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U.S. Department of Health and Human Services


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Third Annual Meeting, Hepatotoxicity Steering Group Meeting, February 5, 2004, Rockville, MD

Meeting Agenda


Mark Avigan, M.D., FDA
Study of Drug-Induced ALF in a Liver Transplant Network: Study Design Issues [PDF]

W. Beierschmitt, Pfizer
The Amphioxus ACTIVTox System [PDF]

Kenneth L. Hastings, Dr.P.H., D.A.B.T., FDA
Thiazolidinedione Hepatotoxicity: The PPAR Paradigm [PDF]

William M. Lee, M.D., UT Southwestern Medical Center
Drug-Induced Hepatotoxicity 2004: Current Issues [PDF]

Abstract: This presentation was made before the Hepatotoxicity Steering Committee on February 5, 2004. The Hepatotoxicity Steering Committee was an outgrowth of the 2001 Chantilly meeting which began a dialogue between the Food and Drug Administration (FDA), academic hepatologists represented by members of the American Association for the Study of Liver Diseases and the pharmaceutical industry represented by the Pharmaceutical Research Manufacturers Association (PhRMA).  The purpose was to provide an update on the Acute Liver Failure Group and some perspectives on drug hepatotoxicity from the viewpoint of an academic clinical researcher with a specific interest in the field.

The Acute Liver Failure (ALF) Study Group began in 1998 to collect prospective, detailed information on this rare condition, initially from 14 and now from 24 centers around the United States.  A similar ALF pediatric study was initiated in 2000, with similar design and, currently 24 sites as well including 3 in the United Kingdom or Canada. The results show that the cause for ALF in at least 40% of adult patients was acetaminophen toxicity, due largely to unintentional but also to intentional overdoses.  Idiosyncratic drug reactions account for 12% of cases and the prominent individual drugs include isoniazid, dilantin and propylthiouracil, among others.  A similar study performed as a chart review from six sites and focusing on serious liver injury short of ALF disclosed similar figures but approximately 20% were due to idiosyncratic injury. Setting the threshold for inclusion so that encephalopathy was not required resulted in an additional 50% more cases. Studies such as the recently formed Drug Induced Liver Injury Network (DILIN) will comprise all degrees of severity of liver injury including outpatients, but there are limitation to this approach in terms of obtaining liver tissue for example.

Other imitations of these studies include the relatively small numbers of patients but this implies that drug hepatotoxicity other than acetaminophen overdoses, is rare.  Retrospective chart reviews such as the severe liver injury study are likely to be less revealing or accurate than prospective data collections.  Use of academic centers, usually transplant referral centers, as study sites introduces the bias of not being representative of community hospital experience.  However, enlarging a drug-reporting network into the community will be difficult, because reporting of drug-related liver injury is likely to be minimal and spotty unless a significant commitment is made to support information retrieval. 

John Navarro, M.D., FDA 
Liver Work Tool [PDF]

Lana Pauls, M.P.H., FDA
Can We Predict Hepatotoxicity Based on MO Reviews of Submitted Data? A review of selected NDAs [PDF]

John Senior, M.D., FDA
More Adventures: Placebo Database [PDF]

Biographical Sketch: Associate Director for Science
Office of Pharmacoepidemiology and Statistic Sciences, Food and Drug Administration

John Senior is a native of Philadelphia. He was educated in chemical engineering at Drexel University and in physics at the Pennsylvania State University (B.S. in Physics). After graduating from the School of Medicine of the University of Pennsylvania in 1954, he completed an internal medicine residency program and a clinical fellowship in gastroenterology at the Hospital of the University of Pennsylvania. He then held a National Institutes of Health Special Research Fellowship at Harvard University and the Massachusetts General Hospital (1959-62), where he worked out the mechanisms of intestinal absorption of fats across the small intestinal epithelial cells into the lymph and blood. Returning to Penn, he set up a Gastrointestinal Research Laboratory at the Philadelphia General Hospital (PGH) in 1962, and there worked on detecting and characterizing viral hepatitis after transfusion of blood. That hospital was the first in the world to screen all donor blood for the marker ("Australia antigen") of hepatitis B. He worked closely with the discoverer of that antigen, Baruch Blumberg, who was awarded the Nobel Prize in Medicine or Physiology in 1976 for its discovery. Senior was elected to the Council of the American Association for the Study of Liver Diseases, and became its 24th President in 1973-4.

On sabbatical from PGH, he investigated the possibilities of computer simulation of patients for purposes of testing candidates for certification of medical competence by the American Board of Internal Medicine, and developed the first models of tests that have evolved and currently are in use as the Computer-Based Examination. He returned to Penn at the Graduate Hospital (PGH had been closed by the City) to direct activities of its Clinical Research Center. Later, he opened a Special Treatment Unit for Alcohol-Related Disorders that provided advanced levels of medical care for over 3500 patients with life-threatening medical complications of alcohol abuse who were referred from Philadelphia and its surrounding eight counties over the period from 1974-9.

