Drug-Induced Liver Injury: A National and Global Problem
12-13 February 2001, Westfields Conference Center, Chantilly VA

Final Program

Monday, February 12, 2001
Opening talks - Overview

• Welcome, Program Structure, Goals of the Conference and Workshop
     John Senior, MD, Food & Drug Administration (FDA)
• Drug-Induced Liver Injury Impacts on the Food and Drug Administration (FDA)
     Robert Temple, M.D., Associate Director for Medical Policy
     Center for Drug Evaluation and Research, FDA
• Impact of Hepatotoxicity on the Pharmaceutical Industry
  Bert Spilker, Ph.D., M.D., Senior Vice President, PhRMA, Washington, D.C.
• Impact of Drug-Induced Liver Toxicity on Hepatology and the Practice of Medicine
     William M. Lee, MD, Professor of Medicine, University of Texas Southwestern Medical Center
  

Welcome, Program Structure, Goals of the Conference and Workshop
John R. Senior, M.D., Food & Drug Administration (FDA)

Slide Presentation

Abstract: This program is organized to include active participants from academia, the pharmaceutical industry, the regulatory Agency (FDA), and interested public persons. We welcome them to consider together the problems of drug-induced chemical injury to the liver, and how best we may work together to address, ameliorate, or solve those problems for the benefit of patients and consumers who are using products with medicinal effects.

More and more drugs are being taken by more and more people, not only prescription products but also over-the-counter remedies, herbal agents and dietary supplements, in addition to alcohol in various forms and amounts. The liver is the principal organ for metabolizing, inactivating, and disposing of them. Their metabolites may injure the liver cells, and complex drug-drug interactions complicate the situation. It has become clear that certain individuals are much more susceptible to drug-induced liver damage than are most people, and uncommon but severe idiosyncratic liver damage requires special consideration as a safety problem. Not only are people genetically diverse, which affects the way they metabolize drugs and other chemicals, but each person’s life experience is different. Drug-induced liver injury has become the leading cause of acute liver failure among patients presenting for evaluation at liver transplant centers in the United States, and the leading single cause for having to remove approved drugs from the market.

These harsh facts have had major negative impacts on the Agency, the pharmaceutical industry, and the practice of medicine, as will be delineated by spokespersons from the three sponsoring organizations. We shall then assess the state-of-the-art with respect to pre-clinical, clinical, and post-marketing activities that have been and could be employed to attack the problems. The meeting is not intended to profess what should be done, but to provide an opportunity to work together to ask what more might be done. We shall explore the relationships between members of the sponsoring organizations and a new construct for the public concept of drug safety.

We aim to call attention of the medical profession and the public to the scope of the problem of drug hepatotoxicity. We hope to find better ways to detect it and identify risk factors. We shall seek to develop consensus among the respective constituencies on how they may work cooperatively on constructive research, improved procedures, and communications.

Learning Objectives: After listening to this presentation participants should be able to state two reasons why the problem of drug-induced liver injury has arisen; list consequences of it to the FDA, PhRMA, and the AASLD; explain the derivation and exact meaning of "idiosyncracy."

Biographical Sketch
John R. Senior, M.D.

John Senior is a native of Philadelphia. He was educated in chemical engineering at the 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, 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, where he worked out mechanisms of intestinal absorption of triglyceride fats across the small intestinal epithelial cells. He returned to Penn to set up a Gastrointestinal Research Laboratory at the Philadelphia General Hospital (PGH), and there worked on detecting and characterizing "serum" hepatitis after transfusion of blood. That hospital was the first in the world to screen all donor blood for the marker ("Australia antigen") of the surface coat of viral hepatitis B. He was closely associated 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 1973-4.

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

He worked in pharmaceutical research and development at Squibb as a Director of Regulatory Projects from 1979-81, and at Sterling-Winthrop Research Institute as Vice President for Worldwide Clinical Affairs, 1981-4. Subsequently (1984-95), he was an independent consultant to pharmaceutical companies in Japan, Europe, and North America for design, analysis, and reporting of clinical trials for New Drug Applications (NDAs). 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 moved to the Office of Postmarketing Drug Risk Assessment, where he is currently Senior Scientific Advisor to the Director, with special focus on drug-induced liver injury and drug safety.

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

Back to Top

Drug-Induced Liver Injury Impacts on the Food and Drug Administration (FDA)
Robert Temple, M.D., Associate Director for Medical Policy
Center for Drug Evaluation and Research, FDA

Slide Presentation

Abstract: Hepatotoxicity has been, over the years, the most important single cause of withdrawals and marked limitations of use of drugs or refusal to approve them. In the 1950’s, iproniazid (Marsilid) was probably the most hepatotoxic drug ever marketed, but isoniazid, from the same period, has been found to cause serious hepatotoxicity in about 0.1% of recipients. Benoxaprofen (Oraflex), ticrynafen (Selacryn), bromfenac (Duract) and troglitizone (Rezulin) all were withdrawn because of hepatotoxicity, and ibufenac, perhexilene and dilevalol, all marketed abroad, were never approved in the United States. Hepatotoxicity has caused important limitations of use for many drugs, including isoniazid, labetalol, dantrolene, felbamate, pemoline, tolcapone, and trovafloxacin.

In most cases, the hepatotoxicity of these drugs was recognized late, as neither animal nor human experience before marketing yielded recognizable (or recognized) signals of hepatotoxic potential. Yet most of the drugs did cause a greater rate of transaminase elevation than controls and most also were associated with at least a few instances of transaminase elevation accompanied by elevated bilirubin or jaundice.

Post-marketing surveillance now detects serious hepatotoxins in months (bromfenac, tolcapone, troglitizone, trovafloxacin), in marked contrast to the years of delay in the past (iproniazid, isoniazid), but it is obviously preferable to discover them before marketing.

