David Braunholtz

Ethical issues in the design and conduct of cluster randomised controlled trials

In most randomised controlled trials, individual patients are randomised to a treatment or control group, but sometimes this is undesirable or even impossible and groups (clusters) of people may be randomised instead. These are called cluster randomised controlled trials, and although they have been around for a long time, the need for them is likely to increase in line with growing concern to evaluate the delivery of health services, public education, and policy on social care. ### Summary points Need for cluster trials will increase with concern over health service evaluation, but issues of ethics and guardianship must be addressed In some cluster trials the intervention can be targeted at individuals (individual-cluster); where this would be too difficult or expensive the intervention is targeted at the whole group (cluster-cluster) Autonomy is important in individual-cluster trials, while the utilitarian welfare of the cluster as a whole is of paramount importance in cluster-cluster trials In individual-cluster trials the participants should give consent; cluster-cluster trials need procedural safeguards appropriate to the risks carried by the cluster intervention Guardians should sign a consent form that sets out their duties before they volunteer a cluster for a trial The ethical aspects of medical practice and medical research are most often discussed in the context of two main moral traditions—utilitarianism and Kantian ethics. Broadly speaking, utilitarianism is concerned with increasing social utility (value), which usually means that 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. The Kantian tradition shows why we are duty bound to respect a persons …

Clinical trials and rare diseases: a way out of a conundrum

Currently, clinical trials tend to be individually funded and applicants must include a power calculation in their grant request. However, conventional levels of statistical precision are unlikely to be obtainable prospectively if the trial is required to evaluate treatment of a rare disease. This means that clinicians treating such diseases remain in ignorance and must form their judgments solely on the basis of (potentially biased) observational studies experience, and anecdote. Since some unbiased evidence is clearly better than none, this state of affairs should not continue. However, conventional (frequentist) confidence limits are unlikely to exclude a null result, even when treatments differ substantially. Bayesian methods utilise all available data to calculate probabilities that may be extrapolated directly to clinical practice. Funding bodies should therefore fund a repertoire of small trials, which need have no predetermined end, alongside standard larger studies.

The proportion of upper gastrointestinal symptoms in the community associated with helicobacter pylori , lifestyle factors, and nonsteroidal anti-inflammatory drugs

OBJECTIVE:Upper gastrointestinal disorders are common in the community, yet the determinants of these symptoms are poorly characterized. The association between upper gastrointestinal symptoms and Helicobacter pylori (H. pylori), socioeconomic status, nonsteroidal antiinflammatory drug (NSAID) use, smoking, alcohol, and coffee intake was assessed in a cross-sectional survey.METHODS:Subjects between the ages of 40–49 yr were randomly selected from the lists of 36 primary care centers. Participants attended their local primary care center and were interviewed by a researcher using a validated dyspepsia questionnaire. H. pylori status was determined by a nonfasting 13C-urea breath test.RESULTS:A total of 32,929 subjects were invited, and 8,407 (25%) attended and were eligible. Of these, 2,329 (28%) were H. pylori positive and 3,177 (38%) had dyspepsia. Also, 44% of H. pylori-infected participants reported dyspepsia compared with 36% of uninfected subjects [odds ratio = 1.39; 95% confidence interval (CI) 1.26–1.53]. H. pylori infection remained a significant risk factor for dyspepsia in a multiple logistic regression model (odds ratio = 1.21; 95% CI 1.09–1.34), suggesting that 5% of dyspepsia in the population is attributable to H. pylori. NSAIDs, low educational attainment, renting accommodation, absence of central heating, sharing a bed with siblings, and being married were also significantly associated with dyspepsia in this model. Smoking, but not drinking alcohol or coffee, was marginally associated with dyspepsia, but this finding was not robust. These factors were not associated with any dyspepsia subtype.CONCLUSIONS:H. pylori is significantly associated with dyspepsia and may be responsible for 5% of upper gastrointestinal symptoms in the community.

Trials in surgery.

Trials in surgery pose some special problems. This paper examines these with reference to 10 years of methodological research sponsored by the UK National Health Service Research and Development programme.

Trials and fast changing technologies: the case for tracker studies

New or variant treatments—and we use the word in a wide sense to include procedures and devices as well as drugs—should be subject to randomised controlled trials.1 Treatments may also develop, changing in ways that are widely considered to be improvements. For example, a new version of a surgically fitted device supersedes the old. This complicates existing comparisons of the device compared with medical treatment. And it leads to another issue—when should researchers start a randomised controlled trial in a clinical area where there is rapid technological change? Start too early and the resultant comparisons may seem likely to turn out to be irrelevant, but start too late and the chance of collecting much good quality data will have been lost, perhaps forever if clinical opinion has “gelled” despite the absence of randomised controlled trial data. The problem is compounded by the considerable time it takes to design, commission, and establish a full scale clinical trial. These problems are encountered widely, particularly with devices. These may be licensed even before their health effects have been studied in detail and are subject to frequent modifications in design and use. A good example is endovascular aortic aneurysm repair, in which a Dacron tube is positioned within the abdominal aorta and held in place by an expandable stent. In 1991, Parodi et al showed that aneurysms could be repaired in this way.2 Several stent graft systems have emerged since then, with changes occurring almost monthly. In these circumstances useful evaluation by randomised controlled trial evaluation might be thought impossible, and researchers and commissioners might choose to wait for things to stabilise.3 In this paper we argue against waiting and advocate the use of trials which start early on in periods of rapid technological change and which follow and inform developments. …

The measurement of active errors: methodological issues

The value of research in any topic area turns on its validity. Patient safety research has revealed—or, at least, given renewed urgency to—a raft of methodological issues. The meaning and thus the value of empirical research in this field is contingent on getting the methodology right. The need for good methods for the measurement of error is necessary whenever an inference is intended and, since inferences lie at the heart of research and management, there is a huge need to understand better how to make measurements that are meaningful, precise, and accurate. In this paper we consider issues relating to the measurement of error and the need for more research.

Professional assistance during birth and maternal mortality in two Indonesian districts

OBJECTIVE To examine determinants of maternal mortality and assess the effect of programmes aimed at increasing the number of births attended by health professionals in two districts in West Java, Indonesia. METHODS We used informant networks to characterize all maternal deaths, and a capture-recapture method to estimate the total number of maternal deaths. Through a survey of recent births we counted all midwives practising in the two study districts. We used case-control analysis to examine determinants of maternal mortality, and cohort analysis to estimate overall maternal mortality ratios. FINDINGS The overall maternal mortality ratio was 435 per 100,000 live births (95% confidence interval, CI: 376-498). Only 33% of women gave birth with assistance from a health professional, and among them, mortality was extremely high for those in the lowest wealth quartile range (2303 per 100,000) and remained very high for those in the lower middle and upper middle quartile ranges (1218 and 778 per 100,000, respectively). This is perhaps because the women, especially poor ones, may have sought help only once a serious complication had arisen. CONCLUSION Achieving equitable coverage of all births by health professionals is still a distant goal in Indonesia, but even among women who receive professional care, maternal mortality ratios remain surprisingly high. This may reflect the limitations of home-based care. Phased introduction of fee exemption and transport incentives to enable all women to access skilled delivery care in health centres and emergency care in hospitals may be a feasible, sustainable way to reduce Indonesias maternal mortality ratio.

Lay conceptions of the ethical and scientific justifications for random allocation in clinical trials

Randomised controlled trials (RCTs) play a central role in modern medical advance, and they require participants who understand and accept the procedures involved. Published evidence suggests that RCT participants often fail to understand that treatments are allocated at random and that clinicians are in equipoise about which treatment is best. We examine background assumptions that members of the public might draw upon if invited to take part in a RCT. Four studies (N=82; 67; 67; 128), in the UK, identified whether members of the public (i). accept that an individual clinician might be genuinely unsure which of two treatments was better; (ii). judge that when there is uncertainty it is acceptable to suggest deciding at random; (iii). recognise scientific benefits of random allocation to treatment conditions in a trial. Around half the participants were loathe to accept that a clinician could be completely uncertain, and this was no different whether the context was one of individual treatment or research. Most participants found it unacceptable to suggest allocating treatment at random, though there was weak evidence that a research context may reduce the unacceptability. Participants did not judge that more certain knowledge would be gained about which treatment was best when treatments were allocated at random rather than by patient/doctor choice: scientific benefits of randomisation were apparently not recognised. Judgements were no different in non-medical contexts. Results suggest a large mismatch between the assumptions underlying the trial design, and the assumptions that lay participants can bring to bear when they try to make sense of descriptive information about randomisation and equipoise. Previous attempts to improve understanding by improving the clarity or salience of trial information, or of making explicit the research context, while helpful, may need to be supplemented with accessible explanations for random allocation.

Randomisation in trials: do potential trial participants understand it and find it acceptable?

Objective: To examine lay persons’ ability to identify methods of random allocation and their acceptability of using methods of random allocation in a clinical trial context. Design: Leaflets containing hypothetical medical, non-medical, and clinical trial scenarios involving random allocation, using material from guidelines for trial information leaflets. Setting and participants: Adults attending further education colleges (n = 130), covering a wide range of ages, occupations, and levels of education. Main measures: Judgements of whether each of five methods of allocation to two groups was random in a medical or non-medical scenario. Judgements of whether these allocation methods were acceptable in a randomised clinical trial scenario, with or without a scientific justification for randomisation. Results: The majority of our group of participants judged correctly that allowing people their preference was not random, and that the following were random: using a computer with no information about the individual (recommended wording for MREC trial leaflets), tossing a coin, drawing a name out of a hat. Judgements were split over allocating people in turn (not a random allocation method but shares features with randomisation). Judgements were no different in medical and non-medical scenarios. Few of the correctly identified random methods were judged to be acceptable in a clinical trial scenario. Inclusion of a scientific justification for randomising significantly increased the acceptability of only one random method: allocation by computer. Conclusions: Current UK guidelines’ recommended description of random allocation by computer seems warranted. However, while potential trial participants may understand what random allocation means, they may find it unacceptable unless offered an acceptable justification for its use.

The Ethics of Placebo-controlled Trials: A Comparison of Inert and Active Placebo Controls

Because of the recent and controversial example of sham surgery for the evaluation of fetal tissue transplants for Parkinson’s disease, there is renewed interest in the ethics of using “active” placebos in surgical trials, where otherwise there are no inert procedures available, and in pharmacological trials, where there are inert substances, but where patients may guess to which arm they have been allocated. This paper seeks to clarify the ethical arguments surrounding the use of active placebos in trials, and to set up a notation for assessing the ethics of trials more generally. We first establish an framework by which ethics committees can analyze such trials. We examine (1) the scientific value of the research; (2) the expected risks and benefits to individual patients, and (3) the voluntary nature of consent. We then contrast the implications of this framework for inert and active placebo-controlled trials, respectively. In particular, we analyze their relative expected utility using three main utility factors, namely, treatment effects, placebo effects, and altruism. We conclude that, when the intervention is already widely available, active placebo trials rely more heavily on altruism than do inert placebo trials and, when the intervention is restricted, this excess reliance may not be needed. What our analysis provides is the explicit justification for the apparent caution of Institutional Review Boards or ethics committees when reviewing sham operations, especially when the expected harm is not trivial and the risk of exploitation is high.