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US FDA•United StatesAL•Approval Letter

Approval Letter Other 211413 (Jan 1, 2024)

Issued January 1, 2024

Issued

January 1, 2024

Application

Other • 211413

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due December 31, 2024Product may be marketed.

Summary

The FDA issued a Complete Response letter for NDA 211413 for Cefazolin for Injection USP, indicating non-approval due to deficiencies primarily related to the inadequate safety qualification of identified leachables and incomplete safety updates. The letter provides specific recommendations for addressing these issues and outlines the process for resubmission or further action.

Key points

  • Design nonclinical studies to qualify the safety of leachables such that identified leachables are administered in a clinically relevant manner at levels equivalent to or greater than what patients would be administered, incorporating interspecies allometric scaling.
  • Submit a leachables assessment plan and/or justification that the leachables in the drug product to be administered to animals are qualitatively and quantitatively similar to identified leachables described in Study Report TE190276.
  • Conduct additional (Q)SAR evaluation(s) for bacterial mutagenicity if any additional leachables are characterized or if there are revised structures/identification of new structures compared with previous assessment (TE 190276).
  • Conduct a follow-up Ames test (bacterial reverse mutation assay) to qualify leachables that exceed 120 mcg/day with identified structural alerts for genotoxic potential.
  • Review labeling review resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI).
  • Include updated content of labeling in structured product labeling (SPL) format when revising labeling.
  • Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
  • The safety update must describe in detail any significant changes or findings in the safety profile.

Cited reasons

  • Inadequate Safety Qualification of Identified Leachables
  • Incomplete Clinical Safety Update and Data Reporting
  • The application cannot be approved due to inadequate safety qualification of identified leachables in the drug product and deficiencies in the clinical safety update and data reporting, including missing case report forms, narrative summaries, and updated exposure information.

Recommended actions

  • Design nonclinical studies to qualify the safety of leachables such that identified leachables are administered in a clinically relevant manner at levels equivalent to or greater than what patients would be administered, incorporating interspecies allometric scaling.
  • Submit a leachables assessment plan and/or justification that the leachables in the drug product to be administered to animals are qualitatively and quantitatively similar to identified leachables described in Study Report TE190276.
  • Conduct additional (Q)SAR evaluation(s) for bacterial mutagenicity if any additional leachables are characterized or if there are revised structures/identification of new structures compared with previous assessment (TE 190276).
  • Conduct a follow-up Ames test (bacterial reverse mutation assay) to qualify leachables that exceed 120 mcg/day with identified structural alerts for genotoxic potential.
  • Review labeling review resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI).
  • Include updated content of labeling in structured product labeling (SPL) format when revising labeling.
  • Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
  • The safety update must describe in detail any significant changes or findings in the safety profile.

Deficiency summary

The application cannot be approved due to inadequate safety qualification of identified leachables in the drug product and deficiencies in the clinical safety update and data reporting, including missing case report forms, narrative summaries, and updated exposure information.

Findings

Inadequate Safety Qualification of Identified Leachables

Severity: major

The nonclinical studies (14-day toxicity study in rats) did not achieve clinically relevant leachable exposures, failing to account for interspecies allometric scaling. The proposed acceptable intake for identified leachables was not adequately justified, and QSAR analysis for general toxicity endpoints was deemed insufficient. The applicant inappropriately applied ICH Q3B limits to justify the safety of leachables, which do not apply in this context.

Recommended response: Submit a revised leachables assessment plan and/or justification that leachables in the drug product to be administered to animals are qualitatively and quantitatively similar to identified leachables. Conduct additional (Q)SAR evaluations for bacterial mutagenicity if new leachables are characterized or structures revised. Perform follow-up Ames tests for genotoxic leachables exceeding 120 mcg/day. Conduct a general toxicity study for any leachable exceeding the 5 mcg/day safety qualification threshold for parenteral products.

Incomplete Clinical Safety Update and Data Reporting

Severity: major

The submission requires an updated content of labeling in structured product labeling (SPL) format and a comprehensive safety update as described at 21 CFR 314.50(d)(5)(vi)(b). Specific deficiencies include: lack of separate tables for adverse event frequencies for indications other than the proposed one; missing case report forms and narrative summaries for patient deaths or discontinuations due to adverse events, and for serious adverse events; inadequate updated exposure information for clinical studies/trials; lack of a summary of worldwide safety experience and updated estimate of use for drug marketed in other countries; and missing English translations of current approved foreign labeling.

Recommended response: Provide updated content of labeling in SPL format. Include a comprehensive safety update addressing all specified points: detailed significant changes/findings in safety profile, new safety data tabulations, comparison tables of AE frequencies, separate AE tables for other indications, case report forms and narrative summaries for deaths/discontinuations/serious AEs, updated exposure information, summary of worldwide experience, and English translations of foreign labeling.

Cited: 21 CFR 314.50(l)(1)(i), 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 was not approved primarily due to critical gaps in the nonclinical safety assessment of leachables and significant deficiencies in the clinical safety data presentation and labeling updates required for a complete response.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%

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