It is critical to evaluate the predictive ability (sensitivity, specificity) of various potential signals of injury, notably transaminase elevations of various degrees (3 fold, 5 fold, etc.) and frequencies (2%, 3%, etc.) and serum transaminase elevations accompanied by elevated bilirubin, a particularly troublesome combination that seems to predict a roughly 10% rate of serious injury, as noted by Zimmerman in 1978. This pattern has been seen recently with dilevalol (not approved in U.S.), bromfenac, and troglitizone, and may have predicted the ultimate serious injury rate. For example, the approximately 0.1% rate of that combination with troglitizone is not far from one tenth of the annual rate of 1/10-50,000 of serious trogitizone injury.

Refinement of these possible pre-marketing signals of injury is a major regulatory and public health task.

Biographical Sketch
Robert J. Temple, M.D.

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, and for assessing quality of clinical trials through the Division of Scientific Investigations.

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.

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.

Back to Top

Impact of Hepatotoxicity on the Pharmaceutical Industry
Bert Spilker, Ph.D., M.D.
Senior Vice President, PhRMA, Washington, D.C.

Slide Presentation

Abstract: A fundamental question for various stakeholders to address is "how rare or mild does hepatotoxicity have to be for a drug to be approved and to remain on the market?" At this meeting we will review the relevant factors that go into this decision. Regulatory agency, industry, and societal decisions depend on both sound science and balancing benefits and risks. But if the Food and Drug Administration (FDA) raises standards based on political pressures rather than sound science, it will deter some research and discourage new drug development, The FDA is sometimes pressured by the media to act in haste and set unreasonable standards. The media, in turn, are often responding to outspoken consumer extremists who have other interests than seeking sound scientific answers, and they spread disinformation.

Our challenge is to insure that claims or accusations of hepatotoxicity must be demonstrated with persuasive scientific evidence before a drug is removed from the market. We must be able to separate signals from noise, and anecdotes from facts.

The three goals for this meeting are to consider how to (1) create a sound research agenda that will improve scientific understanding and counter unsupported allegations of drug risk, (2) develop more approaches for extrapolating hepatic data and for using postmarketing data optimally, and (3) develop a mechanism to monitor progress on both the research agenda and development of extrapolation principles and postmarketing approaches. In addition, we must evaluate the various strategies for risk communication and risk management.

Industry is committed to working with all stakeholders on this issue to assure continued patient safety.

Biographical Sketch
Dr. Bert Spilker

Bert Spilker, PhD, MD, FCP, FFPM, is the Senior Vice President of Scientific and Regulatory Affairs for PhRMA (Pharmaceutical Research and Manufacturers of America) based in Washington, D.C. He was President and cofounder (in 1993) of Orphan Medical, Inc., a public pharmaceutical company that develops and markets important medical products for patients with uncommon diseases. He is Clinical Professor of Pharmacy Practice at the University of Minnesota and Adjunct Professor of Medicine and Pharmacy at the University of North Carolina in Chapel Hill. He is well known as the author of 15 books on clinical trial methods and the processes of drug discovery and development. These books are considered by many as the standard references on clinical trials and drug development. He has worked at four major pharmaceutical companies for over 20 years (Pfizer, Philips-Duphar, Sterling-Winthrop, and Burroughs Wellcome) in medicine discovery, development, and management. He serves on the Steering Committee for the International Conference on Harmonization, or ICH, and has received numerous honors including the FDA Commissioner’s Special Citation for work in the orphan medicine area. His medical training in pharmacology and internal medicine was at Cornell Medical College, State University of New York (Downstate Medical Center), University of California at San Francisco, University of Miami Medical School (Ph.D. to M.D. Program) and Brown University Medical School.

Back to Top

Impact of Drug-Induced Liver Injury on Hepatology and the Practice of Medicine
William M. Lee, MD
Professor of Medicine, University of Texas Southwestern Medical Center

Slide Presentation

Abstract: Among the joys of good health are digestion of food and elimination of internally-derived toxins, functions primarily supplied by the gastrointestinal tract and kidneys respectively. However, the processing and excretion of all absorbed xenobiotics (foreign substances) is the province of the liver. Building upon, but exceeding in complexity, the functions of the gut and kidney, normal hepatic function is a third essential for good health. Drug reactions that interfere with hepatic function and are life-threatening are extremely rare, given the number of xenobiotics ingested. The marvel is that a single liver can and does metabolize as many as 12 drugs at a time without evidence of injury or even of buildup of any one of the various compounds ingested. As a result, patients and physicians assume (or take for granted) that the liver will perform its job faithfully with never a complaint.

Metabolism of xenobiotics involves the creation of activated intermediate compounds that rarely bind to cell proteins with subsequent hepatocyte damage, either directly or by invoking immune responses. The final result is often massive and sudden necrosis of liver cells, multi-organ failure and death. This rare but catastrophic event finds clinicians and patients unaware of the potential disaster and un-prepared to deal with a rapidly deteriorating situation. The likelihood of drug toxicity varies among individual agents and among drug classes. Many physicians are not familiar these varying propensities for drug toxicity. Even if they are aware of the possible consequences, physicians seldom give patients specific instructions that might be life-saving such as what to do should dark urine or jaundice develop. The very rarity of severe liver injury due to drugs represents its fundamental virtue and problem. We cannot develop an appropriate cost-effective response for events as infrequent as 1:50,000 prescriptions. How much instruction should a patient receive for such events? If a toxic reaction is recognized with a given agent, how much advertising in the post-marketing period should be directed at education of physicians to potential but rare events that seldom occur? Fear of drugs by physicians or patients limits their use. Withdrawal of drugs due to rare toxicity deprives patients of potential benefits. Caution, particularly in regard to drugs with known hepatotoxicity such as isoniazid, may lead to closer supervision, monitoring of liver function tests, or limitation of use to the least susceptible patients.

Physicians want to know how to avoid the risks and how to become educated regarding drug toxicity. They want safe drugs but realistically know that universal safety cannot be guaranteed. Yet they seldom participate in the efforts to monitor drug reactions; adverse events are reported to FDA less than 10% of the time. Improved methods of post-marketing surveillance should result in more rapid identification of potential toxins whose initial clinical assessments did not identify drug events. Education directed at recognition of the symptoms of acute liver failure might lead to earlier withdrawal of toxins and prompt institution of intensive care.

