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Human Subjects Research I Notes

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Human Subjects Research General Concepts and Distinctions Introduction Basic issue is how to balance the competing interests of society and the individual research subject. This stands as a good example of the conflict between deontological and teleological reasoning. A strict utilitarian approach would conclude that conducting experiments on a small number of people with or without their consent will be justifiable if the benefit to the rest of society is greater. For example, the discovery of smallpox vaccine by Edward Jenner. In contrast, a strict deontological approach would condemn any course of action that disregarded the wellbeing of individual research subjects, regardless of the benefits to the rest of society. Jonas has gone as far to say that research on humans involves treating subjects as 'things' and that we should not permit this, regardless of the consequences it might have for the people suffering from potentially curable diseases. In other words, erosion of morals > scientific progress. Both extremes are unattractive. Bottom line is: we all benefit from living in a society which drugs and other treatments have been properly tested. It might therefore be argued that we are under a moral obligation to incur some inconvenience or slightly increased risk to our health by participating in medical research. If we wish to benefit from experiments on humans, but are not actually willing to take part, could we be said to be 'freeriding'?
It is also important to remember that a third party might also be interested: that of the researcher, and the economic incentives they receive for devising, carrying out and publishing research. This may incentivise cutting corners at the cost of others' interests. Arguably boiling down to a utilitarian perspective: why make drugs for sick people who cannot afford them?
i. The position under international guidelines Under the Helsinki Declaration, in paragraph 5, it is said that "In medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of science and society". As a general remark about the obligations of the research community, the health care system, society or indeed of the world community, Harris finds that this remark is not sustainable. In particular, the rights and interests of research subjects are surely not served by privileging them at the expense of the rights and interests of those who will benefit from research. Both these groups are potentially vulnerable, neither is obviously prima facie more vulnerable or deserving of special protection. If anything, the research subjects are part of the larger group which will ultimately benefit from research. Harris suggests to say that the interests of the subject must take precedence over those of others, if it means anything, must be understood as a way of reasserting that a researcher's narrowly conceived professional interests must not have primacy over the human rights of research subjects. A. The dimensions of human subjects research a) What is 'research'?

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Research is generally any form of study undertaken to produce generalisable results. Clinical trials will often give rise to the doctor/patient duty of care. Great deals of medical research are carried out without making contact with patients e.g. research on health data and biomaterials as opposed to persons. Major difficulties would be posed if patients had to give informed consent to the use of information from things like medical notes taken by their doctors. Ideally, the patient's agreement to use of the information gathered during treatment should be sought, but if it would be impossible to obtain consent, then there are times, when anonymised data can be used for research purposes. The issues with this have been discussed previously and will also be briefly considered below. Compare this with innovative treatments/therapy, which may occur outside a doctor/patient relationship. The Helsinki Declaration endorses the use of unproven treatment where no other option exists. These are intended to achieve results for certain individual patients, and not generally for the purposes of creating generalisable knowledge. The desire of a desperately ill patient to try anything is understandable, but at the same time, patients may overestimate the likelihood of success and underestimate the risks of untested treatments. Expanded access to yet unapproved medicines may represent a clash between autonomy and informed consent. Accordingly, the fact that treatment is untested may be a material fact, nondisclosure of which might trigger negligence. b) What are the stages of research?
After satisfactory evidence from animal trials has been gathered, there are usually three phases of trials on humans. Phase 1 trials involve a small number of healthy volunteers, who are given the drug so that researchers can study its toxicity, and the way in which it is absorbed. Phase 2 trials involve giving the drug to a group of people suffering from the condition it is intended to treat in order to evaluate its effectiveness, and discover if it has any side effects. Phase 3 trials involve monitoring a larger group of subjects who take the medicine under supervision for a longer period of time (here, typically involve RCTs). Phase 4 trials involve looking at how the drug works in the real world, after distribution to the market, and will include patients normally excluded from the previous trials e.g. pregnant women and children. c) Distinction between therapeutic and nontherapeutic research Phase 1 trials are normally nontherapeutic, whereas Phase 2 and 3 are therapeutic. For certain drugs, it will be unethical to start on Phase 1 e.g. chemo drugs. The possible dangers of Phase 1 trials was illustrated in 2006 re the trial of TGN1412. The therapeutic and nontherapeutic distinction may be difficult to draw at times. As Levine explains, every trial has some components which are nontherapeutic. The principal consequences of labelling research as therapeutic is to weaken the protection available to vulnerable subjects. Patients who lack capacity can be enrolled in a research trial more easily if the trial can be described as 'therapeutic' even if it contains elements that are quite selfevidently nontherapeutic. VerdunJones and Weisstub are very critical of things being labelled therapeutic when the benefits are merely 'possible', 'hypothetical' or 'speculative'. There is also the issue of saying something is therapeutic when research is being conducted on its efficacy if it was therapeutic, then research wouldn't need to be done on it. Randomised control trials (RCTs) give rise to further issues in this context: in a placebo controlled RCT, there may be a 50% chance the patient will receive no treatment at all. Is such a trial 'therapeutic'?
i. Component risk analysis an alternative approach

