Insufficient Confirmatory Efficacy Evidence from Clinical Trials
Severity: criticalEASE-2 and EASE-3 did not provide confirmatory evidence to support EASE-1 results, lacking independent evidence of effectiveness. EASE-1 had numerous uncertainties including protocol deviations in PS adjustments, incomplete/missing urinary output documentation, eDiary configuration issues, and inadequate qualitative/quantitative analyses for clinical meaningfulness. EASE-3 lacked concurrent control and objective criteria for weaning PS volume.
Recommended response: Conduct a second adequate and well-controlled trial, leveraging existing data to inform the design, to confirm efficacy and generate additional controlled safety data. The new study design should address all uncertainties listed in the letter.
Inadequate Mechanistic and Confirmatory Evidence from Metabolic Studies
Severity: majorMetabolic studies ZP1848-15073 and EASE-4 did not provide adequate mechanistic or confirmatory evidence. ZP1848-15073 showed inconsistent dose response and no clear improvement in absorption of electrolytes. EASE-4 failed its primary endpoint, had a small sample size, lacked a concurrent control arm, and used a different dosage.
Recommended response: Ensure future mechanistic and confirmatory studies are adequately designed with appropriate controls, sample sizes, and dosages to provide robust and interpretable evidence.
Limited Safety Database and Unresolved Safety Concerns
Severity: criticalThe safety database is limited for a New Molecular Entity (NME) intended for chronic administration, not meeting the recommended ~100 subjects treated for at least 1 year. Multiple safety concerns were identified, including potential drug-induced liver injury, cancers (gastric neuroendocrine carcinoma, basal cell carcinoma, basosquamous carcinoma), and gastric polyps, some of which are unique adverse events of special interest.
Recommended response: Expand the safety database with controlled safety data from a new trial, extending the controlled period to at least 52 weeks to better characterize the safety profile of glepaglutide and assess durability of response.
Unreliable Clinical Data Due to Inspection Findings
Severity: criticalAn FDA inspection of one clinical investigator site identified numerous unreported adverse events, including serious adverse events and adverse events of special interest, in 6 out of 9 enrolled subjects. Given the site's significant representation in the study population (approximately 9%), these findings raise significant concerns regarding the reliability of the safety data to inform the benefit-risk assessment.
Recommended response: Address the inspection findings, ensure data integrity, and potentially re-evaluate the data from the affected site or conduct a new study to generate reliable safety data.
Proprietary Name Conditionally Acceptable
Severity: minorThe proposed proprietary name was found conditionally acceptable pending approval of the application in the current review cycle. Resubmission of the proposed proprietary name is required when all application deficiencies have been resolved.
Recommended response: Resubmit the proposed proprietary name once all other deficiencies identified in the Complete Response Letter are fully addressed and resolved.
Requirement for Comprehensive Safety Update
Severity: infoA comprehensive safety update is required upon resubmission, as described at 21 CFR 314.50(d)(5)(vi)(b). This includes data from all nonclinical and clinical studies, detailed changes in the safety profile, tabulations of new and combined safety data, comparison of adverse event frequencies, separate tables for other indications, retabulation of discontinuations, case reports for deaths/serious AEs, description of changes in common AEs, updated exposure information, worldwide experience summary, and English translations of foreign labeling.
Recommended response: Prepare a detailed and comprehensive safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b) for inclusion in the resubmission package.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
