  A Trial within Cohorts (TwiCs) study design is a trial design that uses the
infrastructure of an observational cohort study to initiate a randomized trial.
Upon cohort enrollment, cohort participants provided consent for being
randomized in future studies without being informed. Once a new treatment is
available, eligible cohort participants are randomly assigned to this new
treatment or standard of care. Patients randomized to the treatment arm are
offered this new treatment, which they can refuse. Patients who refuse will
receive standard of care instead. Patients randomized to the standard of care
arm, receive no information about the trial and continue receiving standard of
care as part the cohort study. Standard cohort measures are used for outcome
comparisons. The TwiCs study design aims to overcome some issues encountered in
standard Randomized Controlled Trials (RCTs). An example of an issue in
standard RCTs is the slow patient accrual, which a TwiCs study aims to improve
by selecting patients using a cohort and only offering the intervention to
patients in the active arm. In oncology, the TwiCs study design has gained
increasing interest during the last decade. Despite its potential advantages
over RCTs, the TwiCs study design is concerned with several methodological
challenges that need careful consideration when planning a TwiCs study. In this
article, we focus on these methodological challenges and reflect on them using
experiences from TwiCs studies initiated in oncology. Important methodological
challenges that are discussed are the timing of randomization, the issue of
non-compliance (refusal) after randomization in the intervention arm, and the
definition of the intention-to-treat effect in a TwiCs study and how this
effect is related to its counterpart in standard RCTs.
