FDA releases draft guidance for drugs under development for celiac disease
The FDA has issued a draft guidance for sponsors developing drugs as adjunctive treatment to a gluten-free diet in adults with celiac disease.
“Specifically, this guidance addresses the FDA’s current recommendations on clinical trials,” the agency wrote. “This guidance also addresses considerations for eligibility criteria, trial design features, efficacy evaluations, clinical outcome assessments and safety assessments.”
The agency noted that the guidance is intended only to provide clarity regarding existing requirements and should be viewed solely as recommendations, unless specific regulatory or statutory requirements are mentioned.
- Patients should undergo diagnostic esophagogastroduodenoscopy with multiple biopsies to confirm celiac diagnosis, including one or two biopsies of the duodenal bulb and at least four biopsies of the distal duodenum.
- Screening esophagogastroduodenoscopy with biopsy should also be performed to ensure patients meet histologic eligibility criteria at the time of trial enrollment; relying on symptomatic assessment alone may result in the inclusion of patients whose symptoms are not caused by celiac disease.
- To allow for evaluation of symptom improvement, patients should be symptomatic at baseline, based on enrollment criteria.
- Prior to trail enrollment and throughout the duration of the trial patients should adhere to a strict gluten-free diet with assistance from experienced dietitians.
- The FDA recommends using randomized, double-blind, placebo-controlled trial design.
- Before randomization of participants, sponsors should include a screening period to confirm histologic eligibility criteria, document clinical signs and symptoms, and train patients and/or providers in collecting clinical outcome assessment data.
- Trial duration and outcome assessments should be informed by the therapy goal, expected drug onset of action and the time frame in which clinical benefit is observable.
- The FDA recommends a placebo-controlled treatment period of at least 52 weeks for drugs intended for chronic use, with continued patient adherence to a gluten-free diet.
- Efficacy assessments for both clinical and histologic endpoints may be evaluated at week 24, and esophagogastroduodenoscopy with biopsy should be performed at week 52 to assess durability of response.
- During the treatment period, sponsors should assess patient adherence to the gluten-free diet.
Efficacy and clinical outcome assessments
- Sponsors should include coprimary endpoints to evaluate a drug’s effect on clinical signs, symptoms and related underlying mucosal inflammation in trials intended to support market approval.
- The FDA recommends a prespecified secondary endpoint to assess the number of patients who observe improvement of clinical signs, symptoms and mucosal inflammation.
- Sponsors should seek FDA input early and when critical milestones are met throughout drug development; patient input should also be utilized to identify disease and treatment burdens.
- Assessments of symptom severity and event-related signs and symptoms should include asking patients to rate their worst experience and frequency of a specific sign or symptom over a 24-hour period.
Statistical and safety considerations
- Trial results should demonstrate statistical significance for both clinical and histological endpoints to support efficacy; analyses should include all randomized patients.
- Sponsors should analyze gluten-free diet adherence, as it could impact efficacy outcomes. Further, sponsors should inform patients of the importance of adhering to a gluten-free diet, given that the therapeutic benefit of the drug is not yet known.
- To characterize the safety profile of drugs intended for long-term use, patients should be exposed to the to-be-marketed dosing regimen for at least 52 weeks.
- The FDA recommends that sponsors plan for safety analyses to compare treatment groups with respect to risk and confidence interval.