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AASLD-FDA-NIH-PhRMA*- Hepatotoxicity Special Interest Group Meeting
2008 Presentations
Idiosyncratic hepatotoxicity is one of the most serious forms of clinical toxicity [PDF] 
Robert W. Tipping, MS, Merck
Abstract:
The quest for a reliable predictor of drug-induced hepatotoxicity
encountered with drugs.
Because drug-induced liver injury (DILI) is a rare event, the pre-approval evaluation of a drug often relies on various biomarkers alone and in combination to assess the potential for acute hepatocellular injury. Elevated serum alanine (ALT) and aspartate (AST) aminotransferase activities are often used as the criteria to identify potential for toxicity, yet it must be appreciated that abnormal liver chemistries can arise from many causes unrelated to drug. It has been postulated that elevated transaminase activity concurrent with elevated bilirubin levels may be a more reliable predictor of DILI than transaminases alone, however, this has yet to be evaluated in large databases. There is clearly a need for a better and more complete understanding of both the background rates of elevated biomarkers and the measurement characteristics of these biomarkers in various disease populations. Using data from 3248 apparently healthy study participants randomized to placebo and followed serially for 5 years in a double-blind clinical trial, this session will present information on the:
- incidence of maximum elevations of various biomarkers relative the upper limit of normal (ULN).
- specificity, sensitivity, and predictive value of various biomarkers, alone and in combination, for predicting serious liver injury.
- measurement characteristics including intra- and inter-subject variability and reliability of various biomarkers.
- strategies and tactics for improving reliability.
Biography
Robert W. Tipping
Mr. Tipping has an MS degree in statistics and has been working as a Biostatistician in the pharmaceutical industry for 23 years. His experience spans seven different therapeutic drug classes and his responsibilities include statistical activities (protocol design, data review, analysis and reporting of results) pertaining to these projects. Mr. Tipping has been closely involved with the submission of several NDAs and he has extensive experience interacting with the FDA and various European Regulatory Agencies. He has played an active role in five FDA Advisory Committee Meetings. In addition, Mr. Tipping has collaborated with his clinical colleagues on several publications in the medical literature and has assisted outside legal counsel in litigation regarding claims made by or against approved products.
Mr. Tipping is an active member of the PhRMA/FDA Hepatotoxicity Steering Committee. He has worked in a unique collaboration with Dr. John Senior at the FDA examining incidence of transaminase elevations in large placebo databases.
Finally, Mr. Tipping and his team actively work to identify and develop new methodologies appropriate for the design and analysis clinical studies. He has established and maintains consulting arrangements with statistical experts at several universities including Harvard, University of North Carolina, and Johns Hopkins. He has made several presentations at professional statistical meetings.
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Date created: April 29, 2008 |
