Approval Letter Other (Nov 13, 2025)

Summary

The FDA issued a 'not approvable' letter for New Drug Application (NDA) 21-164 for Gepirone Hydrochloride Extended Release tablets, citing a lack of substantial evidence for its effectiveness in treating major depressive disorder (MDD) and several Chemistry, Manufacturing, and Controls (CMC) deficiencies. The agency found that only 2 out of 12 studies showed a significant effect, with active comparators often outperforming gepirone ER, and a meta-analysis of the failed studies showed no significant effect. Additionally, the longer-term maintenance efficacy trial yielded negative results, and the applicant's post-hoc attempt to repair it was deemed invalid. The FDA also noted deficiencies in impurity acceptance criteria and stability data.

Key points

• Provide substantial evidence for the effectiveness of gepirone ER in the short-term or longer-term treatment of major depressive disorder (MDD).
• Address the deficiencies related to the inconsistent antidepressant effect of gepirone ER across clinical trials, including those where active comparators demonstrated superiority.
• Provide a credible and valid approach to address the negative outcome of the longer-term maintenance efficacy trial (study 28709).
• Revise the acceptance criterion for Individual unspecified impurity to NMT % in accordance with ICH Q3B guideline.
• Provide long-term and accelerated stability data for the commercial to-be-marketed drug product in each of the proposed packaging configurations to support the requested expiration date.
• Amend the application, notify the FDA of intent to file an amendment, or follow other options under 21 CFR 314.120 within 10 days of the letter date.
• Ensure any amendment responds to all listed deficiencies.
• The application failed to provide substantial evidence for the effectiveness of gepirone ER in the short-term or longer-term treatment of major depressive disorder (MDD). Only two out of twelve studies showed a significant effect, while the remaining ten studies did not show evidence of an antidepressant effect or even favorable trends. Three trials showed active comparators were statistically superior to gepirone ER, and in two trials, active comparators were superior to placebo while gepirone ER was not. A meta-analysis of the ten failed studies showed an effect size of essentially zero. The negative outcome of the longer-term maintenance efficacy trial (study 28709) further casts doubt on the drug's effectiveness, and the post hoc attempt to repair the study by eliminating patients was deemed not credible or valid. The agency expressed low optimism for a path forward for this drug as an antidepressant.

Cited reasons

• Lack of Substantial Evidence for Effectiveness in Major Depressive Disorder (MDD)
• Impurity Acceptance Criterion Revision
• Insufficient Stability Data for Expiration Date
• The application was deemed 'not approvable' primarily due to a lack of substantial evidence for the effectiveness of gepirone ER in treating Major Depressive Disorder (MDD). Only two out of twelve clinical trials showed a significant effect, with several studies indicating inferiority to active controls or no favorable trends. Additionally, Chemistry, Manufacturing, and Controls (CMC) deficiencies related to impurity acceptance criteria and insufficient stability data were noted, requiring resolution.

Recommended actions

• Provide substantial evidence for the effectiveness of gepirone ER in the short-term or longer-term treatment of major depressive disorder (MDD).
• Address the deficiencies related to the inconsistent antidepressant effect of gepirone ER across clinical trials, including those where active comparators demonstrated superiority.
• Provide a credible and valid approach to address the negative outcome of the longer-term maintenance efficacy trial (study 28709).
• Revise the acceptance criterion for Individual unspecified impurity to NMT % in accordance with ICH Q3B guideline.
• Provide long-term and accelerated stability data for the commercial to-be-marketed drug product in each of the proposed packaging configurations to support the requested expiration date.
• Amend the application, notify the FDA of intent to file an amendment, or follow other options under 21 CFR 314.120 within 10 days of the letter date.
• Ensure any amendment responds to all listed deficiencies.

Deficiency summary

The application was deemed 'not approvable' primarily due to a lack of substantial evidence for the effectiveness of gepirone ER in treating Major Depressive Disorder (MDD). Only two out of twelve clinical trials showed a significant effect, with several studies indicating inferiority to active controls or no favorable trends. Additionally, Chemistry, Manufacturing, and Controls (CMC) deficiencies related to impurity acceptance criteria and insufficient stability data were noted, requiring resolution.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA 505(b)

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is a fundamental failure to demonstrate clinical efficacy for the proposed indication, compounded by secondary quality control issues. The agency's stance suggests a significant hurdle for future development, indicating that the current data package is insufficient to support approval and raises doubts about the drug's overall clinical value.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%