Issued January 1, 2021
Issued
January 1, 2021
Application
Other • 209511
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
The FDA issued a Complete Response letter for New Drug Application (NDA) 209511 for bupivacaine hydrochloride collagen-matrix implants, indicating that the application cannot be approved in its current form. The letter details several nonclinical, product quality, and safety deficiencies, along with issues regarding the proposed indication and labeling, and provides recommendations for addressing these issues.
The application cannot be approved in its current form due to significant deficiencies across nonclinical safety (systemic exposure characterization, genotoxicity assay), product quality (extractables/leachables evaluation, impurity specification justification), and clinical data not supporting the proposed broad indication. Several administrative and labeling comments were also provided.
Existing toxicology data in the rat model do not provide adequate coverage for human exposures (AUC and Cmax) via the drug product, which are twice that of the referenced product.
Recommended response: Conduct adequate toxicology studies in two species that provide adequate coverage for the proposed human exposures (AUC and Cmax) or provide clinical data to support the safety of the proposed exposure.
The high dose selected for the assay did not result in frank toxicity, rendering the assay invalid.
Recommended response: Repeat the in vivo micronucleus assay for bupivacaine testing doses that result in frank toxicity in accordance with the ICH S2(R1) guidance document.
Cited: ICH guidance document: S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use
Many compounds detected above the safety concern threshold in extraction studies were not identified. Inadequate leachables data from multiple batches at release, with compounds identified in extraction studies not targeted using validated methods.
Recommended response: Identify the compounds detected in extraction studies, evaluate drug product stability batches for the presence of any extractable detected at the safety concern threshold or higher, and provide a toxicological risk assessment for any leachable compound present.
The proposed specification for an impurity (b)(4) in the drug product formulation lacks adequate justification.
Recommended response: Either reduce the specification for the impurity to NMT (b)(4) mcg/day or provide an adequate toxicological risk assessment to justify the proposed specification in accordance with ICH M7(R1).
Cited: ICH guidance document: M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk
An analytical method for the detection of leachables has not been provided, preventing a correlation between extractables and leachables. Leachables testing should be performed on (b)(4) manufactured product.
Recommended response: Identify target leachables from robust extractables profiles, develop methods to detect these leachables in the drug product, and test 3 batches of drug product at multiple time-points on stability, with emphasis on (b)(4) manufactured product that includes ink labeling.
Cited: USP <1663>, USP <1664>
Comments on the proposed labeling are reserved until the application is otherwise adequate. The agency encourages review of PLR Requirements and SRPI checklist.
Recommended response: Review labeling review resources, including PLR requirements, related guidance documents, and the SRPI checklist. If labeling is revised, ensure it conforms to format items and include updated content in SPL format.
Cited: 21 CFR 314.50(l)(1)(i)
The proposed proprietary name, XARACOLL, was found acceptable pending approval of the application. It must be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name when responding to the application deficiencies.
A comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included with the response, detailing any significant changes or findings in the safety profile from all nonclinical and clinical studies/trials.
Recommended response: Include a safety update with the resubmission, covering all nonclinical and clinical studies/trials, significant changes, new data tabulations, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
The proposed broad indication 'for placement into the surgical site to produce postsurgical analgesia following (b)(4)' is not supported by the clinical data presented in the NDA submission. This concern was previously communicated.
Recommended response: Acknowledge that the final determination of the indication will likely be limited to the surgical population in which the drug product was tested and demonstrated to be safe and effective.
The application is deficient across multiple critical areas including nonclinical safety (toxicology, genotoxicity), product quality (extractables/leachables, impurity control), and clinical efficacy (unsupported broad indication). These issues necessitate substantial additional studies and data generation before approval can be considered.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 25%
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