(240 days)
The Omics Core assay is a qualitative in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed paraffinembedded tumor tissue matched with normal specimens with solid malignant neoplasms to detect tumor gene alterations in a broad multi gene panel. The test is intended to provide informations (point mutations (point mutations and deletions) and tumor mutational burden (TMB) 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. Omics Core is a single-site assay performed at NantHealth, Inc.
The NantHealth Omics Core assay is a custom targeted whole exome sequencing platform, utilizing solution-phase exon capture and sequencing, to report somatic alterations (point mutations, small insertions and deletions) in 468 genes and sequencing of 19,396 protein-coding genes (whole exome) to determine overall tumor mutation burden in tumor specimens. Genomic DNA is extracted from both a tumor and a patient-matched normal control sample. Sequence libraries are prepared through a series of enzymatic steps including shearing of double-stranded DNA, end repair, A-base addition, ligation of barcoded sequence adaptors, and low cycle PCR amplification. Single barcoded sequence libraries are captured using the biotinylated probes. Captured DNA fragments are then pooled and sequenced on an Illumina NovaSeq 6000 as paired-end reads. Sequence reads are then aligned to the reference human genome. Somatic alterations are identified in the tumor DNA by direct comparison to the matched normal DNA.
The Omics Core assay, a targeted next-generation sequencing test, was evaluated to determine its performance specifications, including precision, analytical sensitivity (Limit of Detection), and accuracy.
Here's a breakdown of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly list "acceptance criteria" as a separate column with specific numerical thresholds for each performance metric. Instead, it presents "Performance Specifications" as the expected or demonstrated performance of the device based on the studies. The reported device performance is then detailed under each characteristic.
Table: Omics Core Performance Specifications and Reported Device Performance
| Characteristic | Performance Specifications (Implicit Acceptance Criteria) | Reported Device Performance |
|---|---|---|
| Precision – Panel-Wide Reproducibility | Demonstrated with a high overall positive call rate for all variants analyzed. | The overall positive call rate for all variants analyzed across the 12 FFPE clinical samples and one commercial cell line was 2607/2650, or 98.4% (97.8-98.8% CI). |
| Precision – Per Specimen | Demonstrated with consistent repeatability and reproducibility. | Per specimen variant analysis for 12 clinical specimens and a commercial cell line demonstrated 100% concordance for 511 out of 530 unique mutations, or 96.4% (94.5%-97.8% CI). |
| Precision - Well Characterized Reference Material | Demonstrated consistent repeatability and reproducibility. | Analysis of the well-characterized sample demonstrated an overall positive call rate of 99.86% (99.75%-99.93% CI). |
| Precision - TMB | Demonstrated repeatable and reproducible TMB rates. | TMB precision analysis based on 12 clinical samples and 1 commercial cell line showed repeatable and reproducible TMB rates with a %CV <10% for all 13 samples. |
| Analytical Sensitivity - LoD (SNVs and Indels) | Ability to detect and reliably call each variant class at a specified mutant allele frequency with a high success rate. | The results from 13 FFPE clinical samples demonstrated the ability to detect and reliably call each variant class at the 5% mutant allele frequency with a success rate of ≥ 95%: SNVs at 96.7% (82.8%-99.9% CI), insertions at 100% (83.2%-100.0% CI), and deletions at 100.0% (78.2%-100.0% CI). |
| Analytical Sensitivity - LoD (TMB) | Demonstrated consistent repeatability and reproducibility for TMB rates for samples with relevant tumor purities. The assay will report TMB rates for clinical samples with tumor purities ≥ 20%. | Ten (10) FFPE tumor specimens (tumor purities 10-20%) demonstrated consistent repeatability and reproducibility, with all samples having a %CV < 10%. The Omics Core assay will evaluate and report TMB rates for clinical samples with tumor purities ≥ 20%. |
| Accuracy – SNVs and Indels (Comparison To Orthogonal Method) | Demonstrated high accuracy compared to an orthogonal method. | Omics Core successfully detected mutations in all 401 samples assessed, representing accuracy of 100% (99.08-100% CI). 2634 unique SNVs: PPA of 99.76% (99.50-99.90% CI), PPV of 99.93% (99.75-99.99% CI). 125 unique small insertions: PPA of 100% (97.20-100.00% CI), PPV of 100% (97.20-100.00% CI). 313 unique small deletions: PPA of 99.71% (98.38-99.99% CI), PPV of 99.71% (98.38-99.99% CI). |
| Accuracy – TMB (Comparison To Orthogonal Method) | Demonstrated high correlation between TMB rates generated by Omics Core and the orthogonal method. | A linear regression demonstrated high correlation between the two methods (R² = 0.9899). |
| Accuracy – Supplemental Method Comparisons Study for Wildtype Calls | Demonstrated high positive percentage agreement (PPA) and negative percentage agreement (NPA). | An analysis of 220 positive mutations and 12,612 wildtype calls demonstrated a PPA of 99.54% (97.48-99.99%) and NPA of 99.99% (99.99-100%). |
| Assay Cut-Off | Mutations below a certain percentage should not be reported for SNVs and Indels, and TMB calculation should have a minimum allele frequency. | Omics Core does not report mutations below 2% MAF. Mutations included in the calculation of TMB must be present at 5% allele frequency or greater. |
2. Sample Size Used for the Test Set and the Data Provenance:
- Precision Studies:
- Panel-Wide Reproducibility, Per Specimen, and TMB Precision: 12 FFPE clinical tumor samples and 1 commercial cell line.
