This paper discusses the issue of overriding the right of individual consent to participation in cluster randomised trials (CRTs). We focus on CRTs testing the efficacy of non-pharmaceutical interventions. As an example, we consider school closures during the COVID-19 pandemic. In Norway, a CRT was promoted as necessary for providing the best evidence to inform pandemic management policy. However, the proposal was rejected by the Norwegian Research Ethics Committee since it would violate the requirement for individual informed consent. (...) This sparked debate about whether ethics stand in the way of evidence-based health policy, since the Norwegian Research Ethics law’s strict requirements for individual consent make it practically impossible to carry out CRTs of public health interventions. We argue that, in the case of the school closure trial, the suggested CRT would not have eliminated an epistemic gap and thus would not have justified the violation of consent rights. First, we focus on the methodological challenges to estimating quantifiable effects of school closures in the specific case of an airborne infectious disease. Second, in line with Evidential Pluralism, we highlight the value of alternative lines of evidence for informing school closure policy in a pandemic. In general, we propose that a trial requiring the waiver of participants’ consent rights must be highly likely to eliminate an epistemic gap. We elaborate on the practical aspects of this criterion and discuss the potential advantages of adding it to the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. (shrink)

Cluster randomised trials are an increasingly important methodological tool in health research but they present challenges to the informed consent requirement. In the relatively limited literature on the ethics of cluster research there is not much clarity about the reasons for which seeking informed consent in cluster randomised trials may be morally challenging. In this paper, I distinguish between the cases where informed consent in cluster trials may be problematic due to the distinct features of (...) ‘population-based’ interventions, which have not been adequately discussed in the research ethics literature, and the cases where informed consent may be problematic for reasons that investigators also encounter in other research designs. I claim that informed consent requirements in cluster trials should be adjusted to the level of risk involved, arguing for a more comprehensive notion of research risk than that currently found in the research ethics guidelines, and the amount of freedom to be sacrificed in relation to a particular research aim. I conclude that these two factors are the most important to consider when assessing whether a cluster study should proceed when informed consent is infeasible or difficult to obtain. (shrink)

The most recent (Fifth) revision of the Declaration of Helsinki, adopted in October 2000 by the World Medical Association (WMA), reinforces the longstanding prohibition against offering placebo instead of effective therapy. The WMA left no doubt that if a beneficial treatment for a condition has already been recognised, it is unethical to offer placebo in place of such treatment to anyone in a study of the same condition. We have previously drawn attention to the discrepancy between the spirit of the (...) Declaration and the common practice of using placebo controls in randomised trials even if effective treatment exists. Despite the mandates of the Declaration of Helsinki and concern from ethicists and scientists, the US Food and Drug Administration (FDA) continues to demand and defend placebo‐controlled evidence of efficacy and safety for the development of many new pharmaceuticals, even if effective therapy exists. We suggest that the FDA's arguments defending their practice are insufficient to justify medical research that violates the Declaration of Helsinki. (shrink)

In response to concern over the numeracy skills deficit displayed by student nurses, an online computer programme, ?Authentic World??, which aims to simulate a real-life clinical environment and improve the medication dosage calculation skills of users, was developed (Founded in 2004 Authentic World Ltd is a spin out company of Glarmorgan and Cardiff Universities, Cardiff, Wales UK.). Two randomised controlled trials were conducted, each at a UK University, in order to investigate the impact of Authentic World? on student (...) nurses? general numeracy abilities. All first year nursing students who gave consent were randomised equally into an intervention or control group. The intervention group were given access to Authentic World?. The primary outcome measure was the students? scores on a general numeracy test. The Intention to Treat (ITT) analysis in both trials revealed a small negative effect of Authentic World? on general numeracy, which was statistically significant in one trial. However, compliance with the intervention was very low in both trials, with only 24 and 12% of students allocated to the intervention groups spending more than 15 minutes using the programme. Providing nursing students with access to Authentic World? is not an effective use of resources since use of the programme appears to be very low. (shrink)

Next SectionObjectives To evaluate the adequacy of paediatric informed consent and its augmentation by a supplemental computer-based module in paediatric endoscopy. Methods The Consent-20 instrument was developed and piloted on 47 subjects. Subsequently, parents of 101 children undergoing first-time, diagnostic upper endoscopy performed under moderate IV sedation were prospectively and consecutively, blinded, randomised and enrolled into two groups that received either standard form-based informed consent or standard form-based informed consent plus a commercial (Emmi Solutions, Inc, Chicago, Il), sixth grade (...) level, interactive learning module (electronic assisted consent). Anonymously and electronically, the subjects' anxiety (State Trait Anxiety Inventory), satisfaction (Modified Group Health Association of America), number of questions asked, and attainment of informed consent were assessed (Consent-20). Statistics were calculated using t test, paired t test, and Mann Whitney tests. Results The ability to achieve informed consent, as measured by the new instrument, was 10% in the control form-based consent group and 33% in the electronic assisted consent group (p<0.0001). Electronically assisting form-based informed consent did not alter secondary outcome measures of subject satisfaction, anxiety or number of questions asked in a paediatric endoscopy unit. Conclusions This study demonstrates the limitations of form-based informed consent methods for paediatric endoscopy. It also shows that even when necessary information was repeated electronically in a comprehensive and standardised video, informed consent as measured by our instrument was incompletely achieved. The supplemental information did, however, significantly improve understanding in a manner that did not negatively impact workflow, subject anxiety or subject satisfaction. Additional study of informed consent is required. Clinical trial registration number ClinicalTrials.gov Identifier NCT00899392. (shrink)

