Approval Letter Other 213953 (Jan 1, 2022)

Summary

The FDA issued a Complete Response Letter for New Drug Application (NDA) 213953 for testosterone undecanoate, citing that the application cannot be approved in its present form due to unreliable pharmacokinetic (PK) data from the pivotal efficacy and safety trial (MRS-TU-2019EXT). The unreliability stems from inadequate documentation of PK sample handling and processing at multiple clinical sites, which raised significant uncertainties about the integrity of the entire study's PK data.

Key points

• Conduct a new Phase 3 efficacy and safety trial with an adequate number of hypogonadal subjects treated with the product.
• Ensure the new trial provides reliable data to demonstrate the drug's safety and effectiveness with the proposed dose, dosing regimen, and dose titration scheme.
• Maintain adequate documentation of PK sample collection, handling, processing, and storage in the new trial to verify adherence to prespecified procedures and ensure reliability of PK results.
• If relying on plasma T concentrations for dose titration and assessments but intending to label for serum T concentrations, measure T concentrations in both plasma and serum from all PK blood samples in the new trial.
• Submit the Phase 3 protocol for FDA review and concurrence prior to conducting the study.
• Submit a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to the deficiencies.
• The safety update must describe in detail any significant changes or findings in the safety profile.
• The safety update must incorporate new safety data from studies/clinical trials for the proposed indication, presenting it in the same format as the original submission.

Cited reasons

• Unreliable PK Data due to Inadequate Sample Handling Documentation
• Requirement for Comprehensive Safety Update
• Resubmit Proprietary Name with Response
• The application for testosterone undecanoate cannot be approved in its present form due to critical deficiencies related to the integrity and reliability of pharmacokinetic (PK) data from the pivotal clinical trial (MRS-TU-2019EXT). Inadequate documentation of PK sample handling and processing at multiple clinical sites has led the agency to question the reliability of the entire study's PK data, preventing a conclusion of substantial evidence of effectiveness. Consequently, a new Phase 3 efficacy and safety trial is required. Additionally, a comprehensive safety update and resubmission of the proprietary name are necessary.

Recommended actions

• Conduct a new Phase 3 efficacy and safety trial with an adequate number of hypogonadal subjects treated with the product.
• Ensure the new trial provides reliable data to demonstrate the drug's safety and effectiveness with the proposed dose, dosing regimen, and dose titration scheme.
• Maintain adequate documentation of PK sample collection, handling, processing, and storage in the new trial to verify adherence to prespecified procedures and ensure reliability of PK results.
• If relying on plasma T concentrations for dose titration and assessments but intending to label for serum T concentrations, measure T concentrations in both plasma and serum from all PK blood samples in the new trial.
• Submit the Phase 3 protocol for FDA review and concurrence prior to conducting the study.
• Submit a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to the deficiencies.
• The safety update must describe in detail any significant changes or findings in the safety profile.
• The safety update must incorporate new safety data from studies/clinical trials for the proposed indication, presenting it in the same format as the original submission.

Deficiency summary

The application for testosterone undecanoate cannot be approved in its present form due to critical deficiencies related to the integrity and reliability of pharmacokinetic (PK) data from the pivotal clinical trial (MRS-TU-2019EXT). Inadequate documentation of PK sample handling and processing at multiple clinical sites has led the agency to question the reliability of the entire study's PK data, preventing a conclusion of substantial evidence of effectiveness. Consequently, a new Phase 3 efficacy and safety trial is required. Additionally, a comprehensive safety update and resubmission of the proprietary name are necessary.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2)

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the critical lack of data integrity and reliability for the pivotal clinical pharmacology data, necessitating a new clinical trial. Secondary themes include standard requirements for comprehensive safety updates and administrative tasks related to proprietary name resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%