Rapid Responses to:

LEARNING IN PRACTICE: V Jenkins, L Fallowfield, I Solis-Trapala, C Langridge, and V Farewell Discussing randomised clinical trials of cancer therapy: evaluation of a Cancer Research UK training programme BMJ 2005; 0: bmj.38366.562685.8Fv1 [Abstract]

Rapid Responses: Submit a response to this article

Rapid Responses published:

RCTs gold or copper?!

Dr Payam Fazel MD   (4 September 2007)

RCTs gold or copper?! 4 September 2007
Dr Payam Fazel MD, Specialist registrar public health Yorkshire , LS6 Send response to journal: Re: RCTs gold or copper?!	Since the introduction of randomised controlled trials as the gold standard for public health research, both professionals and lay public have expressed concern over whether doing this sort of experiment in humans is ethical. It has been argued that participants may be called to sacrifice their own best interests for the benefit of future patients (Edwards SJL, Lilford RJ, Jackson JC, Hewison J, Thornton J. Ethical issues in the design and conduct of randomised controlled trials. Health Technology Assessment, 1998; Vol. 2: No. 15). The scientific rationale for conducting a trial is equipoise - that the medical community as a whole should be genuinely uncertain over which treatment is best. In these circumstances, it is assumed the intervention and control groups are subject to an equally good bet prospectively(Lilford RJ, Jackson JC. Equipoise and the ethics of randomisation. J R Soc Med 1995; 88: 552-559). The main reason for using the RCT design is a scientific one- society is likely to suffer as a direct result of avoiding high quality evidence (utilitarian argument). utilitarianism is concerned with increasing societal utility - the individuals maximise their expected utility and so act in their own best interests-in the long run social utility will not be served by demanding that individuals be self sacrificing for the common good. This leads to matters of distributive justice whereby utility and disutility, benefits and costs, are distributed as fairly and evenly as possible across society (Sarah J L Edwards , Ethical issues in the design and conduct of cluster randomised controlled trials, BMJ 1999;318:1407- 1409 ). The utilitarian perspective distinguishes between “needs of patients” which in from this perspective is something more general than the “needs of the patient”. From this viewpoint participation in RCTs may rarely be in the direct interests of the trial subjects whereas it may - to be ethically Justified- serve- the good of society as a whole. This more general approach to determining what is ethical creates a very convenient climate for the trialists who want to pursue their experiments (Ethical issues in headache research and management Report and recommendations of the ethics subcommittee, Cephalalgia 1998;18:505±29. Oslo) .One pro-RCT argument can be that at any rate, patients are not required to sacrifice themselves (whether voluntarily or not) for the benefit of society if we assume equipoise, whereby both treatment and control arms have an 'equal bet' in prospect. Utilitarian perspective can argue that when equipoise applies, patients do not lose out prospectively, in order to benefit others. The pro-RCT argument assumes that, given equipoise, a trial should be acceptable from both utilitarian and Kantian perspectives, and hence ethical (Lilford RJ, Jackson JC. Equipoise and the ethics of randomisation. J R Soc Med 1995; 88: 552-559). The other ethical framework that can argue in favour of RCTs is the “principlist” approach (based on the four principles of beneficence, non- maleficence, autonomy and justice). However even principlism would struggle over its two last principles -autonomy and justice- (Richard E Ashcroft et al, Implications of socio-cultural contexts for the ethics of clinical trials, Health Technology Assessment 1997; Vol. 1: No. 9). From this perspective, alternative constructions of the foundations of the RCT ethics may be possible. Beneficence of the RCTs to the majority, most of the times, non-maleficence of the researcher (if we choose to ignore ulterior motives of the researchers) against the trial subjects would be the corner stone of this argument of this school of thought. The most commonly expressed criticism to the RCTs is that patients necessarily sacrifice themselves for the benefit of future patients by participating in trials. Evidence also points to the unpleasant facts that doctors do not seem to take informed consent from competent patients as seriously as they should do (Williams CJ, Zwitter M. Informed consent in European multicentre randomized clinical trials are patients really informed? Eur J Cancer 1994; 30: 907-910) ;most doctors are willing to enter their patients in trials even when the treatments offered are not an equal bet prospectively (Alderson P, Madden M, Oakley A, Wilkins R. Women's knowledge and experience of breast cancer treatment and research. London: Social Science Research Unit , 1994) ; and that participants’ willingness to take part in randomisation drops as patients are given more pre-trial data and as they are made aware of availability of any accumulating evidence of effectiveness (Sarah J L Edwards, The ethics of randomised controlled trials from the perspectives of patients, the public, and healthcare professionals, BMJ 1998;317:1209-1212). RCTs can be criticised from Kantian perspective as that people should not be used as a mere means to societal ends. The Kantian perspective is of the view that public health practitioners are duty bound to respect a person's autonomy. Setting up a system that perpetuates ignorance as mentioned above violates Kant's injunction that people should not be used merely as means to an end. Even utilitarian perspective would struggle, as facilitating individual choice is more important than maximising recruitment, because patients may vote with their feet if they see through the subtle coercion to participate in randomised clinical trials inherent in the use of culpably obscurant language.