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Summary: After more than 120 hand‐upper extremity and 37 face transplant procedures performed worldwide, vascularized composite allotransplantation (VCA) now falls under the scope of organ transplant legislation in Europe and the United States. While in the USA, VCA has been considered as standard care since 2014, VCA in Europe is still performed through clinical research trials, except in United Kingdom. However, after two decades of favourable experience with upper extremity transplantation (UET), professionals in Europe are proposing hand allotransplantation as "controlled standard" care, as opposed to face transplantation (FT), which is still a challenging activity. The European Committee on Organ Transplantation (CD‐P‐TO) has elaborated a position paper to provide recommendations concerning regulatory aspects for UET and FT. It is aimed at Health Authorities in charge of the oversight – and coordination – of organ donation and transplantation, and at professional groups to help them manage such complex and costly programs dedicated to properly selected patients. [ABSTRACT FROM AUTHOR]

Background: Stroke survivors with aphasia want to improve their everyday talking (discourse). In current UK practice, 90% of speech and language therapists believe discourse assessment and treatment is part of their role but are hampered by barriers in resources, time and expertise. There is a clinical need for well-articulated discourse assessment and treatments. LUNA is a multi-level treatment targeting words, sentences and discourse macrostructure in personal stories that addresses this clinical need. Objectives: This study aimed to assess the feasibility and acceptability of LUNA trial procedures in a randomised waitlist-controlled trial; and to evaluate preliminary efficacy. Methods: This paper reports a phase II, waitlist-controlled, proof-of-concept feasibility trial. Participants with chronic aphasia (n = 28) were recruited from the community and randomised to an Immediate (n = 14) or Delayed (n = 14) group. LUNA treatment was delivered twice weekly for 10 weeks via the videoconferencing technology, Zoom. Feasibility was assessed in terms of participant recruitment and retention, adherence, missing data, and treatment fidelity. Preliminary treatment efficacy was assessed in terms of between group differences in outcome measures relating to discourse, language, and psychosocial state. Results: The remote LUNA trial was feasible: 85% of those eligible consented to the trial; trial retention was 86%; 87% of treatment sessions were delivered as scheduled, and 79% of participants completed 80%+ of the treatment programme; data was missing only for participants who withdrew; treatment fidelity was high at 92% adherence; and only one clinical outcome measure demonstrated ceiling effects. ANCOVA analysis of the clinical outcome measures revealed group differences with medium and large effect sizes, indicating, improvements in the production of words, sentences, discourse macrostructure, overall language functioning (WAB-R), and psychosocial state (VAMS) following LUNA treatment. For most outcomes measured, similar treatment benefits were suggested in a secondary, non-parametric analysis. Conclusions: Large-scale evaluation of the clinical efficacy and cost-effectiveness of LUNA is warranted and supported by these findings. Trial registration: Clinical trials registration: NCT05847023 (clinical trials.gov). [ABSTRACT FROM AUTHOR]

Objective: This paper presents the findings of a study evaluating the effectiveness, accessibility, sustainability and patient satisfaction of the Assessment PLUS model. This model aimed to reduce patients' symptomology, improve their functioning and alleviate the demand on Psychological Therapies Team (PTT) staff, particularly in response to the challenges posed by the COVID‐19 pandemic. Methods: The intervention was offered to 55 patients with mild‐to‐moderate mental health conditions across three localities in Lanarkshire, UK, of whom only 25 completed the sessions. Clinical outcome measure scores, patients' feedback, wait times, discharge, returning patients and re‐referral rates were analysed using a mixed methods approach. Results: The results of the statistical analysis highlight a statistically significant improvement (p < 0.001) in patients' presentations and results of the thematic analysis reveal that almost all patients found the intervention helpful and returned overall positive feedback. On completing the intervention, less than a third of patients returned to the waiting list, while more than half were discharged completely. At the 6‐month follow‐up, those returning to the PTT waitlists (n = 12) had between 6 and 8 sessions on average, while over the 80% of those discharged from A+ did not require further psychological input. The average wait time across the full sample was 6 weeks. Conclusions: In summary, the results of the mixed methods analysis demonstrate a significant improvement in patients' presentations after completing the A+ intervention. The majority of patients found the intervention helpful and provided positive feedback. Moreover, a significant proportion of patients were discharged completely, and those who returned to the PTT waitlists required fewer sessions on average. The average wait time for the full sample was just over 6 weeks. [ABSTRACT FROM AUTHOR]

Thousands of clinical trials are conducted globally each year. Yet, little is known about their environmental impact. This paper presents the results of a high-level literature review of the carbon footprint of clinical trials. Five papers were identified and their contents summarised qualitatively. All papers were authored by UK researchers. Carbon footprint metrics from 14 trials were presented in carbon dioxide equivalents (CO2e). Emissions were broken down by three broadly defined clinical trial activities: operations, travel, and supplies. Recommen - dations for carbon reduction are discussed. The review showed a dearth of publications on greenhouse gas emissions generated by clinical trials. More work in this area is needed to achieve sustainable, low carbon clinical research. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment. This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within approximately 24-48 h of their test result.Methods: A multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (approximately within 24-48 h of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology.Results: Prior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1013 recruits to PRINCIPLE at the start of October 2020 to 2802 recruits by 20 December 2020. Whilst procedural caveats were identified by the public consultation, out of 2639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached.Conclusions: This paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness. This approach increased recruitment and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions.Trial Registration: PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research. EudraCT number: 2020-001209-22 . 26/03/2020 ISRCTN registry: ISRCTN86534580 . 20/03/2020 REC number: 20/SC/058 IRAS number: 281958. [ABSTRACT FROM AUTHOR]

Background: Dysarthria after stroke is when speech intelligibility is impaired, and this occurs in half of all stroke survivors. Dysarthria often leads to social isolation, poor psychological well-being and can prevent return to work and social lives. Currently, a variety of outcome measures are used in clinical research and practice when monitoring recovery for people who have dysarthria. When research studies use different measures, it is impossible to compare results from trials and delays our understanding of effective clinical treatments. The aim of this study is to develop a core outcome set (COS) to agree what aspects of speech recovery should be measured for dysarthria after stroke (COS-Speech) in research and clinical practice. Methods: The COS-Speech study will include five steps: (1) development of a long list of possible outcome domains of speech that should be measured to guide the survey; (2) recruitment to the COS-Speech study of three key stakeholder groups in the UK and Australia: stroke survivors, communication researchers and speech and language therapists/pathologists; (3) two rounds of the Delphi survey process; (4) a consensus meeting to agree the speech outcomes to be measured and a follow-up consensus meeting to match existing instruments/measures (from parallel systematic review) to the agreed COS-Speech; (5) dissemination of COS-Speech. Discussion: There is currently no COS for dysarthria after stroke for research trials or clinical practice. The findings from this research study will be a minimum COS, for use in all dysarthria research studies and clinical practice looking at post-stroke recovery of speech. These findings will be widely disseminated using professional and patient networks, research and clinical forums as well as using a variety of academic papers, videos, accessible writing such as blogs and links on social media. Trial registration: COS-Speech is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database, October 2021 https://www.comet-initiative.org/Studies/Details/1959. In addition, "A systematic review of the psychometric properties and clinical utility of instruments measuring dysarthria after stroke" will inform the consensus meeting to match measures to COS-Speech. The protocol for the systematic reviews registered with the International Prospective Register of Systematic Reviews. PROSPERO registration number: CRD42022302998. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics which include the gastroscopy rate in general practitioner practice populations in Great Britain, randomised prospective trial of transnasal and standard upper diagnostic endoscopy under local anesthetic, and guidelines on the endoscopic assessment of gastric polyps.

