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Background: Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people's chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person's health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem., Methods: A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day's discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination., Results: Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event., Conclusions: The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Healthcare systems data (HSD) has the potential to optimise the efficiency of randomised controlled trials (RCTs), by decreasing trial-specific data demands. Therefore, the use of HSD in trials is expected to increase. In 2019, it was estimated that 47% of NIHR-funded trials were planning to use HSD. We aim to understand the extent and nature of its current use and its evolution over time., Methods: We identified a cohort of RCTs within the NIHR Journals Library that commenced after 2019 and were described as being in progress on 6 June 2022. Details on the source and use of HSD were extracted from eligible RCTs. The use of HSD was categorised according to whether it was used as the sole data source for outcomes and whether the outcomes were primary or secondary. HSD is often insufficient for patient-reported outcomes (PROs). We aimed to determine methods used by trialists for collecting PRO data alongside HSD., Results: Of the 84 eligible studies, 52 (62%) planned to use HSD and 79 (94%) planned to collect PROs. The number of RCTs planning to use HSD for at least one outcome was 28 (54%) with 24 of these planning to use HSD as the sole data source for at least one outcome. The number of studies planning to use HSD for primary and secondary outcomes was 10 (20%) and 21 (40%) respectively. The sources of HSD were National Health Service (NHS) Digital (n = 37, 79%), patient registries (n = 7, 29%), primary care (n = 5, 21%), The Office for National Statistics (ONS) (n = 3, 13%) and other (n = 2, 8%). PROs were collected for 92% of the trials planning to use HSD. Methods for collection of PROs included in-person (n = 26, 54%), online (n = 22, 46%), postal (n = 18, 38%), phone (n = 14, 29%) and app (n = 2, 4%)., Conclusions: HSD is being used in around two thirds of the studies but cannot yet be used to support PRO data collection within the cohort we examined. Comparison with an earlier cohort demonstrates an increase in the number of RCTs planning to use HSD., (© 2024. The Author(s).)

Background: During the COVID-19 pandemic, in-person healthcare visits were reduced. Consequently, trial teams needed to consider implementing remote methods for conducting clinical trials, including e-Consent. Although some clinical trials may have implemented e-Consent prior to the pandemic, anecdotes of uptake for this method increased within academic-led trials. When the increased use of this process emerged, representatives from several large academic clinical trial groups within the UK collaborated to discuss ways in which trialists can learn from one another when implementing e-Consent., Methods: A survey of UKCRC-registered Clinical Trials Units (CTUs) was undertaken in April-June 2021 to understand the implementation of and their views on the use of e-Consent and experiences from the perspectives of systems programmers and quality assurance staff on the use of e-Consent. CTUs not using e-Consent were asked to provide any reasons/barriers (including no suitable trials) and any plans for implementing it in the future. Two events for trialists and patient and public involvement (PPI) representatives were then held to disseminate findings, foster discussion, share experiences and aid in the identification of areas that the academic CTU community felt required more research., Results: Thirty-four (64%) of 53 CTUs responded to the survey, with good geographical representation across the UK. Twenty-one (62%) of the responding CTUs had implemented e-Consent in at least one of their trials, across different types of trials, including CTIMPs (Clinical Trial of Investigational Medicinal Product), ATIMPs (Advanced Therapy Medicinal Products) and non-CTIMPs. One hundred ninety-seven participants attended the two workshops for wide-ranging discussions., Conclusion: e-Consent is increasingly used in academic-led trials, yet uncertainties remain amongst trialists, patients and members of the public. Uncertainties include a lack of formal, practical guidance and a lack of evidence to demonstrate optimal or appropriate methods to use. We strongly encourage trialists to continue to share their own experiences of the implementation of e-Consent., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology., Methods: The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice., Discussion: Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained., Core Outcome Set Registration: COMET Initiative as study 118 ., (© 2022. The Author(s).)

Background: Core outcome sets (COS) are standardised sets of outcomes, which represent the minimum outcomes that should be measured and reported in clinical trials. COS can enhance comparability across health trials by reducing heterogeneity of outcome measurement and reporting and potentially minimising selective outcome reporting. Examining what researchers involved in trials know and think about COS is essential to increase awareness and promote COS uptake. The aim of this study is therefore to examine clinical trialists' knowledge, perceptions and experiences of COS., Methods: An online survey design was used. Participants were clinical trialists, operationalised for the current study as researchers named as the contact person on a trial registered on the International Standard Randomised Controlled Trial Number (ISRCTN) Trial repository between 1 January 2019 and 21 July 2020. Survey items assessed clinical trialists' familiarity with and understanding of COS, along with experiences of COS use and development., Results: Of 1913 clinical trialists contacted to participate, 62 (3%) completed the survey. Forty (65%) participants were familiar with COS and, of those familiar with COS, 21 (55%) had been involved in a trial that used a COS. Of clinical trialists who used COS in a trial(s), less than half (n = 9, 41%) reported that all COS outcomes were used. The main barriers to using COS are poor knowledge about COS (n = 43, 69%) and difficulties identifying relevant COS (n = 42, 68%). Clinical trialists also reported perceptions of COS as restrictive and often containing too many outcomes. The main enablers to using COS are clear understanding (n = 51, 82%) and perceived importance of COS (n = 44, 71%)., Conclusions: Enhancing clinical trialists' use of all COS outcomes is needed to reduce outcome heterogeneity and enhance comparability across trial findings. Enhancing awareness of COS importance among researchers and funders is needed to ensure that COS are developed and used by clinical trialists. Education and training may further promote awareness and understanding of COS., (© 2021. The Author(s).)

Background: Routinely recorded data held in electronic health records can be used to inform the conduct of randomised controlled trials (RCTs). However, limitations with access and accuracy have been identified., Objective: Using epilepsy as an exemplar condition, we assessed the attributes and agreement of routinely recorded data compared to data collected using case report forms in a UK RCT assessing antiepileptic drug treatments for individuals newly diagnosed with epilepsy., Methods: The case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK multicentre RCT assessing the clinical and cost-effectiveness of antiepileptic drugs as treatments for epilepsy. Ninety-eight of 470 eligible participants provided consent for access to routinely recorded secondary care data that were retrieved from NHS Digital Hospital Episode Statistics (N=71) and primary and secondary care data from The Secure Anonymised Information Linkage Databank (N=27). We assessed data items relevant to the identification of individuals eligible for inclusion in SANAD II, baseline and follow-up visits. The attributes of routinely recorded data were assessed including the degree of missing data. The agreement between routinely recorded data and data collected on case report forms in SANAD II was assessed using calculation of Cohen's kappa for categorical data and construction of Bland-Altman plots for continuous data., Results: There was a significant degree of missing data in the routine record for 15 of the 20 variables assessed, including all clinical variables. Agreement was poor for the majority of comparisons, including the assessments of seizure occurrence and adverse events. For example, only 23/62 (37%) participants had a date of first-ever seizure identified in routine datasets. Agreement was satisfactory for the date of prescription of antiepileptic drugs and episodes of healthcare resource use., Conclusions: There are currently significant limitations preventing the use of routinely recorded data for participant identification and assessment of clinical outcomes in epilepsy, and potentially other chronic conditions. Further research is urgently required to assess the attributes, agreement, additional benefits, cost-effectiveness and 'optimal mix' of routinely recorded data compared to data collected using standard methods such as case report forms at clinic visits for people with epilepsy., Trial Registration: Standard and New Antiepileptic Drugs II (SANAD II (EudraCT No: 2012-001884-64, registered 05/09/2012; ISRCTN Number: ISRCTN30294119 , registered 03/07/2012)).

