• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services


  • Print
  • Share
  • E-mail

FDA-PhRMA-AASLD Hepatotoxicity Steering Committee Meeting, January 28, 2005 - Presentations

John Senior, M.D., FDA 
Recognizing Drug-Induced Liver Injury in Exposed Populations [PDF]


Drug-induced liver injury (DILI) is a serious and growing problem. It is serious because it now accounts for more United States cases of acute liver failure than all other causes combined, and is growing because more and more people are consuming more and more drugs, prescription and non-prescription, plus so-called “dietary supplements,” “recreational” substances, special diets, and alcohol. In dealing with this problem in our population, a first requirement is that we detect it, soon enough that the offending agent is stopped before irreversible liver injury occurs.

We need to develop methods to be reasonably certain that the observed liver injury is indeed probably caused by the drug in question, and that the injury is likely to become worse to produce disabling, life-threatening, or fatal DILI. Fortunately, drug development safeguards of animal studies and controlled clinical trials eliminate most of the truly toxic agents, but these safeguards do not detect the uncommon but serious DILI that results from human individual idiosyncrasies in genetic or acquired factors that increase the susceptibility of a few persons to DILI. This occurs despite that fact that the great majority tolerate the drug without adverse liver effects, or that most of those who do not initially do so can successfully adapt to the drug and tolerate it thenceforth.

Given that some drugs are more likely to cause DILI than others, we should also bear in mind that in some cases it is not so much a toxic drug as an hypersusceptible patient that is responsible for the observed DILI. We need to study patients more closely, to discern what factors make certain people idiosyncratically susceptible to drug doses and regimens that are not injurious to most people, to investigate the mechanisms of the DILI and hepatic responses, and understand why the susceptible people are different. We need to appreciate the limitations of our principal detection tool, the elevated serum transaminase activity, and to identify which DILI cases are likely to progress to serious injury rather than to adapt successfully and become tolerant.

Present methods for screening populations for DILI are inadequate, Voluntary, spontaneous reporting of adverse events is plagued by both severe under-reporting and insufficient information content. Retrospective epidemiological analyses of collected databases are somewhat better in yielding information about incidence and risk factors, but are limited in their restriction to who may have been included the the database and what information was recorded. They do not allow effective attribution of causality as drug-induced, nor collection of biologic materials and data for study of mechanisms by which the DILI was produced. We offer, for consideration and debate, a proposal that prospective safety studies of the case-control type be authorized and funded for conduct by impartial agencies when signals of serious DILI are discovered.

Biographical Sketch: John Senior is the Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science (OPaSS), Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), where he has served for the past five years as principal consultant in hepatology for the Agency. His work is focused on evaluation of problems of possible drug-induced liver injury (DILI) in drugs under evaluation for approval by the 18 review divisions of CDER, and in drugs that have been approved and marketed. In addition, he consults to other centers of the Agency, including the Center for Biologics Evaluation and Research, Center for Food Safety and Nutrition, and the National Center for Toxicology Research (NCTR), and is active in teaching, within the Agency and outside to other government agencies, academic medical centers, and professional societies. His current research interests are in working on better methods for quantitative assessment of the likelihood that observed hepatic injury is caused by drug and not by some other cause, better methods for detecting and investigating DILI in populations of people exposed to drugs, determining accurately the true incidence and risk factors of DILI for development of rational risk management programs and measuring their effect, and investigation of the mechanisms of DILI (in collaboration with NCTR). He is past president of the American Association for the Study of Liver Diseases (1973-4), and continues active as an Adjunct Professor of Medicine, University of Pennsylvania. He is retired as a Rear Admiral, Medical Corps, U.S. Naval Reserve.

William Lee, M.D., Southwestern Medical School
Drug-Induced Acute Liver Failure in the US 2005: Results from the US Acute Liver Failure Study Group [PDF]

Biographical Sketch: Dr. Lee was educated at Amherst College and received his medical degree from Columbia University College of Physicians and Surgeons, completing his training in Internal Medicine at the Presbyterian Hospital, New York City (Columbia-Presbyterian Medical Center). He served as Honorary Registrar and Research Fellow to Dr. Roger Williams at the Liver Unit, Kings College Hospital, London from 1973-74, then was on the faculty of Columbia-Presbyterian and later served as Chief of Gastroenterology at the MUSC, Charleston, SC. Since 1990 he has been Professor of Internal Medicine at UT Southwestern Medical Center at Dallas. He is Principal Investigator for the NIH-sponsored Acute Liver Failure Study Group comprising 25 adult and 25 pediatric sites. In addition, he is Principal Investigator for one of the 10 sites participating in the NIH HALT-C study, a long-term treatment program for patients who are non-responders to interferon therapy. His group currently is conducting more than 10 trials of new agents for the treatment of viral hepatitis.