The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home.Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK.The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring.Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future.The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use. [ABSTRACT FROM AUTHOR]

Summary: Over a decade ago, bibliometric analysis predicted the disappearance of UK publishing in anaesthesia by 2020. We repeated this analysis to assess if this had turned out to be the case, searching PubMed for papers associated with UK consultant anaesthetists for 2017–2019 across 15 journals. Although the rate of decline has flattened using the same search filter, including a wider range of publication types shows that outputs still remain at half 1990s levels (381 papers for all 3 years combined), authored by 769 anaesthetists, 274 of whom are associated with an academic centre. There are now 11 identifiable academic units, and a further 15 places where anaesthetists have affiliations with academic centres as individuals. The majority of papers (71%) are in secondary analysis (observational, database and association studies, surveys and meta‐analyses), rather than in primary research (clinical trials or laboratory studies). These data reflect the current academic capacity in terms of publications, academic units and staffing. We discuss how this information can be used to inform a new strategy for UK academic anaesthesia. [ABSTRACT FROM AUTHOR]

The UK neurosurgical community has a track record of delivering high-quality, practice-changing clinical research studies, facilitated by a robust clinical research infrastructure and close collaborations between neurosurgical centers. More recently, these large-scale studies have been conceived, developed, and delivered by neurosurgical trainees, working under the umbrella of the British Neurosurgical Trainee Research Collaborative (BNTRC). In this paper, we outline the current landscape of large-scale neurosurgical studies in the UK, focusing on the role of trainees in facilitating this research. Importantly, we focus on our experience of trainee-led studies, including the development of the network, current challenges, and future directions. We believe that a similar model can be applied in different settings and countries, which will drive up the quality of neurosurgical research, ultimately benefiting future neurosurgical patients. [ABSTRACT FROM AUTHOR]

Background: The E-Freeze trial is a multi-centre randomised controlled trial of fresh versus frozen embryo transfer for women undergoing in vitro fertilisation. This paper describes the statistical analysis plan for the E-Freeze trial.Methods and Design: E-Freeze is a two-arm parallel-group, multi-centre, individually randomised controlled trial to determine if a policy of freezing embryos, followed by thawed frozen embryo transfer, results in a higher healthy baby rate when compared with the current policy of transferring fresh embryos. Couples undergoing their first, second or third cycle of in vitro fertilisation at fertility centres in the UK were randomised to either fresh or frozen embryo transfer. The primary outcome is a healthy baby, defined as a live singleton baby born at term with an appropriate weight for gestation. This paper describes the statistical analysis plan for the trial, including the analysis principles, definitions of outcomes, methods for primary analysis, pre-specified subgroup analysis and sensitivity analysis. This plan was finalised prior to completion of recruitment to the trial.Trial Registration: ISRCTN registry: ISRCTN61225414 . Registered on 29 December 2015. [ABSTRACT FROM AUTHOR]

Physical inactivity has been identified as a leading risk factor for premature mortality globally, and adolescents, in particular, have low physical activity levels. Schools have been identified as a setting to tackle physical inactivity. Economic evidence of school-based physical activity programmes is limited, and the costs of these programmes are not always collected in full. This paper describes a micro-costing and cost-consequence analysis of the ‘Girls Active’ secondary school-based programme as part of a cluster randomised controlled trial (RCT). Micro-costing and cost-consequence analyses were conducted using bespoke cost diaries and questionnaires to collect programme delivery information. Outcomes for the cost-consequence analysis included health-related quality of life measured by the Child Health Utility-9D (CHU-9D), primary care General Practitioner (GP) and school-based (school nurse and school counsellor) service use as part of a cluster RCT of the ‘Girls Active’ programme. Overall, 1,752 secondary pupils were recruited and a complete case sample of 997 participants (Intervention n = 570, Control n = 427) was used for the cost-consequence analysis. The micro-costing analysis demonstrated that, depending upon how the programme was delivered, ‘Girls Active’ costs ranged from £1,054 (£2 per pupil, per school year) to £3,489 (£7 per pupil, per school year). The least costly option was to absorb ‘Girls Active’ strictly within curriculum hours. The analysis demonstrated no effect for the programme for the three main outcomes of interest (health-related quality of life, physical activity and service use).Micro-costing analyses demonstrated the costs of delivering the ‘Girls Active’ programme, addressing a gap in the United Kingdom (UK) literature regarding economic evidence from school-based physical activity programmes. This paper provides recommendations for those gathering cost and service use data in school settings to supplement validated and objective measures, furthering economic research in this field. Trial registration: -ISRCTN, . [ABSTRACT FROM AUTHOR]

Background: Melanoma incidence has quadrupled since 1970 and melanoma is now the second most common cancer in individuals under 50. Targeted immunotherapies for melanoma now potentially enable long-term remission even in advanced melanoma, but these melanoma survivors require ongoing surveillance, with implications for NHS resources and significant social and psychological consequences for patients. Total skin self-examination (TSSE) can detect recurrence earlier and improve clinical outcomes but is underperformed in the UK. To support survivors, the Achieving Self-directed Integrated Cancer Aftercare (ASICA) intervention was developed to prompt and improve TSSE performance, with subsequent reporting of concerns and submission of skin photos to a Dermatology Nurse Practitioner (DNP). ASICA was delivered as a randomized pilot trial.Methods: This paper reports on process evaluation. Data on participants' demographics and the concerns they reported during the trial were tabulated and displayed using Microsoft Excel and SPSS. We explored which participants used ASICA, and how frequently, to report any skin concerns. We also determined how the interactions had worked in terms of quality of skin photographs submitted, clinical assessments made by the DNP, and the assessments and decisions made for each concern. Finally, we explored significant events occurring during the trial. Data on participants' demographics and the concerns they reported during the trial were tabulated and displayed using SPSS. A semi-structured interview was undertaken with the DNP to gain perspective on the range of concerns presented and how they were resolved.Results: Of 121 recruited melanoma patients receiving ASICA for 12 months, 69 participants submitted a total of 123 reports detailing 189 separate skin-related concerns and including 188 skin photographs. Where participants fully complied with follow-up by the DNP, concerns were usually resolved remotely, but 19 (10.1%) were seen at a secondary care clinic and 14 (7.4%) referred to their GP. 49 (25.9%) of concerns were not completely resolved due to partial non-compliance with DNP follow-up.Conclusion: Melanoma patients randomized to the ASICA intervention were able to report skin-related concerns that could be resolved remotely through interaction with a DNP. Feasibility issues highlighted by ASICA will support further development and optimization of this digital tool.Trial Registration: Clinical Trials.gov , NCT03328247 . Registered on 1 November 2017. [ABSTRACT FROM AUTHOR]

