Articles Advancing Celiac Disease Clinical Trials Why Standardized Trial Design Is Critical for Patient Outcomes With over 1% of the global population affected by celiac disease, the necessity for efficacious pharmacological treatments has never been clearer.¹ While a gluten-free diet is still the cornerstone of management, strict adherence can be expensive, socially isolating, and it can negatively influence quality of life. Despite substantial investments in pharmaceutical development over the past two decades, no therapies have passed the threshold of demonstrating efficacy and safety in a registrational, Phase III randomized controlled trial to date.¹ But the challenge facing researchers and pharmaceutical companies today isn’t just developing new therapies — it’s designing clinical trials that are robust enough to demonstrate their efficacy in a standardized, reproducible manner. The Current Celiac Disease Clinical Trial Landscape: Fragmented and Inconsistent The celiac disease drug development space has been characterized by heterogeneously defined disease populations, interventions, and outcome measures. This fragmentation stems from fundamental challenges that have plagued researchers for years. The discussion around regulatory endpoints is ongoing, which means that different studies use varying methodologies. This results in a situation where it is difficult to build upon previous findings effectively.² Recent regulatory guidance has begun to address these challenges. The FDA’s draft guidance provides recommendations regarding clinical trials for drugs being developed for the treatment of celiac disease as an adjunct to a gluten-free diet in adults, providing much-needed direction for pharmaceutical sponsors.³ However, given that regulatory agencies must balance patient safety with the need for meaningful efficacy data, methodological concerns remain. This is particularly the case when considering gluten challenges that could adversely affect study participants. Two Distinct Scenarios, Two Distinct Approaches Leading experts in the field have found that successful celiac disease drug development depends on recognizing two fundamentally different clinical scenarios, each demanding appropriate trial methodologies: Scenario 1: Gluten Challenge Studies — These trials enroll patients with symptomatically well-controlled celiac disease on a gluten-free diet who subsequently undergo gluten challenge; these studies evaluate treatments that could be used “on-demand” for intermittent and inadvertent gluten exposure, or potentially for continuous and intentional exposure Scenario 2: Persistent Disease Activity Studies — These trials target patients with ongoing symptomatic and histologic disease activity despite attempted adherence to a gluten-free diet, evaluating agents for patients with persistently active celiac disease Each scenario requires distinct methodological considerations that must be addressed in trial design. These range from patient selection criteria to strategies for endpoint measurement. Establishing International Standards Through Collaboration An 18-member panel of international experts, including gastroenterologists, pediatric gastroenterologists and gastrointestinal pathologists, collaborated to develop standardized recommendations.¹ Using a modified Research and Development/University of California Los Angeles Appropriateness Method (RAND/UCLA), this multidisciplinary team reviewed 312 statements to establish an evidence-based consensus on celiac disease clinical trial design. The findings were published in Gastroenterology in 2024, under the title “Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.” The panel’s work was a key milestone in celiac disease research, as it addressed critical elements such as inclusion and exclusion criteria, outcome measures, gluten challenge methodology, and histologic assessment protocols. Their recommendations serve as a basis for more consistent and reliable study outcomes across the global research community. For gluten challenge studies, the panel found that participants should have adhered to a gluten-free diet for at least 12 months prior to screening, with minimal gastrointestinal symptoms reported in the four weeks before gluten challenge initiation. They also determined that a maximum daily gluten dose of 9 grams, formulated to be low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), was appropriate for simulating real-world gluten exposure. Transforming Endpoint Selection Through Evidence-Based Innovation One of the most consequential advances from this standardization effort involves endpoint selection and measurement. The panel concluded that histologic outcomes should be viewed as primary or co-primary endpoints in future celiac disease trials, based on the fundamental importance of demonstrating mucosal healing. However, traditional histologic assessment methods face significant limitations. The widely used Marsh classification system is associated with poor inter-pathologist reproducibility and may not be adequately responsive to therapeutic changes. To address these concerns, the panel endorsed more quantitative approaches, including the Quantitative-Mucosal Algorithmic Rules for Scoring Histology (Q-MARSH) system, plus the separate assessment of intraepithelial lymphocyte density and villus height-to-crypt depth ratios.⁴ Patient-reported outcomes, histology, serology, gene expression analysis, and other tests all play crucial roles in comprehensive efficacy evaluation.