# Presentation: 659775

## MCASE Prediction of Hepatotoxicity usingPost-Market Adverse Effects Data

**FDA’s Center for Drug Evaluation and Research (CDER)**
**Office of Pharmaceutical Science (OPS)**
**Informatics and Computational Safety Analysis Staff (ICSAS)**
**Office of Testing and Research (OTR) **

- 1

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

_**FDA / CDER / OPS / ICSAS**_**                      **
** ****Joseph F. Contrera, Ph.D.**
** ****Edwin J. Matthews, Ph.D.***
** ****R. Daniel Benz, Ph.D. **
** ****Naomi L. Kruhlak, Ph.D. **

_**FDA / CDER / OPS / OTR**_
** ****James L. Weaver, Ph.D.**
** ****Joseph P. Hanig, Ph.D.   **

**Hepatoxicity Steering Committee Meeting**
**Rockville, MD 01-21-03**

## Outline

**   ****Future Pilot Study Goals & Objectives**

- 2

**   *****MCASE***** QSAR Software Program & Prediction of**
**    ****Adverse Effects of Drugs**

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**   ****FDA/CDER and ICSAS Post-Market Adverse Effect**
**    ****Databases**

**   ****Extra Slides on *****MCASE***** Methodology**

## I.  FDA/CDER and ICSAS Post-Market Adverse Effect Databases

- 3

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Spontaneous Reporting System (SRS) 

_***Spontaneous Reporting System (SRS)***__*** ***_
**  ****Early warning system for adverse effects **_**not**_
**    ****reported in pre-market clinical trials**
**  ****Adverse drug reactions (ADRs) reported to**
**    ****FDA/CDER 1969 - October, 1997**
**  ****Electronic database with > 1,600,000 reports**

- 4

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Spontaneous Reporting System (SRS) 

**  ****COSTAR (**_**CO**_**ding **_**S**_**ymbols for **_**T**_**hesaurus of**
**   **_**A**_**dverse **_**R**_**eaction) terms Medical Dictionary**
**   ****(1,169 terms)**
**   ****8,628 Pharmaceutical Trade Names**
**  ****~1,500 Generic Pharmaceuticals**
**  ****Non-proprietary Data (www.ntis.gov)  **

- 5

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**FDA/CDER Post-Market Adverse Effect Databases**

## Adverse Event Reporting System (AERS)

**  ****November, 1997 - Present**
**  ****MedDRA (Medical Dictionary for Regulatory**
**   ****Activities) with >60,000 terms**
**  ****www.meddramsso.com**

- 6

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**FDA/CDER Post-Market Adverse Effect Databases**

## Pharmaceuticals [n=665]

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

_***Pharmaceuticals***_*** ******[n=665]***
**Group 1:  358 drugs  (approved 1978 -1997)**
**  ****First 5-year SRS adverse drug reaction (ADR) data**
***  ******Historically the most sensitive reporting period***

**  ****First 5-year drug shipment unit data (IMS Health****TM****)**
***  ******Used for active and inactive compounds in MCASE modules***

## Pharmaceuticals [n=665]

**Group 2:  307 older drugs (approved < 1978)**
**  ****5-year adverse drug reaction (ADR) data for the same period**
***  ******Less sensitive reporting period***

- 8

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**  ****Steady state 5-year shipment unit data (1978-1983)**
**  *****  ******Only used  for active drugs in MCASE modules***

## ICSAS Post-Market Adverse Effect Database

- 9

**  ****Cardiac toxicity****	****  70,897****	****	****         59**
**  ****Immunotoxicity****	****104,670****	****	****         29**
**  **_**Kidney toxicity**__**	**__**  35,934**__**	**__**	**_**       **_**  58**_

**      ****Organ****	****	****	****ADR****	****	****	****SRS COSTAR**
**     **_**System**__**	**__**	**__**Reports**__**	**__**	**_**   **_**Endpoints**_
**  ****Liver toxicity****	****	****  39,044****	****	****         32**

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**TOTAL****	****	****	****250,545****	****	****       178**

## Evaluation Criteria for Significant Adverse Effect:

**1)****	**** ******** 3 ADR reports / drug / COSTAR endpoint**

- 10

**3)****	**** ******** 3.0 Adverse Effect Index (AEI)**
**	****  ****[AEI = (ADR# / shipment units) x (1,000,000)]**

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**2)****	**** ******** 20,000 shipment units / drug / 5-year period**

