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US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 218223 (Mar 8, 2024)

Issued March 8, 2024

Issued

March 8, 2024

Application

NDA 505b1 • 218223

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due March 8, 2025Requires resubmission addressing deficiencies.

Summary

This document from the U.S. Food and Drug Administration (FDA) outlines significant deficiencies in New Drug Application (NDA) 218223 for GA Depot as a treatment for relapsing forms of multiple sclerosis (RMS). The FDA found the Phase 3 trial (Study Mapi GA Depot Phase III – 001) did not provide interpretable or persuasive efficacy findings, failed to establish an adequate scientific bridge to Copaxone, and exhibited numerous issues with trial design, data quality, and reliability. Furthermore, the submitted safety data were deemed inadequate, and the study raised new safety concerns, including severe injection site reactions and systemic injection-related reactions, suggesting important differences from Copaxone.

Key points

  • The Phase 3 trial (Study Mapi GA Depot Phase III – 001) must provide interpretable and persuasive findings of efficacy for GA Depot as a treatment for relapsing forms of multiple sclerosis (RMS) to meet the evidentiary standard for substantial evidence of effectiveness.
  • An adequate scientific bridge to Copaxone must be established.
  • The relapse assessment process in clinical trials must be robust, addressing issues such as timely evaluation, blinding of investigators and raters, and potential for recall bias.
  • Clinical trials should consider including an independent Relapse Adjudication Committee to increase objectivity in relapse determination.
  • Magnetic resonance imaging (MRI) should be included as a standard component of relapse evaluation for MS.
  • Clinical trials must minimize major protocol deviations to ensure study interpretability.
  • Data must be collected after treatment discontinuation, including efficacy and safety data via a final study visit, to avoid bias in estimated treatment effects.
  • Applicants must ensure the quality and reliability of all submitted data, addressing errors and omissions in datasets and Clinical Study Reports.

Cited reasons

  • Lack of Substantial Evidence of Efficacy and Inadequate Scientific Bridge
  • Deficiencies in Relapse Evaluation and Definition Process
  • High Number of Major Protocol Deviations
  • Inadequate Collection of Post-Discontinuation Data
  • Data Quality and Reliability Concerns
  • Discordant and Non-Robust MRI-Related Endpoints
  • Inadequate Safety Data for Comprehensive Evaluation
  • New Safety Concerns and Differences in Safety Profile

Recommended actions

  • The Phase 3 trial (Study Mapi GA Depot Phase III – 001) must provide interpretable and persuasive findings of efficacy for GA Depot as a treatment for relapsing forms of multiple sclerosis (RMS) to meet the evidentiary standard for substantial evidence of effectiveness.
  • An adequate scientific bridge to Copaxone must be established.
  • The relapse assessment process in clinical trials must be robust, addressing issues such as timely evaluation, blinding of investigators and raters, and potential for recall bias.
  • Clinical trials should consider including an independent Relapse Adjudication Committee to increase objectivity in relapse determination.
  • Magnetic resonance imaging (MRI) should be included as a standard component of relapse evaluation for MS.
  • Clinical trials must minimize major protocol deviations to ensure study interpretability.
  • Data must be collected after treatment discontinuation, including efficacy and safety data via a final study visit, to avoid bias in estimated treatment effects.
  • Applicants must ensure the quality and reliability of all submitted data, addressing errors and omissions in datasets and Clinical Study Reports.

Deficiency summary

The application for GA Depot received a Complete Response Letter due to a lack of substantial evidence of efficacy from the Phase 3 trial, failure to establish a scientific bridge to Copaxone, significant data quality and reliability issues, inadequate safety data collection, and the emergence of new safety concerns with a different profile than the reference product.

Findings

Lack of Substantial Evidence of Efficacy and Inadequate Scientific Bridge

Severity: critical

The Phase 3 trial (Study Mapi GA Depot Phase III – 001) did not provide interpretable or persuasive findings of efficacy for GA Depot in relapsing forms of multiple sclerosis (RMS) and failed to meet the evidentiary standard for substantial effectiveness. This is compounded by the failure to establish an adequate scientific bridge to Copaxone.

