direct responses due to the vagueness of the justifications or to the lack of a forum where such objections may be raised and will be heard. On the other hand, the presumption that gathering more genetic information will facilitate research is difficult to challenge, in part because scientific advances really do depend on good data, rigorous method, and serendipity.

The tendency for intellectual property claims to move from products to processes and now research tools means that the investment in biobanks can be billed as good business, as well as good science. But the priority of making profit from personal information and biological samples donated for research purposes, once again, raises the issues of benefit sharing and the speculative nature of the benefits

Protecting privacy “Privacy” in the critique and structuring of biobanks is a complex matter. The issues can be sorted into arguments against biobanks per se (i.e., biobanks pose an unjustifiable risk to privacy), concern over mechanisms to prevent the inappropriate use of biobanks (e.g., the unauthorized or inappropriate use of biobank information by insurance companies), and concern over protecting privacy within biobanks (e.g., through encryption, unlinked data and materials, software design and security measures).

Regulations that affect biobanks are usually the result of privacy legislation intended to manage a broad range of public and private entities. As described above, access to private information and privacy protection are often covered in the same legislation (Edwards, 2001). With the exception of legislation to prevent the unauthorized use of

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genetic information by the insurance industry, most regulation does not explicitly regulate genetic information or materials, but treats them as another form of health record or personal information (Burgess, Lewis et al. 2002). As a result, the norms guiding the establishment of biobanks are the product of interpretations of privacy laws combined with established ethical guidelines for medical research, which carry sanctions related to loss of funding or status, rather than legal limitations. As articulated by Bernard Dickens, in Canada “[l]aw applies almost inadvertently to the enterprise of biomedical research.” (Dickens 2000).

Objections to creating biobanks Most objections to creating biobanks are based on the inability of individuals to protect their own privacy by refusing to be included in a biobank; there is a certain irrelevance to individual privacy protection when community and family participation will still produce information that may be used in a discriminatory manner toward non-participants. Responses to privacy objections typically propose mechanisms that will protect all individuals from the inappropriate or discriminatory use of genetic information, and against unauthorized data or material collection by a biobank.

Kerr points out that trust in traditional authority roles is at an all-time low (Kerr 2003), so public sensitivity to privacy issues has increased. This declining trust is most often viewed in marginal or incremental terms, and is seen as resulting from the poor performance of a specific administration or agency. However, it may also be the case that while specific “performance gaps” are significant, there is also an underlying structural change in the role of authority in modern industrial societies independent of the shorter term fluctuations in institutional performance.

That said, privacy objections to creating biobanks per se are rare. The routine collection of information about individuals may seem such a common feature of contemporary life that biobanks may appear to be one of the more trustworthy and publicly useful instances. It is also possible that biobanks are seen to propose a sufficient public benefit and avoidance of harm that some sacrifice of personal privacy appears warranted. This rationale may be hard to sustain unless benefits from biobanks are shown in more concrete terms than is currently the case.

The inappropriate use of genetic information

The special nature of genetic information was identified by (among others) the Public and Professional Policy Committee (PPPC) of the European Society of Human Genetics. The Statements and Recommendations developed from a 1999 workshop acknowledge the risk to family members of an individual undergoing genetic screening (European Society of Human Genetics 2003c), and the concerns over discrimination by insurers and employers as a result of genetic testing. Another set of recommendations (Godard, Raeburn et al. 2003; European Society of Human Genetics 2003b) deals specifically with insurance and employment. Among other things, the recommendations highlight the need for transparency, and the desirability of limiting the genetic information disclosed to insurers to information that is specifically relevant to the insurance policy. The PPPC states that, while “[t]here is currently very little use of genetic information in relation to employment… [this] situation should be kept under review” (European Society of

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Human Genetics, 2003b), and that genetic information is not an acceptable ground for exclusion from a position except in the case where the safety of clients and/or the public would be compromised by not excluding an individual.

Early discussions of discrimination related to genetic testing focused on insurance, workplace, health care and the courts. Some of these discussions presumed that any disadvantage based on genetic information was morally offensive discrimination59. This presumption is apparent in a 2001 joint statement issued by the United Kingdom Forum for Genetics and Insurance, the Association of British Insurers, and the British Society for Human Genetics. The statement, intended to allay the public’s fears, “promised not to use genetic test results obtained from research projects when calculating insurance premiums” (Kmietowicz 2001).

