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CINtec® Histology is a qualitative immunohistochemistry (IHC) test using mouse monoclonal anti-p16 antibody clone E6H4, and is intended for use in the light microscopic assessment of the p16INK4a protein in formalin-fixed, paraffinembedded (FFPE) cervical punch biopsy tissues using OptiView DAB IHC Detection Kit on a VENTANA BenchMark ULTRA instrument. The test is indicated as an adjunct to examination of hematoxylin and eosin (H&E) stained slide(s), to improve consistency in the diagnosis of cervical intraepithelial neoplasia (CIN). Diagnosis of CIN presence or level should be based on H&E stained slide(s) and other clinical and laboratory test information.

Intended for in vitro diagnostic (IVD) use. Prescription Use Only.

CINtec® Histology is a single dispenser immunohistochemical (IHC) assay system comprised of an anti-p16 primary antibody optimized for use with the BenchMark ULTRA automated slide staining instrument and the OptiView DAB IHC Detection Kit. The antibody is diluted in a Tris-HCl buffer containing carrier protein and 0.1% ProClin 300 as a preservative and provided as a ready-to-use liquid in a FloLock dispenser. CINtec Histology is available in a 50-test size and a 250-test size.

The OptiView DAB IHC Detection Kit (OptiView) is an indirect, biotin-free system for detecting mouse IgG, mouse IgM, and rabbit IgG primary antibodies and is comprised of 6 dispensers packaged together in one box.

Ancillary reagents required to perform the CINtec Histology assay include EZ Prep, Reaction Buffer, ULTRA High Temperature Liquid Coverslip (LCS), ULTRA Cell Conditioning 1 Solution (CC1), Hematoxylin II Counterstain, and Bluing Reagent.

Positive and negative tissue controls that are fixed and processed in the same manner as the test specimens should be used when performing this test. A negative reagent control mouse monoclonal antibody shall be used to evaluate nonspecific staining.

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text.

Device Name: CINtec® Histology
Description: A qualitative immunohistochemistry (IHC) test using mouse monoclonal anti-p16 antibody clone E6H4, intended for use in the light microscopic assessment of the p16INK4a protein in formalin-fixed, paraffin-embedded (FFPE) cervical punch biopsy tissues. It's an adjunct to H&E stained slides for improving consistency in diagnosing cervical intraepithelial neoplasia (CIN).

1. Table of Acceptance Criteria and Reported Device Performance

The provided text focuses on the non-clinical performance evaluation of a recombinant CINtec Histology device compared to a hybridoma predicate device, primarily to show their equivalency. The tests are designed to demonstrate the recombinant device's performance against established criteria.

2. Sample sizes for the test set and data provenance

The document describes non-clinical performance evaluation, not a typical "test set" in the machine learning sense with a distinct training/test split for generalizability. The sample sizes are specific to each validation test:

• Peptide Inhibition: Multi-tissue block (MTB) containing various cervical diagnoses.
• Between Lots precision: 26 cervical cases with various diagnoses.
• Immunoreactivity: Tour of Body (TOB), Tour of Tumor (TOT), and 20 additional cases.
• Equivalency/Method Comparison: 249 cervical cases with various diagnoses.
• Stability: Normal cervix, cervical squamous cell carcinoma (SCC), tonsil.

The data provenance (country of origin, retrospective/prospective) is not specified in the provided text. Given it's a device submission, it's likely retrospective use of archived FFPE tissue blocks.

3. Number of experts and qualifications for ground truth

The document does not specify the number of experts or their qualifications used to establish ground truth for the non-clinical performance evaluation. It mentions "qualified reader" for morphology assessment in Immunoreactivity and Equivalency/Method Comparison studies, implying expert assessment, but no details are provided. For the Indications for Use, it states "Diagnosis of CIN presence or level should be based on H&E stained slide(s) and other clinical and laboratory test information," implying that the final diagnosis relies on established pathology expertise in a clinical setting.

4. Adjudication method

The document does not specify any formal adjudication method (e.g., 2+1, 3+1) for the non-clinical performance studies. The "within 0.5 point" criteria for duplicate samples in the Peptide Inhibition test suggests internal consistency checks rather than multi-reader adjudication of a ground truth.

5. Multi-Reader Multi-Case (MRMC) comparative effectiveness study

The document explicitly states: "The substantial equivalence is not based on an assessment of clinical performance data." This indicates that an MRMC comparative effectiveness study, which would typically assess human reader improvement with AI assistance, was not performed or submitted as part of this specific 510(k) (which focuses on equivalency of recombinant vs. hybridoma antibody).

6. Standalone (algorithm only without human-in-the-loop) performance

The device described is an immunohistochemistry (IHC) test (a laboratory assay), not an AI algorithm. Therefore, "standalone (algorithm only without human-in-the-loop) performance" is not applicable in the typical sense of AI device evaluation. The performance metrics focus on the assay's biochemical and staining characteristics, and its interpretation is intended to be by a human pathologist as an "adjunct to examination of hematoxylin and eosin (H&E) stained slide(s)."

7. Type of ground truth used

For the peptide inhibition, immunoreactivity, and equivalency/method comparison studies, the ground truth implied is the known characteristics of the tissue samples (e.g., tissues with varying levels of p16 expression, normal vs. carcinoma, various diagnoses). The "qualified reader" assessment of morphology and staining intensity serves as a measure against accepted pathology interpretations for those samples.

8. Sample size for the training set

This document pertains to the submission of an IHC assay, not a machine learning or AI device. Therefore, the concept of a "training set" for an algorithm is not applicable here. The focus is on the analytical and technical performance of the assay itself.

