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US FDA•United StatesAL•Approval Letter

Approval Letter Other 210735 (Jan 1, 2022)

Issued January 1, 2022

Issued

January 1, 2022

Application

Other • 210735

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2023Product may be marketed.

Summary

The FDA issued a Complete Response letter for AuroMedics Pharma LLC's New Drug Application (NDA) 210735 for Cyclophosphamide Injection, indicating that the application cannot be approved in its current form due to several deficiencies. These deficiencies include unresolved issues from a facility inspection, non-conformance of proposed Prescribing Information (PI) with regulatory requirements, and incomplete safety update information.

Key points

  • Satisfactorily resolve deficiencies noted during the inspection of the drug substance manufacturing facility.
  • List all communications submitted to or held with the Agency to facilitate resolution of observed objectionable conditions or deficiencies at the facility.
  • Ensure the proposed Prescribing Information (PI) conforms to the content and format regulations at 21 CFR 201.56(a) and (d) and 201.57.
  • Review labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites.
  • Submit draft labeling that addresses the FDA's proposed revisions.
  • Use the SRPI checklist to correct any formatting errors in the PI to ensure conformance with regulations and guidances.
  • Submit updated content of labeling in Structured Product Labeling (SPL) format as described at FDA.gov, per 21 CFR 314.50(l)(1)(i).
  • Provide a highlighted or marked-up copy of the labeling showing all changes, along with a clean Word version, including annotations to support proposed changes.

Cited reasons

  • Unresolved Manufacturing Facility Deficiencies
  • Non-conformance of Prescribing Information (PI)
  • Carton and Container Labeling Revisions Required
  • Inadequate Safety Update
  • The application cannot be approved in its present form due to unresolved deficiencies from a manufacturing facility inspection, non-conformance of Prescribing Information and carton/container labeling with regulations and proposed revisions, and the need for a comprehensive safety update.

Recommended actions

  • Satisfactorily resolve deficiencies noted during the inspection of the drug substance manufacturing facility.
  • List all communications submitted to or held with the Agency to facilitate resolution of observed objectionable conditions or deficiencies at the facility.
  • Ensure the proposed Prescribing Information (PI) conforms to the content and format regulations at 21 CFR 201.56(a) and (d) and 201.57.
  • Review labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites.
  • Submit draft labeling that addresses the FDA's proposed revisions.
  • Use the SRPI checklist to correct any formatting errors in the PI to ensure conformance with regulations and guidances.
  • Submit updated content of labeling in Structured Product Labeling (SPL) format as described at FDA.gov, per 21 CFR 314.50(l)(1)(i).
  • Provide a highlighted or marked-up copy of the labeling showing all changes, along with a clean Word version, including annotations to support proposed changes.

Deficiency summary

The application cannot be approved in its present form due to unresolved deficiencies from a manufacturing facility inspection, non-conformance of Prescribing Information and carton/container labeling with regulations and proposed revisions, and the need for a comprehensive safety update.

Findings

Unresolved Manufacturing Facility Deficiencies

Severity: major

During a recent inspection of the drug substance manufacturing facility, field investigators conveyed deficiencies that require satisfactory resolution before approval. The company needs to list communications submitted to, or held with, the Agency to facilitate resolution of the observed objectionable conditions.

Recommended response: Address all observed objectionable conditions at the manufacturing facility and provide documentation of resolution efforts and communications with the Agency.

Non-conformance of Prescribing Information (PI)

Severity: major

The proposed Prescribing Information (PI) does not conform to content and format regulations (21 CFR 201.56(a) and (d) and 201.57). Revisions are required based on attached labeling, and the SRPI checklist must be used to correct formatting errors. Updated content of labeling in structured product labeling (SPL) format is also required as per 21 CFR 314.50(l)(1)(i).

Recommended response: Revise the Prescribing Information to comply with 21 CFR 201.56(a), (d), and 201.57, utilizing the SRPI checklist. Submit updated content in SPL format as per 21 CFR 314.50(l)(1)(i), providing marked-up and clean versions.

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

Carton and Container Labeling Revisions Required

Severity: major

Draft carton and container labeling needs to be revised based on the agency's proposed revisions.

Recommended response: Submit revised draft carton and container labeling incorporating the agency's proposed changes.

Inadequate Safety Update

Severity: major

A comprehensive safety update is required as described in 21 CFR 314.50(d)(5)(vi)(b). This includes detailed changes in safety profile, new safety data from studies/trials (for proposed and other indications), retabulation of adverse events and discontinuations, case reports for deaths/serious adverse events, updated exposure information, worldwide experience summary, and English translations of foreign labeling.

Recommended response: Provide a complete safety update as per 21 CFR 314.50(d)(5)(vi)(b), including detailed analysis of safety profile changes, new and retabulated safety data, case reports, updated exposure, worldwide experience, and translated foreign labeling.

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

Regulatory context

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

Impact

Impact score
0.75
Estimated delay
365 days
Estimated rework cost
$0
Subsequent action
resubmission

Strategic insights

The application for Cyclophosphamide Injection received a Complete Response Letter due to unresolved manufacturing facility deficiencies, non-compliant prescribing and carton/container labeling, and an incomplete safety update.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%

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