® BACKGROUND
® OBJECTIVES
® ACCOMPLISHMENTS
® FUTURE ACTIVITIES
® ANTICIPATED IMPACT
® PROJECT COMMITTEE PARTICIPANTS
® LEADERSHIP AND INFORMATION
MISSION
The mission of the HESI Biomarkers Technical Committee is to advance the scientific basis for the development and application of biomarkers of target organ toxicity; to develop a systematic approach for the evaluation of biomarkers that bridge from the pre-clinical to clinical stages of drug development; and to provide a scientific forum for building consensus regarding how to apply biomarkers of toxicity in risk assessment.
Most biomarkers used for pre-clinical and clinical evaluations have been available since the 1950s. While these markers have stood the test of time, there has been little progress in the development of new, more sensitive indicators of cellular and tissue damage over the past 50 years. Furthermore, there exists a dearth of biomarkers that bridge from pre-clinical testing methodologies to clinical evaluations.
The advent of new “-omic” technologies (genomics, proteomics, and metabonomics) promises to provide immense opportunity for the discovery and development of new markers of cellular and tissue integrity. Such biomarkers should be easily measurable at low concentrations in accessible tissues such as blood and urine. In addition, they should be specific and sensitive indicators of target organ toxicity.
With the introduction of these new technologies, interest in developing new biomarkers for the prediction of toxicity has expanded rapidly. The U.S. Food and Drug Administration has established a new initiative to improve the use of biomarkers for the identification of drug-related organopathies. In addition, a full scientific program was dedicated to biomarkers at the 2002 Annual HESI meeting.
The membership of the Health and Environmental Sciences Institute identified this challenging new area as a top emerging issue in 2002 and established the Development and Application of Biomarkers of Toxicity Technical Committee to develop a program of activities to address some of these issues. The committee has established an international collaborative research program to identify, develop, and evaluate biomarkers of toxicity for their utility in preclinical animal studies.
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The objectives of the Biomarkers Technical Committee are to:
n Engage in a broad-based, multinational collaborative research program to advance the development and application of biomarkers of target organ toxicity;
n Identify accessible biomarkers with the potential to bridge from the pre-clinical to the clinical stages of drug development;
n Evaluate the potential utility of newly identified markers of tissue injury for preclinical safety studies;
n Build consensus regarding how to apply newly identified biomarkers of toxicity in risk assessment; and
n Provide an ongoing scientific forum to facilitate discussion of the evolving state of the science related to biomarkers and proteomic technologies.
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n The Development and Application of Biomarkers of Toxicity Technical Committee held its first committee meeting in November 2002, in Washington, DC. Based on the outcome of this meeting, the Biomarkers Technical Committee set forth on a collaborative research program aimed at identifying, evaluating, and validating accessible biomarkers for the use in screening, preclinical, clinical, and post-market surveillance applications.
n In April 2003, the Biomarkers Technical Committee solicited biomarker candidate nominations from its membership and abroad, for assay development and evaluation by participating laboratories. In July 2003, three biomarkers were selected. These are:
· Biomarkers of Nephrotoxicity
· Serum Cardiac Troponins
· Inhibin B as a Biomarker of Testicular Toxicity
n Three expert Working Groups were formed in order to address each of the biomarker categories separately. The Working Groups are responsible for assay development and evaluation of the selected biomarkers.
n During 2004, the Working Groups identified the specific markers on which their group will focus and the assays that will be used to evaluate those markers.
n As of June 2007, the working groups have accomplished the following:
o Troponins – Nine commercially available troponin assays were evaluated for their utility in assessing cardiotoxicity in rats, dog, and monkey. Some biological validation studies in the rat have also been performed. Manuscripts describing both the biological and technical validation studies are under development and anticipated to be submitted to peer-reviewed literature in third quarter 2007.
o Nephrotoxicity – In vivo rodent studies and biomarker evaluation has been conducted using region-specific kidney biomarker (including collection and biomarker analysis of serum and urine samples). Biomarker assay development for clusterin, GST, and RPA was conducted as part of the initiative. Data analysis is scheduled for early 2007 and manuscript development is anticipated by mid-2007. The data will also be submitted to the FDA as part of the Agency’s draft process for biomarker qualification.
o Inhibin B - Assay validation studies to determine the sensitivity, linearity, and reproducibility of a commercially available Inhibin B ELISA assay were conducted. The assay was determined to be of limited value for use in rodents. The working group has since discontinued their activities.
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Expert Working Groups will continue to meet by teleconference and in person during 2007. The Committee anticipates publication of multiple manuscripts by early 2008 and anticipates ongoing interactions with FDA’s Biomarker Qualification Review Team to discuss the data generated by HESI.
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This project provides an important opportunity to develop a broad-based, multinational collaborative program with participation across government, industry, and academia, pooling both financial and intellectual resources. The development and application of bridging biomarkers will allow for better linkage between the results of animals studies done at the pre-clinical stage with human outcomes observed during clinical evaluation. Several innovative biomarkers of target organ toxicity are being utilized in clinical medicine; the potential utility of these biomarkers needs to be confirmed for pre-clinical safety assessments. In addition, the use of such biomarkers will allow integrated mechanistic and hypothesis-building studies done in the laboratory to be confirmed in humans.
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Public Participation
European Centre for the Validation of Alternative
Methods (ECVAM)
Interagency Coordinating Committee for the
Validation of Alternative Methods (ICCVAM)
National Center for Toxicological Research
National Institutes of Health
U.S. Environmental Protection Agency
U.S. Food and Drug Administration
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Member Participation
Abbott Laboratories
Allergen
Amgen, Inc.
AstraZeneca Pharmaceuticals
Bayer Healthcare Pharmaceuticals.
Biogen Idec MA, Inc.
Boehringer Ingelheim GmbH
Bristol-Myers Squibb Company
Eli Lilly and Company
GlaxoSmithKline
Hoffmann-La Roche, Inc.
Johnson & Johnson Pharmaceuticals
Merck & Co., Inc.
Pfizer, Inc.
Purdue Pharma LP
sanofi-aventis
Schering-Plough Research Institutute
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Chair................................................... Dr. Jack Dean
Vice-chair.................................. Dr. Denise Bounous
HESI Staff...................................... Ms. Syril D. Pettit
Ms. Cyndi Nobles
For more information, please contact: Ms. Syril D. Pettit at 202-659-3306 or spettit@hesiglobal.org.
Click here to download the English Biomarkers of Toxicity Committee fact sheet.