Retention strategies are routinely communicated to potential trial participants but often differ from what was planned in the trial protocol: an analysis of adult participant information leaflets and their corresponding protocols.

BACKGROUND: Retaining participants in randomised controlled trials (RCTs) is challenging and trial teams are often required to use strategies to ensure retention or improve it. Other than monetary incentives, there is no requirement to disclose the use of retention strategies to the participant. Additionally, not all retention strategies are developed at the planning stage, i.e. post-funding during protocol development, but some protocols include strategies for participant retention as retention is considered and planned for early in the trial planning stage. It is yet unknown if these plans are communicated in the corresponding participant information leaflets (PILs). The purpose of our study was to determine if PILs communicate plans to promote participant retention and, if so, are these outlined in the corresponding trial protocol. METHODS: Ninety-two adult PILs and their 90 corresponding protocols from Clinical Trial Units (CTUs) in the UK were analysed. Directed (deductive) content analysis was used to analyse the participant retention text from the PILs. Data were presented using a narrative summary and frequencies where appropriate. RESULTS: Plans to promote participant retention were communicated in 81.5% (n = 75/92) of PILs. Fifty-seven percent (n = 43/75) of PILs communicated plans to use "combined strategies" to promote participant retention. The most common individual retention strategy was telling the participants that data collection for the trial would be scheduled during routine care visits (16%; n = 12/75 PILs). The importance of retention and the impact that missing or deleted data (deleting data collected prior to withdrawal) has on the ability to answer the research question were explained in 6.5% (n = 6/92) and 5.4% (n = 5/92) of PILs respectively. Out of the 59 PILs and 58 matching protocols that both communicated plans to use strategies to promote participant retention, 18.6% (n = 11/59) communicated the same information, the remaining 81.4% (n = 48/59) of PILs either only partially communicated (45.8%; n = 27/59) the same information or did not communicate the same information (35.6%; n = 21/59) as the protocol with regard to the retention strategy(ies). CONCLUSION: Retention strategies are frequently communicated to potential trial participants in PILs; however, the information provided often differs from the content in the corresponding protocol. Participant retention considerations are best done at the planning stage of the trial and we encourage trial teams to be consistent in the communication of these strategies in both the protocol and PIL.

Participant characteristics and exclusion from phase 3/4 industry funded trials of chronic medical conditions: meta-analysis of individual participant level data.

Objectives: To assess whether age, sex, comorbidity count, and race and ethnic group are associated with the likelihood of trial participants not being enrolled in a trial for any reason (ie, screen failure). Design: Bayesian meta-analysis of individual participant level data. Setting: Industry funded phase 3/4 trials of chronic medical conditions. Participants: Participants were identified using individual participant level data to be in either the enrolled group or screen failure group. Data were available for 52 trials involving 72 178 screened individuals of whom 24 733 (34%) were excluded from the trial at the screening stage. Main outcome measures: For each trial, logistic regression models were constructed to assess likelihood of screen failure in people who had been invited to screening, and were regressed on age (per 10 year increment), sex (male v female), comorbidity count (per one additional comorbidity), and race or ethnic group. Trial level analyses were combined in Bayesian hierarchical models with pooling across condition. Results: In age and sex adjusted models across all trials, neither age nor sex was associated with increased odds of screen failure, although weak associations were detected after additionally adjusting for comorbidity (odds ratio of age, per 10 year increment was 1.02 (95% credibility interval 1.01 to 1.04) and male sex (0.95 (0.91 to 1.00)). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (0.97 per additional comorbidity (0.94 to 1.00), adjusted for age and sex). People who self-reported as black seemed to be slightly more likely to fail screening than people reporting as white (1.04 (0.99 to 1.09)); a weak effect that seemed to persist after adjustment for age, sex, and comorbidity count (1.05 (0.98 to 1.12)). The between-trial heterogeneity was generally low, evidence of heterogeneity by sex was noted across conditions (variation in odds ratios on log scale of 0.01-0.13). Conclusions: Although the conclusions are limited by uncertainty about the completeness or accuracy of data collection among participants who were not randomised, we identified mostly weak associations with an increased likelihood of screen failure for age, sex, comorbidity count, and black race or ethnic group. Proportionate increases in screening these underserved populations may improve representation in trials. Trial registration number: PROSPERO CRD42018048202.