Recommended response: Conduct new, adequate, and well-controlled clinical trials designed to definitively demonstrate efficacy and establish a scientific bridge to the reference product, if applicable.

Deficiencies in Relapse Evaluation and Definition Process

Severity: major

Concerns regarding the interpretability of efficacy data due to issues in relapse evaluation, including potential recall bias, uninterpretable EDSS scores due to delayed assessments, lack of blinding between Treating Investigator and EDSS rater, absence of an independent Relapse Adjudication Committee, and exclusion of MRI as a standard component of relapse evaluation.

Recommended response: Revise clinical trial protocols to ensure robust and objective relapse assessment, including appropriate blinding, independent adjudication, and integration of objective measures like MRI.

High Number of Major Protocol Deviations

Severity: major

The high number of major protocol deviations pertaining to missed study drug doses in Study Mapi GA Depot Phase III – 001 limits study interpretability, especially for a monthly depot injection.

Recommended response: Implement stricter protocol adherence monitoring and management strategies in future clinical trials to minimize deviations and ensure data integrity.

Inadequate Collection of Post-Discontinuation Data

Severity: major

Data were not collected after treatment discontinuation, which could lead to bias in the estimated treatment effect and loss of context for interpreting primary efficacy outcome data. Collection of post-discontinuation efficacy and safety data via a final study visit is an expectation for adequate and well-controlled trials.

Recommended response: Ensure future clinical trial protocols include provisions for comprehensive data collection, including efficacy and safety data, after treatment discontinuation.

Data Quality and Reliability Concerns

Severity: major

Errors in datasets and the Clinical Study Report, acknowledged via IRs, raised concerns regarding the quality and reliability of all submitted data. Examples include irreconcilable errors in study period end dates and inconsistent coding of protocol deviations.

Recommended response: Implement rigorous data management, quality control, and validation processes to ensure accuracy, consistency, and reliability of all submitted data. Address all identified data discrepancies.

Discordant and Non-Robust MRI-Related Endpoints

Severity: major

Secondary MRI-related endpoints yielded discordant results, failing to demonstrate a statistically or clinically significant effect on new or enlarging T2 hyperintense lesions. Concerns exist regarding the robustness of the effect on T1 gadolinium-enhancing lesions due to assumptions about missing data. Inconsistencies compared to Copaxone further preclude reliance on the listed drug.

Recommended response: Conduct additional studies to clarify MRI findings, ensure robustness of results, and address inconsistencies with the reference product. Re-evaluate statistical analysis plans for MRI endpoints.

Inadequate Safety Data for Comprehensive Evaluation

Severity: major

The submitted safety data are inadequate to inform a comprehensive safety evaluation, lacking routine safety laboratory assessments (e.g., detailed urinalysis, serum immunoglobulins, pancreatic enzymes, certain electrolytes) and adequate electrocardiogram (ECG) data.

Recommended response: Expand the scope of safety data collection in future studies to include all necessary routine laboratory assessments and comprehensive ECG data to enable a thorough safety evaluation.

New Safety Concerns and Differences in Safety Profile

Severity: major

The Phase 3 study raised new safety concerns for GA Depot and suggested important differences in safety profiles compared to Copaxone, particularly severe injection site reactions (including abscesses at a higher frequency than Copaxone) and systemic injection-related reactions (influenza-like illness, pyrexia) not typically associated with glatiramer acetate.

Recommended response: Conduct further safety studies to thoroughly characterize the new safety signals, understand their clinical significance, and investigate the differences in safety profile compared to Copaxone.

Proprietary Name Correspondence

Severity: info

Refer to correspondence dated [date] which addresses the proposed proprietary name. This is an administrative item and not a deficiency preventing approval.

Recommended response: Address the proprietary name issues as per the agency's correspondence.

Regulatory context

Submission stage
final decision
Regulatory pathway
NDA

Impact

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

Strategic insights

The primary themes for the Complete Response are the failure to demonstrate robust efficacy and safety, compounded by critical data integrity issues and an inability to establish bioequivalence or a scientific bridge to the reference product, Copaxone. This indicates fundamental flaws in the clinical development program.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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