Background: Core outcome sets (COS) should be relevant to key stakeholders and widely applicable and usable. Ideally, they are developed for international use to allow optimal data synthesis from trials. Electronic Delphi surveys are commonly used to facilitate global participation; however, this has limitations. It is common for these surveys to be conducted in a single language potentially excluding those not fluent in that tongue. The aim of this study is to summarise current approaches for optimising international participation in Delphi studies and make recommendations for future practice., Methods: A comprehensive literature review of current approaches to translating Delphi surveys for COS development was undertaken. A standardised methodology adapted from international guidance derived from 12 major sets of translation guidelines in the field of outcome reporting was developed. As a case study, this was applied to a COS project for surgical trials in gastric cancer to translate a Delphi survey into 7 target languages from regions active in gastric cancer research., Results: Three hundred thirty-two abstracts were screened and four studies addressing COS development in rheumatoid and osteoarthritis, vascular malformations and polypharmacy were eligible for inclusion. There was wide variation in methodological approaches to translation, including the number of forward translations, the inclusion of back translation, the employment of cognitive debriefing and how discrepancies and disagreements were handled. Important considerations were identified during the development of the gastric cancer survey including establishing translation groups, timelines, understanding financial implications, strategies to maximise recruitment and regulatory approvals. The methodological approach to translating the Delphi surveys was easily reproducible by local collaborators and resulted in an additional 637 participants to the 315 recruited to complete the source language survey. Ninety-nine per cent of patients and 97% of healthcare professionals from non-English-speaking regions used translated surveys., Conclusion: Consideration of the issues described will improve planning by other COS developers and can be used to widen international participation from both patients and healthcare professionals.

Background: Cleft palate is among the most common birth abnormalities. The success of primary surgery in the early months of life is crucial for successful feeding, hearing, dental development, and facial growth. Over recent decades, age at palatal surgery in infancy has reduced. The Timing Of Primary Surgery for cleft palate (TOPS) trial aims to determine whether, in infants with cleft palate, it is better to perform primary surgery at age 6 or 12 months (corrected for gestational age)., Methods/design: The TOPS trial is an international, two-arm, parallel group, randomised controlled trial. The primary outcome is insufficient velopharyngeal function at 5 years of age. Secondary outcomes, measured at 12 months, 3 years, and 5 years of age, include measures of speech development, safety of the procedure, hearing level, middle ear function, dentofacial development, and growth. The analysis approaches for primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The TOPS protocol has been published previously., Discussion: This paper provides details of the planned statistical analyses for the TOPS trial and will reduce the risk of outcome reporting bias and data-driven results., Trial Registration: ClinicalTrials.gov NCT00993551 . Registered on 9 October 2009.

Background: It is increasingly accepted that insufficient attention has been given to the patient health outcomes that are important to measure in comparative effectiveness research that will inform decision-making. The relationship between outcomes chosen for comparative effectiveness research, outcomes used in decision-making in routine care, and outcome data recorded in electronic health records (EHR) is also poorly understood. The COMET Initiative (http://www.comet-initiative.org/. Accessed 3 Apr 2020) supports and encourages the development and use of 'core outcome sets' (COS), which represent the minimum set of patient health outcomes that should be measured and reported for a specific condition. There is growing interest in identifying how COS might fit into the different stages of the healthcare research and delivery ecosystem, and whether inclusion in the EHR might facilitate this., Methods: We sought to determine the degree of overlap between outcomes within COS for research and routine care, EMA, FDA and NICE guidelines, NICE quality statements/indicators, EHR and a point-of-care randomised clinical trial, using type 2 diabetes (T2D) as a case study., Results: There is substantial agreement about important patient outcomes for T2D for research and healthcare, with associated coverage within the UK general practice EHR., Conclusions: This case study has demonstrated the potential for efficient research and value-based healthcare when the EHR can include COS for both research and care, where the COS comprises outcomes of importance to all relevant stakeholders. However, this concordance may not hold more generally, as the focus on patient-centred outcomes may well be greater in T2D than in other conditions. Work is ongoing to examine other clinical areas, in order to highlight any current inefficiencies when health outcomes in research and healthcare do not agree with core outcomes identified by patients, clinicians and other key stakeholders.

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has an unacceptably low cure rate. In recent years, a number of new treatment strategies and compounds were developed for the treatment of AML. There were several randomized controlled clinical trials with the objective to improve patients' management and patients' outcome in AML. Unfortunately, these trials are not always directly comparable since they do not measure the same outcomes, and currently there are no core outcome sets that can be used to guide outcome selection and harmonization in this disease area. The HARMONY (Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology) Alliance is a public-private European network established in 2017 and currently includes 53 partners and 32 associated members from 22 countries. Amongst many other goals of the HARMONY Alliance, Work Package 2 focuses on defining outcomes that are relevant to each hematological malignancy. Accordingly, this pilot study will be performed to define a core outcome set in AML., Methods: The pilot study will use a three-round Delphi survey and a final consensus meeting to define a core outcome set. Participants will be recruited from different stakeholder groups, including patients, clinicians, regulators and members of the European Federation of Pharmaceutical Industries and Associations. At the pre-Delphi stage, a literature research was conducted followed by several semi-structured interviews of clinical public and private key opinion leaders. Subsequently, the preliminary outcome list was discussed in several multi-stakeholder face-to-face meetings. The Delphi survey will reduce the preliminary outcome list to essential core outcomes. After completion of the last Delphi round, a final face-to-face meeting is planned to achieve consensus about the core outcome set in AML., Discussion: As part of the HARMONY Alliance, the pilot Delphi aims to define a core outcome set in AML on the basis of a multi-stakeholder consensus. Such a core outcome set will help to allow consistent comparison of future clinical trials and real-world evidence research and ensures that appropriate outcomes valued by a range of stakeholders are measured within future trials.

The evidence base available to trialists to support trial process decisions-e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants-is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process.SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste.This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.

Background: Internal pilots provide useful information which can help to optimise the running of the main trial. Although some recommendations exist in the literature for the design of internal pilots, little is known about current practice in terms of the specification and also the assessment of progression criteria. The aim of the review is to provide an overview of current practice., Methods: A cohort of clinical trials with an internal pilot, funded by the National Institute for Health Research (NIHR), Health Technology Assessment programme (HTA), extracted in 2017 was reviewed. Data were extracted from: project descriptions; summary of changes from the first stage; feedback about the full application; monitoring notes; progress report history and protocols, for information about the design and assessment of internal pilots., Results: Fifty-seven studies were reviewed. An internal pilot was first proposed in the early stages of the trial in the majority of cases. Target number for recruitment, rate of randomisation, retention/primary outcome ascertainment rate, rate of treatment adherence and consent rate were included as progression criteria. All but one study was permitted to continue to the main trial; however, 25% did not strictly meet the progression criteria. Changes were made to the design of the main trial for 25% of studies, mainly in terms of conduct of recruitment., Conclusions: This review provides insight into the process of designing and assessing internal pilots. Progression criteria are sometimes not met; however, committees involved in the reviewing process will recommend continuation to the main trial, usually accompanied by a second review or close monitoring. Recommendations are made to optimise the process.

