Designing and undertaking randomised implementation trials: guide for researchers.
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ABSTRACT:
SUBMITTER: Wolfenden L
PROVIDER: S-EPMC7812444 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Designing and undertaking randomised implementation trials: guide for researchers.
Wolfenden Luke L Foy Robbie R Presseau Justin J Grimshaw Jeremy M JM Ivers Noah M NM Powell Byron J BJ Taljaard Monica M Wiggers John J Sutherland Rachel R Nathan Nicole N Williams Christopher M CM Kingsland Melanie M Milat Andrew A Hodder Rebecca K RK Yoong Sze Lin SL
BMJ (Clinical research ed.) 20210118
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Project description:BackgroundConducting effective and translational research can be challenging and few trials undertake formal reflection exercises and disseminate learnings from them. Following completion of our multicentre randomised controlled trial, which was impacted by the COVID-19 pandemic, we sought to reflect on our experiences and share our thoughts on challenges, lessons learned, and recommendations for researchers undertaking or considering research in primary care.MethodsResearchers involved in the Prediction of Undiagnosed atriaL fibrillation using a machinE learning AlgorIthm (PULsE-AI) trial, conducted in England from June 2019 to February 2021 were invited to participate in a qualitative reflection exercise. Members of the Trial Steering Committee (TSC) were invited to attend a semi-structured focus group session, Principal Investigators and their research teams at practices involved in the trial were invited to participate in a semi-structured interview. Following transcription, reflexive thematic analysis was undertaken based on pre-specified themes of recruitment, challenges, lessons learned, and recommendations that formed the structure of the focus group/interview sessions, whilst also allowing the exploration of new themes that emerged from the data.ResultsEight of 14 members of the TSC, and one of six practices involved in the trial participated in the reflection exercise. Recruitment was highlighted as a major challenge encountered by trial researchers, even prior to disruption due to the COVID-19 pandemic. Researchers also commented on themes such as the need to consider incentivisation, and challenges associated with using technology in trials, especially in older age groups.ConclusionsUndertaking a formal reflection exercise following the completion of the PULsE-AI trial enabled us to review experiences encountered whilst undertaking a prospective randomised trial in primary care. In sharing our learnings, we hope to support other clinicians undertaking research in primary care to ensure that future trials are of optimal value for furthering knowledge, streamlining pathways, and benefitting patients.
| S-EPMC10759575 | biostudies-literature
Project description:BackgroundRecent cohort studies of randomised controlled trials have provided evidence of within-study selective reporting bias; where statistically significant outcomes are more likely to be more completely reported compared to non-significant outcomes. Bias resulting from selective reporting can impact on meta-analyses, influencing the conclusions of systematic reviews, and in turn, evidence based clinical practice guidelines.In 2006 we received funding to investigate if there was evidence of within-study selective reporting in a cohort of RCTs submitted to New Zealand Regional Ethics Committees in 1998/99. This research involved accessing ethics applications, their amendments and annual reports, and comparing these with corresponding publications. We did not plan to obtain informed consent from trialists to view their ethics applications for practical and scientific reasons. In November 2006 we sought ethical approval to undertake the research from our institutional ethics committee. The Committee declined our application on the grounds that we were not obtaining informed consent from the trialists to view their ethics application. This initiated a seventeen month process to obtain ethical approval. This publication outlines what we planned to do, the issues we encountered, discusses the legal and ethical issues, and presents some potential solutions.Discussion and conclusionMethodological research such as this has the potential for public benefit and there is little or no harm for the participants (trialists) in undertaking it. Further, in New Zealand, there is freedom of information legislation, which in this circumstance, unambiguously provided rights of access and use of the information in the ethics applications. The decision of our institutional ethics committee defeated this right and did not recognise the nature of this observational research. Methodological research, such as this, can be used to develop processes to improve quality in research reporting. Recognition of the potential benefit of this research in the broader research community, and those who sit on ethics committees, is perhaps needed. In addition, changes to the ethical review process which involve separation between those who review proposals to undertake methodological research using ethics applications, and those with responsibility for reviewing ethics applications for trials, should be considered. Finally, we contend that the research community could benefit from quality improvement approaches used in allied sectors.
| S-EPMC2846843 | biostudies-literature
Project description:It is common to undertake qualitative research alongside randomised controlled trials (RCTs) when evaluating complex interventions. Researchers tend to analyse these datasets one by one and then consider their findings separately within the discussion section of the final report, rarely integrating quantitative and qualitative data or findings, and missing opportunities to combine data in order to add rigour, enabling thorough and more complete analysis, provide credibility to results, and generate further important insights about the intervention under evaluation. This paper reports on a 2 day expert meeting funded by the United Kingdom Medical Research Council Hubs for Trials Methodology Research with the aims to identify current strengths and weaknesses in the integration of quantitative and qualitative methods in clinical trials, establish the next steps required to provide the trials community with guidance on the integration of mixed methods in RCTs and set-up a network of individuals, groups and organisations willing to collaborate on related methodological activity. We summarise integration techniques and go beyond previous publications by highlighting the potential value of integration using three examples that are specific to RCTs. We suggest that applying mixed methods integration techniques to data or findings from studies involving both RCTs and qualitative research can yield insights that might be useful for understanding variation in outcomes, the mechanism by which interventions have an impact, and identifying ways of tailoring therapy to patient preference and type. Given a general lack of examples and knowledge of these techniques, researchers and funders will need future guidance on how to undertake and appraise them.