Background: Advancing physical therapy interventions for children and young people is a high research priority. This includes research to describe and specify the control condition, typically 'current care', for effectiveness trials. This paper aims to identify physical therapy outcomes commonly targeted, and intervention techniques and approaches commonly used, by physiotherapists working with children (aged 2–19 years) with mobility limitations in the United Kingdom. Methods: A cross‐sectional survey. Participants were recruited through the interactive Chartered Society of Physiotherapy members‐only online discussion forum, the Association of Paediatric Chartered Physiotherapists, direct emails and snowball sampling within the authors' professional networks and Twitter. Data were collected using a structured online questionnaire and analysed using descriptive statistics. Results: We received 146 responses, 95/146 (65.1%) of which were fully complete. Therapists reported targeting 367 unique outcome constructs, of which 193 (52.6%) mapped onto activities and participation (e.g. moving around using equipment, maintaining body position and walking), 158 (43.1%) on body functions (e.g. muscle strength, joint mobility and gait functions), 11 (3.0%) on body structure (e.g. muscle length) and 3 (0.8%) on environmental factors (e.g. access home environment, access school environment and family confidence). The most commonly used interventions related to postural management (115/133 of respondents, 86.4%) and exercise therapy (116/137, 84.67%) and included techniques such as 'use equipment' (118/137, 86.1%), 'instruct how to do something' (117/137, 85.4%), 'practice' (105/137, 76.6%) and 'stretch' (99/137, 72.3%). Conclusions: In designing trials, current care can be described as a combination of biomechanical and physiological techniques and approaches targeted at body functions and through that to activity and participation. Although some environmental behaviour change techniques and strategies were reported, the explicit use of these in current care appears limited. [ABSTRACT FROM AUTHOR]

Background: Routinely collected electronic health records (EHRs) have the potential to enhance randomised controlled trials (RCTs) by facilitating recruitment and follow-up. Despite this, current EHR use is minimal in UK RCTs, in part due to ongoing concerns about the utility (reliability, completeness, accuracy) and accessibility of the data. The aim of this manuscript is to document the process, timelines and challenges of the application process to help improve the service both for the applicants and data holders.Methods: This is a qualitative paper providing a descriptive narrative from one UK clinical trials unit (MRC CTU at UCL) on the experience of two trial teams' application process to access data from three large English national datasets: National Cancer Registration and Analysis Service (NCRAS), National Institute for Cardiovascular Outcomes Research (NICOR) and NHS Digital to establish themes for discussion. The underpinning reason for applying for the data was to compare EHRs with data collected through case report forms in two RCTs, Add-Aspirin (ISRCTN 74358648) and PATCH (ISRCTN 70406718).Results: The Add-Aspirin trial, which had a pre-planned embedded sub-study to assess EHR, received data from NCRAS 13 months after the first application. In the PATCH trial, the decision to request data was made whilst the trial was recruiting. The study received data after 8 months from NICOR and 15 months for NHS Digital following final application submission. This concluded in May 2020. Prior to application submission, significant time and effort was needed particularly in relation to the PATCH trial where negotiations over consent and data linkage took many years.Conclusions: Our experience demonstrates that data access can be a prolonged and complex process. This is compounded if multiple data sources are required for the same project. This needs to be factored in when planning to use EHR within RCTs and is best considered prior to conception of the trial. Data holders and researchers are endeavouring to simplify and streamline the application process so that the potential of EHR can be realised for clinical trials. [ABSTRACT FROM AUTHOR]

This paper examines the introduction to Britain of the Gräfenberg ring, an early version of what later became known as an intrauterine device (IUD). The struggle during the interwar years to establish the value of the ring provides an opportunity for a case study of the evaluation and acceptance of a new medical device. With the professionalization of the birth control movement and the expansion of birth control clinics in interwar Britain, efforts to develop better scientific means for contraception grew rapidly. At the end of the nineteenth century, methods for controlling fertility ranged from coitus interruptus and abstinence, to diverse substances ingested or placed into the vagina, to barrier methods. The first decades of the twentieth century brought early work on chemical contraceptives as well as a number of new intrauterine devices, among them the Gräfenberg ring. Developing a cheap, reliable, and widely acceptable contraceptive became a pressing goal for activists in the voluntary birth control movement in Britain between the wars. Yet, tensions developed over the best form of contraception to prescribe. By situating the Gräfenberg ring within the context of the debates and competition among British medical and birth control professionals, this paper reveals broader issues of power relationships and expertise in the assessment of a new medical technology. [ABSTRACT FROM AUTHOR]

Background: Trial oversight is important for trial governance and conduct. Patients and/or lay members of the public are increasingly included in trial oversight committees, influenced by international patient and public involvement (PPI) initiatives to improve the quality and relevance of research. However, there is a lack of guidance on how to undertake PPI in trial oversight and tokenistic PPI remains an issue. This paper explores how PPI functions in existing trial oversight committees and provides recommendations to optimise PPI in future trials. This was part of a larger study investigating the role and function of oversight committees in trials facing challenges.Methods: Using an ethnographic study design, we observed oversight meetings of eight UK trials and conducted semi-structured interviews with members of their trial steering committees (TSCs) and trial management groups (TMGs) including public contributors, trial sponsors and funders. Thematic analysis of data was undertaken, with findings integrated to provide a multi-perspective account of how PPI functions in trial oversight.Results: Eight TSC and six TMG meetings from eight trials were observed, and 66 semi-structured interviews conducted with 52 purposively sampled oversight group members, including three public contributors. PPI was reported as beneficial in trial oversight, with public members contributing a patient voice and fulfilling a patient advocacy role. However, public contributors were not always active at oversight meetings and were sometimes felt to have a tokenistic role, with trialists reporting a lack of understanding of how to undertake PPI in trial oversight. To optimise PPI in trial oversight, the following areas were highlighted: the importance of planning effective strategies to recruit public contributors; considering the level of oversight and stage(s) of trial to include PPI; support for public contributors by the trial team between and during oversight meetings.Conclusions: We present evidence-based recommendations to inform future PPI in trial oversight. Consideration should be given at trial design stage on how to recruit and involve public contributors within trial oversight, as well as support and mentorship for both public contributors and trialists (in how to undertake PPI effectively). Findings from this study further strengthen the evidence base on facilitating meaningful PPI within clinical trials. [ABSTRACT FROM AUTHOR]

Background: The incidence of chronic subdural haematoma (CSDH) is increasing. Although surgery remains the mainstay of management for symptomatic patients, uncertainty remains regarding the role of steroids. Hence, the Dex-CSDH trial was launched in the UK in 2015 aiming to determine whether, compared to placebo, dexamethasone can improve the 6-month functional outcome of patients with symptomatic CSDH by reducing the rate of surgical intervention and recurrence rate.Methods and Design: Dex-CSDH is a multi-centre, pragmatic, parallel group, double-blind, randomised trial assessing the clinical utility of a 2-week course of dexamethasone following a CSDH. Seven hundred fifty patients were randomised to either dexamethasone or placebo. The primary outcome is the modified Rankin Scale at 6 months which is dichotomised to favourable (a score of 0-3) versus unfavourable (a score of 4-6).Conclusions: This paper and the accompanying additional material describe the statistical analysis plan for the trial.Trial Registration: ISRCTN, ISRCTN80782810. Registered on 7 November 2014. http://www.isrctn.com/ISRCTN80782810. EudraCT, 2014-004948-35. Registered on 20 March 2015. [ABSTRACT FROM AUTHOR]