Describing the content of trial recruitment interventions using the TIDieR reporting checklist: a systematic methodology review.

BACKGROUND: Recruiting participants to clinical trials is an ongoing challenge, and relatively little is known about what recruitment strategies lead to better recruitment. Recruitment interventions can be considered complex interventions, often involving multiple components, targeting a variety of groups, and tailoring to different groups. We used the Template for Intervention Description and Replication (TIDieR) reporting checklist (which comprises 12 items recommended for reporting complex interventions) to guide the assessment of how recruitment interventions are described. We aimed to (1) examine to what extent we could identify information about each TIDieR item within recruitment intervention studies, and (2) observe additional detail for each item to describe useful variation among these studies. METHODS: We identified randomized, nested recruitment intervention studies providing recruitment or willingness to participate rates from two sources: a Cochrane review of trials evaluating strategies to improve recruitment to randomized trials, and the Online Resource for Research in Clinical triAls database. First, we assessed to what extent authors reported information about each TIDieR item. Second, we developed descriptive categorical variables for 7 TIDieR items and extracting relevant quotes for the other 5 items. RESULTS: We assessed 122 recruitment intervention studies. We were able to extract information relevant to most TIDieR items (e.g., brief rationale, materials, procedure) with the exception of a few items that were only rarely reported (e.g., tailoring, modifications, planned/actual fidelity). The descriptive variables provided a useful overview of study characteristics, with most studies using various forms of informational interventions (55%) delivered at a single time point (90%), often by a member of the research team (59%) in a clinical care setting (41%). CONCLUSIONS: Our TIDieR-based variables provide a useful description of the core elements of complex trial recruitment interventions. Recruitment intervention studies report core elements of complex interventions variably; some process elements (e.g., mode of delivery, location) are almost always described, while others (e.g., duration, fidelity) are reported infrequently, with little indication of a reason for their absence. Future research should explore whether these TIDieR-based variables can form the basis of an approach to better reporting of elements of successful recruitment interventions.

Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials: lessons learnt from the PROMETHEUS research programme.

Background: Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives: PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design: A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting: Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants: Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions: Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures: Number of host trials funded. Results: Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations: The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions: PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work: Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration: All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

A Study Within A Trial is a research study nested inside a larger 'host trial', promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. The best way to test health and social care treatments is to do a randomised controlled trial ('trial'), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found 'pre-notifying' before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future.

Understanding implementation of findings from trial method research: a mixed methods study applying implementation frameworks and behaviour change models.

BACKGROUND: Trial method research produces recommendations on how to best conduct trials. However, findings are not routinely implemented into practice. To better understand why, we conducted a mixed method study on the challenges of implementing trial method research findings into UK-based clinical trial units. METHODS: Three stages of research were conducted. Firstly, case studies of completed projects that provided methodological recommendations were identified within trial design, conduct, analysis, and reporting. These case studies were used as survey examples to query obstacles and facilitators to implementing method research. Survey participants were experienced trial staff, identified via email invitations to UK clinical trial units. This survey assessed the case studies' rates of implementation, and demographic characteristics of trial units through the Consolidated Framework for Implementation Research. Further, interviews were conducted with senior members of trial units to explore obstacles and facilitators in more detail. Participants were sampled from trial units that indicated their willingness to participate in interviews following the survey. Interviews, and analysis, were structured via the Capability, Opportunity, Motivation Model of Behaviour. Finally, potential strategies to leverage lessons learned were generated via the Behaviour Change Wheel. RESULTS: A total of 27 UK trial units responded to the survey. The rates of implementation across the case studies varied, with most trial units implementing recommendations in trial conduct and only few implementing recommendations in reporting. However, most reported implementing recommendations was important but that they lacked the resources to do so. A total of 16 senior members of trial units were interviewed. Several themes were generated from interviews and fell broadly into categories related to the methods recommendations themselves, the trial units, or external factors affecting implementation. Belief statements within themes indicated resources issues and awareness of recommendations as frequent implementation obstacles. Participation in trial networks and recommendations packaged with relevant resources were cited frequently as implementation facilitators. These obstacles and facilitators mirrored results from the survey. Results were mapped, via the Behaviour Change Wheel, to intervention functions likely to change behaviours of obstacles and facilitators identified. These intervention functions were developed into potential solutions to reduce obstacles and enhance facilitators to implementation. CONCLUSIONS: Several key areas affecting implementation of trial method recommendations were identified. Potential methods to enhance facilitators and reduce obstacles are suggested. Future research is needed to refine these methods and assess their feasibility and acceptability.

Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial.

OBJECTIVE: To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. DESIGN: Parallel group, pragmatic randomised, superiority trial. SETTING: 20 secondary care centres in the UK. PARTICIPANTS: 434 adults (>18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. INTERVENTIONS: Conservative management or surgical removal of the gallbladder. MAIN OUTCOME MEASURES: The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. RESULTS: Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval -1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference -£1033, (-$1334; -€1205), 95% credible interval -£1413 to -£632) and QALYs did not differ (mean difference -0.019, 95% credible interval -0.06 to 0.02). CONCLUSIONS: In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN55215960.

Involving patients and the public In sTatistIcal Analysis pLans (INITIAL): A delphi survey.

BACKGROUND: Patient and public involvement (PPI) in trials aims to enhance research by improving its relevance and transparency. Planning for statistical analysis begins at the design stage of a trial within the protocol and is refined and detailed in a Statistical Analysis Plan (SAP). While PPI is common in design and protocol development it is less common within SAPs. This study aimed to reach consensus on the most important and relevant statistical analysis items within an SAP to involve patients and the public. METHODS: We developed a UK-based, two-round Delphi survey through an iterative consultation with public partners, statisticians, and trialists. The consultation process started with 55 items from international guidance for statistical analysis plans. We aimed to recruit at least 20 participants per key stakeholder group for inclusion in the final analysis of the Delphi survey. Participants were asked to vote on each item using a Likert scale from 1 to 9, where a rating of 1 to 3 was labelled as having 'limited importance'; 4 to 6 as 'important but not critical' and 7 to 9 as 'critical' to involve patients and the public. Results from the second round determined consensus on critical items for PPI. RESULTS: The consultation exercise led to the inclusion of 15 statistical items in the Delphi survey. We recruited 179 participants, of whom 72% (129: 36 statisticians, 29 patients or public partners, 25 clinical researchers or methodologists, 27 trial managers, and 12 PPI coordinators) completed both rounds. Participants were on average 48 years old, 60% were female, 84% were White, 64% were based in England and 84% had at least five years' experience in trials. Four items reached consensus regarding critical importance for patient and public involvement: presentation of results to trial participants; summary and presentation of harms; interpretation and presentation of findings in an academic setting; factors impacting how well a treatment works. No consensus was reached for the remaining 11 items. In general, the results were consistent across stakeholder groups. DISCUSSION: We identified four critical items to involve patients and the public in statistical analysis plans. The remaining 11 items did not reach consensus and need to be considered in a case-by-case basis with most responders considering patient and public involvement important (but not critical). Our research provides a platform to enable focused future efforts to improve patient and public involvement in trials and enhance the relevance of statistical analyses to patients and the public.

How do trial teams plan for retention during the design stage of the trial? A scoping review.