| S-EPMC6886933 | biostudies-literature
Project description:BackgroundEffectiveness-implementation hybrid designs are a relatively new approach to evaluate efficacious interventions in real-world settings while concurrently gathering information on the implementation. Intervention fidelity can significantly influence the effectiveness of an intervention during implementation. However little guidance exists for applied researchers conducting effectiveness-implementation hybrid trials regarding the impact of fidelity on intervention effects and power.MethodsWe conducted a simulation study based on parameters from a clinical example study. For the simulation, we explored parallel and stepped-wedge cluster randomized trials (CRTs) and hypothetical patterns of fidelity increase during implementation: slow, linear, and fast. Based on fixed design parameters, i.e., the number of clusters (C = 6), time points (T = 7), and patients per cluster (n = 10) we used linear mixed models to estimate the intervention effect and calculated the power for different fidelity patterns. Further, we conducted a sensitivity analysis to compare outcomes based on different assumptions for the intracluster-correlation coefficient and the cluster size.ResultsEnsuring high fidelity from the beginning is central to achieve accurate intervention effect estimates in stepped-wedge and parallel CRTs. The importance of high fidelity in the earlier stages is more emphasized in stepped-wedge designs than in parallel CRTs. In contrast, if the increase of fidelity is too slow despite relatively high starting levels, the study will likely be underpowered and the intervention effect estimates will also be biased. This effect is more accentuated in parallel CRTs, here reaching 100% fidelity within the next measurement points is crucial.ConclusionsThis study discusses the importance of intervention fidelity for the study`s power and highlights different recommendations to deal with low fidelity in parallel and stepped-wedge CRTs from a design perspective. Applied researchers should consider the detrimental effect of low fidelity in their evaluation design. Overall, there are fewer options to adjust the trial design after the fact in parallel CRT as compared to stepped-wedge CRTs. Particular emphasis should be placed on the selection of contextually relevant implementation strategies.
| S-EPMC10183132 | biostudies-literature
Project description:In a cluster randomised trial (CRT), intact groups-such as communities, clinics or schools-are randomised to the study intervention or control conditions. The issue of informed consent in CRTs has been particularly challenging for researchers and research ethics committees. Some argue that cluster randomisation is a reason not to seek informed consent from research participants. In fact, systematic reviews have found that, relative to individually randomised trials, CRTs are associated with an increased likelihood of inadequate reporting of consent procedures and inappropriate use of waivers of consent. The objective of this paper is to clarify this confusion by providing a practical and useful framework to guide researchers and research ethics committees through consent issues in CRTs. In CRTs, it is the unit of intervention-not the unit of randomisation-that drives informed consent issues. We explicate a three-step framework for thinking through informed consent in CRTs: (1) identify research participants, (2) identify the study element(s) to which research participants are exposed, and (3) determine if a waiver of consent is appropriate for each study element. We then apply our framework to examples of CRTs of cluster-level, professional-level and individual-level interventions, and provide key lessons on informed consent for each type of CRT.
| S-EPMC8477335 | biostudies-literature
Project description:ObjectiveTo assess the extent to which consumers are involved in the work of clinical trial coordinating centres in the United Kingdom and the nature of consumers' involvement in randomised trials coordinated by these centres.DesignNational surveys using structured questionnaires with some open ended sections.Setting103 clinical trial coordinating centres in the United Kingdom identified through a database assembled in 1997 by the NHS clinical trials adviser.ParticipantsNamed contacts at 62 coordinating centres and investigators in 60 trials that were identified as involving consumers.Main outcome measuresNumber of coordinating centres and number of trials in which consumers were involved and the nature of consumers' involvement.ResultsOf the 62 eligible centres, 23 reported that consumers had already been involved in their work, and most respondents were positive about this involvement. 17 centres planned to involve consumers. 15 centres had no plans to involve consumers, but only four of these considered such involvement irrelevant. Responses from investigators about the 48 individual trials were mostly positive, with respondents commenting that input from consumers had helped refine research questions, improve the quality of patient information, and make the trial more relevant to the needs of patients.ConclusionsConsumer involvement in the design and conduct of controlled trials seems to be growing and seems to be welcomed by most researchers. Such involvement seems likely to improve the relevance to consumers of the questions addressed and the results obtained in controlled trials.
