US FDA•United StatesAL•Approval Letter

Approval Letter Other (Nov 13, 2025)

Issued November 13, 2025

Issued

November 13, 2025

Application

Other

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due November 13, 2026Product may be marketed.

Summary

This is a Complete Response letter from the FDA to AVEO Pharmaceuticals, Inc. regarding their New Drug Application (NDA 204408) for tivozanib hydrochloride capsules. The FDA has determined that the application cannot be approved in its current form due to deficiencies in clinical data (inconsistent progression-free survival and overall survival results, uninterpretable trial results), product quality (unsupported dissolution acceptance criterion), and pending labeling review. The letter outlines specific recommendations and requirements for addressing these issues for a potential resubmission.

Key points

Perform an adequate and well-controlled randomized trial(s) of tivozanib using Progression-Free Survival (PFS) as the primary endpoint and Overall Survival (OS) as a secondary endpoint.
Ensure the applicability of the results from the new trial to the US population.
Power the new trial to detect a difference in PFS and adequately size it to reassure no adverse effect on OS.
Implement a dissolution acceptance criterion of Q= (b)(4)% at (b)(4) minutes for the product at release and on stability.
Include the revised specifications table for the drug product with the updated dissolution acceptance criterion in the resubmission.
Include an updated content of labeling in Structured Product Labeling (SPL) format if labeling is revised.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
Describe in detail any significant changes or findings in the safety profile within the safety update.

Cited reasons

Inconsistent PFS and OS results, uninterpretable risk-benefit
Unsupported dissolution acceptance criterion
Comprehensive safety update required upon resubmission
The application cannot be approved in its present form due to significant clinical efficacy and safety concerns, specifically an uninterpretable risk-benefit assessment from inconsistent progression-free survival (PFS) and overall survival (OS) data. Additionally, the proposed dissolution acceptance criterion is not supported by data, and a comprehensive safety update is required upon resubmission.

Recommended actions

Perform an adequate and well-controlled randomized trial(s) of tivozanib using Progression-Free Survival (PFS) as the primary endpoint and Overall Survival (OS) as a secondary endpoint.
Ensure the applicability of the results from the new trial to the US population.
Power the new trial to detect a difference in PFS and adequately size it to reassure no adverse effect on OS.
Implement a dissolution acceptance criterion of Q= (b)(4)% at (b)(4) minutes for the product at release and on stability.
Include the revised specifications table for the drug product with the updated dissolution acceptance criterion in the resubmission.
Include an updated content of labeling in Structured Product Labeling (SPL) format if labeling is revised.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
Describe in detail any significant changes or findings in the safety profile within the safety update.

Deficiency summary

The application cannot be approved in its present form due to significant clinical efficacy and safety concerns, specifically an uninterpretable risk-benefit assessment from inconsistent progression-free survival (PFS) and overall survival (OS) data. Additionally, the proposed dissolution acceptance criterion is not supported by data, and a comprehensive safety update is required upon resubmission.

Findings

Inconsistent PFS and OS results, uninterpretable risk-benefit

Severity: critical

The single Phase 3 trial showed statistically favored PFS for tivozanib but also a potential 25% decrease in overall survival (OS), which is unacceptable given available therapies. The inconsistent PFS and OS results, coupled with an imbalance in post-study treatments, render the trial's results uninterpretable and inconclusive for a risk-benefit assessment necessary for drug approval.

Recommended response: Perform an adequate and well-controlled randomized trial(s) of tivozanib using PFS as the primary endpoint and OS as a secondary endpoint. The trial should be powered for PFS and adequately sized to ensure no adverse effect on OS, with results applicable to the US population.

Unsupported dissolution acceptance criterion

Severity: major

The proposed dissolution acceptance criterion (Q= % at (b)(4) minutes) is not supported by the provided dissolution data and is deemed unacceptable. The agency's data analysis supports a different dissolution acceptance criterion of Q= % at (b)(4) minutes.

Recommended response: Revise the dissolution acceptance criterion to Q= % at (b)(4) minutes, implement this criterion at release and on stability, and include the updated specifications table in the resubmission.

Comprehensive safety update required upon resubmission

Severity: major

A comprehensive safety update is required upon resubmission, as described in 21 CFR 314.50(d)(5)(vi)(b). This includes data from all nonclinical and clinical studies, detailed descriptions of significant safety profile changes, presentation of new safety data, combined tabulations with original NDA data, comparisons of adverse event frequencies, separate tables for other indications, retabulation of premature discontinuations, case report forms and narratives for deaths/serious adverse events, updated exposure information, worldwide safety experience summary, and English translations of foreign labeling.

Recommended response: Prepare a comprehensive safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b), ensuring all new nonclinical and clinical safety data, adverse event reporting, exposure information, worldwide experience, and translated foreign labeling are included.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Regulatory context

Submission stage: final decision
Regulatory pathway: NDA 505(b)

Impact

Impact score: 0.95
Estimated delay: 545 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The application received a Complete Response due to fundamental issues with clinical efficacy and safety data, specifically an unfavorable risk-benefit profile for tivozanib, and an inadequate dissolution specification. A substantial safety data update is also mandated for any future resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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