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Research with Vulnerable Human Subjects Central Controversy and Regulatory Mechanisms Vulnerable human subjects Vulnerable research subjects can generally be classified under two broad headings: (1) those who are unable to give informed consent; and (2) those who are vulnerable for policy reasons. Children and incapacitated adults fall under the first category, whereas prisoners, asylum seekers, third world country residents, and junior medical professionals are examples of those whom fall under the second. However, the main issue with classifying vulnerable research subjects by category is that this may hide individual vulnerabilities and may gloss over contextdependent factors. a) What are the issues?
The main issues concerning research with vulnerable subjects are as follows:
1. Lack of adequate protection;
2. Heightened need for the benefits of medical progress; and
3. Invisibility in terms of research participation seen but not heard. b) Sources of legal protection, regulation and governance The main sources of legal protection come from various pieces of legislation e.g. the Mental Capacity Act, the Data Protection Act, the Human Tissue Act etc. These are then supplemented by various domestic and international guidelines: the Helsinki Declaration, the ICHGCP Guidelines, the CIOMS Guidelines, the EU Clinical Trials Directive etc. The main legal and regulatory tools used to manage research in general include: research reporting requirements, monitoring and tracking of research projects and participants, setting standards for institutional responsibility, informed consent requirements, the concept of clinical equipoise, compensation and insurance requirements, research ethics committee approvals and oversight, principles on risk/benefit ratios, payment/inducement restrictions, research suspension powers etc. Additional tools augment the playing field when vulnerable research subjects are involved to ensure their inclusion: proxy consent mechanisms, best interest considerations, altruistic decision making, substituted consent etc. The common law would also occasionally be relevant. For example, a researcher may be potentially liable in battery or negligence for acts done to incapacitated adults which normally require consent if those acts were not consistent with their 'best interests' and the Bolam principle. On this basis, 'nontherapeutic research' is very unlikely to meet the 'best interests' test. Additionally, one might consider whether the Montgomery test would apply in this context, and whether there should be a recognised fiduciary duty between the researcher and the patient. c) Ethical accounts of research with vulnerable subjects i. Consequentialist account Involving vulnerable patients in research produces the maximal balance of positive value over disvalue for all those affected. The knowledge we learn from exposing a few say, incapacitated adults, to the risk of untested drugs and procedures will help prevent deaths and suffering in a
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much larger number of incapacitated adults who suffer from the same condition or disease. For example, there is no other way to ensure reliable therapies for Alzheimer's than to test the therapy on those patients. The utilitarian argument does not however advocate unconditioned research. The calculus gives weight to the importance of being able to trust that doctors will not seriously harm their patients, and that individuals will not be unfairly singled out for research, and that patients' individuality and dignity will be respected. Critics would raise that the utilitarian concern for these values unreliably protects them in the face of their overriding concern to maximise good consequences. Furthermore, the utilitarian rarely has proof these values do in fact improve utility. Accordingly, if we take the flaws in utilitarian reasoning seriously, we must reject the proresearch arguments. ii. Political consensus Liddell et al. argue that political consensus is a sensible way to establish and assess the fairness and legitimacy of a legal policy given the extensive moral pluralism that characterises debates about bio law. The logic behind this is that it is preferable for the sake of social stability to introduce laws that reflect an overlapping consensus of reasonable moral beliefs rather than assert that one particular moral viewpoint is true and others false. This view assumes of course a stable and acceptable baseline of moral viewpoints in a particular society, which itself may run into troubles if political consensus is to be obtained crossborder (which may be necessary re global health policy). Expanding on the idea of overlapping consensus, it gives all those affected genuine reason to think that their moral viewpoints have been understood valued and respected. We lacked the detailed empirical data to know whether Lewis is right to think that international agreements that support research with say, incapacitated adults, are merely a front for utilitarianism or whether they were aimed at moral overlap. Liddell et al. seem to think they suggest the latter, especially in light of the extensive conditions and constraints decided upon things like the Helsinki Declaration. iii. Ethical principalism Ackerman argues that moral beings have three relevant interests: exercising autonomous choice, securing fair treatment, and protecting and promoting high standards of personal welfare. These interests generate obligations owed by other individuals, including doctors, and putative research subjects: 1
Autonomous choice reflected in obligations of interpersonal conduct, including obligations to respect the capacity of persons to deliberate about, and act on, their life plans. In research settings, this is generally given more specific recognition in duties to secure informed consent, and to respect the privacy of persons and the confidentiality of data.
4. Fair treatment generates an obligation to distribute the benefits and burdens of cooperative social endeavours so that each person has an equal opportunity to pursue their life plans. In the research setting, this means subjects should be selected in ays that do not impose arbitrary or heavy burdens on specific classes of persons, that subjects with special vulnerabilities should be more strongly protected than less vulnerable subjects, and that the benefits of research should be fairly allocated.