The three constituencies represented at this conference should dedicate their efforts to greater education of physicians and patients concerning drug toxicity and severe liver injury with the goal of identifying harmful effects more reliably and preventing these potentially avoidable events.

Biographical Sketch
William M. Lee, MD
Professor of Internal Medicine and Director, Clinical Center for Liver Disease
University of Texas Southwestern Medical School, Dallas, Texas.

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 until 1980. In that year, he became an Associate Professor and later, Professor and Chief of the Division of Gastroenterology at the Medical University of South Carolina, Charleston, SC between 1980 and 1990. Since his arrival at UT Southwestern in 1990, he has continued to do clinical and basic research. Four review articles in the New England Journal of Medicine define his main areas of research and clinical interest: The Extra-Cellular Actin-Scavenger System, 1992, Acute Liver Failure 1993, Drug-Induced Hepatotoxicity 1995, Hepatitis B Virus Infection 1997.

The Clinical Center at UT Southwestern is the largest site in Texas performing viral hepatitis clinical trials (9 on payroll, 22 active protocols). Dr. Lee serves as one of 10 principal investigators in the HALT-C study sponsored by the NIDDK, an 8 year study to determine the safety and efficacy of long-term interferon therapy for hepatitis C non-responder patients. He is the principal investigator for the Acute Liver Failure Study Group comprising 39 sites around the U.S. sponsored by the NIDDK.

Back to Top

State-of-the-Art Presentations

• Pre-Clinical Issues in Drug Development
     François Ballet M.D., Ph.D., Aventis, Paris
• Clinical Picture and Issues in the Clinical Phases of Drug Development
     Neil Kaplowitz, M.D., University of Southern California, Los Angeles
• Post-Marketing: State of the Art and Issues Defined
     Peter K Honig, MD, MPH,Director, Office of Postmarketing
  Drug Risk Assesment, FDA

Pre-Clinical Issues in Drug Development
François Ballet M.D., Ph.D.
Aventis, Paris

Slide Presentation

Abstract: Despite considerable progress in the understanding of the mechanisms of liver toxicity, we are not yet able to design non-hepatotoxic drugs rationally. Also there are no " universal " high throughput molecular or cellular screening approaches that could be apply systematically at the hit or lead generation phase of drug development to screen for hepatotoxicity. Therefore it is not surprising that in most cases hepatotoxicity is detected at later stages of drug development when animal (usually rat and dog) toxicity studies are performed, during the course of clinical trials or even at a later stage when a drug is on the market.

Very few studies have been conducted on the incidence of hepatotoxicity in drug development and on the predictive value of animal toxicity studies. Based on available data the liver appears to be the most common target organ for toxicity encountered during the course of drug development. Also, based on available surveys, the predictive value of animal hepatotoxicity studies appears to be limited. Idiosyncratic hepatotoxicity cannot be detected by conventional animal toxicity studies. Interspecies differences in bioavailability, distribution and metabolism may also explain a number of false positives and false negatives. There is clearly a need to better understand the drug metabolism enzyme profile of the most commonly used non-rodent species i.e. the dog and the monkey. Some false negative results may be related to insufficient exposure of the animals either because the doses tested were too low or because intestinal absorption was poor. Certain liver abnormalities may occur only in diseased models (e.g. drug-induced hyperbilirubinemia in severe infection) and therefore cannot be detected in healthy laboratory animals. Finally certain liver changes, e.g. liver hyperplasia, are common findings in laboratory animals butb are considered to be of no clinical significance in man.

A number of criteria are being used to assess the clinical significance of animal toxicity data : (a) type/severity of injury (b) reversibility (c) mechanism of toxicity (d) interspecies differences (e) availability of sensitive biomarkers of toxicity (e) safety margin (non toxic dose/pharmacologically active dose) (f) therapeutic potential. Contrary to other target organs (e.g. kidney, adrenal, heart), minimal and reversible liver injury can be detected in early clinical trials by monitoring liver enzymes. Therefore in certain cases it may be justified to test in man a drug found to be hepatotoxic in pre-clinical studies, especially when the therapeutic value is high.

In recent years toxicogenomic and proteomic approaches have been tested with the aim of developing more efficient in vitro screening assays. It is important to realize that these technologies are based on cellular models with intrinsic limitations in term of in vivo relevance. Also they represent a formidable challenge in term data management and interpretation. Based on current experience the most valuable use of these "transcript expression profile" approaches appears to be "secondary" screening for back-up selection and investigation of toxicity mechanisms.

A better understanding in the molecular mechanisms of hepatotoxicity in man is a critical prerequisite for any improvement in the detection of hepatotoxicity during the pre-clinical phase of drug development. Identification of critical molecular toxicity targets can lead to the design of pertinent molecular or cellular screening assays or to the development of new biomarkers/endpoints for in vivo studies. Pharmacogenetic techniques should be more systematically applied to patients with idiosyncratic toxicity in order to identify critical suceptibility genes which could lead secondarily to identification of mechanisms. Also a more systematic/prospective analysis of animal and human hepatotoxicity data encountered during the course of drug development should be carried-out as a joint effort between industry and regulatory agencies to improve the toxicology strategy.

Finally another important aspect is the need to improve communication and to foster exchanges between toxicologists (Ph.Ds/DVMs) and clinicians (M.Ds) in industry and in academia. Indeed, in the opinion of the author, an inter-disciplinary and more integrated approach is a key factor to improve the testing strategy for hepatotoxicity in the pre-clinical phase of drug development.

Learning objectives:   After hearing this presentation, listeners should be able to list or outline

• The different steps of the drug discovery and development process;
• Main principles of animal toxicology studies;
• How to use data from animal toxicology studies for go/no go decision;
• Specific issues related to hepatotoxicity in animals (liver hyperplasia, enzyme induction…);
• Predictive value of animal toxicity studies. Causes for false-negatives and false-positives;
• Screening strategy for hepatotoxicity;
• Role of mechanistic studies;
• New approaches (toxicogenomics, proteomics, pharmacogenetics…);
• How to improve predictivity of animal toxicity studies ?

Biographical Sketch
François Ballet M.D., Ph.D.

