The U.S. Food and Drug Administration (FDA) has released a guidance "Technical Specifications for Submitting Clinical Trial Data Sets for Treatment of Noncirrhotic Nonalcoholic Steatohepatitis (NASH)" outlining the technical specifications for submitting clinical trial data sets for the treatment of noncirrhotic nonalcoholic steatohepatitis (NASH). This guidance serves as a comprehensive resource for sponsors conducting clinical trials in this field, ensuring consistency and compliance with regulatory requirements for data submission.
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) that can progress to cirrhosis, liver failure, and liver cancer. This guidance offers a comprehensive framework for submitting tabulated and analytical datasets to enhance the reviewability of regulatory submissions.
While it focuses on data presentation, the guidance aligns with previous FDA recommendations for clinical development of NASH drugs, including addressing unique challenges like differentiating drug-induced liver injury (DILI) from the progression of liver disease.
This guidance acknowledges the 2023 revision of NASH terminology, where NAFLD is now termed Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and NASH is Metabolic Dysfunction-Associated Steatohepatitis (MASH).
The key components covered in Data Standards:
Sponsors must adhere to CDISC standards like the Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM).
All datasets should align with the FDA Data Standards Catalog to ensure compatibility with FDA systems.
Dataset Types:
The guidance covers SDTM domains and ADaM datasets, offering specifications for handling biospecimens, laboratory results, concomitant medications, imaging findings, and more.
Notable domains include:
Microscopic Findings (MI) for liver histology.
Biospecimen Events (BE) for specimen handling.
Laboratory (LB) for critical lab parameters like fibrosis markers.
Disease Response (RS) for MELD and Child-Pugh scores.
Analysis datasets like ADLB (Laboratory Analysis) and ADMI (Microscopic Findings Analysis) ensure traceability between raw data and derived values.
Domain-Specific Guidance:
Each SDTM and ADaM domain is broken down to include essential variables, relationships, and applicable controlled terminology.
For example:
Microscopic Findings: This domain addresses liver biopsy evaluations using the NASH CRN scoring system, capturing fibrosis stages and inflammation markers.
Laboratory Domain: Focuses on liver-related parameters, including advanced fibrosis biomarkers like Cytokeratin-18 (CK-18) and Enhanced Liver Fibrosis (ELF) score.
Integration with Study Design:
Sponsors are encouraged to engage with the FDA during trial design to ensure alignment with these technical requirements.
Custom domains, such as Imaging Results (ZI) for liver imaging biomarkers, can be utilized to include exploratory endpoints.
Sponsors are encouraged to consult the Study Data Technical Conformance Guide and FDA's data standards resources for comprehensive support.
For more details, visit the FDA webpage for NASH guidance:
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