**2. Ethical considerations in human biobanking**

### **2.1 Novel challenges associated with biobanking**

The idea of a biobank to facilitate medical research would appear to be a worthwhile and commendable activity to most people. However, the establishment of such archives raise not only many of the same ethical problems that face the medical community (particularly those involved in recruiting organ donations), but also some unique questions of their own, for example:


### **2.2 An ethical framework**

To answer such questions biobanks (and their regulators) must draw on contemporary ethical codes, attitudes and opinions to provide guidance to best practice. Whilst this approach can provide discussion points to it does not always produce definitive answers (Gillon, 1985). The earliest consideration of medical ethics was probably the Hippocratic Oath, which introduced the concepts of respecting patients as individuals and doing no

archives can be subdivided into those which have the aim of answering one specific research question (*e.g.* the Multiple Sclerosis Brain bank) as opposed to systematic biobanks such as the Infectious Diseases Biobank (IDB) at King's College London (KCL) (Williams *et al*., 2009), which collects clinical materials with no specific research question in mind. The growing popularity of biobanks in medical research in recent years has inevitably raised new and important ethic and legal questions regarding how they should be managed and regulated. For example, recently, the German Ethics Council has proposed that biobanks should be regulated on the basis of five 'pillars' including the concepts of: confidentiality; open informed consent; careful ethics review; sample qualityassurance; and, a transparency of the biobank's goals (Deutscher Ethikrat, 2010). Here some of the most contentious ethico-legal issues facing clinical archives are considered, including: (i) the nature of the contract (*i.e.* informed consent) between the subject and the researcher; (ii) the concept of property or ownership rights in respect to body tissues and fluids; (iii) the duty of care of a biobank to the donor, the sample, the researcher and, society. This is contextualised against historic turning points which have led to the regulatory structures currently in force in the UK. Finally, the organization of the UK's IDB at KCL is described and proposed as a model system for facilitating research into

The idea of a biobank to facilitate medical research would appear to be a worthwhile and commendable activity to most people. However, the establishment of such archives raise not only many of the same ethical problems that face the medical community (particularly those involved in recruiting organ donations), but also some unique questions of their own, for





To answer such questions biobanks (and their regulators) must draw on contemporary ethical codes, attitudes and opinions to provide guidance to best practice. Whilst this approach can provide discussion points to it does not always produce definitive answers (Gillon, 1985). The earliest consideration of medical ethics was probably the Hippocratic Oath, which introduced the concepts of respecting patients as individuals and doing no


'controversial' (*e.g.* stem cell, cloning *etc.*) research?

infectious diseases.

the donated sample?

**2.2 An ethical framework** 

vaso-vagal reflex: Garozzo *et al.*, 2010). - Who actually owns the donated sample?

example:

**2. Ethical considerations in human biobanking 2.1 Novel challenges associated with biobanking** 

harm (Farnell, 2004). Similar sentiments are expressed in the payer of Maimonides, originally believed to have been written by the 12th-century physician-philosopher (Friedenwald, 1917). More probably, this prayer was written by M. Herz, a physician and pupil of the Konigsberg philosopher Immanuel Kant, as print versions can only be traced back until 1793. More contemporary views on medical ethics were crystallized in a 1902 book by Dr Albert Moll on 'Ethics of the Physician:' Hahn, 1984). Two major ethical issues raised by biobanks revolve around consent and the ownership in human tissues.

The justification for consent stems from the notion of personal sovereignty; the exclusive right an individual holds over their own person. This concept is historically rooted in liberal and political thought, as noted by JS Mills: '*over himself, over his own body and mind, the individual is sovereign*' (Mills 1972). Equally though, Kant believed that the humans '*exists as an end in itself, not merely as a means to be used by this or that will at its discretion*' (Gregor, 1998). Indeed, personal sovereignty now serves as the justification for the majority of articles enshrined in the Universal Declaration of Human Rights. Whilst consent is a necessary component in everyday life and medical research it is debatable how 'informed' consent need be. On the one extreme consent procured through misleading information (or under duress) cannot be considered valid. At the other end of the scale an individual may be informed of the risks and side effects of a medical procedure, but is not expected to comprehend the full complexities of the issues. Consent is often reduced to a subtle paternalism in regards to the unequal position of patient-subject to the researcher, as well as addressing how 'informed' a *research* project can be.

