Assyro AI
US FDA•United StatesAL•Approval Letter

Approval Letter Other 761115 (Jan 1, 2020)

Issued January 1, 2020

Issued

January 1, 2020

Application

Other • 761115

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Product may be marketed.

Summary

This is a Complete Response Letter (CRL) from the FDA regarding Biologics License Application (BLA) 761115 for sacituzumab govitecan, indicating that the application cannot be approved in its present form due to various deficiencies related to product quality, manufacturing, labeling, facility inspections, and safety data.

Key points

  • Provide information and data to support the manufacture of a product with continued safety, purity, and potency, addressing issues identified during the pre-license inspection and subsequent communications.
  • Provide evidence to support manufacturing information provided during the pre-license inspection and in response to agency IRs.
  • Provide adequate data and information to confirm the product is currently intended for commercial manufacture.
  • Provide a root cause analysis, supported by appropriate documentation, for observed trends.
  • Provide adequate information and data to support the testing strategy.
  • Implement appropriate assay controls as committed in response to the agency's IR dated November 13, 2018.
  • Revise the specifications, as appropriate, and provide information and data.
  • Provide additional information and data to support insufficient information previously provided.

Cited reasons

  • Insufficient Manufacturing Information and Data
  • Inadequate Method Validation
  • Insufficient Shipping Validation
  • Non-conformance of Prescribing Information (PI)
  • Deficiencies in Carton and Container Labeling
  • Unresolved Objectionable Conditions at Manufacturing Facility
  • Requirement for Comprehensive Safety Update
  • The application cannot be approved in its present form due to significant product quality issues identified during pre-license inspection and subsequent communications, insufficient data to support manufacturing processes, testing strategies, specifications, method validation, and shipping validation. Additionally, there are deficiencies in prescribing information and carton/container labeling, and unresolved objectionable conditions at the manufacturing facility. A comprehensive safety update is also required upon resubmission.

Recommended actions

  • Provide information and data to support the manufacture of a product with continued safety, purity, and potency, addressing issues identified during the pre-license inspection and subsequent communications.
  • Provide evidence to support manufacturing information provided during the pre-license inspection and in response to agency IRs.
  • Provide adequate data and information to confirm the product is currently intended for commercial manufacture.
  • Provide a root cause analysis, supported by appropriate documentation, for observed trends.
  • Provide adequate information and data to support the testing strategy.
  • Implement appropriate assay controls as committed in response to the agency's IR dated November 13, 2018.
  • Revise the specifications, as appropriate, and provide information and data.
  • Provide additional information and data to support insufficient information previously provided.

Deficiency summary

The application cannot be approved in its present form due to significant product quality issues identified during pre-license inspection and subsequent communications, insufficient data to support manufacturing processes, testing strategies, specifications, method validation, and shipping validation. Additionally, there are deficiencies in prescribing information and carton/container labeling, and unresolved objectionable conditions at the manufacturing facility. A comprehensive safety update is also required upon resubmission.

Findings

Insufficient Manufacturing Information and Data

Severity: critical

The agency cannot approve the application due to concerns regarding the manufacturing process, specifically related to ensuring continued safety, purity, and potency. This includes issues identified during the pre-license inspection (Form 483), insufficient data to support manufacturing processes, testing strategies, and specifications. There's a need for root cause analysis for observed trends and implementation of appropriate assay controls.

Recommended response: Provide comprehensive information and data to support all manufacturing processes, testing strategies, and specifications. Conduct a thorough root cause analysis for any observed trends and implement appropriate assay controls. Address all observations from the pre-license inspection and Form 483.

Cited: 21 CFR 601.20 (c) 'No product shall be licensed if any pa1i of the process of or relating to the m anufacture of such product. .. wo uld impair the assurances of continued safety, purity, and potency ... '

Inadequate Method Validation

Severity: major

The information provided regarding method validation is insufficient. Specific details are redacted, but the general nature indicates a lack of adequate data and documentation.

Recommended response: Provide complete and adequate data and documentation for method validation, addressing the specific deficiencies identified by the agency.

Insufficient Shipping Validation

Severity: major

The shipping validation studies submitted for hRS7 antibody intermediate and IMMU-132 DP are insufficient. Detailed information (e.g., study conditions, justification) and data (e.g., product quality data before and after shipping) are required to assess the impact of shipping on product quality and to support validation of all shipping routes, modes of transportation, and containers for commercial use.

Recommended response: Conduct and submit detailed shipping validation studies, including comprehensive data and justification, to demonstrate that shipping conditions do not adversely impact the quality of hRS7 and IMMU-132 DP. Ensure all commercial shipping parameters are validated.

Non-conformance of Prescribing Information (PI)

Severity: major

The proposed prescribing information does not conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57. The agency has provided proposed revisions and encourages review of labeling resources.

Recommended response: Revise the prescribing information to conform to 21 CFR 201.56(a), (d), and 201.57, incorporating agency-proposed revisions. Utilize the SRPI checklist and submit updated content in SPL format with a marked-up copy.

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

Deficiencies in Carton and Container Labeling

Severity: major

Draft carton and container labeling needs to be submitted based on agency-proposed revisions.

Recommended response: Submit revised draft carton and container labeling that incorporates the agency's proposed revisions.

Unresolved Objectionable Conditions at Manufacturing Facility

Severity: critical

During a recent inspection of the Immunomedics, Inc. manufacturing facility (FEI 1000526871), objectionable conditions were observed. Satisfactory resolution of these observations is required before BLA approval.

Recommended response: Address and satisfactorily resolve all objectionable conditions observed during the manufacturing facility inspection. Provide documentation of corrective and preventive actions.

Requirement for Comprehensive Safety Update

Severity: major

Upon resubmission, a comprehensive safety update is required 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 combining new and original data, comparison tables, separate tables for other indications, retabulation of premature trial discontinuations, case report forms/narratives for deaths/serious adverse events, information on changes in common adverse events, updated exposure information, and a summary of worldwide experience.

Recommended response: Prepare and submit a complete safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b), ensuring all specified data and analyses are included.

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

Regulatory context

Submission stage
final decision
Regulatory pathway
Biologics License Application (BLA) under section 351(a) of the Public Health Service Act

Impact

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

Strategic insights

The application received a Complete Response Letter primarily due to significant manufacturing and product quality deficiencies, unresolved facility inspection findings, and non-compliance in labeling. A comprehensive safety update is also mandated for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

Document viewer

Read the FDA letter and send context to the co-pilot at any time.

Loading document viewer…