Dr. Ballet received his M.D. degree in 1976 from the University of Paris. He subsequently completed a board certification in Hepatology and Gastroenterology at the Saint-Antoine Hospital of the University of Paris. He then held a French Association for Cancer Research fellowship at the Hepatology Department of the Saint-Antoine Hospital where he worked on in vitro models for predicting sensitivity of tumors cells to anticancer drugs. He then joined INSERM (French National Institute of Health) in 1980 as a research scientist and there worked in particular on hepatic transport of drugs, liver microcirculation in normal and cirrhotic liver, hepatocellular carcinoma and hepatotoxicity. In 1985, he became head of Liver Physiology and Pharmacology group at INSERM at Hospital Saint-Antoine in Paris. In 1988 he completed a Ph.D. in Pharmacology at the University of Paris. Concomitantly between 1979 and 1989 he worked as a consulting Hepatologist and Gastroenterologist in the Hepatology Department of Saint-Antoine Hospital.In 1989, he joined the Research Center of Rhône-Poulenc Rorer at Vitry-sur-Seine, France (near Paris) in the Drug Safety Department as a senior toxicologist. The department carried out all regulatory pre-clinical toxicology studies (general, reproductive and genetic toxicology as well as carcinogenicity assessment) for NCE registration, in vitro screening for early compound selection and investigative studies to determine mechanism(s) of toxicity and included 120 scientists and technicians. He then became Director of Investigative and Genetic Toxicology and in 1996 he was appointed head of the Drug Safety Department. In October 1999, following the merger of Rhône-Poulenc Rorer and Hoechst Marion Roussel, he was appointed Vice-President in the new Aventis Pharma organization in charge of the Drug Innovation and Approval (R&D) Operations in France. In this position he had in particular to manage the integration and reorganization of the R&D activities and sites of the former companies in France and UK.

Dr. Ballet is member of several expert committees at the European Commission and at the French Ministry of Research and Education. He is board certified by the American Board of Toxicology.

Back to Top

Clinical Picture and Issues in the Clinical Phases of Drug Development
Neil Kaplowitz, M.D.
University of Southern California, Los Angeles

Slide Presentation
Slide:  Risk of Hepatotoxicity

Drug-induced liver disease can mimic all forms of acute and chronic hepatic diseases. However, the predominant clinical presentations resemble acute icteric hepatitis or cholestatic liver disease. The former is of grave significance as the mortality approximates 10% due to acute liver failure. Hepatitis-like reactions are accompanied by systemic symptoms, jaundice, markedly increased serum transaminases, and, in more severe cases coagulopathy and encephalopathy. Cholestatic reactions, although not usually life threatening, present with jaundice, disproportionate increased serum alkaline phosphatase and pruritus: these reactions may resolve slowly and lead to vanishing bile duct disease and rarely biliary cirrhosis.

Some presumptive mechanistic information can be deduced from the frequency and the latency of adverse events. High frequency and short latency suggest that the parent drug or metabolite is directly toxic. Low frequency and longer latency suggest either immune-mediated (within 4-6 weeks), or metabolic idiosyncratic toxicity (variable but delayed). Irrespective of the mechanism, i.e. immune-mediated or "idiosyncratic", and notwithstanding low incidence, these reactions often occur on the background of more frequent anicteric, transient milder liver injury. The relationship between the frequent mild injury and rare severe injury is unclear. Does the mild injury reflect a propensity or signal for serious problems? Does severe injury reflect impaired adaptation - in other words is it the handling of the drug or of the injury or both which determines the occurrence of overt or severe liver injury?

The pre-approval clinical phases of drug development represent a key arena for identification of hepatotoxic potential. At this stage drugs with significant toxic potential are easily recognized but those with low toxic potential may be less easily recognized, particularly if identification of overt (symptomatic jaundice) or serious injury is used as the marker. The rule of three’s predicts that to insure not missing an overt adverse event occurring in 1 per 1000 requires studying 3000 individuals. Thus, the absence of overt disease in 3000 study patients (typical pre-approval cohort) does not prove it will not occur and only predicts an incidence of overt disease of less than 1 per 1000 and life threatening disease of less than 1 per 10,000. Furthermore, if the adverse reaction is of the delayed idiosyncratic type, the clinical trials may have included a far smaller number of subjects at risk for sufficient duration. Furthermore, the frequency of testing and rules for stopping may confound the identification of a significant signal. Despite the low incidence of over liver injury, less severe injury may be found more frequently and constitute a possible or probable indicator. What then is a significant and specific signal for concern during the clinical phase of drug development? - increased incidence of ALT >3X ULN versus matched controls?, ALT > 8-10X ULN?, hyperbilirubinemia?

The discussions at this conference should lead to the design of an approach to verifying liver abnormalities in drug development which constitute a possible or probable signal for concern and what to do with that information with respect to drug approval.

Biographical Sketch
Neil Kaplowitz

Neil Kaplowitz, M.D. is Director and Principal Investigator of the NIDDK-supported USC Research Center of Liver Diseases, Associate Director and Co-Principal Investigator of NIAA- supported USC-UCLA Research Center for Alcoholic Liver and Pancreatic Disease, and Chief of the Division of Gastrointestinal and Liver Diseases of the Keck USC School of Medicine. He holds the endowed USC Associates/Thomas Brem Professorship of Medicine and is also Professor of Physiology & Biophysics and Molecular Pharmacology & Toxicology.

Dr. Kaplowitz has held a number of important national positions including President of the American Association for the Study of Liver Diseases, President of the Western Society for Clinical Investigation, and Vice Chair for Research of the American Liver Foundation. He is the recipient of the Middleton Award, the highest research honor given by the Department of Veteran Affairs, and is a member of the prestigious American Society for Clinical Investigation and the American Association of Physicians. He has edited several textbooks on liver diseases and served as associate editor of major medical journals including Hepatology, Gastroenterology and the American Journal of Physiology. He is editor of Drug Hepatotoxicity, a new textbook in the final stages of preparation.

