Health Technology Assessment 1998; Vol. 2: No. 15 (Executive
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Ethical issues in the design and conduct of randomised controlled trials
1Department of Public Health and Medicine, University of Birmingham,
2 Department of Philosophy, University of Leeds, UK
3Department of Psychology, University of Leeds, UK
4Department of Epidemiology, University of Leeds, UK
- To review ethical arguments put forward in the literature which bear on randomised
controlled trials (RCTs), focusing particularly on uncertainty as an underpinning issue.
- To review empirical data (from comparative, observational and qualitative studies) which
may be relevant to the ethics of conducting trials.
A review of the literature was conducted. The aims were achieved by completing the
- development of an intellectual framework to structure the ethics literature
- creation of a database containing references relating to the ethics of conducting
clinical trials, including any methodological papers which have implications for medical
- classification of the articles, according to the type of information contained within
(e.g. 'under-powered' trials versus replication of trials)
- summary of the ethical arguments and commentary on those arguments.
- Empirical data:
- classification of studies according to topic and study design
- creation of a database containing empirical studies relevant to the ethics of conducting
- abstraction and quality assessment of relevant empirical data
- summary of the primary data.
The main reason for using the RCT design is a scientific one: society is likely to
suffer as a direct result of avoiding such high quality evidence. The most widely cited
assaults on the RCT are claims that patients necessarily sacrifice themselves for the
benefit of future patients by participating in trials, and look to Kantian ethics for
support. Kantians would object, however, if the investigators use patients merely as the
means to societal ends and, given voluntary consent, this is not the case. At any rate,
patients are not required to sacrifice themselves (whether voluntarily or not) for the
benefit of society if we endorse the uncertainty principle, or, less ambiguously,
equipoise, whereby each (or all) comparator treatments are an 'equal bet' in prospect.
When equipoise applies, patients do not lose out prospectively, in order to benefit
others. Given equipoise, a trial should be acceptable to both utilitarians and Kantians,
and hence ethical in its use of patients. If known or potential side-effects of the
comparator treatments are unequal, then a trial should be acceptable to both parties
provided the expected utilities are equivalent, that is, equipoise is only a 'null' prior
belief if there are no trade-offs to be made. Although there are possibly valid objections
to the use of RCTs in particular disciplines or cases (e.g. if the offer of trial entry
will make the patient very upset), such arguments do not make the RCT necessarily
unethical. Further argument concerns the idea of uncertainty as a moral basis for trials
as well as the significance of different, less ambiguous, constructs, i.e. collective
versus individual equipoise.
The empirical evidence on the whole was seen to support the view that RCTs are
justified in clinical practice, contingent, however, on the existence of patient equipoise
(informed consent). Indeed, trials themselves may have a beneficial effect on patients'
outcome both in terms of physical prognosis (at least, when an effective treatment is
already available) and psychological experience, perhaps due to increased levels of care
that are unintended. Any such benefit should be incidental to routine care and not used as
an incentive to increase recruitment rate, lest the principle laid down in the Helsinki
Declaration (that non-participation in a study will not intentionally affect the standard
of care) be violated.
It is evident that patients are unlikely to understand all the information which is
given to them by whatever means during consent consultations. Patients have particular
problems grasping abstract, as opposed to concrete, information. Consequently, fully
informed consent for all patients at least is an unobtainable ideal. There are three
possible responses to this problem: (1) declare all trials unethical, unless the
participants are themselves medical experts (or as expert as anyone else in the relevant
field), (2) abandon the requirement of informed consent, but rely on other safeguards such
as ethics committees to protect individual participants, or (3) retain the spirit of
informed consent, taking all practical measures to maximise patient understanding, but
still rely on ethics committees as a further level of protection. The authors favour the
third option. While difficulties with communication are regrettable and should be reduced
as much as possible, some failure would appear inevitable. The need to advance medical
understanding is important, but communication difficulties remain ethically critical if a
patient decides to participate on the basis that he/she will benefit therapeutically in a
way incommensurate with clinical prior belief. It is therefore important that the patient
understands that equipoise exists, and so has realistic expectations.
- The caring professions must articulate clear, ethical justification for trials if public
confidence is to be retained.
- Patients should not lose out in prospect by taking part in a trial.
- Given treatments which are generally available, patients do not lose out in prospect
when prior estimates of effectiveness and values interact to produce equal expected
- When treatments are not generally available, patients do not lose out by participating
in trials when the expected utility of the new treatment is at least as high as that of
- The term 'uncertainty' prevaricates on prior probabilities and values, making it an
inadequate moral basis for trials. It should not be used to disguise such existing data as
may affect patient preferences, even when such data are insufficient to engender
- Patients must be given as much information as they need to bring their values into play.
- Patients are least alarmed and understand the issues most clearly when they have
encountered the concept of comparative trials before.
- Practitioners should pay particular attention to explaining abstract ideas (especially
that of randomisation).
- Small trials of existing therapies are not necessarily unethical provided that they are
- Clinical trials should start early in the life of a new treatment.
- The idea that patients in trials do better than average, even when the trial produces a
negative result, may be true. If the effect is real, it would seem to come from enhanced
attention to detail inherent in following the trial protocol for both control and
experimental groups. It should not, however, be used as an inducement to accept
randomisation since the Helsinki accord requires that the intention should be to provide
the 'best' care for all patients.
Recommendations for research
Areas in the ethics of RCTs which need to be further analysed, include:
- ethical issues in the design and conduct of cluster trials
- ethical issues in interim analysis
- the conduct and constitution of ethics committees.
There are a number of empirical questions which also need to be addressed, and these
are detailed in the main report.
Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.
Ethical issues in the design and conduct of randomised controlled trials.Health
Technol Assessment 1998; 2(15).
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