He is currently Director of the Clinical Center for Liver Diseases and holds the Meredith Mosle Chair in Liver Disease at UT Southwestern Medical Center.

Robert Fontana, M.D., University of Michigan
Causality Assessment in Drug Induced Liver Injury [PDF]


Causality assessment is the Achilles heel of drug induced liver injury (DILI). However, causality assessment is not only an absolute necessity for conducting research into the risk factors, mechanisms and natural history of DILI, it is also a vitally important tool for clinicians in practice managing individual patients. To make a diagnosis of DILI requires a “high index of suspicion” since there are always more common, alternative causes of identifiable liver injury to consider in afflicted patients. However, a diagnosis of DILI is usually only made after a retrospective review of the available serological, histological, laboratory, and radiological studies following drug cessation. Causality assessment in individual patients is further complicated by the fact that patients with suspected DILI are frequently receiving multiple, potentially hepatotoxic drugs and have concomitant heart, renal, or other systemic disease(s) that may contribute to liver injury (i.e. TPN in hospitalized patients). In addition, liver injury due to a particular drug may present in a plethora of clinical, biochemical, and histological forms making it more difficult to identify a specific “phenotype”. Lastly, at a population level, attribution of liver injury to drugs is complicated by the background rate of idiopathic acute hepatitis, liver failure, and cryptogenic cirrhosis in the general population.

Causality assessment in DILI provides a semi-quantitative estimate of the likelihood that a drug was involved in the observed illness and is essentially based upon “circumstantial evidence” since there are no objective or specific laboratory markers of DILI (1). Most attempts at causality assessment are founded on the 3 key clinical features of DILI 1) A definable temporal relationship between drug exposure and liver injury 2) DILI presents with a “signature” phenotype or typical clinical profile of symptoms, laboratory, and/ or histological features 3) DILI improves with drug discontinuation and will recur upon rechallenge. Because of the lack of specificity, sensitivity, and validation of the available causality assessment instruments, most studies rely upon the opinion of an “expert panel” of experienced hepatologists as an approximation of the “Gold Standard” for causality assessment.

The Roussel Uclaf Causality Assessment Method (RUCAM) is the most widely used instrument. This instrument has 7 domains and provides a semi-quantitative scaled score ranging from -8 to + 14. The RUCAM domains and weighting were developed from a consensus opinion of an expert panel in 1990 and “validated” from a group of 49 published DILI cases which had been rechallenged and compared to 28 controls (2,3). Determination of the serum ALT to alkaline phosphatase ratio allows for the categorization of cases into hepatocellular, cholestatic, and mixed liver injury patterns for subsequent scoring. Limitations of the RUCAM include ambiguous instructions for use, reliance on rechallenge, and lack of evidence supporting the weighting and selection of domains (1). The Clinical Diagnostic Scale (CDS) is a simplified 5 domain instrument which initially was proposed for patients with a predominance of extrahepatic immunoallergic features (4). However, the CDS was inferior to the RUCAM in assigning causality in a large cohort of Spanish patients (5). In addition, both instruments performed poorly in the most severe cases of DILI that resulted in death, transplant, or prolonged cholestasis mostly due to the lack of dechallenge data. Therefore, the first generation causality assessment instruments have limited utility due to their attempt to classify all DILI cases using the same methodology and a lack of primary data to support the selection and weighting of component domains. Since DILI as a disease entity is highly variable between drugs, patient populations (i.e. valproate in children vs adults), and even within individual patients given the same drug (granulomatous hepatitis vs cholestasis from dilantin), it is unlikely that a single causality assessment instrument will be accurate and reliable in all patients with DILI from all agents unless there is dynamic weighting of component variables. In addition, mathematical methods to account for missing data will need to be incorporated. Bayesian approaches to adverse drug reactions that utilize mathematical calculations to develop prior and posterior probabilities of causality in individual cases have been proposed but require the accumulation of large datasets of cases and development of computerized algorithims (6).