This paper examines the role of clinical trials in regenerative medicine innovation, exploring how trials have contributed to translational challenges in the field. Using data from an ethnographic study of UK cell therapy trials I interrogate the institutional framework for clinical trials and the identity-making of trialists. This analysis uncovers a disconnect between a commercially-aligned regulatory framework and a clinical-academic identity apparent in the majority of current trialling activity. These different pathways appear to represent two distinct sociotechnical imaginaries for cell therapies; one which reflects the assumptions of commercial innovation and prioritizes economic success, and another which embodies the cultural expectations of academia and emphasizes the importance of clinical care. These two imaginaries operate in synergy to some extent but there are significant tensions between them. How and to what extent these tensions are reconciled is likely to determine both the long-term success and the future shape of the field. [ABSTRACT FROM AUTHOR]

International efforts to minimize coercive practices include the US Six Core Strategies© (6CS). This innovative approach has limited evidence of its effectiveness, with few robustly designed studies, and has not been formally implemented or evaluated in the UK. An adapted version of the 6CS, which we called 'REsTRAIN Yourself' (RY), was devised to suit the UK context and evaluated using mixed methods. RY aimed to reduce the use of physical restraint in mental health inpatient ward settings through training and practice development with whole teams, directly in the ward settings where change was to be implemented and barriers to change overcome. In this paper, we present qualitative findings that report on staff perspectives of the impact and value of RY following its implementation. Thirty‐six staff participated in semi‐structured interviews with data subject to thematic analysis. Eight themes are reported that highlight perceived improvements in every domain of the 6CS after RY had been introduced. Staff reported more positively on their relationships with service users and felt their attitudes towards the use of coercive practices such as restraint were changed; the service as a whole shifted in terms of restraint awareness and reduction; and new policies, procedures, and language were introduced despite certain barriers. These findings need to be appreciated in a context wherein substantial reductions in the use of physical restraint were proven possible, largely due to building upon empathic and relational alternatives. However, yet more could be achieved with greater resourcing of inpatient care. [ABSTRACT FROM AUTHOR]

Aim: Neurodevelopment is a key outcome for many childhood trials and observational studies. Clinically important decisions may rest on finding relatively small differences in neurodevelopment between groups receiving complex and costly interventions. Our purpose was to determine whether studies which measure neurodevelopment report the numbers, training, and auditing of assessors and, for multiple assessor studies, whether the results were adjusted and if so by which method?Method: Electronic searches were conducted using Medline, Embase, Cinahl, PsycINFO, and the Cochrane Library. A study was eligible if it reported neurodevelopmental outcome in children resident in the UK, less than or equal to 18 years and was published between 2000 and 2015. Trials and observational studies were included.Results: Three hundred and seven full papers were reviewed: 52% of papers did not report the number of assessors used; 21% used a single assessor; and 27% used multiple assessors. Thirty-five per cent mentioned that assessors were trained in the use of the neurodevelopmental tool; 13% of assessors were audited; and only 1% of studies adjusted statistically for the number of assessors.Interpretation: At the very least, the quality of reporting the use of assessors in these research publications is poor, while at worst, the variability of assessors may mask the true relationship between an intervention/observation and neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The Association of Coloproctology of Great Britain and Ireland (ACPGBI) Delphi process identified prevention and treatment of parastomal hernia (PSH) as the second highest priority non‐cancer related colorectal pathology. This position statement aims to summarize the current evidence base. Methods: Four broad themes were identified (prevention, diagnosis/classification, management and operative repair). Guidelines are based on evidence from an extensive literature review using organized searches on the PubMed, MEDLINE, Embase and Cochrane databases. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adhered to for classifying the quality of evidence and reporting the strength of recommendations. Results: The suture repair of PSH other than for patients in extremis is not recommended. Synthetic non‐absorbable mesh can be used safely in the short term in the construction of colostomies post rectal surgery, but longer‐term follow‐up is needed. Other broad recommendations are made around access to stoma care nurses, prevention classification and management. Conclusion: There is a lack of high quality evidence for many domains in the prevention and treatment of PSH but the results of several studies are awaited. What does this paper add to the literature?: Parastomal hernias are a common and debilitating condition following stoma formation. This position statement from ACPGBI details the current evidence base and ongoing research for the prevention, diagnosis and management of parastomal hernias. [ABSTRACT FROM AUTHOR]

Clinical trials are typically conducted over a population within a defined time period in order to illuminate certain characteristics of a health issue or disease process. Cross-sectional studies provide a snapshot of these disease processes over a large number of people but do not allow us to model the temporal nature of disease, which is essential for modelling detailed prognostic predictions. Longitudinal studies, on the other hand, are used to explore how these processes develop over time in a number of people but can be expensive and time-consuming, and many studies only cover a relatively small window within the disease process. This paper explores the application of intelligent data analysis techniques for building reliable models of disease progression from both cross-sectional and longitudinal studies. The aim is to learn disease 'trajectories' from cross-sectional data by building realistic trajectories from healthy patients to those with advanced disease. We focus on exploring whether we can 'calibrate' models learnt from these trajectories with real longitudinal data using Baum-Welch re-estimation so that the dynamic parameters reflect the true underlying processes more closely. We use Kullback-Leibler distance and Wilcoxon rank metrics to assess how calibration improves the models to better reflect the underlying dynamics. [ABSTRACT FROM AUTHOR]

Background: There is little published guidance as to the sample size required for a pilot or feasibility trial despite the fact that a sample size justification is a key element in the design of a trial. A sample size justification should give the minimum number of participants needed in order to meet the objectives of the trial. This paper seeks to describe the target sample sizes set for pilot and feasibility randomised controlled trials, currently running within the United Kingdom. Methods: Data were gathered from the United Kingdom Clinical Research Network (UKCRN) database using the search terms 'pilot' and 'feasibility'. From this search 513 studies were assessed for eligibility of which 79 met the inclusion criteria. Where the data summary on the UKCRN Database was incomplete, data were also gathered from: the International Standardised Randomised Controlled Trial Number (ISRCTN) register; the clinicaltrials.gov website and the website of the funders. For 62 of the trials, it was necessary to contact members of the research team by email to ensure completeness. Results: Of the 79 trials analysed, 50 (63.3%) were labelled as pilot trials, 25 (31.6%) feasibility and 14 were described as both pilot and feasibility trials. The majority had two arms (n = 68, 86.1%) and the two most common endpoints were continuous (n = 45, 57.0%) and dichotomous (n = 31, 39.2%). Pilot trials were found to have a smaller sample size per arm (median = 30, range = 8 to 114 participants) than feasibility trials (median = 36, range = 10 to 300 participants). By type of endpoint, across feasibility and pilot trials, the median sample size per arm was 36 (range = 10 to 300 participants) for trials with a dichotomous endpoint and 30 (range = 8 to 114 participants) for trials with a continuous endpoint. Publicly funded pilot trials appear to be larger than industry funded pilot trials: median sample sizes of 33 (range = 15 to 114 participants) and 25 (range = 8 to 100 participants) respectively. Conclusion: All studies should have a sample size justification. Not all studies however need to have a sample size calculation. For pilot and feasibility trials, while a sample size justification is important, a formal sample size calculation may not be appropriate. The results in this paper describe the observed sample sizes in feasibility and pilot randomised controlled trials on the UKCRN Database. [ABSTRACT FROM AUTHOR]

