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Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

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

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Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

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

  2. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 Leonard B. Seeff, M.D.National Institute of Diabetes and Digestive andKidney 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.

  3. Classification of Hepatotoxicity Intrinsic Toxicity:  Direct  Indirect Host Idiosyncrasy:  Immunologic  Metabolic Zimmerman HJ. Hepatotoxicity 2nd Ed.

  4. 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

  5. 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?

  6. 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

  7. Other Approaches to Assessmentof Hepatotoxicity Expert opinion (Bayesian Adverse Reactions Diagnostic Instrument)

  8. Drug-Induced Liver Injury Network: DILIN A Cooperative Agreement funded by the Liver Disease Research Branch, DDDN, NIDDK

  9. 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

  10. Drug Induced Liver Injury Network •  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

  11. 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

  12. 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

  13. Drug-Induced Liver Injury (DILIN) Network Study Causality Adjudication Process Highly refined evaluation using expert opinion vs RUCAM

  14. 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

  15. 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

  16. Sequence of DILIN Causality Assessment PI downloads CRF from DILIN website and completes CRF CRF forwarded to DCC Potential case of DILI identified by PI Committee of 3 download the data forms as well as forms they must complete: Data Completeness Checklist Clinical Assess/Severity Forms RUCAM 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 The completed forms are returned to the DCC who then arrange for a teleconference to discuss the cases Causal Comm reviews and, if necessary, reconciles scores in teleconference Results recorded by the DCC and the PI notified for later selection of controls

  17. 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

  18. DILIN Causality Assessment Form • Definite > 95% • Highly likely 75-95% • Probable 50-74% • Possible 25-49% • Unlikely < 25%

  19. DILIN Clinical Severity Index Form GradeDefinition 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

  20. Adjudication Process for Multiple Drugs Is it DILI?  If yes, which drug likeliest culprit? If more than one drug possible, each is adjudicated separately

  21. Current Assessment of the Effectiveness of RUCAM 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

  22. Telithromycin

  23. 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

  24. 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

  25. Scoring for Hepatotoxicity of Adjudicated Cases of Telithromycin (n=53) InitialFinal 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

  26. 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%)

  27. 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

  28. 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?

  29. 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!!!

  30. Criteria for Consideringthe 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

  31. Return Return to agenda

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