Those objecting to this presumption pointed out that common insurance and employment practices evaluate people and often family histories for insurance in an attempt to predict whether they will remain healthy or be able to perform the duties of employment. Employment, insurability and premium rates are often based on these calculations. To exempt genetic information from such uses would in effect be to perhaps unfairly impose costs on others in the risk pool.

Disability and life insurance vary in their significance to the well-being of people depending on the extent of the social safety net a society provides independent of privately purchased insurance. When clients with strongly predictive health indicators are permitted to purchase insurance, they are purchasing it at the same rate as others, despite predictably higher payouts60. In the long-run, this raises premium rates across the board—companies have to be able to afford the payouts—making insurance a less desirable commodity to clients in general.

If maintaining life and disability insurance is an important social good, then it seems important to avoid a chain of events that would result in unaffordable premium rates. This public good issue is further emphasized by the way mortgages and other financial arrangements have come to depend on life and disability insurance to subsidize losses and reduce the costs of loans.

To summarize a complex international debate, the most egregious discrimination and social penalty seems to be when people cannot buy a modest level of life and disability insurance. In the face of a vast commercial insurance sector, this minimum standard requires the establishment of relatively strong governance mechanisms. The best policy response seems to be to prohibit using genetic (and other) predictive testing below a certain level of coverage (European Society of Human Genetics, 2003b; Godard et al., 2003c), and then require that the insurer have access to the same information as the client above that level, allowing the insurer to rate the client in the competitive market and the client to evaluate the worth of the insurance product61. Although such measures have not

59 U.S. Joint Working Group on Ethical Legal and Social Issues in Human Genome Research (ELSI) (1991). "ELSI Working Group Studies Genetic Bias." Human Genome News 3(3 (September 1991)).. 60 Conversely, potential insurance applicants may want to disclose their genetic status in the hope that the results may prove fitness and hence lead to reduced insurance premiums (Godard, Raeburn et al., 2003). 61 Godard, B., S. Raeburn, M. Pembrey, M. Bobrow, P. Farndon and S. Aymé (2003). "Genetic information and testing in insurance and employment: technical, social and ethical issues." European Journal of Human Genetics 11(Supplement 2 (December)): S123-S142.

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been universally enacted, the availability of such a social response probably reduces some of the concerns about inappropriate use of genetic information that might follow from the development of biobanks.

Currently, donors to the Estonian biobank, Eesti Geenivaramu, are protected against discrimination through the Human Genes Research Act, which prohibits discrimination “…on the basis of genetic information, especially in insurance and employment relations. Such organisations [sic] shall not be issued any data” (Eesti Geenivaramu n.d.). The UNESCO Declaration also aims to prevent discrimination, particularly with regard to “…employers, insurance companies, educational institutions and the family…,” and allows access by these groups to data or samples only in the case of prior consent by the subject, or “…for an important public interest reason in cases restrictively provided for by domestic law consistent with the international law of human rights…” (United Nations Educational Scientific and Cultural Organization 2003, Article 14(b)).

Edwards (2002, p. 15 and p. 18) has noted evidence within employment and insurance literature in the United States of biological samples being used for purposes other than those for which the sample was provided and for which informed consent was given. Discrimination against individuals may result from this abuse of personal health information. Furthermore, “[a]dvances in genetic testing techniques make non-consensual, covert testing easier and less expensive all the time” (Edwards 2002, p. 15). Among other things, this raises the additional potential harm of infringing an individual’s right to not know (Edwards 2002, p. 23). This right to not know, according to Edwards who describes it as “…an issue that is unique to the context of genetic privacy,” must be addressed by genetic privacy laws. The right to not know is explicitly protected by the legislation governing the Estonian biobank (Eesti Geenivaramu n.d.; Eesti Geenivaramu n.d.), and in Article 10 of the UNESCO Declaration (United Nations Educational Scientific and Cultural Organization 2003)

Interviews conducted by Burgess and Lewis et al. (2002, p. 19) revealed that industry informants consider genetic information to be a component of health information and a reason for concern only insofar as unauthorized access to that information may lead to discrimination. Other commentators maintain that genetic information is personal in a unique sense, or that genetic risk is not something an individual can be held responsible for, and therefore it deserves special privacy protections (see for example Edwards 2002.). In fact, the special status of human genetic data is explicitly described in Article 4 of the UNESCO Declaration (United Nations Educational Scientific and Cultural Organization 2003).

