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US FDA•United StatesAL•Approval Letter

Approval Letter Other 210605 (Jan 1, 2020)

Issued January 1, 2020

Issued

January 1, 2020

Application

Other • 210605

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due December 31, 2020Product may be marketed.

Summary

The FDA issued a Complete Response letter for Mylan GmbH's New Drug Application (NDA 210605) for insulin glargine injection 100 units/mL, indicating that the application cannot be approved in its current form. Key deficiencies include unresolved objectionable conditions at the Biocon Sdn. Bhd. manufacturing facility, non-conformance of proposed Prescribing Information (PI) and Instructions for Use (IFU) with regulatory requirements, and the need for a comprehensive safety update. The letter provides detailed recommendations for addressing these issues and outlines the process for resubmission.

Key points

  • Satisfactorily resolve objectionable conditions observed during the inspection of the Biocon Sdn. Bhd. manufacturing facility (FEI#3011248248).
  • Work with the manufacturing facility to apply necessary resources to address inspectional observations in a timely manner.
  • Ensure proposed Prescribing Information (PI) conforms to content and format regulations at 21 CFR 201.56(a) and (d) and 201.57.
  • Review FDA's labeling review resources, including PLR Requirements and Pregnancy and Lactation Labeling Final Rule websites, for PI development.
  • Update language in the Instructions for Use (IFU) to consistently reference 'Step 8 Needle disposal' where appropriate.
  • Revert to prior sub-bullet letter designations (A, B, C, etc.) under each numbered step in the pen IFUs, as used in the Human Factors study.
  • Use the Selected Requirements for Prescribing Information (SRPI) checklist to correct any formatting errors in the labeling.
  • Submit updated content of labeling in Structured Product Labeling (SPL) format as described at FDA.gov, per 21 CFR 314.50(l)(1)(i).

Cited reasons

  • Unresolved Manufacturing Facility Inspection Observations
  • Prescribing Information (PI) Content and Format Issues
  • Structured Product Labeling (SPL) and Formatting Errors
  • Carton and Container Labeling Discrepancy
  • Proprietary Name Resubmission Required
  • Incomplete Safety Update
  • Clinical-Related Major Deficiencies (Process VI Product)
  • The FDA issued a Complete Response Letter for the insulin glargine injection NDA, citing unresolved manufacturing facility inspection observations, multiple deficiencies in prescribing information and other labeling, the need for a proprietary name resubmission, and a requirement for a comprehensive safety update. A critical clinical deficiency regarding manufacturing process changes was also identified.

Recommended actions

  • Satisfactorily resolve objectionable conditions observed during the inspection of the Biocon Sdn. Bhd. manufacturing facility (FEI#3011248248).
  • Work with the manufacturing facility to apply necessary resources to address inspectional observations in a timely manner.
  • Ensure proposed Prescribing Information (PI) conforms to content and format regulations at 21 CFR 201.56(a) and (d) and 201.57.
  • Review FDA's labeling review resources, including PLR Requirements and Pregnancy and Lactation Labeling Final Rule websites, for PI development.
  • Update language in the Instructions for Use (IFU) to consistently reference 'Step 8 Needle disposal' where appropriate.
  • Revert to prior sub-bullet letter designations (A, B, C, etc.) under each numbered step in the pen IFUs, as used in the Human Factors study.
  • Use the Selected Requirements for Prescribing Information (SRPI) checklist to correct any formatting errors in the labeling.
  • Submit updated content of labeling in Structured Product Labeling (SPL) format as described at FDA.gov, per 21 CFR 314.50(l)(1)(i).

Deficiency summary

The FDA issued a Complete Response Letter for the insulin glargine injection NDA, citing unresolved manufacturing facility inspection observations, multiple deficiencies in prescribing information and other labeling, the need for a proprietary name resubmission, and a requirement for a comprehensive safety update. A critical clinical deficiency regarding manufacturing process changes was also identified.

Findings

Unresolved Manufacturing Facility Inspection Observations

Severity: critical

During a recent inspection of Biocon Sdn. Bhd. FEI#3011248248, a manufacturing facility for this NDA, our field investigator observed objectionable conditions. Satisfactory resolution of the observations is required before this NDA may be approved. This is the second Complete Response letter identifying inspectional observations at this facility.

Recommended response: Work with the manufacturing facility to address inspectional observations and apply necessary resources for timely resolution.

Prescribing Information (PI) Content and Format Issues

Severity: major

Proposed Prescribing Information (PI) must conform to 21 CFR 201.56(a) and (d) and 201.57. Specific issues include: updating language in IFU for pen injector presentations (e.g., 'Step 8 Needle disposal' consistency) and reverting sub-bullet designations in IFU to prior letter designations (A, B, C, etc.) as used in Human Factors study, as current change is considered major.

Recommended response: Review and revise PI to conform to 21 CFR 201.56(a), (d) and 201.57. Specifically, ensure consistency in IFU language and revert sub-bullet formatting to match the Human Factors study.

Cited: 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57

Structured Product Labeling (SPL) and Formatting Errors

Severity: major

Use the SRPI checklist to correct any formatting errors to ensure conformance with regulations and guidances. Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov. Provide a highlighted/marked-up copy showing changes and a clean Word version.

Recommended response: Utilize the SRPI checklist for formatting corrections. Submit updated content of labeling in SPL format and provide both marked-up and clean Word versions of all changes.

Cited: 21 CFR 314.50(l)(1)(i)

Carton and Container Labeling Discrepancy

Severity: minor

Submit draft carton and container labeling that is identical to the carton and container labels submitted on August 28, 2019.

Recommended response: Ensure submitted carton and container labeling is identical to the version submitted on August 28, 2019.

Proprietary Name Resubmission Required

Severity: info

The proposed proprietary name, Semglee, was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name 'Semglee' along with the response to other application deficiencies.

Incomplete Safety Update

Severity: major

When responding to deficiencies, include a comprehensive safety update as described at 21 CFR 314.50(d)(5)(vi)(b). This includes detailed changes in safety profile, new safety data from studies/trials, tabulations of new and combined data, comparison tables, separate tables for other indications, retabulation of premature trial discontinuations, case report forms/narrative summaries for deaths/serious adverse events, information on common adverse events, updated exposure information, worldwide safety experience, and English translations of foreign labeling.

Recommended response: Provide a complete safety update in the resubmission, adhering to 21 CFR 314.50(d)(5)(vi)(b), including all specified data and analyses from nonclinical and clinical studies.

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

Clinical-Related Major Deficiencies (Process VI Product)

Severity: critical

The 505(b)(2) application requests approval of an insulin glargine product manufactured using Process VI, while the product studied in phase 3 clinical trials was manufactured using a different process. This implies a discrepancy between the product used in clinical trials and the product for which approval is sought.

Recommended response: Address the discrepancy between the manufacturing process of the product studied in phase 3 clinical trials and the proposed Process VI product for approval. This may require bridging studies or further justification.

Regulatory context

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

Impact

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

Strategic insights

The application's approval is hindered by persistent manufacturing quality control issues, significant non-compliance with labeling content and formatting regulations, and a fundamental mismatch between the clinically studied product and the proposed commercial product, necessitating substantial re-evaluation and data submission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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