BACKGROUND: Retention to trials is important to ensure the results of the trial are valid and reliable. The SPIRIT guidelines (18b) require "plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols" be included in trial protocols. It is unknown how often protocols report this retention information. The purpose of our scoping review is to establish if, and how, trial teams report plans for retention during the design stage of the trial. MATERIALS AND METHODS: A scoping review with searches in key databases (PubMed, Scopus, EMBASE, CINAHL (EBSCO), and Web of Science from 2014 to 2019 inclusive) to identify randomised controlled trial protocols. We produced descriptive statistics on the characteristics of the trial protocols and also on those adhering to SPIRIT item 18b. A narrative synthesis of the retention strategies was also conducted. RESULTS: Eight-hundred and twenty-four protocols met our inclusion criteria. RCTs (n = 722) and pilot and feasibility trial protocols (n = 102) reported using the SPIRIT guidelines during protocol development 35% and 34.3% of the time respectively. Of these protocols, only 9.5% and 11.4% respectively reported all aspects of SPIRIT item 18b "plans to promote participant retention and to complete follow-up, including list of any outcome data for participants who discontinue or deviate from intervention protocols". Of the RCT protocols, 36.8% included proactive "plans to promote participant retention" regardless of whether they reported using SPIRIT guidelines or not. Most protocols planned "combined strategies" (48.1%). Of these, the joint most commonly reported were "reminders and data collection location and method" and "reminders and monetary incentives". The most popular individual retention strategy was "reminders" (14.7%) followed by "monetary incentives- conditional" (10.2%). Of the pilot and feasibility protocols, 40.2% included proactive "plans to promote participant retention" with the use of "combined strategies" being most frequent (46.3%). The use of "monetary incentives - conditional" (22%) was the most popular individual reported retention strategy. CONCLUSION: There is a lack of reporting of plans to promote participant retention in trial protocols. Proactive planning of retention strategies during the trial design stage is preferable to the reactive implementation of retention strategies. Prospective retention planning and clear communication in protocols may inform more suitable choice, costing and implementation of retention strategies and improve transparency in trial conduct.

Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Exploring the perspectives of selectors and collecters of trial outcome data: an international qualitative study.

INTRODUCTION: Selecting and collecting data to support appropriate primary and secondary outcomes is a critical step in designing trials that can change clinical practice. In this study, we aimed to investigate who contributes to the process of selecting and collecting trial outcomes, and how these people are involved. This work serves two main purposes: (1) it provides the trials community with evidence to demonstrate how outcomes are currently selected and collected, and (2) it allows people involved in trial design and conduct to pick apart these processes to consider how efficiencies and improvements can be made. METHODS: One-with-one semi-structured interviews, supported by a topic guide to ensure coverage of key content. The Framework approach was used for thematic analysis of data, and themes were linked through constant comparison of data both within and across participant groups. Interviews took place between July 2020 and January 2021. Participants were twenty-nine international trialists from various contributor groups, working primarily on designing and/or delivering phase III pragmatic effectiveness trials. Their experience spanned various funders, trial settings, clinical specialties, intervention types, and participant populations. RESULTS: We identified three descriptive themes encompassing the process of primary and secondary outcome selection, collection, and the publication of outcome data. Within these themes, participants raised issues around the following: 1) Outcome selection: clarity of the research question; confidence in selecting trial outcomes and how confidence decreases with increased experience; interplay between different interested parties; how patients and the public are involved in outcome selection; perceived impact of poor outcome selection including poor recruitment and/or retention; and use of core outcome sets. 2) Outcome collection: disconnect between decisions made by outcome selectors and the practical work done by outcome collectors; potential impact of outcome measures on trial participants; potential impact on trial staff workload; and use of routinely collected data. 3) Publication of outcome data: difficulties in finding time to write and revise manuscripts for publication due to time and funding constraints. Participants overwhelmingly focused on the process of outcome selection, a topic they talked about unprompted. When prompted, participants do discuss outcome collection, but poor communication between selectors and collectors at the trial design stage means that outcome selection is rarely linked with the data collection workload it generates. DISCUSSION: People involved in the design and conduct of trials fail to connect decisions around outcome selection with data collection workload. Publication of outcome data and effective dissemination of trial results are hindered due to the project-based culture of some academic clinical trial research.

