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US FDA•United StatesAL•Approval Letter

Approval Letter Other 210875 (Jan 1, 2020)

Issued January 1, 2020

Issued

January 1, 2020

Application

Other • 210875

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Product may be marketed.

Summary

This document is a Complete Response letter from the FDA to Sunovion Pharmaceuticals Inc. regarding their New Drug Application (NDA) 210875 for Kynmobi (apomorphine) sublingual film. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to human factors (HF) validation study, clinical pharmacology and biopharmaceutics, and safety characterization of oropharyngeal adverse events. The letter outlines specific reasons for the non-approval and provides recommendations for addressing these issues, including conducting a new HF validation study, completing a specific clinical study, and providing a comprehensive discussion and re-examination of safety data.

Key points

  • Conduct a human factors validation study using the intend-to-market user interface (i.e., (b)(4) packaging) to demonstrate that mitigations are effective and do not introduce new risks.
  • Evaluate use-related errors observed in the HF study, employ additional mitigation strategies, and update the use-related risk analysis prior to conducting the new HF validation study.
  • Submit the HF validation study protocol for feedback before commencing the study.
  • Complete Study CTH-203 and provide the final report to justify the relevance of comparative data and support the scientific appropriateness of reliance on FDA’s finding of safety for Apokyn.
  • Clearly describe the data and information that supports the scientific bridge between Kynmobi and the listed drug Apokyn.
  • Provide a comprehensive discussion and summary of oropharyngeal adverse events with Kynmobi, including an expert review from a qualified dermatologist.
  • Reexamine the safety database for Study 300 and Study 301, pooling all related oropharyngeal adverse events in appropriate clusters.
  • Identify the number of oropharyngeal adverse events, unique patients reporting them, and discontinuations for each event and cluster.

Cited reasons

  • Insufficient Human Factors Validation Study
  • Incomplete Clinical Pharmacology and Biopharmaceutics Data
  • Inadequate Characterization of Oropharyngeal Adverse Events
  • Required Safety Update for Resubmission
  • The New Drug Application for Kynmobi cannot be approved in its present form due to insufficient human factors validation study data, inadequate characterization of oropharyngeal adverse events, and incomplete clinical pharmacology data required to support the scientific bridge to the listed drug.

Recommended actions

  • Conduct a human factors validation study using the intend-to-market user interface (i.e., (b)(4) packaging) to demonstrate that mitigations are effective and do not introduce new risks.
  • Evaluate use-related errors observed in the HF study, employ additional mitigation strategies, and update the use-related risk analysis prior to conducting the new HF validation study.
  • Submit the HF validation study protocol for feedback before commencing the study.
  • Complete Study CTH-203 and provide the final report to justify the relevance of comparative data and support the scientific appropriateness of reliance on FDA’s finding of safety for Apokyn.
  • Clearly describe the data and information that supports the scientific bridge between Kynmobi and the listed drug Apokyn.
  • Provide a comprehensive discussion and summary of oropharyngeal adverse events with Kynmobi, including an expert review from a qualified dermatologist.
  • Reexamine the safety database for Study 300 and Study 301, pooling all related oropharyngeal adverse events in appropriate clusters.
  • Identify the number of oropharyngeal adverse events, unique patients reporting them, and discontinuations for each event and cluster.

Deficiency summary

The New Drug Application for Kynmobi cannot be approved in its present form due to insufficient human factors validation study data, inadequate characterization of oropharyngeal adverse events, and incomplete clinical pharmacology data required to support the scientific bridge to the listed drug.

Findings

Insufficient Human Factors Validation Study

Severity: critical

The human factors (HF) validation study did not provide sufficient evidence to demonstrate safe and effective use, identified several use errors and close calls on critical tasks, and failed to validate proposed mitigations. The study also did not evaluate the final intend-to-market user interface, specifically the (b)(4) packaging, which raises concerns for the intended user population (Parkinson's patients) due to dexterity issues and potential delays in therapy.

Recommended response: Conduct a new HF validation study using the intend-to-market user interface, evaluate observed use-related errors, employ additional mitigation strategies, update the use-related risk analysis, and submit the protocol for feedback prior to commencing the study.

Incomplete Clinical Pharmacology and Biopharmaceutics Data

Severity: major

Study CTH-203 is incomplete, and its final report is necessary to justify the relevance of comparative data between Kynmobi and Apo-go. The application lacks sufficient data to support the scientific appropriateness of reliance on FDA’s finding of safety for Apokyn, requiring a clear scientific bridge between Kynmobi and the listed drug.

Recommended response: Complete Study CTH-203 and provide the final report. Clearly describe the data and information that supports the scientific bridge between Kynmobi and Apokyn.

Inadequate Characterization of Oropharyngeal Adverse Events

Severity: critical

Oropharyngeal adverse events were reported in over 25% of patients treated with Kynmobi in Study 300 and were common in Study 301, leading to discontinuations. The applicant has not adequately characterized these events, which were reported under multiple terms such as pain, swelling, and ulceration.

Recommended response: Provide a comprehensive discussion and summary of oropharyngeal adverse events, including an expert review from a qualified dermatologist. Reexamine the safety database, pool related events, identify unique patients, discontinuations, severity, time to onset/resolution, and association with systemic hypersensitivity. Obtain photographs and dermatologist diagnoses for new events in ongoing Study CTH-301.

Required Safety Update for Resubmission

Severity: major

A comprehensive safety update, as described in 21 CFR 314.50(d)(5)(vi)(b), is required upon resubmission. This includes new data from all nonclinical and clinical studies, retabulations, comparisons of adverse event frequencies, case reports for deaths/serious AEs, updated exposure information, worldwide experience, and English translations of current approved foreign labeling.

Recommended response: Prepare a complete safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b) for inclusion with the resubmission, addressing all specified data and analyses.

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 was not approved primarily due to critical deficiencies in human factors validation for the combination product, unaddressed safety concerns regarding oropharyngeal adverse events, and missing clinical pharmacology data necessary for bridging to the listed drug. A comprehensive safety update is also required for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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