Although respecting personal sovereignty is necessary, there are also ethical principles in favour of a communal duty to society. As the aim of a biobank is to facilitate medical research (which in turn will aid the development of future treatments for the general good of society), the question arises as to whether there is an obligation to assist such endeavours. As Mills states '*there are also many positive acts for the benefit of others that he may rightfully be compelled to perform: such as to give evidence in courts of justice; to bear his fair share in a common defence; or in any other joint work necessary to the interests of the society of which he enjoys the protection*' (Mills, 1972). Thus, respecting personal sovereignty does not negate the argument in favour of a public duty to assist such endeavours. Indeed, utilitarian arguments for the 'greatest good for the greatest number' (Bentham's *'felicific calculus'*: Mitchell, 1918) and Kant's transcendental deduction of a moral duty (Paton, 1948) may to some degree also imply an obligation to donate samples to a biobank.

Locke's concept of property is based on the premise that an individual owns the labour of their body, which when mixed with something in nature, confers a property right in the produced object. Indeed a Lockean justification of property rights was accepted in the US case *John Moore v The Regents of the University of California* (1990) as a foundation for a claim on a human cell-line. Thus, Lockean justification for ownership of samples in a biobank could be constructed in a similar fashion; the labour expended in collecting, preparing and storing A biobank's samples confers a right of ownership. Although a degree of ownership exists in relation to human samples it is better to conceive this as conditional ownership (or 'custodianship') rather than an absolute ownership.

### **2.3 Some historical precedents leading to research ethics regulation**

Self-regulation of biobanks based upon general ethical principles may seem a reasonable approach to managing a few samples of blood or urine which have been willingly donated for research. However, a series of notorious cases from the 19th century up to the present day have so shocked the public that legislation of medical ethics and the storage of human body parts became inevitable: some of the most infamous cases are outlined below.

*Body-snatching:* The UK Murder Act of 1752 meant that the only legal source of corpses for anatomy was those of executed prisoners: however, this was insufficient to supply the demand from medical schools. Stealing a corpse was only regarded as a minor crime and thus evolved into a lucrative business. In 1827/8, the Edinburgh grave-robbers Burke and Hare realized that institutions paid more for fresh corpses and thus graduated from bodysnatching to murder in order to meet this demand (Lancet, 1829; Howard & Smith, 2004). The subsequent conviction of Burke in 1829 led to the UK Anatomy Act of 1832 which stipulated that anyone practising anatomy must hold a licence and be responsible for the correct treatment of corpses. This act was repealed by the Anatomy act of 1984 which, in turn, was replaced by the Human Tissue Act of 2004 (below).

*Genocide:* In the 1930s/40s the National Socialist German Worker's party (NSDAP) became obsessed with the ideas of social Darwinism, eugenics and the Nietzsche concept of 'superman' (Taha, 2005). On this basis the regime initially justified killing those with congenital defects in the T4 (Tiergarten-4) euthenasia programme (Freidlander, 1995). This was criminal programme was subsequently extended to include anyone that the NSDAP deemed 'sub-human' (political opponents, Russian prisoners of war, and, notably the near genocides of European Jews and Roma: Bachrach, 2004). As part of this holocaust some victims were also subjected to non-consensual medical experiments (*e.g.* LD50 type testing of humans exposed to hypobaric or hypothermic conditions). Additionally, the NSDAP also assembled a collection of skeletons from euthanized prisoners for the Institute of Racial Hygiene to act as a historic record (and the basis for scientific study of) extinct human 'races'. At the end of the war the Nuremberg 'Doctors Trial' sentenced some of those responsible and resulted in the development of the Nuremberg code of practice for research involving humans (Table 1: US Government Printing Office, 1949). This is an important document since it has served as the basis of almost all subsequent refinements in medical ethics such as the most recent version of the Declaration of Helsinki (World Medical Association [WMA], 2009).

*Unit 731:* A less-well publicised series of medical crimes of the Second World War included those perpetrated by the Imperial Japanese Army's Unit 731. This was euphemistically named the 'Epidemic Prevention and Water Purification Department' of the Kwantung Army Group in Harbin, occupied China (Alibewk & Handelman, 1999). This unit experimented on over 10,000 humans in studies involving conscious, non-anaesthetised, *vivisections*, weapons testing (*e.g.* the effects of flamethrowers, hand grenades *etc.* upon live humans), as well as bio-weapons research (Harris, 1994; Kristof, 1995; Barrenblat, 2004).