- Well-Characterized Reference Material: 1 well-characterized sample.
- Analytical Sensitivity (LoD) Studies:
- SNVs and Indels: 13 FFPE clinical samples.
- TMB: 10 FFPE tumor specimens.
- Accuracy – Comparison to Orthogonal Method: 401 FFPE tumor samples.
- Accuracy – Supplemental Method Comparisons Study for Wildtype Calls: 220 positive mutations and 12,612 wildtype calls (implied as part of a larger dataset from clinical samples, likely from the accuracy comparison or other internal data).
Data Provenance: The document does not explicitly state the country of origin for the clinical samples. They are referred to as "FFPE clinical tumor samples" and "clinical specimens," suggesting they are real-world patient samples. The studies are described as "Performance Data" supporting the submission, implying they are retrospective analyses of collected samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts:
The document does not provide information on the number of experts or their qualifications specifically for establishing the ground truth for the test set.
For the predicate device (MSK-IMPACT), it mentions "Classification criteria were developed by MSK using the in-house OncoKB database. OncoKB undergoes periodic updates through the review of new information by a panel of experts."
For the subject device (Omics Core), it states: "Classification criteria were developed by NantHealth, Inc. NantHealth periodically updates Omics Core through the review of new information available."
However, this refers to the curation and classification of clinical evidence and mutations, not the establishment of ground truth for the analytical performance studies (precision, accuracy, LoD). The ground truth for the analytical studies appears to be based on:
- Orthogonal methods: For accuracy studies, results from an alternative, validated method are used for comparison.
- Known characteristics: For precision with a well-characterized reference material, the known variants in that material serve as ground truth.
- Internal consistency/comparison: For precision and LoD studies, the consistency and detection rates across replicates and dilutions are evaluated.
4. Adjudication Method for the Test Set:
The document does not describe an explicit adjudication method (e.g., 2+1, 3+1) for establishing ground truth for the test set. The nature of the studies (NGS analytical performance) relies on comparison to orthogonal methods or predefined characteristics of reference materials rather than expert review of images or clinical reports that might require such adjudication.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
No, an MRMC comparative effectiveness study was not done. This device is a diagnostic test (Next Generation Sequencing based tumor profiling test), not an imaging AI device that would typically involve human "readers" and MRMC studies. The "performance data" relate to the analytical validity of the test (how accurately it detects gene alterations and TMB), not its impact on human clinical decision-making or interpretation.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done:
The studies described primarily represent the standalone (algorithm and laboratory process only) performance of the Omics Core assay in detecting mutations and TMB. The "human-in-the-loop" aspect is implicitly through laboratory technicians performing the test and the medical director signing off on reports, but the reported performance metrics (precision, accuracy, LoD) assess the analytical capabilities of the system itself, independent of immediate human interpretive assistance on a case-by-case basis during the core analysis.
7. The Type of Ground Truth Used:
The ground truth used in the performance studies varied:
- Orthogonal Method: For accuracy studies of SNVs, indels, and TMB, the Omics Core results were compared to results obtained from an "orthogonal method." The specific method is not detailed, but it implies a different, validated technology used to confirm the presence and characteristics of mutations.
- Well-Characterized Reference Material: For precision, a "well-characterized sample" (likely with known variant profiles) was used.