Background: Inadequate and poor quality outcome reporting in clinical trials is a well-documented problem that impedes the ability of researchers to evaluate, replicate, synthesize, and build upon study findings and impacts evidence-based decision-making by patients, clinicians, and policy-makers. To facilitate harmonized and transparent reporting of outcomes in trial protocols and published reports, the Instrument for reporting Planned Endpoints in Clinical Trials (InsPECT) is being developed. The final product will provide unique InsPECT extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines., Methods: The InsPECT SPIRIT and CONSORT extensions will be developed in accordance with the methodological framework created by the EQUATOR (Enhancing the Quality and Transparency of Health Research Quality) Network for reporting guideline development. Development will consist of (1) the creation of an initial list of candidate outcome reporting items synthesized from expert consultations and a scoping review of existing guidance for reporting outcomes in trial protocols and reports; (2) a three-round international Delphi study to identify additional candidate items and assess candidate item importance on a 9-point Likert scale, completed by stakeholders such as trial report and protocol authors, systematic review authors, biostatisticians and epidemiologists, reporting guideline developers, clinicians, journal editors, and research ethics board representatives; and (3) an in-person expert consensus meeting to finalize the set of essential outcome reporting items for trial protocols and reports, respectively. The consensus meeting discussions will be independently facilitated and informed by the empirical evidence identified in the primary literature and through the opinions (aggregate rankings and comments) collected via the Delphi study. An integrated knowledge translation approach will be used throughout InsPECT development to facilitate implementation and dissemination, in addition to standard post-development activities., Discussion: InsPECT will provide evidence-informed and consensus-based standards focused on outcome reporting in clinical trials that can be applied across diverse disease areas, study populations, and outcomes. InsPECT will support the standardization of trial outcome reporting, which will maximize trial usability, reduce bias, foster trial replication, improve trial design and execution, and ultimately reduce research waste and help improve patient outcomes.

Background: Several hundred core outcome set (COS) projects have been systematically identified to date which, if adopted, ensure that researchers measure and report those outcomes that are most likely to be relevant to users of their research. The uptake of a COS by COS users will depend in part on the transparency and robustness of the methods used in the COS development study, which would be increased by the use of a standardised protocol. This article describes the development of the COS-STAP (Core Outcome Set-STAndardised Protocol Items) Statement for the content of a COS development study protocol., Methods: The COS-STAP Statement was developed following the Enhancing the Quality and Transparency Of Health Research (EQUATOR) Network's methodological framework for guideline development. This included an initial item generation stage, a two-round Delphi survey involving more than 150 participants representing three stakeholder groups (COS developers, journal editors and patient and public involvement researchers interested in COS development), followed by a consensus meeting with eight voting participants., Results: The COS-STAP Statement consists of a checklist of 13 items considered essential documentation in a protocol, outlining the scope of the COS, stakeholder involvement, COS development plans and consensus processes., Conclusions: Journal editors and peer reviewers can use the guidance to assess the completeness of a COS development study protocol submitted for publication. By providing guidance for key content, the COS-STAP Statement will enhance the drafting of high-quality protocols and determine how the COS development study will be carried out.

Background: Recent recommendations promote the inclusion of people living with dementia beyond the role of 'participant' to involvement in all areas of the research process. This reflects shifts in dementia studies from 'research on' to 'research with' people living with the condition. In this paper, we describe the design process and features of a modified Delphi survey devised through consultation with people living with dementia., Methods: This article focusses on consultation with people living with dementia and care partners to design an accessible Delphi survey to facilitate participation in core outcome set development. We used the COINED model of co-research developed through the ESRC/NIHR Neighbourhoods and Dementia Study to structure consultation on three features of modified Delphi design. Consultation was achieved through 1:1 and group sessions with a total of 28 individuals (18 people living with dementia and seven care partners)., Results: A flexible, responsive and adaptive approach to ongoing consultation with people living with dementia and care partners through 1:1 face-to-face sessions facilitated: (1) the development of a 3-point non-categorical importance scale; (2) the translation of 54 outcome areas into 'accessible statements' for a two-round Delphi survey administered to five stakeholder groups (people living with dementia, care partners, health and social care professionals, policy-makers and researchers); and (3) the delivery of a Delphi survey. These features of core outcome set development facilitated the involvement of people living with dementia in study design and as research participants in the data collection phase., Conclusions: Involvement of people living with dementia as a key stakeholder group is not reflected in studies using Delphi survey methods for core outcome set development. Time, resources, researcher expertise and support, underpinned through targeted funding facilitate meaningful and productive inclusive approaches, now an expectation of dementia research., Trial Registration: The study is registered on the COMET Initiative .

Background: Site performance is key to the success of large multicentre randomised trials. A standardised set of clear and accessible summaries of site performance could facilitate the timely identification and resolution of potential problems, minimising their impact. The aim of this study was to identify and agree a core set of key performance metrics for managing multicentre randomised trials., Methods: We used a mixed methods approach to identify potential metrics and to achieve consensus about the final set, adapting methods that are recommended by the COMET Initiative for developing core outcome sets in health care. We used performance metrics identified from our systematic search and focus groups to create an online Delphi survey. We invited respondents to score each metric for inclusion in the final core set, over three survey rounds. Metrics scored as critical by ≥70% and unimportant by <15% of respondents were taken forward to a consensus meeting of representatives from key UK-based stakeholders. Participants in the consensus meeting discussed and voted on each metric, using anonymous electronic voting. Metrics with >50% of participants voting for inclusion were retained., Results: Round 1 of the Delphi survey presented 28 performance metrics, and a further six were added in round 2. Of 294 UK-based stakeholders who registered for the Delphi survey, 211 completed all three rounds. At the consensus meeting, 17 metrics were discussed and voted on: 15 metrics were retained following survey round 3, plus two others that were preferred by consensus meeting participants. Consensus was reached on a final core set of eight performance metrics in three domains: (1) recruitment and retention, (2) data quality and (3) protocol compliance. A simple tool for visual reporting of the metrics is available from the Nottingham Clinical Trials Unit website., Conclusions: We have established a core set of metrics for measuring the performance of sites in multicentre randomised trials. These metrics could improve trial conduct by enabling researchers to identify and address problems before trials are adversely affected. Future work could evaluate the effectiveness of using the metrics and reporting tool.

In the original publication [1] the abbreviation for Core outcome sets (COS) was pluralized unnecessarily throughout the next.

Background: Type 2 diabetes is characterised by abnormal glucose metabolism, and treatment is aimed at normalising glycaemia. Outcomes measured in clinical trials should be meaningful to patients, health care professionals and researchers, yet there is heterogeneity in the outcomes used across trials of glucose-lowering interventions. This inconsistency affects the ability to compare findings and may mean that the results have little importance to health care professionals and the patients for whom they care. The SCORE-IT study aims to develop a core outcome set (COS) for use in all trials of glucose-lowering interventions for people with type 2 diabetes., Methods/design: This study will involve three key stages in the development of a COS: (1) A list of outcomes will be identified from multiple sources, specifically registered clinical trials, online patient resources, the qualitative literature and landmark studies identified by a Study Steering Committee. (2) The list of outcomes will be scored by multiple stakeholder groups in a two-round online international Delphi survey. (3) The results of the online Delphi will be summarised and discussed at a face-to-face consensus meeting with representation from all stakeholder groups., Discussion: The SCORE-IT study aims to develop an internationally relevant set of core outcomes for use in future trials of glucose-lowering interventions for type 2 diabetes. The use of a COS will improve the consistency of outcomes, allowing results of studies to be compared and combined and for new effective treatments to made available more quickly., Trial Registration: The COS study, of which this is a part, is registered in the Core Outcome Measures in Effectiveness Trials (COMET) database, http://www.comet-initiative.org/studies/details/956 . Registered January 2017.

