← Product Code [NOT](/submissions/HE/subpart-b%E2%80%94biological-stains/NOT) · K121033 # VIRTUOSO SYSTEM FOR IHC KI-67 (30-9) (K121033) _Ventana Medical Systems, Inc. · NOT · Sep 6, 2013 · Hematology · SESE_ **Canonical URL:** https://fda.innolitics.com/submissions/PA/subpart-b%E2%80%94biological-stains/NOT/K121033 ## Device Facts - **Applicant:** Ventana Medical Systems, Inc. - **Product Code:** [NOT](/submissions/HE/subpart-b%E2%80%94biological-stains/NOT.md) - **Decision Date:** Sep 6, 2013 - **Decision:** SESE - **Submission Type:** Traditional - **Regulation:** 21 CFR 864.1860 - **Device Class:** Class 2 - **Review Panel:** Hematology ## Indications for Use The Virtuoso™ system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape. The Virtuoso™ System for Ki67 (30-9) is for digital read and image analysis applications. This particular Virtuoso™ system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of Ki67 (30-9) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with this assay, the Virtuoso™ System for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki67 status in breast cancer patients (but is not the sole basis for treatment). ## Device Story Virtuoso System is an instrument-plus-software digital pathology solution for pathology laboratories. Input: digital images of formalin-fixed, paraffin-embedded tissue slides captured by iScan scanner. Operation: pathologist selects fields of view (FOVs) for analysis; software provides quantitative data on Ki-67 protein expression; pathologist reviews, verifies, or overrides software-generated scores. Output: quantitative scores for FOVs and aggregate slide scores. Used in clinical pathology labs by pathologists to assist in assessing Ki-67 status in breast cancer patients. System includes image quality assessment algorithms to ensure slide suitability. Benefits: provides consistent, semi-quantitative assessment of protein expression to aid clinical decision-making; requires human intervention for all analysis steps. ## Clinical Evidence Concordance studies evaluated 120 cases comparing digital read (DR) and image analysis (IA) against manual microscopic read (reference). For DR: PPA 100%, NPA 82.4%, OPA 90%. For IA: PPA ranged 67.5%–85.5%, NPA 95.6%–98.0%, OPA 78.0%–90.8% across three sites. All results met the 75% acceptance criterion. ## Technological Characteristics System includes iScan slide scanner, computer, monitor, and proprietary software. Operates on formalin-fixed, paraffin-embedded tissue slides stained with Ventana CONFIRM Ki-67 (30-9) antibody and DAB chromogen. Uses Benchmark ULTRA or XT automatic stainers. Software performs image quality assessment and quantitative analysis of nuclear staining. Web-based user interface. ## Regulatory Identification Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's. ## Special Controls (2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer. ## Predicate Devices - Virtuoso System for IHC Ki-67 (30-9) ([K111755](/device/K111755.md)) ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a 510(k)](https://innolitics.com/services/510ks/), [a De Novo](https://innolitics.com/services/regulatory/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). {0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY A. 510(k) Number: k121033 B. Purpose for Submission: Device modification. Clearance for use with the Benchmark ULTRA™ stainer. C. Manufacturer and Instrument Name: Ventana Medical Systems, Inc., Virtuoso™ System for IHC Ki67 (30-9) D. Type of Test or Tests Performed: Computer-assisted image analysis scoring and manual scoring of digital images of Ki67 immunohistochemistry stained slides. E. System Descriptions: 1. Device Description: No change. See k111755. 2. Principles of Operation: No change. See k111755. 3. Modes of Operation: No change. See k111755. 4. Specimen Identification: No change. See k111755. 5. Specimen Sampling and Handling: No change. See k111755. 6. Calibration: Calibration is performed at installation and annually by a Ventana Medical Services Inc. {1} field service technician. 7. Quality Control: No change. See k111755. 8. Software: FDA has reviewed applicant’s Hazard Analysis and Software Development processes for this line of product types: Yes ☐ x or No ☐ F. Regulatory Information: 1. Regulation section: 21 CFR §864.1860, Immunohistochemistry reagents and kits 2. Classification: Class II 3. Product code: NQN – Microscope, automated, image analysis, immunohistochemistry, operator intervention, nuclear intensity and percent positivity NOT – Microscope, Automated, Image Analysis, Operator Intervention OEO – Automated Digital Image Manual Interpretation Microscope 4. Panel: Pathology (88) G. Intended Use: 1. Indication(s) for Use: The Virtuoso™ system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape. The Virtuoso™ System for Ki67 (30-9) is for digital read and image analysis applications. This particular Virtuoso™ system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of Ki67 (30-9) protein 2 {2} in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with this assay, the Virtuoso™ System for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki67 status in breast cancer patients (but is not the sole basis for treatment). Note: The IHC Ki67 (30-9) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of Ki67 protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the IHC staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the Virtuoso™ System for Ki67 (30-9) Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established. 