Nomenclature Subcommittee Drug Hepatotoxicity Steering Committee

1. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 1 Nomenclature Subcommittee Drug Hepatotoxicity Steering Committee Hepatic Adverse Event Nomenclature Document Victor Navarro, MD Hepatotoxicity Steering Committee Meeting January 28, 2005

2. Nomenclature SubcommitteeMembers Lori Beth Cirangle, MD Alan Goldhammer, PhD Will Lee, MD Lana Pauls, MPH Victor Navarro, MD Jerry Stern, MD Jennifer Stotka, MD Paul Watkins, MD Songlin Xue, MD

3. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 3 Hepatic Adverse Event Nomenclature PresentationFebruary 2003Discussion/Conclusions Standard nomenclature Expedites signal detection of hepatic adverse events Promotes consistency of event description in product labeling International reporting of adverse events Should use accepted standard definitions Should employ criteria to assign causality CIOMS Should be updated The broad use of standard terms needs to be reasserted Steering committee decided to move ahead with plans for publication

4. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 4 Hepatotoxicity Nomenclature Publication Timeline

5. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 5 Introduction & Objectives To briefly describe current DILI nomenclature To propose an update to CIOMS To propose ways in which DILI nomenclature can be more broadly applied

6. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 6 Introductory highlights The success of any initiative to study and potentially avert DILI hinges upon a mechanism to facilitate its rapid and precise identification. Such a mechanism is hindered by lack of uniformity in the way DILI is defined by clinicians, researchers, and regulatory authorities. Uniform and widely adopted nomenclature is an important step towards accumulating more complete and reliable data on DILI. �has assumed the task of reassessing and attempting to standardize nomenclature for DILI. The objective of this perspective document is to propose (highlight the importance of) a nomenclature that can be widely applied to DILI detection, prevention, and research.

7. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 7 2. DILI and its nomenclature Global impact of DILI Description of DILI�s impact on global public health and industry The FDA/AASLD/PhRMA 2001 Hepatotoxicity meeting in Chantilly VA Formation of the Hepatotoxicity Steering Committee

9. 3. DILI and its nomenclature Brief overview of current nomenclature 1978 Fogerty International Center Conference on HT 1989 Council for International Organizations of Medical Sciences (CIOMS) 2002 Steering committee �white paper�

11. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 11 Hepatic Adverse Event NomenclatureLiver Injury Based on 1990 CIOMS�below were proposed Definition ALT > 3xULN; or AP > 2xULN; or TB > 2xULN if assoc. with any elevation of ALT or AP ALT, AST, AP, or TB < 3xULN = �abnormality of liver tests� The term �hepatitis� should be used only to characterize histology.

12. Hepatic Adverse Event NomenclatureLiver Injury Liver injury should be classified according to ratio of ALT to AP(ALT/AP), normalized to respective ULN: Hepatocellular (ALT) R > 5 Cholestatic (AP) R < 2 Mixed (ALT and AP) 2 < R < 5 ALT, AP values falling outside of these parameters may represent injury without classification, or non-hepatic injury.

13. Hepatic Adverse Event NomenclatureLiver Injury Acute Liver Injury Injury < 6 months, with or without symptoms Chronic Liver Injury Injury > 6 months, with or without symptoms Severe Liver Injury Jaundice INR > 1.5 ULN Encephalopathy Fulminant Liver Injury Rapid onset, days to 4 weeks, of coagulopathy and encephalopathy

14. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 14 Hepatic Adverse Event NomenclatureData needed for causality assessments Temporal relationship Serial measurement of liver tests Description of clinical findings Evaluation of alternative causes Concomitant medications/xenobiotics Dechallenge/reexposure Extrahepatic manifestations Laboratory tests

15. 3. DILI and its nomenclature Qualitative assessment of the need for standard DILI nomenclature Involved professionals can �speak the same language� Standardized Liver toxicity and safety data is required for efficient reporting Facilitates research and more effective data collection/analysis/interpretation Potential reduction in the incidence of DILI through early recognition and earlier reporting

16. 3. DILI and its nomenclature Qualitative assessment of the limitations of current DILI nomenclature Variable/non-standard terms limits applicability Changes in the field of DILI may not be reflected thus limiting effective communications Characteristic patterns of injury are not incorporated into current nomenclature Nomenclature does not prove causality; assessment tools which add complexity may limit applicability Transient liver test abnormalities, not leading to serious injury need to be recognized

17. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 17 (4) Proposal to update DILI nomenclature Incorporation of AASLD/FDA/PhRMA Hepatotoxicity Nomenclature Document (white paper) into the body of this publication Add characteristic patterns of injury to nomenclature Incorporate time trend in liver test abnormalities to definition of injury; ie, sustained versus transient Plans for dissemination of the updated nomenclature

18. 28 January 2005 FDA/CDER-AASLD-PhRMA HepTox Steering Group 18 Hepatic Adverse Event Nomenclature Document Annals of Internal Medicine Perspectives Hal Sox: �I do think that the piece could fit into the Perspectives category� �I suggest that you try us. Our turnover is quick enough that you don't have much to lose by submitting.