Takeda Pharmaceuticals U.S.A., Inc.: Eohilia

Drug, and Cosmetic Act for Eohilia (budesonide oral suspension).

In situations such as this one we must incorporate regulatory flexibility, while still ensuring there is substantial evidence of effectiveness.

Based upon our review of your submitted data, we are unable to conclude that there is substantial evidence of effectiveness.

We have completed our review of NDA 213976, and have determined that neither the data submitted in the NDA, nor the data submitted to the NDA during review of the application, are adequate to support the demonstration of efficacy of BOS for the treatment of EoE in adult and adolescent patients 11 years and older.

SHP621-301, while statistically significant, were not representative of clinically meaningful change.

Throughout the conduct of the development program and the course of the review, we expressed our concerns with the selection of the 230 percent Dysphagia Symptom Questionnaire (DSQ) responder threshold and cautioned you that evidence was needed to support its clinical meaningfulness.

12-week initial treatment phase 3 trial SHP621-301, do not support that the selected threshold constituted a clinically meaningful within-patient change.

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 that subjects treated with BOS had meaningful benefit compared to those treated with placebo.

To resolve the above-noted deficiencies, we recommend you leverage the existing data to inform the design of 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) to support chronic administration of BOS.

This new study should assess prespecified symptomatic and histologic coprimary endpoints.

To aid in the interpretation of the DSQ results, an appropriate range of within-patient score change that patients consider to be clinically meaningful should be proposed 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.

We look forward to engaging with you as you consider the study design and population selection for a future trial of BOS in patients with EoE and advise you to continue to benefit from the frequent interactions with FDA available to you under your granted breakthrough therapy designation.

This application may need discussion at an advisory committee meeting during the next review cycle.

We have determined that the potential effect of food on budesonide exposure from BOS cannot be predicted based on available data/rationale, and a dedicated food effect study is needed.

Your product is an oral suspension of corticosteroid budesonide, where adverse events including hypercortisolism and adrenal axis suppression have been shown to be concentration dependent.

Therefore, you should conduct a dedicated food effect study to inform the prescribing information for BOS and include the results of this study in the resubmission.

If approval of your proposed product needs manufacturing any new batch to resolve the deficiencies, provide full-profile dissolution data (n= 12) from that newly manufactured batch collected at the time of batch-release in the next submission.

If no new batch manufacturing is required for approval of your product in terms of resolving the deficiencies, only upon approval of the proposed drug product, collect full-profile dissolution data (n= 12) for the first six commercial batches at the time of batch-release and provide these data to the FDA in your annual report.

(5) The human factors (HF) validation study results for your Entyvio prefilled pen submitted on March 7, 2019 identified several use errors, close calls, and use difficulties with critical and non-critical tasks.

Labeling) are based on our review of the subjective feedback and root cause analysis of the use-related issues.

We recommend that you implement these revisions along with additional mitigations that you determine to be necessary to address these use-related issues and conduct and submit results of another human factors validation study to demonstrate that the mitigations are effective and do not introduce new risks.

1. Based on the errors observed and subjective feedback related to removing the cap and placing the needle against the skin, we recommend labeling the needle end on the device body to minimize the risk of a needle stick injury and an underdose.

We acknowledge you submitted a HF study results report on December 9, 2019;

FDA recommends that the human-readable expiration date on the drug package label include a year, month, and non-zero day.

FDA recommends that the expiration date appear in YYYY-MMDD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month.

FDA recommends that a hyphen or a space be used to separate the portions of the expiration date.

Therefore, vedolizumab will be the proper name designated in the license should your 351(a) BLA be approved in a future resubmission.

Satisfactory resolution of these deficiencies is required before this application may be approved in a future resubmission.

1. Reference is made to the deficiencies related to product quality (i.e., for device design, control and performance) and the recommended resolution to these deficiencies as conveyed above.

Therefore, the Chemistry, Manufacturing and Control (CMC) information and data provided are considered inadequate to support the intended performance of the proposed combination products from a biologic product quality perspective.

You should perform a risk assessment to determine the type and amount of additional CMC information and data (e.g., process development, process validation, comparability, compatibility, stability data, etc.) that need to be provided in the BLA resubmission, and update the appropriate Module 3 sections to reflect any CMC changes made to fully address these deficiencies.

CMC changes and/or the manufacture of vedolizumab, device, and final combination product(s) in the resubmission, provide appropriate justification to support the relevance of the information and data.

The updated CMC information and data provided in the resubmission will be evaluated to support the licensure of the proposed combination product(s).

The response to question 5 of sequence 0022 indicates that the rabbit pyrogen test (RPT) will be implemented as an interim release test for the drug product until a suitable in vitro endotoxin method is developed.