Background: Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology., Methods: This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop., Results: A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was "How can randomised trials become part of routine care and best utilise current clinical care pathways?" The top 10 research questions can be viewed at www.priorityresearch.ie ., Conclusion: The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

Background: There are numerous challenges in including patients in a core outcome set (COS) study, these can vary depending on the patient group. This study describes current efforts to include patients in the development of COS, with the aim of identifying areas for further improvement and study., Methods: Using the COMET database, corresponding authors of COS projects registered or published from 1 January 2013 to 2 February 2017 were invited via a personalised email to participate in a short online survey. The survey and emails were constructed to maximise the response rate by following the academic literature on enhancing survey responses. Personalised reminder emails were sent to non-responders. This survey explored the frequency of patient input in COS studies, who was involved, what methods were used and whether or not the COS development was international., Results: One hundred and ninety-two COS developers were sent the survey. Responses were collected from 21 February 2017 until 7 May 2017. One hundred and forty-six unique developers responded, yielding a 76% response rate and data in relation to 195 unique COSs (as some developers had worked on multiple COSs). Of focus here are their responses regarding 162 COSs at the published, completed or ongoing stages of development. Inclusion of patient participants was indicated in 87% (141/162) of COSs in the published completed or ongoing stages and over 94% (65/69) of ongoing COS projects. Nearly half (65/135) of COSs included patient participants from two or more countries and 22% (30/135) included patient participants from five or more countries. The Delphi survey was reported as being used singularly or in combination with other methods in 85% (119/140) of projects. Almost a quarter (16/65) of ongoing studies reported using a combination of qualitative interviews, Delphi survey and consensus meeting., Conclusions: These findings indicated that the Delphi survey is the most popular method of facilitating patient participation, while the combination of qualitative interviews, Delphi survey and consensus meetings is the most popular combination of methods. The increased inclusion of patient participants in the development of COSs is encouraging, as is the international approach to COS development that some developers are adopting.

Background: Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions., Methods: An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics., Findings: Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff., Conclusion: By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Background: Outcomes measured in clinical trials should be meaningful to patients, healthcare professionals and researchers, yet there is heterogeneity in the outcomes used across trials. This inconsistency impacts on the ability to compare findings and may mean that the results have little importance to healthcare professionals and the patients that they care for. The aim of the present study is to review the outcomes used in registered trials of therapies for type 2 diabetes mellitus as the first step in the development of a core outcome set for effectiveness trials in type 2 diabetes., Methods: A systematic review of clinicaltrials.gov entries was completed for randomised, open (actively recruiting or in follow-up period), phase 3 and 4 trials of type 2 diabetes mellitus in adults. Trials of the treatment of diabetes complications, co-morbidities, prevention and surgery were excluded. Each trial was screened for eligibility and outcomes extracted from the primary and secondary outcomes data fields and free text study information. The outcomes were recorded verbatim and classified into core outcome domains according to the COMET taxonomy., Results: A total of 354 trial registrations were reviewed for eligibility and 138 trials included. In total, 1444 outcomes were extracted with a median of eight outcomes per trial (range = 1-60). Outcomes were categorised into 30 different outcome domains according to the COMET taxonomy, but no single domain or outcome was measured in 100% of trials. The majority of trials (88%) included outcomes in the 'metabolism and nutrition' domain, such as lipids and lipoproteins (21%), HbA1c (18%), hypoglycaemia (14%), fasting plasma/blood glucose (11%), glycaemic variability (8%), postprandial response (8%) and insulin sensitivity (5%). Only 10% of trials included one or more patient reported outcomes; of these, 29% included the Diabetes Treatment Satisfaction Questionnaire., Conclusions: There is marked heterogeneity in the outcomes measured in registered therapeutic intervention trials for type 2 diabetes. The use of an agreed set of core outcomes will improve the consistency of reporting in clinical trials for type 2 diabetes., Trial Registration: The core outcome set study, of which this is a part, is registered in the COMET database, http://www.comet-initiative.org/studies/details/956 . Registered on 24 January 2017.

Background: There is increasing recognition that establishing a core set of outcomes to be evaluated and reported in trials of interventions for particular conditions will improve the usefulness of health research. There is no established core outcome set for childhood epilepsy. The aim of this work is to select a core outcome set to be used in evaluative research of interventions for children with rolandic epilepsy, as an exemplar of common childhood epilepsy syndromes., Methods: First we will identify what outcomes should be measured; then we will decide how to measure those outcomes. We will engage relevant UK charities and health professional societies as partners, and convene advisory panels for young people with epilepsy and parents of children with epilepsy. We will identify candidate outcomes from a search for trials of interventions for childhood epilepsy, statutory guidance and consultation with our advisory panels. Families, charities and health, education and neuropsychology professionals will be invited to participate in a Delphi survey following recommended practices in the development of core outcome sets. Participants will be able to recommend additional outcome domains. Over three rounds of Delphi survey participants will rate the importance of candidate outcome domains and state the rationale for their decisions. Over the three rounds we will seek consensus across and between families and health professionals on the more important outcomes. A face-to-face meeting will be convened to ratify the core outcome set. We will then review and recommend ways to measure the shortlisted outcomes using clinical assessment and/or patient-reported outcome measures., Discussion: Our methodology is a proportionate and pragmatic approach to expediently produce a core outcome set for evaluative research of interventions aiming to improve the health of children with epilepsy. A number of decisions have to be made when designing a study to develop a core outcome set including defining the scope, choosing which stakeholders to engage, most effective ways to elicit their views, especially children and a potential role for qualitative research.

Background: In the UK, routinely recorded data may benefit prospective studies including randomised controlled trials (RCTs). In an on-going study, we aim to assess the feasibility of access and agreement of routinely recorded clinical and non-clinical data compared to data collected during a RCT using standard prospective methods. This paper will summarise available UK routinely recorded data sources and discuss our experience with the feasibility of accessing routinely recorded data for participants of a RCT before finally proposing recommendations for improving the access and implementation of routinely recorded data in RCTs., Methods: Setting: the case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK, multicentre, phase IV RCT assessing the clinical and cost-effectiveness of antiepileptic drug treatments for newly diagnosed epilepsy., Participants: 98 participants have provided written consent to permit the request of routinely recorded data. Study procedures: routinely recorded clinical and non-clinical data were identified and data requested through formal applications from available data holders for the duration that participants have been recruited into SANAD II. The feasibility of accessing routinely recorded data during a RCT is assessed and recommendations for improving access proposed., Results: Secondary-care clinical and socioeconomic data is recorded on a national basis and can be accessed, although there are limitations in the application process. Primary-care data are recorded by a number of organisations on a de-identified basis but access for specific individuals has not been feasible. Access to data recorded by non-clinical sources, including The Department for Work and Pensions and The Driving and Vehicle Licensing Agency, was not successful., Conclusions: Recommendations discussed include further research to assess the attributes of routinely recorded data, an assessment of public perceptions and the development of strategies to collaboratively improve access to routinely recorded data for research., Trial Registration: International Standard Randomised Controlled Trials, ISRCTN30294119 . Registered on 3 July 2012. EudraCT No: 2012-001884-64. Registered on 9 May 2012.

The selection of appropriate outcomes is crucial when designing clinical trials in order to compare the effects of different interventions directly. For the findings to influence policy and practice, the outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. It is now widely acknowledged that insufficient attention has been paid to the choice of outcomes measured in clinical trials. Researchers are increasingly addressing this issue through the development and use of a core outcome set, an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area.Accumulating work in this area has identified the need for guidance on the development, implementation, evaluation and updating of core outcome sets. This Handbook, developed by the COMET Initiative, brings together current thinking and methodological research regarding those issues. We recommend a four-step process to develop a core outcome set. The aim is to update the contents of the Handbook as further research is identified.

