Approval Letter Other 210282 (Jan 1, 2022)

Summary

This is a Complete Response letter from the FDA to Hospira, Inc. regarding their New Drug Application (NDA) 210282 for Daptomycin for Injection. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to facility inspections, product quality (elemental impurities), and prescribing information. The letter outlines specific requirements for addressing these issues, including a comprehensive safety update, and provides instructions for resubmission or other actions.

Key points

• Satisfactorily resolve deficiencies identified during the manufacturing facility inspection.
• Provide a product risk assessment focused on assessing the levels of elemental impurities in the drug product in relation to the safety recommendations in the ICH Q3D Elemental Impurities guidance.
• Review labeling resources and revise labeling to conform with 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 [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format.
• 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.
• The safety update must incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, presenting new data from studies/clinical trials for the proposed indication, tabulations of new safety data combined with original application data, tables comparing frequencies of adverse events, and separate tables for adverse events in clinical trials for other indications.
• The safety update must present a retabulation of reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns.

Cited reasons

• Unresolved Manufacturing Facility Deficiencies
• Elemental Impurities Risk Assessment
• Incomplete Clinical Safety Data Update
• Missing Case Report Forms and Narrative Summaries
• Incomplete Foreign Labeling Translations
• Labeling Content and Format Issues
• The application for Daptomycin for Injection was not approved due to unresolved manufacturing facility deficiencies, a lack of a comprehensive elemental impurities risk assessment, significant missing clinical safety data including case report forms and a complete safety update, and incomplete labeling information requiring specific content and formatting updates.

Recommended actions

• Satisfactorily resolve deficiencies identified during the manufacturing facility inspection.
• Provide a product risk assessment focused on assessing the levels of elemental impurities in the drug product in relation to the safety recommendations in the ICH Q3D Elemental Impurities guidance.
• Review labeling resources and revise labeling to conform with 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 [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format.
• 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.
• The safety update must incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, presenting new data from studies/clinical trials for the proposed indication, tabulations of new safety data combined with original application data, tables comparing frequencies of adverse events, and separate tables for adverse events in clinical trials for other indications.
• The safety update must present a retabulation of reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns.

Deficiency summary

The application for Daptomycin for Injection was not approved due to unresolved manufacturing facility deficiencies, a lack of a comprehensive elemental impurities risk assessment, significant missing clinical safety data including case report forms and a complete safety update, and incomplete labeling information requiring specific content and formatting updates.

Findings

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 primary themes for non-approval are critical manufacturing quality issues, insufficient product quality data regarding elemental impurities, and substantial deficiencies in clinical safety data reporting and analysis, compounded by incomplete and improperly formatted labeling.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%