Approval Letter Other 761045 (Jan 1, 2019)

Summary

The FDA issued a Complete Response letter for Sandoz Inc.'s Biologics License Application (BLA) 761045 for LA-EP2006, a proposed biosimilar to US-licensed Neulasta. The application cannot be approved in its current form due to deficiencies in demonstrating pharmacokinetic (PK) similarity, establishing a scientific bridge between products, and various product quality issues including media fill validation, requalification strategy, microbial challenge data, container closure integrity, and simulated air transportation study data. The letter also requires a comprehensive safety update, updated labeling, and addresses pediatric presentation requirements.

Key points

• Conduct further root cause analyses to identify factors leading to the inability to demonstrate PK similarity between LA-EP2006 and US-licensed Neulasta.
• Conduct a feasibility assessment to determine if developing LA-EP2006 as a biosimilar under section 351(k) is still a viable option.
• Consider conducting an adequately designed study to demonstrate PK and PD similarity of LA-EP2006 and US-licensed Neulasta in healthy subjects, potentially as a 3-arm cross-over study including EU-approved Neulasta to establish the scientific bridge.
• Provide media fill data from three successful runs, including representative manipulations and interventions, and specify the container-closure system.
• Address comments and update section 3.2.P.3.5 of the BLA regarding the requalification strategy for (b)(4).
• Address comments and update section 3.2.P.3.5 of the BLA regarding insufficient microbial challenge data for validation studies.
• Conduct a new container closure integrity (CCI) qualification study for the LA-EP2006 drug product prefilled syringe (PFS) using a sufficiently sensitive method and compromised syringes as positive controls.
• Ensure routine dye ingress CCI testing includes at least one compromised PFS unit as a system suitability control.

Cited reasons

• Lack of Demonstrated PK Similarity
• Insufficient Media Fill Data
• Insufficient Requalification Strategy Data
• Insufficient Microbial Challenge Data
• Inadequate Container Closure Integrity (CCI) Test Method Validation
• Insufficient Simulated Air Transportation Study Data
• Prescribing Information Comments Reserved
• Container Label and Carton Labeling Comments Reserved

Recommended actions

• Conduct further root cause analyses to identify factors leading to the inability to demonstrate PK similarity between LA-EP2006 and US-licensed Neulasta.
• Conduct a feasibility assessment to determine if developing LA-EP2006 as a biosimilar under section 351(k) is still a viable option.
• Consider conducting an adequately designed study to demonstrate PK and PD similarity of LA-EP2006 and US-licensed Neulasta in healthy subjects, potentially as a 3-arm cross-over study including EU-approved Neulasta to establish the scientific bridge.
• Provide media fill data from three successful runs, including representative manipulations and interventions, and specify the container-closure system.
• Address comments and update section 3.2.P.3.5 of the BLA regarding the requalification strategy for (b)(4).
• Address comments and update section 3.2.P.3.5 of the BLA regarding insufficient microbial challenge data for validation studies.
• Conduct a new container closure integrity (CCI) qualification study for the LA-EP2006 drug product prefilled syringe (PFS) using a sufficiently sensitive method and compromised syringes as positive controls.
• Ensure routine dye ingress CCI testing includes at least one compromised PFS unit as a system suitability control.

Deficiency summary

The application cannot be approved in its present form due to a lack of demonstrated PK similarity between the proposed biosimilar and the reference products, and significant product quality deficiencies related to manufacturing process validation (media fills, microbial challenge, CCI) and stability data (transportation study). Labeling comments are reserved until other issues are resolved.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

351(k) Biosimilar BLA

Impact

Impact score

0.95

Estimated delay

545 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application faces significant hurdles primarily due to a failure to demonstrate pharmacokinetic similarity, which is foundational for biosimilar approval, compounded by multiple critical product quality and manufacturing control deficiencies. A comprehensive resubmission addressing these core issues is required.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%