1 / 26

Ted Guo, Ph.D. John Senior, M.D. Kate Gelperin, M.D., M.P.H FDA

How a SAS/IntrNet tool was created at the FDA for the detection of potential drug-induced liver injury using data with CDISC standard. Ted Guo, Ph.D. John Senior, M.D. Kate Gelperin, M.D., M.P.H FDA. I SPEAK FOR MYSELF. FDA Disclaimer.

aya
Download Presentation

Ted Guo, Ph.D. John Senior, M.D. Kate Gelperin, M.D., M.P.H FDA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. How a SAS/IntrNet tool was created at the FDA for the detection of potential drug-induced liver injury using data with CDISC standard Ted Guo, Ph.D. John Senior, M.D. Kate Gelperin, M.D., M.P.HFDA WUSS

  2. I SPEAK FOR MYSELF FDA Disclaimer THIS PRESENTATION REPRESENTS THE PERSONAL OPINIONS OF THE SPEAKER AND DOES NOT NECESSARILY REPRESENT THE VIEWS OR POLICIES OF THE U.S. FOOD AND DRUG ADMINISTRATION WUSS

  3. How a SAS/IntrNet tool was created at the FDA for the detection of potential drug-induced liver injury using data with CDISC standard Objective • FDA to ensure the safety and effectiveness of the drug applied to be marketed in the US • Tasks: drug evaluations, scientific research, education • Critical Path Initiative, Safety First • Drug and liver: What do they do to each other (Staff College at the FDA) • The term, DILI – Drug-Induced Liver Injury WUSS

  4. How a SAS/IntrNet tool was created at the FDA for the detection of potential drug-induced liver injury using data with CDISC standard “The right tool for the right job”for DILI detection • Enables rapid identification of outliers in large clinical trial datasets • Suitable for large number of subjects (e.g. N>6,000), long-term studies (e.g., 3 years) • Enables at-a-glance summary view of clinical lab results for all study subjects • rapid inspection on one screen • Enables drill-down to individual subjects of interest • patient demographics, lab results over time, clinical narrative WUSS

  5. How a SAS/IntrNet tool was created at the FDA for the detection of potential drug-induced liver injury using data with CDISC standard • Medical backdrop • Hepatotoxicity usually detected by finding elevated serum enzymes (traditional, existing thinking, practice) • alanine aminotransferase (ALT) • aspartate aminotransferase (AST), usually redundant, indicates acute hepatocellular injury • alkaline phosphatase (ALP)  cholestasis • gamma-glutamyltransferase (GGT) WUSS

  6. How a SAS/IntrNet tool was created at the FDA for the detection of potential drug-induced liver injury using data with CDISC standard • Medical backdrop (cont.) • Serum enzymes do not measure liver functionBut, bilirubin clearance does • A fresh concept in 1968 • Hy Zimmerman’s speech “The Spectrum of Hepatotoxicity” at the George Kober Lecture: “The hepatocellular type of drug-induced jaundice is a grave illness with an estimated mortality of 10-50 per cent."R. Temple: “Hy’s Law” ALT >3xULN & TBL >2xULN (2000) • Regulatory implementation: John Senior • Need data, need review tool WUSS

  7. drug X placebo An Idea and its visualization • ALT is a sensitive test for severe liver injury, TBL improves specificity. Analyze both together to detect cases of DILI. Source: John Senior WUSS

  8. A real-life example AC recommended NA because of hepatotoxicity Source: John Senior WUSS

  9. The road to review tool creation • Retrieve data from EDR • Search, locate data sets containing serial ALT, TBL, AST, and ALP; Drug starting, ending, and exam dates • Select, decide variables • Truly important, minimal, original • Calculate benchmark data using Excel (John Senior) • Restructure data, create SAS data sets using as many as CDISC terms – future: direct upload • Liver data set (ALT, BILI, AST, ALP) – multi records per subject • Demography data set - one record per subject • Patient clinical narrative data set – SAS (PDF, DOC?) WUSS

  10. The review tool eDISH • eDISH - Evaluation of Drug-Induced Serious Hepatotoxicity • Use SAS/IntrNet as the foundation for the development • Running on Windows XP • Add Windows component IIS • Configure SAS/IntrNet • Use Microsoft Office FrontPage 2003 to organize and edit programs and html files • Operate eDISH from a web browser • Remote access via VPN available • https (potential) WUSS

  11. The eDISH main page FDA Intranet Only WUSS

  12. eDISH Requirements for Liver Data WUSS

  13. eDISH Requirements for Demography Data WUSS

  14. Based on FDA IR letter eDISH Requirements for Clinical Narrative data WUSS

  15. eDISH in action Action SAS program WUSS

  16. eDISH in actionImport data Steps 1-7 • Import DILI and demography data sets • Do only once, analysis data saved for repeated evaluation • Statistician initiates the data gate-keeping and uploading • Interact with the sponsor WUSS

  17. eDISH in actionImport demography data Step 5 • Match variables to accommodate CDISC and non-standard data • Similar to data requirement sheet, but with drill down lists • eDISH is somewhat forgiving WUSS

  18. eDISH in actionAnalysis-ready data • Use the user-specified data for repeated analysis (medical reviewer) • Dynamically generated variable list allowing for various selections • Output options (print one-page PDF per subject) WUSS

  19. eDISH in actionall subjects at a glance • 15 out of 3900 are potential Hy’s Law cases, in need of serious exam WUSS

  20. eDISH in actionbehind the scene WUSS

  21. eDISH in actionone subject at a time • A delayed elevation of TBL following the elevation of ALT • Drill-down to patient’s clinical narrative WUSS

  22. eDISH in actionnarratives explain chemical enzyme data • Serum enzymes data (eDISH graph) need interpretation • Patients’ clinical narratives help determine DILI • Case report form (CRF), physician notes, other clinical records – by medical writer • Push for data set for the narrative WUSS

  23. eDISH Clinical Narrative Creator (Utility) • Clinical narrative: An importance piece of the puzzle • Utility programs are under construction… • Check CDISC compliance • Narrative creator WUSS

  24. eDISH and beyond • “The right tool for the right job” • eDISH is task specific • Represents the best regulatory practice • eDISH is a living and breathing tool, adapting to increasing demands for changes • Interaction and collaboration between software developer and medical experts at FDA is the key to a successful creation of an effective, practical, therefore, useful review tool • Regulator weekly meeting to envision future improvement • FDA is a unique environment for tool development • Unique opportunity to see all applications from all drug makers, suitable for tool development WUSS

  25. Acknowledgments • I want to thank WUSS for the invitation of this paper • My appreciations go to Drs John Senior and Kate Gelperin for their vision and medical expertise in the development of eDISH • My thanks to Mr. Wei Cheng of ISIS Pharmaceuticals for his input regarding the improvement of the eDISH graph and other invaluable suggestions for tool development WUSS

  26. Q&A Time • Vicinity of Rm3664 • Change has to be incremental • CDISC implementation • Tool - agile and flexible • SAS/IntrNet – stable, light-weight, suitable • 100% CDISC - data upload WUSS

More Related