ted guo, ph.d. john senior, m.d. kate gelperin, m.d., m.p.h fda

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


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




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




“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




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)




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


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


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


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


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)


The eDISH main pageFDA Intranet Only


eDISH Requirements for Liver Data


eDISH Requirements for Demography Data


eDISH Requirements for Clinical Narrative data

Based on FDA IR letterBased on FDA IR letter


eDISH in action

Action

SAS program


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


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


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)


eDISH in actionall subjects at a glance

15 out of 3900 are potential Hy’s Law cases, in need of serious exam


eDISH in actionbehind the scene


eDISH in actionone subject at a time

A delayed elevation of TBL following the elevation of ALT Drill-down to patient’s clinical narrative


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


eDISH Clinical Narrative Creator (Utility) Clinical narrative: An importance piece of the puzzle Utility programs are under construction…

– Check CDISC compliance – Narrative creator


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


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


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

ted guo, ph.d. john senior, m.d. kate gelperin, m.d., m.p.h fda

Documents

drug evaluations

drug administrationwusshow

severe liver injury

sasintrnet tool

liver function

hepatocellular type

induced jaundice

john seniorneed data