Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safetyand 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

Causality Assessment for Drug-Induced Liver Injury

Leonard B. Seeff, M.D.NIDDK, NIH

Leonard B. Seeff, M.D.Leonard B. Seeff, M.D.National Institute of Diabetes and Digestive andNational Institute of Diabetes and Digestive andKidney Diseases, National Institutes of HealthKidney Diseases, National Institutes of Health

I have no financial relationship(s) to I have no financial relationship(s) to disclose within the past 12 months disclose within the past 12 months

relevant to my presentation.relevant to my presentation.

ANDAND

My presentation does not include My presentation does not include discussion of off-label or investigational discussion of off-label or investigational

use.use.Joint Meeting of the Anti-Infective Drugs Advisory Committee Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee and the Drug Safety and Risk Management Committee Meeting Meeting December 14 & 15, 2006December 14 & 15, 2006

Classification of Hepatotoxicity

Intrinsic Toxicity: Direct Indirect

Host Idiosyncrasy: Immunologic Metabolic

Zimmerman HJ. Hepatotoxicity 2nd Ed.

BackgroundBackground

Idiosyncratic hepatotoxicity can manifest as threeIdiosyncratic hepatotoxicity can manifest as three broad categories of liver injury:broad categories of liver injury:

- hepatocellular liver disease- hepatocellular liver disease - cholestatic liver disease- cholestatic liver disease - mixed hepatocellular/cholestatic liver disease- mixed hepatocellular/cholestatic liver disease

There is no form of liver disease, acute or chronic,There is no form of liver disease, acute or chronic, that is not mimicked by drug injurythat is not mimicked by drug injury

How is Hepatotoxicity How is Hepatotoxicity Diagnosed?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 Other Approaches to AssessmentAssessment

of Hepatotoxicityof Hepatotoxicity

Expert opinionExpert opinion

(Bayesian Adverse Reactions(Bayesian Adverse Reactions

Diagnostic Instrument)Diagnostic Instrument)

Drug-Induced Liver Injury Network: DILIN

A Cooperative Agreement funded by the Liver Disease Research Branch,

DDDN, NIDDK

  

 

  

Drug Induced Liver Injury Drug Induced Liver Injury Network ParticipantsNetwork Participants

Investigators:Paul Watkins – University of North CarolinaHerbert Bonkovsky – Univ. MassachusettsNaga Chalasani – Indiana UniversityTimothy Davern – UC, San FranciscoRobert Fontana – Michigan UniversityJames Rochon (DCC) – Duke University

NIDDK, NIH:Jose Serrano, Project OfficerLeonard Seeff; Jay Hoofnagle

FDA Advisors:John Senior; Mark Avigan

  

 

  

Drug Induced Liver Injury Drug Induced Liver Injury NetworkNetwork

Limited retrospective 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 Drug Induced Liver Injury NetworkNetwork

Protocol for EvaluationProtocol 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 casesand reconcile differences

If the 3 members cannot agree, the full committee convenes andvotes on the case

Sequence of DILIN Causality Assessment

Potential case ofDILI identified by PI

PI downloads CRF from DILIN website

and completes CRF

CRF forwardedto DCC

DCC cleans the data and extracts apre-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 downloadthe data forms as well as

forms they must complete:Data Completeness Checklist

Clinical Assess/Severity FormsRUCAM

Causal Comm reviews

and, if necessary, reconciles scores in teleconference

The completed forms arereturned to the DCC who

thenarrange for a

teleconferenceto discuss the cases

Results recorded bythe DCC and the PInotified for later

selection of controls

Causality CommitteeAssessment 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, totalserum bilirubin <2.5 mg/dl, INR <1.5not hospitalized for DILI

2 Raised ALT, AST or AP levels, totalserum bilirubin >2.5 mg/dl, or INR >1.5not hospitalized for DILI

3 Hospitalized for DILI or hospitalizationprolonged 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

Causality assessment in DILI is complex and not well 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 theEffectiveness of RUCAM

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 throughseveral 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 2causality assessments: first, is it Dili, second which drug?

Will pharmacogenetics, proteomics, metabolomicsbe helpful in the future?

Will other specific biomarkers be identified?

This is a work in progress!!!

Criteria for ConsideringCriteria for Consideringthe Diagnosis of DILIthe Diagnosis of DILI

Temporal receipt of a drug or herbalTemporal receipt of a drug or herbal

associated with:associated with:

- ALT - ALT >> 5X ULN or baseline X 2 5X ULN or baseline X 2

- AP - AP >> 2X ULN or baseline X 2 2X ULN or baseline X 2

- Any in ALT, AST or AP with T.Bil - Any in ALT, AST or AP with T.Bil >> 2.5 2.5

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