Abstract Background A significant proportion of patients with inflammatory bowel disease (IBD) do not respond to treatment. Recently, criteria to define difficult-to-treat (DTT) IBD have been proposed1. These include IBD refractory to at least 2 advanced therapies with different mechanisms of action. We aim to review the representation of patients with prior exposure to biologics, DTT-IBD, and other challenging phenotypes in randomized clinical trials (RCTs). Methods A scoping review was performed by reviewing all RCTs of advanced therapies in IBD. We updated the literature searches of two published systematic reviews of ulcerative colitis (UC)2 and Crohn’s disease (CD)3 searching MEDLINE, EMBASE, and the Cochrane Library up to December 2023. Results We included 140 RCTs, 73 in ulcerative colitis (UC), and 67 in Crohn’s disease (CD), comprising 44.799 patients. In UC, 53% (39/73) of studies included patients with prior exposure to other biologics, but only 19% (14/73) included patients exposed to two or more biologics. Moreover, only 5% (4/73) of studies included participants exposed to biologics with multiple mechanisms of action, or DTT, and these accounted for 2% of the total participants of UC RCTs. None of the trials reported efficacy results specific for DTT. In CD, 60% (47/67) of studies included patients with any prior biologic exposure, and 31% (21/67) allowed the participation of patients who received two or more biologics. Only one study (1.5%) reported efficacy results for patients exposed to multiple mechanisms of action, DTT-IBD, which accounted for 7.4% of the study participants and 0.1% of all those in CD trials. In CD, history of prior intestinal surgery was reported only in 28 of 67 studies (42%) for 2977 patients, or 14.5% of the total participants. Similarly, upper gastrointestinal involvement of CD was included only in 21 trials (31%) and present in 808 participants (3.9%). Instead, the majority of trials either excluded patients with locations proximal to the terminal ileum (35 RCTs; 52%) or did not report whether some participants had upper gastrointestinal locations (11 RCTs; 16%) In both UC and CD there was a trend towards greater inclusion of exposed and refractory patients in recent years. Conclusion Patients exposed to multiple advanced therapies and those with phenotypes of CD more challenging to manage remain underrepresented in clinical trials of IBD. References 1.Parigi TL, et al. Lancet Gastroenterol Hepatology 2023 2.Sedano R, et al. Journal Crohn & Colitis 2021 3.Almradi A, et al. Journal Crohn & Colitis 2021