The increasing use of cluster randomised trials in low-resource settings raises unique ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomised Trials is the first international ethical guidance document specific to cluster trials, but it is unknown if it adequately addresses issues in low-resource settings. In this paper, we seek to identify any gaps in the Ottawa Statement relevant to cluster trials conducted in low-resource settings. Our method is to (...) analyse a prototypical cluster trial conducted in a low-resource setting with the Ottawa Statement; to identify ethical issues in the design or conduct of the trial not captured adequately and to make recommendations for issues needing attention in forthcoming revisions to the Ottawa Statement. Our analysis identified six ethical aspects of cluster randomised trials in low-resource settings that require further guidance. The forthcoming revision of the Ottawa Statement should provide additional guidance on these issues: streamlining research ethics committee review for collaborating investigators who are affiliated with other institutions; the classification of lay health workers who deliver study interventions as health providers or research participants; the dilemma experienced by investigators when national standards seem to prohibit waivers of consent; the timing of gatekeeper engagement, particularly when researchers face funding constraints; providing ancillary care in health services or implementation trials when a routine care control arm is known to fall below national standards and defining vulnerable participants needing protection in low-resource settings. (shrink)

Objective Cluster randomised trial (CRT) investigators face challenges in seeking informed consent from individual patients (cluster members). This study examined associations between reporting of patient consent in healthcare CRTs and characteristics of these trials. Study design Consent practices and study characteristics were abstracted from a random sample of 160 CRTs performed in primary or hospital care settings that were published from 2000 to 2008. Multivariable logistic regression was used to examine associations between reporting of patient consent and methodological (...) characteristics, as well as publication features such as date and journal of publication. Results 82 (53.8%) of 160 studies reported obtaining informed consent from individual patients. Reporting of patient consent was independently and positively associated with: smaller cluster size, the evaluation of experimental interventions targeted at patients, data collection from individual patients, publication later than 2004 and publication in higher-impact journals. Conclusions Reporting of consent practices in published CRTs should be improved. Consent practices in published CRTs appear to be related to the type of interventions under study, as well as journal impact and trends in research ethics practices. These findings will inform best practices in trial conduct and ethics review, remediation of errors in consent practices and ethics review and the development of regulatory guidance for CRTs. (shrink)

Context Physicians are regularly confronted with research that is funded or presented by industry. Objective To assess whether physicians discount for conflicts of interest when weighing evidence for prescribing a new drug. Design and setting Participants were presented with an abstract from a single clinical trial finding positive results for a fictitious new drug. Physicians were randomly assigned one version of a hypothetical scenario, which varied on conflict of interest: ‘presenter conflict’, ‘researcher conflict’ and ‘no conflict’. Participants 515 randomly selected (...) Fellows in the American College of Obstetricians and Gynecologists' Collaborative Ambulatory Research Network; 253 surveys (49%) were returned. Main object measures The self-reported likelihood that physicians would prescribe the new drug as a first-line therapy. Results Physicians do not significantly discount for conflicts of interest in their self-reported likelihood of prescribing the new drug after reading the single abstract and scenario. However, when asked explicitly to compare conflict and no conflict, 69% report that they would discount for researcher conflict and 57% report that they would discount for presenter conflict. When asked to guess how favourable the results of this study were towards the new drug, compared with the other trials published so far, their perceptions were not significantly influenced by conflict of interest information. Conclusion While physicians believe that they should discount the value of information from conflicted sources, they did not do so in the absence of a direct comparison between two studies. This brings into question the effectiveness of merely disclosing the funding sources of published studies. (shrink)

The ethics of the Flexibility In duty hour Requirements for Surgical Trainees trial have been vehemently debated. Views on the ethics of the FIRST trial range from it being completely unethical to wholly unproblematic. The FIRST trial illustrates the complex ethical challenges posed by cluster randomised trials of policy interventions involving healthcare professionals. In what follows, we have three objectives. First, we critically review the FIRST trial controversy, finding that commentators have failed to sufficiently identify and address many (...) of the relevant ethical issues. The 2012 Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides researchers and research ethics committees with specific guidance for the ethical design and conduct of CRTs. Second, we aim to demonstrate how the Ottawa Statement provides much-needed clarity to the ethical issues in the FIRST trial, including: research participant identification; consent requirements; gatekeeper roles; benefit-harm analysis and identification of vulnerable participants. We nonetheless also find that the FIRST trial raises ethical issues not adequately addressed by the Ottawa Statement. Hence, third and finally, we raise important questions requiring further ethical analysis and guidance, including: Does clinical equipoise apply to policy interventions with little or no evidence-base? Do healthcare providers have an obligation to participate in research? Does the power-differential in certain healthcare settings render healthcare providers vulnerable to duress and coercion to participant in research? If so, what safeguards might be implemented to protect providers, while allowing important research to proceed? (shrink)

Background: There is a growing interest in using cognitive behavioural therapy with people who have Asperger Syndrome and comorbid mental health problems. Aims: To examine whether modified group CBT for clinically significant anxiety in an AS population is feasible and likely to be efficacious. Method: Using a randomised assessor-blind trial, 52 individuals with AS were randomised into a treatment arm or a waiting-list control arm. After 24 weeks, those in the waiting-list control arm received treatment, while those initially (...) randomised to treatment were followed-up for 24 weeks. Results: The conversion rate for this trial was high, while attrition was 13%. After 24 weeks, there was no significant difference between those randomised to the treatment arm compared to those randomised to the waiting-list control arm on the primary outcome measure, the Hamilton Rating Scale for Anxiety. Conclusions: Trials of psychological therapies with this population are feasible. Larger definitive trials are now needed. Declaration of Interest: None Trial Registration: ISRCTN 30265294, UKCRN 8370. (shrink)