## Evaluation Criteria for Significant Adverse Effect:

**4)****	****One or more significant *****MCASE***** ‘decision’ structural**
**	****alerts (******** 150 Total CASE units)****	**

- 11

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**5)****	****Significant effect at 2 or more COSTAR endpoints****	**

##  Evaluation Criteria for Biological Potency of an Adverse Effect:

**  ****Biological potency is proportional to the drug’s adverse effect index (AEI) value (3.0 - >1000)**

- 12

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**  ****Biological potency is proportional to the number of related adverse effect endpoints with significant effects (2 or more)**
**  ****Biological potency is proportional to the number of significant *****MCASE *****adverse effect structural alerts (1 or more)**

## SRS Liver Function Endpoints

_**Endpoint**__**	**__**	**__**	**__**Reports**__**	**__**Drugs***_
**Liver function abnormal****	****	****11,116 / 31,556****	****227 / 665**
**-----**

- 13

_***SRS Liver Function Endpoints***_

****Active Drugs: The number of 665 drugs with >3 ADR, >3.0 AEI***

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**SGOT increase                ****	**** ****	****  3,959****	****	****100**
**Hepatitis                           ****	****	****  3,762****	****	****102**
**SGPT increase                 ****	****	****  3,655****	****	****  98**
**Bilirubinemia                    ****	****	****  3,454****	****	****  99**
**Jaundice                           ****	****	****  2,478****	****	****  74**
**Jaundice, cholestatic****	****	****  1,564****	****	****  47**
**Amylase increase****	****	****  1,214****	****	****  38**
**Lipase increase****	****	****     354****	****	****  13**

## SRS Liver Pathology Endpoints

_**Endpoint**__**	**__**	**__**	**__**Reports**__**	**__**Drugs***_
**Liver failure****	****	****	****1,689  / 31,556****	****47 / 665**

- 14

_***SRS Liver Pathology Endpoints***_

****Active Drugs: Number of 665 drugs with >3 ADR, >3.0 AEI***

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**Liver Damage****	****	****	****1,152****	****	****33**
**Necrotic liver****	****	****	****   722****	****	****15**
**Hepatomegaly****	**** ****	****	****   542****	****	****21**
**Liver, fatty****	**** ****	****	****   446****	****	****13**
**Liver cirrhosis****	**** ****	****	****   414****	****	****  6**
**Liver carcinoma****	****	****   202****	****	****  7**
**Neoplastic liver****	****	****     52****	****	****  1**
**Liver, tender               ****	****	****     48****	****	****  0**
**Hepatoma               ****	****	****     39 ****	****	****  0**

## Other SRS Liver related endpoints

***COSTAR******	*****	****	****ADR****	****	****Active**
_***Endpoint***__***	***__**	**__**	**__**Reports**__**	**__**Drugs***_
**Bilirubinuria                  ****	****      ****	****  55 / 31,556****	****  0 / 665**

_***Other SRS Liver related endpoints***_

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**ICSAS Post-Market Adverse Effect Database**

**Cholangitis****	****                ****	****	****  92****	**** ****	****  0**
**Cholecystitis                    ****	****	****531 ****	****	****12**
**Cholethithiasis ****	****	****532 ****	****	****  7****	**
**Hepatic coma****	**** ****	****	****196 ****	****	****  3**
**Hepatitis C                        ****	****     ****	****  52 ****	****	****  1**
**Hepatitis HBsAg               ****	****     ****	****  32****	****	****  1**
**Hepatitis non-specific     ****	****    ****	****  16****	****	****  0**
**Hepatorenal syndrome    ****	****    ****	****378****	****	****  7**
**Hepatosplenomegaly       ****	****    ****	****145****	****	****  1**
**Jaundice, neonatal          ****	****  ****	****  17****	****	****  0**
**Liver damage aggravated****	****	****  19****	****	****  0**
**Venoocclus liver syn.      ****	****   ****	****  97****	****	****  7**

## II.  MCASE QSAR software program and prediction of adverse effects

- 16

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Optimization of an In Silico Program