*Tuskagee syphilis study:* A study of 400 poor African-American men with syphilis was initiated in 1932. To induce participation, recruits were given free medical care, meals and burials and in return provided samples of blood and cerebro-spinal fluids to researchers (Roy, 1995; Crenner, 2011). At no point were the recruits informed that they had syphilis, nor were they treated for it. The 40-year study was particularly controversial because the researchers failed to treat patients even after the discovery that penicillin was an effective cure. In 2010 it was subsequently revealed that in Guatemala the same study had been extended, between 1946-1948, to include actually infecting prisoners, soldiers, and patients in a mental hospital. A total of 696 men and women were exposed to syphilis without their informed consent. As a direct result of these revelations the US Congress passed the National Research Act in 1974 and created a commission to study construct regulations governing studies which involve human participants (Prograis, 2010).

day have so shocked the public that legislation of medical ethics and the storage of human

*Body-snatching:* The UK Murder Act of 1752 meant that the only legal source of corpses for anatomy was those of executed prisoners: however, this was insufficient to supply the demand from medical schools. Stealing a corpse was only regarded as a minor crime and thus evolved into a lucrative business. In 1827/8, the Edinburgh grave-robbers Burke and Hare realized that institutions paid more for fresh corpses and thus graduated from bodysnatching to murder in order to meet this demand (Lancet, 1829; Howard & Smith, 2004). The subsequent conviction of Burke in 1829 led to the UK Anatomy Act of 1832 which stipulated that anyone practising anatomy must hold a licence and be responsible for the correct treatment of corpses. This act was repealed by the Anatomy act of 1984 which, in

*Genocide:* In the 1930s/40s the National Socialist German Worker's party (NSDAP) became obsessed with the ideas of social Darwinism, eugenics and the Nietzsche concept of 'superman' (Taha, 2005). On this basis the regime initially justified killing those with congenital defects in the T4 (Tiergarten-4) euthenasia programme (Freidlander, 1995). This was criminal programme was subsequently extended to include anyone that the NSDAP deemed 'sub-human' (political opponents, Russian prisoners of war, and, notably the near genocides of European Jews and Roma: Bachrach, 2004). As part of this holocaust some victims were also subjected to non-consensual medical experiments (*e.g.* LD50 type testing of humans exposed to hypobaric or hypothermic conditions). Additionally, the NSDAP also assembled a collection of skeletons from euthanized prisoners for the Institute of Racial Hygiene to act as a historic record (and the basis for scientific study of) extinct human 'races'. At the end of the war the Nuremberg 'Doctors Trial' sentenced some of those responsible and resulted in the development of the Nuremberg code of practice for research involving humans (Table 1: US Government Printing Office, 1949). This is an important document since it has served as the basis of almost all subsequent refinements in medical ethics such as the most recent version of the Declaration of Helsinki (World

*Unit 731:* A less-well publicised series of medical crimes of the Second World War included those perpetrated by the Imperial Japanese Army's Unit 731. This was euphemistically named the 'Epidemic Prevention and Water Purification Department' of the Kwantung Army Group in Harbin, occupied China (Alibewk & Handelman, 1999). This unit experimented on over 10,000 humans in studies involving conscious, non-anaesthetised, *vivisections*, weapons testing (*e.g.* the effects of flamethrowers, hand grenades *etc.* upon live humans), as well as bio-weapons research (Harris, 1994; Kristof,

*Tuskagee syphilis study:* A study of 400 poor African-American men with syphilis was initiated in 1932. To induce participation, recruits were given free medical care, meals and burials and in return provided samples of blood and cerebro-spinal fluids to researchers (Roy, 1995; Crenner, 2011). At no point were the recruits informed that they had syphilis, nor were they treated for it. The 40-year study was particularly controversial because the researchers failed to treat patients even after the discovery that penicillin was an effective cure. In 2010 it was subsequently revealed that in Guatemala the same study had been extended, between 1946-1948, to include actually infecting prisoners, soldiers, and patients in a mental hospital. A total of 696 men and women were exposed to syphilis without their informed consent. As a direct result of these revelations the US Congress passed the National Research Act in 1974 and created a commission to study construct

regulations governing studies which involve human participants (Prograis, 2010).

body parts became inevitable: some of the most infamous cases are outlined below.

turn, was replaced by the Human Tissue Act of 2004 (below).

Medical Association [WMA], 2009).

1995; Barrenblat, 2004).

**1. The voluntary consent of the human subject is absolutely essential.** This means that the person involved should have legal capacity to give consent; should be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him/her to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonable expected; and the effects upon his health which may possibly arise from participation. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

**2. The experiment should be such as to yield fruitful results for the good of society**, unprocurable by other methods or means of study, and not random and unnecessary in nature.