Dr. Kaplowitz has trained hundreds of physicians and scores of scientists who work throughout the world. He has more than 200 publications and is an authority on the mechanisms of chemical and drug-induced liver injury, the role of oxidative stress and cell defense mechanisms in the evolution of liver diseases, and the fundamentals of how the liver functions in the processing of chemicals from import to metabolism to excretion. He currently is principal investigator of individual research grants from NIDDK and NIAAA which deal with molecular physiology of organic anion transport and the molecular pathophysiology of alcohol-induced and toxin-induced liver cell death.

Dr. Kaplowitz received his B.S. (Cum Laude) and M.D. from New York University where he was elected to Phi Beta Kappa and Alpha Omega Alpha. He trained in internal medicine at Bellevue and Jacobi Hospitals, in gastroenterology at Cornell University Medical College, and in research at Rockefeller University. He was a faculty member at the UCLA School of Medicine for 15 years and has been at USC for the past 11 years.

Back to Top

Post-Marketing: State of the Art and Issues Defined
Peter K. Honig, MD, MPH
Director, Office of Postmarketing Drug Risk Assesment, FDA

Slide Presentation

Abstract: Acute hepatic injury is one of the most common forms of pre-clinical and clinical toxicity encountered with drugs. Fortunately, most drugs with the potential for substantial hepatotoxicity will be identified during early testing. Yet, pre-approval testing cannot be relied upon to identify less common drug-related hepatotoxicity because of the recognized and accepted limitations of the safety database submitted in support of a drug licensing application. Phase 3 clinical trials are designed, powered, and reviewed to detect relatively common dose-related adverse drug reactions (ADR) whether or not these are predicted from the drug’s pharmacology. However, a database of several thousand patients, which is typical of most marketing applications, lacks the power to observe rare adverse reactions (i.e. those occurring at rate of 1 per 1000 exposures or less). Furthermore, short trial duration and, in some cases, specific patient selection criteria contribute to the inability of pre-marketing studies to detect the rare, drug-related adverse events that may occur when the drug is given to a larger numbers and a broader range of patients following approval. ADRs with a long induction period will not be detected in brief trials and adverse reactions resulting from specific interactions with personal characteristics, concurrent diseases and concomitant drug therapies will not be found. Therefore, it is critically important that new information regarding severe drug-induced hepatotoxicity appearing postmarketing regarding drug product safety be collected, analyzed, and acted upon in an expeditious manner. One of the main objectives of post-marketing safety surveillance is to detect rare adverse events associated with the use of drugs, to assess the likelihood of a causal relationship of the event to the drug and, when a drug cause seems likely, estimate the rate of the event. This responsibility is shared by the regulatory authorities, drug manufacturers and by physicians, whose timely reports of adverse drug events are the main source of information about rare adverse effects. The strengths and limitations of the current tools and mechanisms for identifying signals of serious hepatoxicity of marketed drugs and the methods used to quantify the population risk and identification of risk factors that may confer individual susceptibility to drug-induced hepatic injury using population-based resources will be discussed. Additionally, regulatory considerations in the benefit:risk assessment of drugs that are identified as hepatotoxic and the strengths and limitations of existing risk management tools will be highlighted. Finally, knowledge gaps and issues requiring further research or development will be outlined for further discussion in the conference breakout groups. These include but are not limited to: 1) development of a standardized nomenclature and definitions for liver test abnormalities and liver injury, 2) improving the quality and quantity of voluntary reporting, 3) quantifying the frequency of LFT abnormalities and evaluating the usefulness of liver monitoring recommendations as a risk management strategy in preventing drug injury, 4) development of active and sentinel surveillance strategies for drug-induced liver injury, and 5) development of a nationwide research proposal to determine mechanisms of individual susceptibility to drug-induced hepatic injury.

Biographical Sketch
Peter K. Honig, MD, MPH

Peter K. Honig, MD, MPH is Director of the Office of Postmarketing Drug Risk Assessment (OPDRA) of the Center for Drug Evaluation and Research (CDER) of the Food and Drug Administration (FDA). He received his baccalaureate, medical and public health degrees from Columbia University and is Board Certified in Internal Medicine and Clinical Pharmacology. He joined FDA/CDER in 1993 as a medical review officer in the Division of Pulmonary and Allergy Drug Products and served as a medical team leader before joining OPDRA in 1999. He retains faculty appointments at the Uniformed Services University of the Health Sciences and Georgetown University where the Department of Medicine recognized him for excellence in house staff teaching with the Sol Katz award. Dr. Honig is the CDER liaison to the Harvard Clinical Investigators training program and is the FDA representative to the CERTs (Centers for Education and Research in Therapeutics) Steering Committee. He also represents FDA at the International Conference on Harmonization (ICH) and the MedDRA Management Board (MSSO). Dr. Honig is a fellow of the American College of Physicians (FACP) and a Vice-President of the American Society of Clinical Pharmacology and Therapeutics (ASCPT).

Tuesday, February 13, 2001
Current Topics in Hepatology

• How are these problems being addressed in Europe?
     Roger Williams, Professor of Hepatology, Institute of Hepatology, University College, London
• Looking for hepatotoxicity, working up patients, and assessing causality
     James W. Freston, M.D., Ph.D., University of Connecticut Heath Center, Farmington, CT
• Emerging Trends in Acute Liver Failure in the United States
    William M. Lee, MD, University of Texas Southwestern
• Pharmacogenomics: Dangerous drug or susceptible patient?
  Paul B. Watkins, M.D., University of North Carolina at Chapel Hill, NC

How are these problems being addressed in Europe?
Roger Williams, Professor of Hepatology,
Institute of Hepatology, University College, London
Slide Presentation

Abstract: The European Agency for Evaluation of Medicinal Products (EMEA) established in 1995 by the European Union, has to some extent supplanted the work of the Medicines Control Agency in the UK, as well as that of other similar national bodies in assessing the efficacy and safety of new drugs. The Agency, located in London, offers two routes for authorisation of medicinal products: 1) the centralised procedure, compulsory for products derived from biotechnology, requires that at the conclusion of the scientific evaluation the opinion of the Scientific Committee be transmitted to the Commission to be transferred into a single market authorisation applying to the whole European Union.; 2) the decentralised procedure applies to the majority of conventional medicinal products and is based upon the principle of mutual recognition of national authorisation procedures. An information network links all partners in the EMEA allowing rapid exchange of reports of adverse reactions occurring once the drug is marketed. In the UK a further new body - the National Institute for Clinical Excellence (NICE) - came into being on 1 April 1999, to provide patients, health professionals and the public with authoritative guidance on current best practice in health technology including medicines. Before licensed new medicinal products can be prescribed on the National Health Service (NHS), they have to have the blessing of NICE on the basis of cost benefit analyses of efficacy data. Regarded by many as a rationing device it can certainly delay the introduction of new agents into NHS prescribing.