9. How the ground truth for the training set was established

As this is not an AI/ML device, there is no "training set" or corresponding ground truth establishment process for algorithm training. The ground truth for the various performance evaluation studies (e.g., confirming p16 expression in Western Blots, identifying known tissue types) would be established through standard laboratory and pathological methods.

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CINtec Histology is a qualitative immunohistochemistry (IHC) test using mouse monoclonal anti-p16 antibody clone E6H4. and is intended for use in the light microscopic assessment of the p16thK4a protein in formalin-fixed, paraffin-embedded (FFPE) cervical punch biopsy tissues using OptiView DAB IHC Detection Kit on a VENTANA BenchMark ULTRA instrument. The test is indicated as an adjunct to examination of hematoxylin and eosin (H&E) stained slide(s), to improve consistency in the diagnosis of cervical intraepithelial neoplasia (CIN). Diagnosis of CIN presence or level should be based on H&E stained slide(s) and other clinical and laboratory test information.

The CINtec Histology test is a single dispenser IHC assay system comprised of an anti-p16 primary antibody optimized for use with the BenchMark ULTRA automated slide staining instrument and the OptiView DAB IHC Detection Kit. The antibody is diluted in a Tris-HCl buffer containing carrier protein and 0.1% ProClin 300 as a preservative, and provided as a ready-to-use liquid in a FloLock dispenser. CINtec Histology is available in a 50 test size and a 250 test size.

The OptiView DAB IHC Detection Kit (OptiView) is an indirect, biotin-free system for detecting mouse IgG, mouse IgM, and rabbit primary antibodies and is comprised of 6 dispensers packaged together in one box.

Here's a breakdown of the acceptance criteria and study details for the CINtec Histology device:

1. Acceptance Criteria and Reported Device Performance

The general acceptance criteria for this device type are outlined in 21 CFR 864.1865, specifically under "Special Controls." The clinical study data demonstrated a statistically significant improvement in the consistency of diagnoses by Community Pathologists (CPs) when using CINtec Histology staining. The reported performance relates to the improvement in agreement rates.

2. Sample Size Used for the Test Set and Data Provenance

The primary clinical study evaluating diagnostic consistency used 1,100 retrospectively collected FFPE cervical punch biopsy specimens.

The data provenance is described as: "retrospectively collected FFPE cervical punch biopsy specimens, which represent a colposcopy referral population." The study involved Board Certified CPs from across the United States.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

• Number of Experts: Three (3) Expert Pathologists (XPs).
• Qualifications of Experts: Not explicitly stated beyond "Expert pathologists" and "Board Certified CPs" (for community pathologists). However, the role and processes imply their expertise in cervical pathology.

4. Adjudication Method for the Test Set

The ground truth (Expert-derived Reference Diagnosis) for the test set was established using a 3+1 adjudication method:

• Two XPs initially established independent diagnoses based on H&E-stained slides.
• Discordant cases were evaluated by a third XP.
• Cases for which a "2 out of 3 majority diagnosis" was not achieved were reviewed during an adjudication review meeting that included all three XPs.
• "Majority (or consensus) results established the Expert-derived Reference Diagnosis for each case."

This process was repeated for establishing the reference diagnosis based on H&E and CINtec Histology stained slides.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

Yes, an MRMC comparative effectiveness study was done. This study compared the diagnostic consistency of community pathologists (CPs) with and without the aid of CINtec Histology staining.

The "effect size" can be quantified by the observed differences in Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) between the "H&E Only" and "H&E and CINtec Histology" conditions. The study demonstrated a statistically significant improvement in consistency.

• PPA Improvement for ≥HSIL-histology (LAST Cases): 29.5% (from 66.4% to 95.9%)
• NPA Improvement for ≤LSIL-histology (LAST Cases): 7.1% (from 42.5% to 49.6%)
• PPA Improvement for ≥HSIL-histology (ALL Cases): 22.8% (from 71.3% to 94.1%)
• NPA Improvement for ≤LSIL-histology (ALL Cases): 7.9% (from 56.5% to 64.4%)

These values represent the improvement in agreement rates of CPs with the expert reference diagnosis when using CINtec Histology as an adjunct to H&E.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

No, a standalone (algorithm only) performance study was not done or described. The CINtec Histology device is a qualitative immunohistochemistry test where results are "interpreted using a light microscope by a pathologist." Its indication for use is "as an adjunct to examination of hematoxylin and eosin (H&E) stained slide(s), to improve consistency in the diagnosis of cervical intraepithelial neoplasia (CIN)."

7. The Type of Ground Truth Used

The primary ground truth used for the clinical study was an Expert Consensus Diagnosis (referred to as "Expert-derived Reference Diagnosis"). This was established by a panel of three expert pathologists through initial independent readings and subsequent adjudication (2 out of 3 majority, followed by a review meeting for persistent discordance). This consensus was established twice: once based on H&E alone, and once based on H&E + CINtec Histology.

8. The Sample Size for the Training Set

The document does not explicitly state a separate "training set" for the CINtec Histology product itself. As an immunohistochemistry (IHC) assay for detecting a protein marker, it is a laboratory test with defined reagents and protocols, rather than a machine learning algorithm that requires a dedicated training set. The various analytical and precision studies describe the evaluation of the assay's performance characteristics.

9. How the Ground Truth for the Training Set Was Established

As noted above, there is no explicit mention of a "training set" for the device in the context of an algorithm. The development and optimization of the IHC assay would have involved standard laboratory practices, including using known positive and negative control tissues. For instance, the analytical performance section mentions using "cervical carcinoma or CIN2/3 cervical tissue positive for CINtec Histology staining" as a positive control and "normal cervical tissue with negative staining" as a negative control. These are used to confirm assay performance rather than to "train" an algorithm.

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