Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design - A scoping review.

OBJECTIVES: Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies. STUDY DESIGN AND SETTING: Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with postrandomization consent for the intervention group and no specific postrandomization consent for the usual care control group. Information from identified TwiCs was extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to nonuptake of interventions and informed consent procedure. RESULTS: We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46; 17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46; 100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for nonuptake of the intervention, anticipating a median nonuptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for nonuptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%). CONCLUSION: Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial nonuptake of the intervention warrants further research to guide the planning, implementation, and analysis of TwiCs.

Randomised trials conducted using cohorts: a scoping review.

INTRODUCTION: Cohort studies generate and collect longitudinal data for a variety of research purposes. Randomised controlled trials (RCTs) increasingly use cohort studies as data infrastructures to help identify and recruit trial participants and assess outcomes. OBJECTIVE: To examine the extent, range and nature of research using cohorts for RCTs and describe the varied definitions and conceptual boundaries for RCTs using cohorts. DESIGN: Scoping review. DATA SOURCES: Searches were undertaken in January 2021 in MEDLINE (Ovid) and EBM Reviews-Cochrane Methodology Registry (Final issue, third Quarter 2012). ELIGIBILITY CRITERIA: Reports published between January 2007 and December 2021 of (a) cohorts used or planned to be used, to conduct RCTs, or (b) RCTs which use cohorts to recruit participants and/or collect trial outcomes, or (c) methodological studies discussing the use of cohorts for RCTs. DATA EXTRACTION AND SYNTHESIS: Data were extracted on the condition being studied, age group, setting, country/continent, intervention(s) and comparators planned or received, unit of randomisation, timing of randomisation, approach to informed consent, study design and terminology. RESULTS: A total of 175 full-text articles were assessed for eligibility. We identified 61 protocols, 9 descriptions of stand-alone cohorts intended to be used for future RCTs, 39 RCTs using cohorts and 34 methodological papers.The use and scope of this approach is growing. The thematics of study are far-ranging, including population health, oncology, mental and behavioural disorders, and musculoskeletal conditions.Authors reported that this approach can lead to more efficient recruitment, more representative samples, and lessen disappointment bias and crossovers. CONCLUSION: This review outlines the development of cohorts to conduct RCTs including the range of use and innovative changes and adaptations. Inconsistencies in the use of terminology and concepts are highlighted. Guidance now needs to be developed to support the design and reporting of RCTs conducted using cohorts.

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.