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US FDA•United StatesAL•Approval Letter

Approval Letter Other 213586 (Jan 1, 2024)

Issued January 1, 2024

Issued

January 1, 2024

Application

Other • 213586

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due December 31, 2024Product may be marketed.

Summary

This is a Complete Response Letter from the FDA to Teva Neuroscience, Inc. regarding New Drug Application (NDA) 213586 for risperidone extended-release injectable suspension. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to clinical data quality, syringe and carton labeling, and proprietary name submission. The letter outlines specific reasons for non-approval and provides recommendations for addressing these issues, including requirements for a safety update and options for resubmission or further action.

Key points

  • Submit results of an independent third-party audit or post-study monitoring for all sites and subjects of Study TV-46000-CNS-30072 and Study TV-46000-CNS-30078 to establish the extent of investigational product (IP) dosing errors and lack of IP dose documentation, and to determine what study data can be relied upon for regulatory decision making.
  • Submit relevant updated analyses and dosing datasets based on the audit findings.
  • Alternatively, submit a new adequate and well-controlled clinical efficacy and safety study.
  • Add the 'Rx Only' statement to syringe labels.
  • Specify the expiration date format on syringe labels, recommending YYYY-MM-DD or YYYY-MMM-DD format.
  • Add the route of administration to syringe labels.
  • Add a statement of dosage (e.g., 'Recommended Dosage: See Prescribing Information') to carton labeling.
  • Clarify whether a 2D data matrix barcode is on the carton labeling and review guidance for product identifier requirements if not present.

Cited reasons

  • Inadequate Efficacy Evidence Due to IP Dosing Errors and Documentation Issues
  • Missing 'Rx Only' Statement on Syringe Labels
  • Unspecified Expiration Date Format on Syringe Labels
  • Missing Route of Administration on Syringe Labels
  • Missing Statement of Dosage on Carton Labeling
  • Unclear Product Identifier (2D Data Matrix Barcode) on Carton Labeling
  • Unspecified Expiration Date Format on Carton Labeling
  • Missing Strength on Carton Side Panel

Recommended actions

  • Submit results of an independent third-party audit or post-study monitoring for all sites and subjects of Study TV-46000-CNS-30072 and Study TV-46000-CNS-30078 to establish the extent of investigational product (IP) dosing errors and lack of IP dose documentation, and to determine what study data can be relied upon for regulatory decision making.
  • Submit relevant updated analyses and dosing datasets based on the audit findings.
  • Alternatively, submit a new adequate and well-controlled clinical efficacy and safety study.
  • Add the 'Rx Only' statement to syringe labels.
  • Specify the expiration date format on syringe labels, recommending YYYY-MM-DD or YYYY-MMM-DD format.
  • Add the route of administration to syringe labels.
  • Add a statement of dosage (e.g., 'Recommended Dosage: See Prescribing Information') to carton labeling.
  • Clarify whether a 2D data matrix barcode is on the carton labeling and review guidance for product identifier requirements if not present.

Deficiency summary

The application cannot be approved in its current form due to critical clinical data integrity issues impacting efficacy determination, numerous labeling deficiencies for both syringe and carton labels, and the need for a comprehensive safety update upon resubmission. The agency could not verify investigational product dosing, making efficacy findings unreliable.

Findings

Inadequate Efficacy Evidence Due to IP Dosing Errors and Documentation Issues

Severity: critical

Investigational product (IP) dosing errors, including patients receiving higher doses than assigned, lack of IP administration documentation, and dually/triply enrolled patients, rendered dosing data from Study TV-46000-CNS-30072 and Study TV-46000-CNS-30078 unreliable. This prevents the Agency from making an efficacy finding for the new formulation as IP doses could not be verified, and the exposure-response relationship of safety findings could not be evaluated.

Recommended response: Submit results of an independent third-party audit or post-study monitoring for all sites and subjects to establish the extent of IP dosing errors and lack of documentation, and to determine reliable study data. Submit updated analyses and dosing datasets based on audit findings. Alternatively, submit a new adequate and well-controlled clinical efficacy and safety study.

Missing 'Rx Only' Statement on Syringe Labels

Severity: major

The 'Rx Only' statement is not present on the syringe labels.

Recommended response: Add the 'Rx Only' statement to the syringe labels.

Unspecified Expiration Date Format on Syringe Labels

Severity: major

The expiration date format is not specified on the syringe labels, which could lead to confusion and medication errors.

Recommended response: Specify the expiration date format. FDA recommends YYYY-MM-DD or YYYY-MMM-DD format, with a slash or hyphen separator.

Missing Route of Administration on Syringe Labels

Severity: major

The route of administration is not present on the syringe labels.

Recommended response: Add the route of administration to the syringe labels.

Missing Statement of Dosage on Carton Labeling

Severity: major

There is no statement of dosage on the carton labeling.

Recommended response: Add a statement of dosage (e.g., 'Recommended Dosage: See Prescribing Information') or similar verbiage to the carton labeling.

Unclear Product Identifier (2D Data Matrix Barcode) on Carton Labeling

Severity: major

It is unclear whether a human-readable and machine-readable (2D data matrix barcode) product identifier is present on the carton labeling, which is used for identification and tracing purposes.

Recommended response: Clarify whether a 2D data matrix barcode is on the carton labeling. If not present, review the 'Guidance for Industry: Product Identifiers under the Drug Supply Chain Security Act - Questions and Answers (June 2021)' to determine applicability.

Unspecified Expiration Date Format on Carton Labeling

Severity: major

The expiration date format is not specified on the carton labeling, which could lead to confusion and medication errors.

Recommended response: Specify the expiration date format. FDA recommends YYYY-MM-DD or YYYY-MMM-DD format, with a slash or hyphen separator.

Missing Strength on Carton Side Panel

Severity: major

While the proprietary name, established name, and dosage form are on a side panel, the strength is missing.

Recommended response: Add the strength (e.g., 50 mg/0.14 mL) to the carton side panel.

Missing 'For administration by a healthcare professional' Statement on Carton Labeling

Severity: major

The product is intended for administration by a healthcare professional, but this statement is not on the carton labeling.

Recommended response: Add the statement 'For administration by a healthcare professional' (or similar verbiage) to the principal display panel of the carton labeling.

Resubmission of Proprietary Name Required

Severity: minor

The proposed proprietary name, Uzedy, was found acceptable pending approval of the application. It needs to be resubmitted when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name when responding to the application deficiencies.

Requirement for Comprehensive Safety Update

Severity: major

A comprehensive safety update, as described in 21 CFR 314.50(d)(5)(vi)(b), is required when responding to the deficiencies. This includes new nonclinical and clinical data, tabulations, comparisons, case reports, exposure information, and worldwide experience.

Recommended response: Include a comprehensive safety update with new nonclinical and clinical data, tabulations, comparisons, case reports, exposure information, and worldwide experience, as described in 21 CFR 314.50(d)(5)(vi)(b).

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

Regulatory context

Submission stage
final decision
Regulatory pathway
505(b)(2)

Impact

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

Strategic insights

The application received a Complete Response Letter primarily due to significant clinical data integrity issues that undermine efficacy findings, coupled with numerous labeling non-compliance issues across syringe and carton labels. A full safety update is also required for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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