Incomplete Patent Certification or Statement
Severity: majorThe 505(b)(2) application references a listed drug in its annotated labeling but lacks patent certifications or statements for all relevant patents listed in the Orange Book for that drug, as required by 21 CFR 314.54(a)(1)(vi).
Recommended response: Either remove references to the listed drug or submit appropriate patent certifications/statements. If a paragraph IV certification is chosen, comply with notice requirements under 21 CFR 314.52(a) and (c).
Cited: 21 CFR 314.54(a)(1)(vi), paragraph IV certification (21 CFR 314.50(i)(1)(i)(A)(4)), 21 CFR 314.52(a), 21 CFR 314.52(c)
Insufficient Scientific Justification for Literature References
Severity: majorThe application relies on published literature for approval but lacks scientific justification for this reliance. Additionally, copies of all referenced literature are not included, and listed drugs within them are not identified.
Recommended response: Provide scientific justification for each essential literature reference, include copies of all referenced literature, and identify any listed drugs described.
Inadequate Adhesion Data for Proposed Labeling
Severity: majorOnly a one-time adhesion evaluation after 48 hours was submitted, which is insufficient to assess adhesion for a product intended for 12-hour use, failing to meet current patch adhesion expectations (90% adhesion in 90% of subjects).
Recommended response: Submit adhesion data after 12 hours of use from Study SCI-LIDO-DERM-001, or conduct a new study evaluating adhesion for the proposed labeling duration and method.
Flawed Bioequivalence Study Design
Severity: majorThe comparative bioavailability study (SCI-LIDO-PK-001) cannot establish bioequivalence because surgical tape was used to secure the Lidoderm 5% patches, and no adequate evidence was provided to justify that tape would not affect lidocaine absorption.
Recommended response: Conduct a new, adequately designed comparative bioavailability study to demonstrate equivalent systemic exposure to Lidoderm patch 5%, using the listed drug product according to its approved package insert (e.g., without tape).
Unacceptable Specification for 2,6-xylidine Degradant
Severity: criticalThe proposed specification for the drug product degradant 2,6-xylidine (a known rat carcinogen) exceeds the acceptable daily intake level of 10 mcg per day per ICH M7 guidance. The justification provided does not adequately consider the amount released from the patch.
Recommended response: Reduce the specification of 2,6-xylidine to NMT 10 mcg per day or provide data demonstrating that the level released from ZTlido under conditions of use is within the level released from the listed drug.
Cited: ICH guidance for industry: M7 Assessment And Control of DNA Reactive (Mutagenic) Impurities In Pharmaceuticals To Limit Potential Carcinogenic Risk
Inadequate Qualification of Impurities Exceeding Thresholds
Severity: majorProposed specifications for other impurities exceed the qualification threshold of 0.2% or 3 mg total daily intake per ICH Q3B(R2). The toxicological risk assessment based on ICH Q3C is unacceptable for drug product degradants.
Recommended response: Reduce proposed specifications to NMT 0.2% or 3 mg TDI, or adequately qualify safety via genetic toxicology screen (point mutation, chromosome aberration) and a 90-day repeat-dose toxicology study. Alternatively, justify safety via comparative analytical studies showing levels are equal to or below the referenced drug product.
Cited: ICH guidance for industry: Q3B(R2) Impurities in New Drug Products, ICH guidance for industry: Q3C Impurities: Residual Solvents, FDA guidance for industry: ANDAs: Impurities in Drug Products
Inadequate Systemic Safety Justification for Excipients
Severity: majorInsufficient information to justify the systemic safety of dipropylene glycol, isostearic acid, SIS block copolymer, and terpene resin for the intended clinical use, specifically regarding exposure compared to accepted uses in FDA-approved products.
Recommended response: Submit a toxicological risk assessment supporting systemic safety based on maximum recommended daily dose, including data on release from patch (leachables), systemic absorption, or molecular weight justification. Address general chronic toxicity, genetic toxicity, reproductive and developmental toxicity, and carcinogenic potential. Provide adequate safety justification for at least 3 months of treatment and assessment of reproductive/developmental effects.
Inadequate Safety Information for Polyisobutylene Excipient
Severity: minorInsufficient information regarding polyisobutylene in the drug product formulation to permit a complete safety evaluation or extrapolation of safety via comparison to its use in an FDA-approved drug product, specifically regarding the molecular weight range.
Recommended response: Submit the specific molecular weight range for the low and high molecular weight polyisobutylenes.
