Celiac Disease: FDA Offers Guidance on Drug Development
The US Food and Drug Administration (FDA) on Friday issued draft guidance to the industry on developing drugs or biologics to treat celiac disease (CeD) as a complement to a gluten-free diet.
The guidance was developed by the FDA’s Division of Gastroenterology in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The document includes details on eligibility criteria, trial design, considerations for efficacy and safety, and clinical outcome assessments. It does not address the development of drugs intended to replace a gluten-free diet or for treating asymptomatic patients with minimal histologic inflammation.
FDA defines the disease as an “autoimmune condition in which dietary gluten triggers small bowel inflammation and villous atrophy, causing malabsorption and gastrointestinal symptoms. The only treatment for CeD is a strict, lifelong gluten-free diet.” The disease affects approximately 1% of the US population.
The agency said that “proper” biopsy techniques are critical to confirm the disease’s presence and that “multiple” histologic scoring systems have been created to identify and classify the severity of small bowel inflammation.
“The goals of treatment in patients with CeD include resolution of intestinal inflammation and associated clinical signs and symptoms,” the guidance states. “For many adults, strict adherence to a gluten-free diet will result in improvement in both histologic findings and signs and symptoms; however, some adults may not be able to achieve normalization of the mucosa.” It further notes that “complications of CeD include poor growth, osteoporosis, tooth enamel defects, neuropathy, and vitamin deficiencies.”
FDA recommends sponsors confirm a patient’s eligibility to participate by using an esophagogastroduodenoscopy with biopsy to ensure histologic criteria are met at the time of enrollment. Sponsors are encouraged to use a “central reader” to ensure the consistency of histologic evaluations.
Patients should also be “sufficiently symptomatic at baseline” to observe treatment improvements and should “strictly” adhere to a gluten-free diet through the trial’s duration.
Clinical trials should be randomized, double-blind, and controlled by a placebo. The treatment duration should be at least 52 weeks to characterize the drug’s safety profile and durability of response. Patients should record any “unintentional or suspected inadvertent gluten exposure” during the trial.
The recommended primary endpoint for trials is to “assess symptomatic improvement” based on prespecified core signs and symptoms of the disease. The endpoint should not be limited to a single sign or symptom. A secondary endpoint is to evaluate the proportion of patients with improved signs and symptoms of mucosal inflammation.
Sponsors should use “well-defined and reliable” patient-reported outcome (PRO) instruments to assess clinical outcomes. These instruments should be completed by patients at the same time each day.
To ensure that trial results are statistically valid, the guidance recommends that analyses be adjusted to reflect patient characteristics that may impact efficiency outcomes, such as age, duration of disease, disease severity, and the duration of adherence to a gluten-free diet.