People with learning disability sometimes display challenging behaviour. This can be managed by use of antipsychotic medication or behavioural therapy or both. There is no solid evidence, however, that these therapies are safe and effective. A randomised controlled trial of antipsychotic medication has been proposed to deliver such evidence. However, this presents difficult issues in the ethics of research with learning disabled people. In particular, is a trial the most efficient and fairest way to evaluate practice in this area? (...) This paper reviews the clinical situation, gives the rationale for the trial, and analyses the ethical arguments for and against such a trial. (shrink)

In recent years, there has been a surge of high-profile publications on applications of artificial intelligence (AI) systems for medical diagnosis and prognosis. While AI provides various opportunities for medical practice, there is an emerging consensus that the existing studies show considerable deficits and are unable to establish the clinical benefit of AI systems. Hence, the view that the clinical benefit of AI systems needs to be studied in clinical trials—particularly randomised controlled trials (RCTs)—is gaining ground. However, (...) an issue that has been overlooked so far in the debate is that, compared with drug RCTs, AI RCTs require methodological adjustments, which entail ethical challenges. This paper sets out to develop a systematic account of the ethics of AI RCTs by focusing on the moral principles of clinical equipoise, informed consent and fairness. This way, the objective is to animate further debate on the (research) ethics of medical AI. (shrink)

Background The post-trial period is the time period after the end of study drug administration. It is unclear whether post-trial arrangements for patient surveillance are routinely included in study protocols and consents, and whether research ethics boards (REB) consider the post-trial period. Objectives The objective was to determine whether trial protocols and consent forms reviewed by the REB describe procedures for post-trial period surveillance. Methods An observational study of protocols of randomised trials of chronic therapies for cardiac conditions, (...) approved by the REB of two academic institutions affiliated with the University of Toronto in Canada (University Health Network and Mount Sinai Hospital) from 1995 to 2007. Plans for patient surveillance in the post-trial period described in the protocol or in the consent form before and after REB approval were recorded. Results 42 studies were identified including 18 heart failure and 15 coronary artery disease trials. Only four studies planned a clinical visit after trial termination, and an additional three planned a telephone contact after trial completion. Five trials submitted consent forms to the REB with a discussion of the post-trial period. Conclusions The majority of protocols and consent forms did not discuss plans for post-trial period surveillance. The post-trial period and the REB approval process could be improved by systematic follow-up being described in the protocol and consent form. The small number of trial protocols evaluated in the study may impair the degree to which the results can be generalised. (shrink)

Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: the presence of equipoise, defined as a lack of unbiased evidence for efficacy of (...) an intervention; clinically important research question; the risk to patients is minimised and reasonable; there is uncertainty about treatment allocation rather than deception; there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial should be sufficiently powered and standardised so that its results are valid, consent should be valid, the standard treatment or rescue medication should be provided if possible, and after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association. (shrink)

The maternal‐fetal HIV transmission trials, conducted in developing countries in the 1990s, undoubtedly generated one of the most intense, high profile controversies in international research ethics. They sparked off a prolonged acrimonious and public debate and deeply divided the scientific community. They also provided an impetus for the revision of the Declaration of Helsinki – the most widely known guideline for international research. In this paper, I provide a brief summary of the context, outline the arguments for and against (...) the controversial use of placebo controls, and focus on particular areas that I believe merit further discussion or clarification. On balance, I argue that the researchers failed in their duties to protect the best interests of their research subjects, and to promote distributive justice. I discuss the difficulties of obtaining valid consent in this research context, and argue that it is unethical to inform women of their HIV status without at least offering them prophylactic treatment for their unborn children. A global view of justice, which endorses international equity, cannot be squared with international research guidelines that allow ‘local conditions’ to define the scope of duty to the control group. Finally, I suggest that the heated debate reflects a tension, if not an outright war, between two conflicting meta‐ethical systems, or incommensurable paradigms, that underpin scientific research involving human subjects. (shrink)

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 , 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 , tossing a coin, drawing a name out of a hat. Judgements were split over allocating people in turn . 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. (shrink)

Introduction No consent for health and medical research is appropriate when the criteria for a waiver of consent are met, yet some ethics committees and data custodians still require informed consent. Methods A single-blind parallel-group randomised controlled trial: 1129 families of children born at a South Australian hospital were sent information explaining data linkage of childhood immunisation and hospital records for vaccine safety surveillance with 4 weeks to opt in or opt out by reply form, telephone or email. A (...) subsequent telephone interview gauged the intent of 1026 parents (91%) in relation to their actions and the sociodemographic differences between participants and non-participants in each arm. Results The participation rate was 21% (n=120/564) in the opt-in arm and 96% (n=540/565) in the opt-out arm (χ2 (1 df) = 567.7, p<0.001). Participants in the opt-in arm were more likely than non-participants to be older, married/de facto, university educated and of higher socioeconomic status. Participants in the opt-out arm were similar to non-participants, except men were more likely to opt out. Substantial proportions did not receive, understand or properly consider study invitations, and opting in or opting out behaviour was often at odds with parents' stated underlying intentions. Conclusions The opt-in approach resulted in low participation and a biased sample that would render any subsequent data linkage unfeasible, while the opt-out approach achieved high participation and a representative sample. The waiver of consent afforded under current privacy regulations for data linkage studies meeting all appropriate criteria should be granted by ethics committees, and supported by data custodians. Trial registration number Australian New Zealand Clinical Trials Registry ACTRN12610000332022. (shrink)