5. High standards of personal welfare generates obligations of beneficence. This means doctors and society generally have a duty to avoid designing trials that would deprive individuals of reasonable standards of medical care, to assess the safety and efficacy of
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standard medical procedures whose value is uncertain, to minimise risk and to avoid exposing any person to serious risks not intended for their benefit. An obligation also exists to provide and enhance the essential conditions its members need to pursue their life plans e.g. health care, of which medical research is a major component.
iv. Kantian obligations O'Neill explains that Kantian autonomy is very different from the standard bioethical understanding that portrays autonomy as an entitlement to independence and the freedom to make objective choices (which is more like liberty). Kantian autonomy is the obligation to reason rationally; more specifically, an obligation to live a life according to laws or principles which could be chosen by all, or in other words, according to reasons that are acceptable to other rational beings. This is a kind of principled autonomy. The Kantian notion that we should respect the autonomy of others is really saying we should respect the principled autonomy (rational decisions) of others. The principles that comprise principled autonomy are constrained by the idea they should be universalisable, and not selfdefeating. They are best formed as obligations e.g. obligation not to deceive or coerce; obligation to support and assist others who are vulnerable even were it exposes people to risks that they may themselves not elected. This latter obligation is the groundwork for O'Neill's views on public health ethics: "Although [the rejection of indifference] cannot require any individual to render all needed assistance to all others in all predicaments (an impossibility), it demands more than the sporadic meeting of others' needs, for example, by the episodic charitable donations or emergency aid... [In most circumstances] it is best expressed by supporting social and political institutions and practices that reliably reduce and limit vulnerability by providing a reliable degree of security and subsistence for all." These ideas have major implications for the governance of research: 1
An individual's consent is not absolutely essential to justify research although consent can be a way to respect another person's autonomy, Kantians are not wedded to the idea of respecting an individual's mere sheer choice. An irrational, unprincipled granting or withholding of consent is not held in high regard. Autonomy is an obligation which should be met over the course of a life, and not at every instant. Especially re those who are unable to consent e.g. incapacitated adults or mentally retarded children, it might be said they have no rationality to respect and so there is no need to respect their autonomy. This is not to say we should disrespect them, because others will be expected to support their capacity for rational action as far as possible.
6. Rational beings are morally obliged to support research activities that work towards safe, effective health care, if the risks are not serious a Kantian could be expected to agree that a policy based on cooperation is better than conscription, but that limited exceptions are permissible where the efforts to seek the individual's views, or that of their personal rep, are impractical or impossible, and the patient has not actively refused. v. Summary of position The ethics of research involving vulnerable subjects is not dependent alone on utilitarian reasoning. Provided it is properly conditioned, there are several established lines of ethical
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reasoning that regard it as being consistent with respect for the equality of persons, human dignity and individual integrity as well as serving the public interest. Unless all these diverse lines of reasoning are to be dismissed---and another theory shown clearly to be preferable---laws and proposals that facilitate research with vulnerable subjects to strict conditions and oversight deserve more than the ambivalent support they currently receive. d) Conditions under which research with vulnerable subjects should be allowed Liddell et al. argue that research involving vulnerable subjects should be based on a good scientific case, including sound prior research, clinical equipoise and sensible methodology. It should occur only when there are no alternative means to carry out the research without involving vulnerable persons, and the benefits to society are broadly proportionate to the risks to the individual. It is also important to abandon the notion that 'therapeutic research' is 'better' than nontherapeutic research, turning instead to component risk analysis. In this framework, the research risks (including physical, psychological and social risks) must be minimal, minimised and monitored. Liddell et al. also support the need for procedural safeguards including ethics committee review (by independent people who have the knowledge and experience to ascertain whether the risks are reasonable and proportionate) and, where contactable, review by a representative who knows the individual and can thus attempt to reason as the individual would. Together, these requirements respect the autonomy of the individual (so far as possible), provide an environment for improving medical standards, ensure that harm and infringements of privacy are minimal or nonexistent, insist researchers abide by professional obligations to act beneficently and in the best interests of patients and protect vulnerable patients as people with equal rights to privacy, dignity and well being.
Case Study: Research on children What is the problem?
