To the editor:
We commend Shamy and Fedyk for their thoughtful commentary [
[1]
] on the ethical and scientific justification for clinical trials and accompanying cross-sectional study of De Meulemeester et al. [[2]
]. We generally agree with the three proposed criteria for ethical justification of randomized control trials (RCTs): nonredundancy, scientific plausibility, and methodological rigor. Yet, these criteria are broad, and moreover, the end users (eg, ethical review boards [ERBs], funders, or both) and practical implementation of this framework in practice are not entirely clear.We believe that tools exist, readily applicable for ERBs, which can help in making the scientific approach applicable also to ethical questions and practice. In general, ethics approval systems can be opaque. We believe the composition of review boards (eg, specific professions, patients, stakeholders) and evaluation criteria can be made be more transparent. We propose the following actions for applicability of Shamy and Fedyk's criteria to the ethical review process.
- (1)Requiring adherence to existing reporting guidelines for clinical trial proposals. SPIRIT is available for use with RCT protocols. Other guidelines can be used to ensure that information that needs to be reported at the end was considered in designing the study [3,4]. Requiring a statistical analysis plan, preferably assessed by a statistical reviewer, allows for a better assessment of the methodological rigor of studies [The EQUATOR Network
Reporting guidelines|The EQUATOR Network.http://www.equator-network.org/Date accessed: March 16, 2017[5]]. - (2)Authors can be invited to clearly document patient and public involvement (PPI) at different stages of the study, from the proposal, through to the conduct and dissemination of the results. PPI should also be a part of the ERB involved in the evaluation.
- (3)Where applicable, uptake and implementation of well-developed core outcome sets should be encouraged, thus ensuring that outcomes are free from selective reporting bias and heterogeneity and that trial endpoints are meaningful to all relevant stakeholders [[6]]. This in turn leads to the next item.
- (4)In addition to the clinical outcome of a trial, that is, the prespecified statistical measure, the outcome's translational implications should also be defined. For example, how the clinical outcome(s) can be used for evaluating or changing clinical care, for decision-making, or other measurable end values for practice, patients, and/or public for example, by using benefit-harm charts as proposed by Puhan et al., 2015 [[7]]. If the outcomes are not put into context of benefit, harm or clinical need, how would it ever be ethical to conduct an RCT?
We believe that, despite the great diversity of review processes within and between countries, these proposals are generalizable and independent of the individual legislation and requirements.
Within the multidisciplinary MiRoR consortium (“Methods in Research on Research”), we are working to reduce research waste and improve clinical research value by developing and implementing interventions, tools, guidance, and expertise. Strengthening ethical and scientific justification for clinical trials will help us all to improve the value of research, to the benefit of current and future patients and other stakeholders.
Supplementary data
- Data Profile
References
- Why the ethical justification of randomized clinical trials is a scientific question.J Clin Epidemiol. 2018; 97: 126-132
- Many randomized clinical trials may not be justified: a cross-sectional analysis of the ethics and science of randomized clinical trials.J Clin Epidemiol. 2018; 97: 20-25
- SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials.BMJ. 2013; 346: e7586
- Reporting guidelines|The EQUATOR Network.(Available at)http://www.equator-network.org/Date accessed: March 16, 2017
- Guidelines for the content of statistical analysis plans in clinical trials.JAMA. 2017; 318: 2337-2343
- Core outcome set-STAndards for development: the COS-STAD recommendations.PLoS Med. 2017; 14: e1002447
- Benefit-harm analysis and charts for individualized and preference-sensitive prevention: example of low dose aspirin for primary prevention of cardiovascular disease and cancer.BMC Med. 2015; 13: 250
Article info
Publication history
Published online: March 26, 2018
Footnotes
On behalf of the Methods in Research on Research (MiRoR) project.
Funding: This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 676207.
Conflicts of interest: The authors declare no conflicts of interest.
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- Reply to: Letter to the Editor by M. Olsen, M. K. Sharp, and P. M. BossuytJournal of Clinical EpidemiologyVol. 99
- PreviewOn behalf of our coauthors, we thank Olsen, Sharp, and Bossuyt for their insightful comments [1]. We agree that a major challenge to ensuring that proposed randomized clinical trials are ethically justified is developing a system to evaluate their ethics in practical terms. One of the great weaknesses of the concept of equipoise is that no widely accepted operationalization has been developed, despite its widespread use for 30 years. In the absence of such a system, an ethical principle may be used unethically, that is, unfairly and in a biased manner.
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