- Clinical Samples: For precision and LoD, findings from "FFPE clinical tumor samples" and "commercial cell line" were used, with the "truth" being established through consistent detection across replicates or successful reliable calling at certain frequencies. This implies that for clinical samples, the ground truth was based on the consensus of repeated measurements or the expectation of what should be detected in those samples.
The document does not mention pathology re-read, expert consensus, or outcomes data as direct ground truth for these analytical performance studies.
8. The Sample Size for the Training Set:
The document does not specify the sample size for the training set. The provided performance data relates to verification and validation studies (test set), not the development or training of the assay's bioinformatics component. The "Omics Core software" is mentioned as part of the bioinformatics workflow, but details on how its underlying algorithms (for variant calling, TMB calculation) were trained are not provided.
9. How the Ground Truth for the Training Set Was Established:
As the document does not specify a training set sample size, it also does not explain how the ground truth for a training set was established. The process description focuses on the analytical performance of the finished device. It mentions "Assay optimization" and that "High analytical specificity is maintained by paired tumor/matched normal sequencing, and established during assay optimization," suggesting that internal data or processes were used during development, but without details on ground truth establishment for such activities.
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November 18. 2019
Image /page/0/Picture/1 description: The image shows the logos of the Department of Health and Human Services and the Food and Drug Administration (FDA). The Department of Health and Human Services logo is on the left, and the FDA logo is on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.
NantHealth, Inc. Aleece Nolasco Vice President, Regulatory Affairs 9920 Jefferson Blvd Culver City, CA 90232
Re: K190661
Trade/Device Name: Omics Core Regulation Number: 21 CFR 866.6080 Regulation Name: Next generation sequencing based tumor profiling test Regulatory Class: Class II Product Code: PZM Dated: September 26, 2019 Received: September 27, 2019
Dear Aleece Nolasco:
This letter corrects our substantially equivalent letter of November 9, 2019.
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You mav, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration. listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's
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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Donna M. Roscoe -S
Donna Roscoe, Ph.D. Chief. Molecular Genetics Branch Division of Molecular Genetics and Pathology OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K190661
Device Name
Omics Core
Indications for Use (Describe)
The Omics Core assay is a qualitative in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed paraffinembedded tumor tissue matched with normal specimens with solid malignant neoplasms to detect tumor gene alterations in a broad multi gene panel. The test is intended to provide informations (point mutations (point mutations and deletions) and tumor mutational burden (TMB) 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. Omics Core is a single-site assay performed at NantHealth, Inc.
| Type of Use (Select one or both, as applicable) | Prescription Use (Part 21 CFR 801 Subpart D) Over-The-Counter Use (21 CFR 801 Subpart C) | Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
|---|---|---|---|
| Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
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TABLE OF CONTENTS
| 510(K) SUMMARY | ||
|---|---|---|
| 1. | SUBMITTER | |
| 2. | DEVICE | |
| 3. | PREDICATE DEVICE | |
| 4. | DEVICE DESCRIPTION | |
| 4.1. | Test Principle | |
| 4.2. | Equipment, Supplies and Reagents | |
| 4.3. | Omics Core Workflow | |
| 4.4. | Indications For Use | |
| ર્ . | COMPARISON OF TECHNOLOGICAL CHARACTERISTICSWITH THE PREDICATE DEVICE | |
| 6. | PERFORMANCE DATA | |
| 7. | SUMMARY |
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LIST OF TABLES
| Table 1: Equipment Supplies, Reagents, and Software | 5 |
|---|---|
| Table 2: Comparison of Omics Core with Predicate Device | 9 |
| Table 3: Omics Core Performance Specifications | 11 |
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LIST OF FIGURES
| Figure 1: Laboratory Workflow |
|---|
| Figure 2: Bioinformatics Workflow |
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510(K) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
1. SUBMITTER
NantHealth, Inc. 9920 Jefferson Blvd. Culver City, CA 90232
Contact Person: Aleece Nolasco Vice President, Regulatory Affairs Phone: 310-405-7549 Email: Aleece.Nolasco@NantHealth.com
Date prepared: October 21, 2019
2. DEVICE
| Name of Device | Omics Core |
|---|---|
| Common Name | Next Generation Sequencing Tumor Profiling Test |
| Classification Name | Next Generation Sequencing Based Tumor Profiling Test(21CFR 866.6080) |
| Regulatory Class | II |
| Product Code | PZM |
PREDICATE DEVICE 3.