Learning Objectives: After hearing this presentation, listeners should be able to

• outline the relationship between the different National Regulatory and Safety agencies and the European Wide Agency of the European Union;
• identify how the information available throughout Europe is disseminated at national level;
• describe the main weakness of the system, i.e., the detection and reporting of adverse drug reactions in the context of hepatotoxicity and the general poor understanding of the speciality.

Biographical Sketch
Professor Roger Williams
CBE, MD, FRCP, FRCS, FRCPE, FRACP, FRCPI, FMedSci, FACP (Hon)

The work of Professor Roger Williams in clinical liver disease and research has brought him a national and international reputation and has been marked by Presidencies of both the British and European Associations for the Study of the Liver in 1983 - 85 and 1983, respectively. He has published over 1,500 papers, journals and books and has served on 17 editorial boards. The Liver Unit which he started at King’s College Hospital in 1966 was recognised as an Institute of Liver Studies by King’s College, London in 1990. Professor Williams has been involved in the work of the British Society of Gastroenterology over many years. He has given the Sir Arthur Hurst Memorial Lecture and was President of the Society from 1990 - 91. At the Royal College of Physicians he has been Goulstonian Lecturer and was Second Vice-President from 1991 - 1993. Other honorary positions include the Presidency of the Harveian Society of London 1974-75 and the Chairmanship of the International Medical Club, 1990 to 1993. He has been Honorary Consultant Physician in Medicine to the Army since 1988. Professor Williams has received a number of prizes including the Legg Award of the Royal Free Hospital; the Nightingale Prize of the International Federation of Medical and Biochemical Engineering and most recently, the Gold Medal of the Canadian Liver Foundation. He was honoured by election as Fellow of the Royal College of Surgeons in recognition of his contribution to development of liver transplantation and has also been given the Fellowship of the Edinburgh College and that of the Royal College of Physicians of Australasia. In 1992 he was made a Fellow of King’s College, London, and in that year was also awarded an Honorary Fellowship of the American College of Physicians. He was appointed a CBE in the Queen’s Birthday Honours list of 1993, and the title of Professor of Hepatology was conferred by the University of London in May 1994.

Since 1 October 1996, Professor Williams continues his commitment to hepatology as Director of the new Institute of Hepatology at University College London and Honorary Consultant Physician in Medicine at UCL Hospitals Trust. Professor Williams’ aim is to make the Institute, which has been established by the Liver Research Trust, a centre of excellence in the UK and to forge links with other liver centres around the world in areas of work including virus-induced liver disease, auto-immune liver disorders, gene therapy, novel therapeutic agents and bio-artificial liver support devices.

Back to Top

Looking for hepatotoxicity, working up patients, and assessing causality
James W. Freston, M.D., Ph.D.
University of Connecticut Heath Center, Farmington, CT

Slide Presentation

The best time to look seriously for evidence of hepatotoxicity is in Phase II and III clinical trials. The setting is optimal for obtaining the data necessary to establish the clinical profile of the reaction and to determine causality with better precision than is ordinarily the case after the drug is approved. Of course, uncommon idiosyncratic reactions can usually be detected only after the drug is used broadly in the population. In designing clinical trials of new drugs, sponsors and investigators often face the issue of excluding or including patients with abnormal LFTs. Subject with severe liver disease usually are excluded. However, subjects with mild LFT elevations, for example, ALT values less than 2-3 times the upper limit of normal, should be included. This will enable the trial results to be applicable to the general populations, about 2 % of which harbor such abnormalities, usually due to ethanol use, hepatitis C and, possibly, NASH. Such patients are not at increased risk of suffering idiosyncratic drug reactions, although their hepatic response to an idiosyncratic reaction may be exaggerated. While they may be more susceptible to dose-related hepatic reactions, such are usually reversible upon discontinuation of the drug, and there is a large margin between these mild abnormalities and those associated with hepatocellular reactions that result in hyperbilirubinemia, a prolonged INR and other clinical indicators of severe hepatic dysfunction. Trial protocols must, of course, provide for LFT measurements at intervals that are sufficiently frequent to detect significant increases in LFTs before serious hepatic dysfunction has occurred. There also is value in determining if mild liver abnormalities worsen or improve during drug therapy. Improvements might occur, for example, in diabetics with NASH when they are treated with an experimental drug that improves glucose control. This may have been the case in clinical trials of rosiglitazone and pioglitazone, although the appropriate tests were not done to determine if the improvements in mild LFT abnormalities were due to improvements in NASH. Such studies are underway, which may not have been the case if patients with abnormal LFTs had been excluded from the large Phase III trials, thereby obviating the opportunity to document improved LFTs with improved glucose control. Thus, by including subjects with mild LFT abnormalities in trials, other potential benefits of a drug can be uncovered and more precise labeling can be developed to aid clinicians in optimizing the drug’s benefits and reducing its risks.

