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

Edwards, Sarah; Braunholtz, David; Lilford, Richard; Stevens, Andrew

doi:10.1136/bmj.318.7195.1407

Cited by 234 publications

(260 citation statements)

References 3 publications

Supporting

Mentioning

258

Contrasting

Unclassified

Order By: Relevance

“…The HTA review highlighted the problem of underpowered RCTs, which were described as 'necessarily unethical' as they were unlikely to produce clear-cut answers. 5 This argument was supported by 15 articles that stipulated the statistical necessity for random errors in measured effects of treatments to be small in comparison with the size of the therapeutic effect sought. Other articles in the review discussed the ethics of stopping RCTs early when there is some evidence of efficacy and the subsequent problems that this may cause, with reduced statistical precision, clinicians not being persuaded by results and secondary trial aims being compromised being some of the key problems.…”

Section: Chapter 2 Backgroundmentioning

confidence: 99%

See 1 more Smart Citation

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Hettle

Corbett

Hinde

et al. 2017

Health Technol Assess

103

143

View full text Add to dashboard Cite

BackgroundThe National Institute for Health and Care Excellence (NICE) commissioned a ‘mock technology appraisal’ to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal.MethodsOur research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia.ResultsAn assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately. Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision.ConclusionsIt is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further.FundingThe National Institute for Health Research Health Technology Assessment programme.

show abstract

Section: Chapter 2 Backgroundmentioning

confidence: 99%

“…unmet need); and when a disease is rare and recruitment is slow. 5 Additionally, when trial populations are small, it may be difficult to differentiate a true treatment effect from a chance effect. Important chance imbalances in relevant prognostic factors between groups at baseline are more likely in small trials.…”

Section: Chapter 2 Backgroundmentioning

confidence: 99%

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Hettle

Corbett

Hinde

et al. 2017

Health Technol Assess

103

143

View full text Add to dashboard Cite

show abstract

“…The treatment options being compared must look as acceptable tradeoffs between risks and benefits, perhaps for different reasons -and this is what will ultimately make a trial ethically acceptable to the participating investigators and eventually lead an informed patient to volunteer as a trial participant. Disturbingly, in this context, there are data suggesting that patients are less likely to consent to randomization if they get more detailed information on trial arms [26,27] and also that the willingness to volunteer seems to be inversely correlated with the level of education of the research subject or their medical legal proxy [28]. Would a patient information sheet for a proton vs. photon trial include an explained case of a plot of isodose contours on a CT scan for example?…”

Section: Whose Equipoise?mentioning

confidence: 99%

Randomized controlled trials in health technology assessment: Overkill or overdue?

Bentzen

2008

Radiotherapy and Oncology

View full text Add to dashboard Cite

Evidence-based medicine has become a cornerstone in the development of radiation oncology and the randomized controlled phase III trial remains the gold standard for assessing differential benefits in clinical outcome between therapies. Health technologies aimed at improving treatment quality should primarily be tested using process measures or operational characteristics, the reason being that the sensitivity and specificity of clinical outcome is low for detecting quality improvements. The ongoing discussion of the relative merits of intensity modulated photon vs. proton radiotherapy is used to illustrate these concepts. Concerns over clinical and individual equipoise as well as the potential limitations of health economics considerations in this setting are also discussed. Working in a technology and science based medical discipline, radiation oncology researchers need to further develop methodology for critical assessment of health technologies as a complement to randomized controlled trials."Only two options exist. The first is that we accept that, under exceptional circumstances, common sense might be applied when considering the potential risks and benefits of interventions. The second is that we continue our quest for the holy grail of exclusively evidence based interventions and preclude parachute use outside the context of a properly conducted trial." Evidence-based medicine and randomized controlled trialsEvidence-based medicine is a compelling paradigm as a rational road-map, some would argue the only rational road-map, for improving the standard of health care [2,3]. The role of randomized controlled trials in this context cannot be overstated: while the allocation to different treatment options may be skewed even in a specific randomized trial, randomization is the only method that on average safe-guards against prognostic imbalances that could bias therapy effect estimates. History shows, that even when there has been overwhelming support for a novel therapeutic intervention in terms of a well-proven mechanism of action, promising pre-clinical and early clinical data as well as wide-spread consensus regarding an expected benefit among the experts, the cold-hearted scrutiny of a,

show abstract

“…11,40,41 This requirement is sometimes referred to as "the uncertainty principle" 42 or "equipoise." 36,41,43,44 We previously hypothesized that there is a predictable relationship between the uncertainty principle, that is, the moral principle, upon which trials are based and the ultimate outcomes of clinical trials.…”

Section: Commentmentioning

confidence: 99%

Evaluation of New Treatments in Radiation Oncology

Soares¹,

Kumar²,

Daniels³

et al. 2005

JAMA

View full text Add to dashboard Cite

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

Cited by 234 publications

References 3 publications

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Randomized controlled trials in health technology assessment: Overkill or overdue?

Evaluation of New Treatments in Radiation Oncology

Contact Info

Product

Resources

About