MSK-IMPACT (Integrated Mutation Profiling Of Actionable Cancer Targets): A Hybridization-Capture Based Next Generation Sequencing Assay, DEN170058
This predicate device has not been subject to a design-related recall.
No reference devices were used in this submission.
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DEVICE DESCRIPTION 4.
Test Principle 4.1.
The NantHealth Omics Core assay is a custom targeted whole exome sequencing platform, utilizing solution-phase exon capture and sequencing, to report somatic alterations (point mutations, small insertions and deletions) in 468 genes and sequencing of 19,396 protein-coding genes (whole exome) to determine overall tumor mutation burden in tumor specimens.
Genomic DNA is extracted from both a tumor and a patient-matched normal control sample. Sequence libraries are prepared through a series of enzymatic steps including shearing of double-stranded DNA, end repair, A-base addition, ligation of barcoded sequence adaptors, and low cycle PCR amplification. Single barcoded sequence libraries are captured using the biotinylated probes. Captured DNA fragments are then pooled and sequenced on an Illumina NovaSeq 6000 as paired-end reads. Sequence reads are then aligned to the reference human genome. Somatic alterations are identified in the tumor DNA by direct comparison to the matched normal DNA.
4.2. Equipment, Supplies and Reagents
Table 1 summarizes some of the main equipment, supplies, reagents, and software used by the Omics Core assay.
All reagents, materials and equipment needed to perform the assay are qualified by NantHealth.
| Library Prep | Kapa Hyper Prep Kit |
|---|---|
| Hybridization | IDT xGen® Exome Research Panel v1.0 |
| Sequencer Chemistry | 2-Channel SBS Chemistry |
| Sequencer | Illumina NovaSeq 6000 |
| Bioinformatics | Omics Core software |
Table 1: Equipment Supplies, Reagents, and Software
Omics Core Workflow 4.3.
The following figures provide an illustrated overview of the flow of the Omics Core testing process from sample receipt, through testing, to the report. Detailed descriptions of each aspect of the assay are provided in subsequent sections.
The laboratory workflow for Omics Core is illustrated in Figure 1.
The bioinformatics workflow for Omics Core is illustrated in Figure 2.
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Image /page/8/Figure/2 description: The image shows the title of a figure. The title is "Figure 1: Laboratory Workflow". The words are written in a bold, sans-serif font.
Image /page/8/Figure/3 description: This image shows a laboratory workflow. The workflow starts with specimen preparation, which includes FFPE tumor tissue (5-20 x 10 μm) and whole blood (2 x 2.5 mL). The next step is library preparation, which includes fragmentation, adapters added, and library amplification. The final step is sequencing, which includes sequencing ready targeted libraries and sequencing using Illumina NovaSeq 6000 and PhiX Control v3.
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Bioinformatics Workflow Figure 2:
Image /page/9/Figure/3 description: This image is a flowchart that describes the process of sequencing data. The process starts with sequencing data, which is then used to generate tumor and normal FASTQ files. These files are then used to align the tumor and normal DNA, which is followed by variant calling. The variants are then classified, interpreted, and evaluated for TMB. Finally, a report is finalized and released, and the report is made available to the physician.
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Indications For Use 4.4.
The Omics Core 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 tumor mutational burden (TMB) 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. Omics Core is a single-site assay performed at NantHealth, Inc.
The Indications For Use statement for Omics Core is not identical to the predicate device. Omics Core is intended to provide information on tumor mutational burden (TMB) and not intended to provide information on microsatellite instability. Omics Core reports TMB as additional information on the tumor tissue. TMB is reported via two metrics: (1) total number of somatic non-synonymous exonic variants within the 19,396 genes (whole exome) surveyed and (2) a calculation of mutation rate by counting all somatic, synonymous and non-synonymous variants detected in gene coding regions and dividing by the approximate size of the exome (33.7 Mb). TMB is reported as mutations per megabase (mut/Mb) unit. Mutations included in the calculation of TMB must be present at 5% allele frequency or greater after direct comparison between tumor and matched normal DNA. TMB is reported as rate (not as High/Low) and as a mutation within the category of "Cancer Mutations with Potential Clinical Significance" to be signed off by the Medical Director. This difference does not constitute a new Indications For Use nor raises different issues of safety and effectiveness.
