Anne C Seagrove

Involving service users in trials: developing a standard operating procedure

BackgroundMany funding bodies require researchers to actively involve service users in research to improve relevance, accountability and quality. Current guidance to researchers mainly discusses general principles. Formal guidance about how to involve service users operationally in the conduct of trials is lacking. We aimed to develop a standard operating procedure (SOP) to support researchers to involve service users in trials and rigorous studies.MethodsResearchers with experience of involving service users and service users who were contributing to trials collaborated with the West Wales Organisation for Rigorous Trials in Health, a registered clinical trials unit, to develop the SOP. Drafts were prepared in a Task and Finish Group, reviewed by all co-authors and amendments made.ResultsWe articulated core principles, which defined equality of service users with all other research team members and collaborative processes underpinning the SOP, plus guidance on how to achieve these. We developed a framework for involving service users in research that defined minimum levels of collaboration plus additional consultation and decision-making opportunities. We recommended service users be involved throughout the life of a trial, including planning and development, data collection, analysis and dissemination, and listed tasks for collaboration. We listed people responsible for involving service users in studies and promoting an inclusive culture. We advocate actively involving service users as early as possible in the research process, with a minimum of two on all formal trial groups and committees. We propose that researchers protect at least 1% of their total research budget as a minimum resource to involve service users and allow enough time to facilitate active involvement.ConclusionsThis SOP provides guidance to researchers to involve service users successfully in developing and conducting clinical trials and creating a culture of actively involving service users in research at all stages. The UK Clinical Research Collaboration should encourage clinical trials units actively to involve service users and research funders should provide sufficient funds and time for this in research grants.

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial

Summary Background Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness. Methods In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival—ie, the area under the curve (AUC) of scores from the Crohns and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589. Findings Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI −22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707–912] days in the infliximab group vs 744 [638–850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group). Interpretation There was no significant difference between ciclosporin and infliximab in clinical effectiveness. Funding NIHR Health Technology Assessment programme.

Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT)

Introduction Many patients with ulcerative colitis (UC) present with acute exacerbations needing hospital admission. Treatment includes intravenous steroids but up to 40% of patients do not respond and require emergency colectomy. Mortality following emergency colectomy has fallen, but 10% of patients still die within 3 months of surgery. Infliximab and ciclosporin, both immunosuppressive drugs, offer hope for treating steroid-resistant UC as there is evidence of their short-term effectiveness. As there is little long-term evidence, this pragmatic randomised trial, known as Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), aims to compare the clinical and cost-effectiveness of infliximab and ciclosporin for steroid-resistant UC. Methods and analysis Between May 2010 and February 2013, 52 UK centres recruited 270 patients admitted with acute severe UC who failed to respond to intravenous steroids but did not need surgery. We allocated them at random in equal proportions between infliximab and ciclosporin.The primary clinical outcome measure is quality-adjusted survival, that is survival weighted by Crohns and Colitis Questionnaire (CCQ) participants’ scores, analysed by Cox regression. Secondary outcome measures include: the CCQ—an extension of the validated but community-focused UK Inflammatory Bowel Disease Questionnaire (IBDQ) to include patients with acute severe colitis and stoma; two general quality of life measures—EQ-5D and SF-12; mortality; survival weighted by EQ-5D; emergency and planned colectomies; readmissions; incidence of adverse events including malignancies, serious infections and renal disorders; disease activity; National Health Service (NHS) costs and patient-borne costs. Interviews investigate participants’ views on therapies for acute severe UC and healthcare professionals’ views on the two drugs and their administration. Ethics and dissemination The Research Ethics Committee for Wales has given ethical approval (Ref. 08/MRE09/42); each participating Trust or Health Board has given NHS Reseach & Development approval. We plan to present trial findings at international and national conferences and publish in high-impact peer-reviewed journals. Trial registration number ISRCTN: 22663589; EudraCT number: 2008-001968-36

Bureaucracy stifles medical research in Britain: a tale of three trials

BackgroundRecent 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.MethodsEmpirical 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.ResultsDifficulties 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%.ConclusionsWhilst 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 numbersSAFER 2: ISRCTN 60481756; COnStRUCT: ISRCTN22663589; Family Links: ISRCTN 13929732

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT)

BACKGROUND The efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness. OBJECTIVE To compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC. METHOD Between May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohns and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1-3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years. RESULTS The 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouring ciclosporin, 95% confidence interval (CI) -0.0088 to 0.0682; p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouring ciclosporin, 95% CI -0.032 to 0.096; p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouring ciclosporin, 95% CI -0.0250 to 0.0353; p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188; p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouring ciclosporin, 95% CI 0.590 to 1.493; p = 0.788); participants with serious adverse reactions (OR 0.660 favouring ciclosporin, 95% CI 0.282 to 1.546; p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917; p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114; p = 0.998); deaths (all three who died received infliximab; p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference -£5632, 95% CI -£8305 to -£2773; p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin. CONCLUSIONS Total cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1-3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin. TRIAL REGISTRATION Current Controlled Trials ISRCTN22663589. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 44. See the NIHR Journals Library website for further project information.

