Issued January 1, 2020
Issued
January 1, 2020
Application
Other • 209575
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This document is a Complete Response letter from the FDA to Lannett Holdings, Inc. regarding their New Drug Application (NDA) 209575 for Cocaine Hydrochloride Topical Solution, 4% and 10%. The FDA has determined that the application cannot be approved in its present form due to several deficiencies in clinical, nonclinical, and regulatory aspects, and provides recommendations for addressing these issues.
The application cannot be approved in its current form due to significant deficiencies across clinical, nonclinical, and regulatory aspects. Key issues include inadequate characterization of the product's effect on the QT interval, insufficient leachables evaluation for the container closure system, missing purity data for nonclinical test articles, and issues with the justification and sourcing of information for the proposed labeling. A comprehensive safety update is also required upon resubmission.
You have not provided adequate information to characterize the effects of your product on the QTc interval.
Recommended response: Submit the results of a thorough QT study.
You have not provided adequate leachables evaluation to justify the safety of the proposed container closure system. Specifically, your leachables evaluation did not evaluate at least three batches of your to-be-marketed drug product for leachables and include assessments at multiple timepoints over the course of your stability studies as advised at the Pre-NDA meeting and in accordance with best practices per USP <1664>. Further, you have not provided an adequate extractables-leachables correlation.
Recommended response: Conduct a new leachables study under standard storage conditions that evaluates at least three batches of the to-be-marketed topical cocaine solution products for leachables and include assessments at multiple timepoints over the course of your stability studies. Submit a toxicological assessment justifying the safety of the maximum level achieved over the course of stability for any leachable that exceeds 5 mcg/day. Submit a discussion of the extractables leachables correlation of the findings.
Cited: USP <1664>: Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems
Several of your final study reports did not report the purity of the test articles.
Recommended response: Revise the final study reports for Study 16-0l 138-G2, 16-0l 139-G2, and 16-0l 140-G2 to include purity information of the test articles evaluated.
Your annotated draft labeling did not adequately identify the appropriate source(s) of information upon which you propose to rely. This includes issues with relying on non-US conclusions, identifying listed drugs, and establishing a 'bridge' for 505(b)(2) reliance.
Recommended response: Identify appropriate sources of information, including published literature or listed drugs in accordance with 21 CFR 314.54. Establish a 'bridge' (e.g., via comparative bioavailability data) between your proposed drug product and each listed drug upon which you propose to rely.
Cited: 21 CFR 314.54
Your response must include updated content of labeling in structured product labeling (SPL) format.
Recommended response: Review labeling review resources and the SRPI checklist. Ensure updated content of labeling is provided in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
Cited: 21 CFR 314.50(l)(1)(i)
The proposed proprietary name, NUMBRINO, was found acceptable pending approval of the application. Please resubmit the proposed proprietary name request when you respond to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name request with the complete response to the application deficiencies.
A comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required upon resubmission. This includes detailing significant changes, new safety data, tabulations, case reports, updated exposure information, and worldwide experience.
Recommended response: Prepare a detailed safety update including all new nonclinical and clinical study data, changes in safety profile, tabulations of adverse events, case report forms for deaths or serious adverse events, updated exposure information, and a summary of worldwide experience and foreign labeling.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
The application received a Complete Response Letter due to critical data gaps in clinical safety (QT interval), product quality (container closure leachables), and nonclinical study reporting. Additionally, regulatory compliance for labeling and the 505(b)(2) reliance pathway requires further justification and a comprehensive safety update is mandated for resubmission.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 25%
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