Detecting hepatic abnormalities at an early stage and assessing their causality appropriately are challenging. Data safety monitoring boards (DSMBs) are increasingly used in non-hepatology fields, particularly cardiology. DSMBs typically consist of experts in clinical medicine, biostatistics and epidemiology, operate independently from the sponsor, and provide interim reviews of accumulating safety data. Properly organized and functioning, they define in advance statistically valid study discontinuation rules, detect serious safety issues, and provide feedback to the sponsor about a range of areas of concern, including reasons for slow patient accrual, excessive dropouts, and non-compliance with protocols. DSMBs and more informal safety assessment committees can also assess causation. This requires the consistent application of a validated system for determining if the observed hepatic reaction was likely due to the test drug. The pattern of abnormal LFTs should be determined, e.g. hepatocellular, cholestatic, or mixed. The severity should be assessed, e.g. mild, moderate, severe, and causality assessed, usually on the basis of temporal exposure, lack of confounding causes, and positive dechallenge. The value of this assessment is critically dependent on a supply of accurate data, which often requires access to the clinician/investigator and the opportunity obtain follow up tests. This is facilitated if the protocols include specific language about steps to take at the study site when LFT abnormalities of a certain type and severity are detected. Typically, hepatitis serologies and a hepatocellular ultrasound exam should be obtained immediately upon confirmation of LFT rises beyond the limits specified in the protocol. The LFTs should be followed after drug discontinuation until they return to normal. If they are abnormal after 3-6 months, an evaluation for chronic liver disease should be undertaken to include serum protein electropheresis, if not already obtained, antinuclear antibody titer, and LKM antibody. Liver biopsy should also be obtained to better assess the cause and nature of the liver reaction.

Even the best of detection and assessment methodologies commonly fail to establish causality, but at least the observed reactions can be categorized according to probability, e.g. definitely related, probably related, possibly related, probably not related, definitely related. In comparative trials this approach should distinguish between the study drug and the comparator in terms of the frequency of reactions. The approach is also useful in the absence of a comparator group although it may be exceedingly difficult to separate a drug effect from other causes operating in the background in a given population, e.g. diabetics, patients with congestive heart failure.

Learning Objectives: after hearing this presentatiom, listeners should be able to

• describe the rationale for including patients with mildly abnormal serum tests of liver function or injury in clinical trials;
• outline a cost-effective and ethically acceptable program for assessing causality;
• apply a methodology for establishing causality.

Biographical Sketch
James W. Freston, M.D., Ph.D.

Dr. Freston is Professor of Medicine (Gastroenterology), Boehringer Ingelheim Chair of Clinical Pharmacology, and Director of Clinical Research Programs at The University of Connecticut Health Center in Farmington, Connecticut. He was Chairman of the Department of Medicine at the University of Connecticut from 1980 to 1997, a position he relinquished to direct the health Center’s clinical research programs, which include an NIH-sponsored General Clinical Research Center, a Clinical Trials Office, and investigator training and education services.

Formerly, Dr. Freston was Professor of Medicine and Pharmacology at the University of Utah, where he won the Outstanding Professor Award 6 times, and directed the Gastroenterology and Clinical Pharmacology Divisions.

Dr. Freston is Chairman of the American Digestive Health Foundation and Past President of the American Gastroenterology Association. He was consultant to the Surgeon General for gastrointestinal section of The Health Consequences of Smoking and a member of two FDA Gastrointestinal Advisory Panels, as well as numerous NIH panels and committees. He is internationally recognized for his expertise in the clinical pharmacology of gastrointestinal drugs and diseases, particularly the acid-related disorders. He has lectured worldwide and is the author of over 100 peer-reviewed journal articles and 35 books and chapters. He has served as a member of the editorial boards of several journals, including Annals of Internal Medicine, Practical Gastroenterology, Clinical Advances in Gastroenterology, and The Journal of Drug Development.

Dr. Freston received his M.D. degree from the University of Utah and his Ph.D. degree from the University of London.

Back to Top

Emerging Trends in Acute Liver Failure in the United States
William M. Lee, MD
University of Texas Southwestern

Slide Presentation

Abstract: Acute liver failure (ALF) is a rare condition in which a variety of agents cause severe and sudden liver cell dysfunction. Sometimes termed fulminant hepatic failure, ALF is thought to affect about 2,000 in the U.S. per year. This overwhelming catastrophe leads to coma, multi-organ dysfunction, and death, primarily affecting young and previously healthy people. Over the past 30 years, the most frequent causes of ALF worldwide have been viral hepatitis, and drug-induced liver injury, with smaller numbers of cases due to a variety of etiologies. Until recently, little data have been available on ALF in the United States, the relative rarity of cases and lower population density in the U.S. limiting clinical studies. The ALF Study Group was formed in 1997 as a consortium of centers with experience in ALF from around the United States. The current report describes in detail the demographic profile, clinical features and outcome of patients developing ALF in the U.S. between 1998 and 2000, based on data collected prospectively by the ALF Study Group. Between January 1998 and October 2000, 258 patients were enrolled from 17 academic liver units around the United States. To be admitted to the study, patients met standard entry criteria for acute liver failure, i.e., coagulopathy (PT > 15 seconds or INR 1.5) and hepatic encephalopathy within 8 weeks of the first symptoms or jaundice without previous underlying liver disease.

Of the 258 patients, 190 (74%) were female. The reasons for the preponderance of women in this series have not been elucidated, as the underlying etiologies encountered do not share a female preponderance. Whether genetic or hormonal differences are important has not been explored. The impact of drug hepatotoxicity is exemplified by the finding that ALF due to acetaminophen or due to idiosyncratic drug reactions accounted for 52% of the total. Acetaminophen (ACM) poisoning was the most common cause of ALF, accounting for 98 (38%) cases. Although 79% of the ACM group were women, similar percentages were seen for the idiosyncratic drug reactions (74%) and for other causes of ALF. A dose-related toxin, acetaminophen is the single most common etiology for ALF in the U.S., Europe and Australia, although acetaminophen is rarely implicated in Asia. Only 12% of acetaminophen-related hospital admissions reach the threshold of developing symptoms of ALF, suggesting that the 98 cases observed in this study represent only a small fraction of the acetaminophen burden. The proportion of accidental cases in the present series was 60%% while 38% were thought to be overt suicidal ingestions. Accidental toxicity due to acetaminophen occurs when patients consume large amounts of drug over several days seeking pain relief, without realizing its possible harmful effects. Acetaminophen intoxication represents an acute event limited to a single-time-point ingestion or to a brief interval of exposure. As a result, ALT levels are extraordinarily high, bilirubin levels low and evidence of acute renal insufficiency and acidosis characterize the most severe cases, whose severity in terms of coma grade on admission equals that of other forms of ALF. Remarkably, these patients have a high spontaneous survival, perhaps attributable to the brevity of their drug exposure. Idiosyncratic drug reactions were responsible for another 35 (14%) cases, and included cases of troglitazone (4), bromfenac (4) and isoniazid (5). By comparison with the ACM cases, idiosyncratic reactions are characterized by slower onset, lower ALT, higher bilirubin levels, normal renal function but much poorer spontaneous survival. Hepatitis A and B caused 11 (4%) and 21 (8%) cases respectively. Seventy-three (28%) patients underwent hepatic transplantation, 61 of whom survived (84% short-term survival). One hundred and twelve (43%) patients survived without transplantation (spontaneous survivors). Seventy-three (28%) patients died without transplantation. Overall survival in the group was 67%. Only 6% of acetaminophen patients were transplanted, 69% surviving spontaneously, while 25 died without receiving a liver graft. By contrast, 54% of the idiosyncratic group received a transplant, 20% died and 26% recovered spontaneously.