Background: Patients with moderate-to-severe atopic eczema (AE) often require photo- or systemic immunomodulatory therapies to induce disease remission and maintain long-term control. The current evidence to guide clinical management is small, despite the frequent and often off-label use of these treatments. Registries of patients on photo- and systemic immunomodulatory therapies could fill this gap, and the collection of a core set concerning these therapies in AE will allow direct comparisons across registries as well as data sharing and pooling. Using an eDelphi approach, the international TREatment of ATopic eczema (TREAT) Registry Taskforce aims to seek consensus between key stakeholders internationally on a core set of domains and domain items for AE patient registries with a research focus that collect data of children and adults on photo- and systemic immunomodulatory therapies., Methods/design: Participants from six stakeholder groups will be invited: doctors, nurses, non-clinical researchers, patients, as well as industry and regulatory body representatives. The eDelphi will comprise three sequential online rounds, requesting participants to rate the importance of each proposed domain and domain items. Participants will be able to add domains and domain items to the proposed list in round 1. A final consensus meeting will be held with representatives of each stakeholder group., Discussion: Identifying a uniform core set of domains and domain items to be captured by AE patient registries will increase the utility of individual registries, and provide greater insight into the effectiveness, safety and cost-effectiveness of photo- and systemic immunomodulatory therapies to guide clinical management across dermatology centres and country borders., Trial Registration: Not applicable. This eDelphi study was registered in the Core Outcome Measures for Effectiveness Trials (COMET) database.

Background: In cooperation with the Core Outcome Measures in Effectiveness Trials (COMET) initiative, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) initiative aimed to develop a guideline on how to select outcome measurement instruments for outcomes (i.e., constructs or domains) included in a "Core Outcome Set" (COS). A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population., Methods: Informed by a literature review to identify potentially relevant tasks on outcome measurement instrument selection, a Delphi study was performed among a panel of international experts, representing diverse stakeholders. In three consecutive rounds, panelists were asked to rate the importance of different tasks in the selection of outcome measurement instruments, to justify their choices, and to add other relevant tasks. Consensus was defined as being achieved when 70 % or more of the panelists agreed and when fewer than 15 % of the panelists disagreed., Results: Of the 481 invited experts, 120 agreed to participate of whom 95 (79 %) completed the first Delphi questionnaire. We reached consensus on four main steps in the selection of outcome measurement instruments for COS: Step 1, conceptual considerations; Step 2, finding existing outcome measurement instruments, by means of a systematic review and/or a literature search; Step 3, quality assessment of outcome measurement instruments, by means of the evaluation of the measurement properties and feasibility aspects of outcome measurement instruments; and Step 4, generic recommendations on the selection of outcome measurement instruments for outcomes included in a COS (consensus ranged from 70 to 99 %)., Conclusions: This study resulted in a consensus-based guideline on the methods for selecting outcome measurement instruments for outcomes included in a COS. This guideline can be used by COS developers in defining how to measure core outcomes.

Background: Rosacea is a chronic inflammatory disorder affecting millions of individuals worldwide. Diagnosis is based on signs and symptoms with management and treatment aimed to suppress inflammatory lesions, erythema, and telangiectasia. While many clinical trials of rosacea exist, the lack of consensus in outcome reporting across all trials poses a concern. Proper evaluation and comparison of treatment modalities is challenging. In order to address the inconsistencies present, this project aims to determine a core set of outcomes which should be evaluated in all clinical trials of rosacea., Methods/design: This project will utilize a methodology similar to previous core outcome set research. A long list of outcomes will be extracted over four phases: (1) systematic literature review, (2) patient interviews, (3) other published sources, and (4) stakeholder involvement. Potential outcomes will be examined by the Steering Committee to provide further insight. The Delphi process will then be performed to prioritize and condense the list of outcomes generated. Two homogenous groups of physicians and patients will participate in two consecutive rounds of Delphi surveys. A consensus meeting, composed of physicians, patients, and stakeholders, will be conducted after the Delphi exercise to further select outcomes, taking into account participant scores. By the end of the meeting, members will vote and decide on a final recommended set of core outcomes. For the duration of the study, we will be in collaboration with both the Core Outcome Measures in Effectiveness Trials (COMET) and Cochrane Skin Group - Core Outcome Set Initiative (CSG-COUSIN)., Discussion: This study aims to develop a core outcome set to guide assessment in clinical trials of rosacea. The end-goal is to improve the reliability and consistency of outcome reporting, thereby allowing sufficient evaluation of treatment effectiveness and patient satisfaction.

Background: Methods for developing a core outcome or information set require involvement of key stakeholders to prioritise many items and achieve agreement as to the core set. The Delphi technique requires participants to rate the importance of items in sequential questionnaires (or rounds) with feedback provided in each subsequent round such that participants are able to consider the views of others. This study examines the impact of receiving feedback from different stakeholder groups, on the subsequent rating of items and the level of agreement between stakeholders., Methods: Randomized controlled trials were nested within the development of three core sets each including a Delphi process with two rounds of questionnaires, completed by patients and health professionals. Participants rated items from 1 (not essential) to 9 (absolutely essential). For round 2, participants were randomized to receive feedback from their peer stakeholder group only (peer) or both stakeholder groups separately (multiple). Decisions as to which items to retain following each round were determined by pre-specified criteria., Results: Whilst type of feedback did not impact on the percentage of items for which a participant subsequently changed their rating, or the magnitude of change, it did impact on items retained at the end of round 2. Each core set contained discordant items retained by one feedback group but not the other (3-22 % discordant items). Consensus between patients and professionals in items to retain was greater amongst those receiving multiple group feedback in each core set (65-82 % agreement for peer-only feedback versus 74-94 % for multiple feedback). In addition, differences in round 2 scores were smaller between stakeholder groups receiving multiple feedback than between those receiving peer group feedback only. Variability in item scores across stakeholders was reduced following any feedback but this reduction was consistently greater amongst the multiple feedback group., Conclusions: In the development of a core outcome or information set, providing feedback within Delphi questionnaires from all stakeholder groups separately may influence the final core set and improve consensus between the groups. Further work is needed to better understand how participants rate and re-rate items within a Delphi process., Trial Registration: The three randomized controlled trials reported here were each nested within the development of a core information or outcome set to investigate processes in core outcome and information set development. Outcomes were not health-related and therefore trial registration was not applicable.

Background: Clinical trials with longitudinally measured outcomes are often plagued by missing data due to patients withdrawing or dropping out from the trial before completing the measurement schedule. The reasons for dropout are sometimes clearly known and recorded during the trial, but in many instances these reasons are unknown or unclear. Often such reasons for dropout are non-ignorable. However, the standard methods for analysing longitudinal outcome data assume that missingness is non-informative and ignore the reasons for dropout, which could result in a biased comparison between the treatment groups., Methods: In this article, as a post hoc analysis, we explore the impact of informative dropout due to competing reasons on the evaluation of treatment effect in the MAGNETIC trial, the largest randomised placebo-controlled study to date comparing the addition of nebulised magnesium sulphate to standard treatment in acute severe asthma in children. We jointly model longitudinal outcome and informative dropout process to incorporate the information regarding the reasons for dropout by treatment group., Results: The effect of nebulised magnesium sulphate compared with standard treatment is evaluated more accurately using a joint longitudinal-competing risk model by taking account of such complexities. The corresponding estimates indicate that the rate of dropout due to good prognosis is about twice as high in the magnesium group compared with standard treatment., Conclusions: We emphasise the importance of identifying reasons for dropout and undertaking an appropriate statistical analysis accounting for such dropout. The joint modelling approach accounting for competing reasons for dropout is proposed as a general approach for evaluating the sensitivity of conclusions to assumptions regarding missing data in clinical trials with longitudinal outcomes., Trial Registration: EudraCT number 2007-006227-12 . Registration date 18 Mar 2008.