COMPARISON OF TECHNOLOGICAL ട. CHARACTERISTICS WITH THE PREDICATE DEVICE
The primary technological characteristics and indications for use of the Omics Core assay are substantially equivalent to MSK-IMPACT. A substantial equivalence table comparing overall similarities and differences between Omics Core and MSK-IMPACT is provided in Table 2.
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| Characteristics | Predicate Device:MSK-IMPACT (DEN170058) | Subject Device:Omics Core |
|---|---|---|
| Similarities | ||
| Indications ForUse | The MSK-IMPACT assay is aqualitative in vitro diagnostic testthat uses targeted next generationsequencing of formalin-fixedparaffin-embedded tumor tissuematched with normal specimensfrom patients with solid malignantneoplasms to detect tumor genealterations in a broad multi genepanel. The test is intended toprovide information on somaticmutations (point mutations andsmall insertions and deletions) andmicrosatellite instability for use byqualified health care professionalsin accordance with professionalguidelines, and is not conclusiveor prescriptive for labeled use ofany specific therapeutic product.MSK-IMPACT is a single-siteassay performed at MemorialSloan Kettering Cancer Center. | The Omics Core assay is aqualitative in vitro diagnostic testthat uses targeted next generationsequencing of formalin-fixedparaffin-embedded tumor tissuematched with normal specimensfrom patients with solid malignantneoplasms to detect tumor genealterations in a broad multi genepanel. The test is intended toprovide information on somaticmutations (point mutations andsmall insertions and deletions) andtumor mutational burden (TMB)for use by qualified health careprofessionals in accordance withprofessional guidelines, and is notconclusive or prescriptive forlabeled use of any specifictherapeutic product. Omics Core isa single-site assay performed atNantHealth, Inc. |
| Technology | Hybrid Capture | Same |
| Specimen Types | Formalin-fixed, paraffin-embedded (FFPE) tumor tissuematched with normal specimensfrom patients with solid malignantneoplasms | Same |
| Target Population | Patients with solid malignantneoplasms | Same |
| Genes on Panel forReporting SNVsand Indels | 468 | Same |
| Test Environment | Single-site assay (performed atMemorial Sloan Kettering CancerCenter) | Same. Single-site assay(performed at NantHealth, Inc.) |
| Controls | Matched normal Positive control Negative control No template control (NTC) | Omics Core uses the same types ofcontrols. |
| Characteristic | Predicate Device:MSK-IMPACT (DEN170058) | Subject Device:Omics Core |
| Differences | ||
| Black List | 73 exons | 203 exons |
| Variant types | Intended to provide informationon somatic mutations (pointmutations and small insertionsand deletions), andmicrosatellite instability | Same except Omics Core providesinformation on tumor mutationalburden (TMB) and notmicrosatellite instability (MSI). |
| Instrument | Illumina HiSeq® 2500Sequencing System | Illumina NovaSeq™ 6000Sequencing System |
| Determination ofPipeline Thresholds | Based on >200X target coverage 100X for ≥ 98% target exons hotspot mutation calling threshold (mutation coverage (DP) ≥ 20, mutant reads (AD) ≥ 8, mutation frequency (VF) ≥ 2%, and non-hotspot mutation threshold (DP ≥ 20, AD ≥ 10, VF ≥ 5%)). | Based on ≥ 500X target coverage ≥ 100X for 95% of target exons, and a mutation calling threshold of allele frequency (AF) ≥ 2% with Conf > 15 and heuristic filters The minimum read depth for variants in the Omics Core assay are allele depth (AD) ≥ 2 and overall depth (DP) ≥ 4. |
| Assay cut-off | MSK-IMPACT does not reportmutations below 2% for knownhotspot mutations and 5% fornon-hotspot mutations. | Omics Core does not reportmutations below 2% for allmutations. |
| Clinical EvidenceCurationOncopanel results arereported under one ofthese two categories: | Classification criteria weredeveloped by MSK using thein-house OncoKB database.OncoKB undergoes periodicupdates through the review ofnew information by a panel ofexperts | Classification criteria weredeveloped by NantHealth, Inc.NantHealth periodically updatesOmics Core through the review ofnew information available. |
| "Cancer Mutations with Evidence of Clinical Significance" or "Cancer Mutations with Potential Clinical Significance." |
Comparison of Omics Core with Predicate Device Table 2:
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PERFORMANCE DATA 6.
