Improving trial conduct for late-phase, randomised clinical trials that utilise innovative trial designs and platforms

During my PhD I assessed how novel approaches could be used to improve trial conduct, specifically across late-phase trials utilising innovative designs, and related findings back to my sub-speciality and area of clinical interest, a condition called Inflammatory Bowel Disease (IBD). My thesis focused on complementary topics across five main chapters. First, I reported on the experiences and challenges for investigators in delivering a biomarker-guided trial in Crohn’s disease (CD), seeking to stratify management based on different risk profiles of CD. Second, I expanded on this concept of heterogenous outcomes, by addressing a novel treatment strategy for patients with lower-risk CD. Third, given the impact of Coronavirus disease (COVID) on my studies, I was able to modify my doctoral study plans and assess the impact of COVID on delivery of IBD clinical trials. This allowed me to better understand challenges to overcome and the need for more efficient trial designs in IBD. Fourth, I evaluated the conduct of multi-arm, multi-stage (MAMS) adaptive platform trials across disease areas, in order to understand how best to implement a MAMS platform approach to higher-risk CD. Fifth, I examined issues of conduct for Data Monitoring Committees (DMCs), with specific focus on both novel designs and the potential role for patient and public involvement/engagement. I report novel findings in each chapter. These a) help increase understanding on how to deliver innovative trials in the IBD field; b) provide a global consensus on the concept of biological treatment cycling for lower-risk patients with CD; c) demonstrate the lasting impact of COVID on IBD clinical trials; d) support increased understanding on the conduct of MAMS protocols and map out potential application to patients with higher-risk CD; e) highlight factors for consideration by DMCs overseeing trials using more innovative designs

Moving towards more patient-centred clinical trials in IBD.

Declining recruitment rates in inflammatory bowel disease (IBD) trials have resulted in calls to modify the conduct of trials in IBD in order to make them more efficient and patient centred. Here, we propose a number of potential modifications

Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

BACKGROUND: For medical conditions with numerous interventions worthy of investigation, there are many advantages of a multi-arm multi-stage (MAMS) platform trial approach. However, there is currently limited knowledge on uptake of the MAMS design, especially in the late-phase setting. We sought to examine uptake and characteristics of late-phase MAMS platform trials, to enable better planning for teams considering future use of this approach. DESIGN: We examined uptake of registered, late-phase MAMS platforms in the EU clinical trials register, Australian New Zealand Clinical Trials Registry, International Standard Randomised Controlled Trial Number registry, Pan African Clinical Trials Registry, WHO International Clinical Trial Registry Platform and databases: PubMed, Medline, Cochrane Library, Global Health Library and EMBASE. Searching was performed and review data frozen on 1 April 2021. MAMS platforms were defined as requiring two or more comparison arms, with two or more trial stages, with an interim analysis allowing for stopping of recruitment to arms and typically the ability to add new intervention arms. RESULTS: 62 late-phase clinical trials using an MAMS approach were included. Overall, the number of late-phase trials using the MAMS design has been increasing since 2001 and been accelerated by COVID-19. The majority of current MAMS platforms were either targeting infectious diseases (52%) or cancers (29%) and all identified trials were for treatment interventions. 89% (55/62) of MAMS platforms were evaluating medications, with 45% (28/62) of the MAMS platforms having at least one or more repurposed medication as a comparison arm. CONCLUSIONS: Historically, late-phase trials have adhered to long-established standard (two-arm) designs. However, the number of late-phase MAMS platform trials is increasing, across a range of different disease areas. This study highlights the potential scope of MAMS platform trials and may assist research teams considering use of this approach in the late-phase randomised clinical trial setting. PROSPERO REGISTRATION NUMBER: CRD42019153910

The overlap between randomised evaluations of recruitment and retention interventions:An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature

Background: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Methods: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. Results: In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as ‘randomised evaluation’, of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Conclusion: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.</p

The overlap between randomised evaluations of recruitment and retention interventions:An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature

Background: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Methods: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. Results: In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as ‘randomised evaluation’, of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Conclusion: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.</p

Access to routinely collected health data for clinical trials - review of successful data requests to UK registries.

BACKGROUND: Clinical trials generally each collect their own data despite routinely collected health data (RCHD) increasing in quality and breadth. Our aim is to quantify UK-based randomised controlled trials (RCTs) accessing RCHD for participant data, characterise how these data are used and thereby recommend how more trials could use RCHD. METHODS: We conducted a systematic review of RCTs accessing RCHD from at least one registry in the UK between 2013 and 2018 for the purposes of informing or supplementing participant data. A list of all registries holding RCHD in the UK was compiled. In cases where registries published release registers, these were searched for RCTs accessing RCHD. Where no release register was available, registries were contacted to request a list of RCTs. For each identified RCT, information was collected from all publicly available sources (release registers, websites, protocol etc.). The search and data extraction were undertaken between January and May 2019. RESULTS: We identified 160 RCTs accessing RCHD between 2013 and 2018 from a total of 22 registries; this corresponds to only a very small proportion of all UK RCTs (about 3%). RCTs accessing RCHD were generally large (median sample size 1590), commonly evaluating treatments for cancer or cardiovascular disease. Most of the included RCTs accessed RCHD from NHS Digital (68%), and the most frequently accessed datasets were mortality (76%) and hospital visits (55%). RCHD was used to inform the primary trial (82%) and long-term follow-up (57%). There was substantial variation in how RCTs used RCHD to inform participant outcome measures. A limitation was the lack of information and transparency from registries and RCTs with respect to which datasets have been accessed and for what purposes. CONCLUSIONS: In the last five years, only a small minority of UK-based RCTs have accessed RCHD to inform participant data. We ask for improved accessibility, confirmed data quality and joined-up thinking between the registries and the regulatory authorities. TRIAL REGISTRATION: PROSPERO CRD42019123088

ECCO Topical Review on Biological Treatment Cycles in Crohn’s Disease

There are now a growing number of licensed biological therapies for patients with Crohn’s disease. However, there can be significant costs associated with long-term maintenance treatment, as well as some concerns about potential side-effects. As a result, there has been increasing interest in elective biological treatment discontinuation in selected patients, after a sustained period of remission. Following discontinuation, in cases of relapse, evidence to date has suggested that remission may often be regained by re-treatment with the same biological agent. Therefore, a concept has emerged in which cycles of biological therapy might be used. If this treatment strategy were to be applied in a subgroup of patients at low risk of relapse, cycling might allow a substantial number of patients to have a lower, overall therapeutic burden—ensuring decreased exposure to biological therapy but still enabling appropriate disease control.Currently, there remains uncertainty about the benefit–risk balance for using cycles of biological treatment for patients with Crohn’s disease. Accordingly, an expert panel was convened by the European Crohn’s and Colitis Organisation [ECCO] to review the published literature and agree a series of consensus practice points. The panel aimed to provide evidence-based guidance on multiple aspects of biological treatment discontinuation and cycling, including the risk of relapse after elective treatment discontinuation, predictors of probable relapse or remission, safety, patient preferences, and pharmacoeconomic aspects. Crucially, discussions about biological treatment discontinuation and cycling should be individualized, to enable shared decision-making by patients with their clinicians

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

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

The overlap between randomised evaluations of recruitment and retention interventions: An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature

Background The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Methods Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. Results In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as ‘randomised evaluation’, of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Conclusion Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa