AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: The critical path to new medical products
Yvonne P. Dragan, PhD
Director, Division of Systems Toxicology
National Center for Toxicology Research, Food and Drug Administration
The critical path to new medical products [PDF]
Hepatotoxicity is the leading cause of withdrawal of drugs from clinical development. Certain drugs have intrinsic characteristics that can result in hepatotoxicity, while some individuals are more sensitive to the adverse hepatic actions of other drugs. The window in which FDA can intervene to obtain information on the safety of an agent is during the actual execution of the clinical trial pre-marketing prior to approval. Despite the safe harbor principle, drug companies are reluctant to perform and provide OMICs data. Yet a sensitive mechanism is necessary for exclusion from further development of agents that will need to be removed post-marketing due to liver toxicity. Alternatively, if methods could be developed to determine which individuals should not be given specific drugs under selected conditions, then useful therapeutics could be used in subpopulations which respond favorably to their efficacy, while limiting exposure of individuals susceptible to their hepatotoxic potential. Since the OMIC technologies are quite sensitive to changes in the physiology of the individual, gene expression, protein expression, and metabolite profiles provide a clinically useful snapshot of the status of the individual at the time of measurement. Although sampling is restricted to available biofluids, blood and urine provide convenient “tissues” for analysis of the health and safety of an individual. White blood cells provide DNA for polymorphism analysis and RNA for gene expression analysis, additionally serum and urine provide the samples needed for global hepatotoxicity biomarker development and application. When a compound provides a hepatotoxicity signal during a phase 2 clinical trial, these patients provide the source of the biofluids required for a matched case control study for biomarker development. The developed biomarkers can then be used in a predictive manner in any subsequent clinical trials. Thus, the effects of therapeutic agents during a clinical trial, including their toxicity, can be detected in biofluids with OMIC technologies.
Dr Yvonne Dragan received her Ph.D. in Pharmacology and Toxicology from the Medical College of Virginia in 1988. She performed postdoctoral work in the Department of Oncology at the University of Wisconsin in Madison at the McArdle Laboratory for Cancer Research followed by several research faculty appointments from 1988 until 1998. She was a member of the School of Public Health faculty at the Ohio State University from 1998-2001. Dr. Dragan is currently the Director of the Division of Systems Toxicology at the FDA’s National Center for Toxicological Research in Jefferson, Arkansas. She has worked at the NCTR since 2002 as the Director of the Program in Hepatotoxicity and is an adjunct Associate Professor in Pharmacology and Toxicology at the University of Arkansas for Medical Sciences. She has been an active member of the Society of Toxicology (SOT) since 1988. Dr. Dragan has served as President of the Ohio Valley Regional Chapter (2001), Member (1999-2001) and Chair of the Continuing Education Committee (2001), and President of the Carcinogenesis Specialty Section (2001) of the Society of Toxicology. She is currently an elected member of the SOT Council with Liaison roles to the Education and Continuing Education Committee. She additionally holds memberships in the American Association for Cancer Research, Society of Toxicologic Pathology, American Society for Pharmacology and Experimental Therapeutics and the American Association for the Study of Liver Disease. Dr Dragan has over 70 peer reviewed papers and more than a dozen book chapters. Dr Dragan is a member of the Interdisciplinary Pharmacogenomics Review Group and is an active member of the Voluntary Genomics Data Submissions Review Group at FDA.