**              ****Software developed at Case Western**
**              ****Reserve University (~1985-1997)**

**New: FDA *****MCASE:ES***
**	****Software developed under FDA and**
**	****Multicase, Inc. CRADA (1997-2003)**

**Optimization of an *****In Silico***** Program**
**for Risk Identification at the FDA**

***MCASE-ES: multiple computer automated statistical evaluation expert system***

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

- 17

## Using MCASE-ES to Identify

**Adverse Effects of Drugs in Humans**

**Identify and Code toxic & non-toxic compounds**
**Reduce ~400 molecules to 2-10 atom fragments (n ~ 300,000) **
**Analyze toxicity correlated fragments**

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

- 18

## Using MCASE-ES to Identify

_**Adverse Effect **__**	**__**AEI Value**__**	**__**	**__**Activities**_
**Ex. Active****	****	**** ********100.0****	****	****60 - 80**
**Very Active****	****	**** ********10.0****	****	****	****40 - 59**
**Active ****	****	****	****4-9.9****	****	****	****30 - 39**
**Marginal****	****	****3-3.9****	****	****	****20 - 29**
**Non-significant****	****<3.0****	****	****	****10 - 19**

***“******Compounds that induce trans-species tumors present the highest degree of risk because they adversely alter mechanisms that are conserved across species.” ***
***Tennant, Mutation Research (1993) 286:111-118.***

**Using *****MCASE-ES***** to Identify**
***Adverse Effects of Drugs in Humans***

_***Coding of Drug Adverse Effect Activities***_

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

- 19

## Using MCASE-ES to Identify

**	****(chemical class, size, mixture, ...)**	** **

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

- 20

**Using *****MCASE-ES***** to Identify**
***Adverse Effects of Drugs in Humans***

##     MCASE: Liver Effects Discovery System

***Mod.******	******	******	******	******	******	******Drug******	******	******Active***
_***Code***__***	***__***COSTAR Endpoint***__***	***__***	***__***	***__***No.***__***	***__***	***__***(%)***_
**A22****	****Liver Adverse Effects **_***Combo***_**	****	****436****	****	****45**
**A15****	****Bilirubinemia****	****	****	****	****400****	****	****30**
**A14****	****SGPT increase****	****	****	****	****392****	****	****30**
**A13****	****SGOT increase****	****	****	****	****386****	****	****31**
**A11****	****Amylase increase****	****	****	****366****	****	****13**
**A21****	****Liver Pathology **_***Combo***_**	****	****438****	****	****38**
**A17****	****Hepatitis****	****	****	****	****409****	****	****32**
**A18****	****Jaundice****	****	****	****	****384****	****	****23**
**A19****	****Jaundice cholestatic****	****	****	****366****	****	****15**
**-----**
***A10******	******Liver function abnormal******	******	******453******	******	******52***

- 21

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Internal Cross Validation Studies

***Organ*****	****	****	****Val.****	****Pred.****	****	**
_***System***__**	**__**	**__**	**__**Test**__**	**__**Value**__**	**__**Specif.**__**	**__**F.Pos.**__**	**__**Sensit.**_
**Liver ****	****	****	****(a)****	****88.9****	****97.0****	****3.0****	****52.0**
**Liver****	****	****	****(b)****	****90.9****	****97.9****	****2.1****	****34.6**

- 22

_***MCASE Predictive Performance***_

***Validation Test (a): leave one out; (b) leave 2.5% out***

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**Kidney****	****	****	****(a)****	****89.0****	****97.0****	****3.0****	****55.6**
**Skin Immune System****	****(a)****	****88.0****	****99.0****	****1.7****	****37.9**
**Non-Skin Immune System****	****(a)****	****93.8****	****98.3****	****3.0****	****35.3****	**
**Heart****	****	****	****(a)****	****95.2****	****98.9****	****1.1****	****32.6**

##      Concordance of Pre- & Post Market Liver Effects for 19 Pharmaceuticals   

- 23

_***	***__**	**__**	**__**Workgroup**__**	**__**ICSAS**_
_**Drug**__**	**__**	**__** Pre-Market**__**	**__**Post-Market**_
**Acetaminophen****	****	****+****	****	****+**
**Diclofenac****	****	****+****	****	****+**
**Felbamate****	****	****+****	****	****+**
**Flutamide****	****	****+****	****	****+**
**Isoniazid****	****	****+****	****	****+**
**Labetalol (Dilevalol)****	****+****	****	****-**
**Pemoline****	****	****+****	****	****+**
**Zidovudine****	****	****+****	****	****+**
**Zileuton****	****	****+****	****	****+**
**-----**