He then worked in corporate pharmaceutical research and development, at Squibb as Director of Regulatory Projects (1979-81), then at Sterling-Winthrop Research Institute as Vice President for Worldwide Clinical Affairs (1981-4). Subsequently (1984-95), he was an independent consultant to numerous pharmaceutical companies in Japan, Europe, and North America for the design, analysis, and reporting of clinical trials for New Drug Applications. In June 1995 he joined the Center for Drug Evaluation and Research of the Food and Drug Administration as a medical reviewer for gastrointestinal drug products. In January 2000 he was named Senior Scientific Advisor to the Director of the Office of Drug Safety, with special focus on the problems of detecting and attributing causality for idiosyncratic drug-induced liver injury. In July 2003 he became Associate Director for Science, Office of Pharmacoepidemiology and Statistical Sciences that has both the Office of Drug Safety and the Office of Biostatistics as its subsidiary components.

He is married to the former Sara Elizabeth Spedden, of Philadelphia; they have three grown children and seven grandchildren. He remains active as an Adjunct Professor of Medicine at the School of Medicine of the University of Pennsylvania, and he is retired from the Navy as a Rear Admiral, Medical Corps, United States Naval Reserve.

Ana Szarfman, M.D., Ph.D., FDA
Safety Data Mining of Hepatotoxic Signals: Using Data Mining to Systematically Identify Hepatotoxic Signals in the Presence of Noise [PDF]

Abstract: Drug safety databases containing huge amounts of data continue to rapidly expand each year due to submission of reports. Examples of such databases include FDA’s Adverse Events Reporting System (containing over 2.3 million records) and the military's centrally-managed Composite Health Care System (containing over 9 million records). As these databases expand, the importance of rapidly extracting useful, updated drug safety information will inevitably increase.

The systematic extraction of useful information from these rapidly evolving databases can be facilitated and enhanced by applying novel, computer-based analytical methods to these databases. Such methods include “data mining” whereby empirical Bayesian algorithms are applied to databases to identify signals or patterns of adverse events associated with drugs.

Over the past few years, the FDA has explored the Multi-Item Gamma Poisson Shrinker (MGPS) data mining method as part of its pharmacovigilance armamentarium. Developed by DuMouchel (1,2), MGPS signals potential adverse drug events by analyzing frequency data with regard to associations among drugs and events in a database. Complex stratification techniques control for confounders.

This presentation illustrates the potential of MGPS to systematically identify hepatotoxic signals in the presence of noise and the unique advantage of MGPS in greatly reducing false signals based on low counts of adverse events.

We present examples of data mining outputs for selected hepatotoxins. We illustrate why we should use safety data mining and adjusted N/E, and why we cannot automatically look at the raw numbers or at unadjusted N/E to determine signals. Examples of how MGPS has been utilized to study the potential Hepatotoxicity of an Index Drug by Comparing Confidence Limits (CL) of the Index drug with the CLs of hepatotoxic drugs and drugs having the same indications as the Index drug will also be presented.

Data mining using MGPS can assist in signaling potential hepatotoxic drug events, and in managing the risk of hepatotoxic drugs more efficiently. This technique is particularly important for early detection of serious events, such as hepatic failure and hepatic necrosis from noisy data.


1. DuMouchel W, Pregibon D. Empirical bayes screening for multi-item associations. Proceedings of the conference on knowledge discovery and data; 2001 Aug 26-29; San Diego (CA): ACM Press: 67-76.
2. Szarfman A, Machado SG, O’Neill RT. Use of Screening Algorithms and Computer Systems to Efficiently Signal Higher-Than-Expected Combinations of Drugs and Events in the US FDA’s Spontaneous
Reports Database. Drug Safety 2002; 25:381-392.

Robert J. Temple, M.D., FDA
Health Canada Guidance [PDF]

Biographical Sketch:  Dr. Robert Temple is Director of the Office of Medical Policy of FDA’s Center for Drug Evaluation and Research and is also Acting Director of the Office of Drug Evaluation I (ODE-I). ODE-I is responsible for the regulation of cardio-renal, oncologic and neuropharmacologic/psychopharmacologic drug products. The Office of Medical Policy is responsible for regulation of promotion though the Division of Drug Marketing, Advertising, and Communication, for assessing quality of clinical trials and helping to assure human subject protection through the Division of Scientific Investigations. Dr. Temple has a long-standing interest in the design and conduct of clinical trials and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active control trials, trials to evaluate dose-response, and trials using “enrichment” designs.

