# Presentation: 093142

## Causality Assessment for Drug-

- Joint Meeting of the Anti-Infective Drugs
- Advisory Committee and the Drug Safety
- and Risk Management Advisory Committee
-            Silver Spring, Maryland
-             December 14-15, 2006

**Causality Assessment for Drug-**
**Induced Liver Injury**
**Leonard B. Seeff, M.D.**
**NIDDK, NIH**

## Leonard B. Seeff, M.D.National Institute of Diabetes and Digestive andKidney Diseases, National Institutes of Health

**I have no financial relationship(s) to disclose within the past 12 months relevant to my presentation.**
**AND**
**My presentation does not include discussion of off-label or investigational use.**

## Classification of Hepatotoxicity

**Intrinsic Toxicity:**
**	******** ****Direct**
**	******** ****Indirect**
**Host Idiosyncrasy:**
**	******** ****Immunologic**
**	******** ****Metabolic**
**	****	**

**Zimmerman HJ. Hepatotoxicity 2****nd**** Ed.**

## Background

**   **
**   ****Idiosyncratic hepatotoxicity can manifest as three**
**   ****broad categories of liver injury:**
**      ****- hepatocellular liver disease**
**      ****- cholestatic liver disease**
**      ****- mixed hepatocellular/cholestatic liver disease**
**   ****There is no form of liver disease, acute or chronic,**
**   ****that is not mimicked by drug injury**

## How is Hepatotoxicity Diagnosed?

**   **

**   ****Presently, there is no biomarker for the **
**   ****diagnosis of hepatotoxicity**
**   ****Because hepatotoxicity can simulate all**
**   ****known causes of liver disease, drug-**
**   ****induced liver disease is largely a**** **
**   ****diagnosis of exclusion**
**   ****What instrument is currently available or**
**   ****needs to be developed to improve diagnosis?**

## Early Efforts to Develop Causality

** ****Assessment for Hepatotoxicity**

**1989 RUCAM (Roussel Uclaf Causality **
**       ****Assessment Method)**
**	**** ****- points awarded in 7 categories**
**1997 M & V Scale (Maria and Victorino)**
**       ****- subsequently found less effective**
**         ****than RUCAM**

## Other Approaches to Assessmentof Hepatotoxicity

**	****	****        ****Expert opinion**
**	****	****(Bayesian Adverse Reactions**
**       ****Diagnostic Instrument)****   **

## Drug-Induced Liver Injury Network: DILIN

** ****A Cooperative Agreement funded by the **
**Liver Disease Research Branch, **
**DDDN, NIDDK**

** **
** **
** **

**Drug Induced Liver Injury Network Participants**

**Investigators:**
**	****Paul Watkins – University of North Carolina**
**	****Herbert Bonkovsky – Univ. Massachusetts**
**	****Naga Chalasani – Indiana University**
**	****Timothy Davern – UC, San Francisco**
**	****Robert Fontana – Michigan University**
**	****James Rochon (DCC) – Duke University**
**NIDDK, NIH:**
**	****Jose Serrano, Project Officer**
**	****Leonard Seeff; Jay Hoofnagle**
**FDA Advisors:**
**	****John Senior; Mark Avigan**
**	**** **
**	**** **

** **
** **
** **

**Drug Induced Liver Injury Network**

******  ****Limited *****retrospectiv*****e**** study focusing upon four**
**   ****well-established causes of Dili: Isoniazid,**
**   ****Valproic Acid, Phenytoin, and Augmentin **
**   ****(amoxacillin/clavulanic acid)**
**  *****Prospective***** study enrolling all cases of drug-**
**   ****induced liver disease seen at the clinical**
**   ****centers and their catchment areas**

## Drug-Induced Liver Disease Network

**(DILIN):  Objectives**

****** ****To provide a prospective clinical database on**
**   ****unselected cases of hepatotoxicity**
****** ****To obtain biological samples for studies on the**
**  ****pathogenesis of hepatotoxicity using biochemical,**
**  ****molecular, immunologic and genetic techniques**
****** ****To evaluate susceptibility and genetics of drug-**
**   ****induced liver injury**

