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

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

doi:10.1016/j.jclinepi.2024.111469

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

J Clin Epidemiol. 2024 Oct:174:111469. doi: 10.1016/j.jclinepi.2024.111469. Epub 2024 Jul 19.

Authors

Alain Amstutz¹, Christof M Schönenberger², Benjamin Speich³, Alexandra Griessbach³, Johannes M Schwenke³, Jan Glasstetter³, Sophie James⁴, Helena M Verkooijen⁵, Beverley Nickolls⁶, Clare Relton⁶, Lars G Hemkens⁷, Frédérique Chammartin⁸, Felix Gerber⁹, Niklaus D Labhardt⁸, Stefan Schandelmaier¹⁰, Matthias Briel¹¹

Affiliations

¹ CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; Oslo Center for Biostatistics and Epidemiology, Oslo University Hospital, University of Oslo, Oslo, Norway; Bristol Medical School, University of Bristol, Bristol, UK.
² CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: ChristofManuel.Schoenenberger@usb.ch.
³ CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
⁴ York Trials Unit, Department of Health Sciences, University of York, York, UK.
⁵ Imaging Division, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁶ Wolfson Institute of Population Health, Queen Mary University, London, UK.
⁷ Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland; Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, USA.
⁸ International Clinical Health Services Research Unit, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
⁹ International Clinical Health Services Research Unit, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Medicine, Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
¹⁰ CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; School of Public Health, University College Cork, Cork, Ireland; MTA-PET Lendület "Momentum" Evidence Group, Medical School, University of Pécs, Pécs, Hungary.
¹¹ CLEAR Methods Center, Division of Clinical Epidemiology, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, Canada.

PMID: 39032590
DOI: 10.1016/j.jclinepi.2024.111469

Abstract

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.

Keywords: Metaresearch; Randomized clinical trial; Trial design; Trials within cohorts; TwiCs; cmRCT.

Publication types

Review

MeSH terms

Cohort Studies
Humans
Informed Consent* / statistics & numerical data
Randomized Controlled Trials as Topic* / methods
Research Design*