BackgroundThe ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines are widely endorsed but compliance is limited. We sought to determine whether journal-requested completion of an ARRIVE checklist improves full compliance with the guidelines.MethodsIn a randomised controlled trial, manuscripts reporting in vivo animal research submitted to PLOS ONE (March–June 2015) were randomly allocated to either requested completion of an ARRIVE checklist or current standard practice. Authors, academic editors, and peer reviewers were blinded to group allocation. Trained reviewers performed outcome (...) adjudication in duplicate by assessing manuscripts against an operationalised version of the ARRIVE guidelines that consists 108 items. Our primary outcome was the between-group differences in the proportion of manuscripts meeting all ARRIVE guideline checklist subitems.ResultsWe randomised 1689 manuscripts (control: n = 844, intervention: n = 845), of which 1269 were sent for peer review and 762 (control: n = 340; intervention: n = 332) accepted for publication. No manuscript in either group achieved full compliance with the ARRIVE checklist. Details of animal husbandry (ARRIVE subitem 9b) was the only subitem to show improvements in reporting, with the proportion of compliant manuscripts rising from 52.1 to 74.1% (X2 = 34.0, df = 1, p = 2.1 × 10−7) in the control and intervention groups, respectively.ConclusionsThese results suggest that altering the editorial process to include requests for a completed ARRIVE checklist is not enough to improve compliance with the ARRIVE guidelines. Other approaches, such as more stringent editorial policies or a targeted approach on key quality items, may promote improvements in reporting. (shrink)

The randomised controlled trial (RCT) constitutes a quantitative, comparative, controlled study of a particular treatment, and provides invaluable evidence regarding its pharmacotherapeutic efficacy. These studies are generally predicated upon the ethical principle of clinical equipoise. However, this may be insufficient to justify withholding treatment from a control group while assessing drug therapy in a potentially fatal disease. Thus, the criteria for randomisation, informed consent methodology and timing, and consideration of treatment options in such a scenario remain the province of (...) medical ethics. This paper addresses the need for an RCT of ribavirin in the treatment of Crimean Congo haemorrhagic fever, and highlights underlying ethical concerns in light of the current medical, virological and ethical literature. (shrink)

Randomized controlled trials (RCTs) are widely taken as the gold standard for establishing causal conclusions. Ideally conducted they ensure that the treatment ‘causes’ the outcome—in the experiment. But where else? This is the venerable question of external validity. I point out that the question comes in two importantly different forms: Is the specific causal conclusion warranted by the experiment true in a target situation? What will be the result of implementing the treatment there? This paper explains how the probabilistic (...) theory of causality implies that RCTs can establish causal conclusions and thereby provides an account of what exactly that causal conclusion is. Clarifying the exact form of the conclusion shows just what is necessary for it to hold in a new setting and also how much more is needed to see what the actual outcome would be there were the treatment implemented. (shrink)

Background: Although ethics consultation has been introduced to clinical practice for many years, the results of empirical studies to evaluate the effectiveness of ethics consultation are still controversial. The design of randomised controlled trials is considered the best research design to evaluate the effect of a clinical practice on the outcomes of interests. In order to understand the effects of ethics consultation, we conducted this search for studies with the design of randomised controlled trials to evaluate (...) ethics consultation.Objective: To provide an integrated review of studies with the design of randomised controlled trials to evaluate the effectiveness of ethics consultation.Methods: PubMed was used to search for studies using the randomised controlled trial design to evaluate the effectiveness of ethics consultation. The search term used was “ethics consultation”. The selection criterion was limited to “randomised controlled trial”.Results: Four articles that met both search criteria were retrieved. One of these articles reported a study that did not actually use the design of a randomised controlled trial and is excluded from the following discussion.Conclusions: To apply randomised controlled trials to evaluate the effectiveness of ethics consultation is extremely difficult as long as two issues are not resolved: the standardisation of ethics consultation and a placebo for ethics consultation to eliminate the placebo effect. Thus, the results generated by the design of randomised controlled trials are always problematic. Furthermore, as long as the two issues exist, the results generated by the design of quantitative research methods always pose problems. (shrink)

Randomised clinical trials involve procedures such as randomisation, blinding, and placebo use, which are not part of standard medical care. Patients asked to participate in RCTs often experience difficulties in understanding the meaning of these and their justification.

This paper argues for more randomised controlled trials in educational research. Educational researchers have largely abandoned the methodology they helped to pioneer. This gold-standard methodology should be more widely used as it is an appropriate and robust research technique. Without subjecting curriculum innovations to a RCT then potentially harmful educational initiatives could be visited upon the nation's children.

Advances in medicine are closely linked to clinical research, but certain study procedures may be in conflict with the fundamental principles of ethics and codes of conduct in medicine. Following an analysis of two studies involving treatments for acute myocardial infarction (AMI), the admissibility of continuing a study was questioned after the initial results for two types of treatment showed that one was significantly better than the other. Also considered doubtful was the information provided to patients with the object of (...) obtaining their informed consent. (shrink)

