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Regulatory Focus™ > News Articles > 2020 > 9 > FDA finalizes guidance on clinical trials, drug development for EoE

FDA finalizes guidance on clinical trials, drug development for EoE

Posted 24 September 2020 | By Renee Matthews 

FDA finalizes guidance on clinical trials, drug development for EoE

The US Food and Drug Administration (FDA) has finalized a guidance for industry on development of drugs and therapeutic biologics for treating eosinophilic esophagitis (EoE), a chronic, allergic inflammatory disease of the esophagus, for which there are currently no approved therapies.
 
The guidance addresses the agency’s thinking on clinical trials and development programs, focusing on trial population and design, efficacy and safety, as well as pediatric considerations. It also includes a change in recommendations for analyzing clinical outcome assessments (COAs), which are measures for describing outcomes based on how a patient feels or functions. The information can be patient, observer, or clinician reported.
 
Patient population
In regard to trial population, the guidance notes patients should be screened before randomization to confirm histologic eligibility and their symptoms documented. Esophagogastroduodenoscopy (EGD) can be used for histologic diagnosis and trial eligibility, and biopsies should be taken at the proximal and distal esophagus. In pediatric patients, biopsy specimens should also be taken during EGD from the stomach and duodenum to rule out other etiologies. The guidance recommends area of the high-power field (HPF) be expressed in mm2 or μm2 and eosinophil density as per mm2 to avoid variability across trial sites. In addition, having a central reader could help ensure consistency in histologic evaluations.
 
Patients with a history of stricture should be included in clinical trials if existing data suggest they may respond to the trial therapy. All patients should also maintain a stable diet and medication doses for the duration of the trial.
 
Trial design
The guidance recommends sponsors use a randomized, double-blind, placebo-controlled trial design, with pre-randomization screening for eligibility. Trials of medications intended for chronic administration should include a treatment period of at least 24 weeks for assessing clinical and histologic efficacy, extended to a 52-week treatment period for evaluating safety and durability of response.
 
“Long-term data from the treatment and extension period should be available before the submission of an application for registration,” the guidance notes, adding that sponsors should inform FDA how many patients with a minimum exposure of a year will be available on submission of the application. When appropriate, a randomized withdrawal design included after efficacy has been established could help understand relapse and the need for redosing.
 
Efficacy assessment
When assessing efficacy, clinical trials to support marketing approval of the EoE therapy should evaluate the trial drug’s impact on disease signs and symptoms and associated inflammation. The guidance suggests including coprimary endpoints in Phase 3 trials that assess both EoE signs and symptoms using a reliable COA instrument and the histologic response of peak esophageal eosinophil count per HPF of ≤6 at final evaluation. It also suggests collection of additional data on endoscopic findings, such as edema and exudates, and histologic features, such as eosinophil density and dilated intercellular spaces.
 
Sponsors planning to use a COA instrument should be in contact with the agency throughout drug development to address potential challenges in developing the instrument. The guidance suggests sponsors develop or adapt existing instruments for gathering patient- and observer-reported outcomes (PROs and ObsROs)on disease symptoms because there is currently no reliable PRO or ObsRO instrument for EoE that is acceptable for regulatory use. It recommends sponsors use Phase 2 trial data for finalizing scoring algorithms and defining endpoints. The instruments should be used with daily assessments and completed at the same time each day.  
 
Regarding statistical considerations, the guidance says sponsors should “prespecify a primary estimand of interest for each endpoint” and justify that it is meaningful. For more precise evaluation of the overall treatment effects, it suggests adjusting statistical analyses of baseline patient characteristics, such as strictures or dietary restrictions, which could affect efficacy outcomes. Moreover, the sponsor should propose a clinically meaningful range of within-patient score change to facilitate interpretation of COA endpoint results. Interpretation can be supplemented with empirical cumulative distribution function (eCDF) curves. The sponsor should submit eCDF curves by treatment arm and descriptive analyses of within-patient changes from baseline to the FDA for review.
 
Safety considerations
If the study drug is a corticosteroid, the guidance suggests patients be examined for signs of glucocorticoid excess at each visit and assessed for hypothalamic-pituitary-adrenal (HPA) axis suppression at preestablished points during Phase 2 and 3 trials, extension trials, and 6 weeks post trial.
 
For trials using potentially immunogenic therapeutic protein products (e.g., monoclonal antibodies), sponsors should follow existing guidance for immunogenicity assessment for those products.
 
Inclusion of younger patients
The guidance encourages inclusion of adolescent patients (aged 12-17 years) with EoE in drug development trials should adult safety and efficacy data support such a move. Adolescent trials should be followed by trials for pediatric patients younger than 12 years, again guided by safety and efficacy data from adolescent and adult trials. EGD can be used to assess EoE histologic diagnostic criteria in this younger population.
 
Pediatric patients in trials with corticosteroid therapies should be monitored for HPA suppression, growth and Tanner sexual maturity stages.
 
The latest guidance finalizes a draft issued in February 2019. The FDA notes the current guidance does not address clinical development of therapies for non-EoE eosinophilic gastrointestinal disorders

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