**3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease** or other problem under study that the anticipated results will justify the performance of the experiment.

**4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.**

**5. No experiment should be conducted where there is a prior reason to believe that death or disabling injury will occur**; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

**6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.**

**7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.** 

**8. The experiment should be conducted only by scientifically qualified persons.** The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

**9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end** if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

**10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment** at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Table 1. The Nuremberg code for medical research involving humans.

*Alder Hey hospital scandal:* An investigation into the retention of hearts at hospitals in Bristol UK in the early 1990s led to a public inquiry. This subsequently found that a large number of hearts were also being held by the Alder Hey Children's Hospital and the Walton Hospital. In 2001 the Redfern Report (Royal Liverpool Hospital Children's enquiry, 2001) was published and this led to public outcry when it was revealed that Prof van Velzen had archived organs from every child subjected to a *post mortem.* Around 500,000 tissue samples were being held without any realistic likelihood of them ever being used for research. These revelations led to the creation of the Human Tissue Authority and the 2004 Human Tissue Act and in the UK.

*Desecration of Alaister Cooke's remains*: In 2005 it was discovered that the bones of Alaister Cooke (a distinguished BBC correspondent) and those of others had been surgically excised without permission prior to cremation by Biomedical Tissue Services Ltd. (Smit, 2008). The company then sold the treated bones for use as surgical grafts. Cooke was suffering from bone cancer when he died which would have made his tissues unsuitable for such a purpose. Reports revealed that the people involved in selling the bones altered his death certificate to hide this fact: subsequently M. Mastromarino, a former New Jersey dentist, was sentenced to between 18 and 54 years imprisonment.

The more contemporary of these cases illustrate that body-snatching is a practice which is not restricted to the dark days of the 19th century and will no doubt continue in illicit markets for the foreseeable future. Common themes linking all of these examples include: a dereliction of basic medical responsibilities by physicians; lack of compassion; complete disregard of the dignity and autonomy of the participants (and/or that of the relatives of the deceased); the *storage of body parts*; and, *the absence of consent* by the participants.

### **2.4 Informed consent and tissue banks**

A fundamental requirement of contemporary medical ethics is that of 'informed consent' be provided by a participant before any study, or procedure, can be performed as discussed above (2.2). However, the phrase is fundamentally misleading (Kaye, 2004), since it implies a comprehension of the relevant facts and all possible outcomes of the research. However, how can non-medically qualified members of the public truly be considered to be fully 'informed'? Indeed, by definition the researchers themselves can only best-guess the possibilities ('*if we knew what we were doing, it wouldn't be called research, would it?*' Albert Einstein). This situation is exacerbated in the case of biobanks where samples may be used in future research projects that have not yet been envisioned using techniques and technologies which have yet to be developed. Indeed, one study of biobank donors found that they did not consider themselves well informed about what their samples would be used for (Hoeyer *et al.,* 2005).

This issue was been addressed by the German Ethics Council which takes the view that: *'if donors have been informed of the indefinite nature of the actual future applications, they will be aware that they are agreeing to an uncertainty. This uncertainty is not acceptable if it involves more than minimum health risk which is not the case with Biobanks'* (Deutscher Ethikrat, 2010). Thus 'open' or 'broad' consent to future usage of donated samples has been proposed as best practice for biobanks (Hansson *et al.*, 2006). Similarly, the council of Europe's biobanking recommendation acknowledges the conflict between the traditional informed consent and the needs of population genetic databases, and as a result stated that consent need not be specific, but it must be as specific as possible with regard to unforeseen uses (Council of Europe, 2006).

Such proposals are not without their critics who see equivalence between the broadening of consent and the dilution of ethics which may result in increased public distrust (Hofmann, 2009). Though others have noted that actually the reverse may be true (Lipworth *et al.,* 2009). Some commentators have gone further, suggesting that for genebanks and for population databases, informed consent should be abandoned altogether (Kaye, 2004). Furthermore, in countries such as the UK where free healthcare is provided to all by the state, there is debate as to whether there is an automatic moral obligation upon patients to automatically donate any excess clinical material taken for diagnostic purposes to medical research: *i.e.* the introduction of an 'opt-out' as opposed to the current 'opt-in' system. Such 'opt-out' genebanks are already in operation in Europe (*e.g.* the Vanderbilt DNA databank) and have driven the development of new approaches to the governance as well as innovative public education and communications strategies (Pulley *et al*., 2010).
