Patricia Swift, BSc, RN
Clinical Trials Coordinator/Nurse Practitioner, East Kent Gynaecological/oncology Centre, Queen Elizabeth the Queen Mother Hospital, Margate, Kent
Clinical trials are carried out at most cancer centres and are an important part of implementing best treatment across the UK. Clinical trials relate to all cancer treatments: surgical, pharmacological - such as chemotherapy, and gene therapy - and radiotherapy. Such trials normally work by comparing the present known best treatment with the new proposed treatment, sometimes with a third option of combining the proposed treatment with the current treatment in oncology-related trials.
This paper looks at the ethical issues within clinical trials, in the context of the utilitarian philosophy of John Stuart Mill (Norman, 1983) which advocates the ‘greatest happiness to the greatest number’. The ethical issues of research aims, autonomy, truth and value (Figure 1) are discussed, together with the historical issues that led to the Declaration of Nuremberg in 1947 (US Government Printing Office, 1949; Shuster, 1998) and the International Harmonisation Tripartite Guidelines of Good Clinical Practice (International Conference on Harmonisation, 1997).
These issues are particularly topical in the light of the Government’s cancer plan (Department of Health, 2000) and reorganisation of cancer research structures, alongside a major increase in investment in cancer research (DoH, 2002).
Issues discussed in this paper are particularly relevant to the oncology patient. There are issues surrounding the phase 1 and 2 trials (discussed in the section on ‘Value’) where a patient with metastatic cancer is asked to travel for treatment that may not be of benefit - where a degree of altruism is asked of the consenting patient. In addition, there are emotive issues. A patient whose aim is survival may want the ‘new treatment’ in a trial. Protocols for oncology patients have to include provision for the possibility of relapse. Surgical protocols have to have provision for diverting from the protocol at the time of surgery in the light of hitherto unknown findings. The Research Governance Framework for Health and Social Care (DoH, 2001) includes ‘Respect for participant’s dignity, rights, safety and well-being’ but even within this context the above issues present particular dilemmas for oncology patients.
An ethical framework
A good understanding of the ethics behind clinical trials is essential, along with a grasp of the formats and legislation that surround research. The framework used here is based on the components of an ethical question (Johnson, 1990), which are:
This structure allows for the inclusion of the ethical principles of autonomy, beneficence, non-maleficence and justice.
Before the first Declaration of Helsinki in 1964 (World Medical Association, 1975) the first attempt to protect patients from inappropriate research was the Declaration of Nuremberg in 1947 (US Government Printing Office, 1949).
In spite of this, patients continued to be randomised into clinical trials without their knowledge or consent. The Declaration of Helsinki was updated in 2000, and is the most recent multinational tool for monitoring clinical trials. The purpose of the Declaration of Helsinki is to remind the medical profession of their ethical duties towards their patients in order to protect the patients.
This is reiterated by the Declaration of Geneva (WMA, 1994), which states: ‘The health of my patient shall be my first consideration’ and the International Code of Medical Ethics (WMA, 1983), which states: ‘A physician shall act only in the patient’s interest when providing medical care.’ These two principles suggest that the interests of the patient are well protected, but aspects of the clinical trial are still open to question.
A philosophical framework
The most fitting underlying philosophy for application to clinical trials is the utilitarianism of John Stuart Mill (Norman, 1983), because in a medical trial the main beneficiary is not the subject.
From this perspective, the purpose of clinical trials is to produce an improved, safe, treatment to be used for others, in line with the view: ‘The first principle is that our actions should produce the greatest happiness overall’ (Crisp, 1997). Duty is seen as ‘a form of moral obligation (which) may become a vital constituent of human happiness itself’ (Crisp, 1997). These two principles provide an ethical reason for clinical trials and a sense that in doing so, duty is being done.