| S-EPMC26555 | biostudies-literature
Project description:The use of preprints, research manuscripts shared publicly before completing the traditional peer-review process, is becoming a more common practice among life science researchers. Early-career researchers (ECRs) benefit from posting preprints as they are shareable, citable, and prove productivity. However, preprinting a manuscript involves a discussion among all co-authors, and ECRs are often not the decision-makers. Therefore, ECRs may find themselves in situations where they are interested in depositing a preprint but are unsure how to approach their co-authors or advisor about preprinting. Leveraging our own experiences as ECRs, and feedback from the research community, we have constructed a guide for ECRs who are considering preprinting to enable them to take ownership over the process and to raise awareness about preprinting options. We hope that this guide helps ECRs to initiate conversations about preprinting with co-authors and encourage them to preprint their future research.
| S-EPMC9346271 | biostudies-literature
Project description:BackgroundExercise intervention research has shown promising results in preventing and reversing the side effects caused by prostate cancer and its' treatment. However, there are still unanswered questions and the need for additional research. As the field of exercise oncology in the context of prostate cancer presents unique challenges and complexities, seeking the advice of experienced exercise oncology researchers before initiating a similar trial could help to design more effective and efficient studies and help avoid pitfalls.MethodsA qualitative descriptive study design and a nonprobability, purposive sampling method was employed. An interview guide was developed and included topics such as recruitment, retention, programme goals, research design, health considerations, treatment considerations, adverse events, exercise prescription and outcome tools. Individual semi-structured interviews were conducted and interviews were transcribed and analysed using thematic analysis.ResultsEight individuals with extensive experience working with prostate cancer patients in exercise oncology research settings were interviewed. Four main themes and seven subthemes were generated and supported by the data. Theme 1 highlighted the critical role of recruitment, with associated subthemes on recruitment barriers and recruitment methods. Theme 2 explored the positives and negatives of home-based programmes. Theme 3 focused on specific health characteristics, exercise prescription and outcome measure factors that must be considered when working with prostate cancer cohorts. Finally, theme 4 centered around the emotional dimensions present in exercise oncology trials, relating to both researchers and study participants.ConclusionExercise oncology remains a challenging area in which to conduct research. Learning from experienced personnel in the field offers valuable information and guidance that could impact the success of future trials.
| S-EPMC10614306 | biostudies-literature
Project description:The use of real-world evidence (RWE) studies, including pragmatic randomised controlled trials (RCTs; randomised RWE studies), to aid the development of treatment guidelines, is gradually becoming a mainstay within clinical practice. RWE is an integral part of patient-driven decision-making and offers important value to add complimentary evidence to traditional RCTs; these provide a more well-rounded view of the benefits to patient-reported outcomes and improve the external validity of a given treatment versus findings from traditional RCTs alone. Discussions in recent scientific workshops explored the importance of pragmatic RCTs in optimising guideline development and patient care in chronic obstructive pulmonary disease (COPD) and asthma. The Salford Lung Study in patients with COPD (NCT01551758) and asthma (NCT01706198) were the world's first prelicence pragmatic RCTs that compared novel investigational treatments with existing COPD and asthma treatments and, more recently (2021), RWE studies have been used by the American Thoracic Society and the US Food and Drug Administration to support the approval of an immunosuppressant drug in patients receiving lung transplants. This highlights the importance of RWE data in supporting clinical guideline development and emphasises the advantages for the use of pragmatic RCTs in guiding clinical practice.
| S-EPMC9528570 | biostudies-literature
Project description:BackgroundIt has long been advised to account for baseline covariates in the analysis of confirmatory randomised trials, with the main statistical justifications being that this increases power and, when a randomisation scheme balanced covariates, permits a valid estimate of experimental error. There are various methods available to account for covariates but it is not clear how to choose among them.MethodsTaking the perspective of writing a statistical analysis plan, we consider how to choose between the three most promising broad approaches: direct adjustment, standardisation and inverse-probability-of-treatment weighting.ResultsThe three approaches are similar in being asymptotically efficient, in losing efficiency with mis-specified covariate functions and in handling designed balance. If a marginal estimand is targeted (for example, a risk difference or survival difference), then direct adjustment should be avoided because it involves fitting non-standard models that are subject to convergence issues. Convergence is most likely with IPTW. Robust standard errors used by IPTW are anti-conservative at small sample sizes. All approaches can use similar methods to handle missing covariate data. With missing outcome data, each method has its own way to estimate a treatment effect in the all-randomised population. We illustrate some issues in a reanalysis of GetTested, a randomised trial designed to assess the effectiveness of an electonic sexually transmitted infection testing and results service.ConclusionsNo single approach is always best: the choice will depend on the trial context. We encourage trialists to consider all three methods more routinely.
| S-EPMC9014627 | biostudies-literature