² Further work is needed to operationalize patient-reported outcome (PRO) symptom endpoints that are meaningful to patients, valued by payers, and acceptable to regulators for demonstrating efficacy.⁵ The integration of advanced imaging techniques also represents a significant opportunity for trial enhancement. Specialized imaging solutions can provide objective, quantitative measures of intestinal healing that complement traditional histologic assessments, offering researchers and regulators additional confidence in treatment efficacy data. Standardizing Gluten Challenge Methodology The expert panel addressed one of the most controversial aspects of celiac disease clinical trials: gluten challenge protocols. To minimize expectation bias and placebo effects, they recommended including both sham gluten arms and placebo run-in periods to evaluate nocebo effects and exclude placebo responders. These methodological refinements are crucial given that symptoms such as diarrhea and bloating are highly sensitive to expectation bias in trial settings. The standardized approach helps ensure that observed treatment effects represent genuine therapeutic benefit rather than psychological responses to study participation. Global Network Capabilities: Accelerating Patient Access Diagnosis delays often hinder trial recruitment efforts. In the U.S., individuals may wait 10 years or more from symptom onset to celiac diagnosis.⁶⁻⁷ As such, successful celiac disease trials require access to diverse patient populations across multiple geographic regions. The ability to efficiently identify and enroll patients through extensive site networks spanning North America, Europe, and Asia-Pacific regions is paramount to achieving adequate statistical power and regulatory acceptance. Specialized expertise in gastroenterology site activation becomes particularly important given the complexity of these standardized protocols. Expert central reading capabilities ensure consistent histopathologic interpretation across multiple study sites, minimizing inter-observer variability and strengthening the reliability of trial results. The integration of translational medicine approaches, including advanced biomarker research and immunohistochemistry techniques, promises to further enhance our understanding of treatment mechanisms and optimize patient selection strategies. The Future of Celiac Disease Drug Development The establishment of standardized clinical trial methodologies is in progress, and that work promises to be a turning point for celiac disease drug development. With consistent frameworks in place, pharmaceutical companies can design more efficient studies, regulatory agencies can make more informed decisions, and patients can benefit from accelerated access to breakthrough therapies. Success in celiac disease drug development requires more than just innovative compounds; it demands expertise in specialized trial design, access to global patient populations, and the infrastructure to execute complex studies with scientific rigor. The organizations that combine deep gastroenterology expertise with operational excellence, standardized methodologies, and comprehensive endpoint assessment capabilities will be best positioned to bring life-changing therapies to the millions of patients who need them. Alimentiv brings over 30 years of GI clinical research leadership to celiac disease trials, applying the same proven approach that made us leaders in inflammatory bowel disease research. We accelerate celiac disease drug development through: Medical research expertise: Access to clinical trial design and outcome measures development expertise Strategic KOL network: Active collaboration and engagement with celiac KOLs and key advocacy groups Global site network: 5,000+ specialized GI sites across 60+ countries Expert histopathology readers: Consistent, accurate assessments, standardized scoring Advanced imaging solutions: Objective, quantitative measures Translational medicine: Advanced biomarker research and centralized histopathology Our commitment goes beyond running trials — we’re advancing the science itself by contributing to the research priorities experts identified as crucial for optimizing celiac disease studies. When the bar for new therapies is exceptionally high, you need a CRO that combines deep scientific expertise with proven operational excellence. Contact Alimentiv to discuss your goals. References Lebwohl, B., Ma, C., Lagana, S., et al. Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study. Gastroenterology. Published 2024 January. Gottlieb, K., Dawson, J., Hussain, F., et al. Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials. Gastroenterol Report. Published 2015 February 26. United States Food and Drug Administration. Draft Guidance: Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet. FDA.gov. Published 2022 April. Adelman, D.C., Murray, J., Wu, T.T., et al. Measuring Change In Small Intestinal Histology In Patients With Celiac Disease. American Journal of Gastroenterology. Published 2018 February 20. Clifford S., Taylor, A., Gerber, M., et al. Concepts and Instruments for Patient-Reported Outcome Assessment in Celiac Disease: Literature Review and Experts’ Perspectives. Value in Health. Published 2020 January. Norström, F., Lindholm, L., Sandström, O. et al. Delay to celiac disease diagnosis and its implications for health-related quality of life. BMC Gastroenterology. Published 2011 November. Beyond Celiac. (n.d.). Celiac Disease: Facts and Figures. https://www.beyondceliac.org/celiac-disease/facts-and-figures.
