Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges.

Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)-go to ( http://www.aasld.org/dili/Pages/default.aspx ). Observations by Dr. Hyman J. Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion" with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x-y log-log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury (DILI) in clinical trials.

The Australia antigen and role of the late Philadelphia General Hospital in reducing post-transfusion hepatitis and sequelae.

Baruch Blumberg, who received the Nobel Prize for Physiology or Medicine for his discovery of the Australia antigen, died on April 5, 2011. Arguably, that discovery has been the most important advance in the field of Hepatology. It led to the virtual elimination of transfusion related hepatitis B in most parts of the world and was essential to the identification of hepatitis A, C, D and E viruses. Credit for this is due Dr. Blumberg and teams in Philadelphia and Tokyo. In lieu of an Associate Editor commentary, Drs. Senior, London, and Sutnick, who were members of that remarkable team, tell us their inspiring story.

Unintended hepatic adverse events associated with cancer chemotherapy.

Chemotherapy is meant to be toxic, but it is particularly aimed at the tumor cells. Collateral damage may occur to normal cells and tissues, especially if they are fairly rapidly regenerating, as is the case for bone marrow cells, intestinal epithelial cells, and liver cells after hepatic injury. The liver has a great capacity to resist injury, overcome it, and to regenerate, even after quite massive injury (resection of 50%-65%, for example). This capacity may make it susceptible to chemotherapeutic toxicity, and a struggle between injury and adaptation, leading to recovery and tolerance or to failure and death. If the chemotherapy is aimed just at delaying progression of the cancer for a few weeks or months, it may not be worth the risk of irreversible liver injury developing in that time. Close clinical observation and sound clinical judgment are required.

Using controlled clinical trials to learn more about acute drug-induced liver injury.

Drug-induced liver injury (DILI) is of major interest to hepatologists and clinicians in general, patients, government regulators, and the pharmaceutical industry. Understanding why this form of injury occurs only in certain individuals has major implications for the development and availability of drug therapies and in the prevention of these events. A single controlled clinical trial may be unlikely to show cases of such rare events, but in the aggregate, clinical trials offer a unique resource for learning more about individual susceptibility and developing truly predictive new biomarkers for DILI. We pose the question as to whether clinical trials could be modified or improved to provide data that would better answer some of the outstanding issues. At a recent (March 2008) public meeting, experts from academia, industry, and regulatory bodies discussed several major issues regarding liver safety in clinical trials including: what signals of liver injury should justify stopping administration of study drug or allowing it to continue; if deliberate rechallenge should be done and under what circumstances; whether patients with liver disease should be included in clinical trials; and what kinds of new biomarkers will be needed to answer these questions more clearly. Past clinical trials have not provided data to settle those issues, and reliance has defaulted to consensus of expert opinions. Modified and better clinical trials with standardized collection of data and biospecimens are probably the best source of new and potentially valuable information to supplant current rules based on consensus of expert opinions and to understand by what mechanisms and how to distinguish those individuals who are susceptible to severe DILI.

Drug hepatotoxicity from a regulatory perspective.

This article summarizes problems of drug-induced liver injury (DILI), as seen from the perspective of the Food and Drug Administration (FDA). After brief consideration of the scope of FDA activities and processes of new drug development and review for possible approval of products for clinical use and marketing, some of the perceived current problems in detection, confirmation, close observation, differential diagnosis, and follow-up of cases of possible DILI in controlled clinical trials are described. Readers are invited to consider possible solutions to the many problems of DILI, propose ways to support research in the field, and keep abreast of progress by visiting the web site at www.fda.gov/cder/livertox.

Recognizing drug-induced liver injury: current problems, possible solutions.

Currently there are three major problems in understanding drug-induced liver injury (DILI): (1) reliably establishing whether the liver disease was caused by the drug, or by another process; (2) determining the true incidence of and clinical risk factors for drug-induced hepatotoxicity; and(3) elaborating the mechanisms by which injury occurs to hepatocytes and other liver cells. We have focused here on the first two problems, as issues that may be amenable to actions in the near future, but the third may take substantially longer to work out. The first problem requires sufficient information for medical differential diagnosis. There are no pathognomonic indicators of DILI; even liver biopsy is not diagnostic. Making the correct attribution of causality requires analyzing the temporal relationship of drug exposure to illness and excluding all other possible causes. The second problem, determining incidence, cannot be done entirely adequately using currently available methods, whether by clinical trials, by spontaneous adverse event reports, or by retrospective epidemiologic studies. There is need for prospective safety studies to establish the true incidence of DILI caused by a drug, to identify risk factors for it, and to collect biologic materials for analytic studies toward better understanding mechanisms of DILI.

Troglitazone-induced liver failure: a case study.

BACKGROUND: Troglitazone was removed from the U.S. market because its use was associated with an increased risk of liver failure. We evaluated the clinical features of all cases reported to the Food and Drug Administration and estimated the duration and magnitude of the risk of liver failure associated with continued use of the drug. METHODS: Data from cases of liver failure associated with troglitazone use were abstracted and analyzed. The extent of troglitazone use was determined from national marketing data, and the duration of use was estimated with data from a large, multistate, health care company. Survival analysis was performed to estimate monthly incidence rates and the cumulative risk of liver failure. RESULTS: Ninety-four cases of liver failure (89 acute, 5 chronic) were reported. Of the acute cases, 58 (67%) were women and only 11 (13%) recovered without liver transplantation. Progression from normal hepatic functioning to irreversible liver injury occurred within 1 month in 19 patients who were indistinguishable clinically from the 70 patients who had an unknown time course to irreversibility, except for the post hoc observation that prior cholecystectomy was less common in those with rapid onset. The incidence of liver failure was elevated from the first through at least the 26th month of troglitazone use. Accounting for case underreporting, the number needed to harm from troglitazone use was between 600 to 1500 patients at 26 months. CONCLUSION: The progression to irreversible liver injury probably occurred within a 1-month interval in most patients, casting doubt on the value of monthly monitoring of serum aminotransferase levels as a means of preventing troglitazone-induced acute liver failure. The cumulative risk of hepatic failure increased with continued use.