Insufficient Scientific Bridge to Published Clinical Studies
Severity: criticalThe applicant has not provided a sufficient scientific bridge between their product (Avaclyr) and the one used in the published clinical studies, which is a fundamental requirement for a 505(b)(2) application. The agency suggests conducting a controlled clinical trial with Avaclyr as an alternative option.
Recommended response: Provide robust scientific bridging data or conduct a controlled clinical trial with Avaclyr to establish the necessary scientific bridge.
Inadequate In Vitro Release Testing (IVRT) Method Validation
Severity: majorThe IVRT method, intended to demonstrate suitability and establish a scientific bridge between Avaclyr and the comparator product (Zovirax), is inadequately validated. Specific issues include method failure (details redacted), lack of an investigational report and description of the final method, and absence of a full validation report addressing method sensitivity.
Recommended response: Provide a comprehensive investigational report, a detailed description of the final IVRT method, and a full validation report demonstrating method sensitivity and compliance with validation standards.
Cited: USP<1724>
Unresolved Acyclovir Polymorphism Influence on IVRT
Severity: majorIt is unclear if polymorphism of the acyclovir drug substance influences the IVRT results. The agency requires solubility data and intrinsic dissolution rate for acyclovir drug substance used in Avaclyr, Zovirax, and other formulations, with a comparison to literature reports on various polymorphs.
Recommended response: Conduct studies to clarify the influence of acyclovir polymorphism on IVRT results and provide the requested solubility and intrinsic dissolution rate data, comparing findings to existing literature.
Cited: USP<1087> Apparent Intrinsic Dissolution
Labeling Deficiencies
Severity: minorComments on the proposed labeling are reserved until the application is otherwise adequate. The applicant is required to provide updated content of labeling in Structured Product Labeling (SPL) format, adhering to PLR requirements and related guidance documents.
Recommended response: Review PLR requirements and relevant guidance, then prepare and submit updated labeling in SPL format once other deficiencies are resolved.
Cited: 21 CFR 314.50(l)(1)(i)
Incomplete Safety Update
Severity: majorA comprehensive safety update is required upon resubmission, as per 21 CFR 314.50(d)(5)(vi)(b). This includes detailing significant changes, presenting new and combined safety data, comparing adverse event frequencies, providing retabulations for premature discontinuations, case reports for deaths/serious adverse events, updated exposure information, a worldwide experience summary, and English translations of foreign labeling.
Recommended response: Compile and submit a complete safety update according to regulatory requirements, ensuring all specified data and analyses are included.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
