Nested Randomized Controlled Trials in Large Databases: An Opportunity for Inflammatory Bowel Disease?

Introduction Although randomized controlled trials (RCTs) are the gold standard for investigating the efficacy and safety of interventions, they present major operational challenges due to their complexity, time-consuming nature, and costs. To address some of these difficulties, RCTs nested in cohorts (RCTsNC) have been developed. The aim was to review the opportunities and challenges of RCTsNC in inflammatory bowel disease (IBD). Methods A literature search was conducted using MEDLINE, Embase, Cochrane and Clinicaltrials.gov from inception until March 2024 to identify studies focusing on this topic. Results RCTsNC is an emerging trial design, which has been successfully utilized across several medical disciplines but not IBD. It enables the use of longer-term longitudinal data for safety and efficacy assessment, and enhanced recruitment and follow up processes. Observational data for IBD, derived from research (cohort and case-control studies) and non-research sources (electronic health records and registries), provides access to comprehensive records for a large number of IBD patients, which could present an opportunity to enhance the performance of RCTsNC. Leveraging pre-existing cohorts and their organizational structures improves patient acceptance and is more economical compared to traditional randomized trials. It may permit researchers to address knowledge gaps in IBD (specific sub-populations, or the effect of environmental exposures on disease course). Limitations of RCTsNC include the risk of selection bias and constraints related to comparisons with placebo. Conclusion RCTsNC offers a promising opportunity for IBD research and provides an alternative study design given the challenges of conventional trial designs in the current IBD RCT landscape.