 |
FDA-PhRMA-AASLD
Hepatotoxicity Steering Committee Meeting, February, 2005
Presentations
John Senior, M.D., FDA
Recognizing
Drug-Induced Liver Injury in Exposed Populations
[PPT]
Abstract:
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 [PPT]
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 [PPT]
Abstract:
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 [PPT]
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 [PPT]
Abstract:
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 [PPT]
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 [PPT]
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 [PPT]
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 [PPT]
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 [PPT]
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 [PPT]
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.
 Back
to Top 
Back to Liver Toxicity
Date created: June 3, 2005 |
|