Table 3 summarizes the performance data that are provided in support of the substantial equivalence determination. Performance specifications were established following special controls outlined for next generation sequencing based tumor profiling test (21 CFR 866.6080).
| Characteristic | Performance Specifications |
|---|---|
| Specimens | The specimens accepted for testing are formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks and two vials of wholeblood for the normal comparator. If a tumor block is not available,slides containing tumor sections are acceptable. The FFPE blocksand slides are prepared per industry standards by the requestingmedical facility.Tumor sample requirements are 5-20 unstained sections,10 microns thick. Tumor sections must have more than 10% oftumor cells; however, sections containing >20% viable tumor arepreferred for testing. |
| Pre-Analytical | DNA samples are normalized to yield 50-300ng input in 60μlprior to shearing. |
| Characteristic | Performance Specifications |
| Precision | Precision was assessed using 12 FFPE clinical tumor samples and1 commercial cell line. A total of 530 variants were identified inthe samples that included 483 SNVs, 32 deletions, and15 insertions. |
| Precision – Panel-Wide Reproducibility: | |
| The overall positive call rate for all variants analyzed across the12 FFPE clinical samples and one commercial cell line was2607/2650, or 98.4% (97.8-98.8% CI). Three-hundred and ninety-eight (398) of 521 (76%) mutations in the clinical specimens had%CV ≤ 10%; 91 of 521 (17%) were between 10 and 20%; and32 of 521 (6%) were > 20%. | |
| Precision – Per Specimen: | |
| Per specimen variant analysis for 12 clinical specimens and acommercial cell line demonstrated consistent repeatability andreproducibility by showing 100% concordance for 511 out of530 unique mutations, or 96.4% (94.5%-97.8% CI). | |
| Precision - Well Characterized Reference Material: | |
| Analysis of the well characterized sample demonstrated consistentrepeatability and reproducibility by achieving an overall positivecall rate of 99.86% (99.75%-99.93% CI). | |
| Precision - TMB: | |
| TMB precision analysis was based on 12 clinical samples and1 commercial cell line. The tumor purity for these samples rangedfrom 25% to 90%. The per sample TMB analysis demonstratedrepeatable and reproducible TMB rates with a %CV <10% for all13 samples. | |
| Analytical Sensitivity -Limit of Detection | LoD - SNVs and Indels: |
| The results from 13 FFPE clinical samples demonstrated theability to detect and reliably call each variant class at the 5%mutant allele frequency with a success rate of ≥ 95%, with SNVscalled at 96.7% (82.8%-99.9% CI), insertions at 100% (83.2%-100.0% CI) and deletions at 100.0% (78.2%-100.0% CI). | |
| LoD - TMB:Ten (10) FFPE tumor specimens, with tumor purities ranging from10 to 20%, demonstrated consistent repeatability andreproducibility as all samples evaluated had a %CV < 10%. TheOmics Core assay will evaluate and report TMB rates for clinicalsamples with tumor purities ≥ 20%. | |
| Characteristic | Performance Specifications |
| Accuracy – ComparisonTo Orthogonal Method | Accuracy – SNVs and Indels:Accuracy was assessed by comparing Omics Core results to results obtained from the orthogonal method in a total of 401 FFPE tumor samples representing mutations covering 2,634 SNVs, 125 small insertions and 313 small deletions. Omics Core successfully detected mutations in all 401 samples assessed, representing accuracy of 100% (99.08-100% CI). 2634 unique SNVs demonstrated PPA of 99.76% (99.50-99.90% CI), PPV of 99.93% (99.75-99.99% CI) 125 unique small insertions demonstrated PPA of 100% (97.20-100.00% CI), PPV of 100% (97.20-100.00% CI) 313 unique small deletions demonstrated a PPA of 99.71% (98.38-99.99% CI), PPV of 99.71% (98.38-99.99% CI) Accuracy – TMB:TMB accuracy was assessed by comparing the TMB rates generated by Omics Core and the orthogonal method. A linear regression demonstrated high correlation between the two methods ( $R^2 = 0.9899$ ). |
| Accuracy – SupplementalMethod ComparisonsStudy for Wildtype Calls | An analysis of 220 positive mutations and 12,612 wildtype calls demonstrated a PPA of 99.54% (97.48-99.99%) and NPA of 99.99% (99.99-100%). |
| Traceability | Omics Core assay is not traceable to any known standard. The assay uses matched normal whole blood as a matched normal control, a No Template Control (NTC), and positive and negative controls to monitor the ongoing performance of the assay. |
| Stability | Reagent stability is based on manufacturer expiration dating and supported by NantHealth verification. Stability of the reagent is monitored through the use of consistent controls. |
| Expected Values | The Omics Core assay does not use calibrators; however, the verification of mutant allele frequency is maintained by analysis of a positive control with expected allele frequencies. |