Examples of cancer trials
Clinical trials in oncology, as in other specialties, are the main way to prove the efficacy of new medications, forms of chemotherapy, radio-therapy and surgical procedures. In human subjects, trials are conducted over a long time, often in three phases. The first stage may include small numbers of patients with severe metastatic disease, investigating the increase or frequency of drug dosages and monitoring adverse side-effects. The second stage may investigate the overall effectiveness of the treatments; and the third may compare the proposed new treatment regimen with other current treatments. It can be seen therefore - particularly in phase 1 and phase 2 trials - that the subjects are being asked to take part in something from which they may not benefit at all.
Aims of research
The aims of the clinical trial, according to the Declaration of Helsinki (WMA, 2000) are: ‘To improve diagnostic, therapeutic, and prophylactic procedures, and the aetiology of the disease.’ These aims appear to be basically scientific, with the researchers as the main beneficiaries. However, the danger of over-scientific research is that: ‘The self-absorption of the expert tends to work against the client’ (Keohn, 1994). This can arise when the expert wishes to delve ever deeper, perhaps losing sight of the initial purpose of the research. For this reason, a monitor is appointed to all clinical trials, as well as the regulation on local research ethics committees. Committee members are drawn from professional members of the community to give an unbiased view. However, because of their excessive workload it is difficult to monitor every trial and they rely on the honesty of the medical staff in charge of the trial.
The expected outcome of any clinical trial - to benefit future patients - does meet with Mill’s utilitarian philosophy: ‘Actions are right in proportion as they tend to produce happiness’ (Himmelfarb, 1985). If, however, the outcome of the trial is opposite to the intended outcome/ hypothesis, then, according to this philosophical point of view, conducting it would have been wrong - ‘(Actions) are wrong as they tend to produce the reverse of happiness’ (Himmelfarb, 1985).
To follow this consequentialist philosophy to its natural conclusion could lead to the absence of trials altogether, because of the fear of doing wrong. Yet not conducting medical trials would in turn lead to potentially greater unhappiness, due to lack of progress in treatments and cures, producing a fresh ethical or philosophical conflict.
To facilitate safe clinical trials the Declaration of Helsinki (WMA, 1975) declares: ‘Medical research involving human subjects should be under the supervision of a clinically competent medical person.’ As a part of the protection mechanism for the patient, the trial protocol is always presented to the local ethics committee for approval. For further guidance, the International Harmonisation Tripartite Guidelines for Good Clinical Practice (ICH, 1996) contain detailed procedures for all involved in conducting trials to follow. They state: ‘The rights, safety and well-being of the trial subjects are the most important consideration and should prevail over the interests of science and society.’
Hope (2000) has argued that, in the long term, the part of the Declaration of Helsinki concerning the interests of the patient over those of society may not, in fact, be in the best interests of society (WMA, 2000). He raises concerns about the practice of stopping a randomised controlled trial when one treatment is seen to be superior. This results in a shorter testing time for the treatment, even though, in the longer-term, ‘by establishing with higher levels of certainty what treatments are best, it is likely that therapeutic progress will be more rapid’ (Hope, 2000).
Running the trial for longer means patients randomised to the previous best treatment might not receive the most up-to-date treatment. But they are receiving the previously thought best, he argues. This gives a greater chance to both prove the new treatment and eliminate possible late side-effects.
Hope’s view begs the question of how long a trial should continue after one treatment is shown to be more beneficial than another. What if the media discover the outcome of the trial early, leading to all patients opting for the improved treatment regimen, bringing the trial to an early and natural close? At present, if one or other of the treatments is shown to be the best for the patient, the trial is stopped, and all patients can be given the new best treatment.
The principle of beneficence appears to lean in favour of patients of the future, although one could argue that current patients are benefiting from previous trials. Non-maleficence is ensured as far as possible by both the Declaration of Helsinki (WMA, 2000) and the International Harmonisation Tripartite Guidelines for Good Clinical Practice (ICH, 1996).