Objective: Inhibitory control training has shown promise for improving health behaviours, however, less is known about its mediators of effectiveness. The current paper reports whether ICT reduces smoking-related outcomes such as craving and nicotine dependence, increases motivation to quit and whether reductions in smoking or craving are mediated by response inhibition or a devaluation of smoking stimuli.Method: Adult smokers were randomly allocated to receive 14 days of smoking-specific ICT or active control training. Participants were followed up to 3-months post-intervention. This (...) trial was preregistered.Results: There were no significant differences between ICT and active control training groups. Specifically, participants in both groups showed significant reductions in craving, nicotine dependence, motivation and a devaluation of smoking-stimuli up to 3-months follow-up compared to baseline. Inhibition and devaluation of smoking stimuli did not act as mediators. Devaluation of smoking stimuli was an independent predictor of smoking and craving at follow-up.Conclusion: Inhibitory control training was no more effective at reducing smoking-related outcomes compared to the active control group, however, significant improvements in craving, dependence indicators and evaluation of smoking stimuli were observed across both groups. A return to basic experimental research may be required to understand the most effective ICT approach to support smoking cessation. (shrink)

Randomised controlled trials (RCTs) are often seen as the 'gold standard' of evaluative research. However, whilst randomisation will ensure comparable groups, trials are still vulnerable to a range of biases that can undermine their internal validity. In this paper we describe a number of common threats to the internal validity of RCTs and methods of countering them. We highlight a number of examples from randomised trials in education and health care where problems of execution and (...) analysis of the RCT has undermined their internal validity. However, awareness of these potential biases can lead to careful planning to avoid or reduce their occurrence. If good quality randomised trials are to inform policy and practice in education then rigorous trials need to be designed that are the least susceptible to threats to their validity. (shrink)

Background Ethically, informed consent regarding randomised controlled trials (RCTs) should be understandable to patients. The patients can then give free consent or decline to participate in a RCT. Little is known about what patients really understand in consultations about RCTs. Methods Cancer patients who were asked to participate in a randomised trial were surveyed using a semi-standardised interview developed by the authors. The interview addresses understanding, satisfaction and needs of the patients. The sample included eight patients who (...) participated in a trial and two who declined. The data were analysed on the basis of Mayring's qualitative analysis. Results Patients' understanding of informed consent was less developed than anticipated, especially concerning key elements such as randomisation, content and procedure of RCTs. Analysing the result about satisfaction of the patients, most of the patients described their consultations as hectic and without advance notice. Health limitations due to cancer played a decisive role. However, most of the patients perceived their physician to be sympathetic. Analysing the needs of patients, they ask for a clear informed consent consultation with enough time and adequate advance notice. Conclusion This study fills an important empirical research gap of what is ethically demanded in an RCT consultation and what is really understood by patients. The qualitative approach enabled us to obtain new results about cancer patients' understanding of informed consent, to clarify patients' needs and to develop new ideas to optimise the informed consent. (shrink)

The effects of distant, intercessory prayer on health outcomes have been studied in a range of randomised, blinded clinical trials. However, while seeking the evidentiary status accorded this ‘gold standard’ methodology, many prayer studies fall short of the requirements of the World Medical Association's Declaration of Helsinki for the ethical conduct of trials involving human subjects. Within a sample of 15 such studies published in the medical literature, many were found to have ignored or waived key ethical (...) precepts, including adequate standards of care, patient confidentiality and informed consent. Prayer was considered in most studies to pose negligible or no risk to subjects, despite the fact that no clear mechanism of action nor any safety monitoring procedures were described. As a result, many studies did not meet basic ethical standards required of clinical trials of biophysical interventions, making application of their results ethically problematic. If investigators wish their data to adequately inform the use or rejection of intercessory prayer to improve health, these shortcomings should be addressed in future studies. (shrink)

In this article, we examine the ethical implications of randomised control trials (RCTs) as a practice of quantification in international development. Often referred to as the “gold standard” for the evaluation of development interventions, RCTs are lauded for their ability to generate supposedly objective, unbiased, and rigorous evidence to inform policy decisions for poverty alleviation. At the same time, critiques of quantification within and beyond development challenge claims of objectivity and neutrality, raising epistemological and ethical questions regarding the (...) role of quantitative research, the numbers they produce, and the processes triggered by practices of quantification. Building on these critiques, this study develops a decolonial analysis of the RCT methodology. We argue that RCTs, by enacting the coloniality of being, knowledge, and power, serve to perpetuate global coloniality, and its core organising principle, namely colonial difference. The study contributes to ongoing conversations addressing the ethical stakes of knowledge production and (de)coloniality. (shrink)

One important ethical issue in randomised controlled trials is randomisation. Relatively little is known about how participating individuals and communities understand and perceive central aspects of randomisation such as equality, fairness, transparency and accountability in community-based trials. The aim of this study was to understand and explore study communities’ perspectives of the randomisation process in a cluster RCT in rural Zambia studying the effectiveness of different support packages for adolescent girls on early childbearing. In this explorative study, (...) in-depth semi-structured interviews were carried out in 2018 with 14 individuals who took part in the randomisation process of the Research Initiative to Support the Empowerment of Girls project in 2016 and two traditional leaders. Two of the districts where the trial is implemented were purposively selected. Interviews were audio recorded and fully transcribed. Data were analysed by coding and describing emergent themes. The understanding of the randomisation process varied. Some respondents understood that randomisation was conducted for research purposes, but most of them did not. They had trouble distinguishing research and aid. Generally, respondents perceived the randomisation process as transparent and fair. However, people thought that there should not have been a “lottery” because they wanted all schools to receive equal or balanced benefits of the interventions. Randomisation was misunderstood by most respondents. Perceived procedural fairness was easier to realize than substantive fairness. Researchers working on Cluster Randomised Controlled Trials should consider carefully how to explain randomisation. (shrink)

