Systematic Review: Inclusion of Patients With Difficult‐to‐Treat Inflammatory Bowel Disease in Randomized Controlled Trials of Advanced Therapies

ABSTRACT Background Criteria to define difficult‐to‐treat (DTT) inflammatory bowel disease (IBD) have recently been proposed, yet the inclusion and participation of patients with DTT‐IBD in randomized controlled trials (RCTs) are heterogeneous and poorly defined. Aims To explore inclusion and representation of patients with DTT‐IBD in RCTs. Methods We reviewed RCTs of advanced therapies (ATs) in ulcerative colitis (UC) and Crohn's disease (CD). DTT‐IBD was defined as active disease despite exposure to ATs with ≥ 2 different mechanisms of action. Secondary analyses assessed eligibility and participation of patients exposed to ≥ 1 or ≥ 2 ATs irrespective of mechanism of action, and in CD only, active disease after ≥ 2 intestinal resections and fistulizing disease. Results We included 179 RCTs, 93 in UC and 86 in CD, comprising 54,258 patients. In UC, 72% (67/93) of studies included patients with prior exposure to ATs and 16.1% (15/93) included participants exposed to agents with ≥ 2 mechanisms of action (DTT); among the 10 trials reporting patient‐level data, DTT‐UC accounted for 16.2% (814/5019). In CD, 73.3% (63/86) of RCTs included patients with prior exposure to ATs, and 10.5% (9/86) reported patients with DTT‐CD due to exposure to multiple classes of ATs. Patients with multifailure DTT‐CD accounted for 22.4% (773/3455) of the reported study populations. Subgroup‐specific efficacy outcomes for DTT‐IBD were not reported, except for one small trial that enrolled only DTT‐UC. Conclusions Few RCTs of advanced medications include patients with DTT‐IBD. In most trials, participants with DTT‐IBD represent a minority of the study population, and subgroup‐specific data are lacking.