The medicines regulatory environment is evolving rapidly in response to the changing environment. Advances in science and technology have led to a vast field of increasingly complicated pharmaceutical and medical device products; increasing globalization of the pharmaceutical industry, advances in digital technology and the internet, changing patient populations, and shifts in society also affect the regulatory environment. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood products to protect and improve public health, and supports innovation through scientific research and development. It works closely with other bodies in a single medicines network across Europe and takes forward UK health priorities. This paper discusses the range of initiatives in the UK and across Europe to support innovation in medicines regulation. The MHRA leads a number of initiatives, such as the Innovation Office, which helps innovators to navigate the regulatory processes to progress their products or technologies; and simplification of the Clinical Trials Regulations and the Early Access to Medicines Scheme, to bring innovative medicines to patients faster. The Accelerated Access Review will identify reforms to accelerate access for National Health Service patients to innovative medicines and medical technologies. PRIME and Adaptive Pathways initiatives are joint endeavours within the European regulatory community. The MHRA runs spontaneous reporting schemes and works with INTERPOL to tackle counterfeiting and substandard products sold via the internet. The role of the regulator is changing rapidly, with new risk-proportionate, flexible approaches being introduced. International collaboration is a key element of the work of regulators, and is set to expand. [ABSTRACT FROM AUTHOR]

Background: In healthcare research the randomised controlled trial is seen as the gold standard because it ensures selection bias is minimised. However, there is uncertainty as to which is the most preferred method of randomisation in any given setting and to what extent more complex methods are actually being implemented in the field. Methods: In this paper we describe the results of a survey of UK academics and publicly funded researchers to examine the extent of the use of various methods of randomisation in clinical trials. Results: Trialists reported using simple randomisation, permuted blocks and stratification more often than more complex methods such as minimisation. Most trialists believed that simple randomisation is suitable for larger trials but there is a high probability of possible imbalance between treatment groups in small trials. It was thought that groups should be balanced at baseline to avoid imbalance and help face-validity. However, very few respondents considered that more complex methods offer any advantages. Conclusions: This paper demonstrates that for most UK trialists the preferred method of randomisation is using permuted blocks of varying random length within strata. This method eliminates the problem of predictability while maintaining balance across combinations of factors. If the number of prognostic factors is large, then minimisation can be used to provide treatment balance as well as balance over these factors. However, only those factors known to affect outcome should be considered. [ABSTRACT FROM AUTHOR]

Background: Public involvement is health research policy in the UK and internationally. There is a need to establish a robust evidence base on the impact of public involvement on research processes and outcomes. Purpose: To review examples of public involvement in the design and conduct of clinical trials, to synthesise the contributions of the public, as well as the identified tensions and facilitating strategies. Method: Systematic literature search and narrative review. Results: Nine papers were identified, covering the following topics: breast-feeding, antiretroviral and nutrition interventions; paediatric resuscitation; exercise and cognitive behavioural therapy; breast cancer; stroke; chronic suppurative otitis media; Paget's disease; and shared decision-making in patient consultations. Six papers reported on public involvement at the trial design stage, while three reported on public involvement at the design and conduct stages of clinical trials. It was found that the public contributed at the consultation, collaboration and publicly-led levels of involvement. Four main public contributions to trial design were identified: review of consent procedures and patient information sheets; suggestion of additional trial outcomes; review of trial data collection procedures; and recommendations on the timing and location of follow-up data collection. Two main contributions that the public made to the conduct of trials were identified: scrutiny of the conduct of the trial through membership of the Trial Steering Committee; and delivering the trial protocol after completing relevant training. Numerous tensions and facilitating strategies were identified. Limitations: Papers on public involvement in the design and conduct of clinical trials may have been overlooked due to the difficulty of searching for, and identifying, papers in this area. Only English publications were searched for and the review focused on evidence in peer-reviewed journal articles only. Conclusions: The issues raised here should assist researchers in developing and conducting clinical trials with the involvement of the public. [ABSTRACT FROM AUTHOR]

PRINCE2, which stands for Projects in Controlled Environments, is a project management method covering the organisation, management, and control of projects and is widely used in both government and commercial IT and building projects in the UK. This paper describes the application of PRINCE2 to the management of large clinical trials (specifically, of a Phase III trial of a candidate microbicide to prevent vaginally acquired HIV infection). It reviews the challenge of ensuring that the project management tools add value to the project overall and are not perceived as an overly administrative burden. It reviews the requirement for high level summary reports for use by an executive committee and funding bodies, highlighting the reasons for taking this approach -- in particular, not only to manage the science, but to link expenditure to activities at geographically separate trial sites and to key performance indicators, and to provide tools for monitoring risks and possible re-alignment of budgets to reflect changing activities and outputs by collaborators. The paper considers the wider costs and benefits to researchers and funders of taking this approach and explores implications for research administrators and managers at institutions involved in large, complex collaborative research projects, whether clinical or not. [ABSTRACT FROM AUTHOR]

In recent years lung cancer specialists have complained that due to stigma resulting from the association of the disease with smoking, theirs is a neglected field. This paper demonstrates that in the 1950s and 1960s, when the British Medical Research Council (MRC) started to organize clinical trials for various forms of cancer, this was not the case. Rather, the organizers of these trials saw lung cancer as a particularly promising object of research, for much was known about the disease. The cancer trials were part of a strategy to use the Randomized Controlled Trial (RCT) technology to cement the role of the MRC as the dominant body overseeing medical research in Britain. The organization of the trials, however, turned out to be very difficult, due to ethical problems and the dominance of one form of therapy, surgery. The trial results were deeply disappointing. I argue that these frustrating results contributed to the notion of hopelessness that has come to surround lung cancer, and to the shift of focus from cure to prevention that was triggered by epidemiologic studies identifying tobacco smoke as the main cause of the disease. The paper deals with an important episode in the history of clinical cancer research in postwar Britain, illustrating the ethical and practical problems faced by the organizers. [ABSTRACT FROM AUTHOR]

This paper considers the assessment of the impact of a community-based randomized controlled trial to reduce repeat deliberate self-harm. It considers the drawbacks in simplistic applications of conventional significance testing procedures, as well as possible failures regarding the statistical assumptions underlying such tests. Instead, the paper considers how relevant prior information might be incorporated within a fully Bayesian-model-based assessment procedure. The model includes a latent trait approach to patient morbidity; controlling for morbidity and other patient characteristics enhances the impact of the intervention (measured by a hazard rate ratio). If allowance is made for external information (e.g. ethical approval of the treatment), the weight of evidence shifts towards a positive intervention effect. [ABSTRACT FROM AUTHOR]

The first paper in this section is a review by several highly respected authors of diagnostic criteria for evaluating patients with symptomatic stress urinary incontinence, and is followed by a review of the role of urgency and its measurement in the overactive bladder symptom syndrome, with emphasis on current concepts and future prospects. These are two important papers, which point the reader in the direction of a greater understanding of these conditions.The concept ofα-blockade before a trial without catheter after acute urinary retention is revisited by authors from the UK, who used tamsulosin in a randomized controlled trial. They found that it is appropriate to recommend tamsulosin for such use in this condition. [ABSTRACT FROM AUTHOR]