My aim is to suggest that there is a case for using a randomised consent design in some neonatal trials. As an example I use the trials of extracorporeal membrane oxygenation (ECMO) in neonates suffering pulmonary hypertension. In some trials the process of obtaining consent has the potential to harm the subject, for example, by disappointing those who end in the control group and by creating additional anxiety at times of acute illness. An example of such (...) were the trials of extracorporeal membrane oxygenation (ECMO) in neonates suffering pulmonary hypertension. Pre-randomised consent could avoid or lessen these harms. However, a number of ethical objections are made to these research designs. They involve denial of information, using people, denial of choice, and "overselling" of allocated treatment. Furthermore, they are the wrong response; better communication might be the answer, for example. I argue that these objections are not completely persuasive. However, they are enough to suggest caution in the use of such designs. (shrink)

Randomised clinical trials provide the most valid means of establishing the efficacy of clinical therapeutics. Ethical standards dictate that patients and clinicians should not consent to randomisation unless there is uncertainty about whether any of the treatment options is superior to the others ("equipoise"). However, true equipoise is rarely present; most randomised trials, therefore, present challenging ethical dilemmas. Minimising the tension between science and ethics is an obligation of investigators and clinicians. This article briefly reviews several (...) techniques for addressing this issue and suggests that unbalanced randomisation, a technique rarely employed in current clinical trial practice, may be useful for enhancing the ethical design of human experimentation. (shrink)

The use of placebos in randomised controlled trials is a subject of considerable ethical debate. In this paper we present a set of considerations to evaluate the ethics of placebo controlled trials that includes: social value of the study; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and the harm benefit balance; clinical equipoise; and double standards. We illustrate the application of these considerations using a (...) case study of a large ongoing multicentre, placebo-controlled, double-blinded, randomised trial to determine primaquine anti-relapse efficacy in vivax malaria. There is an urgent need for primaquine anti-relapse studies in order to rationalise the management of a potentially fatal disease. An ethical justification for the use of the placebo arm is provided on the grounds that the actual current applied standard of care in most endemic places does not include primaquine. It has also been argued that there is clinical equipoise among the primaquine study arms and that the risk of harms of being in the placebo arm is the risk of having relapse, which is no more than not being included in the trial, and that there are no double standards. Based on our set of considerations, we conclude that a placebo arm is not only justified but imperative in this study. We propose that similar considerations should be prospectively applied to other placebo controlled trials and observational control arms where no treatment is offered. (shrink)

BackgroundAs the number of randomised controlled trials of medicines for children increases, it becomes progressively more important to understand the experiences of parents who are asked to enrol their child in a trial. This paper presents a narrative review of research evidence on parents' experiences of trial recruitment focussing on qualitative research, which allows them to articulate their views in their own words.DiscussionParents want to do their best for their children, and socially and legally their role is to (...) care for and protect them yet the complexities of the medical and research context can challenge their fulfilment of this role. Parents are simultaneously responsible for their child and cherish this role yet they are dependent on others when their child becomes sick. They are keen to exercise responsibility for deciding to enter a child in a trial yet can be fearful of making the 'wrong' decision. They make judgements about the threat of the child's condition as well as the risks of the trial yet their interpretations often differ from those of medical and research experts. Individual parents will experience these and other complexities to a greater or lesser degree depending on their personal experiences and values, the medical situation of their child and the nature of the trial. Interactions at the time of trial recruitment offer scope for negotiating these complexities if practitioners have the flexibility to tailor discussions to the needs and situation of individual parents. In this way, parents may be helped to retain a sense that they have acted as good parents to their child whatever decision they make.SummaryDiscussing randomised controlled trials and gaining and providing informed consent is challenging. The unique position of parents in giving proxy consent for their child adds to this challenge. Recognition of the complexities parents face in making decisions about trials suggests lines for future research on the conduct of trials, and ultimately, may help improve the experience of trial recruitment for all parties. (shrink)

Randomised controlled trials (RCTs) sometimes recruit participants who are desperate to receive the experimental treatment. This paper defends the practice against three arguements that suggest it is unethical first, desperate volunteers are not in equipoise. Second clinicians, entering patients onto trials are disavowing their therapeutic obligation to deliver the best treatment; they are following trial protocols rather than delivering individualised care. Research is not treatment; its ethical justification is different. Consent is crucial. Third, desperate volunteers do not (...) give proper consent: effectively, they are coerced. This paper responds by advocating a notion of equipoise based on expert knowledge and widely shared values. Where such collective, expert equipoise exists there is a prima facie case for an RCT. Next the paper argues that trial entry does not involve clinicians disavowing their therapeutic obligation; individualised care based on insufficient evidence is not in patients best interest. Finally, it argues that where equipoise exists it is acceptable to limit access to experimental agents; desperate volunteers are not coerced because their desperation does not translate into a right to receive what they desire. (shrink)

This paper outlines the approaches of two apparently competing schools of statistics. The criticisms made by supporters of Bayesian statistics about conventional Frequentist statistics are explained, and the Bayesian claim that their method enables research into new treatments without the need for clinical trials is examined in detail. Several further important issues are considered, including: the use of historical controls and data routinely collected on patients; balance in randomised trials; the possibility of giving information to patients; patient (...) choice and patient autonomy; and how widely the results of clinical trials can be used. It is concluded that good statistical techniques in the design and analysis of medical studies are essential, but the statistical school used in developing such techniques is relatively unimportant. (shrink)