Protecting privacy within biobanks Protecting individuals from inappropriate identification, or their data and biological materials from unauthorized use, is probably the most developed discussion in the area of privacy and biobanks. If privacy cannot be protected, then a population’s willingness to provide data and materials will be undermined and the biobank will fail to provide the intended research base. That said, the definition of the level of protection within a biobank (i.e., “inadequate”, “adequate”, “good”, etc.) may depend on a number of factors.

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A significant issue in establishing a biobank is how identifying information is disconnected from the samples and data, and whether re-establishing the connection is possible. The recent literature on biobanks and genomic research has developed complex categories describing the possible relations between identifying information and data, or materials. Most proposed banks have one-way coding with encryption that permits new data to be linked to numbered samples and databases without the possibility of backwards identification. Other banks have an administrative system that keeps the codes, maintaining the possibility of reverse identification. While the former probably provides better protection against unauthorized identification, it undermines the biobanker’s ability to disclose research results related to individuals.

Edwards (2002) questions whether genetic information can ever be completely anonymous, raising the concern that even anonymized and aggregated genetic data may not be sufficiently protected. For example, it may be possible to identify individuals within aggregate samples by linking different databases and additional genomic testing; deCODE has admitted that this is at least technically feasible in Iceland (Edwards 2002: 16). Ultimately the challenge lies in the unique nature of genetic information which means that reverse matching of a patient to genetic material is almost always technically feasible. Anticipating this, Article 3.6 of the Tri-Council Policy Statement (Tri-Council Policy Statement 2003) requires the implications of any data linkages, which may cause individuals to become identifiable to be reviewed and approved by a research ethics board

There are innovations that add “noise” to databases to reduce the chance that individuals can be identified through combining data from different sources. However, the hazard with adding noise is that it can reduce the validity of research if the noise affects data important to the research questions.

Research into methods to increase data security and prevent inadvertent or unauthorized identification of individuals is ongoing. For example, Eesti Geenivaramu—which established and maintains the Estonian biobank including collecting, processing and releasing data—protects individuals through a number of measures, including (Eesti Geenivaramu n.d.): • unlinking genetic data from identifying information, and identifying samples

through unique 16-digit codes; • prohibiting connecting the biobank’s database to the Internet; • retaining an individual’s right to withdraw from the bank, including the right to

demand deletion of personally identifying information or all information stored about that individual; and

• prohibiting removal of the database beyond Estonia’s borders.

However, regardless of these protections, the Act states that: “Blood samples and health and genetic data are the property of the Gene Bank” (Eesti Geenivaramu n.d.). Although donors may withdraw from participating in the biobank, they must release proprietary rights to the samples they provided: when a donor ceases to participate, only information on the donor is destroyed, not the samples, with the result that the samples can no longer be associated with an individual. In terms of consent, it appears that an individual’s free

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and informed consent under the Act is limited to whether or not to provide a sample; what is done with that sample is not within the control of the donor.

This approach complies with Article 9(b) of the UNESCO Declaration, which states:

When a person withdraws consent, the person’s genetic data, proteomic data and biological samples should no longer be used unless they are irretrievably unlinked to the person concerned. (United Nations Educational Scientific and Cultural Organization 2003)

While this approach circumvents issues of re-consent and makes the research process more efficient, the unique nature of genetic information is such that it might never be fully anonymous. This must be considered in light of the fact that, in most cases, DNA records in state-established biobanks are kept in perpetuity, often with no limits on future unrelated forms of testing.

There are also concerns about whether confidential health information can truly be kept confidential when a private company is involved. Defenders of the Icelandic initiative argue that the encryption model will ensure anonymity is maintained. They also suggest that the up-front capital investment by deCODE in creating the biobank acts as a kind of security bond; regulations stipulate that if the government’s rules are violated, the company could loose its licence to use the data (Jonatansson 2000).