Research on young children is important for a number of reasons e.g. their bodies respond to treatment differently to adults, and some illnesses only affect children. Because of this, it is important to find ways to make sure children and young people are given the option of taking part in research, and not simply subjected to it. A corollary is to make sure they are protected from harm whilst being a research subject. The Nuffield Council on Bioethics (NCB) have made clear that research must not be carried on children, but with them. a) Context surrounding the problem The way in which children, young people, and parents respond to the possibility of participating in clinical research is likely to depend on three factors: the nature of the research, the situation of the children and their families, and the relationships between researchers and families. Children and young people themselves are involved in participation decisions in very different ways, and these do not simply correlate with age, but also other factors like the severity of illness, the suddenness of the diagnosis or the opportunity to partake in research, the children's prior experiences, and the general family dynamics. In contrast with the contextspecific decision making described above, the regulatory approaches focus more on the role and status of the decision maker. In most cases, children or minors are assumed to be unable to make their own decisions, and authorisation is required from a parent or legal guardian. International declarations, regulations and guidance take diverse approaches to the extent to which children or young people should be involved in the decision (which makes
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sense since childhood and maturity is a cultural construct). They also set a number of threshold criteria that studies must meet, relating to the value of the research, the balance between benefits and burdens, and the management of risk. The design of research studies is subject to a detailed scrutiny process, involving both scientific (peer) and ethical review, to ensure that these requirements are met. In particular, the younger the potential participants, the more research ethics committees tend to lean towards a protective or 'parentalist' approach. a) Distinction between involving competent child and competent adult in research In order to consider what it is that is potentially different, ethically speaking, about children and young people in research, we identify three distinct paradigm cases: situations in which a child's or young person's potential for input into a decision about research raises distinct ethical questions: 1
Children who are not able at this time to contribute their own view as to whether they should take part in research, such as babies and very young children, or children who are temporarily unable to contribute because they are so unwell or are unconscious (Case One);
7. Children who are able at this time to form views and express wishes, but who are clearly not yet able to make their own independent decisions about research involvement (Case Two); and
8. Children and young people who potentially have the intellectual capacity and maturity to make their own decisions about taking part in a particular research study, but who are still considered to be minors in their domestic legal system (Case Three). All children, at the beginning of their lives, will fall into Case One. Most will progress over time to Case Two and Three. This progression need not be linear, and the nature of the particular research decision to be taken, and children's and young people's physical, emotional and mental condition at the time, will also determine which case is applicable for this child or young person for this decision. Notably though, a factor that unites all three cases, correlating directly with this developmental nature of childhood, is that children have parents who play an important role, from both legal and ethical perspectives, with respect to making decisions on their behalf. i. Responsibilities of parents Ethical considerations that parents should take into account when making decisions with or on behalf of their children include:
* Respect for children as individuals, regardless of their age or capacity. This may, for example, be expressed through consideration of children's wishes, and respect for their bodily integrity, although children's wishes may not always be determinative
* Recognition of children's developing capacity for autonomous agency and the supportive or educational role of parents in helping their child develop and 'practise' decisionmaking skills and confidence
* Concern for children's immediate and longer term welfare. Immediate welfare interests at the time of the research may relate to factors such as any pain, anxiety, distress, or enjoyment associated with participation in research. Longerterm welfare interests relate to children's and young people's future 'good' including, but not limited to, questions of what is 'best' for them in terms of their physical health or personal interests. Parents also have a responsibility to seek to influence the values that their child acquires as they grow up, and to shape the kind of person
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their child becomes. This 'shaping' includes influencing how children understands their responsibilities to others, as social beings. ii. Decision making in the three cases In Case One, the sole focus is on the role of others in making decisions on their behalf. Children in Case One are clearly vulnerable in ways that children in Cases Two and Three are not. Parents' primary concern will be the welfare of their child. In Case Two, parents will need to determine how their child's views should be balanced against their welfare. In Case Three, the distinctive feature is the children or young person's potential capacity to make research participation decisions for themselves. Nevertheless, parents still retain important responsibilities with respect to promoting their children's welfare and seeking to influence the way they grow. The NCB suggest that instead of seeking primarily to identify who is able to provide legally effective consent, the ethical focus should be on obtaining agreement within the family unit. Accordingly, there is a morally significant difference between 'competent children' and 'adults', which may potentially justify differential treatment. Children, however intellectually capable, do not have full adult powers - and the corollary of that is that they also do not have full adult responsibilities. Parents are there, both ethically and legally, to share that responsibility until the agreed threshold of adulthood is reached. In making this claim, it is crucial to acknowledge that 'childhood' is, at least in part, a social characterisation that will vary from society to society. The law in each society will set a norm judged appropriate for this parental power and responsibility to end: that is, the age of majority. It will vary around the world, and move over time; some jurisdictions may also choose to specify different ages for particular aspects of parental power to end. However, a line is always drawn somewhere. b) Are children vulnerable?
The straightforward association often made between 'childhood' and 'vulnerability' was strongly challenged throughout the NCB's consultative activities. In many cases, the factors that may potentially make children feel, or be, vulnerable in the context of clinical research do not arise inevitably because of the nature of childhood; and nor are they necessary features of research. Rather, they arise in the context of the developmental nature of childhood - experienced, for example, in young children's need for practical and emotional support in understanding what is proposed, or anxiety about the impact of research participation on their school life. Once the relevance of this context is recognised, there will often be scope to reduce vulnerability by modifying some aspects of the research. The risk is that an unduly protective response to perceived or actual vulnerability may not only exclude children and young people from opportunities to participate in research activities, but also harm the interests of many children in the future by preventing potentially valuable research from taking place. NCB suggest an appropriate response by professionals to concerns about children's potential vulnerability in research is to ensure that they work in partnership with children, young people and parents throughout the whole endeavour of research. Such an approach implies a fundamental shift from seeking to protect children 'from' research, to protecting them through their own active engagement with the way that research with children and young people is designed and carried out. i. Payments and distortion of worth by children
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