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

Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design A scoping review
Original Research
Alain Amstutz, Christof M. Schönenberger, Benjamin Speich, Alexandra Griessbach, Johannes M. Schwenke, Jan Glasstetter, Sophie James, Helena M. Verkooijen, Beverley Nickolls, Clare Relton, Lars G. Hemkens, Frédérique Chammartin, Felix Gerber, Niklaus D. Labhardt, Stefan Schandelmaier, Matthias Briel
Journal of Clinical Epidemiology, 19 July 2024
Open Access
Abstract
Objective
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 post-randomization consent for the intervention group and no specific post-randomization consent for the usual care control group. Information from identified TwiCs were extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to non-uptake 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 non-uptake of the intervention, anticipating a median non-uptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for non-uptake. 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%).
Conclusions
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 non-uptake of the intervention warrants further her research to guide the planning, implementation, and analysis of TwiCs.