The standardised randomised clinical trial (RCT) has been exceedingly popular in medical research, economics, and practical policy making. Recently, RCTs have faced criticism. First, it has been argued by John Worrall that we cannot be certain that our sample is not atypical with regard to possible confounding factors. I will argue that at least in the case of medical research, we know enough about the relevant causal mechanisms to be justified to ignore a number of factors we have good (...) reason not to expect to be disruptive. I will also argue against an argument provided by Nancy Cartwright and Eileen Munro that RCTs should not be taken to deductively infer probabilistic causal claims, but ampliatively. The paper will end on a discussion of evidence hierarchies and a defence of the stance of evidence-based medicine that RCTs are the best available method to assess a treatment’s efficacy. (shrink)

Background: Privacy laws have recently created restrictions on how researchers can approach study participants.Method: In a randomised trial of 152 patients, 50–74 years old, in a family practice, 60 were randomly selected to opt-out and 92 to opt-in methods. Patients were sent an introductory letter by their doctor in two phases, opt-out before and opt-in after introduction of the new Privacy Legislation in December 2001. Opt-out patients were contacted by researchers. Opt-in patients were contacted if patients responded by email, (...) free telephone number or a reply-paid card.Results: Opt-in recruited fewer patients after invitation compared with opt-out ; . No proportional difference in recruitment was found between opt-in and opt-out groups varied by age, sex or socioeconomic status. The opt-in group had significantly more people in active decision-making roles . Non-significant trends were observed towards opt-in being less likely to include people with lower education and people who were not screened . Opt-in was more likely to recruit people with a family history of colorectal cancer .Conclusions: The number of participants required to be approached was markedly increased in opt-in recruitment. Existing participants with a vested interest such as increased risk, and those preferring an active role in health decision making and with less education were likely to be recruited in opt-in. Research costs and generalisability are affected by implementing privacy legislation. (shrink)

Objective: To assess whether continuous consent, a process in which information is given to research participants at different stages in a trial, and clinician training in that process were effective when used by clinicians while gaining consent to the Total Body Hypothermia (TOBY) trial. The TOBY trial is a randomised controlled trial (RCT) investigating the use of whole-body cooling for neonates with evidence of perinatal asphyxia. Obtaining valid informed consent for the TOBY trial is difficult, but is a good (...) test of the effectiveness of continuous consent. Methods: Semistructured interviews were conducted with 30 sets of parents who consented to the TOBY trial and with 10 clinicians who sought it by the continuous consent process. Analysis was focused on the validity of parental consent based on the consent components of competence, information, understanding and voluntariness. Results: No marked problems with consent validity at the point of signature were observed in 19 of 27 (70%) couples. Problems were found mainly to lie with the competence and understanding of the parents: mothers, particularly, had problems with competence in the early stages of consent. Problems in understanding were primarily to do with side effects. Problems in both competence and understanding were observed to reduce markedly, particularly for mothers, in the post-signature phase, when further discussion took place. Randomisation was generally understood but unpopular. Information was not always given by clinicians in stages during the short period available before parents gave consent. Most clinicians, however, were able to give follow-up information. Discussion: Consent validity was found to compare favourably with similar trials examined in the Euricon study. Conclusion: Adopting the elements of the continuous consent process and clinician training in RCTs should be considered by researchers, particularly when they have concerns about the quality of consent they are likely to obtain by using a conventional process. (shrink)

The purpose of this study is to examine the importance that real patients attach to their right to withdraw from an on-going feasibility randomised trial (RCT) evaluating types and timings of breast reconstruction (two parallel trials) following mastectomy for breast cancer. Our results show that, while some respondents appreciated that exercising the right to withdraw would defeat the scientific objective of the trial, some patients with a surgical preference consented only given the knowledge they could withdraw if they (...) were not allocated to their preferred treatment. (shrink)

BackgroundImplementation of recommendations from clinical practice guidelines is essential for evidence based clinical practice. However, the most effective methods of implementation are unclear. We conducted a national, cluster-randomised, blinded implementation trial to determine if midwife or doctor local implementation leaders are more effective in implementing a guideline for use of oral dextrose gel to treat hypoglycaemic babies on postnatal wards. To prevent any conscious or unconscious performance bias both the doctor and midwife local implementation leaders were kept unaware of (...) the trial. This paper reports the ethical dilemmas and practical challenges of ensuring clinicians remained unaware of their involvement in an implementation trial.MethodsWe sought approval from the National Health and Disability Ethics committee to keep clinicians unaware of the trial by waiving the standard requirement for locality approval usually required for each district health board. The ethics committee did not approve a waiver of consent but advised that we approach the chief executive of each district health board to ask for provisional locality approval. Ultimately it was necessary to seek ethics approval for three separate study designs to keep clinicians unaware of the trial.ResultsThe median time for chief executive approval was 16 days and for locality approval was 57 days. We completed 21 different locality approval forms for 27 hospitals.ConclusionsKeeping clinicians unaware of their involvement in a national implementation cluster-randomised trial is feasible. However, despite a national ethics committee, significant logistical challenges were time consuming and delayed trial completion. Co-ordination of the locality approval process would help facilitate multi-centre trials. (shrink)

Physical activities are generally accepted as promoting important psychological benefits. However, studies examining martial arts as a form of physical activity and mental health have exhibited many methodological limitations in the past. Additionally, recent philosophical discussion has debated whether martial arts training promotes psychological wellbeing or illness. Self-efficacy has an important relationship with mental health and may be an important mechanism underpinning the potential of martial arts training to promote mental health. This study examined the effect of martial arts training (...) on the psychological construct of self-efficacy. A total of 283 secondary school students with a mean age of 12.76 (SD = 0.68) years were recruited to complete a time-limited (10-session) martial arts intervention, which was examined using a randomised controlled trial. Univariate ANOVAs found that the intervention improved the experimental group’s self-efficacy compared to the control group, which was sustained at follow-up. Regression analysis indicated that socio-educational status moderated this outcome. These findings support the martial arts-based intervention’s potential to improve self-efficacy and promote wellbeing through physical activity. Martial arts training may be an efficacious psychosocial treatment that can be used as a complementary approach to promote mental health. (shrink)

Madole & Harden argue that the Mendelian reshuffling of genes and genomes is analogous to randomised controlled trials. We are not convinced by their arguments. First, their recipe for meeting the demands on randomised experiments is inherently inconsistent. Second, disequilibrium across chromosomes conflicts with their assumption of statistical independence. Third, the genome-wide association study (GWAS) method has many pitfalls, including low repeatability.