Background: The process of obtaining informed consent for participation in randomised controlled trials (RCTs) was established as a mechanism to protect participants against undue harm from research and allow people to recognise any potential risks or benefits associated with the research. A number of interventions have been put forward to improve this process. Outcomes reported in trials of interventions to improve the informed consent process for decisions about trial participation tend to focus on the 'understanding' of trial information. However, the operationalization of understanding as a concept, the tools used to measure it and the timing of the measurements are heterogeneous. A lack of clarity exists regarding which outcomes matter (to whom) and why. This inconsistency between studies results in difficulties when making comparisons across studies as evidenced in two recent systematic reviews of informed consent interventions. As such, no optimal method for measuring the impact of these interventions aimed at improving informed consent for RCTs has been identified., Methods/design: The project will adopt and adapt methodology previously developed and used in projects developing core outcome sets for assessment of clinical treatments. Specifically, the work will consist of three stages: 1) A systematic methodology review of existing outcome measures of trial informed consent interventions; 2) Interviews with key stakeholders to explore additional outcomes relevant for trial participation decisions; and 3) A Delphi study to refine the core outcome set for evaluation of trial informed consent interventions. All stages will include the stakeholders involved in the various aspects of RCT consent: users (that is, patients), developers (that is, trialists), deliverers (focusing on research nurses) and authorisers (that is, ethics committees). A final consensus meeting including all stakeholders will be held to review outcomes., Discussion: The ELICIT study aims to develop a core outcome set for the evaluation of interventions intended to improve informed consent for RCTs for use in future RCTs and reviews, thereby improving the reliability and consistency of research in this area.

Background: Core outcome sets can increase the efficiency and value of research and, as a result, there are an increasing number of studies looking to develop core outcome sets (COS). However, the credibility of a COS depends on both the use of sound methodology in its development and clear and transparent reporting of the processes adopted. To date there is no reporting guideline for reporting COS studies. The aim of this programme of research is to develop a reporting guideline for studies developing COS and to highlight some of the important methodological considerations in the process., Methods/design: The study will include a reporting guideline item generation stage which will then be used in a Delphi study. The Delphi study is anticipated to include two rounds. The first round will ask stakeholders to score the items listed and to add any new items they think are relevant. In the second round of the process, participants will be shown the distribution of scores for all stakeholder groups separately and asked to re-score. A final consensus meeting will be held with an expert panel and stakeholder representatives to review the guideline item list. Following the consensus meeting, a reporting guideline will be drafted and review and testing will be undertaken until the guideline is finalised. The final outcome will be the COS-STAR (Core Outcome Set-STAndards for Reporting) guideline for studies developing COS and a supporting explanatory document., Discussion: To assess the credibility and usefulness of a COS, readers of a COS development report need complete, clear and transparent information on its methodology and proposed core set of outcomes. The COS-STAR guideline will potentially benefit all stakeholders in COS development: COS developers, COS users, e.g. trialists and systematic reviewers, journal editors, policy-makers and patient groups.

Background: Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory disorder associated with significant morbidity and mortality. International collaboration is necessary to better understand the pathogenesis of the disease, response to treatment and long-term outcome. To aid international collaboration, it is essential to have a core set of data that all researchers and clinicians collect in a standardised way for clinical purposes and for research. This should include demographic details, diagnostic data and measures of disease activity, investigations and treatment. Variables in existing clinical registries have been compared to produce a provisional data set for JDM. We now aim to develop this into a consensus-approved minimum core dataset, tested in a wider setting, with the objective of achieving international agreement., Methods/design: A two-stage bespoke Delphi-process will engage the opinion of a large number of key stakeholders through Email distribution via established international paediatric rheumatology and myositis organisations. This, together with a formalised patient/parent participation process will help inform a consensus meeting of international experts that will utilise a nominal group technique (NGT). The resulting proposed minimal dataset will be tested for feasibility within existing database infrastructures. The developed minimal dataset will be sent to all internationally representative collaborators for final comment. The participants of the expert consensus group will be asked to draw together these comments, ratify and 'sign off' the final minimal dataset., Discussion: An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. The final approved minimum core dataset could be rapidly incorporated into national and international collaborative efforts, including existing prospective databases, and be available for use in randomised controlled trials and for treatment/protocol comparisons in cohort studies.

Background: Prostate cancer is a growing health problem worldwide. The management of localised prostate cancer is controversial. It is unclear which of several surgical, radiotherapeutic, ablative, and surveillance treatments is the most effective. All have cost, process and recovery, and morbidity implications which add to treatment decision-making complexity for patients and healthcare professionals. Evidence from randomised controlled trials (RCTs) is not optimal because of uncertainty as to what constitutes important outcomes. Another issue hampering evidence synthesis is heterogeneity of outcome definition, measurement, and reporting. This project aims to determine which outcomes are the most important to patients and healthcare professionals, and use these findings to recommend a standardised core outcome set for comparative effectiveness trials of treatments for localised prostate cancer, to optimise decision-making., Methods/design: The range of potentially important outcomes and measures will be identified through systematic reviews of the literature and semi-structured interviews with patients. A consultation exercise involving representatives from two key stakeholder groups (patients and healthcare professionals) will ratify the list of outcomes to be entered into a three round Delphi study. The Delphi process will refine and prioritise the list of identified outcomes. A methodological substudy (nested RCT design) will also be undertaken. Participants will be randomised after round one of the Delphi study to one of three feedback groups, based on different feedback strategies, in order to explore the potential impact of feedback strategies on participant responses. This may assist the design of a future core outcome set and Delphi studies. Following the Delphi study, a final consensus meeting attended by representatives from both stakeholder groups will determine the final recommended core outcome set., Discussion: This study will inform clinical practice and future trials of interventions of localised prostate cancer by standardising a core outcome set which should be considered in comparative effectiveness studies for localised prostate cancer.

Background: To investigate the nature of the research process as a whole, factors that might influence the way in which research is carried out, and how researchers ultimately report their findings., Methods: Semi-structured qualitative telephone interviews with authors of trials, identified from two sources: trials published since 2002 included in Cochrane systematic reviews selected for the ORBIT project; and trial reports randomly sampled from 14,758 indexed on PubMed over the 12-month period from August 2007 to July 2008., Results: A total of 268 trials were identified for inclusion, 183 published since 2002 and included in the Cochrane systematic reviews selected for the ORBIT project and 85 randomly selected published trials indexed on PubMed. The response rate from researchers in the former group was 21% (38/183) and in the latter group was 25% (21/85). Overall, 59 trialists were interviewed from the two different sources. A number of major but related themes emerged regarding the conduct and reporting of trials: establishment of the research question; identification of outcome variables; use of and adherence to the study protocol; conduct of the research; reporting and publishing of findings. Our results reveal that, although a substantial proportion of trialists identify outcome variables based on their clinical experience and knowing experts in the field, there can be insufficient reference to previous research in the planning of a new trial. We have revealed problems with trial recruitment: not reaching the target sample size, over-estimation of recruitment potential and recruiting clinicians not being in equipoise. We found a wide variation in the completeness of protocols, in terms of detailing study rationale, outlining the proposed methods, trial organisation and ethical considerations., Conclusion: Our results confirm that the conduct and reporting of some trials can be inadequate. Interviews with researchers identified aspects of clinical research that can be especially challenging: establishing appropriate and relevant outcome variables to measure, use of and adherence to the study protocol, recruiting of study participants and reporting and publishing the study findings. Our trialists considered the prestige and impact factors of academic journals to be the most important criteria for selecting those to which they would submit manuscripts.