| Analytical Specificity | High analytical specificity is maintained by paired tumor/matched normal sequencing, and established during assay optimization. Interference is minimized with pre-analytic steps. Invalid rates in historical testing from >2,000 samples support that any interference from any challenging tissues is minimized. |
| Assay Cut-Off | Omics Core does not report mutations below 2% MAF. Mutations included in the calculation of TMB must be present at 5% allele frequency or greater. |
| Characteristic | Performance Specifications |
| Clinical Performance | The genes in the panel include those that play a role in cancerpathogenesis and tumor suppression, or for clinical or mechanisticinformation of relevance in the management of cancer patients.The assay reports mutations under two categories: "CancerMutations with Evidence of Clinical Significance" and "CancerMutations with Potential Clinical Significance" consistent with theintended use clinical settings. Mutations with evidence of clinicalsignificance are represented in professional guidelines asestablished by consensus opinion of experts in the healthcarecommunity. |
| Software Verification andValidation Testing | Software level of concern: MODERATEVerification and validation testing conducted as per FDA'sGuidance for Industry and FDA Staff, "Guidance for the Contentof Premarket Submissions for Software Contained in MedicalDevices" and "Content of Premarket Submissions forManagement of Cybersecurity in Medical Devices" |
Table 3: Omics Core Performance Specifications
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7. SUMMARY
The submitted information in this 510(k) notification supports the Indications For Use for Omics Core and demonstrates that the Omics Core assay is as safe and effective as the predicate device and therefore supports a substantial equivalence conclusion.
§ 866.6080 Next generation sequencing based tumor profiling test.
(a)
Identification. A next generation sequencing (NGS) based tumor profiling test is a qualitative in vitro diagnostic test intended for NGS analysis of tissue specimens from malignant solid neoplasms to detect somatic mutations in a broad panel of targeted genes to aid in the management of previously diagnosed cancer patients by qualified health care professionals.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information:
(i) A detailed description of all somatic mutations that are intended to be detected by the test and that are adequately supported in accordance with paragraph (b)(1)(v) of this section and reported in the test results in accordance with paragraph (b)(2)(iv) of this section, including:
(A) A listing of mutations that are cancer mutations with evidence of clinical significance.
(B) As appropriate, a listing of mutations that are cancer mutations with potential clinical significance.
(ii) The indications for use must specify the following:
(A) The test is indicated for previously diagnosed cancer patients.
(B) The intended specimen type(s) and matrix (
e.g., formalin-fixed, paraffin-embedded tumor tissue).(C) The mutation types (
e.g., single nucleotide variant, insertion, deletion, copy number variation or gene rearrangement) for which validation data has been provided.(D) The name of the testing facility or facilities, as applicable.
(iii) A detailed device description including the following:
(A) A description of the test in terms of genomic coverage, as follows:
(
1 ) Tabulated summary of all mutations reported, grouped according to gene and target region within each gene, along with the specific cDNA and amino acid positions for each mutation.(
2 ) A description of any within-gene targeted regions that cannot be reported and the data behind such conclusion.(B) Specifications for specimen requirements including any specimen collection devices and preservatives, specimen volume, minimum tumor content, specimen handling, DNA extraction, and criteria for DNA quality and quantity metrics that are prerequisite to performing the assay.
(C) A detailed description of all test components, reagents, instrumentation, and software required. Detailed documentation of the device software including but not limited to, software applications and hardware-based devices that incorporate software.
(D) A detailed description of the methodology and protocols for each step of the test, including description of the quality metrics, thresholds, and filters at each step of the test that are implemented for final result reporting and a description of the metrics for run-failures, specimen-failures, invalids, as applicable.
(E) A list of links provided by the device to the user or accessed by the device for internal or external information (
e.g., decision rules or databases) supporting clinical significance of test results for the panel or its elements in accordance with paragraphs (b)(1)(v) and (b)(2)(vi) of this section.(F) A description of internal and external controls that are recommended or provided and control procedures. The description must identify those control elements that are incorporated into the testing procedure.