Dr. Temple was born in New York City, July 18, 1941. He received a B.A. Magna cum Laude from Harvard College in 1963 and received the M.D. degree from New York University School of Medicine in 1967. At NYU he was elected to Alpha Omega Alpha. He completed an internship and residency in internal medicine at the Columbia Presbyterian Medical Center in 1969. He is board-certified in internal medicine and clinical pharmacology.

Dr. Temple was a Clinical Associate and then Chief Clinical Associate in the Clinical Endocrinology Branch of the National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health from 1969-1972, investigating the effects of lithium on the thyroid and examining the effects of agents that disrupt microtubules on steroid secretion.

He became a reviewing Medical Officer in the Division of Metabolic and Endocrine Drug Products in 1972, and moved to become Assistant to the Director of the Bureau of Drugs in 1974. In 1976, he became the Director of the Division of Cardio-Renal Drug Products, serving in that role until 1982. From 1982 to 1988 he was Acting Director and then Director of the Office of Drug Research and Review. The responsibilities of that office have been divided in various ways, most recently (since 1995) among five Offices of Drug Evaluation (ODE’s 1-5). Among other awards, he has received FDA’s Award of Merit on six occasions, three Commissioner’s Special Citations, the Public Health Service Superior Service Award, the DHHS Distinguished Service Award, the Secretary’s Special Citation, and the Drug Information Association Outstanding Service Award. He received the American Society for Clinical Pharmacology and Therapeutics’ Rawls-Palmer Progress in Medicine Lecture and Award in 2001. He also received the National Organization for Rare Disorders Public Health Leadership Award in 2001. In 2002, he received FDLI’s Distinguished Service and Leadership Award.

Dr. Temple is on the editorial board of Clinical Pharmacology and Therapeutics. He was on the Board of Directors of the Society for Clinical Trials from 1983-1987 and was President of the Society in 1987. He is an honorary Fellow of the American College of Clinical Pharmacology.

Paul B. Watkins, M.D. University of N. Carolina, Chapel Hill
Drug Induced Liver Injury Network: DILIN [PDF]

Abstract: Progress in understanding drug induced liver injury been hindered by the lack of an organized mechanism to collect data on patients with DILI, and a systematic means to collect blood and other tissues from these patients for analysis. To address this critical need, the National Institute of Diabetes and Digestive and Kidney Diseases of The National Institutes of Health has recently sponsored a cooperative agreement (UO1) to create a Drug Induced Liver Injury Network (DILIN). DILIN consists of University of Michigan (PI. Robert Fontana), University of Indiana (PI.Naga Chalasani), University of Connecticut (PI. Herbert Bonkovsky), University of California, San Francisco (PI. Timothy Davern) and University of North Carolina (PI. Paul Watkins). The data coordinating center is Duke University (PI. Jim Rochon). This network will begin in the summer of 2004 to create a registry and obtain tissues and genomic DNA from patients who have sustained severe idiosyncratic liver injury due to isoniazid, phenytoin, valproic acid, and combination amoxacillin/clavulonate. In addition, the network will commence a second study that will prospectively enroll patients who have sustained DILI due to any medications. The establishment of this network should greatly speed progress in DILI research.

Biographical Sketch: Paul Watkins received his M.D. degree from Cornell Medical School in 1979. He completed his internship and residency in Internal Medicine at the New York Hospital – Cornell Medical Center, and then completed a Gastroenterology Fellowship at the Medical College of Virginia. He joined the faculty at the University of Michigan in 1986 as an Assistant Professor. He became Director of the General Clinical Research Center (GCRC) at the University of Michigan in 1992. He was promoted to the rank of Professor of Medicine and Professor of Pharmacology in 1997. He remained Director of the GCRC at University of Michigan until he was recruited to the University of North Carolina in July of 1999. There he became the Verne S. Caviness Distinguished Professor of Medicine and Professor of Pharmacotherapy, and assumed the role as Director of the GCRC. Dr. Watkins’ area of research has been Drug Metabolism and Disposition. In particular, his interests have focused on the enzyme termed CYP3A4, which is present in human liver and intestine. He has had continual support from the NIH for his research since 1986, and in 1998 received an NIH MERIT Award. He has received several honors for his research, including the Therapeutic Frontiers’ Lecture Award from the American College of Clinical Pharmacy in 1998.

Dr. Watkins’ clinical area of interest is Drug-Induced Liver Disease, and he has consulted widely for industry and governmental agencies in this area.

Dr. Watkins has numerous other academic credentials. He has served on several national committees, including Toxicology I Study Section of the National Institutes of Health and the Committee for the Comparative Toxicity of Naturally Occurring Carcinogens at the National Academy of Sciences. He is currently Chair of the Steering Committee for the Drug Induced Liver Injury Network (DILIN) funded by the National Institute for Diabetes Digestive and Kidney Diseases.