Understanding pre-hospital blood transfusion decision-making for injured patients: an interview study.

BACKGROUND: Blood transfusion for bleeding trauma patients is a promising pre-hospital intervention with potential to improve outcomes. However, it is not yet clear which patients may benefit from pre-hospital transfusions. The aim of this study was to enhance our understanding of how experienced pre-hospital clinicians make decisions regarding patient blood loss and the need for transfusion, and explore the factors that influence clinical decision-making. METHODS: Pre-hospital physicians, from two air ambulance sites in the south of England, were interviewed between December 2018 and January 2019. Participants were involved in teaching or publishing on the management of bleeding trauma patients and had at least 5 years of continuous and contemporary practice at consultant level. Interviews were semi-structured and explored how decisions were made and what made decisions difficult. A qualitative description approach was used with inductive thematic analysis to identify themes and subthemes related to blood transfusion decision-making in trauma. RESULTS: Ten pre-hospital physicians were interviewed and three themes were identified: recognition-primed analysis, uncertainty and imperfect decision analysis. The first theme describes how participants make decisions using selected cues, incorporating their experience and are influenced by external rules and group expectations. What made decisions difficult for the participants was encapsulated in the uncertainty theme. Uncertainty emerged regarding the patient's true underlying physiological state and the treatment effect of blood transfusion. The last theme focuses on the issues with decision-making itself. Participants demonstrated lapses in decision awareness, often incomplete decision evaluation and described challenges to effective learning due to incomplete patient outcome information. CONCLUSION: Pre-hospital clinicians make decisions about bleeding and transfusion which are recognition-primed and incorporate significant uncertainty. Decisions are influenced by experience and are subject to bias. Improved understanding of the decision-making processes provides a theoretical perspective of how decisions might be supported in the future.

Qualitative data sharing practices in clinical trials in the UK and Ireland: towards the production of good practice guidance.

Background: Data sharing enables researchers to conduct novel research with previously collected datasets, thus maximising scientific findings and cost effectiveness, and reducing research waste. The value of sharing, even de-identified, quantitative data from clinical trials is well recognised with a moderated access approach recommended. While substantial challenges to sharing quantitative data remain, there are additional challenges for sharing qualitative data in trials. Incorporating the necessary information about how qualitative data will be shared into already complex trial recruitment and consent processes proves challenging. The aim of this study was to explore whether and how trial teams share qualitative data collected as part of the design, conduct, analysis, or delivery of clinical trials. Methods: Phase 1 involved semi-structured, in-depth qualitative interviews and focus groups with key trial stakeholder groups including trial managers and clinical trialists (n=3), qualitative researchers in trials (n=9), members of research funding bodies (n=2) and trial participants (n=1). Data were analysed using thematic analysis. In Phase 2, we conducted a content analysis of 16 participant information leaflets (PIL) and consent forms (CF) for trials that collected qualitative data. Results: Three key themes were identified from our Phase 1 findings: ' Understanding and experiences of the potential benefits of sharing qualitative data from trials', 'Concerns about qualitative data sharing', and ' Future guidance and funding'. In phase 2, the PILs and CFs received revealed that the benefits of data sharing for participants were only explained in two of the study documents. Conclusions: The value of sharing qualitative data was acknowledged, but there are many uncertainties as to how, when, and where to share this data. In addition, there were ethical concerns in relation to the consent process required for qualitative data sharing in trials. This study provides insight into the existing practice of qualitative data sharing in trials.

Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial.

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants.

Developing strategies to address disparities in retention communication during the consent discussion: development of a behavioural intervention.