Autonomy has been defined as ‘the capacity to think, decide, and act on the basis of such thought and decision freely and independently’ (Gillon, 1990). In clinical trials, patient autonomy is protected by criteria laid down by the Declaration of Helsinki (WMA, 2000), and by informed consent.
The basic criteria are:
- Human subjects must be treated humanely
- The subject must be given the right to withdraw
- The trial should be patient-oriented.
Mill’s view on autonomy (as discussed in Singleton and McLaren, 1985) seems clear: ‘That the only purpose for which power can be rightfully exercised over any member of a civilised community against his will is to prevent harm to others; his own good, either physical or moral, is not sufficient warrant … over himself, over his body, and mind, the individual is sovereign’. Thus the only legitimate reason for power to be exercised over another person is to prevent him harming others. To simply restrict an individual for his own good is not reason enough. This view appears to suggest that utilitarianism is pro-autonomy, and therefore in favour of informed consent.
Informed consent is summarised as: ‘To be given a clear explanation of any treatment proposed, including any risks, and any alternative, before deciding whether to agree to treatment’ (DoH, 1992).
How much information to give the patient is often an issue, although now that widespread information is available on the internet, to withhold information is not practical. Nor does it comply with the International Harmonisation Tripartite Guidelines of Good Clinical Practice (ICH, 1996).
It is usual to offer a verbal explanation, followed by a written leaflet explaining the trial processes and the treatment, randomisation, and pointing out that the patient has the right to withdraw at any time. The information has to be written in clear and non-technical language (ICH, 1996).
At first glance, informed consent seems to be only a good thing, giving the patient a chance to accept or refuse a particular treatment. However, giving consent has been interpreted as foregoing autonomy, and handing over, temporarily, power to the physician (Habiba, 2000). Consent is therefore only required ‘as a defence for doctors against legal liabilities, to encourage patient co-operation, to provide a response to society’s emphasis on individual’s dignity and rights’ (Habiba, 2000). On the other hand, as well as being a legal requirement, giving consent can make the patient feel that he or she is in control and has knowledge of the procedure.
Preserving patient autonomy complies with the principle of beneficence, and this includes both offering the patient information about the treatment and the patient giving informed consent.
The principle of non-maleficence is covered in the points about the humane treatment of human subjects and not harming the patient. The principle of justice revolves, again, around informed decision-making by the patient.
The truth about any clinical trial is that the patient is being asked to take part in a venture that may, or may not benefit him or her, depending on the randomisation, and that may or may not benefit future patients, depending on the trial outcome. A lot is being asked of the patient. Using the principle of justice as the tool, the patient should be allowed to consider the (utilitarian) ratio of pleasure over pain (Crisp, 1997) before consenting to any treatment.
Telling the truth about the extent of a patient’s disease and the proposed treatment is a relatively recent concept. The paternalistic view that the doctor knew best was, and still is, accepted by many people. Mill’s view on truth-telling appears to be in opposition to his view on autonomy, with the utilitarian principle stating that: ‘In order to improve outcome, it may be necessary to withhold, or give biased information even if this diminishes autonomy’ (Singleton and McLaren, 1996).
As 1954, it was stated that ‘Deception is completely moral when it is used for the benefit of the patient’ (Leslie, 1954). Even in the present day, there is a case for ‘therapeutic privilege, if there is deemed a possible risk of harm through information’ (Dimond, 1993). Tradition, and the paternalistic view of the physician, can lead to involuntary coercion to take part in trials, with patients only consenting because they believe the physician knows best. Further coercion can occur with the patient wanting to ‘assume that (the research project) is well designed, and well executed, that the investigator is competent to undertake the study, (and) that the study will be run efficiently and safely’ (Jamarozik, 2000). Jamarozik compares the efficiency and safety of clinical trials to riding on a bus, where autonomy is temporarily compromised, but the client enters willingly. To ensure safety, ethics committees should have more power and time to oversee the progress of research trials, he argues.