Background: The development and application of standardised sets of outcomes to be measured and reported in clinical trials have the potential to increase the efficiency and value of research. One of the most notable of the current outcome sets began nearly 20 years ago: the World Health Organization and International League of Associations for Rheumatology core set of outcomes for rheumatoid arthritis clinical trials, originating from the OMERACT (Outcome Measures in Rheumatology) Initiative. This study assesses the use of this core outcome set by randomised trials in rheumatology., Methods: An observational review was carried out of 350 randomised trials for the treatment of rheumatoid arthritis identified through The Cochrane Library (up to and including September 2012 issue). Reports of these trials were evaluated to determine whether or not there were trends in the proportion of trials reporting on the full set of core outcomes over time. Researchers who conducted trials after the publication of the core set were contacted to assess their awareness of it and to collect reasons for non-inclusion of the full core set of outcomes in the study., Results: Since the introduction of the core set of outcomes for rheumatoid arthritis, the consistency of measurement of the core set of outcomes has improved, although variation in the choice of measurement instrument remains. The majority of trialists who responded said that they would consider using the core outcome set in the design of a new trial., Conclusions: This observational review suggests that a higher percentage of trialists conducting trials in rheumatoid arthritis are now measuring the rheumatoid arthritis core outcome set. Core outcome sets have the potential to improve the evidence base for health care, but consideration must be given to the methods for disseminating their availability amongst the relevant communities.

Background: Cleft palate (CP) has an incidence of approximately 1 in 700. Children with CP are also susceptible to otitis media with effusion (OME), with approximately 90% experiencing nontrivial OME. There are several approaches to the management of OME in children with CP. The Management of Otitis Media with Effusion in Children with Cleft Palate (MOMENT) study is a feasibility study that includes the development of a core outcome set for use in future trials of the management of OME in children with CP., Methods/design: The MOMENT study will include a systematic review of the literature to identify a list of outcomes that have previously been reported. This list of outcomes will be used in a Delphi study with cleft clinicians. The Delphi study is anticipated to include three rounds. The first round will ask clinicians to score the outcome list and to add any outcomes they think are relevant. The second round involves presentation of scores according to stakeholder group and the opportunity for participants to rescore outcomes. To ensure that the opinion of parents and children are sought, qualitative interviews will be completed with a purposive sample in parallel. In the final round of the Delphi process, participants will be shown the distribution of scores, for each outcome, for all stakeholder groups separately as well as a summary of the results concerning outcomes from the qualitative interviews with parents. A final consensus meeting will be held with all stakeholders, including parents and children, to review outcomes., Discussion: A core outcome set represents the minimum that should be measured in a clinical trial for a particular condition. The MOMENT study will aim to identify a core outcome set that can be used in future trials of the management of OME, improving the consistency of research in this clinical area.

Background: Missing outcome data or the inconsistent reporting of outcome data in clinical research can affect the quality of evidence within a systematic review. A potential solution is an agreed standardized set of outcomes known as a core outcome set (COS) to be measured in all studies for a specific condition. We investigated the amount of missing patient data for primary outcomes in Cochrane systematic reviews, and surveyed the Co-ordinating Editors of Cochrane Review Groups (CRGs) on issues related to the standardization of outcomes in their CRG's reviews. These groups are responsible for the more than 7,000 protocols and full versions of Cochrane Reviews that are currently available, and the several hundred new reviews published each year, presenting the world's largest collection of standardized systematic reviews in health care., Methods: Using an unselected cohort of Cochrane Reviews, we calculated and presented the percentage of missing patient data for the primary outcome measure chosen for each review published by each CRG. We also surveyed the CRG Co-ordinating Editors to see what their policies are with regards to outcome selection and outcomes to include in the Summary of Finding (SoF) tables in their Cochrane Reviews. They were also asked to list the main advantages and challenges of standardizing outcomes across all reviews within their CRG., Results: In one fifth of the 283 reviews in the sample, more than 50% of the patient data for the primary outcome was missing. Responses to the survey were received from 90% of Co-ordinating Editors. Thirty-six percent of CRGs have a centralized policy regarding which outcomes to include in the SoF table and 73% of Co-ordinating Editors thought that a COS for effectiveness trials should be used routinely for a SoF table., Conclusions: The reliability of systematic reviews, in particular meta-analyses they contain, can be improved if more attention is paid to missing outcome data. The availability of COSs for specific health conditions might help with this and the concept has support from the majority of Co-ordinating Editors in CRGs.

The selection of appropriate outcomes or domains is crucial when designing clinical trials in order to compare directly the effects of different interventions in ways that minimize bias. If the findings are to influence policy and practice then the chosen outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set, which should be measured and reported, as a minimum, in all trials for a specific clinical area. Accumulating work in this area has identified the need for general guidance on the development of core outcome sets. Key issues to consider in the development of a core outcome set include its scope, the stakeholder groups to involve, choice of consensus method and the achievement of a consensus.

Background: In clinical trials in childhood asthma, outcomes reflecting short-term disease activity are frequently measured, whilst functional status, quality of life (QoL), and long-term treatment effects are rarely assessed. There is also non-uniformity across studies in the selection and measurement of outcomes within these domains. The development of a core outcome set has the potential to reduce heterogeneity between trials, lead to research that is more likely to have measured relevant outcomes, and enhance the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute usable information., Methods: Paediatricians and specialist nurses, identified through the British Paediatric Respiratory Society, completed a two-round Delphi survey. Separate cohorts of parents of children younger than 18 years, recruited in clinics, participated in each round. Young people with asthma, aged at least 13 years, participated in the first round. Outcomes were identified separately for preschool and school-aged children.We identified outcomes considered important in routine clinical assessment by clinicians and parents/young people. In round 1, 46 clinicians suggested outcomes they considered important when deciding whether to adjust a child's asthma therapy regime, and 49 parents/young people were asked, using open questions, how they judged whether their child's (for young people, their own) asthma therapy was appropriate. Two researchers independently classified responses into appropriate, corresponding outcomes.In round 2, 43 clinicians and 50 parents scored, from 0-4, the importance of each outcome suggested by at least 10 % of round 1 responders and selected the three most important., Results: The most important outcomes, when making shared decisions about regular therapies for school-aged and preschool children with asthma, were daytime and nocturnal symptoms, exacerbations, QoL, and mortality. Results from parents and clinicians were generally concordant, but parents placed more emphasis on long-term treatment effects., Conclusions: We have developed a methodology to identify outcomes of most relevance to clinicians, parents, and young people when evaluating regularly administered therapies for asthma. Daytime and nocturnal symptoms, exacerbations, QoL, and mortality are particularly important outcomes that should be measured and reported in all clinical trials of regular therapies for children with asthma.

