US FDA•United StatesAL•Approval Letter

Approval Letter Other 761184 (Jan 1, 2023)

Issued January 1, 2023

Issued

January 1, 2023

Application

Other • 761184

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2024Product may be marketed.

Summary

The FDA issued a Complete Response letter for Biologic License Application (BLA) 761184 for MOD-4023 injection, indicating that the application cannot be approved in its present form. The primary reasons for non-approval include concerns regarding immunogenicity, specifically high rates of anti-drug antibody (ADA) formation and potential for cross-reactivity with other human growth hormone (hGH) products, which could lead to attenuation of effectiveness and non-responsiveness to other therapies. The FDA also noted that required facility inspections could not be completed due to travel restrictions. The letter outlines specific recommendations and requirements for the applicant to address these deficiencies.

Key points

Provide reassurance that anti-drug antibody (ADA) formation caused by MOD-4023 is not expected to impact long-term growth or interfere with other hGH formulations.
Provide data to show that ADA (including neutralizing antibodies) meaningfully decrease or resolve with MOD-4023 discontinuation and/or changing patients to other approved hGH formulations.
If neutralizing antibodies do not resolve, provide data that long-term growth is not impacted.
Provide mitigation strategies to address the potential impact of neutralizing antibodies.
Review labeling review resources, regulations, and guidance documents for the proposed labeling.
Resubmit the proposed proprietary name when responding to the application deficiencies.
Address findings from required facility inspections of Pfizer Ireland Pharmaceuticals and Pfizer Manufacturing Belgium NV once completed.
Include a safety update when responding to deficiencies, detailing any significant changes or findings in the safety profile.

Cited reasons

Unfavorable Benefit-Risk Profile due to Immunogenicity
Uncompleted Manufacturing Facility Inspections
Comprehensive Safety Update Required
Proprietary Name Resubmission
Prescribing Information and Carton/Container Labeling Comments Reserved
The application for MOD-4023 injection received a Complete Response due to an unfavorable benefit-risk profile primarily driven by significant immunogenicity (high rates of anti-drug antibody and neutralizing antibody formation) and uncompleted manufacturing facility inspections. Additional issues include the need for a comprehensive safety update and resubmission of the proprietary name.

Recommended actions

Provide reassurance that anti-drug antibody (ADA) formation caused by MOD-4023 is not expected to impact long-term growth or interfere with other hGH formulations.
Provide data to show that ADA (including neutralizing antibodies) meaningfully decrease or resolve with MOD-4023 discontinuation and/or changing patients to other approved hGH formulations.
If neutralizing antibodies do not resolve, provide data that long-term growth is not impacted.
Provide mitigation strategies to address the potential impact of neutralizing antibodies.
Review labeling review resources, regulations, and guidance documents for the proposed labeling.
Resubmit the proposed proprietary name when responding to the application deficiencies.
Address findings from required facility inspections of Pfizer Ireland Pharmaceuticals and Pfizer Manufacturing Belgium NV once completed.
Include a safety update when responding to deficiencies, detailing any significant changes or findings in the safety profile.

Deficiency summary

The application for MOD-4023 injection received a Complete Response due to an unfavorable benefit-risk profile primarily driven by significant immunogenicity (high rates of anti-drug antibody and neutralizing antibody formation) and uncompleted manufacturing facility inspections. Additional issues include the need for a comprehensive safety update and resubmission of the proprietary name.

Findings

Unfavorable Benefit-Risk Profile due to Immunogenicity

Severity: critical

High rate of anti-drug antibody (ADA) formation (77% vs 16% for comparator) and persistent antibodies (76% vs 5%) in MOD-4023 treated subjects. Five subjects developed neutralizing antibodies, with one showing a concerning reduction in annualized height velocity (AHV). Concerns exist regarding potential cross-reactivity with other hGH products and non-responsiveness to alternative therapies. Given the availability of other hGH therapies without this risk, MOD-4023 does not address an unmet need, leading to an unfavorable benefit-risk profile.

Recommended response: Provide reassurance that ADA formation will not impact long-term growth or interfere with other hGH formulations. Submit data demonstrating ADA/neutralizing antibody resolution upon discontinuation or switching to other hGH products. If neutralizing antibodies persist, provide data that long-term growth is not impacted. Propose mitigation strategies for the potential impact of neutralizing antibodies.

Uncompleted Manufacturing Facility Inspections

Severity: critical

Required inspections of Pfizer Ireland Pharmaceuticals (Dublin) and Pfizer Manufacturing Belgium NV facilities could not be completed during the current review cycle due to U.S. Government and/or Agency-wide travel restrictions. Approval is contingent upon successful completion and assessment of these inspections for CGMP compliance.

Recommended response: Address all other deficiencies in the Complete Response letter. The application cannot be approved until the required FDA inspections are completed and their findings assessed.

Comprehensive Safety Update Required

Severity: major

A comprehensive safety update is required with the response to the deficiencies. This update must include data from all nonclinical and clinical studies/trials, detailed changes in the safety profile, updated tabulations of adverse events (including comparisons to original data), case report forms and narrative summaries for deaths or discontinuations due to adverse events, updated exposure information, and a summary of worldwide safety experience.

Recommended response: Prepare and submit a detailed safety update as specified, incorporating all new safety data and analyses from all relevant studies and worldwide experience.

Proprietary Name Resubmission

Severity: minor

The proposed proprietary name, Ngenla, was found acceptable pending approval of the application. Resubmission of the proposed proprietary name is required when responding to the application deficiencies.

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

Prescribing Information and Carton/Container Labeling Comments Reserved

Severity: info

Comments on the proposed prescribing information and carton/container labeling are reserved until the application is otherwise adequate. The agency encourages review of available labeling resources.

Recommended response: Review the Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents, in preparation for future labeling updates once other deficiencies are resolved.

Regulatory context

Submission stage: final decision
Regulatory pathway: BLA 351(a)

Impact

Impact score: 0.95
Estimated delay: 540 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary themes for this Complete Response are significant clinical immunogenicity concerns leading to an unfavorable benefit-risk assessment for MOD-4023, coupled with uncompleted manufacturing facility inspections that prevent approval. A comprehensive safety update and administrative labeling resubmission are also required.

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…