It can be difficult to articulate the special nature of genetic testing without making the mistake of overestimating the importance of genetics to the “nature” or “essence” of the individual. According to Edwards (2002), this may be particularly pronounced with regard to the means of data storage and transmission:

Many feel that once information has been fed into the ‘electronic highway’ it is irretrievable and any right to ‘withdraw consent’ becomes ineffective. (Edwards 2002, p. 13)

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5. Appendix: Overview of biobanks Location

(Country or province)

Recruitment/bank population

Informed consent

Privacy

Research uses (consent & privacy)

Intellectual Property & Conflict of Interest

Funding

Benefit sharing

Accountability

Administration

Public Consultation & Comment

CARTa-GENE, , Québec, Canada

www.cartagene.qc.ca

50,000 recruits, 25-74, random selection using postalcodes, proportionate distribution across province. Authorization for address and other personal data from Régie de l’assurance maladie du Québec by Personal Information Access Commission, agency.

Voluntary, individual written informed consent required for participation. Law foresees exceptions this requirement.

Right of withdrawal included

Health information via questionnaires..

Comprehensive general legislation for population research, not limited to biobanking. RMGA guidelines on genetic research/sampling and on popn. genetics recommends specific banking policy

Users retain rights of access to data but no proprietary right in the data. Considering giving access to companies and researchers where scientific value and ethical protocols demonstrated.

RMGA guidelines support general principle that research should “promote the attribution of benefits to the population”

Researchers involved must sign a confidentiality agreement. Complex administration: in the absence of a national research ethics board, Tri-Council policy statement requires the agency receiving funding be reviewed by local ethics committees

Provincial ethical guidelines require open, prior, ongoing dialogue between research team and subjects. Must present the state of the project and the scientific, ethical, and legal aspects involved but also to collect comments and suggestions

Iceland

Project initiated by a private company (deCODE). Goal to recruit the entire population. List of possible participants from physicians. Biobank combines health records (including questionnaire), genealogical data and genetic information. Selection following genealogical analysis. 30% of total popn have given sample and medical information, and 90% of those over 65. 20,000 have withdrawn.

Informed consent for biological sampling. for “clearly defined purposes” although wider uses possible with independent oversight.. Sampling from tissue banks allowed without additional consent. Health records accessed without informed consent. Opt out from biobank possible for living, competent individuals, but not from government records. Genealogical records publicly available and company will link them to biological samples.

Linkage of three sources of data by government agency, ensures anonymity, but indirect reverse linkages technically possible. HDB must include at least ten records. Manual upload of analogue records to Health Sector Database (HSDB) funded by deCODE has created concern. Government has full access to database. deCODE has 12 year exclusive licence to build and conduct research using the biobank.

Licensee has rights over biological samples but does not own them. Licensee able to apply for patents for products resulting from research using the database. Licensee able to grant licences for use of results.

Private funding, including company IPO on NASDAQ.

deCODE funded upgrade of HSDB benefits health sector. Annual licence fee paid to the government and a capped share of annual profits. Deal with Roche suggests that subsidized medicine may be a negotiated benefit.

Legislation includes multiple surveillance mechanisms and some influence over research. deCODE may loose the licence if privacy laws violated and may be subject to prosecution. Company is “tethered” to Icelandic territory. Ethics approval from National Bioethics Committee required.

Government agency is responsible for linking and anonymizing data. Employees must sign confidentiality agreement.

Consultation focused on creation of the health sector database, rather than the biobank. Extensive early consultation and strong political support. Critics focus on issues of consent and commodification.

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Location



Informed consent

Privacy



Funding

Benefit sharing

Accountability

Administration


Estonia

http://www.geenivaramu.ee/

Government led project, established a non-profit foundation to implement. Foundation aims to will recruit ~¾ of the 1.4 million population.

Family physicians and GPs, will inform their patients about the Estonian Genome Project, will recruit potential participants and are designated as data collectors, authorized to collect written consent. Participation voluntary, withdrawal possible. Research uses negotiated with the regulator. Government appointed Chief Processor (CP) regulator accountable for gene bank. CP assigns unique anonymous code to sample, although reversals possible within legislation. Use for criminal investigation prohibited. Doctors may access information for treatment purposes.

Processing rights granted by a specific contract. Exclusive commercial licensed processor EGEEN able to sell data and access. Right of ownership over sample transferred to foundation. Researchers may acquire IP over research products. Research by foreigners allowed.

Budget for gene bank directly from state budget to ensure financial independence.