Background: Outcome reporting bias (ORB) occurs when variables are selected for publication based on their results. This can impact upon the results of a meta-analysis, biasing the pooled treatment effect estimate.The aim of this paper is to show how to assess a systematic review and corresponding trial reports for ORB using an example review of intravenous and nebulised magnesium in the treatment of asthma., Methods: The review was assessed for ORB by 1) checking the reasons, when available, for excluding studies to ensure that no studies were excluded because they did not report the outcomes of interest in the review; 2) assessing the eligible studies as to whether the review outcomes of interest were reported. Each study was classified using a system developed in the ORBIT (Outcome Reporting Bias In Trials) project to indicate whether ORB was suspected and a reason for the suspicion. Authors of trials that did not report the outcomes of interest were contacted for information. A sensitivity analysis was performed to assess the robustness of the conclusions of the review to this potential source of bias., Results: Twenty-four studies were included in the review; two studies had been excluded for not reporting either of the two outcomes of interest. Six included studies did not report hospital admission and two did not report pulmonary function. There was high suspicion of outcome reporting bias in four studies. Results from the sensitivity analysis indicate that review conclusions were not overturned., Conclusion: This paper demonstrates, with the example of the magnesium review, how to assess a review for outcome reporting bias. A review should not exclude studies if they have not reported the outcomes of interest and should consider the potential for outcome reporting bias in all included studies.

Background: There are controversies about the most effective treatment to eradicate first growth of Pseudomonas aeruginosa (P aeruginosa) from the lower airways of patients with cystic fibrosis (CF). UK guidelines recommend oral treatment, but some advocate intravenous (IV) treatment. The objective of this study was to assess the feasibility of conducting a randomised controlled trial comparing two treatment strategies to eradicate P aeruginosa in CF patients., Methods/principal Findings: Two surveys were conducted. Survey [1] included clinicians who were responsible for the treatment of individuals with CF, to assess their clinical practice, opinions and numbers of potentially eligible patients. Survey [2] included adults and young people aged 13 years or more with CF and parents of children with CF aged less than 13 years, identified at six UK CF centres, who fulfilled eligibility criteria for the proposed clinical trial, to assess their views about the interventions and their willingness to participate in the trial. Generally clinicians treat first or new growth of P aeruginosa with oral antibiotics, but 90% reported that they would consider IV treatment of first isolation of P aeruginosa. 74% of clinicians would consider recruiting their patients and 45% of consumers would consider entry for themselves or their children into a trial comparing oral with intravenous antibiotics. The median rate per annum for first or new growths of P aeruginosa in adults was 3% (range 1% to 9%) and in children was 10% (range 3% to 23%). If the trial was conducted across the UK, with a consent rate of 45%, then the number of eligible patients per annum who would be willing to take part in a study would be approximately 41 adults and 203 children., Conclusions: This work demonstrates the importance of feasibility studies in preparation for multicentre clinical trials. It confirmed the uncertainty amongst clinicians and patients about the clinical question, enabled assessment of the number of potentially eligible patients, the proportion of patients and clinicians prepared to participate and aspects of trial design which might encourage this. It showed that a clinical trial was feasible, but only if patients were recruited from across United Kingdom.

Background: Randomised controlled trials (RCTs) represent the gold standard methodological design to evaluate the effectiveness of an intervention in humans but they are subject to bias, including study publication bias and outcome reporting bias. National and international organisations and charities give recommendations for good research practice in relation to RCTs but to date no review of these guidelines has been undertaken with respect to reporting bias., Methods: National and international organisations and UK based charities listed on the Association for Medical Research Charities website were contacted in 2007; they were considered eligible for this review if they funded RCTs. Guidelines were obtained and assessed in relation to what was written about trial registration, protocol adherence and trial publication. It was also noted whether any monitoring against these guidelines was undertaken. This information was necessary to discover how much guidance researchers are given on the publication of results, in order to prevent study publication bias and outcome reporting bias., Results: Seventeen organisations and 56 charities were eligible of 140 surveyed for this review, although there was no response from 12. Trial registration, protocol adherence, trial publication and monitoring against the guidelines were often explicitly discussed or implicitly referred too. However, only eleven of these organisations or charities mentioned the publication of negative as well as positive outcomes and just three of the organisations specifically stated that the statistical analysis plan should be strictly adhered to and all changes should be reported., Conclusion: Our review indicates that there is a need to provide more detailed guidance for those conducting and reporting clinical trials to help prevent the selective reporting of results. Statements found in the guidelines generally refer to publication bias rather than outcome reporting bias. Current guidelines need to be updated and include the statement that all primary and secondary outcomes prespecified in the protocol should be fully reported and should not be selected for inclusion in the final report based on their results.

Background: The choice of antiepileptic drug for an individual should be based upon the highest quality evidence regarding potential benefits and harms of the available treatments. Systematic reviews and meta-analysis of randomised controlled trials should be a major source of evidence supporting this decision making process. We summarise all available individual patient data evidence from randomised controlled trials that compared at least two out of eight antiepileptic drugs given as monotherapy., Methods: Multiple treatment comparisons from epilepsy monotherapy trials were synthesized in a single stratified Cox regression model adjusted for treatment by epilepsy type interactions and making use of direct and indirect evidence. Primary outcomes were time to treatment failure and time to 12 month remission from seizures. A secondary outcome was time to first seizure., Results: Individual patient data for 6418 patients from 20 randomised trials comparing eight antiepileptic drugs were synthesized. For partial onset seizures (4628 (72%) patients), lamotrigine, carbamazepine and oxcarbazepine provide the best combination of seizure control and treatment failure. Lamotrigine is clinically superior to all other drugs for treatment failure but estimates suggest a disadvantage compared to carbamazepine for time to 12 month remission [Hazard Ratio (95% Confidence Interval) = 0.87(0.73 to 1.04)] and time to first seizure [1.29(1.13 to 1.48)]. Phenobarbitone may delay time to first seizure [0.77(0.61 to 0.96)] but at the expense of increased treatment failure [1.60(1.22 to 2.10)]. For generalized onset tonic clonic seizures (1790 (28%) patients) estimates suggest valproate or phenytoin may provide the best combination of seizure control and treatment failure but some uncertainty remains about the relative effectiveness of other drugs., Conclusion: For patients with partial onset seizures, results favour carbamazepine, oxcarbazepine and lamotrigine. For generalized onset tonic clonic seizures, results favour valproate and phenytoin.

Background: Retention time (time to treatment failure) is a commonly used outcome in antiepileptic drug (AED) studies., Methods: Two datasets are used to demonstrate the issues in a competing risks analysis of AEDs. First, data collection and follow-up considerations are discussed with reference to information from 15 monotherapy trials. Recommendations for improved data collection and cumulative incidence analysis are then illustrated using the SANAD trial dataset. The results are compared to the more common approach using standard survival analysis methods., Results: A non-significant difference in overall treatment failure time between gabapentin and topiramate (logrank test statistic = 0.01, 1 degree of freedom, p-value = 0.91) masked highly significant differences in opposite directions with gabapentin resulting in fewer withdrawals due to side effects (Gray's test statistic = 11.60, 1 degree of freedom, p = 0.0007) but more due to poor seizure control (Gray's test statistic = 14.47, 1 degree of freedom, p-value = 0.0001). The significant difference in overall treatment failure time between lamotrigine and carbamazepine (logrank test statistic = 5.6, 1 degree of freedom, p-value = 0.018) was due entirely to a significant benefit of lamotrigine in terms of side effects (Gray's test statistic = 10.27, 1 degree of freedom, p = 0.001)., Conclusion: Treatment failure time can be measured reliably but care is needed to collect sufficient information on reasons for drug withdrawal to allow a competing risks analysis. Important differences between the profiles of AEDs may be missed unless appropriate statistical methods are used to fully investigate treatment failure time. Cumulative incidence analysis allows comparison of the probability of failure between two AEDs and is likely to be a more powerful approach than logrank analysis for most comparisons of standard and new anti-epileptic drugs.