NGS ONCOPANELS: FDA S PERSPECTIVE CBA Workshop: Biomarker and Application in Drug Development August 11, 2018 Rockville, MD You Li, Ph.D. Division of Molecular Genetics and Pathology Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) Office of In Vitro Diagnostics and Radiological Health (OIR) 1
Disclaimer The views expressed during this presentation are preliminary and do not necessarily reflect the final policy or position of the US FDA or the US government. 2
What is NGS Oncopanel? Overview Regulatory pathway for NGS Oncopanel Validation Strategy (MSK-IMPACT tumor profiling test case study) Summary and Resource 3
NGS Revolutionized Personalized Genomics & Medicine v NGS is the driving technology for precision medicine. v NGS assays have been widely adopted to clinical use. 4 4
www.genome.org 5
What is NGS Oncology Panel? A NGS based tumor test, which enables systematic interrogation of numerous biomarkers from a predefined cancer-related genes from a patient s tumor specimen. Hybrid-capture vs. Amplicon-based; Tumor only vs. Tumor/ matched normal; DNAseq vs. RNAseq Increasingly employed for various clinical use. 6 6
NGS Oncopanel Review Paradigm CDx vs. Tumor Profiling CDx Level-1 Level-2 Level-3 Cancer mutations with evidence of clinical significance Cancer mutations with potential clinical significance Class II path for NGS tumor profiling tests Level-2 biomarkers: Clinical validity established in professional guidelines, but NOT demonstrated with the test. Level-3 biomarkers: Clinical validity not demonstrated either in professional guidelines or with the test, but suggestive based on clinical/biological evidence. 7
Oncomine Dx Target Test lung cancer panel (June 22, 2017) Qualitative in vitro diagnostic test that uses targeted high throughput, parallel-sequencing technology to detect single nucleotide variants (SNVs) and deletions in 23 genes from DNA and fusions in ROS1 from RNA isolated from formalin- fixed, paraffinembedded (FFPE) tumor tissue samples from patients with nonsmall cell lung cancer (NSCLC) using the Ion PGM Dx System. Gene Variant BRAF BRAF V600E ROS1 ROS1 fusions L858R, Exon 19deletions EGFR Targeted therapy TAFINLAR (dabrafenib) in combination with MEKINIST (trametinib) XALKORI (crizotinib) IRESSA (gefitinib) 8
FoundationOne CDx (F1CDx) (November 30, 2017) Broad-panel follow-on companion diagnostic test for 5 tumor indications Genomic profiling of 324 genes, MSI & TMB in all solid tumors Breakthrough Parallel Review www.fda.gov 9
F1CDx Approved CDx Indications 10
MSK-IMPACT (Nov 15, 2017) De novo authorization of MSK-IMPACT assay established a new class II regulatory pathway for NGS-based tumor profiling tests. This designation makes these tests eligible for the 510(k) clearance process, either by applying to the FDA directly or through an accredited third-party reviewer like NYSDOH. 11
MSK-IMPACT Intended Use The MSK-IMPACT assay is a qualitative in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed paraffin-embedded tumor tissue matched with normal specimens from patients with solid malignant neoplasms to detect tumor gene alterations in a broad multi gene panel. The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center. 12
Device Description Assay Configuration: NGS-based hybrid capture oncology panel (468 genes, 6000+ exons) Tumor/matched normal paired sequencing (minimize errors and detect true somatic mutations) Reportable Range: SNVs/MNVs, small indels from 468 genes (73 exons excluded), MSI-status QC and Optimization: External positive/negative controls included for each run Extensive QC measures for each assay step Quality metrics thresholds (at run, sample, exon and variant level) optimized to improve assay performance Variant Reporting: Use MSK curated public database OncoKB for clinical interpretation. Report variants under two categories (based on levels of clinical evidence) 13
Analytical Performance Accuracy (concordance to orthogonal testing) Limit of Detection (detection sensitivity) Precision (repeatability and reproducibility) Real-World Performance: historical data across different tumor types to support pan-tumor claim. (MSK Nat Medicine manuscript, April 2017) *Additional analytical performance studies to support CDx claim: interference, stability, robustness, etc. 14
Analytical Accuracy Tested 433 FFPE samples across different cancer types. Samples cover clinically significant ( actionable ) mutations from 20 genes (48 exons). 267 unique variants assessed cover different variant types (SNV, MNV, insertions, deletions). Accuracy were demonstrated for both positive and negative (wildtype) calls. 15
LoD and Precision LoD Establishment: Dilution study to estimate LoD for each variant type. LoD Confirmation: Precision using clinical specimens at the LoD level. Precision (sample selection): Clinical FFPE specimens from different tumor types, selected based on presence of clinically significant mutations across different variant types. Precision (panel-wide analysis) - In addition to known mutations, precision analysis was performed for all incidental somatic mutations (82 total) identified from replicate testing. - Precision analysis not only on variant call agreement, but also on key quality metrics (coverage, VAF, normalized coverage etc.) 16
MSI Validation MSI status determined by tumor/matched normal comparison of 1000+ microsatellite loci using MSIsensor algorithm. MSIsensor score (% unstable loci) >=10 is used to define MSI-H. (Different MSI-H definition from clinical practice guidelines, clearly stated in the test report) Cutoff established using 201 colorectal and endometrial carcinoma (CRC/EC) cases (training dataset). Independently validated by concordance to PCR-MSI or IHC-dMMR results from both CRC/EC and Non-CRC/ Non-EC cohorts. MSI LoD and precision were assessed. Supplemental data from MSK s recent publication (>12,000 patient cohort) to support pan-tumor MSI validation. 17
Test Report Use OncoKB database for clinical evidence curation. Report variants under two categories, based on cancer-specific levels of clinical evidence. - Cancer Mutations with Evidence of Clinical Significance - Cancer Mutations of Potential Clinical Significance Transparent test limitation statements. 18
NGS Oncopanels: Tumor Profiling vs. CDx Difference between NGS CDx and Tumor Profiling Assays CDx Tumor Profiling IU Conclusive/Prescriptive use for specific therapeutics? Yes (IU specifies CDx biomarker and approved drug indications) No Clinical Clinical validity (for selecting treatment) established using the test? Yes (clinical efficacy or clinical concordance) No Analytical Variant level validation data provided? Yes (for each CDx biomarker) Regulatory Currently eligible for 510(k) clearance? Pathway No (PMA) Not always Yes 19
Conclusion NGS oncopanel allows to detect the genomic landscape (somatic mutations) from a tumor specimen. The tumor genomic profiling has become critical for treatment and management of cancer patients. Two regulatory pathways available for NGS oncopanels. - CDx vs. Tumor profiling Analytical and clinical validation are needed to demonstrate safe & effective use of the test. 20
Resources CDRH Pre-Submission Program: https://www.fda.gov/downloads/medicaldevices/ deviceregulationandguidance/guidancedocuments/ucm311176.pdf Questions? You.Li@fda.hhs.gov CDRH FACT SHEET - Tumor Profiling NGS Tests: https://www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/ InVitroDiagnostics/UCM584603.pdf MSK-IMPACT Decision summary: https://www.accessdata.fda.gov/cdrh_docs/reviews/den170058.pdf Oncomine Dx Target Test SSED: https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160045b.pdf F1CDx SSED: https://www.accessdata.fda.gov/cdrh_docs/pdf17/p170019b.pdf 21