Complete Response Letter NDA 505b1 210934 (Dec 20, 2024)

Summary

The FDA has issued a Complete Response Letter for NDA 210934 for sotagliflozin, indicating that the application is not approvable. The agency concluded that the submitted data did not support a favorable benefit-risk assessment for sotagliflozin in patients with Type 1 Diabetes (T1D) and eGFR ≥60 ml/min/1.73m2 and UACR ≥30 mg/g, primarily due to the risk of Diabetic Ketoacidosis (DKA) outweighing the modest glycemic and other non-glycemic benefits. The letter outlines deficiencies and suggests potential paths forward, including conducting new clinical safety trials to demonstrate adequate DKA risk mitigation and providing additional data for T1D patients with eGFR <60 ml/min/1.73m2.

Key points

• Demonstrate in a prospective, pragmatic open-label randomized clinical safety trial with a standard-of-care active comparator arm (or potentially a single-arm study with an external control) that patient selection criteria and/or risk mitigation strategies adequately mitigate the risk of DKA.
• Provide additional glycemic control data in patients with T1D and eGFR <60 ml/min/1.73m2 to support dosing recommendations.
• Resubmit the application or take other actions available under 21 CFR 314.110 within one year after the date of this letter.
• If revising labeling, use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure conformity with format items in regulations and guidances.
• Include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format in any response.
• Provide any information that suggests a substantial change in the incidence of common, but less serious, adverse events between new data and original application data.
• Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
• Provide a summary of worldwide experience on the safety of this drug, including an updated estimate of use for drug marketed in other countries.

Cited reasons

• Inadequate Benefit-Risk Assessment for DKA in Type 1 Diabetes with CKD
• Missing Updated Clinical Exposure Information
• Missing Summary of Worldwide Safety Experience
• Missing English Translations of Foreign Labeling
• Labeling Comments Reserved Pending Overall Adequacy
• The application received a Complete Response Letter primarily due to an insufficient benefit-risk assessment for the proposed glycemic control indication in Type 1 Diabetes (T1D) patients with Chronic Kidney Disease (CKD), specifically concerning the risk of Diabetic Ketoacidosis (DKA). The agency requires additional clinical safety data demonstrating adequate mitigation of DKA risk. Other deficiencies include missing updated clinical exposure information, a summary of worldwide safety experience, and English translations of foreign labeling. Labeling comments are reserved until the application is otherwise adequate.

Recommended actions

• Demonstrate in a prospective, pragmatic open-label randomized clinical safety trial with a standard-of-care active comparator arm (or potentially a single-arm study with an external control) that patient selection criteria and/or risk mitigation strategies adequately mitigate the risk of DKA.
• Provide additional glycemic control data in patients with T1D and eGFR <60 ml/min/1.73m2 to support dosing recommendations.
• Resubmit the application or take other actions available under 21 CFR 314.110 within one year after the date of this letter.
• If revising labeling, use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure conformity with format items in regulations and guidances.
• Include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format in any response.
• Provide any information that suggests a substantial change in the incidence of common, but less serious, adverse events between new data and original application data.
• Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
• Provide a summary of worldwide experience on the safety of this drug, including an updated estimate of use for drug marketed in other countries.

Deficiency summary

The application received a Complete Response Letter primarily due to an insufficient benefit-risk assessment for the proposed glycemic control indication in Type 1 Diabetes (T1D) patients with Chronic Kidney Disease (CKD), specifically concerning the risk of Diabetic Ketoacidosis (DKA). The agency requires additional clinical safety data demonstrating adequate mitigation of DKA risk. Other deficiencies include missing updated clinical exposure information, a summary of worldwide safety experience, and English translations of foreign labeling. Labeling comments are reserved until the application is otherwise adequate.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the critical need for additional clinical safety data to demonstrate adequate mitigation of Diabetic Ketoacidosis (DKA) risk in Type 1 Diabetes patients with Chronic Kidney Disease, to support a favorable benefit-risk assessment. Secondary themes include administrative updates for clinical exposure, global safety, and labeling translations.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%