Anne Daykin

What are the roles and valued attributes of a Trial Steering Committee? Ethnographic study of eight clinical trials facing challenges

BackgroundClinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference.MethodsAn ethnographic study was conducted during 2013–2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC.ResultsEight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a ‘critical friend’ or a provider of ‘tough love’. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise.ConclusionsWe found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs’ quality assurance role. Concerns were raised regarding whose interests are served by funders’ criteria of independence; in particular, funders’ selection of TSC members was thought to potentially inhibit TSCs’ ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.

An ethnographic study of group decision making to understand and improve how trial steering committees contribute to trial conduct

According to the MRC Guidelines for Good Clinical Practice, the role of Trial Steering Committees (TSCs) is to provide overall supervision of a trial. While the HTA DAMOCLES project resulted in a charter for Data Monitoring Committees, there is currently little empirical evidence regarding how TSCs oversee trials and make decisions about trial conduct.

‘Recruitment, recruitment, recruitment’ – the need for more focus on retention: a qualitative study of five trials

BackgroundLoss to follow-up (attrition) is a frequent problem in clinical trials and can introduce bias or reduce power. So, understanding retention issues and strategies to address these are important. As part of a multi-method project, this qualitative study aimed to explore retention strategies used by trial teams and factors which may influence strategy adoption.MethodA purposive sample of active trials was selected from the UK NIHR HTA portfolio of ongoing trials in 2014/2015. Semi-structured interviews with several trial team members from each trial and supplementary interviews with experienced trial managers explored strategies in collecting clinical outcome data and retaining participants. Interview data were analysed thematically using techniques of constant comparison.ResultsTwenty-two semi-structured interviews with trial team members including chief investigators, trial managers, nurses and research administrators revealed strategies used to enhance retention. Some were recognised methods and planned from trial outset whilst others were implemented more responsively. Interviewees placed great value on fostering positive relationships with trial participants to enhance retention. However, these strategies took time which was not always appreciated by the wider trial team or funding bodies. The national focus on recruitment targets in networks posed a challenge to staff and was deemed detrimental to retention. The ‘moral compass’ of individual researchers relied on their own beliefs and values and research experience and the factors affected their confidence to pursue participant data during follow-up.ConclusionThe role of trial staff and their underlying behaviours influence retention practices and, combined with emphasis on recruitment targets, can be detrimental to motivation and retention activities. There is a need to consider how to train and support trial staff involved in retention practices and recognition of retention from funding bodies and oversight organisations.

Identifying research priorities for effective retention strategies in clinical trials

BackgroundThe failure to retain patients or collect primary-outcome data is a common challenge for trials and reduces the statistical power and potentially introduces bias into the analysis. Identifying strategies to minimise missing data was the second highest methodological research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs) and is important to minimise waste in research. Our aim was to assess the current retention practices within the UK and priorities for future research to evaluate the effectiveness of strategies to reduce attrition.MethodsSeventy-five chief investigators of NIHR Health Technology Assessment (HTA)-funded trials starting between 2009 and 2012 were surveyed to elicit their awareness about causes of missing data within their trial and recommended practices for improving retention. Forty-seven CTUs registered within the UKCRC network were surveyed separately to identify approaches and strategies being used to mitigate missing data across trials.Responses from the current practice surveys were used to inform a subsequent two-round Delphi survey with registered CTUs. A consensus list of retention research strategies was produced and ranked by priority.ResultsFifty out of seventy-five (67%) chief investigators and 33/47 (70%) registered CTUs completed the current practice surveys. Seventy-eight percent of trialists were aware of retention challenges and implemented strategies at trial design. Patient-initiated withdrawal was the most common cause of missing data. Registered CTUs routinely used newsletters, timeline of participant visits, and telephone reminders to mitigate missing data. Whilst 36 out of 59 strategies presented had been formally or informally evaluated, some frequently used strategies, such as site initiation training, have had no research to inform practice.Thirty-five registered CTUs (74%) participated in the Delphi survey. Research into the effectiveness of site initiation training, frequency of patient contact during a trial, the use of routinely collected data, the frequency and timing of reminders, triggered site training and the time needed to complete questionnaires was deemed critical. Research into the effectiveness of Christmas cards for site staff was not of critical importance.ConclusionThe surveys of current practices demonstrates that a variety of strategies are being used to mitigate missing data but with little evidence to support their use. Six retention strategies were deemed critically important within the Delphi survey and should be a primary focus of future retention research.

