US FDA•United StatesAL•Approval Letter

Approval Letter Other 213426 (Jan 1, 2022)

Issued January 1, 2022

Issued

January 1, 2022

Application

Other • 213426

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2023Product may be marketed.

Summary

This is a Complete Response Letter from the FDA to Esteve Pharmaceuticals, S.A. regarding their New Drug Application (NDA) 213426 for celecoxib and tramadol hydrochloride tablets. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to facility inspections, prescribing information, proprietary name resubmission, Risk Evaluation and Mitigation Strategy (REMS) requirements, and safety updates.

Key points

The applicant must ensure a satisfactory inspection of the manufacturing facility is completed before the application can be approved.
The applicant must notify the FDA in writing when the manufacturing facility is ready for inspection.
The proposed Prescribing Information (PI) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.
The applicant should review labeling review resources on the PLR and Pregnancy and Lactation Labeling Final Rule websites.
The applicant must resubmit the revised draft labeling and medication guide with their complete response submission.
Prior to resubmitting the labeling, the applicant must use the SRPI checklist to correct any formatting errors to ensure conformance with regulations and guidances.
The applicant must submit updated content of labeling (21 CFR 314.50(l)(1)(i)) in structured product labeling (SPL) format.
To facilitate review, the applicant must provide a highlighted or marked-up copy showing all proposed changes, as well as a clean Word version, with annotations supporting changes.

Cited reasons

Incomplete Manufacturing Facility Inspection
Prescribing Information (PI) Format and Content Deficiencies
Proprietary Name Resubmission Required
Risk Evaluation and Mitigation Strategy (REMS) Discussion Pending
Comprehensive Safety Update Required
Nonclinical Literature Review for PLLR Labeling
The application cannot be approved in its present form due to an incomplete manufacturing facility inspection, significant deficiencies in Prescribing Information format and content, pending discussion on the Risk Evaluation and Mitigation Strategy (REMS), and the need for a comprehensive safety update and nonclinical literature review to support labeling.

Recommended actions

The applicant must ensure a satisfactory inspection of the manufacturing facility is completed before the application can be approved.
The applicant must notify the FDA in writing when the manufacturing facility is ready for inspection.
The proposed Prescribing Information (PI) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.
The applicant should review labeling review resources on the PLR and Pregnancy and Lactation Labeling Final Rule websites.
The applicant must resubmit the revised draft labeling and medication guide with their complete response submission.
Prior to resubmitting the labeling, the applicant must use the SRPI checklist to correct any formatting errors to ensure conformance with regulations and guidances.
The applicant must submit updated content of labeling (21 CFR 314.50(l)(1)(i)) in structured product labeling (SPL) format.
To facilitate review, the applicant must provide a highlighted or marked-up copy showing all proposed changes, as well as a clean Word version, with annotations supporting changes.

Deficiency summary

The application cannot be approved in its present form due to an incomplete manufacturing facility inspection, significant deficiencies in Prescribing Information format and content, pending discussion on the Risk Evaluation and Mitigation Strategy (REMS), and the need for a comprehensive safety update and nonclinical literature review to support labeling.

Findings

Incomplete Manufacturing Facility Inspection

Severity: critical

The field investigator could not complete the inspection of the manufacturing facility because it was not ready for inspection. A satisfactory inspection is required before the application can be approved. The company must notify the agency when the facility is ready.

Recommended response: Ensure the manufacturing facility is fully prepared for inspection and promptly notify the FDA in writing to schedule a re-inspection.

Prescribing Information (PI) Format and Content Deficiencies

Severity: major

The proposed Prescribing Information (PI) does not conform to content and format regulations 21 CFR 201.56(a), (d), and 201.57. Formatting errors need correction using the SRPI checklist, and updated content of labeling (21 CFR 314.50(l)(1)(i)) must be submitted in Structured Product Labeling (SPL) format. A highlighted/marked-up copy and a clean Word version are required.

Recommended response: Revise the draft labeling and medication guide to comply with 21 CFR 201.56(a), (d), 201.57, and 314.50(l)(1)(i). Utilize the SRPI checklist for formatting, submit in SPL format, and provide both marked-up and clean Word versions.

Cited: 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57, 21 CFR 314.50(l)(1)(i)

Proprietary Name Resubmission Required

Severity: minor

The proposed proprietary name, Seglentis, was found acceptable pending approval of the application. It must be resubmitted when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name 'Seglentis' as part of the complete response submission.

Risk Evaluation and Mitigation Strategy (REMS) Discussion Pending

Severity: major

Discussion of the proposed REMS will continue after the complete response to this action letter has been submitted. The proposed REMS and related materials should be submitted in Microsoft Word format and clearly designated.

Recommended response: Prepare for further discussion on the proposed REMS and submit all related materials in Microsoft Word format, clearly labeling them as 'PROPOSED REMS for NDA 213426-AMENDMENT'.

Cited: Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA)

Comprehensive Safety Update Required

Severity: major

A comprehensive safety update, as described in 21 CFR 314.50(d)(5)(vi)(b), is required. This includes data from all nonclinical and clinical studies, detailed changes in the safety profile, updated adverse event tabulations, reasons for premature trial discontinuations, case reports for deaths/serious adverse events, and worldwide experience.

Recommended response: Provide a detailed safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b), incorporating all requested nonclinical and clinical safety data and analyses.

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

Nonclinical Literature Review for PLLR Labeling

Severity: major

The previous literature search for PLLR labeling was insufficient. The company must provide summaries of published nonclinical literature for tramadol or celecoxib, including specific articles identified by the FDA, that could inform labeling regarding pregnancy, lactation, and fertility, and discuss their relevance.

Recommended response: Conduct a thorough review of the cited nonclinical literature for tramadol and celecoxib, provide summaries, and discuss the implications for pregnancy, lactation, and fertility labeling.

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b)(2)

Impact

Impact score: 0.95
Estimated delay: 365 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

Approval is withheld due to critical manufacturing site readiness issues and substantial deficiencies across labeling, safety data, and regulatory compliance, necessitating a comprehensive resubmission addressing all identified concerns.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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