Barriers and facilitators to change in the organisation and delivery of endoscopy services in England and Wales: a focus group study

Objective Explore professional views of changes to gastroenterology service organisation and delivery and barriers and facilitators impacting on change. The work was undertaken as part of an evaluation in endoscopy service provision catalysed by the Modernising Endoscopy Services Programme of the Modernisation Agency. Design Focus groups followed by analysis and group-working activities identifying key themes. Setting English and Welsh secondary care gastroenterology units. Participants 20 professionals working in gastroenterology in England and Wales. Medical, surgical and nursing specialists including endoscopy nurses. Opportunistic sampling to include senior people in leadership and management roles who were directly involved in service modernisation, excluding those involved in the Modernisation Endoscopy Services Programme. Results Four 1.5 h focus groups took place in 2007. Summative and thematic analyses captured essential aspects of text and achieved consensus on key themes. 4 themes were revealed: ‘loss of personal autonomy and erosion of professionalism’, ‘lack of senior management understanding’, ‘barriers and facilitators to change’ and ‘differences between English and Welsh units’. Themes indicated that low staff morale, lack of funding and senior management support were barriers to effective change. Limitations to the study include the disproportionately low number of focus group attendees from English units and the time delay in reporting these findings. Conclusions Despite ambitions to implement change, ineffective management support continued to hamper modernisation of service organisation and delivery. While the National Health Service Modernisation Agency Modernising Endoscopy Services Programme acted as a catalyst for change, affecting the way staff work, communicate and think, it was not effective in heralding change itself. However, gastroenterologists were keen to consider the potential for change and future service modernisation. The methodological framework of innovative qualitative enquiry offers comprehensive and rigorous enhancement of quantitative studies, including randomised trials, when a mixed methods approach is needed.

Evaluating Innovations in the Delivery and Organization of Endoscopy Services in England and Wales

This article presents four focus groups conducted with health professionals, part of a mixed-method evaluation of modernization of endoscopy services in England catalyzed by the UK National Health Service Modernisation Agency. Transcripts were analyzed adapting van Manen’s “sententious” or “wholistic” approach to thematic analysis. Seven analysts worked to distil lengthy transcripts into summative paragraphs to capture the essentiality of text. Five major themes emerged: lack of senior management understanding and appropriate management systems, inadequate resources, loss of personal autonomy and erosion of professionalism, barriers and facilitators to change, and differences between English and Welsh units—the Welsh perspective. Achieving long-lasting, positive effects of modernization within complex systems demands senior management to actively support innovations, consider staff morale, and provide appropriate levels of funding. However, although professional morale was low, ambition to improve services was strong. The methodological framework offered a comprehensive and applicable approach to data analysis, and our analysis approach was inclusive and collaborative, with far-reaching possibilities for experimental studies and large-scale, mixed-method studies, including trials.

Including service users in trials and rigorous studies in health and social care: developing a standard operating procedure for researchers

Background Involving service users in research is encouraged as a way to improve research quality, relevance and accountability and is a pre-requisite for many funding bodies. Existing guidance for researchers on how to do this mainly discusses general principles. Some researchers may question the value, feasibility and impact of including service users and limit the scope of involvement. We defined service users as patients, carers, people eligible for a service or anyone relevant to the trial inclusion criteria.

PTU-061 Infliximab Or Ciclosporin: Patients’ Treatment Preferences And The Impact Of Ulcerative Colitis (uc) On Their Lives

Introduction The qualitative element of CONSTRUCT, a randomised controlled trial comparing clinical and cost effectiveness of infliximab and ciclosporin in steroid resistant UC, contributed to the specific trial objectives of examining quality of life (QoL) across the two groups. The qualitative element concentrated on patient and professional perceptions, and we describe patients’ opinions about treatments and other UC therapies. Methods Semi-structured telephone interviews with patients three and 12 months after admission with acute severe UC and randomisation. Thematic analysis was conducted by three qualitative researchers, followed by group analysis by seven members of CONSTRUCT. This abstract concentrates on the three month data. Results 20 interviews were completed. Length of disease duration varied but similar stories emerged about living and coping with UC, the physical, mental and emotional impact of the disease, treatment options and concerns and hopes for the future. The main issues were: Patients favour infliximab because they perceive a more positive treatment outcome, easier treatment regime and fewer side effects The dramatically debilitating symptoms that impact on patients’ QoL, their family and friends, are particularly noticeable in this disease Patients live with the ongoing unpredictability of symptoms and treatment, making it particularly difficult for patients and healthcare professionals to manage care Unlike other chronic diseases, UC is considered embarrassing, making it an isolating and awkward experience for patients and difficult to manage work and life routines The lack of visibility of symptoms or outcomes impacts on patients’ ability to share and discuss openly with others Surgery is feared but most patients experience relief and subsequent recognition of health benefits following surgery Patients would like to understand what causes UC, its links to stressors and diet and would welcome more extensive information provision Ready access to IBD Nurses was considered important. Conclusion Study findings indicate that UC patients live with constant, unpredictable symptoms, where a flare-up becomes socially isolating along with anxieties of deteriorating health. Patients need support to manage the impact of UC on their lives, consider prompt diagnosis to be important, and need relevant treatment provided quickly. Patients clearly prefer infliximab because of the easier treatment regime and fewer side effects. The views of patients after surgery were generally positive, but more research is required into surgical treatment of UC to support those facing surgery and as an alternative to medical treatment. The profile of UC should be raised to destigmatise the disease and thus the embarrassment felt by sufferers and those living with the outcomes of surgery. Disclosure of Interest None Declared.

MATRICS: A Method for Aggregating The Reporting of Interventions in Complex Studies

Background There are few rigorous methods for combining qualitative and quantitative findings from studies with complex interventions using multiple research methods and giving appropriate weight to each without introducing bias to the overall conclusions. We developed a Method for Aggregating The Reporting of Interventions in Complex Studies (MATRICS) for the ENIGMA study (Evaluating Innovations in Gastroenterology by the NHS Modernisation Agency) – a multicentre, mixed-methods study to evaluate the impact of the Modernising Endoscopy Services programme [1], funded by the UK National Institute for Health Research (NIHR SDO ref 08/1304/46).