;)
Designing Pivotal IBD Trials: Aligning Evidence Generation with Development Strategy
In IBD development, trial design is no longer principally a choice between conventional induction and maintenance templates. Trial design determines whether a development programme can establish a credible relationship between drug exposure, inflammatory control, patient benefit and long-term disease modification. (Bossuyt et al, 2026).
Eligibility criteria remain a central issue. Enriching for objectively active disease can improve assay sensitivity and reduce noise introduced by functional symptoms, irreversible bowel damage or non-inflammatory drivers of patient-reported outcomes. However, increasingly restrictive entry criteria may produce a population that bears limited resemblance to the patients in whom a therapy will ultimately be prescribed and will make recruitment challenging in an already crowded clinical trial space. Prior therapeutic exposure and failure history should therefore be treated as a biological and strategic variable, not merely a stratification factor, particularly where mechanism-specific resistance, disease severity, and treatment sequencing may influence effect size (Outtier et al, 2025).
Endpoint selection requires similar discipline. Symptoms are directly meaningful to patients and remain indispensable, but symptom control does not always demonstrate suppression of intestinal inflammation. Contemporary treat-to-target frameworks therefore retain clinical remission and endoscopic healing as long-term targets, while regarding biomarker normalisation as an intermediate measure. Histological healing in ulcerative colitis (UC) and transmural healing in Crohn’s Disease are currently adjunctive measures rather than formal treatment targets. Development programmes should accordingly pre-specify a coherent endpoint hierarchy that reflects the anticipated onset, mechanism and achievable depth of response, rather than accumulating multiple outcomes with uncertain decision value (Turner et al, 2021).
As development moves towards combination and sequencing strategies, trial design must also clarify whether the objective is to establish the value of a regimen or the incremental contribution of an individual component. Choices around background therapy, co-initiation versus add-on design, comparators, rescue rules and estimands should be made accordingly, with benefit interpreted against the additional safety, treatment burden and cost that combination treatment may bring (Solitano et al, 2025).
Endoscopy remains pivotal but is neither a simple nor cost-free measurement. Central reading, standardised acquisition, reader calibration, handling of non-evaluable procedures and timing relative to induction kinetics all affect both measurement reliability and apparent efficacy. These practical issues are especially important when a small change in an endoscopic threshold determines success on a composite endpoint. The regulatory environment also remains jurisdiction-sensitive: FDA and EMA expectations for UC remission definitions differ in the required symptom thresholds and composite construction (Vieujean et al, 2025).
Maintenance design is equally consequential. Treat-through studies preserve randomisation and provide a more direct estimate of sustained benefit across the original population. Randomised-withdrawal designs enrich for induction responders and may sharpen the maintenance question, but they answer a narrower question and can complicate interpretation of generalisability, durability and safety. The appropriate choice depends on the development objective, anticipated induction-response kinetics, ethical acceptability of placebo exposure and the intended label claim (Ma et al, 2025).
The practical conclusion is not that IBD trials require greater complexity. It is that each design feature must earn its place by reducing uncertainty relevant to clinical, regulatory or payer decisions. Programmes that verify inflammatory activity at baseline, integrate symptoms with objective disease measures, anticipate regional regulatory distinctions and align induction-to-maintenance estimands with the target product profile are more likely to generate evidence that remains persuasive beyond the primary analysis.
References:
Bossuyt P, Moscicka K, Stoyanova K, Zalud J, Shelton LM. Optimising clinical trial design choices in inflammatory bowel disease. BMJ Open Gastroenterol. 2026 Sep 22;13(1):e002489. doi: 10.1136/bmjgast-2026-002489.
Ma C, Jairath V, Feagan BG, Peyrin-Biroulet L, Danese S, Sands BE, Panaccione R. Interpreting modern randomized controlled trials of medical therapy in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2024 Nov;21(11):792-808. doi: 10.1038/s41575-024-00989-y. Epub 2024 Oct 8. PMID: 39379665.
Outtier A, Janssens R, Barbier L, et al. Evolution of Eligibility Criteria in Inflammatory Bowel Disease Clinical Trials: A Clinical Trial Databank Analysis. United European Gastroenterology Journal. 2025;13(4):542–551. doi:10.1002/ueg2.12731.
Solitano V, Hanžel J, Ma C, Battat R, Raine T, Siegmund B, Peyrin-Biroulet L, Verstockt B, Torres J, Mehandru S, D’Haens G, Hogan M, Ungaro F, Atreya R, Panés J, Panaccione R, Parker CE, Sands BE, Feagan BG, Danese S, Jairath V. An international consensus on the design of clinical trials for advanced combination treatment (ACT) in inflammatory bowel disease. EClinicalMedicine. 2025 Oct 23;89:103582. doi: 10.1016/j.eclinm.2025.103582. PMID: 41210380; PMCID: PMC12593430.
Turner D, Ricciuto A, Lewis A, D’Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583. doi: 10.1053/j.gastro.2020.12.031. Epub 2021 Feb 19.
Vieujean S, Sands BE, Panaccione R, Rubin DT, Jairath V, Danese S, Peyrin-Biroulet L, Schreiber S, Vermeire S, D’Haens G, Dignass A, Dulai PS, Narula N, Reinisch W. Comparison of the FDA and EMA guidance on drug development in ulcerative colitis: an expert panel review. J Crohns Colitis. 2025 Jul 3;19(7):jjaf111. doi: 10.1093/ecco-jcc/jjaf111.