- Concordance
- 78.9%

- Sensitivity
- 88.9 %

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

**Atorvastatin****	****	****-****	****	****+**
**Bisoprolol****	****	****-****	****	****-**
**Carvedilol****	****	****-****	****	****-**
**Indapamide****	****	****-****	****	****-**
**Metformin****	****	****-****	****	****-**
**Nefazadone****	****	****-****	****	****-**
**Tacrine****	****	****-****	****	****+**
**Topiramate****	****	****-****	****	****-**
**Zafirlukast****	****	****-****	****	****+**
**Zolpidem****	****	****-****	****	****-**

## III.  Future Goals and Objectives

- 24

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Future Goals & Objectives

**Future Goals & Objectives**

_***1) Complete Phase 1 SRS Pilot Study***_
**  ****Summarize results and methods in publication (nearly complete)**
**  ****Submit *****MCASE***** modules to MULTICASE Inc. for distribution**

_***2) Conduct Phase 2 AERS Pilot Study ***_
**  ****Compile adverse effects for new drugs in AERS database**
**  ****Convert AERS data to COSTAR format (started)**
**  ****Conduct AERS drug validation experiment**
**  ****Enhance *****MCASE***** database modules with AERS data**

_***3) Conduct Phase 3 SRS Pilot Study***_
**  ****Compile ADRs for additional COSTAR term endpoints (complete)**
**  ****Prepare *****MCASE***** modules for  the new endpoints**

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Future Goals & Objectives

**  ****Use proprietary PhRMA data to validate FDA model**
**  ****Enhance FDA Hepatotoxicity Database and Liver Effects Discovery**
**    ****System with PhRMA data**
**  ****Distribute enhanced FDA software and database to PhRMA**

- 26

**Future Goals & Objectives**

_***4) Conduct Phase 4 Pre-Market Pilot Study***__*** ***_
** ****Compile adverse effects for drugs from Agency files and labeling**
** ****Construct a COSTAR like format for the adverse effect data**
** ****Compare Pre-Market and Post-Market findings**
** ****Prepare *****MCASE***** modules for Pre-Market / Post-Market findings**
** ****Publish Findings**

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Extra Slides on

_***MCASE***__** Methodology**_

- 27

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Properties of MCASE-ES Decision Alerts

_**Total CASE Unit Activity**__**	**__**	**__**Units**__**	**__**	**__**Call**_
**Decision Alert****	****	****	**** ******** 150****	****	****  +**
**Possible Alert****	****	****	****100-149****	****  ?**
**Non-significant Alert****	****	****<100****	****	****  –****	**

_**Representation in Related Endpoints**__**	**__**	**__**	**_
**Decision Alert****	****	****	****2-4 Modules****	****  +**
**Possible Alert****	****	****	****1****	****	****  ?**

**Using *****MCASE-ES***** to Identify**
***Adverse Effects of Drugs in Humans***

- 28

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

## Effect of AEI value on Structural Similarity of Decision Alerts in 9 Liver Endpoints  

**AEI****	****- Alerts****	****? Alerts****	****Decision Alerts**
_**Value**__**	**__**<100**__**	**__**	**__**100-149**__**	**__**>150 Units**_
**1.0****	****	****22.7****	****	****70.9****	****	****78.2****	****	**
**2.0****	****	****18.1****	****	****54.7****	****	****76.7**
***3.0******	******	******21.5******	******	******65.6******	******	******85.1***
**5.0****	****	****25.2****	****	****62.2****	****	****83.6**
**10.****	****	****25.7****	****	****68.8****	****	****86.6**

- 29

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**

***MCASE***** Adverse Effect Optimization Experiments**

## MCASE Adverse Effect Optimization Experiments

_***Effect of AEI value on the absolute number of Liver Adverse Effect Decision Alerts***_
**AEI****	****	****Other *****MCASE*****	****Decision**
_**Value**__**	**__**	**__**Fragments**__**	**__**	**__**Alerts**_
**1.0****	****	****	****408.0****	****	****	****250.5****	****	**
**2.0****	****	****	****315.5****	****	****	****161.0**
**3.0****	****	****	****246.0****	****	****	****161.0**
**5.0****	****	****	****207.5****	****	****	****140.5**
**10.****	****	****	****150.5****	****	****	****  63.5**

- 30

**PhRMA     -----     FDA / CDER / OPS / ICSAS     -----      E. Matthews     -----     01-21-03**