Approval Letter Other 213976 (Jan 1, 2024)

The results from the evaluation of the symptomatic coprimary endpoint in trial SHP621-301, while statistically significant, were not representative of clinically meaningful change. The anchor-based analyses did not support the clinical meaningfulness of the ≥30 percent Dysphagia Symptom Questionnaire (DSQ) responder threshold. Additionally, the contribution of the statistically significant histologic coprimary endpoint in trial SHP621-301 is unclear due to the lack of sustained histologic response in trial SHP621-302 and inadequate data to demonstrate that short-term histologic improvement predicts meaningful clinical outcomes.

Recommended response: Leverage existing data to inform the design of a new adequate and well-controlled study. This new study should assess prespecified symptomatic and histologic coprimary endpoints. Propose an appropriate range of clinically meaningful within-patient DSQ score change using anchor-based methods (e.g., patient global impression scale as an anchor), supplemented with empirical cumulative distribution function (eCDF) curves using data pooled across treatment arms. Complete this study before resubmitting the application.

The evaluation of the key secondary efficacy endpoint of absolute change from baseline in 14-day DSQ combined score for trial SHP621-301 did not demonstrate meaningful benefit compared to placebo. The treatment difference was small, and the assessment period was not supported by the 7-day Patient Global Impression of Severity (PGIS). No treatment difference was observed when assessed over 7 days to match PGIS.

Recommended response: Ensure consistency in assessment periods for symptomatic endpoints and their anchors in future studies, as part of the overall new study design.

As EoE is a chronic relapsing condition, data to establish the benefit of long-term treatment is needed to support durability of effect. Despite prior communications emphasizing this need, the submitted phase 3 trial SHP621-302 efficacy data did not establish the benefit of long-term treatment, failing to show statistically significant results on the pre-specified long-term efficacy endpoint of relapse.

Recommended response: Conduct a new study with a treatment period of at least 24 weeks’ duration to assess efficacy for both clinical and histologic endpoints, followed by an extension period to provide a total treatment period of at least 52 weeks’ duration to ensure adequate exposure for safety characterization and durability of response.

Data from post hoc subgroup analyses of subjects without prior history of dilation for the 12-week initial treatment period are inadequate to support efficacy. Dilation status was identified as a subgroup of interest only after data unblinding, and the variable used was unreliable as a substantial portion of subjects were identified by self-report without medical record confirmation. Analysis of subjects with medical record confirmation showed minimal separation between treatment groups.

Recommended response: Design a new adequate and well-controlled study including adolescent and adult subjects with EoE in a prespecified subpopulation (e.g., subjects without a prior history of dilation, subjects with more severe dysphagia symptoms at baseline). If subjects with a prior history of dilation are to be included for analysis, medical record documentation of the procedure should be available for these subjects.

A food effect study was not conducted with either the phase 3 or to-be-marketed formulation. The effect of food on the pharmacokinetics (PK) and safety of budesonide oral suspension (BOS) is unknown, which is critical given that adverse events like hypercortisolism and adrenal axis suppression are concentration-dependent. A dedicated food effect study is needed to inform prescribing information.

Recommended response: Conduct a dedicated food effect study and include results in the resubmission to inform prescribing information.

Only limited dissolution data with the proposed dissolution method collected at the time of batch release were provided. Full-profile dissolution data (n=12) are required for any newly manufactured batches to resolve deficiencies, or for the first six commercial batches post-approval for annual reports.

Recommended response: If manufacturing any new batch to resolve deficiencies, provide full-profile dissolution data (n=12) from that newly manufactured batch at the time of batch-release in the next submission. If no new batch manufacturing is required, collect full-profile dissolution data (n=12) for the first six commercial batches at the time of batch-release upon approval and provide these data in annual reports.

The proposed proprietary name, Eohilia, was found acceptable pending approval of the application in the current review cycle. It needs to be resubmitted when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name with the response to deficiencies.

A safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included with the response to deficiencies. It should cover data from all nonclinical and clinical studies/trials, describe significant changes or findings in the safety profile, and include sections on discontinuations due to adverse events.

Recommended response: Prepare and submit a comprehensive safety update with the resubmission, detailing any changes in the safety profile and discontinuations due to adverse events.

Cited: 21 CFR 314.50(d)(5)(vi)(b)