BACKGROUND: Clinical trials are essential to evidence-based medicine. Their success relies on recruitment and retention of participants: problems with either can affect validity of results. Past research on improving trials has focused on recruitment, with less on retention, and even less considering retention at the point of recruitment, i.e., what retention-relevant information is shared during consent processes. The behaviour of trial staff communicating this information during consent is likely to contribute to retention. So, developing approaches to mitigate issues in retention at the point of consent is necessary. In this study, we describe the development of a behavioural intervention targeting the communication of information important to retention during the consent process. METHODS: We applied the Theoretical Domains Framework and Behaviour Change Wheel to develop an intervention aimed at changing the retention communication behaviours of trial staff. Building on findings from an interview study to understand the barriers/facilitators to retention communication during consent, we identified behaviour change techniques that could moderate them. These techniques were grouped into potential intervention categories and presented to a co-design group of trial staff and public partners to discuss how they might be packaged into an intervention. An intervention was presented to these same stakeholders and assessed for acceptability through a survey based on the Theoretical Framework of Acceptability. RESULTS: Twenty-six behaviour change techniques were identified with potential to change communication of retention-information at consent. Six trial stakeholders in the co-design group discussed means for implementing these techniques and agreed the available techniques could be most effective within a series of meetings focussed on best practices for communicating retention at consent. The proposed intervention was deemed acceptable through survey results. CONCLUSION: We have developed an intervention aimed at facilitating the communication of retention at informed consent through a behavioural approach. This intervention will be delivered to trial staff and will add to the available strategies for trials to improve retention.

Challenges and opportunities for conducting pre-hospital trauma trials: a behavioural investigation.

BACKGROUND: Trials in pre-hospital trauma care are relatively uncommon. There are logistical and methodological challenges related to designing and delivering trials in this setting. Previous studies have assessed challenges reported in individual trials rather than across the pre-hospital trial landscape to identify over-arching factors. The aim of this study was to investigate the challenges and opportunities related to the set-up, design and conduct of pre-hospital trauma trials from across the pre-hospital trial landscape and a specific pre-hospital trauma feasibility study. METHODS: Semi-structured interviews were conducted with two cohorts of participants: research personnel who had experience of pre-hospital trials, either through direct involvement in conduct or through strategic oversight of national initiatives (n = 7), and clinical staff (n = 16) involved in recruitment to a pre-hospital trauma feasibility study. Thematic analyses were used to assess the barriers and enablers of conducting pre-hospital trauma trials. Two frameworks (The Capability Opportunity Motivation-Behaviour and the Theoretical Domains Framework) were used to guide analyses. RESULTS: The barriers and enablers reported were relevant to several TDF domains and COM-B components. Across both cohorts, challenges associated with opportunities were reported and included the lack of research experience amongst pre-hospital staff, team dynamics within a rotating shift schedule, and the involvement of external organisations with diverse institutional priorities and infrastructures (e.g. Air Ambulances). The infrequency of eligible cases was also reported to affect the trial design, set-up, and conduct. Other barriers reported related to clinical equipoise amongst staff and institutional pressures, which affected motivation. CONCLUSIONS: This study has highlighted that pre-hospital trials face many context-specific but also generic challenges. Pre-hospital trauma trial teams could consider the findings to develop targeted, behaviourally focused, solutions to the challenges identified in order to enhance the set-up and conduct of trials in this setting. TRIAL REGISTRATION: NCT04145271. Trial registration date: October 30, 2019. Note that this paper does not report results from a specific trial but does include participants who were involved in the conduct of a registered pre-hospital feasibility study.

The RoboCOS Study: Development of an international core outcome set for the comprehensive evaluation of patient, surgeon, organisational and population level impacts of robotic assisted surgery.