( Sarah J L Edwards, Ethics of clinical trials from a Bayesian and decision analytic perspective: whose equipoise is it anyway? BMJ 2003;326:980-981). Another con argument would be that collective equipoise is an unrealistic and unachievable assumption (this is well demonstrated in critical appraisal of the enclosed paper). The other argument would be that whose equipoise is the assumed equipoise? Should the equipoise of the patient, or that of the doctor, determine whether a patient enters a clinical trial -that the best treatment is a question of values-. It can be argued that choices should be based both on probabilities of events (which experts might know) and on the value that a patient places on those events (which only the patient can know) ( Ethics of clinical trials from a bayesian and decision analytic perspective: whose equipoise is it anyway? BMJ 2003;326:980-981). The formal method for combining values and bayesian probabilities is decision analysis, and it is used to calculate which treatment maximises welfare or expected utility (Lilford RJ, Jackson JC. Equipoise and the ethics of randomisation. J R Soc Med 1995; 88: 552-559). Lets explain this with an example: If the prior probability that radical treatment would improve mortality from prostate cancer was X percentage points, then a man who was particularly apprehensive about side effects (for example, a newly married man who wanted to have a child) might be better off with conservative treatment, whereas another (one, perhaps, who no longer placed a high premium on his sex life) might gain most from radical surgery. However, the losses and gains might balance for yet another man, both treatments having equal expected utilities, and such a person can accept randomisation without loss he is equipoised. ( Ethics of clinical trials from a bayesian and decision analytic perspective: whose equipoise is it anyway? BMJ 2003;326:980-981). The arguments of the researchers would be that RCT will potentially maximise benefit to all patients and minimise harm to the wider public (future patients). The researchers are not really interested to pay much attention to the ways that harms and benefits would be distributed and how they balance out, nor there is much concern to place a limit on the level of acceptable harm if it proves to be outweighed by a significant benefit. This approach allows the beneficial ends to be chased by potentially harmful means. The utilitarian approach to public health research and randomised trials offers little scope to focus on the impact of RCTs over individuals who participate in the RCT, because that patient will be looked at only a small part of the whole picture. The question is whether it would simply suffice to know that at the end of this trial, the benefits would outweigh the harms, or whether we also need to ascertain if harms and benefits are evenly and fairly distributed and more importantly that harms are limited to an absolute minimum (Sue, Eckstein, Manual for research ethics committees, 6th edition, Kings College London, Cambridge University Press). Lets see this from the deontological perspective: unlike utilitarian perspective that only views things prospectively the deontologist determines the morality of a randomised trial like this by looking back at the motivations and intentions behind it plus the duties and mandates that he needs to fulfil and maintain and honour(Davis. N, contemporary deontology, a companion to ethics, 1991, Blackwell scientific editions). For deontologist a good outcome per se doesn’t justify harm caused through unacceptable means, he would therefore need to examine how this research is conducted, what is done to the participants regardless of the yet unknown potential benefits to future patients. The deontologist would focus on the each individual research participant in the intervention or control arms of the study, and the researchers. He will be serious about duties of the trialists and the rights of the participants. He will also need to prioritise issues of patients’rights and moral duties and particapant’s dignity, on economical concerns and constraints of the researchers and would restrict the trialists to certain absolute and non- negotiable rights, duties and mandates ((Sue, Eckstein, Manual for research ethics committees, 6th edition, Kings College London, Cambridge University Press). Viewing RCTs from the core of Kant’s theory - the‘categorical imperative’- , helps us understand that RCTs bring about an unusual kind of free riding, where potential benefits of a majority of future free-riders is justified at the expense of potential harm to the RCT subjects. The minority of individuals who do not benefit, and who may indeed be harmed, also deserve our consideration. Ultimately, the utilitarian is obliged to argue, if a small number suffer so that the population group can prosper and flourish, then so be it (Horner 2000: 50, from S. Holland class notes, York University, public health ethics). But this argument doesn’t satisfy the deonologist. Let s view RCTs from the perspective of virtue ethics. Virtue ethics is a framework that focuses on the innate character of the moral agent rather than the rightness of an action. From this perspective it is not sufficient to follow rules irrespective of internal attitudes, feelings, and reason. The virtuous moral researcher has a deep innate desire to behave well. This contrasts with Kant’s view that suggests that it is more virtuous to act well from duty even if one is not disposed to do so. Virtue perspective suggests that Kantian view may allow good action, but it does not encourage us to live well, and develop virtuous characteristics. From this view point the trialist ought to imagine what it must be like to be a person who is going through different arms of the trial. Would they accept for themselves or their loved ones to be subject to the experiment? Would they want to be subject to a double blind non- individualised choice like what they offer to the participants of their randomised controlled trials? (P Gardiner,A virtue ethics approach to moral dilemmas in medicine, Journal of medical ethics, 2003;29;297-302) Conclusion: There is a widespread inclination to consider RCT as the gold standard of public health (and medical) research. Perspectives and values of the researchers, pharmaceutical companies, doctors and patients are so diverse that reaching a universal consensus is impossible. We may all agree that the RCT satisfies preferences of a majority of researchers most of the time, and allows them the convenience of doing what is best for their experiment and trial rather than what is the best alternative for the individual patient who has been tossed electronically like a coin to at least half-blindly belong to one arm of the trial. Researchers need to assure themselves and their patients of the rarely achievable prerequisite of “equipoise”. They should respect their trial subjects enough to spend time explaining details of the research plan, alternative, consequences and uncertainties, even at the expense of losing trial subjects. Competing interests: None declared