US FDA•United StatesAL•Approval Letter

Approval Letter Other 213931 (Jan 1, 2024)

Issued January 1, 2024

Issued

January 1, 2024

Application

Other • 213931

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due December 31, 2024Product may be marketed.

Summary

This is a Complete Response Letter from the FDA to Ardelyx, Inc. regarding their New Drug Application (NDA) for tenapanor hydrochloride tablets. The FDA has determined that the application cannot be approved in its present form due to insufficient evidence of a clinically relevant treatment effect on serum phosphorus, despite acknowledging the drug's efficacy in reducing serum phosphorus. The letter outlines specific deficiencies and requirements for resubmission.

Key points

Conduct an additional adequate and well-controlled trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on a clinical outcome thought to be caused by hyperphosphatemia in CKD patients on dialysis.
Review labeling review resources and use the Selected Requirements for Prescribing Information (SRPI) checklist if revising labeling.
Include updated content of labeling in structured product labeling (SPL) format if revising labeling.
Resubmit the proposed proprietary name (Xphozah) when responding to the application deficiencies.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
Describe in detail any significant changes or findings in the safety profile within the safety update.
Incorporate new safety data from studies/clinical trials for the proposed indication using the same format as in the original submission.
Present tabulations of new safety data combined with the original application data.

Cited reasons

Unclear Clinical Significance of Treatment Effect on Serum Phosphorus
Proprietary Name Resubmission Required
Comprehensive Safety Update Required
Labeling Comments Reserved
The application cannot be approved in its present form primarily due to the unclear clinical significance of the observed treatment effect on serum phosphorus. While efficacy was demonstrated, the magnitude of the effect was deemed small and insufficient for approval without further evidence. An additional adequate and well-controlled clinical trial is required. Other deficiencies include administrative requirements for proprietary name resubmission and a comprehensive safety update upon resubmission.

Recommended actions

Conduct an additional adequate and well-controlled trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on a clinical outcome thought to be caused by hyperphosphatemia in CKD patients on dialysis.
Review labeling review resources and use the Selected Requirements for Prescribing Information (SRPI) checklist if revising labeling.
Include updated content of labeling in structured product labeling (SPL) format if revising labeling.
Resubmit the proposed proprietary name (Xphozah) when responding to the application deficiencies.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
Describe in detail any significant changes or findings in the safety profile within the safety update.
Incorporate new safety data from studies/clinical trials for the proposed indication using the same format as in the original submission.
Present tabulations of new safety data combined with the original application data.

Deficiency summary

The application cannot be approved in its present form primarily due to the unclear clinical significance of the observed treatment effect on serum phosphorus. While efficacy was demonstrated, the magnitude of the effect was deemed small and insufficient for approval without further evidence. An additional adequate and well-controlled clinical trial is required. Other deficiencies include administrative requirements for proprietary name resubmission and a comprehensive safety update upon resubmission.

Findings

Unclear Clinical Significance of Treatment Effect on Serum Phosphorus

Severity: critical

Although tenapanor is effective in reducing serum phosphorus in CKD patients on dialysis, the magnitude of the treatment effect is small and its clinical significance is unclear. The primary efficacy analysis based on a responder-enriched subset (Efficacy Analysis Set) was considered clinically irrelevant. Analyses based on the ITT population showed a small treatment effect (0.66-0.72 mg/dL), which is smaller than currently marketed products (~1.5-2.2 mg/dL) and lacks precedent for approval at this magnitude. An additional adequate and well-controlled trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on a clinical outcome thought to be caused by hyperphosphatemia in CKD patients on dialysis is required.

Recommended response: Conduct an additional adequate and well-controlled clinical trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on a clinical outcome thought to be caused by hyperphosphatemia in CKD patients on dialysis. Consider prospectively testing an individualized treatment strategy based on early response.

Cited: section 505(b) of the Federal Food, Drug, and Cosmetic Act

Proprietary Name Resubmission Required

Severity: minor

The proposed proprietary name, Xphozah, 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: Resubmit the proposed proprietary name (Xphozah) with the complete response to the application deficiencies.

Comprehensive Safety Update Required

Severity: major

A comprehensive safety update, as described in 21 CFR 314.50(d)(5)(vi)(b), is required with the resubmission. This includes detailed descriptions of significant changes, new safety data from studies/trials, tabulations of new and combined data, comparison of adverse event frequencies, separate tables for other indications, retabulation of premature discontinuations, case report forms/narrative summaries for deaths/serious adverse events, information on changes in common adverse events, updated exposure information, worldwide safety experience summary, and English translations of foreign labeling.

Recommended response: Prepare a detailed safety update adhering to 21 CFR 314.50(d)(5)(vi)(b), including all specified components, for inclusion in the resubmission.

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

Labeling Comments Reserved

Severity: info

Comments on proposed labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review labeling resources, regulations, guidance documents, and the Selected Requirements for Prescribing Information (SRPI) checklist. Any revised labeling must include updated content in SPL format.

Recommended response: Review FDA labeling resources and guidance documents. Prepare to revise labeling according to the SRPI checklist and submit updated content in SPL format once clinical deficiencies are addressed.

Cited: 21 CFR 314.50(l)(1)(i)

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b) of the Federal Food, Drug, and Cosmetic Act

Impact

Impact score: 0.95
Estimated delay: 730 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary theme is the lack of demonstrated clinically relevant efficacy for tenapanor in reducing serum phosphorus, necessitating further clinical trials. Secondary themes include administrative requirements for proprietary name resubmission and a comprehensive safety update upon resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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