‘We all want to succeed, but we’ve also got to be realistic about what is happening’: an ethnographic study of relationships in trial oversight and their impact

BackgroundThe oversight and conduct of a randomised controlled trial involves several stakeholders, including a Trial Steering Committee (TSC), Trial Management Group (TMG), Data Monitoring Committee (DMC), funder and sponsor. We aimed to examine how the relationships between these stakeholders affect the trial oversight process and its rigour, to inform future revision of Good Clinical Practice guidelines.MethodsUsing an ethnographic study design, we observed the oversight processes of eight trials and conducted semi-structured interviews with members of the trials’ TSCs and TMGs, plus other relevant informants, including sponsors and funders of trials. Data were analysed thematically, and findings triangulated and integrated to give a multi-perspective account of current oversight practices in the UK.ResultsEight TSC and six TMG meetings from eight trials were observed and audio-recorded, and 66 semi-structured interviews conducted with 52 purposively sampled key informants. Five themes are presented: (1) Collaboration within the TMG and role of the CTU; (2) Collaboration and conflict between oversight committees; (3) Priorities; (4) Communication between trial oversight groups and (5) Power and accountability. There was evidence of collaborative relationships, based on mutual respect, between CTUs, TMGs and TSCs, but also evidence of conflict. Relationships between trial oversight committees were influenced by stakeholders’ priorities, both organisational and individual. Good communication following specific, recognised routes played a central role in ensuring that relationships were productive and trial oversight efficient. Participants described the possession of power over trials as a shifting political landscape, and there was lack of clarity regarding the roles and accountability of each committee, the sponsor and funder. Stakeholders’ perceptions of their own power over a trial, and the power of others, influenced relationships between those involved in trial oversight.ConclusionsRecent developments in trial design and conduct have been accompanied by changes in roles and relationships between trial oversight groups. Recognising and respecting the value of differing priorities among those involved in running trials is key to successful relationships between committees, funders and sponsors. Clarity regarding appropriate lines of communication, roles and accountability is needed. We present 10 evidence-based recommendations to inform updates to international trial guidance, particularly the Medical Research Council guidelines.

Reported reasons for missing data and the interplay with trial setting.

Missing data in clinical trials is common. It can reduce trial efficiency and bias the estimate of treatment effect. Much emphasis is placed on addressing missing data in trial design. However, strategies need to be informed by the reasons for attrition which are likely to vary according to trial context. In order to develop effective interventions to minimise missing data, it is important to not only understand the causes but also their interplay with the trial setting. We present the reported reasons for missing data within a cohort of 168 randomised trials published in four major journals in 2013 and 36 Health Technology Assessment programme monographs published 2009-2014. We discuss the frequency of missing data and differential attrition resulting from causes such as withdrawals due to treatment tolerance or efficacy, inability to measure the primary outcome due to intervening outcomes such as death or illness, laboratory or technological problems, missed measurements by clinical staff and failure of patients to attend visits or return measurements. The frequency of Investigator led post randomisation exclusions will also be reviewed, looking at data excluded for reasons such as protocol violations, post randomisation ineligibility, patients not receiving the intervention or poor treatment adherence. Levels of missing data and associations with trial setting such as clinical speciality, method and location of primary outcome measurement, nature of the intervention and control, mean age of recruited patients, number of trial centres and countries will be presented.

“To have, to hold, from this day forward”: understanding current practice regarding the retention of trial participants

Findings Clear and cohesive definitions of retention were given. However, there was less agreement about the concept of ‘withdrawal’ from a trial. More experienced trialists emphasised different levels of withdrawal and were happy to negotiate with participants in order to at least collect primary outcome data. Novice trialists presumed the participants wanted to withdraw from all aspects of the trial and made no further contact with them. Research Nurses used their interpersonal skills to motivate participants to remain in their trials. This required time not routinely acknowledged within the funding of trials. Participants described proactive and reactive approaches to retention. Proactive approaches involved anticipated and considered strategies, both formal and informal, to maintain retention. Conversely, reactive approaches were typified by unanticipated and spontaneous strategies, some formalised others informal, developed in response to retention problems during the trial.

A review of the description of patient withdrawal in trial protocols and patient information sheets (PIS).

Background Under Good Clinical Practice guidelines, patients have the right to withdraw from a trial at any time, for any reason. However, definitions of withdrawal vary from patients ceasing all trial specific activities to stopping the assigned intervention while continuing with follow up. Early withdrawal with no further follow up is problematic and leads to missing data and research waste. Health Research Authority guidance states that Patient Information Sheets (PIS) should clearly inform patients what is expected with regards to subsequent follow up and the use of existing data if they withdraw.

Enhancing public involvement in trial oversight committees through qualitative research with eight trials facing challenges

Background Trial oversight committees (TOC) including Trial Steering Committees (TSCs) and Trial Management Groups (TMGs) are integral to trial conduct. Patient and public involvement (PPI) in trial design and conduct is frequently stipulated although there is little empirical evidence to optimise roles and inputs. We aimed to use qualitative research to understand the experiences of PPI involvement in TOCs to enhance PPI contributions to trial conduct.

Pragmatic approaches to mitigating missing data and research priorities to assess the effectiveness of interventions

Background Identifying interventions to minimise missing data was the third highest research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs). However, a Cochrane Methodology Review of nested randomised studies of missing data interventions shows a substantial evidence gap, with all but one of the eligible studies targeting questionnaire response rates. Research is needed to identify strategies that effectively address the broader causes of missing data, including minimising withdrawals, ensuring clinical staff capture vital outcome measurements and improving patient attendance at clinic visits.