BACKGROUND: The introduction of robot-assisted surgery is costly and requires whole system transformation, which makes the assessment of benefits (or drawbacks) complex. To date, there has been little agreement on which outcomes should be used in this regard. The aim of the RoboCOS study was to develop a core outcome set for the evaluation of robot-assisted surgery that would account for its impact on the whole system. METHODS: Identification of a long-list of potentially relevant outcomes through systematic review of trials and health technology assessments; interviews with individuals from a range of stakeholder groups (surgeons, service managers, policy makers and evaluators) and a focus group with patients and public; prioritisation of outcomes via a 2-round online international Delphi survey; consensus meeting. RESULTS: 721 outcomes were extracted from the systematic reviews, interviews and focus group which were conceptualised into 83 different outcome domains across four distinct levels (patient, surgeon, organisation and population) for inclusion in the international Delphi prioritisation survey (128 completed both rounds). The consensus meeting led to the agreement of a 10-item core outcome set including outcomes at: patient level (treatment effectiveness; overall quality of life; disease-specific quality of life; complications (including mortality); surgeon level (precision/accuracy; visualisation); organisation (equipment failure; standardisation of operative quality; cost-effectiveness); and population (equity of access). CONCLUSION: The RoboCOS core outcome set, which includes the outcomes of importance to all stakeholders, is recommended for use in all future evaluations of robot-assisted surgery to ensure relevant and comparable reporting of outcomes.

Changing patient preferences toward better trial recruitment: an ethical analysis.

While randomized controlled trials are essential to health research, many of these trials fail to recruit enough participants. Approaching recruitment through the lens of behavioral science can help trialists to understand influences on the decision to participate and use them to increase recruitment. Although this approach is promising, the use of behavioral influences during recruitment is in tension with the ethical principle of respect for persons, as at least some of these influences could be used to manipulate potential participants. In this paper, we examine this tension by discussing two types of behavioral influences: one example involves physician recommendations, and the other involves framing of information to exploit cognitive biases. We argue that despite the apparent tension with ethical principles, influencing trial participants through behavior change strategies can be ethically acceptable. However, we argue that trialists have a positive obligation to analyze their recruitment strategies for behavioral influences and disclose these upfront to the research ethics committee. But we also acknowledge that since neither trialists nor ethics committees are presently well equipped to perform these analyses, additional resources and guidance are needed. We close by outlining a path toward the development of such guidance.

Complex and alternate consent pathways in clinical trials: methodological and ethical challenges encountered by underserved groups and a call to action.

BACKGROUND: Informed consent is considered a fundamental requirement for participation in trials, yet obtaining consent is challenging in a number of populations and settings. This may be due to participants having communication or other disabilities, their capacity to consent fluctuates or they lack capacity, or in emergency situations where their medical condition or the urgent nature of the treatment precludes seeking consent from either the participant or a representative. These challenges, and the subsequent complexity of designing and conducting trials where alternative consent pathways are required, contribute to these populations being underserved in research. Recognising and addressing these challenges is essential to support trials involving these populations and ensure that they have an equitable opportunity to participate in, and benefit from, research. Given the complex nature of these challenges, which are encountered by both adults and children, a cross-disciplinary approach is required. DISCUSSION: A UK-wide collaboration, a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, was formed to collectively address these challenges. Members are drawn from disciplines including bioethics, qualitative research, trials methodology, healthcare professions, and social sciences. This commentary draws on our collective expertise to identify key populations where particular methodological and ethical challenges around consent are encountered, articulate the specific issues arising in each population, summarise ongoing and completed research, and identify targets for future research. Key populations include people with communication or other disabilities, people whose capacity to consent fluctuates, adults who lack the capacity to consent, and adults and children in emergency and urgent care settings. Work is ongoing by the sub-group to create a database of resources, to update NIHR guidance, and to develop proposals to address identified research gaps. CONCLUSION: Collaboration across disciplines, sectors, organisations, and countries is essential if the ethical and methodological challenges surrounding trials involving complex and alternate consent pathways are to be addressed. Explicating these challenges, sharing resources, and identifying gaps for future research is an essential first step. We hope that doing so will serve as a call to action for others seeking ways to address the current consent-based exclusion of underserved populations from trials.