The Oxford English Dictionary’s definition of value is ‘Worth. The ability of a thing to serve its purpose. To attach importance.’ The value of clinical trials is variable, with three potential beneficiaries:
- The hospital/health-care environment in which the trial is taking place
- Future patients
- The patient who is undertaking the trial.
A hospital which holds clinical trials gains kudos from doing so. The fact that the Medical Research Council and/or the drug companies see fit to entrust a research trial to a particular researcher or organisation enhances that hospital’s status. The clinician involved, and the trials investigator, gain from presenting their findings to their colleagues at conferences and in appropriate journals.
Local research ethics committees oversee research within their area, but their workload is often too big to enable absolute monitoring to occur. It is, therefore, important to trust the honesty of the medical personnel in charge of the trial.
Because of the importance of research to advancing careers, and the fact that, from time to time, fraudulent research has been discovered, it has been suggested that local research ethics committees should hand over the responsibility of monitoring to the Research and Development Directorate of the NHS Executive (Pickworth, 2000).
Looking at the second definition, the value of clinical trials to future patients is not in question, but its value to the research subjects is another matter. The Declaration of Helsinki (WHO, 1975) states that all ‘biomedical research projects should be preceded by a careful assessment of the predictable risks, in comparison with foreseeable benefit to the subject or to others’. This means that, on a medical level, the ‘fair return’ has been agreed, although it is a utilitarian return. The ‘fair price’ is a different matter and, using all the information given, it is the patient who has to make his or her own risk-benefit analysis (Kletz, 1980).
The consequentialist view of the dilemma of cost-benefit analysis in the principle of double effect is that if good is achieved through bad, the result, or consequence is good - therefore it is good (Gillon, 1990). It has been stated that ‘People have their own risk budget’ (Fried, 1976), and that this is the essence of informed consent.
‘One of the principles of modern cancer care is that it should be responsive to the patient’s wishes and consistent with their values,’ according to Huijer et al (2000). The value to the patient could be that of taking part in the research project itself; the possibility of receiving a new and better treatment; and the extra attention received by patients taking part in a trial, which may lead to adverse effects, or to advancing disease being noted much earlier than with conventional treatments.
Because the trial patients may have metastatic (secondary) cancer, or at least a high-grade tumour, the potential side-effects of an unknown treatment, coupled with possibly having to travel to a more distant hospital, may sway the patient against the trial. ‘Little attention is devoted to understanding why … cancer patients decide to refuse treatment,’ point out Huijer et al (2001), and it is important again here to resist coercion. Communication skills are all important when discussing any cancer treatment.
Although progress has been made since the 1947 Nuremberg Code (US Government Printing Office, 1949) much work remains to be done on protecting the subject. Each component of the ethical question (Johnson, 1990) - the aim, patient autonomy, the value of the trial and truth - requires further scrutiny. Both the Declaration of Helsinki (WHO, 2000) and the International Harmonisation Tripartite Guidelines of Good Clinical Practice (ICH, 1996) are in place to protect the subject, and to set a standard. They provide a guide to the basic principles of medical research from the perspective of the physician, and also the duties of all personnel involved in the trial.
In spite of all of this, many further questions still need to be answered for each component, regarding the ethical principles of beneficence, non-maleficence, autonomy and justice. It is true that human nature being what it is, whatever is legislated for, and no matter what the guidelines are, somebody will always question them. However, informed consent is improving all the time, with the emphasis on patient information.
The key problem appears to be supervision of the trials, particularly to discourage overambitious doctors. One solution (Pickworth, 2000) would be to pass supervision of trials on to each trust’s research and development committee. These committees currently work with ethics committees, looking at funding availability and distribution and give trials permission to proceed, although dependent on ethics committee approval. If such committees were responsible for supervision, clinical trials would be a safer way to introduce new and improved medical treatments to the benefit of all patients.
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