## Drug-Induced Liver Disease Network

**(DILIN):  Objectives-2**

****** ****To provide the foundation for development of**
**  ****molecular screening tools to prevent or predict**
**  ****drug-induced liver injury**
****** ****To provide a stimulus and resource for research**
**  ****and clinical investigation of all forms of drug-**
**  ****induced liver disease**
****** ****To develop standardized definitions, grading **
**  ****systems and clinical instruments to identify **
**  ****and assign causality to cases of suspected **
**  ****drug-induced liver injury**

## Drug-Induced Liver Injury (DILIN)

**Network Study**
**Causality Adjudication Process**

**Highly refined evaluation using expert opinion**
**vs**
**RUCAM**

** **
** **
** **

**Drug Induced Liver Injury Network**
**Protocol for Evaluation**

******  ****Each case is evaluated in a standardized and**
**   ****formalized fashion with collection of medical **
**   ****history and *****all***** laboratory test results**
******  ****Serum, urine, PBMCs and DNA are obtained from**
**   ****each patients and sent to an NIDDK repository**
****** **** ****Each cases is evaluated by a panel of experts to**
**   ****establish an assessment of causality**
******  ****At least six-month follow-up is obtained**

## DILIN Causality Assessment

**Causality Committee, subcommittee of the Steering Committee**
**Composed of: PI or designate from each of the 5 clinical sites**
**                ****Member from Data Coordinating Center (DCC)**
**                ****Member from NIDDK**
**Cases adjudicated by 3 members – NIDDK/DCC member and PIs **
**or designees selected on rotation to serve for 3 months**
**Causality Committee meets monthly or bimonthly to discuss cases**
**and reconcile differences**
**If the 3 members cannot agree, the full committee convenes and**
**votes on the case**

## Sequence of 

**DILIN Causality Assessment**

**Potential case of**
**DILI identified by PI**

**PI downloads CRF from **
**DILIN website**
**and completes CRF**

**CRF forwarded**
**to DCC**

**DCC cleans the data and extracts a**
**pre-defined subset from the CRF, inserts **
**the information into specially designed **
**data forms to distribute through the  **
**DILIN website to the Causality Committee **

**Committee of 3 download**
**the data forms as well as**
**forms they must complete:**
**Data Completeness Checklist**
**Clinical Assess/Severity Forms**
**RUCAM**

**Causal Comm reviews **
**and, if necessary, **
**reconciles scores **
**in teleconference**

**The completed forms are**
**returned to the DCC who then**
**arrange for a teleconference**
**to discuss the cases **

**Results recorded by**
**the DCC and the PI**
**notified for later**
**selection of controls**

## Causality Committee

**Assessment Forms**

**1. Data Completeness Checklist:**** Consists of 24 yes/no**
**    ****questions for the retrospective and 41 for the prospective;**
**    ****1 question asking about degree of completeness of data; **
**    ****and 1 question asking if more information is needed**
**2. Clinical Assessment Form**: **Assesses causality relationship**
**3. Clinical Severity Form: ****Addresses liver disease severity**
**	**
**4. RUCAM**

## DILIN Causality Assessment Form

-   **Definite****	****	****> 95%**
**  ****Highly likely****	****	****75-95%**
**  ****Probable****	****	****50-74%**
**  ****Possible****	****	****25-49%**
**  ****Unlikely****	****	****< 25%**

## DILIN Clinical Severity Index Form

_**Grade**_**                    **_**Definition**_
**  ****1****	****	****Raised ALT, AST or AP levels, total**
**	****	****serum bilirubin <2.5 mg/dl, INR <1.5**
**	****	****not hospitalized for DILI**
**  ****2****	****	****Raised ALT, AST or AP levels, total**
**	****	****serum bilirubin >2.5 mg/dl, or INR >1.5**
**	****	****not hospitalized for DILI**
**  ****3****	****	****Hospitalized for DILI or hospitalization**
**	****	****prolonged because of DILI**
**  ****4****	****	****Death or liver transplantation due to DILI**

