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U.S. Department of Health and Human Services

About FDA

Develop Biomarkers of Toxicity and Disease

Description: Use omics, imaging and bioinformatics to improve the detection and prevention of toxicity (induced by drugs, dietary supplements, and chemicals) and disease. For example, hepatotoxicity can be induced by drugs and chemicals and can lead to liver failure. This is a major reason for drug withdrawal with approximately 1% of hospitalized patients developing drug-induced liver injury that can be caused by ~1000 marketed drugs.

b. Develop a LTKB Containing Publicly Available Information on Drugs that Cause Hepatotoxicity and Perform Experiments to Supplement this Database.

Definition: Organ toxicity is a major reason for FDA-related product withdrawal. In particular, hepatotoxicity (liver injury) is a major reason for drug withdrawal with approximately 1% of hospitalized patients developing drug-induced liver injury. New imaging approaches can be used, for example, in aiding disease diagnosis. This effort will help to identify new biomarkers to aid in the prevention and/or early assessment of toxicity and disease.

Public Health Outcome: The data will be utilized and referenced by CDER when liver toxicity issues arise during the various stages of the regulatory review process.

Accomplishment: miRNAs are a newly discovered group of noncoding RNA and meet many of the ideal biomarker criteria of high specificity, sensitivity, and accuracy. The discovery of circulating miRNAs in the urine and blood has created a new approach for the discovery of noninvasive biomarkers of organ injury but there are still open questions regarding the utility of circulating miRNAs in reflecting organ injury and classifying that injury between various agents. A major finding of this study is that common urinary miRNA expression profile is able to distinguish the patterns of the responses to hepatotoxicant versus a nonhepatotoxicant and controls. Although a larger number of chemicals will need to be tested, the findings in these study suggest that urinary miRNA might be a more specific and consistent biomarker of chemical-induced liver injury than existing tests.

1. Hepatoxicity Studies

a. Identify new biomarkers of hepatotoxicity caused by drugs and chemicals that will be used during pre-clinical testing. It is likely this will require us to study a total of 20 compounds over a 3 year period to derive common biomarkers.

Milestone DescriptionMilestone DateMilestone StatusMilestone Completion Date

i. Complete the first range-finding study in rodents for biomarkers of hepatotoxicity

5/31/2010

Completed 5/31/2010

ii. Complete in vivo portion of two hepatotoxicity test articles (drug, chemical, etc.)

7/31/2010

Completed 6/30/2010

iii. Perform gene expression analysis and analyze biofluid samples from two in vivo hepatotoxicity studies by NMR-based and LC/MS -based metabolomics

12/31/2010

(7/15/2011)

Completed 7/8/2011

iv. Complete in-life studies for the first 7 compounds for the hepatotoxicity study

12/31/2011

Completed 12/31/2011

v. Complete the assessment of research findings of the hepatotoxicity studies

12/31/2013

Completed 1/1/2013

vi. Develop draft technical report, manuscript, and/or publication

1/1/2013

Completed 1/1/2013

vii. Complete the peer review (NCTR and other FDA researchers) of draft technical report, manuscript, and/or publication

1/1/2013

Completed 1/1/2013

viii. Obtain NCTR Center Director approval on the draft technical report, manuscript, and/or publication via the document tracking system

1/1/2013

Completed 1/1/2013

ix. Submit final technical report, manuscript, and/or publication to a scientific journal

1/1/2013

Completed 1/1/2013

b. Develop a LTKB Containing Publicly Available Information on Drugs that Cause Hepatotoxicity and Perform Experiments to Supplement this Database.

Accomplishment:Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials as well as being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key mechanisms and risk factors contributing to a decline in the drug development pipeline. However, classifying a drug for DILI potential to support such study is a challenge with no existing commonly adopted practices by the research community. We proposed a systematic and objective classification scheme of using FDA-approved labeling to assign each drug’s DILI potential focusing on drugs that have been marketed for 10 years or more. The analysis resulted in the creation of a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The annotation procedure is transparent and can be reproduced by others, and thus offers a method that can be adopted by the research community to consistently and constantly annotate the ever increasing number of drugs in the future to expand the list for drug discovery and biomarker development.

Milestone DescriptionMilestone DateMilestone StatusMilestone Completion Date

i. Develop a benchmark data set of FDA approved drugs for study of DILI, studying the laboratory measurements that signal the potential for DILI

6/30/2010

Completed 5/20/2010

ii. Complete drug classification of the benchmark data set for liver injury based on drug labels

6/30/2010

Completed 5/20/2010

iii. Complete assays using rodent primary hepatocytes for selected drugs from the benchmark data set

6/30/2010

Completed 5/20/2010

iv. Complete analysis of gene expression data using rodent primary hepatocytes for selected drugs from the benchmark data set

6/30/2010

Completed 5/20/2010

v. Perform bioinformatic data analysis on knowledge base

1/1/2011

Completed 1/1/2011

vi. Develop draft technical report, manuscript, and/or publication

1/15/2011

Completed 1/15/2011

vii. Complete the peer review (NCTR and other FDA researchers) of draft technical report, manuscript, and/or publication

1/30/2011

Completed 1/30/2011

viii. Obtain NCTR Center Director approval on the draft technical report, manuscript, and/or publication via the document tracking system

2/16/2011

Completed 2/16/2011

ix. Submit final manuscript on FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury to Drug Discovery Today