(iv) Information demonstrating analytical validity of the device according to analytical performance characteristics, evaluated either specifically for each gene/mutation or, when clinically and practically justified, using a representative approach based on other mutations of the same type, including:
(A) Data that adequately supports the intended specimen type (
e.g., formalin-fixed, paraffin-embedded tumor tissue), specimen handling protocol, and nucleic acid purification for specific tumor types or for a pan-tumor claim.(B) A summary of the empirical evidence obtained to demonstrate how the analytical quality metrics and thresholds were optimized.
(C) Device precision data using clinical samples to adequately evaluate intra-run, inter-run, and total variability. The samples must cover all mutation types tested (both positive and negative samples) and include samples near the limit of detection of the device. Precision must be assessed by agreement within replicates on the assay final result for each representative mutation, as applicable, and also supported by sequencing quality metrics for targeted regions across the panel.
(D) Description of the protocols and/or data adequately demonstrating the interchangeability of reagent lots and multiplexing barcodes.
(E) A description of the nucleic acid assay input concentration range and the evidence to adequately support the range.
(F) A description of the data adequately supporting the limit of detection of the device.
(G) A description of the data to adequately support device accuracy using clinical specimens representing the intended specimen type and range of tumor types, as applicable.
(
1 ) Clinical specimens tested to support device accuracy must adequately represent the list of cancer mutations with evidence of clinical significance to be detected by the device.(
2 ) For mutations that are designated as cancer mutations with evidence of clinical significance and that are based on evidence established in the intended specimen type (e.g., tumor tissues) but for a different analyte type (e.g., protein, RNA) and/or a measurement (e.g., incorporating a score or copy number) and/or with an alternative technology (e.g., IHC, RT-qPCR, FISH), evidence of accuracy must include clinically adequate concordance between results for the mutation and the medically established biomarker test (e.g., evidence generated from an appropriately sized method comparison study using clinical specimens from the target population).(
3 ) For qualitative DNA mutations not described in paragraph (b)(1)(iv)(G)(2 ) of this section, accuracy studies must include both mutation-positive and wild-type results.(H) Adequate device stability information.
(v) Information that adequately supports the clinical significance of the panel must include:
(A) Criteria established on what types and levels of evidence will clinically validate a mutation as a cancer mutation with evidence of clinical significance versus a cancer mutation with potential clinical significance.
(B) For representative mutations of those designated as cancer mutations with evidence of clinical significance, a description of the clinical evidence associated with such mutations, such as clinical evidence presented in professional guidelines, as appropriate, with method comparison performance data as described in paragraph (b)(1)(iv)(G) of this section.
(C) For all other mutations designated as cancer mutations with potential clinical significance, a description of the rationale for reporting.
(2) The 21 CFR 809.10 compliant labeling and any product information and test report generated, must include the following, as applicable:
(i) The intended use statement must specify the following:
(A) The test is indicated for previously diagnosed cancer patients.
(B) The intended specimen type(s) and matrix (
e.g., formalin-fixed, paraffin-embedded tumor tissue).(C) The mutation types (
e.g., single nucleotide variant, insertion, deletion, copy number variation or gene rearrangement) for which validation data has been provided.(D) The name of the testing facility or facilities, as applicable.
(ii) A description of the device and summary of the results of the performance studies performed in accordance with paragraphs (b)(1)(iii), (b)(1)(iv), and (b)(1)(v) of this section.
(iii) A description of applicable test limitations, including, for device specific mutations validated with method comparison data to a medically established test in the same intended specimen type, appropriate description of the level of evidence and/or the differences between next generation sequencing results and results from the medically established test (
e.g., as described in professional guidelines).(iv) A listing of all somatic mutations that are intended to be detected by the device and that are reported in the test results under the following two categories or equivalent designations, as appropriate: “cancer mutations panel with evidence of clinical significance” or “cancer mutations panel with potential clinical significance.”
(v) For mutations reported under the category of “cancer mutations panel with potential clinical significance,” a limiting statement that states “For the mutations listed in [cancer mutations panel with potential clinical significance or equivalent designation], the clinical significance has not been demonstrated [with adequate clinical evidence (
e.g., by professional guidelines) in accordance with paragraph (b)(1)(v) of this section] or with this test.”(vi) For mutations under the category of “cancer mutations panel with evidence of clinical significance,” or equivalent designation, link(s) for physicians to access internal or external information concerning decision rules or conclusions about the level of evidence for clinical significance that is associated with the marker in accordance with paragraph (b)(1)(v) of this section.