Randomised controlled trials (RCTs) are considered to be the gold standard in evaluating medical interventions; however, people from ethnic minorities are frequently under-represented in such studies. The present paper addresses a previously neglected debate about the tensions which inform clinical trial participation amongst people from ethnic minorities, in particular, South Asians, the largest ethnic minority group in the UK. In a narrative review of the available literature, based mainly on US studies, the present authors aim to make sense of the issues around under-representation by providing a theoretical reconciliation. In addition, they identify a number of potential barriers to ethnic minority participation in clinical trials. In so doing, the authors recognise that the recent history of eugenic racism, and more general views on clinical trials as a form of experimentation, means that clinical trial participation among people from ethnic minorities becomes more problematic. Lack of participation and the importance of representational sampling are also considered, and the authors argue that health professionals need to be better informed about the issues. The paper concludes by offering a number of strategies for improving ethnic minority accrual rates in clinical trials, together with priorities for future research. [ABSTRACT FROM AUTHOR]

In this paper, the author argues that the requirement to conduct randomised clinical trials to inform policy in cases where one wants to identify a cheaper alternative to known effective but expensive interventions raises an important ethical issue. This situation will eventually arise whenever there are resource constraints, and a policy decision has been made not to fund an intervention on cost effectiveness grounds. It has been thought that this is an issue only in extremely resource poor settings. This paper gives an example from the United Kingdom illustrating that this is also a problem faced by richer countries. [ABSTRACT FROM AUTHOR]

Purpose: Chemoradiation therapy (CRT) for patients with locally advanced pancreatic cancer (LAPC) provides survival benefits but may result in considerable toxicity. Health-related quality of life (HRQL) measurements during CRT have not been widely reported. This paper reports HRQL data from the Selective Chemoradiation in Advanced Localised Pancreatic Cancer (SCALOP) trial, including validation of the QLQ-PAN26 tool in CRT.Methods and Materials: Patients with locally advanced, inoperable, nonmetastatic carcinoma of the pancreas were eligible. Following 12 weeks of induction gemcitabine plus capecitabine (GEMCAP) chemotherapy, patients with stable and responding disease were randomized to a further cycle of GEMCAP followed by capecitabine- or gemcitabine-based CRT. HRQL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC Pancreatic Cancer module (PAN26).Results: A total of 114 patients from 28 UK centers were registered and 74 patients randomized. There was improvement in the majority of HRQL scales during induction chemotherapy. Patients with significant deterioration in fatigue, appetite loss, and gastrointestinal symptoms during CRT recovered within 3 weeks following CRT. Differences in changes in HRQL scores between trial arms rarely reached statistical significance; however, where they did, they favored capecitabine therapy. PAN26 scales had good internal consistency and were able to distinguish between subgroups of patients experiencing toxicity.Conclusions: Although there is deterioration in HRQL following CRT, this resolves within 3 weeks. HRQL data support the use of capecitabine- over gemcitabine-based chemoradiation. The QLQ-PAN26 is a reliable and valid tool for use in patients receiving CRT. [ABSTRACT FROM AUTHOR]

Background: The LiGHT trial (Laser-1st versus Drops-1st for Glaucoma and Ocular Hypertension Trial) is a multicentre randomised controlled trial of two treatment pathways for patients who are newly diagnosed with open-angle glaucoma (OAG) and ocular hypertension (OHT). The main hypothesis for the trial is that lowering intraocular pressure (IOP) with selective laser trabeculoplasty (SLT) as the primary treatment ('Laser-1st') leads to a better health-related quality of life than for those started on IOP-lowering drops as their primary treatment ('Medicine-1st') and that this is associated with reduced costs and improved tolerability of treatment. This paper describes the statistical analysis plan for the study.Methods/design: The LiGHT trial is an unmasked, multi-centre randomised controlled trial. A total of 718 patients (359 per arm) are being randomised to two groups: medicine-first or laser-first treatment. Outcomes are recorded at baseline and at 6-month intervals up to 36 months. The primary outcome measure is health-related quality of life (HRQL) at 36 months measured using the EQ-5D-5L. The main secondary outcome is the Glaucoma Utility Index. We plan to analyse the patient outcome data according to the group to which the patient was originally assigned. Methods of statistical analysis are described, including the handling of missing data, the covariates used in the adjusted analyses and the planned sensitivity analyses.Trial Registration: The trial was registered with the ISRCTN register on 23/07/2012, number ISRCTN32038223 . [ABSTRACT FROM AUTHOR]

All dental practitioners must be proficient at taking a medical history, examining a clothed patient and recognising relevant clinical signs. The general examination of a patient should take into account findings from the history. This paper does not attempt to address the detailed oral and dental examination carried out by dental practitioners but focuses on the holistic patient assessment - essential for safe patient management. [ABSTRACT FROM AUTHOR]

Background A number of published economic evaluations of elective endovascular aneurysm repair ( EVAR) versus open repair for abdominal aortic aneurysm ( AAA) have come to differing conclusions about whether EVAR is cost-effective. This paper reviews the current evidence base and presents up-to-date cost-effectiveness analyses in the light of results of four randomized clinical trials: EVAR-1, DREAM, OVER and ACE. Methods Markov models were used to estimate lifetime costs from a UK perspective and quality-adjusted life-years ( QALYs) based on the results of each of the four trials. The outcomes included in the model were: procedure costs, surveillance costs, reintervention costs, health-related quality of life, aneurysm-related mortality and other-cause mortality. Alternative scenarios about complications, reinterventions and deaths beyond the trial were explored. Results Models based on the results of the EVAR-1, DREAM or ACE trials did not find EVAR to be cost-effective at thresholds used in the UK (up to £30 000 per QALY). EVAR seemed cost-effective according to models based on the OVER trial. These results seemed robust to alternative model scenarios about events beyond the trial intervals. Conclusion These analyses did not find that EVAR is cost-effective compared with open repair in the long term in trials conducted in European centres. EVAR did appear to be cost-effective based on the OVER trial, conducted in the USA. Caution must be exercised when transferring the results of economic evaluations from one country to another. [ABSTRACT FROM AUTHOR]

Background: Wound-edge protection devices (WEPDs) have been used in surgery for more than 40 years to reduce surgical site infection (SSI). No economic evaluation of WEPDs against any comparator has ever been conducted. The aim of the paper was to assess whether WEPDs are cost-effective in reducing SSI compared to standard care alone in the United Kingdom. Methods and Findings: An economic evaluation was conducted alongside the ROSSINI trial. The study perspective was that of the UK National Health Service and the time horizon was 30 days post-operatively. The study was conducted in 21 UK hospitals. 760 patients undergoing laparotomy were randomised to either WEPD or standard care and 735 were included in the primary analysis. The main economic outcome was cost-effectiveness based on incremental cost (£) per quality adjusted life year (QALY) gained. Patients in the WEPD arm accessed health care worth £5,420 on average and gained 0.02131 QALYs, compared to £5,130 and 0.02133 QALYs gained in the standard care arm. The WEPD strategy was more costly and equally effective compared to standard care, but there was significant uncertainty around incremental costs and QALYs. The findings were robust to a range of sensitivity analyses. Conclusions: There is no evidence to suggest that WEPDs can be considered a cost effective device to reduce SSI. Their continued use is a waste of limited health care resources. [ABSTRACT FROM AUTHOR]

Research applying rational-emotive behavior therapy (REBT) with athletes is sparse and findings are equivocal. REBT can be applied using education workshops, but previous studies in sport have not assessed changes in irrational beliefs following REBT. This paper reports the effects of a single REBT education workshop on irrational beliefs in elite soccer academy athletes from pretest to posttest. Statistical analyses indicate temporary reductions in irrational beliefs following the workshop. Results are discussed with reference to mechanisms of change, study limitations, workshop reflections, and recommendations for developing REBT workshops. [ABSTRACT FROM AUTHOR]

