US FDA•United StatesAL•Approval Letter

Approval Letter Other 200655 (Jan 1, 2019)

Issued January 1, 2019

Issued

January 1, 2019

Application

Other • 200655

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2020Product may be marketed.

Summary

The FDA issued a Complete Response letter for NDA 200655 for Fluorodopa F 18 Injection, indicating that the application cannot be approved in its current form due to significant deficiencies in clinical/statistical data, particularly regarding Study #17's design, conduct, and follow-up, which failed to provide sufficient confirmatory evidence of effectiveness. The letter also outlines requirements for labeling, safety updates, and the resubmission process.

Key points

Address deficiencies in Study #17 regarding effectiveness evidence and characterization of Fluorodopa F 18 PET scan performance.
Develop a plan to make clinical assessments of patients' clinical diagnoses that are not influenced by the results of image reads.
Obtain complete follow-up on all subjects in the study.
Consider extending Study #17 to enroll additional patients who will also have clinical follow-up at a pre-defined interval as an adequate standard of reference.
Correct deficiencies with the study protocol and conduct of the study.
Clearly document which clinical features in each patient were consistent with Parkinsonian or non-Parkinsonian syndrome.
Review labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) checklist.
Ensure that the prescribing information conforms with format items in regulations and guidances if revised.

Cited reasons

Insufficient Confirmatory Evidence of Effectiveness and Inadequate PET Scan Performance Characterization
Inadequate Safety Update
Prescribing Information Update Required
The application for Fluorodopa F 18 Injection cannot be approved in its present form due to critical deficiencies in the clinical study design and conduct, leading to insufficient confirmatory evidence of effectiveness and inadequate characterization of the PET scan's performance. Additionally, a comprehensive safety update and updated labeling in SPL format are required upon resubmission.

Recommended actions

Address deficiencies in Study #17 regarding effectiveness evidence and characterization of Fluorodopa F 18 PET scan performance.
Develop a plan to make clinical assessments of patients' clinical diagnoses that are not influenced by the results of image reads.
Obtain complete follow-up on all subjects in the study.
Consider extending Study #17 to enroll additional patients who will also have clinical follow-up at a pre-defined interval as an adequate standard of reference.
Correct deficiencies with the study protocol and conduct of the study.
Clearly document which clinical features in each patient were consistent with Parkinsonian or non-Parkinsonian syndrome.
Review labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) checklist.
Ensure that the prescribing information conforms with format items in regulations and guidances if revised.

Deficiency summary

The application for Fluorodopa F 18 Injection cannot be approved in its present form due to critical deficiencies in the clinical study design and conduct, leading to insufficient confirmatory evidence of effectiveness and inadequate characterization of the PET scan's performance. Additionally, a comprehensive safety update and updated labeling in SPL format are required upon resubmission.

Findings

Insufficient Confirmatory Evidence of Effectiveness and Inadequate PET Scan Performance Characterization

Severity: critical

Study #17 does not provide sufficient confirmatory evidence of effectiveness, and the Fluorodopa F 18 PET scan’s performance is not adequately characterized. Issues include insufficient clinical follow-up for negative interpretations, lack of independence in clinical diagnosis assessment (potential for test results to influence diagnosis), and inadequate follow-up for positive images.

Recommended response: Develop a plan to address deficiencies, including a method for independent clinical assessment, complete follow-up on all subjects, and correction of study protocol/conduct issues. Consider extending Study #17 or designing a new study. Request a meeting to discuss the design of an appropriate statistical analysis plan.

Inadequate Safety Update

Severity: major

The response must include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). Specific requirements include detailing significant changes in safety profile, presenting new safety data from studies/clinical trials, combining new and original data, comparing frequencies of adverse events, providing separate tables for other indications, providing case report forms and narrative summaries for deaths/discontinuations/serious adverse events, describing changes in common adverse events, providing updated exposure information, summarizing worldwide safety experience, and providing English translations of foreign labeling.

Recommended response: Submit a comprehensive safety update addressing all specified points, including new data, combined tabulations, comparisons, case report forms, narrative summaries, exposure information, worldwide experience, and translated foreign labeling.

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

Prescribing Information Update Required

Severity: minor

The agency reserves comment on proposed labeling until the application is otherwise adequate. However, any revised labeling must include updated content of labeling in structured product labeling (SPL) format as described at 21 CFR 314.50(l)(1)(i).

Recommended response: Review labeling review resources, including PLR Requirements and Pregnancy and Lactation Labeling Final Rule websites. Use the SRPI checklist to ensure compliance with format items. Submit updated content of labeling in SPL format.

Cited: 21 CFR 314.50(l)(1)(i)

Regulatory context

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

Impact

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

Strategic insights

The application for Fluorodopa F 18 Injection was not approved due to critical deficiencies in the clinical study design and conduct, leading to insufficient evidence of effectiveness and inadequate characterization of the product's performance. Additionally, a comprehensive safety update and updated labeling in SPL format are required upon resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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