Direct government oversight of the activities of the foundation, surveillance of biobank, research and the financial status of the foundation. CP reports to a supervisory board. Ethics board oversees gene bank procedures but is purely consultative. Committee composed of relevant specialists with citizenship. Disclosure of data a criminal offence.

Consultation as part legislative process. Small survey suggests 60% support for project and 5% against.

Tonga Led by Autogen Ltd, an Australian biotech company. .Project abandoned due to widespread public opposition.

Individual written informed consent was required for participation, choice was offered to the participants to consent to the use of their samples and data for multiple research projects or for a defined few

Opposition to proprietary interest in DNA.

Free drugs negotiated and royalties paid to Tongan government on any medical products. Opponents argued benefit sharing disproportionately benefited Autogen.

Two ethics committees for the review of one project was already in existence in Australia. Another was to be established in Tonga and would have comprised of at least six lay members of the public

Great opposition from church and pro-democracy groups. Autogen’s ethics policy focuses on prior informed consent of individuals but remains silent on the traditional Tongan role of the extended family in decision-making

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Location



Informed consent

Privacy



Funding

Benefit sharing

Accountability

Administration


United Kingdom

www.biobank.ac.uk

Led by Medical Research Council, the Wellcome Trust, and the Department of Health. 500,000+ volunteer adults aged 45-69 recruited either using GP lists with letter directly from the GP or through primary care trust lists. . Database will include lifestyle data, environment data, clinical data, DNA, and plasma

Patients sent information on the study and an invitation to participate, signed by their GP, along with the study questionnaire and consent form which makes it clear that the biobank is a research not a health care resource. GPs explain the research and obtain the written consent from patients for various analyses, for specified and unspecified biochemical and genetic tests, and for permission to contact participants again at a later date. Withdrawal possible at any time without penalty, ranging from discontinuation of contact through to full extraction of samples and results. Identification data stored separately from research data, but linkage possible in order to allow for follow up. Access by insurers in restricted. External access for the direct benefit of the participant may be considered as an exception.

No single company will be granted exclusive access. Commitment to respect the public health origins of the project. Professional medical codes expected to play a strong role in regulating uses of the databank.

Funding from UK government, MRC and Wellcome Trust. Contracts foresee the return of research results to the biobank in exchange for the use of the samples.

Interim Advisory Group established to develop the appropriate legal and ethical framework. Covered by by the Data Protection Act 1998 (Data Protection Commissioner has oversight) and the Medical Research Council’s. General data protection laws, rather than specific biobanking laws. Oversight body established independent of research group. Ethics and Governance group established to advise specific projects

Consultation with public and health professionals has been completed.

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Location



Informed consent

Privacy



Funding

Benefit sharing

Accountability

Administration


HAPMAP (International)

Partnership of scientists and funding agencies from Canada, China, Japan, Nigeria and UK. Goal is to develop a haplotype map of the human genome which describes common patters of variation in DNA sequence. Alleles that are close together tend to be inherited together and this set of associated alleles is a “haplotype.”

Study will examine 270 genetic samples from four populations in Africa, Asia and the US and will be genotyped for 1 million polymorphisms.

Consent will be obtained not just for the HapMap itself but also for many types of future genetic variation studies, gene-related diseases and pharmacogenomics studies that cannot be specifically detailed at the signature of the consent form. Personally identifiable information not collected and intentional oversampling will help improve anonymity of data. Samples held and publicly available from the Coriell Institute for Medical Research. Analysis will identify haplotype frequencies for each population, allowing for comparison and potentially, stigmatization.

Project not include study of a specific utility such as disease risk or drug response. Project position is that SNP, genotype or haplotype data with no specific utility should not be patentable. Others may patent as long as others not prevented from obtaining data. Since data about function or utility is unavailable, only possible through combination with other studies, under the terms of access.

Funding secured from government agencies and foundations. The resulting haplotype map, will be placed in the public domain, offer a new tool to speed the discovery of genetic contributions to diseases. Users must agree not to reduce other’s access to the data and to ensure those they share it with abide by the agreement.

Community Advisory Group set up for each participating community. Committee will oversee all future uses of the genetic material. Studies will require an ethics review in the country where the material is banked.

Researchers decided not to attempt to recruit individuals from indigenous groups that have historically been disempowered in their own countries in order to avoid the appearance of biopiracy and exploitation.

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