September 2, 2009 WUSS 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
September 2, 2009 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
September 2, 2009 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
September 2, 2009 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
September 2, 2009 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)
September 2, 2009 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 function
But, 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
September 2, 2009 WUSS 7
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.
Distribution of Peak Values
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
Log10(xULRR) peak ALT
Lo
g10(x
UL
RR
) p
eak T
BL
normal rangeTemple's Corollary
Hy's Law
Gilbert's;
cholestasis2xULRR
3xU
LR
R
drug X placebo
Source: John Senior
September 2, 2009 WUSS 8
A real-life example
Peak TBL vs. Peak ALT1960 patients on Drug X, 1962 on Drug C
0.1
1.0
10.0
100.0
0.1 1.0 10.0 100.0
Peak ALT, xULRR
Pe
ak T
BL
, xU
LR
R Drug X
Drug C
normal range
2x
3x Temple's Corollary range
cholestasis range Hy's Law range
Source: John Senior
AC recommended NA because of hepatotoxicity
September 2, 2009 WUSS 9
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 upload1. Liver data set (ALT, BILI, AST, ALP) – multi records per
subject2. Demography data set - one record per subject3. Patient clinical narrative data set – SAS (PDF, DOC?)
The road to review tool creation
September 2, 2009 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)
September 2, 2009 WUSS 14
eDISH Requirements for Clinical Narrative data
Based on FDA IR letterBased on FDA IR letter
September 2, 2009 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
September 2, 2009 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
September 2, 2009 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)
September 2, 2009 WUSS 19
eDISH in actionall subjects at a glance
15 out of 3900 are potential Hy’s Law cases, in need of serious exam
September 2, 2009 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
September 2, 2009 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
September 2, 2009 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
September 2, 2009 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
September 2, 2009 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