Review Article: Accelerating Coeliac Disease Clinical Trials-Beyond Celiac Meeting With Industry, Academics, Patients and the FDA.

backgroundCoeliac disease is due to an acquired, lifelong gluten-specific immune response resulting in a gluten-dependent chronic immune-mediated enteropathy associated with gastrointestinal and extraintestinal morbidity. Strictly avoiding dietary gluten is the only available management but has never been subjected to rigorous efficacy assessment now required for a pharmaceutical agent. Gluten-free diet (GFD) is partially and inconsistently effective, but it places a high burden on patients, families, the food industry, and regulators and is defined inconsistently around the world, highlighting the need for effective and convenient adjunctive pharmacological therapies.

aimsTo summarize key patient, scientific, and regulatory considerations for coeliac disease drug development based on a multi-stakeholder meeting focused on accelerating clinical trials.

methodsA pre-competitive meeting convened by the Beyond Celiac Coalition (May 2024) included patients with coeliac disease, academic experts, pharmaceutical industry representatives, and participants from the US Food and Drug Administration. Moderated panel addressed patient priorities, symptom and histologic endpoints, biopsy and histology methods, gluten challenge design, clinical trial duration, and regulatory expectations. Themes were synthesized qualitatively with focus on trial design implications and unresolved questions.

resultsParticipants described high symptom burden and psychosocial impact despite gluten-free diet adherence underscoring unmet therapeutic need in coeliac disease. Regulatory perspectives emphasized the need for clinically meaningful improvement and evidence of intestinal benefit, framed as symptom and histology co-primary endpoints in clinical trials. These expectations were discussed as most applicable to trial populations with both clinically meaningful symptoms and active histologic injury at baseline; for other phenotypes, it was emphasized that endpoint strategy, the role of gluten exposure, and trial duration should be tailored case by case to the population and mechanism of action. Practical challenges identified included endpoint selection and definition, discordance between symptoms and histology, selecting fit-for-purpose symptom measures; standardizing biopsy acquisition and central histology reads to address patchiness and variability, pre-specifying definitions of meaningful histologic change given ongoing uncertainty about healing, and trial feasibility. Controlled gluten exposure was discussed as a tool to improve interpretability of efficacy outcomes, with careful consideration of dose, duration, patient burden and safety. Discussion addressed the ideal length of the double-blind period, including a shorter 24-week double-blind study with an open-label extension versus a 52-week double-blind design. Trial duration should balance scientific rigour, patient retention, and the need for longer-term safety and durability data, with flexibility to tailor the approach to context.

conclusionsProgress in coeliac disease drug development will require patient-centred, scientifically robust but feasible trial designs with appropriate endpoints, justified use of gluten exposure, consideration of improved biomarkers to reduce patient burden and early regulatory engagement. Continued multi-stakeholder collaboration, including dedicated consideration of paediatric drug development, is essential to advance effective therapies.