Drug-induced liver injury leading to acute liver failure accounts for 52% of all acute liver failure in the U.S. and is a disease of the developed world, since virtually no cases are found in developing countries. As such, developed nations should be able to institute preventive measures for this newly evolving crisis. With regard to acetaminophen, limitation of package size and better patient and physician education might help alleviate this burgeoning health problem.

Biographical Sketch
William M. Lee, MD
Professor of Internal Medicine and Director, Clinical Center for Liver Disease
University of Texas Southwestern Medical School, Dallas, Texas.

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 until 1980. In that year, he became an Associate Professor and later, Professor and Chief of the Division of Gastroenterology at the Medical University of South Carolina, Charleston, SC between 1980 and 1990. Since his arrival at UT Southwestern in 1990, he has continued to do clinical and basic research. Four review articles in the New England Journal of Medicine define his main areas of research and clinical interest: The Extra-Cellular Actin-Scavenger System, 1992, Acute Liver Failure 1993, Drug-Induced Hepatotoxicity 1995, Hepatitis B Virus Infection 1997.

The Clinical Center at UT Southwestern is the largest site in Texas performing viral hepatitis clinical trials (9 on payroll, 22 active protocols). Dr. Lee serves as one of 10 principal investigators in the HALT-C study sponsored by the NIDDK, an 8 year study to determine the safety and efficacy of long-term interferon therapy for hepatitis C non-responder patients. He is the principal investigator for the Acute Liver Failure Study Group comprising 39 sites around the U.S. sponsored by the NIDDK.

Back to Top

Pharmacogenomics: Dangerous drug or susceptible patient?
Paul B. Watkins, M.D.
University of North Carolina at Chapel Hill, NC 27599

Slide Presentation

The rapid application of pharmacogenomics to drug discovery will have many implications for the future of the pharmaceutical industry, including development of drugs that will work optimally only in subsets of patients with a given disease. To identify responders, molecular diagnostic testing will need to become standard medical practice. One anticipated advantage of genotype-tailored medications is that clinical testing could be limited to those with the appropriate genotype, greatly reducing the sample sizes required to show efficacy. However, sample size reductions will increase the chance that potential for serious idiosyncratic toxicity, such as irreversible liver injury, will go unrecognized during clinical development. There is, therefore, increasing urgency to understand the molecular basis for drug induced liver injury, particularly irreversible idiosyncratic injury.

The number of genes potentially involved in idiosyncratic severe liver injury due to drugs is very large and involve many pathways. One approach taken to identify these genes has been to collect genomic DNA from patients experiencing serum alanine aminotransferase (ALT) elevations during clinical trials. The DNA is then screened for known mutations in potentially relevant genes, or subjected to "shot gun" screening for single nucleotide polymorphisms (SNPs). The mutation frequencies found in the patients experiencing ALT elevation are then compared to the corresponding frequencies found in patients who did not manifest ALT elevations. This line of research should allow development of molecular diagnostic tests that could be used to exclude from treatment most patients susceptible to ALT elevations. This practice would obviate the need for routine ALT monitoring of all treated patients and, based on current thinking, would be expected to generally reduce the incidence of severe idiosyncratic liver injury. However, the insight obtained into the basis for severe idiosyncratic liver injury will be limited because only a very small subset of patients manifesting ALT elevations generally go on to develop progressive liver injury, even with continued administration of the drug. This subset can generally not be identified in clinical trials since treatment is usually promptly discontinued in patients experiencing ALT elevations. There is now a pressing need for development of a bank of tissue and genomic DNA obtained from patients who have experienced well-documented severe adverse reactions to specific medications. Such a bank would serve as a critical resource for all researchers in this area.

Learning Objectives:

• The number of genes potentially involved in idiosyncratic severe liver reactions to drugs is very large and involve many pathways.
• Current efforts to associate genetic mutations with ALT elevations observed in clinical trials will probably provide limited insight in the mechanisms underlying idiosyncratic liver injury.
• There is an urgent need to establish a bank of tissue and genomic DNA obtained from patients who have experienced severe liver injury due to drugs.

Biographical Sketch
Paul B. Watkins

Paul B. Watkins is the Verne S. Caviness Distinguished Professor of Medicine and Professor of Pharmacotherapy at the University of North Carolina. He also directs the General Clinical Research Center there. His research has focused on the molecular basis for interindividual differences in drug disposition, particularly as involves cytochromes P450 and drug transporters present in human liver and intestine. Dr. Watkins is also a hepatologist and has consulted widely in both industry and government on issues involving drug-induced liver disease. He is the recipient of the 1998 Therapeutic Frontiers Award from the American College of Clinical Pharmacy and he is a recent recipient of a MERIT award from the National Institutes of Health.

Back to Top     Back to Livertox main

PDF requires the free Adobe Acrobat Reader

Date updated: April 8, 2008

CDER Home Page | CDER Site Info | Contact CDER | What's New @ CDER
FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA | Privacy | Accessibility | HHS Home Page

FDA/Center for Drug Evaluation and Research