Tumor Profiling Assays - American Statistical Association
Transcript of Tumor Profiling Assays - American Statistical Association
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Zhiheng Xu, Ph.D.Mathematical StatisticianFDA/CDRH
ASA Biopharmaceutical Section Regulatory-Industry Statistical Workshop 9/23/2020 11:30am-12:45pm
Tumor Profiling Assays
A Representative Approach in Analytical Accuracy Study
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Disclaimer Statement
The views expressed during this presentation are those of the presenter and do not necessarily reflect finalized policy or position of the US FDA.
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Outline
Introduction Tumor Profiling Assays
Validation Studies Analytical Accuracy
Sampling Method Representative Approach
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Cancer Clinical Trials
Tumor Profiling
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What is tumor profiling assay?“an in vitro diagnostic test that can identify a higher number of genetic mutations (biomarkers) that may be found in various cancers…” *
* https://www.fda.gov/news-events/press-announcements/fda-unveils-streamlined-path-authorization-tumor-profiling-tests-alongside-its-latest-product-action
468 genes324 genes
468 genes
2017
505 genes
2019
https://www.fda.gov/medical-devices/vitro-diagnostics/nucleic-acid-based-tests 5
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Three-Tiered Approach for Reporting Biomarkers in Tumor Profiling NGS Tests
CDRH’s Approach to Tumor Profiling NGS Tests
FDA Fact Sheet
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https://www.fda.gov/media/109050/download
Level 1
Level 2
Level 3
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Validation Studies
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Do they agree?
• Clinical Validation• CDx
• Analytical Validation• LoD• Precision• Interference• Accuracy• ….
Analytical Accuracy Study
New AssayOrthogonal
MethodVs.
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• Protocol• SAP• Sample Size
Study Design
• Clinical Specimens
• Contrived
Samples
• Primary Analysis (PPA/NPA)
• Sensitivity Analysis
Data Analysis
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Analytical Accuracy
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Sample Size
When compared to orthogonal method, how many specimens are needed?
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N=?
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Genes
• Multi-genes
Exons
• Targeted gene panel
Variants
• SNV, Indels, CNV, Fusion
Tumor types
• Solid tumor
Exon intron
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That’s a lot!
# mutations:
500 genes x 10 exons/gene x 300 base pairs per exon
= 1,500,000
A hypothetical example
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Statistical Challenge
How many clinical specimens are needed to validate so many mutations?
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Survey sampling Techniques
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Simple Random SamplingStratified SamplingCluster SamplingMulti-stage Sampling
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Simple Random Sampling
1% x 1,500,000 = 15,000 Still a lot!
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1% Rule
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Law of Large Population (LLP)*
15* Xiao-li, Meng. Statistical Paradise and Paradoxes in Big Data. The Annals of Applied Statistics. 2018: 12(2), 685-726.
n = 1𝜌𝜌2
× 𝑓𝑓1−𝑓𝑓
“A simple random draw of 400 subjects can achieve the same effect as a test of 10,000 out of 1 million subjects (f=1%) assuming the positivity rate is 0.5% (ρ=0.005)… “
MS𝐸𝐸(�̅�𝐺𝑛𝑛) = 𝐸𝐸 �̅�𝐺𝑛𝑛 − �̅�𝐺𝑁𝑁 2
Mean-squared Error (MSE)
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Will a random sample of 400 specimens be adequate for the accuracy study for tumor profiling assays?
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Three-Tiered Approach for Reporting Biomarkers in Tumor Profiling NGS Tests
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Representative approach
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Gene
• Representative• Level 2 genes
Variant
• SNV and indels• CNV and fusion
Tumor type
• Major tumors• Challenging
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How many clinical specimens are needed to validate tumor profiling assays?
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N=?
VariantsGenes Tumor Types
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Good clinical input
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Sound statistical explanation
Consistent regulatory consideration
Representative Approach
Conclusion
A Least Burdensome Approach
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Acknowledgement
I would like to thank Drs. Bipasa Biswas, Changhong Song and other colleagues at FDA/CDRH for their feedback.
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Thank you!
Questions?