The United Kingdom Prospective Diabetes Study, and Diabetes Control and Complications Trial have shown that aggressive glucose control, especially early in the natural history of the disease, might result in a significant reduction of microvascular as well as macrovascular complications. However, more recent trials have increased the level of complexity of the relationship between 'tight glucose control/chronic complications', with several factors influencing the risk-to-benefit ratio to be considered, such as age, presence of established complications and diabetes duration. According to this strategy, a more intensive goal is desirable for young patients with no cardiovascular disease, whereas less stringent control is suitable for all people who are relatively late in the natural history of diabetic complications. Numerous calls for an individualized therapy have been proposed during the past years, but still debated is the level of glucose lowering necessary to reduce complications balanced by the risk and costs of the means used. The present paper briefly reviews the rationale and the clinical trials that support specific glycemic goals towards a 'tailored' approach for the management of hyperglycemia in diabetes. [ABSTRACT FROM AUTHOR]

Background: There is an urgent need for clinically effective and cost-effective methods to manage antisocial and criminal behaviour in adolescents. Youth conduct disorder is increasingly prevalent in the UK and is associated with a range of negative outcomes. Quantitative systematic reviews carried out for the National Institute for Health and Clinical Excellence have identified multisystemic therapy, an intensive, multimodal, home-based, family intervention for youth with serious antisocial behaviour, as one of the most promising interventions for reducing antisocial or offending behaviour and improving individual and family functioning. Previous international trials of multisystemic therapy have yielded mixed outcomes, and it is questionable to what extent positive US findings can be generalised to a wider UK mental health and juvenile justice context. This paper describes the protocol for the Systemic Therapy for At Risk Teens (START) trial, a multicentre UK-wide randomised controlled trial of multisystemic therapy in antisocial adolescents at high risk of out-of-home placement.Methods/design: The trial is being conducted at 10 sites across the UK. Seven hundred participants and their families will be recruited and randomised on a 1:1 basis to multisystemic therapy or management as usual. Treatments are offered over a period of 3 to 5 months, with follow-up to 18 months post-randomisation. The primary outcome is out-of-home placement at 18 months. Secondary outcomes include offending rates, total service and criminal justice sector costs, and participant well-being and educational outcomes. Data will be gathered from police computer records, the National Pupil Database, and interview and self-report measures administered to adolescents, parents and teachers. Outcomes will be analysed on an intention-to-treat basis, using a logistic regression with random effects for the primary outcome and Cox regressions and linear mixed-effects models for secondary outcomes depending on whether the outcome is time-to-event or continuous.Discussion: The START trial is a pragmatic national trial of sufficient size to evaluate multisystemic therapy, to inform policymakers, service commissioners, professionals, service users and their families about its potential in the UK. It will also provide data on the clinical and cost-effectiveness of usual services provided to youth with serious antisocial behaviour problems.Trial Registration: ISRCTN77132214. [ABSTRACT FROM AUTHOR]

NHS research governance makes it almost impossible to collect certain kinds of data on the everyday life of hospitals and the experience of patients. Fortunately, those of us who get sick enough to be admitted can write about the experience without fear of regulation. This paper presents some observations on clinical ethics, ward organization and infection control that would have been difficult to obtain in any other way, but which illustrate the policy and information costs of the present system. While not personally recommending this as a research strategy, the paper identifies a growing evidence gap and comments on its implications for the delivery of humane and well-organized care. [ABSTRACT FROM AUTHOR]

In the past, the Declaration of Helsinki insisted on a fundamental distinction between medical research (of no therapeutic benefit) and clinical research (carried out to gain insight into a patient's condition and inform treatment). However, recent versions of the Helsinki Declaration no longer rehearse this distinction, instead recognising how experimental and clinical practices often and increasingly overlap. This paper argues that this same distinction might also be re-thought within health geography and that much can be gained through exploring how spaces of health can be simultaneously research laboratory and therapeutic place. This is done in two key ways. Firstly, through an analysis of the Common Cold Unit, a medical research facility based near Salisbury in the UK that recruited volunteers by emphasising its qualities as a rather unusual holiday destination. Secondly, by a review of current work in human geography, medical sociology and anthropology that highlights the blending of research and clinical space. I conclude by considering some of the implications and challenges posed by the mixing of experimental and therapeutic space, with an emphasis on ethics, inequality and care. [ABSTRACT FROM AUTHOR]

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of eltrombopag (GlaxoSmithKline) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with chronic immune or idiopathic thrombocytopenic purpura (ITP), as part of the their Single Technology Appraisal (STA) process. The Aberdeen Technology Assessment Review (TAR) Group, commissioned to act as the evidence review group (ERG), critically reviewed and supplemented the submitted evidence. This paper describes the company submission, the ERG review and NICE's subsequent decisions. The ERG critically appraised the clinical and cost-effectiveness evidence submitted by the manufacturer, independently searched for relevant literature, conducted a critical appraisal of the submitted economic models and explored the impact of altering some of the key model assumptions as well as combining relevant sensitivity analyses. Three trials were used to inform the safety and efficacy aspects of this submission; however, one high-quality randomized controlled trial (RAISE study) was the principal source of evidence and was used to inform the economic model. Eltrombopag had greater odds of achieving the primary outcome of a platelet count between 50 × 10^9/L and 400 × 10^9/L during the 6-month treatment period than placebo (odds ratio [OR] 8.2, 99% CI 3.6, 18.7). In the eltrombopag group, 50/83 (60%) of non-splenectomized patients and 18/49 (37%) of splenectomized patients achieved this outcome. The median duration of response was 10.9 weeks for eltrombopag (splenectomized 6 and non-splenectomized 13.4) compared with 0 for placebo. Eltrombopag patients required less rescue medication and had lower odds of bleeding events for both the splenectomized and the non-splenectomized patients. For a watch-and-rescue strategy of care, the comparator was placebo and the ERG found that substantial reductions in the cost of eltrombopag are needed before the incremental cost per QALY is less than d30 000. There was significant uncertainty, with the incremental cost-effectiveness ratio (ICER) reported varying from d33 561 to d103 500 per QALY (splenectomized) and d39 657 to d150 245 per QALY (non-splenectomized). All costs are presented in d, year 2008 values, as this was the costing year for the manufacturer's model. Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG questioned the robustness of the use of non-randomized non-comparative data. The base-case results restricting the time horizon to 2 years and prescribing eltrombopag as second-line treatment post-rituximab were found to be favourable towards eltrombopag. As rituximab is not a licensed treatment for ITP, the ERG were concerned that its inclusion may not be reflective of clinical practice. None of the treatment sequences resulted in an ICER approaching the recommended threshold of d30 000 per QALY gained. Eltrombopag appears to be a safe treatment for ITP (although longterm follow-up studies are awaited) and has short-term efficacy. However, NICE found based on the evidence submitted and reviewed that there was no robust evidence on the long-term efficacy or cost effectiveness of eltrombopag and a lack of direct evidence for eltrombopag tested against other relevant comparators. [ABSTRACT FROM AUTHOR]