2/18/2011

Completed 2/18/2011

2. Characterization of Reference DNA for Genotype Biomarker Development

Accomplishment: The objective of the study presented here was to determinewhether Whole Genome amplified(WGA) samples may be a reliablealternative to native clinical specimens for assessing theperformance of a test under investigation. The conclusionsfrom this study provide scientific input that mayserve to support regulatory decisions in the ascertainmentof safety and effectiveness of diagnostic productsthat use whole genome amplified samples in clinicalstudies. This study may serve as a guide to the technicalqualification of WGA DNA for assessing the performanceof genotyping assays. To view this full report, please visit the following website: http://www.biomedcentral.com/content/pdf/1471-2164-13-217.pdf

Milestone DescriptionMilestone DateMilestone StatusMilestone Completion Date

a. Complete evaluation of high density genomic microarray (multiplex technology used in molecular biology and in medicine) to be used for characterization of reference standards for genotype assay development

7/31/2010

Completed 7/15/2010

b. Complete data gathering and analysis

2/28/2011

Completed 2/28/2011

c. Develop draft technical report, manuscript, and/or publication

8/31/2011

Completed 8/15/2011

d. Complete the peer review (NCTR and other FDA researchers) of draft technical report, manuscript, and/or publication

1/31/2012

Completed 1/10/2012

e. Obtain NCTR Center Director approval on the draft technical report, manuscript, and/or publication via the document tracking system

1/30/2012

Completed 1/18/2012

f. Submit final technical report, manuscript, and/or publication to a scientific journal

2/29/2012

Completed 1/20/2012

3. Development of Non-Clinical Drug-Induced Cardiotoxicity Biomarkers

Briefing Status: ON TRACK

Prior Briefing Status: DELAYED

Milestone DescriptionMilestone DateMilestone StatusMilestone Completion Date

a. Initiate main study for development of genomics biomarkers (refers to a molecule measured in the blood or other tissue whose concentration reflects the severity or presence of some disease state) of cardiotoxicity (condition in which there is damage to the heart muscle)

11/14/2011

Completed 11/14/2011

b. Complete initial treatments

6/7/2012

Completed 6/7/2012

c. Complete hematology and cardiac troponin measurements

10/31/2012

Completed 8/11/2012

d. Complete histopathology and analysis of tissues

10/31/2012

Completed 9/14/2012

e. Complete electron microscropy analysis of heart tissue

3/30/2012

Completed 5/13/2013

f. Complete gene expression analysis

1/31/2013

(3/31/2013)

Completed 5/22/2013

g. Complete metabolomic analysis

3/31/2013

(5/31/2013)

Completed 5/31/2013

h. Complete proteomic analysis

4/30/2013

(FY13 Q4)

(FY14 Q2)

Completed 2/28/2014

i. Complete data analysis

8/31/2013

(FY14 Q1)

(FY14 Q3)

(FY14 Q4)

Completed 7/1/2014

j. Complete assessment of research findings

12/31/2013

(12/31/2014)

On Track

k. Develop draft technical report, manuscript, and/or publication

4/30/2014

(4/30/2015)

Not Yet Started

l. Complete the peer review (NCTR and other FDA researchers) of draft technical report, manuscript, and/or publication

5/31/2014

(5/31/2015)

Not Yet Started

m. Obtain NCTR Center Director approval on the draft technical report, manuscript, and/or publication via the document tracking system

6/30/2014

(6/30/2015)

Not Yet Started

n. Submit final technical report, manuscript, and/or publication to a scientific journal

7/31/2014

(7/31/2015)

Not Yet Started

Footnotes

  • The dates in italics are modified milestone due dates that have been updated due to real-time delays. The milestone status reflects the current reporting quarter’s status. If a milestone is missed, the milestone will remain delayed until the milestone is completed.

Key Projects Legend

Milestone StatusDefinition
Not Yet StartedWork for specific milestone has not yet been started.
CompletedMilestone and/or overall project is completed.
On TrackMilestone - On track for completion by milestone deadline. Quarter status - Project is on track for completion based on overall milestone status.
On HoldMilestone - On hold, but deadline for completion has not passed. Quarter status - Project is on hold, based on overall milestone status.
DelayedMilestone - Delayed as it has not been completed and deadline has passed. Quarter status - Project is delayed based on overall milestone status.

Glossary

hepatotoxicity

chemical-driven liver toxicity

LTKB

Liver Toxicity Knowledge Base

biomarkers

A measurable endpoint that can be used as an indicator of a particular disease or some other physiological state of an organism

CDER

Center for Drug Evaluation and Research

range-finding study

study to determine the correct doses to use to get certain drug effects

in vivo

within a living organism

LC/MS

liquid chromatography/mass spectrometry

gene expression

ability to quantify the level at which a particular gene is expressed within a cell, tissue, or organism

DILI

Drug-induced liver injury

hepatocytes

cells of the main tissues of the liver

microarray

multiplex technology used in molecular biology and in medicine

genomics biomarkers

a molecule measured in the blood or other tissues whose concentration reflects the severity or presence of some diseased state

cardiotoxicity

condition in which there is damage to the heart muscle

Note: The data provided on this website is produced on an ongoing basis for performance management purposes and is subject to change due to updates of preliminary estimates, corrections, or other reasons. In addition, FDA may change the type or amount of data provided on this website at any time. Information marked as "Completed" may include measures and/or key projects for which activities are ongoing but no longer tracked as part of FDA-TRACK.