Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics...
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Transcript of Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics...
![Page 1: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/1.jpg)
Effort 1 – Voluntary Genomics Data Submission (VGDS)
• FDA Guidance to Industry: Pharmacogenomics data submission (Draft
2003, final publication 2005)
– Invite industry to submit microarray data at the voluntary basis – A VGDS
mechanism
– Facilitate scientific progress in the area of pharmacogenomics.
Felix FruehNat. Biotechnol. 24(9):1105-1107, 2006
![Page 2: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/2.jpg)
Effort 2 - ArrayTrack
• Need a bioinformatics tool to accomplish:– Objective 1: Data repository
– Objective 2: Reproduce the sponsor’s results
– Objective 3: Conduct alternative analysis
• ArrayTrack – A FDA genomic tool
– AT version 1 (2001): Filter array; data management tool
– AT version 2 (2002): in-house microarray core facility
– AT version 2.2 (late 2003): Open to public
– AT version 3.1 (2004): VGDS
– AT version 3.2 (2005): MAQC
– AT version 4 (2006 – present): VGDS VXDS
![Page 3: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/3.jpg)
Microarray data
Proteomics data
Metabolomics data
Chemical data
Clinical and non-clinical
data
Public data
ArrayTrack
ArrayTrack: An Integrated Solution for omics research
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ProteinGeneMetabolite
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Study DB
TOOL
Study domain
MicroarrayDB
TOOL
Array domain
LIB
![Page 6: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/6.jpg)
Study Data Management and Analysis
• FDA eSubmission efforts
– Clinical data: Clinical Data Interchanges Standards
Consortium (CDISC)
– Non-clinical data: Standard for Exchange of Nonclinical Data
(SEND)
• Subject, treatment, Clinical pathology, histopathology, …
• Conforming to SDTM used for CDISC/SEND
• Microarray data management and analysis are processed
in Array Domain and the findings are available to correlate
with data in Study Domain
![Page 7: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/7.jpg)
Gene Expression vs Clinical PathologyC
linical p
athology d
ata
R=0.72
Gen
e
Clinical pathologyR
Each cell represents a gene-ClinChem correlation
The color represents the degree of correlation
CL
inC
hem
nam
e is hid
den
Gene name is hidden
Gene
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ProteinLib PathwayLib
ProteinTools
ProteomicsDB
MetaboliteTools
MetabonomicsDB
ToxicantLib
ArrayTrack/SysTox- From VGDS to VXDS
MicroarrayDB
GeneLib
GeneTools
![Page 9: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/9.jpg)
Storing Protein and Metabolite Lists
Examining common pathways and functions shard by expression data from genomics, proteomics and metabolomics
![Page 10: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/10.jpg)
ArrayTrack-Freely Available to Public
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Quarters
# of unique users access the web version of ArrayTrack
# of unique users access the locally installed version of ArrayTrack
Web-access Local installation
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Knowledge Base1. ToxicantLib 2. Liver Tox Knowledge Base (LTKB)3. Sex Determined Toxicity in Gene Expression4. …
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Effort 3 - Best Practice Document
• One of the VGDS objectives is to communicate with the private industry and gain experience on – How to exchange genomic data (data submission)
– How to analyze genomic data
– How to interpret genomic data
• Lessons Learned from VGDS has led to development of Best Practice Document (Led by Federico Goodsaid)– Recommendations for the Generation and Submission of Genomic Data
(Nov 2006) (http://www.fda.gov/cder/genomics/conceptpaper_20061107.pdf)
• ArrayTrack translates “Best Practice” into real practice
![Page 13: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/13.jpg)
• QC issue – How good is good enough?– Assessing the best achievable
technical performance of microarray platforms (QC metrics and thresholds)
• Analysis issue – Can we reach a consensus on analysis methods?– Assessing the advantages and
disadvantages of various data analysis methods
• Cross-platform issue – Do different platforms generate different results? – Assessing cross-platform consistency
Effort 4 - MicroArray Quality Control (MAQC) Project
The number of microarray-related publications indexedin MEDLINE has been increasing exponentially.
3823
2 8 15 51 190 621
1760
6815
(Estimated)11000
0
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12000
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005Year
To
tal
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mb
er
of
Pu
blic
ati
on
s
# of microarray-related publications indexed in PubMed has been increasing exponentially.
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Results from the MAQC Study Published in Nature Biotechnology
on Sept and Oct 2006
Nat. Biotechnol. 24(9) and 24(10s), 2006
Six research papers:
• MAQC Main Paper
• Validation of Microarray Results
• RNA Sample Titrations
• One-color vs. Two-color Microarrays
• External RNA Controls
• Rat Toxicogenomics ValidationPlus:
Editorial Nature BiotechnologyForeword Casciano DA and Woodcock JStanford Commentary Ji H and Davis RWFDA Commentary Frueh FWEPA Commentary Dix DJ et al.
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An Array of FDA Endeavors
ArrayTrack
MAQCVGDS
![Page 16: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/16.jpg)
Not One-Trick-Pony
Computational Toxicology
statistics
Bioinform
aticsC
hem
oinf
orm
atic
s
Regulation-Oriented Projects
Bioinformatics
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Decision Forest – A robust consensus approach
DF-Array: Classification using gene expression data
DF-SELDI: Classification using proteomics data
DF-SNPs: Classification using SNPs profiles
DF-Seq: Sequence-based classification of protein function
DF-SAR: Predictive tox using chemical structure
Tree 1 Tree 4Tree 3Tree 2
Input
Combining Results
Key points• Combining several
identical models produce no gain
• Combining several highly correct models that disagree as much as possible
![Page 18: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/18.jpg)
Not One Trick Pony
Computational Toxicology
statistics
Bioinform
aticsC
hem
oinf
orm
atic
s
Bioinformatics
Predictive Toxicology
![Page 19: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/19.jpg)
Endocrine Disruptors• An international issue
• Two laws passed by US congress require evaluation of
chemicals found in foods and water for endocrine
disruption.
• Similar regulation is also implemented in Europe and
Asia
• ~ 90,000 commercial chemicals needs to be screened
• EPA has identified ~58,000 eligible chemicals
• A minimum of 8,000 of the 58,000 chemicals are FDA-
regulated, including cosmetic ingredients, drug products
…
![Page 20: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/20.jpg)
Overview of NCTR’s Endocrine Disruptor Knowledge Base (EDKB)
• Begun 1996, prior to endocrine disruptor (ED) issues
• ED issues emerge - ACC and EPA collaboration & support results
• Program expands:– Separately assayed over >200 chemicals for estrogen (ER),
androgen (AR), serum protein (AFP and SHBG) receptor binding
– Web-based relational database with in vitro and in vivo assay data, bibliography and chemical structure search
– Exhaustive SAR/QSAR model development for both ER and AR binding, guided by data and crystal structures
![Page 21: Effort 1 – Voluntary Genomics Data Submission (VGDS) FDA Guidance to Industry: Pharmacogenomics data submission (Draft 2003, final publication 2005) –Invite.](https://reader035.fdocuments.in/reader035/viewer/2022062720/56649f175503460f94c2e93d/html5/thumbnails/21.jpg)
3
5
412
12345
124
317
3,183
6,186
30,012
PrioritizedGroups
No. ofChemicals
Priority Setting of 58,000 Chemicals
• Only ~3600 chemicals need to be tested
• ~6200 chemicals might be active with activity below 100,000-fold less than estradiol
• 30,000 chemicals are predicted to be inactive