Previous application of value-of-information methods to optimal clinical trial design have predominantly taken a societal decision-making perspective, implicitly assuming that healthcare costs are covered through public expenditure and trial research is funded by government or donation-based philanthropic agencies. In this paper, we consider the interaction between interrelated perspectives of a societal decision maker (e.g. the National Institute for Health and Clinical Excellence [NICE] in the UK) charged with the responsibility for approving new health interventions for reimbursement and the company that holds the patent for a new intervention. We establish optimal decision making from societal and company perspectives, allowing for trade-offs between the value and cost of research and the price of the new intervention. Given the current level of evidence, there exists a maximum (threshold) price acceptable to the decision maker. Submission for approval with prices above this threshold will be refused. Given the current level of evidence and the decision maker's threshold price, there exists a minimum (threshold) price acceptable to the company. If the decision maker's threshold price exceeds the company's, then current evidence is sufficient since any price between the thresholds is acceptable to both. On the other hand, if the decision maker's threshold price is lower than the company's, then no price is acceptable to both and the company's optimal strategy is to commission additional research. The methods are illustrated using a recent example from the literature. [ABSTRACT FROM AUTHOR]

Background: Recent developments aiming to standardise and streamline processes of gaining the necessary approvals to carry out research in the National Health Service (NHS) in the United Kingdom (UK), have resulted in lengthy and costly delays. The national UK governmental Department of Health's Research Governance Framework (RGF) for Health and Social Care requires that appropriate checks be conducted before research involving human participants, their organs, tissues or data can commence in the NHS. As a result, medical research has been subjected to increased regulation and governance, with the requirement for approvals from numerous regulatory and monitoring bodies. In addition, the processes and outcomes of the attribution of costs in NHS research have caused additional difficulties for researchers. The purpose of this paper is to illustrate, through three trial case studies, the difficulties encountered during the set-up and recruitment phases of these trials, related to gaining the necessary ethical and governance approvals and applying for NHS costs to undertake and deliver the research. Methods: Empirical evidence about delays and difficulties related to regulation and governance of medical research was gathered during the period 2009-2010 from three UK randomised controlled trials with sites in England, Wales and Scotland (1. SAFER 2-- an emergency care based trial of a protocol for paramedics to refer patients directly to community based falls services; 2. COnStRUCT-- a trial of two drugs for acute ulcerative colitis; and 3. Family Links -- a trial of a public health intervention, a 10 week community based parenting programme). Findings and recommendations were reported in response to a call for evidence from The Academy of Medical Sciences regarding difficulties encountered in conducting medical research arising from R&D governance and regulation, to inform national policy. Results: Difficulties and delays in navigating and gaining the appropriate approvals and NHS costs required to undertake the research were encountered in all three trials, at various points in the bureaucratic processes of ethical and research and information governance approvals. Conduct of each of the three trials was delayed by at least 12 months, with costs increasing by 30 - 40%. Conclusions: Whilst the three trials encountered a variety of challenges, there were common issues. The processes for gaining approvals were overly complex and differed between sites and UK countries; guidance about processes was unclear; and information regarding how to define and claim NHS costs for undertaking the research was inconsistent. The competitive advantage of a publicly funded, open access health system for undertaking health services research and clinical trials within the UK has been outweighed in recent years by stifling bureaucratic structures and processes for governance of research. The recommendations of the Academy of Medical Sciences are welcomed, and the effects of their implementation are awaited with interest. Trial Registration numbers: SAFER 2: ISRCTN 60481756; COnStRUCT: ISRCTN22663589; Family Links: ISRCTN 13929732. [ABSTRACT FROM AUTHOR]

Background: Although physical inactivity has been linked with numerous chronic health conditions and overall mortality, the majority of English adults report doing insufficient physical activity. To increase population physical activity levels, researchers have called for more community-level interventions. To evaluate these complex public health interventions, innovative study designs are required. This study protocol describes Devon Active Villages, a community-level intervention providing physical activity opportunities to 128 rural villages in southwest England, and the methods used to evaluate its effectiveness in increasing physical activity levels. Methods/Design: A stepped wedge cluster randomised trial will be used to evaluate whether Devon Active Villages leads to increased physical activity levels in rural communities. Community engagement will help tailor activity programmes for each village; communities will then be supported for a further twelve months. The intervention will be delivered over four periods, each lasting twelve weeks. Data collection consists of a postal survey of a random sample of adults aged 18 years and over, at baseline and after each of the four intervention periods. The questionnaire includes questions on participant demographics, physical activity behaviour, local environment characteristics, awareness of local activity programmes, and psychosocial factors. Based on detecting an increase in the proportion of people who meet physical activity guidelines (from 25% to 30%), at least ten respondents are needed from each of the 128 villages at each stage (80% power at the 5% level of significance). Anticipating a 20% response rate, 6,400 questionnaires will be sent out at each stage (i.e., 50 surveys to each village). Using data from all five periods, a comparison of study outcomes between intervention and control arms will be performed, allowing for time period (as a fixed effect) and the random effect induced by correlation of outcomes (clustering) within villages. Discussion: This paper describes the use of a stepped wedge cluster randomised trial to evaluate a complex, community-level physical activity intervention in an under-studied population of adults in rural communities in southwest England. The study addresses gaps in the current literature by providing new insights into physical activity levels in this population. Trial Registration Number: Current Controlled Trials ISRCTN37321160 [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies. [ABSTRACT FROM AUTHOR]

This paper outlines aspects of the interface between law and science in the domain of treatment induced injury, using examples drawn from litigation on SSRIs. In the face of claims that randomized controlled trials provide uniquely appropriate evidence and that there should be a statistically significant doubling of the risks on treatment, the examples used demonstrate that the methods of assessing the possibility of causal links between treatment and injuries must necessarily be tailored to both the injury and the treatment. [ABSTRACT FROM AUTHOR]

Background: Previous research reviewed treatment success and whether the collective uncertainty principle is met in RCTs in the US National Cancer Institute portfolio. This paper classifies clinical trials funded by the UK HTA programme by results using the method applied to the US Cancer Institute trials, and compares the two portfolios.Methods: Data on all completed randomised controlled trials funded by the HTA programme 1993-2008 were extracted. Each trial's primary results was classified into six categories; 1) statistically significant in favour of the new treatment, 2) statistically significant in favour of the control treatment 3) true negative, 4) truly inconclusive, 5) inconclusive in favour of new treatment or 6) inconclusive in favour of control treatment. Trials were classified by comparing the 95% confidence interval for the difference in primary outcome to the difference specified in the sample size calculation. The results were compared with Djulbegovic's analysis of NCI trials.Results: Data from 51 superiority trials were included, involving over 48,000 participants and a range of diseases and interventions. 85 primary comparisons were available because some trials had more than two randomised arms or had several primary outcomes. The new treatment had superior results (whether significant or not) in 61% of the comparisons (52/85 95% CI 49.9% to 71.6%). The results were conclusive in 46% of the comparisons (19% statistically significant in favour of the new treatment, 5% statistically significant in favour of the control and 22% true negative). The results were classified as truly inconclusive (i.e. failed to answer the question asked) for 24% of comparisons (20/85). HTA trials included fewer truly inconclusive and statistically significant results and more results rated as true negative than NCI trials.Conclusions: The pattern of results in HTA trials is similar to that of the National Cancer Institute portfolio. Differences that existed were plausible given the differences in the types of trials -HTA trials are more pragmatic. The results indicate HTA trials are compatible with equipoise. This classification usefully summarises the results from clinical trials and enables comparisons of different portfolios of trials. [ABSTRACT FROM AUTHOR]