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A better approach outlined by Weijer is to analyse research in terms of its therapeutic and research components. Therapeutic components are the activities researchers do which they know may prove of therapeutic use to the particular individual, and which could be undertaken lawfully and ethically by a doctor treating a patient. In contrast, research components are the activities that are done without any likelihood of benefit for the patient. These activities would not occur save for the fact that the doctor is trying to produce generalisable knowledge. What appears to be a singular research programme will often consist of a mix of components. The value of component risk analysis lies in the fact it enables the activities a researcher carries out with therapeutic warrant to be analysed separately from the thing the researcher does that are solely intended to serve the public. The risks associated with the former (i.e. therapeutic) are not special (researcher only needs to show risks are compatible with normal clinical standards of care, and that they have observed the principle of clinical equipoise), but the risks associated with the latter (nontherapeutic) are. Here, the researcher uses the patient in order to serve a wider population and hence special mechanisms of oversight as warranted to ensure the patient is not exploited or exposed to unnecessary risk. In short, the value of component risk analysis is that it enables the incremental risk associated with the search for scientific knowledge to be distinguished and regulated differently from risks associated with attempts to improve the patient's personal situation. The conventional classification of therapeutic and nontherapeutic research distinguishes risk in a less than sophisticated way by aggregating associated risks (both clinical and research) into a single net calculation. As might be expected, most research related deaths occur in situations where research is classified as having 'direct benefit for the subjects' (i.e. therapeutic research) because aggregate risk analysis does not pressure researchers to minimise research risks. Aggregate risk analysis also tends to preclude research when the patient suffers from a condition which there is no effective therapy, yet the research risks are minimal. B. The regulation of human subjects research As a result of the Nuremberg trials, the court at Nuremberg set out a Code to govern the future conduct of medical research in order to protect the subjects' interest. Although this code has symbolic value, its impact on the medical profession has been limited since most of it was drafted on the basis of addressing the abuses of Nazism. Interestingly, there is a comparison which can be drawn between the Nazi's willingness to sacrifice some lives in order to save others (e.g. Gerhard Rose's consequentialist 'epiphany' of sorts), and the Allies' similar preparedness to knowingly sacrifice some conscripts' lives for the greater good. In 1954, the World Medical Association drafted the Helsinki Declaration. This goes into much greater detail than the Nuremberg Code as to the circumstances in which research on human subjects is legitimate. It now also specifies that its provisions must not be diluted by national legislation. Importantly, para 9 of the Helsinki Declaration states that it is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self determination, privacy and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent. The impact of these international codes can be summarised as follows: A. Before the research starts:

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it must be established that the research is scientifically valid; the risks must be proportionate to the benefits; the research protocol should have been approved by a research ethics committee (REC); if the subject has capacity, they should generally give consent; if the subject lacks capacity, other protections must be in place.

B. During research:

the experimentation must be stopped if there is a risk of injury or death;
the experimentation must be stopped once equipoise is lost;
the subject must be free to withdraw from the trial at any time. C. After research has finished:

the subject should have access to information about the trial, and to treatment which has been proven to be effective as a result of the trial;
research findings should be disseminated;
subjects who have been injured as a result of the trial should be appropriately compensated. More general principles include: (1) to be ethical, research must satisfy the requirements of good scientific practice; and (2) risks to participate must also be reasonable in relation to the trial's anticipated benefits. This latter requirement is somewhat misleading though since it does not make clear how much risk is reasonable to impose on subjects if the benefits might be very great indeed, and because the outcome of the research is necessarily unknown, the researcher will rarely be in a position to know exactly what risks and benefits might flow from the research. a) Regulation of human subject research in the UK i. Clinical Trials Regulation 2014 The EU regulation (which repeals the old Clinical Trials Directive 2001) on clinical trials on medicinal products provides that clinical trials may only be conducted if the rights, safety, dignity, and wellbeing of subjects are protected and prevail over all other interests, and it is designed to generate reliable and robust data. Clinical trials must be subject to scientific and ethical approval, carried out by a properly constituted ethics committee. ii. Guidelines In the UK, a variety of bodies have issued guidance on good practice in research. All reproduce the fundamental principle that the subject's health and wellbeing take priority. iii. Ethics Committee The favourable opinion of an ethics committee is a necessary precondition of any clinical trial. The Clinical Trials Regulation sets a time limit of 60 days between receipt of a valid application and the issuing of the REC's opinion, unless the trial involves something like gene therapy or somatic cell therapy (the time limit is then 180 days). Generally speaking, RECs approve only those studies

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whose risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. RECs commonly comprise between 1218 members. Their responsibility is to ensure the research involving human subjects is ethical. RECs exercise little ongoing scrutiny of research after the protocol has been approved. While progress reports must be submitted, the committee's role is largely confined to collecting information volunteered by the researchers, rather than investigating compliance for itself. There has been some debate over whether they have any role in judging the scientific validity of the research (see below).

Controversies regarding research on persons A. Consent to participation in research a) Competent subject voluntariness and informed consent i) Voluntariness Relevantly, Nelson et al. have argued that voluntariness is not a valueladen concept, and that two conditions are necessary and sufficient for an action to be voluntary: (1) intentionality (which is black or white); and (2) substantial freedom from controlling influences e.g. exploitative or undue influences (which is a spectrum). Accordingly, the concept of voluntariness itself is a one of degree. The moral implications of payments to research subjects, constraining situations, and those suffering from mental illnesses, falls within the latter category. The concerns re those without capacity tend to fall within the former category. It is important at the outset to note the following: the possibility of the exploitation of subjects does constitute a danger, but to deny these subjects the opportunity of participating in research can be paternalistic or at odds with the principle of equality of access to research and medical care. Denial of research opportunities to desperate persons would be to refuse them, in many cases, the very conditions they seek to increase their degree of control and to make voluntary choice meaningful (i.e. a hypocrisy argument). I. Payments Payments are not morally problematic when the offers to participate in research are welcome, persons do not want to refuse, and the risks are fairly low. They do become problematic as (1) risks are increased to an elevated level, (2) more attractive inducements are introduced, and (3) the subjects' economic disadvantage, or lack of alternatives or resources, is increased. If risks, inducement or disadvantage are elevated too far, exploitation (as opposed to undue inducements) may be happening. The condition of an irresistibly attractive offer is necessary for undue inducement but not sufficient itself to make it exploitative or involuntary here see Cohen's definition of exploitation. To conflate exploitation or undue influence with involuntariness is to mix moral questions and psychological questions (which links back to Nelson et al's understanding of voluntariness as a value neutral concept, albeit one linked to the satisfaction of conditions which may of themselves be valueladen). Paying people to participate in research has been criticised for several reasons. First, it has been argued that an offer of money may prove irresistible for the poorest sections of society (a form of undue influence, bordering on exploitation). It is already the poor that are socially disadvantaged and more likely to suffer from illness, and yet it is typically the better off members of society who benefit from research. Thus, inducement to take part in medical research should not be allowed

