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US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 217002 (Feb 26, 2024)

Issued February 26, 2024

Issued

February 26, 2024

Application

NDA 505b1 • 217002

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due February 25, 2025Requires resubmission addressing deficiencies.

Summary

The FDA has identified several deficiencies in the New Drug Application (NDA) for roluperidone for the treatment of negative symptoms of schizophrenia. Key issues include insufficient evidence for efficacy from Study C07, lack of data on co-administration with antipsychotics, unproven clinical meaningfulness of the observed effect on negative symptoms, and inadequate long-term safety data. Additionally, the proposed strategy for mitigating QTc prolongation risk based on CYP2D6 genotyping is deemed insufficient, requiring a robust companion diagnostic device. The FDA requires the submission of additional studies and data to address these deficiencies before the application can be approved.

Key points

  • Submit at least one additional positive, adequate, and well-controlled study to support the safety and effectiveness of roluperidone for the treatment of negative symptoms.
  • Provide additional data to demonstrate the safety and efficacy of roluperidone coadministered with antipsychotic medications.
  • Provide additional data to support that the observed effect on negative symptoms with roluperidone treatment corresponds to a clinically meaningful change.
  • Provide additional data to demonstrate the long-term safety of the proposed dose of roluperidone.
  • Discuss the design of any additional planned study or studies with the Agency prior to study initiation.
  • Develop and obtain contemporaneous authorization for an in vitro companion diagnostic device for CYP2D6 genotyping to ensure robust pharmacogenomic test allele coverage and test accuracy.
  • Resubmit the proposed proprietary name when responding to the application deficiencies.
  • Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, incorporating new safety data, combined tabulations, comparison tables, case reports for deaths/serious adverse events, updated exposure information, and a summary of worldwide experience.

Cited reasons

  • Insufficient evidence of clinical meaningfulness and efficacy for negative symptoms
  • Inadequate data on co-administration with antipsychotic medications
  • Inadequate long-term safety database
  • Inadequate strategy for QTc prolongation risk mitigation and inconsistent CYP2D6 phenotyping
  • Resubmission of proprietary name required
  • Comprehensive safety update required with response
  • The NDA for roluperidone for negative symptoms of schizophrenia received a Complete Response Letter primarily due to insufficient evidence of clinical meaningfulness and long-term safety, particularly concerning co-administration with antipsychotics and QTc prolongation risk management. The agency requires at least one additional positive, adequate, and well-controlled study to support safety and effectiveness.

Recommended actions

  • Submit at least one additional positive, adequate, and well-controlled study to support the safety and effectiveness of roluperidone for the treatment of negative symptoms.
  • Provide additional data to demonstrate the safety and efficacy of roluperidone coadministered with antipsychotic medications.
  • Provide additional data to support that the observed effect on negative symptoms with roluperidone treatment corresponds to a clinically meaningful change.
  • Provide additional data to demonstrate the long-term safety of the proposed dose of roluperidone.
  • Discuss the design of any additional planned study or studies with the Agency prior to study initiation.
  • Develop and obtain contemporaneous authorization for an in vitro companion diagnostic device for CYP2D6 genotyping to ensure robust pharmacogenomic test allele coverage and test accuracy.
  • Resubmit the proposed proprietary name when responding to the application deficiencies.
  • Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, incorporating new safety data, combined tabulations, comparison tables, case reports for deaths/serious adverse events, updated exposure information, and a summary of worldwide experience.

Deficiency summary

The NDA for roluperidone for negative symptoms of schizophrenia received a Complete Response Letter primarily due to insufficient evidence of clinical meaningfulness and long-term safety, particularly concerning co-administration with antipsychotics and QTc prolongation risk management. The agency requires at least one additional positive, adequate, and well-controlled study to support safety and effectiveness.

Findings

Insufficient evidence of clinical meaningfulness and efficacy for negative symptoms

Severity: major

Study C07's post-hoc and exploratory analyses were not robust enough to overcome the lack of a positive primary endpoint, mixed secondary results, and uncertainties regarding clinical meaningfulness. The observed change in negative symptoms was not representative of clinically meaningful within-patient improvement in either Study C03 or C07.

Recommended response: Conduct at least one additional positive, adequate, and well-controlled study to support the safety and effectiveness of roluperidone for the treatment of negative symptoms.

Inadequate data on co-administration with antipsychotic medications

Severity: major

The NDA submission lacks data on the impact of co-administration with antipsychotics on roluperidone's safety and efficacy. This is critical given that current standard of care for schizophrenia includes ongoing antipsychotic treatment, and pharmacodynamic interactions could impact safety and efficacy.

Recommended response: Provide additional data to demonstrate the safety and efficacy of roluperidone coadministered with antipsychotic medications.

Inadequate long-term safety database

Severity: major

The submitted safety database included an inadequate number of subjects exposed to roluperidone at the proposed dose (64 mg) for at least 12 months, which is inconsistent with the ICH E1 Guideline for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening diseases.

Recommended response: Conduct additional studies to demonstrate the long-term safety of the proposed dose, consistent with ICH E1 Guideline.

Cited: ICH E1 Guideline for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening diseases

Inadequate strategy for QTc prolongation risk mitigation and inconsistent CYP2D6 phenotyping

Severity: major

The proposed strategy for reliably identifying patients at greatest risk of QTc prolongation is insufficient. The CYP2D6 phenotype assignments used are inconsistent with current standards, and the definition of IMs/PMs is not consistent with standard phenotype definitions, posing potential safety risks. Development and contemporaneous authorization of an in vitro companion diagnostic device would likely be required.

Recommended response: Re-evaluate and refine the strategy for identifying patients at risk of QTc prolongation, align CYP2D6 phenotyping with standard definitions, and consider additional PK/safety characterization for specific CYP2D6 populations. Develop an in vitro companion diagnostic device.

Resubmission of proprietary name required

Severity: minor

The proposed proprietary name was found acceptable pending approval of the application in the current review cycle. It must be resubmitted when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name with the response to deficiencies.

Comprehensive safety update required with response

Severity: minor

A comprehensive safety update, including new data from all nonclinical and clinical studies/trials, retabulations, worldwide experience, and English translations of foreign labeling, is required as per 21 CFR 314.50(d)(5)(vi)(b) when responding to the deficiencies.

Recommended response: Prepare and submit a comprehensive safety update as specified in 21 CFR 314.50(d)(5)(vi)(b) with the response to deficiencies.

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

Regulatory context

Submission stage
final decision
Regulatory pathway
NDA

Impact

Impact score
0.75
Estimated delay
730 days
Estimated rework cost
$0
Subsequent action
resubmission

Strategic insights

The primary themes are insufficient clinical evidence for efficacy and clinical meaningfulness, inadequate long-term safety data, and an unaddressed risk mitigation strategy for QTc prolongation linked to pharmacogenomics, necessitating further pivotal studies and data generation.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%

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