The Drug Induced Liver Injury Network (DILIN) is a multi-center study funded by NIDDK that is attempting to improve our understanding of the risk factors, outcome, and mechanisms of DILI in the United States (7). A secondary aim of the network is to develop standardized instruments, definitions, and terminology for drug and CAM induced liver injury. In the Prospective DILIN study, patients with suspected liver injury due to any drug or herbal product that meet predefined biochemical criteria are eligible for enrollment within 6 months of DILI onset. All subjects undergo an extensive medical history, liver imaging, and battery of diagnostic laboratory tests to exclude competing causes of acute liver injury. Serum, DNA, and urine samples are collected from all cases as well as drug exposed controls who did not develop liver injury for subsequent mechanistic studies. All verified cases are seen for a 6 month follow-up visit to further assess causality and outcome. A Causality Committee consisting of members from the 5 clinical sites, data coordinating center, and NIDDK prospectively review submitted cases. A subgroup of Committee members independently reviews each case and makes an assessment as to the global likelihood of DILI which is then reviewed and finalized by the committee as a whole. The key data necessary to categorize cases as definite, highly likely, and probable will be derived from the database using multivariate analysis to develop simpler and improved causality assessment instruments that may be drug, drug class, or liver injury/ phenotype specific. Additional steps required to develop new causality assessment instruments proposed by DILIN include reproducibility testing, validation in an independent patient population, testing in patients with non-drug related causes of liver injury (specificity), and testing in the general population by other investigators (generalizability). Other initiatives within the Prospective DILIN study include assessment of immunological and genetic risk factors for DILI as well as development of objective biomarkers for DILI such as acetaminophen-cysteine adducts that could be incorporated into future causality assessment instruments (8,9). Hopefully, this multifaceted approach will provide a more objective, accurate, reproducible, and evidence based approach to causality assessment in DILI.

Biographical Sketch: Dr. Fontana is an academic investigator in drug induced liver disease and acute liver failure. Dr. Fontana completed his gastroenterology/ hepatology training at the University of Michigan and has been on the faculty since 1995. He is currently an Associate Professor of Medicine and Medical Director of Liver Transplantation. He is a principal investigator at one of the 5 clinical sites comprising the Drug Induced Liver Injury Network (DILIN). He has also been involved in the US Acute Liver Failure Study Group as a site principal investigator and lead investigator on the long-term outcomes protocol. He also is involved in several ongoing NIH collaborative network studies of hepatitis C (HALT-C, VIRAHEP-C) and hepatitis B (NIH HBV OLT).

Mark Avigan, M.D., FDA
Case Study of Ximelagatran and Hepatotoxicity [PDF]

Biographical Sketch: Mark Avigan obtained his B.Sc. (1972) and M.D. C.M. degrees (1977) from McGill University in Montreal, Canada. He completed residency training in Internal Medicine at the VA Medical Center/Georgetown University in Washington DC. Subsequently, he served as Chief Medical Resident and completed a clinical GI/Hepatology/Nutrition fellowship. Dr. Avigan served as a staff fellow in the Liver Unit of the National Institute of Arthritis Diabetes, and Digestive and Kidney Diseases in Bethesda Maryland and later moved to NCI where he pursued studies in molecular and cellular biological mechanisms governing the dysfunctional expression of oncogenes during carcinogenesis.

In 1990 he joined the faculty at the School of Medicine at Georgetown University. As an assistant and later associate professor he attended patients on the GI/Liver service at the Georgetown University Medical Center and served as a mentor in the GI clinical fellowship program. In addition, he was the principal investigator of NIH funded R-29 and R0-1 grants that supported studies to elucidate DNA-protein interaction models and growth regulation by cytokines.

After joining the Center for Drug Evaluation of the Food and Drug Administration in 1999 as a Medical Officer in the Division of Gastrointestinal and Coagulation Drug Products he became a Senior Medical Reviewer in 2002. He is currently serving as Director of the Division of Drug Risk Evaluation in the Office of Drug Safety.

Paul Watkins, M.D., University of North Carolina, Chapel Hill
Use of the DILIN Registry and Tissue Bank for Research [PDF]


The DILIN Network has begun to identify and recruit patients who have experienced hepatotoxicity to medications and plans to recruit appropriate control patients who have taken the implicated drug without developing toxicity. Along with extensive historical data, all subjects will give blood for genomic DNA extraction, and for EBV immortalization of lymphocytes. In addition, subjects agree to become part of a registry that will allow investigators to contact the subjects (for up to 20 years) to offer enrollment in additional studies. The NIDDK plans to make the resources of the DILIN network available to investigators outside the network and to announce RFAs that will support such studies. Possible uses of these resources include toxicity studies in the immortalized lymphocytes utilizing cell based array technology, and in vivo changes in peripheral blood transcriptome in response to an acetaminophen “challenge”.

Biographical Sketch: Paul Watkins is the Verne S. Caviness Distinguished Professor of Medicine, Professor of Pharmacotherapy, and Director of the General Clinical Research Center (GCRC) at the University of North Carolina. Dr. Watkins’ research interests include drug metabolism, disposition, and hepatotoxicity. His awards include the Therapeutic Frontiers’ Award from the American College of Clinical Pharmacy, honorary membership in the Society of Toxicologic Pathology, and an NIH MERIT Award. He is currently the chair of the Steering Committee for the Drug Induced Liver Injury Network (DILIN) funded by the National Institute for Diabetes Digestive and Kidney Diseases.