Clinicians are required to act in the best interest of neonates.However, it is not obvious that entry into a randomised controlled trial (RCT) is in a neonate’s best interest because such trials often involve additional onerous procedures (such as intramuscular injections) in return for which the neonate receives unproven treatment or a placebo.On the other hand, neonatology needs to develop its evidence base, and RCTs are central to this task. The solution posited here is based on two points. (...) First, “best interest” is not equivalent to “the best possible interest” only to “best interest within a certain realm”. The realm of deliberation when asking the title question is the neonate’s health. Deliberating in this realm may involve the exclusion from consideration of some factors that might be thought relevant (such as parental wealth). Furthermore, circumstances may dictate the need to deliberate on other factors that might be thought irrelevant (such as health care resources). Second, deciding on a neonate’s best interest does not involve “putting oneself in its shoes”. Rather, it involves asking in what it has an interest, or stake. These will include some things in which we all, as human beings, have a stake, such as medical progress. Putting these two points together, in the realm of health the answer to whether RCT entry is in a neonate’s best interest is usually very finely balanced. Where this is the case, it is reasonable to invoke a broader notion of best interest and include a broader range of elements in which the neonate has a stake, including medical progress. In this way RCT entry can, usually, be said to be in a neonate’s best interest. (Journal of Medical Ethics 2001;27:110–113) Keywords: Neonates; randomised controlled trials; best interest; ethics. (shrink)

Objective: To examine the current ethical review process of ethics committees in a non-pharmacological trial from the perspective of a clinical investigator.Design: Prospective collection of data at the Study Centre of the German Surgical Society on the duration, costs and administrative effort of the ERP of a randomised controlled multicentre surgical INSECT Trial between November 2003 and May 2005.Setting: Germany.Participants: 18 ethics committees, including the ethics committee handling the primary approval, responsible overall for 32 clinical sites throughout Germany. 8 (...) ethics committees were located at university medical schools and 10 at medical chambers. Duration was measured as days between submission and receipt of final approval, costs in euros and administrative effort by calculation of the product of the total number of different types of documents and the mean number of copies required .Results: The duration of the ERP ranged from 1 to 176 days. The median duration was 26 days at MSUs compared with 34 days at medical chambers. The total cost was €2947. 1 of 8 ethics committees at universities and 8 of 10 at medical chambers charged a median fee of €162 . The administrative effort for primary approval was 30. Four ethics committees required a higher administrative effort for secondary approval .Conclusion: The ERP for non-pharmacological multicentre trials in Germany needs improvement. The administrative process has to be standardised: the application forms and the number and content of the documents required should be identical or at least similar. The fees charged vary considerably and are obviously too high for committees located at medical chambers. However, the duration of the ERP was, with some exceptions, excellent. A centralised ethics committee in Germany for multicentre trials such as the INSECT Trial can simplify the ERP for clinical investigators in and outside the country. (shrink)

In the biomedical, behavioural and social sciences, the leading method used to estimate causal effects is commonly randomised controlled trials (RCTs) that are generally viewed as both the source and justification of the most valid evidence. In studying the foundation and theory behind RCTs, the existing literature analyses important single issues and biases in isolation that influence causal outcomes in trials (such as randomisation, statistical probabilities and placebos). The common account of biased causal inference is described in (...) a general way in terms of probabilistic imbalances between trial groups. This paper expands the common account of causal bias by distinguishing between the range of biases arising between trial groups but also within one of the groups or across the entire sample during trial design, implementation and analysis. This is done by providing concrete examples from highly influential RCT studies. In going beyond the existing RCT literature, the paper provides a broader, practice-based account of causal bias that specifies the between-group, within-group and across-group biases that affect the estimated causal results of trials – impacting both the effect size and statistical significance. Within this expanded framework, we can better identify the range of different types of biases we face in practice and address the central question about the overall validity of the RCT method and its causal claims. A study can face several smaller biases (related simultaneously to a smaller sample, smaller estimated effect, greater unblinding etc.) that generally add up to greater aggregate bias. Though difficult to measure precisely, it is important to assess and provide information in studies on how much different sources of bias, combined, can explain the estimated causal effect. The RCT method is thereby often the best we have to inform our policy decisions – and the evidence is strengthened when combined with multiple studies and other methods. Yet there is room for continually improving trials and identifying ways to reduce biases they face and to increase their overall validity. Implications are discussed. (shrink)

Community consultation is increasingly recommended, and in some cases, required by ethical review boards for research that involves higher levels of ethical risk such as international research and research with vulnerable populations. In designing a randomised control trial of a mental health intervention using a wait list control, we consulted the community where the research would be undertaken prior to finalising the study protocol. The study sites were two conflict-affected locations: Grozny in the Chechen Republic and Kitchanga in eastern (...) Democratic Republic of Congo. (shrink)