US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 217724 (Oct 8, 2024)

Issued October 8, 2024

Issued

October 8, 2024

Application

NDA 505b1 • 217724

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due October 8, 2025Requires resubmission addressing deficiencies.

Summary

This letter from the FDA communicates deficiencies found in New Drug Application (NDA) 217724 and outlines requirements for a complete response. Key areas of concern include manufacturing compliance (CGMP), prescribing information (labeling) content and format, proprietary name review, safety updates, and specific clinical data requests related to pediatric dosing, safety, and efficacy, particularly for infants with low body weight or prematurity. The applicant is required to address these deficiencies within one year, with specific instructions for resubmission.

Key points

Address CGMP deficiencies to the FDA office indicated on the FDA 483 prior to your complete response.
Coordinate with the facility for timely resolution of deficiencies identified during the inspection.
Include the date(s) of the facility’s response(s) to the FDA Form 483 in your complete response.
Submit draft labeling that is responsive to the FDA's electronic communication.
Use the Selected Requirement of Prescribing Information (SRPI) checklist to correct any formatting errors in the labeling.
Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov.
Provide a highlighted or marked-up copy that shows all changes to the labeling, as well as a clean Word version.
Ensure the proposed Prescribing Information (PI) conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.

Cited reasons

Unresolved Manufacturing Facility CGMP Deficiencies
Non-conformance of Prescribing Information (PI) with Content and Format Regulations
Proprietary Name Review Terminated Due to Application Deficiencies
Inadequate Safety Update
Missing Clinical Data and Justification for Specific Pediatric Populations (Body Weight < 4.1 kg)
Unclear Indication Statement and Data Gaps for Infants < 7 Days Old / Premature / SGA
Justification for Infusion Pump Use in Low Weight Infants
Lack of Data for Renal Impairment Dosing

Recommended actions

Address CGMP deficiencies to the FDA office indicated on the FDA 483 prior to your complete response.
Coordinate with the facility for timely resolution of deficiencies identified during the inspection.
Include the date(s) of the facility’s response(s) to the FDA Form 483 in your complete response.
Submit draft labeling that is responsive to the FDA's electronic communication.
Use the Selected Requirement of Prescribing Information (SRPI) checklist to correct any formatting errors in the labeling.
Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov.
Provide a highlighted or marked-up copy that shows all changes to the labeling, as well as a clean Word version.
Ensure the proposed Prescribing Information (PI) conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.

Deficiency summary

The application received a Complete Response due to significant deficiencies across several areas. These include unresolved manufacturing facility issues, non-conformance of prescribing information (PI) with regulatory requirements, termination of proprietary name review, and critical gaps in clinical safety data, particularly concerning specific pediatric populations (infants < 4.1 kg, < 7 days old, premature, SGA) and the need for a comprehensive safety update.

Findings

Unresolved Manufacturing Facility CGMP Deficiencies

Severity: major

Deficiencies identified during a CGMP inspection of the manufacturing facility remain unresolved. Satisfactory responses from the facility and potential re-inspection are required. A pre-approval inspection (PAI) may also be needed. The applicant is advised to coordinate with the facility for timely resolution, but a direct response to this specific deficiency is not expected in the complete response.

Recommended response: Coordinate closely with the manufacturing facility to address all identified CGMP deficiencies and ensure satisfactory resolution with the FDA, including potential re-inspection and PAI.

Cited: Compliance Program CP 7356.002

Non-conformance of Prescribing Information (PI) with Content and Format Regulations

Severity: major

The submitted draft labeling is not responsive to previous electronic communication. It contains formatting errors and does not conform to content and format regulations (21 CFR 201.56(a) and (d), 201.57). An updated content of labeling in SPL format (21 CFR 314.50(l)(1)(i)) is required.

Recommended response: Revise the draft labeling to address all previous communications and ensure full compliance with 21 CFR 201.56(a), (d), and 201.57. Submit updated content in SPL format as per 21 CFR 314.50(l)(1)(i), providing both marked-up and clean versions. Utilize the SRPI checklist.

Cited: 21 CFR 314.50(l)(1)(i), 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57

Proprietary Name Review Terminated Due to Application Deficiencies

Severity: minor

The review of the proposed proprietary name has been terminated because of the overall deficiencies in the application. The applicant must resubmit the proposed proprietary name when responding to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name concurrently with the complete response addressing all other application deficiencies.

Inadequate Safety Update

Severity: major

A comprehensive safety update is required as per 21 CFR 314.50(d)(5)(vi)(b). The update must include data from all nonclinical and clinical studies, detail significant changes in the safety profile, present new safety data combined with original NDA data, provide comparative tables, and include separate tables for AEs in non-proposed indications.

Recommended response: Prepare a thorough safety update encompassing all nonclinical and clinical data, presenting it in the requested comparative and tabulated formats, and highlighting any significant changes in the safety profile.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Missing Clinical Data and Justification for Specific Pediatric Populations (Body Weight < 4.1 kg)

Severity: critical

No clinical data was generated for infants < 4.1 kg. The proposed PI lacks information on how prescribers should consider body weight for dosing. Simulated exposures for infants < 4.1 kg are anticipated to exceed the NOAEL for transient freezing absences in rats. Justification with clinical safety data is required to support dosing recommendations for this population.

Recommended response: Conduct additional studies or provide robust justification with existing clinical safety data to support dosing recommendations for infants < 4.1 kg, addressing the pharmacokinetic and safety concerns raised by the simulated exposures. Propose appropriate PI language.

Unclear Indication Statement and Data Gaps for Infants < 7 Days Old / Premature / SGA

Severity: critical

The proposed indication limits age to ≥ 7 days, but study 17103 excluded infants < 7 days. Clarification is needed on benefit/risk for infants < 7 days, inclusion of premature/term infants, and enrollment of premature infants in study 17103. Further justification is needed for safety and efficacy in SGA and premature infants, considering renal impairment, hepatic glycogen stores, and potential increased risk of AEs (e.g., hyponatremia, thrombocytopenia, metabolic acidosis).

Recommended response: Provide comprehensive clarification and justification regarding the proposed indication statement for pediatric patients, specifically addressing the safety and efficacy considerations for infants < 7 days old, premature, and SGA infants, supported by relevant clinical and nonclinical data.

Justification for Infusion Pump Use in Low Weight Infants

Severity: major

Justification is required for the use of the infusion pump and infusion set in infants < 4.1 kg, including premature infants, addressing potential technical challenges with insertion/maintenance due to limited subcutaneous fat.

Recommended response: Provide a detailed justification for the suitability and safety of the infusion pump and set in very low weight and premature infants, considering practical and physiological challenges.

Lack of Data for Renal Impairment Dosing

Severity: major

The effect of moderate to severe renal impairment on dasiglucagon PK has not been investigated. A proposal for the product PI regarding renal impairment, with justification and supporting data, is required.

Recommended response: Conduct studies or provide a robust justification and data-driven proposal for dosing recommendations in patients with renal impairment, and incorporate this into the product PI.

Regulatory context

Submission stage: final decision
Regulatory pathway: NDA

Impact

Impact score: 0.95
Estimated delay: 545 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary themes for this Complete Response are the critical lack of sufficient clinical safety and efficacy data for vulnerable pediatric populations (especially very low birth weight and premature infants), significant deficiencies in the proposed prescribing information and overall safety update, and unresolved manufacturing facility compliance issues. These gaps prevent a comprehensive benefit-risk assessment for the proposed indication.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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