Issued January 1, 2024
Issued
January 1, 2024
Application
Other • 216490
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response letter from the FDA to Ascendis Pharma Bone Diseases A/S regarding their New Drug Application (NDA) 216490 for palopegteriparatide injection. The FDA has determined that the application cannot be approved in its present form due to unresolved deficiencies related to product quality/device, labeling, and requires specific safety updates and postmarketing studies.
The application is not approvable in its current form due to significant unresolved deficiencies primarily related to product quality, including dose variability, inadequate data for revised specifications, and anticipated high batch failure rates. Additionally, a comprehensive safety update is required, and specific postmarketing studies will be mandated upon eventual approval to address pregnancy and lactation risks.
Significant variability of the delivered dose, a product critical quality attribute, was identified.
Recommended response: Conduct further studies to understand and mitigate dose variability, revise manufacturing processes, and update specifications to ensure consistent product quality.
Lack of adequate data to support the feasibility of the revised assay and delivered volume specification with respect to limiting the variability of the deliverable dose at each dose setting.
Recommended response: Generate comprehensive data to validate the revised assay and specifications, demonstrating their ability to effectively control dose variability and ensure product consistency.
An anticipated high-level of batch failure with the proposed specifications, indicative of inadequate formulation and device design.
Recommended response: Re-evaluate and optimize formulation and device design to reduce anticipated batch failure rates and ensure robust product quality and manufacturability.
Inadequate stability data to support shelf-life determination of the product per the revised specification for the delivered dose.
Recommended response: Conduct additional stability studies with the revised specifications to generate sufficient data for establishing a robust and scientifically sound shelf-life.
A comprehensive safety update is required, including detailed changes/findings in the safety profile, new safety data presentation (separate tables for other indications, combined with original data, comparison tables), retabulation of premature trial discontinuation reasons, case report forms and narrative summaries for deaths/adverse event discontinuations and serious adverse events, information on substantial changes in common adverse event incidence, updated exposure information, summary of worldwide safety experience, and English translations of current approved foreign labeling.
Recommended response: Compile and present a comprehensive safety update addressing all specified data requirements, ensuring full compliance with 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
If approved, the applicant will be required to conduct postmarketing studies to assess a known risk of hypocalcemia/hypercalcemia and to identify other unexpected serious risks of pregnancy and maternal complications, adverse effects on the developing fetus and neonate, and adverse effects on the infant potentially associated with palopegteriparatide use during pregnancy and lactation. This includes a lactation study and a worldwide descriptive study.
Recommended response: Develop detailed protocols for the specified postmarketing studies, including a lactation study and a worldwide descriptive study for pregnancy/lactation exposure, to be submitted upon resubmission or approval.
Cited: section 505(o)(3) of the FDCA
The proposed proprietary name, Yorvipath, was found acceptable pending approval of the application in the current review cycle. It must be resubmitted when responding to the application deficiencies.
Recommended response: Include the proprietary name resubmission with the complete response package to ensure it is processed concurrently with the updated application.
Comments on the proposed carton and container labeling are reserved until the application is otherwise adequate.
Recommended response: Address all other deficiencies first; the agency will provide feedback on labeling once the application is deemed otherwise adequate.
The application faces significant hurdles primarily in product quality and manufacturing control, indicated by dose variability and anticipated batch failures. Comprehensive clinical safety data updates are also critical, and future approval is contingent on committing to specific postmarketing studies for pregnancy and lactation risks.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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