Allen Roses, MD, FRCP [Hon] GSK 
Pipeline pharmacogenetics: efficacy and safety applications [PDF]

Biographical Sketch: Allen D. Roses, MD, FRCP (Hon) was appointed as Senior VP for Genetics Research in GlaxoSmithKline in 2000. In 1997, Dr. Roses joined Glaxo Wellcome and was charged with organizing genetic strategies for susceptibility gene discovery, pharmacogenetics strategy and implementation, and integration of genetics into medicine discovery and development. In the GSK R&D structure, genetics, genomics, proteomics and bioinformatics are part of Genetics Research and support the entire R&D pipeline. His group recently published the proof of principle experiments for using linkage disequilibrium mapping to identify susceptibility loci for drug adverse events. In 1997 when he left Duke University Medical Center, Dr. Roses was the Jefferson Pilot Professor of Neurobiology and Neurology, Director of the Joseph and Kathleen Bryan Alzheimer’s Disease Research Center, Chief of the Division of Neurology, and Director of the Center for Human Genetics. Dr. Roses was one of the first clinical neurologists to apply molecular genetic strategies to neurological diseases. His laboratory at Duke reported the chromosomal location for more than 15 diseases, including several muscular dystrophies and Lou Gehrig’s disease. He led the team that identified APOE as a major, widely-confirmed susceptibility gene in common late-onset Alzheimer’s disease. Translation of these findings to pathway analyses, drug discovery and development has continued in GSK.

Jose Serrano, Ph.D., Universidad Autonoma de Barcelona 
Drug Induced Liver Injury: A common challenge for the Drug Induced Liver Injury Network and Industry [PDF]

Biographical Sketch: PhD, Molecular Biology, Universidad Autonoma de Barcelona 1991. MD, Universidad Autonoma de Barcelona 1985. Research Fellow, Diabetes Branch NIDDDK 1985-1990. Internal Medicine, Washington Hospital Center,1995. Gastroenterology/Hepatology, Georgetown University/NIH,1998.

Jose has published over 40 original papers in basic and clinical research in endocrinology and gastroenterology topics.

Clinical Associate in Gastroenterology, NIH Clinical Center1998 to present; Director Liver and Pancreas Program, Division of Digestive Diseases and Nutrition, 1999 to present. In 2003 selected the participating centers and became the Program Officer for the Drug Induced Liver Injury Network, a consortia of 5 clinical centers, a data coordinating center and the NIDDK biosample repository center, aimed to accelerate advances in the understanding and prevention of drug, CAM and toxin-induced liver toxicities.

Victor Navarro, M.D., Thomas Jefferson University Hospital
Hepatic Adverse Event Nomenclature Document [PDF]

Biographical Sketch: Director, Liver Unit and Medical Liver Transplantation
Division of Gastroenterology and Hepatology; Thomas Jefferson University Hospital, Philadelphia, PA . Vic attended Medical School at the Pennsylvania State University. He did his residency and chief residency at Temple, and GI and Liver training at Yale. Assistant Professor of Medicine and Epidemiology at Yale from 1994-2001; Clinical Assoc Professor of Medicine and Director of the liver program at Jefferson from 02-present.

Currently, oversees a group of three hepatologists and one hepatology nurse practitioner, 2 research nurses, 1 MD/PhD candidate, and MPH candidate, and 6 research assistants. The Liver Unit engages in clinical trials in hepatitis C, but also socio-epidemiologic research in hepatitis C, drug safety research in patients with chronic liver disease, and translational research in hepatocellular carcinoma and non-alcoholic fatty liver disease.

Federico Goodsaid, Ph.D., FDA
Mechanistic and Predictive Genomic Biomarkers of Hepatotoxicity [PDF]

Biographical Sketch: Senior Staff Scientist; Office of Clinical Pharmacology and Biopharmaceutics/Center for Drug Evaluation and Research/U.S. Food and Drug Administration

Dr. Goodsaid received a B.A. in Biochemistry and Biophysics from the university of California at Berkeley (1970-1973); Ph.D. from Yale University, New Haven, CT, in Molecular Biophysics and Biochemistry (1973-1979); Postdoctoral Fellow at Cornell University in Ithaca, New York and Washington University in St. Louis (1979-1982).

