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U.S. Department of Health and Human Services

About FDA

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Division of Applied Pharmacology Research Programs

Federal Research Center
Life Sciences Building 64, HFD-910
10903 New Hampshire Avenue
Silver Spring, MD 20993
Phone: (301) 796-0078 Fax: (301) 796-9818

Thomas J. Colatsky, Ph. D., Director


 Biomarkers of Drug-Induced Tissue Injury

PROJECT 1: BIOMARKERS OF MYOCARDIAL DAMAGE

Principal Investigator:  Gene Herman

The models used in this study should define the degree to which troponin T, troponin I, or other newly discovered biomarkers can serve as early indicators for detecting and understanding myocardial damage. It is anticipated that these data will promote general drug development studies to incorporate in IND/NDA information submitted to the Agency, as part of the process to define an agent's safety profile. It is anticipated that the information regarding cardiac biomarkers derived from these studies will benefit patients undergoing clinical trials with agents whose safety profiles are not fully characterized, as well as patients undergoing lifesaving chemotherapy known to cause varying degrees of dose related insidious chronic cardiotoxicity. The identification and characterization of these improved sets of biomarkers will enhance both the pre- and post-marketing phases of drug development by providing clinicians with better tools to monitor for the early onset of adverse events associated with myocardial injury and thereby minimize post market risk.

PROJECT 2: BIOMARKERS TO PREDICT AND ASSESS THE PATHOGENESIS OF VASCULAR LESIONS INDUCED BY VASOACTIVE COMPOUNDS

Principal Investigator:  Jun Zhang

This investigation is expected to provide the Agency with tools to assess drug-induced vascular damage in both preclinical and clinical studies. As a result, it should be possible to better assess whether certain drug-induced vascular injuries found in animals predict accurately for clinical problems if the agents are allowed in human trials. Furthermore, it is anticipated that improved biomarkers such as these will enhance the effectiveness of post-marketing clinical monitoring of new drugs, by providing clinicians with better tools that can herald the early onset of adverse vascular events. With improved methods for identifying such risk, any long term sequelae that would be expected to follow from even subtle vascular lesions (stroke, atherogenic plaque formation, atherosclerosis, circulatory disturbances) should also be minimized.

PROJECT 3: BIOMARKERS OF LIVER TOXICITY

Principal Investigator:  Joseph Hanig

This investigation is expected to provide the Agency with improved animal models for liver toxicity that conform to disease manifestations and syndromes that may be seen in humans exposed to drugs which may compromise liver function. This will then provide an experimental platform for utilizing methods for early identification, improved characterization and quantification of adverse liver responses reproduced in animals by these drugs that are purported or suspected of being hepatotoxic to humans. The use of a "liver compromised" animal as a model may result in a very much higher incidence of liver toxicity at much lower doses of a potential hepatotoxic drug than might not ordinarily be seen in a young normal animal routinely used in toxicology studies. This does not of course preclude the use of transgenic animals possessing genetic modifications predisposing to a particular mechanism of liver toxicity. The use of such models will undoubtedly furnish ample opportunities to discover and evaluate biomarkers utilizing molecular technologies that involve proteomic, genomics and metabonomics. These biomarkers will be useful for differential diagnosis and routine incorporation into clinical trial and postmarketing strategies that reduce risk from drug-induced liver injury.

PROJECT 4: INCORPORATING GENE EXPRESSION BIOMARKERS INTO DRUG SAFETY EVALUATIONS

Principal Investigator:  Karol Thompson

The collaborative approach being taken in conjunction with initiatives underway within ILSI, with other initiatives within DAPR, and with the hepatotoxicity initiative within LCP provides a multidimensional approach to solving major regulatory safety priorities within CDER using a very powerful cutting edge technological innovation. By joining with ILSI and with the Agency's FDA Genomics and Proteomics Working Group, CDER laboratories are poised to contribute substantially to the evolution of guidance to review staff and to the regulated industry dealing with microarray gene expression data generation and interpretation. The formation, through ILSI, of a central multi-platform-compatible database capable of accepting public domain as well as user generated and sponsor submitted gene expression data within CDER will be an extremely powerful drug review resource. It is projected that applications of this technology to measurements of drug induced gene expression alterations in accessible cellular compartments will have a significant impact on both pre-approval and post-approval drug risk minimization by providing critical gene expression biomarkers predictive for morbidity.

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 Development of Models for Improved Evaluation of Human Safety

PROJECT 1: APPLICATIONS OF TRANSGENIC RODENT MODELS FOR IMPROVED EVALUATIONS OF PHARMACEUTICAL SAFETY

Principal Investigator:  Ronald Honchel

The results of this project will continue to contribute significantly to the enhancement of the safety assessment of pharmaceuticals, reduce ambiguities, shorten testing time, and reduce development costs. The project will provide greater mechanistic insight into the appropriate use of transgenic mice and into potential pitfalls associated with the improper conduct of studies with this model and with studies of certain other microinjected transgenic models. The project will also produce a regulatory guidance that will include new standards for transgenic animal models used for regulatory decision making. This is a critical regulatory need because the outcomes of animal carcinogenicity studies can have a major impact on product approvability, impact product labeling, and are the principal means of protecting the consumer against carcinogenic effects of drugs.

Skin cancer is a growing public health concern. Elucidation of improved models and endpoints to better evaluate contributing factors to skin cancer development is an important regulatory goal since a number of pharmaceuticals have been implicated to enhance the carcinogenic activity of solar light. This photocarcinogenicity research is expected to lead to development of more cost effective, faster, and more reliable and robust approaches for evaluating pharmaceutical photocarcinogenicity. The establishment of photocarcinogen related skin biomarkers will provide a rational approach to assessing interspecies extrapolations and rational criteria for further testing. As a result of the studies, the regulatory guidance that DAPR has assisted with will further evolve, FDA and industry evaluations of pharmaceutical photocarcinogenicity risk will improve. Our goal is to complete the ongoing photocarcinogenicity research initiatives by the end of 2001 and provide specific recommendations for continuation, pending outcome of results, for research at NCTR's Phototoxicity Testing Facility.

PROJECT 2: IMMUNOTOXICOLOGY INITIATIVES

Principal Investigator:  James L. Weaver

The information from immuno-depletion studies will provide reviewers and the scientific community with information to guide decisions concerning the potential health risks associated with drug induced depletion of critical circulating immune effector cells. The hypersensitivity research will provide information for reviewers and the scientific community to guide decisions concerning the utility of the modified LLNA to predict drug hypersensitivity of systemically administered drugs, a problem for which current preclinical assays may be of limited use. The "in silico" data base research data should provide reviewers and the scientific community with information to guide decisions concerning the potential of the software modules to predict drug hypersensitivity of systemically administered drugs, a problem for which current preclinical assays may be of limited use.

PROJECT 3: IMPROVED DETECTION AND EVALUATION OF ADVERSE DRUG-DRUG INTERACTIONS RESULTING FROM ALTERED FUNCTION OF CELLULAR TRANSPORT PROTEINS

Principal Investigator:   Vacant

The development of a rapid in vitro screening assay coupled with a simple transgenic reporter gene model will help in predicting and confirming clinical drug-drug interaction potential before approval or post approval but prior to becoming an issue leading to high human morbidity. The prospective outcome will be drug risk minimization at both pre- and post-approval time points.