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when it adds to existing risks, or encourages the taking on of risks which otherwise one might not take on. Not only could money persuade poor people to volunteer for research, but it might also offer an incentive to misrepresent characteristics such as depression or drug use which would otherwise disqualify someone from participation. This may increase the health risks to participants as well as potentially invalidating the trial results. Secondly, the taint of money could be seen to contaminate the ethical virtue of altruism. In other words, some things simply should not be commodified. Thirdly, because payments may skew subject selection, they might also undermine the robustness of the trial's results. In favour of payments, it could be argued, first that since participation in medical research will often be timeconsuming, inconvenient and uncomfortable, without payments it might be difficult to recruit enough participants. Secondly, it is not clear why being paid to assume burdens of research is more problematic than being paid wages to do dangerous jobs e.g. miners. In other words, money is not necessarily coercive. Thirdly, the offer of experimental treatment to desperately ill patients, and the 'therapeutic misconception' will often offer a more powerful incentive than money for agreeing to participate in research, and for misrepresenting disqualifying characteristics. Fourthly, the GMC guidelines on payment accept that they should be provided so long as they are not so large that they might prompt someone to act against their 'better judgement'. In line with this thinking, Grady has argued that modest payments to research subjects are justified. Lemmens and Elliot however think that modest payments are disingenuous. They argue that it would be better if there was a straightforward admission that researchers employed the research subjects as employees, thereby giving them more rights and entitlements. In this regard, there is certainly evidence that some people are professional trial participants. Note however, there is a question here with what is meant by 'better judgement' in this context: surely, where the research is well founded, has important objectives, is of minimal inconvenience and risk to the participants etc., then 'better judgement' could not be overborne by provision of monetary inducement anymore than being paid undermines the ability to engage in voluntary employment. The situation may very well be different if the form of inducement was drugs, and the participant a drug addict (here the influence or inducement is undue, not because it is improper to offer incentives to participate, nor because participation is against the best interests of the subject, nor because the inducements are coercive in the sense that they are irresistible, but rather because the type of incentive offered is illegitimate or against the public interest or immoral in itself). Fundamentally, a distinction must be drawn between undue inducements (inducements which need not be made) and inducements which are undue (wrongful forms of inducement). Harris is of the position that undue inducements are acceptable if the conduct they promote is ethical and worthwhile. Further, underlying these arguments about payments is a deeper concern re whether payments should be capped, and whether the autonomy of the research participants is undermined (something that is glossed over above, but which should be afforded greater weight in an increasingly materialistic society). Arguably, if payments were not capped, then there would be less of an inequality issue, but at the cost of potentially coercing poorer individuals. There would also be the issue of funding the payments. Here, it might be argued, to respect the research participant's autonomy, that it should be allowed for them to pay not to participate in research. Using funds from this could then attract willing research participants. This also respects the fact that the research participant is the best individual to determine what their time, inconvenience etc. is worth to them. II. Patients

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There is a danger, as mentioned, that patients who volunteer may not understand (i.e. going to lack of intentionality) that they are taking part in research, where the purpose is generating generalisable knowledge, rather than improving their health. This is known as the 'therapeutic misconception'. Standard consent forms can exacerbate this problem by setting out what the study hopes to achieve for future patients. Confusion between the goals of the research and what patients hope for themselves is then inevitable. King argues for this reason that consent forms should be more blunt. It is often difficult for patients to understand that, despite the doctor/patient relationship being built on trust, their doctor might be suggesting a course of action that may not be in their best interests. It is indeed common for patients to feel grateful to the medical team which is caring for them, and if asked to participate in research, refusal may not feel like a realistic option, especially if they have an ongoing relationship with the doctor who has invited them to take part. In this regard, a patient's vulnerability and dependency may make it harder for them to object. III. Other vulnerable groups Medical students or junior employees may feel pressure to agree to participate in their teachers' or employers' research projects. The Helsinki Declaration requires researches to be particularly cautious if the subject is an a dependent relationship, and to ensure that consent is taken by an independent physician. Prisoners may also be vulnerable in the sense that small financial rewards may be disproportionately attractive to individuals deprived of earning opportunities. More worryingly, prisoners may also wrongly believe that participating in research may lead to early parole for other privileges, and as a result, feel like refusal is not an option. In this regard, it has been argued that prisoners should only recruited where incarceration is directly relevant. IV. Constraining situations These are situations where the patient feels forced by the circumstances to do something. Constraining situations are not intentionally coercive. A person may feel constrained due to a number of factors e.g. severe illness, lack of basic resource, offer of high risk procedure, emotional burdens etc. Such situations can lead to deprivations of voluntariness. Broadly speaking, the issues discussed above re payments and other vulnerable groups (and to an extent, also the discussion re patients and the therapeutic misconception) are examples of constraining situations. ii) Information Treating someone without their consent may constitute battery. For consent to be valid, the patient must have been informed in 'broad terms' about the nature of the treatment. If someone has not been told that she is participating in a trial, her consent may not be real and a charge of battery might be possible. Of course, the question of informed consent begs the question of how much information an individual has to be given before their consent can be considered 'informed'. GMC guidelines flesh this out a bit more. Subjects must obviously be told of risks involved in the participation, but there are also grey areas e.g. do participants need to know about any personal or financial benefit that the researchers may receive as a result of the trial? Here, compare with the consent requirements re treatment.

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