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Third Annual Meeting, Hepatotoxicity Steering Group Meeting,
February 5, 2004, Rockville, MD
Meeting Agenda
Presentations
Mark Avigan, M.D., FDA
Study of Drug-Induced ALF
in a Liver Transplant Network: Study Design Issues [PPT]
W. Beierschmitt, Pfizer
The Amphioxus ACTIVTox System [PPT]
Kenneth L. Hastings, Dr.P.H., D.A.B.T., FDA
Thiazolidinedione
Hepatotoxicity: The PPAR Paradigm [PPT]
William M. Lee, M.D., UT Southwestern Medical Center
Drug-Induced Hepatotoxicity
2004: Current Issues [PPT]
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
[PPT]
Lana Pauls, M.P.H., FDA
Can We Predict
Hepatotoxicity Based on MO Reviews of Submitted Data? A review of
selected NDAs [PPT]
John Senior, M.D., FDA
More Adventures: Placebo
Database [PPT]
Biographic 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 [PPT]
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.
References
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 [PPT]
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 [PPT]
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.
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Date created: June 3, 2005 |
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