Complete Response Letter NDA 505b1 217338 (Jul 26, 2024)

Summary

The FDA issued a Complete Response letter for NDA 217338 for naproxen sodium, dextromethorphan hydrobromide, guaifenesin extended-release (ER) tablet, indicating that the application cannot be approved in its current form due to insufficient evidence supporting the proposed 12-hour duration of action and dosing regimen.

Key points

• Provide clinical efficacy data to support a 12-hour duration of use when studied in a relevant patient population.
• Conduct a relative bioavailability study to establish a scientific bridge between the proposed product and Aleve-D Sinus and Cold (naproxen sodium 220 mg; pseudoephedrine HCl 120 mg extended-release tablet [NDA 021076]).
• Resubmit the proposed proprietary name when all application deficiencies have been addressed.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) with the response to deficiencies.
• Describe in detail any significant changes or findings in the safety profile in the safety update.
• Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, presenting new data from studies/clinical trials for the proposed indication in the original format, tabulating new safety data combined with original application data, and including tables comparing frequencies of adverse events.
• Provide separate tables for frequencies of adverse events occurring in clinical trials for indications other than the proposed indication.
• Present a retabulation of reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns.

Cited reasons

• Lack of Substantial Evidence for 12-hour Dosing Regimen
• Proprietary Name Resubmission Contingent on Application Approval
• Mandatory Safety Update for Resubmission
• The FDA issued a Complete Response Letter primarily due to insufficient clinical evidence to support the proposed 12-hour duration of action and dosing regimen for the ER product, particularly for the naproxen component. The agency found the scientific literature and indirect PK bridging strategies inadequate and based on inappropriate data sources. Additionally, a proprietary name resubmission and a comprehensive safety update are required upon addressing the primary deficiencies.

Recommended actions

• Provide clinical efficacy data to support a 12-hour duration of use when studied in a relevant patient population.
• Conduct a relative bioavailability study to establish a scientific bridge between the proposed product and Aleve-D Sinus and Cold (naproxen sodium 220 mg; pseudoephedrine HCl 120 mg extended-release tablet [NDA 021076]).
• Resubmit the proposed proprietary name when all application deficiencies have been addressed.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) with the response to deficiencies.
• Describe in detail any significant changes or findings in the safety profile in the safety update.
• Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, presenting new data from studies/clinical trials for the proposed indication in the original format, tabulating new safety data combined with original application data, and including tables comparing frequencies of adverse events.
• Provide separate tables for frequencies of adverse events occurring in clinical trials for indications other than the proposed indication.
• Present a retabulation of reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns.

Deficiency summary

The FDA issued a Complete Response Letter primarily due to insufficient clinical evidence to support the proposed 12-hour duration of action and dosing regimen for the ER product, particularly for the naproxen component. The agency found the scientific literature and indirect PK bridging strategies inadequate and based on inappropriate data sources. Additionally, a proprietary name resubmission and a comprehensive safety update are required upon addressing the primary deficiencies.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA

Impact

Impact score

0.75

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the lack of robust clinical evidence to support the proposed 12-hour extended-release dosing regimen, particularly for the naproxen component, due to inadequate bridging strategies and reliance on inappropriate data sources. Procedural requirements for proprietary name and safety updates are also noted.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%