Approval Letter Other 204803 (Jan 1, 2022)

Summary

The FDA issued a Complete Response letter for DURECT Corporation's New Drug Application (NDA) 204803 for POSIMIR (bupivacaine extended-release solution), indicating that the application cannot be approved in its current form. The primary reasons for non-approval are insufficient clinical data to demonstrate the safety of POSIMIR, specifically regarding adverse events related to shoulder joints, skin/underlying tissues (bruising, hematoma, pruritus, dehiscence), and neurologically related adverse events (dizziness, dysgeusia, headache, hypoesthesia, paresthesia, somnolence). The letter outlines specific additional studies required to characterize the risk profile and details requirements for a comprehensive safety update.

Key points

• Conduct additional studies to adequately characterize the risk profile of SABER-bupivacaine for adverse reactions associated with the shoulder joint and surrounding tissues, including the skin, following arthroscopic subacromial decompression.
• Ensure safety assessments in the shoulder joint study are performed at appropriate intervals and for an appropriate period to capture onset, duration, and late-onset events.
• Solicit input from expert consultants for the design of the shoulder joint study, particularly regarding appropriate assessments, frequency, and duration of follow-up.
• Include SABER-bupivacaine and either bupivacaine HCL or a non-SABER containing placebo (or both) as treatments in the shoulder joint study.
• Design the shoulder joint study as randomized and double-blinded, including enough subjects to detect reactions with an incidence rate of ≥ 1%.
• Collect efficacy data during the shoulder joint study to provide clinical context for safety data.
• Discuss the design of the shoulder joint study with the Division prior to implementation.
• Conduct a safety study evaluating the occurrence of adverse reactions associated with the skin and underlying tissues.

Cited reasons

• Insufficient data on shoulder joint and surrounding tissue adverse events
• Increased risk of skin and underlying tissue adverse events
• Marked increased risk of neurologically related adverse events
• Labeling comments reserved until application is adequate
• Comprehensive safety update required with response
• The application cannot be approved in its present form due to insufficient clinical safety data. The agency identified significant deficiencies related to the characterization of adverse events associated with SABER-bupivacaine, including those affecting the shoulder joint, skin/tissues, and neurological systems. Additional clinical studies are required to adequately assess the product's risk profile.

Recommended actions

• Conduct additional studies to adequately characterize the risk profile of SABER-bupivacaine for adverse reactions associated with the shoulder joint and surrounding tissues, including the skin, following arthroscopic subacromial decompression.
• Ensure safety assessments in the shoulder joint study are performed at appropriate intervals and for an appropriate period to capture onset, duration, and late-onset events.
• Solicit input from expert consultants for the design of the shoulder joint study, particularly regarding appropriate assessments, frequency, and duration of follow-up.
• Include SABER-bupivacaine and either bupivacaine HCL or a non-SABER containing placebo (or both) as treatments in the shoulder joint study.
• Design the shoulder joint study as randomized and double-blinded, including enough subjects to detect reactions with an incidence rate of ≥ 1%.
• Collect efficacy data during the shoulder joint study to provide clinical context for safety data.
• Discuss the design of the shoulder joint study with the Division prior to implementation.
• Conduct a safety study evaluating the occurrence of adverse reactions associated with the skin and underlying tissues.

Deficiency summary

The application cannot be approved in its present form due to insufficient clinical safety data. The agency identified significant deficiencies related to the characterization of adverse events associated with SABER-bupivacaine, including those affecting the shoulder joint, skin/tissues, and neurological systems. Additional clinical studies are required to adequately assess the product's risk profile.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2) New Drug Application

Impact

Impact score

0.75

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the critical need for additional clinical safety studies to adequately characterize the risk profile of SABER-bupivacaine, particularly concerning adverse events affecting various body systems. The current data is insufficient to demonstrate safety as described in the proposed label, necessitating new trials before approval can be considered.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%