Approval Letter Other 761258 (Jan 1, 2025)

Summary

This is a Complete Response letter from the FDA to Akeso Biopharma Co., Ltd. regarding their Biologics License Application (BLA) for AK105 (penpulimab-kcqx). The FDA has determined that the application cannot be approved in its present form due to clinical, quality, labeling, and facility inspection deficiencies, and provides recommendations for addressing these issues.

Key points

• Conduct a multiregional randomized clinical trial comparing penpulimab-kcqx to an acceptable control in patients with metastatic nasopharyngeal carcinoma (NPC), utilizing progression-free survival (PFS) and overall survival (OS) endpoints, and enrolling an adequate representation of U.S. patients.
• Provide additional data to support the suitability of new cell bank(s) for manufacturing, including growth data, drug substance (DS) release data, and extended analytical characterization data.
• Optimize and validate quality control methods for their intended use, and provide updated method procedures and validation/revalidation results.
• Provide additional information and data from appropriate process validation and stability studies to support proposed process control ranges for routine manufacture of the drug product (DP).
• Review labeling review resources, use the Selected Requirements for Prescribing Information (SRPI) checklist, and include updated content of labeling in structured product labeling (SPL) format if labeling is revised.
• Add the bolded statement 'ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide' or an appropriate alternative to the carton and container labeling per 21 CFR 208.24(d).
• Provide satisfactory responses to all deficiencies conveyed by the FDA following the pre-license inspection (PLI) of the manufacturing facility.
• Include a safety update with data from all nonclinical and clinical studies/trials of the product, describing any significant changes or findings in the safety profile.

Cited reasons

• Insufficient Clinical Efficacy for Accelerated Approval
• Inadequate Suitability of Quality Control Methods
• Insufficient Data for Process Control Ranges
• Missing Medication Guide Statement on Labeling
• Unresolved Manufacturing Facility Inspection Deficiencies
• Incomplete Safety Update Requirements for Complete Response
• The FDA issued a Complete Response Letter for AK105, citing several deficiencies across clinical, quality, and manufacturing aspects. Key issues include insufficient clinical efficacy data to demonstrate a meaningful advantage for accelerated approval in nasopharyngeal carcinoma, inadequate suitability of quality control methods, insufficient data to support process control ranges, unresolved manufacturing facility inspection findings, and a missing Medication Guide statement on labeling. A comprehensive safety update is also required for resubmission.

Recommended actions

• Conduct a multiregional randomized clinical trial comparing penpulimab-kcqx to an acceptable control in patients with metastatic nasopharyngeal carcinoma (NPC), utilizing progression-free survival (PFS) and overall survival (OS) endpoints, and enrolling an adequate representation of U.S. patients.
• Provide additional data to support the suitability of new cell bank(s) for manufacturing, including growth data, drug substance (DS) release data, and extended analytical characterization data.
• Optimize and validate quality control methods for their intended use, and provide updated method procedures and validation/revalidation results.
• Provide additional information and data from appropriate process validation and stability studies to support proposed process control ranges for routine manufacture of the drug product (DP).
• Review labeling review resources, use the Selected Requirements for Prescribing Information (SRPI) checklist, and include updated content of labeling in structured product labeling (SPL) format if labeling is revised.
• Add the bolded statement 'ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide' or an appropriate alternative to the carton and container labeling per 21 CFR 208.24(d).
• Provide satisfactory responses to all deficiencies conveyed by the FDA following the pre-license inspection (PLI) of the manufacturing facility.
• Include a safety update with data from all nonclinical and clinical studies/trials of the product, describing any significant changes or findings in the safety profile.

Deficiency summary

The FDA issued a Complete Response Letter for AK105, citing several deficiencies across clinical, quality, and manufacturing aspects. Key issues include insufficient clinical efficacy data to demonstrate a meaningful advantage for accelerated approval in nasopharyngeal carcinoma, inadequate suitability of quality control methods, insufficient data to support process control ranges, unresolved manufacturing facility inspection findings, and a missing Medication Guide statement on labeling. A comprehensive safety update is also required for resubmission.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

BLA (351(a))

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application was not approved due to a combination of insufficient clinical evidence for accelerated approval, unresolved CMC/quality control issues, outstanding manufacturing facility inspection deficiencies, and minor labeling non-compliance. A comprehensive safety update is also mandated for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%