|
AASLD-FDA-NIH-PhRMA*- Hepatotoxicity Special Interest Group Meeting
2008 Presentations
A simple graphic tool for assessing serious liver injury cases in a clinical trial – eDISH [PDF] 
K. Gelperin, M.D.; T. Guo, Ph.D.; J. Senior, M.D.
Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA)
Abstract Many drugs can cause idiosyncratic serious liver injury in some patients.1 2 3 The problem for CDER reviewers of clinical trial data on drugs under consideration for new drug approval is to decide whether the incidence of clinically important liver injury is serious enough to warrant concern, and whether it is meaningfully greater than that from alternative or no treatments.
Concurrence of both liver injury (raised serum alanine aminotransferase [ALT] activity) and reduced liver function (increased total serum bilirubin [TBL] concentration) in a person is a both sensitive and highly specific test for potentially serious liver injury (“Hy’s Law”)4 that may threaten the patient’s life if drug exposure is continued. To translate that idea into a useful tool for reviewers, we have developed and deployed a program using SAS/IntrNet® which we’ve named “eDISH” (Drug Induced Serious Hepatotoxicity). Using eDISH we have generated simple graphic displays of the peak ALT and TBL values observed for each person at any time during a given study, plotting each individual as a single dot on an x-y graph that shows subjects randomized to study drug with one symbol (∆) and those in the control group with another (O). This graphic tool, which is currently accessible on FDA’s intranet, allows reviewers to see at a glance if the incidence of raised ALT or TBL or both is greater on study drug compared to control group(s). Further, by drilling down on selected points representing patients of special interest on the x-y graph, the complete set of data (ALT and TBL, plus other measures) over the course of the whole study for that individual subject can be displayed, for diagnostic evaluation and possible insights.
Application of this new software tool for CDER reviewers for inspection and analysis of clinical study data may speed and improve review for appreciation of study drug-induced serious hepatotoxicity, and may be of assistance to sponsors in analyses of their clinical data as well.
References
- Watkins PB. Idiosyncratic liver injury: challenges and approaches. Toxicol Pathol 2005;33:1–5. [PMID 15805049]
- Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol, 2005; 33:155–164. [PMID 15805067]
- Ulrich R. Idiosyncratic toxicity: a convergence of risk factors. Annu Rev Med 2007:58:17-34. [PMID 16958561]
- Reuben A. Hy's law. Hepatology 2004 Feb; 39(2):574-578. [PMID 14768020]
Biographies
Back to Top
Back to Presentations
PDF requires the free
Adobe Acrobat Reader
Date created: April 29, 2008 |