## Adjudication Process for 

**Multiple Drugs**

******  ****Is it DILI?**
******  ****If yes, which drug likeliest culprit?**
******  ****If more than one drug possible, each**
**    ****is adjudicated separately**

## Current Assessment of the

**standardized. The RUCAM system, although widely used, **
**exhibits substantial inter-individual variability, and **
**correlates rather poorly in either retrospective or **
**prospective identified cases with scores assigned by experts. **
**We conclude that in routine clinical practice, expert opinion **
**is likely to be more reliable than RUCAM, but requires **
**standardization in definitions and scales of likelihood.**
**Don Rockey for the DILI Group**

**Current Assessment of the**
**Effectiveness of RUCAM**

**Notes:**
the

## Telithromycin

## Approach Used to Evaluate 

**Telithromycin for Potential Hepatotoxicity-1**

**Potential cases received by FDA via MedWatch**
**Fifty three cases selected for review by FDA **
**Drug Safety and Risk Management Group**
**Cases sent for evaluation for potential hepato-**
**toxicity by adjudication committee (Mark Avigan,**
**Allen Brinker, William Lee, Jose Serrano, **
**Leonard Seeff) working independently**

## Approach Used to Evaluate 

**Telithromycin for Potential Hepatotoxicity-2**

- DILIN probability assessment and severity scales
- used in adjudicating cases
- Results of evaluation, undertaken independently,
- submitted to FDA
- Reconciliation of cases, if needed, reached through
- several conference calls

## Scoring for Hepatotoxicity of Adjudicated 

**Cases of Telithromycin (n=53)**

**                               **_**Initial**_**	****	**_**Final**_
**Very likely****	****	****	****11 (20.8%)****	****	****9 (17.0%)**
**Probable****	****	****	****19 (35.9%)****	****      19 (35.9%)**
**Possible****	****	****	****14 (26.4%)****	****      17 (32.1%)**
**Insufficient evidence****	**** 8 (15.1%)****	****	****8 (15.1%)**
**Unlikely****	****	****	**** 1  (1.9%)****	****	****0****	****	****	**

## Scoring for Severity of Liver disease

** ****of Adjudicated Cases of Telithromycin **
**(n=53)**

**Grade 1****	****	****	**** 8 (15%)**
**Grade 2****	****	****	**** 1 (2%)**
**Grade 3****	****	****	****37 (70%)**
**Grade 4****	****	****	**** 7 (13%)**
**	****	**

## Mandatory Requirement for 

**Assessing Causality**

**Complete information to permit exclusion of **
**competing causes for liver injury**** **
**Complete information to permit exclusion of **
**competing causes for liver injury**** **
**Complete information to permit exclusion of **
**competing causes for liver injury**

## Some Questions Regarding 

**Causality Assessment - 1**

**Is expert opinion preferable to the existing **
**causality  instruments, i.e., RUCAM or M & V?**
**Can these existing instruments be improved?**
**Might the Bayesian approach be useful?**

## Some Questions Regarding 

**Causality Assessment - 2**

**Distinguish enzyme adaptation from true hepatotoxicity?**
**Single out an implicated drug among many received when **
**there is underlying liver disease? Should there be 2**
**causality assessments: first, is it Dili, second which drug? **
**Will pharmacogenetics, proteomics, metabolomics**
**be helpful in the future?**
** ****Will other specific biomarkers be identified?**
**            ****This is a work in progress!!!**

##  Criteria for Consideringthe Diagnosis of DILI

**    ****Temporal receipt of a drug or herbal**
**               ****associated with:**
**	****- ALT **_**>**_** 5X ULN or baseline X 2**
**	****- AP **_**>**_** 2X ULN or baseline X 2**
**	****- Any  in ALT, AST or AP with T.Bil **_**>**_** 2.5     **

## Return

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