2. Special Conditions for Use Statement(s): For prescription use only Indicated for use with either the Benchmark XT or ULTRA™ stainers. * A precautionary statement indicating that this device has not been tested, or its safety and effectiveness validated, when used with a personal computer (PC) from home was included in the Limitations section of the device package insert. H. Substantial Equivalence Information: 1. Predicate Device Name(s) and 510(k) numbers: Ventana Virtuoso™ System for IHC Ki67 (30-9) for use with the Benchmark XT stainer (k111755) 2. Comparison with Predicate Device: {3} | Similarities | | | | --- | --- | --- | | Item | Device Ventana Virtuoso™ System for IHC Ki67 (30-9) with the Benchmark ULTRA™ stainer | Predicate Ventana Virtuoso™ System for IHC Ki67 (30-9) with the Benchmark XT stainer | | Intended Use | This device is intended for in vitro diagnostic (IVD) use. The Virtuoso™ System provides automated digital slide creation, management, analysis, and viewing. It is intended for IVD use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, size, intensity, pattern, and shape. | Same | | Sample type | Formalin-fixed, paraffin embedded tissue stained by IHC. | Same | | Device components | Automated digital slide scanner, computer, color monitor, and image analysis software and digital pathology information management software. | Same | | Primary Antibody (Assay) Reagent | Ventana CONFIRM™ Ki-67 (30-9) | Same | | Differences | | | | --- | --- | --- | | Item | Device Ventana Virtuoso™ System for IHC Ki67 (30-9) with the Benchmark ULTRA™ stainer | Predicate Ventana Virtuoso™ System for IHC Ki67 (30-9) with the Benchmark XT stainer | | Stainer | Benchmark ULTRA™ Features 30 slide positions and 35 reagents. The Benchmark ULTRA™ is a continuous access stainer, capable of random access processing. | Benchmark XT™ Single drawer of 30 slide positions and 35 reagents. | I. Special Control/Guidance Document Referenced (if applicable): None. J. Performance Characteristics: 1. Analytical Performance: {4} # a. Accuracy: The performance of the Virtuoso™ System for Ki67 (30-9) when used in conjunction with the Benchmark ULTRA™ stainer was validated by assessing the positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement (OPA) between the reference manual method (with a traditional microscope) and both the digital read (DR) and image analysis (IA) applications of the Virtuoso™ system. Patient slides were scored as positive or negative for Ki67 status using the percent positive staining cutoff of $< 10\%$ for the distinction between positive and negative staining. Concordance with manual scoring was assessed between scores assigned to 120 specimens for both digital reads and image analysis. The acceptance criteria of an overall agreement rate of at least $75\%$ were met in these studies. Concordance of digital reads with manual scoring was assessed at one site, whereas concordance of image analysis with manual scoring was performed at 3 study sites. The agreements with the $95\%$ confidence intervals (CI) around the agreements are shown below. All confidence intervals are 2-sided $95\%$ confidence intervals calculated using the score method. Clinical Assessment between Digital Read and Manual Scoring | | Manual Microscopic Read | | | | --- | --- | --- | --- | | Digital Read | Positive | Negative | Total | | Positive | 52 | 12 | 64 | | Negative | 0 | 56 | 56 | | Total | 52 | 68 | 120 | | PPA n/N (%) (95% CI) | 52/52 (100.0%) (93.1-100.0) | | | | NPA n/N (%) (95% CI) | 56/68 (82.4%) (71.6-89.6) | | | | OPA n/N (%) (95% CI) | 108/120 (90.0%) (83.3-94.2) | | | Clinical Assessment between Image Analysis and Manual Scoring | Site 1 | Manual Microscopic Read | | | | --- | --- | --- | --- | | Image Analysis | Positive | Negative | Total | | Positive | 52 | 1 | 53 | | Negative | 25 | 40 | 65 | | Total | 77 | 41 | 118 | | PPA n/N (%) (95% CI) | 52/77 (67.5%) (56.5-76.9) | | | | NPA n/N (%) (95% CI) | 40/41 (97.6%) (87.4-99.6) | | | | OPA n/N (%) (95% CI) | 92/118 (78.0%) (69.7-84.5) | | | | Site 2 | Manual Microscopic Read | | | | --- | --- | --- | --- | | Image Analysis | Positive | Negative | Total | | Positive | 54 | 2 | 56 | | Negative | 13 | 43 | 56 | | Total | 67 | 45 | 112 | {5} | PPA n/N (%) (95% CI) | 54/67 (80.6%) (69.6-88.3) | | --- | --- | | NPA n/N (%) (95% CI) | 43/45 (95.6%) (85.2-98.8) | | OPA n/N (%) (95% CI) | 97/112 (86.6%) (79.1-91.7) | | Site 3 | Manual Microscopic Read | | | | --- | --- | --- | --- | | Image Analysis | Positive | Negative | Total | | Positive | 59 | 1 | 60 | | Negative | 10 | 49 | 59 | | Total | 69 | 50 | 119 | | PPA n/N (%) (95% CI) | 59/69 (85.5%) (75.3-8-91.9) | | | | NPA n/N (%) (95% CI) | 49/50 (98.0%) (89.5-99.6) | | | | OPA n/N (%) (95% CI) | 108/119 (90.8%) (84.2-94.8) | | | Agreement between digital reads and image analysis to manual scoring was assessed using two Ventana DAB detection kits (iVIEW™ vs. ultraView™). Reanalysis of the results summarized in the four tables above by stratification by detection kit also yielded results that met the pre-established acceptance criteria of an overall agreement rate of at least $75\%$ . b. Precision/Reproducibility: Not applicable. c. Linearity: Not applicable. d. Carryover: Not applicable. e. Interfering Substances: Not applicable. 2. Other Supportive Instrument Performance Data Not Covered Above: Not applicable. # K. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. # L. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision. --- **Source:** [https://fda.innolitics.com/submissions/PA/subpart-b%E2%80%94biological-stains/NOT/K121033](https://fda.innolitics.com/submissions/PA/subpart-b%E2%80%94biological-stains/NOT/K121033) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a 510(k)](https://innolitics.com/services/510ks/), [a De Novo](https://innolitics.com/services/regulatory/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact). **Cite:** Innolitics at https://innolitics.com