His relevant research experience includes serving as a Senior Staff Scientist at Applied Biosystems and Lead for the Molecular Toxicology Group at Schering-Plough Research Institute. In this capacity he interacted with the FDA in a collaboration that led to one of the first genomic data submissions (“mock submissions”) to the FDA. Most recently he was Director of Assay Development at the Fluidigm Corporation, a microfluidics company based in South San Francisco, CA.

Vince Meador
Presentation [PDF]

Biographical Sketch: Diplomat, American College of Veterinary Pathology, Anatomic and Clinical Pathology

Vincent Meador is the Director of Toxicology for the Neuroscience and Cardiovascular Division of Eli Lilly and Company. His responsibilities focus on providing Toxicology assessments for the preclinical development of drugs. He also serves as the Toxicology representative for corporate Biomarker initiatives and biomarker transfer from preclinical to clinical studies. Prior to the current position, Vince was a pathologist at Eli Lilly, specializing in both anatomic and clinical pathology, with subspecialty interest in ultrastructural pathology and hepatopathology.

James Sanders, Sanofi Aventis
Prediction of human toxicity from animal data [PDF]

Biographical Sketch: Dr. James. E. Sanders joined Rhône-Poulenc Rorer as Director of Toxicology in 1987 and has continued with the merged companies, Aventis and sanofi aventis, as a Distinguished Scientist. His career in nonclinical safety assessment of pharmaceuticals spans over 20 years. He was previously employed from 1981 to 1987 as a pathologist at Merck, Sharp and Dohme and from 1978 to 1981 as a staff pathologist in the U.S. Army at Walter Reed Army Institute of Research. At Rhône-Poulenc Rorer, he has been responsible for the nonclinical safety sections for submissions to regulatory authorities internationally. He represents his company externally in forums and working parties such as the CPMP’s SWP, DIA, ILSI, Toxicology Forum, ICH and PhRMA. Jim attended Ohio State University where he gained a DVM, an MS in Pharmacology and a PhD in toxicology. He is certified by the American Board of Toxicology and is a member of the SOT, Teratology Society, DIA, and AVMA.

Donna Mendrick, Ph.D.
Toxicogenomics: The Application of Gene Expression in Toxicology Screening [PDF]

Biographical Sketch: Vice President, Toxicogenomics, Gene Logic Inc.

Dr. Mendrick has twenty-four years of experience in the fields of toxicogenomics, pharmacology, immunotoxicology and pathology with in vivo and in vitro systems. She joined Gene Logic in 1998 to spearhead its toxicogenomics effort and formed a pharmaceutical consortium to guide this process. Dr. Mendrick continues to serve as a member of the steering committee for the FDA-PhRMA-PWG Workshops on the FDA’s Genomic Data Submissions Guidance documents. She has spoken on the use of toxicogenomics to diverse audiences including the Woodrow Wilson International Center for Scholars (November, 2002), National Academy of Sciences (February 2003 and August 2004), and the EPA Science Forum (May 2003). Dr. Mendrick was on the Editorial Board of the Journal of Histochemistry and Cytochemistry for 8 years, a member of the NIH SBIR Immunology Study Section for 8 years, and a member of the Board of Directors of the National Kidney Foundation of Massachusetts for 4 years. Prior to joining Gene Logic in 1998, Dr. Mendrick was a Group Leader in Pharmacology at Human Genome Sciences, Inc. where she planned and directed acute and chronic toxicity, developmental, and ADME studies for IND submissions, performed in-house pharmacology experiments, and directed Project Teams. Prior to joining Human Genome Sciences in 1995 she was an Assistant Professor in the Department of Pathology at Harvard Medical School where her research focused on renal immunopathology and endothelial biology.

Holly A. Read, MD, PhD, Eli Lilly 
Liver SAFETY: Risk Management Risk Mitigation [PDF]

Biographical Sketch: Dr. Read is a Medical Advisor at Eli Lilly and Company in Indianapolis. She joined the company in 1994 and began industry experience designing and conducting Phase I studies in the Clinical Pharmacology department. In 2001 she moved to the Global Product Safety Division of Regulatory in the company and focused on the CNS therapeutic area. For the last several years she has chaired a committee of company scientists who consult with colleagues concerning liver safety issues during all phases of drug development. She maintains an active interest in the best practices of other companies, thought leaders in hepatology and the FDA.

Dr. Read graduated from the Pennsylvania State University receiving a B.S. in Biochemistry in 1977. She attended medical school at Indiana University and graduated in 1985.

Journal Article

Lee WM, Senior JR. Recognizing Drug-Induced Liver Injury: Current Problems, Possible Solutions. Toxicologic Pathology. 2005 Jan; 33:155-164.