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.

Device Description

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.

AI/ML Overview

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.

Test	Acceptance Criteria	Reported Device Performance
Western Blot	Single band between 15-20 kDa (~16 kDa) must be detected on the Western blot membrane for those lanes loaded with recombinant p16INK4a protein or with lysates from p16INK4a-expressing cell lines and consequently probed with recombinant anti-p16INK4a antibody or hybridoma anti-p16INK4a antibody.	Pass
Peptide Inhibition	Decreased staining in the tissues stained with recombinant CINtec Histology reagent containing p16 epitope-specific peptide when compared to the tissues stained with recombinant CINtec Histology reagent containing diluent or non-specific peptide. Significant p16 signal reduction with highest concentration of p16-specific peptide. Tissues with diluent only must show appropriate specific staining. Middle and lowest concentrations of p16-specific peptide should score between 0 and control. Duplicate samples must stain equivalently (within 0.5 point). Background ≤ 0.5 point for ≥ 90% of samples. Negative control MTB slide should not have any specific staining.	Pass
Between Lots precision	Stain intensity shall not vary more than 0.5 point from the median score on a 0-4 scale of each sample on ≥ 85% between lots. All samples shall show ≥ 90% positive/negative agreement for CINtec® Histology status. Antibody shall demonstrate background/cross-reactivity ≤ 0.5 points on a 0-4 scale in ≥ 90% of the tissue samples stained.	Pass
Immunoreactivity	Background/cross-reactivity ≤ 0.5 points on a 0-4 scale in ≥ 90% of the tissue samples stained. Recommended staining protocol shall preserve tissue morphology as noted by the qualified reader in a minimum of 90% of interpretable samples stained.	Pass
Equivalency/Method Comparison	Overall percent agreement (OPA) shall demonstrate a lower bound for the two-sided 95% confidence interval (LBCI) of ≥ 85%. Background should be ≤ 0.5 points (on a 0-4 scale) in 90% or greater of the tissue samples stained. Tissue morphology should be preserved as noted by the qualified reader in a minimum of 90% of interpretable samples stained.	Pass
Stability	Stain intensity for all tissue slides stored at 45°C for at least 227 hours or at 37°C for at least 493 hours shall not vary more than 1.0 point in stain intensity as compared to the respective reference tissue slides stained at 0 hour. Background for all tissue slides stored as above shall not exceed 0.5 points as compared to the respective Time 0 reference slides for 24 months' expiration dating.	Pass

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.

Summary

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December 10, 2021

Ventana Medical Systems, Inc. Stacci Cronk, RAC Senior Manager, Regulatory Affairs 1910 E Innovation Park Drive Tucson, AZ 85755

Re: K212176

Trade/Device Name: CINtec Histology Regulation Number: 21 CFR 864.1865 Regulation Name: Cervical Intraepithelial Neoplasia (CIN) Test System Regulatory Class: Class II Product Code: PRB Dated: July 9, 2021 Received: July 12, 2021

Dear Stacci Cronk:

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 may, 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,

Soma Ghosh, Ph.D. Chief Molecular Pathology and Cytology 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) K212176

Device Name CINtec® Histology

Indications for Use (Describe)

ClNtec® 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.

Type of Use (Select one or both, as applicable)
-------------------------------------------------	--

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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CINtec® Histology 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.

Submitter Name	Ventana Medical Systems, Inc.
Address	1910 E Innovation ParkDrive Tucson, AZ.,85755
Contact	Stacci CronkPhone: (520) 302-2193Email: Stacci.cronk@roche.com
Date Prepared	June 30, 2021
Proprietary Name	CINtec® Histology
Common Name	Immunohistochemistry, qualitative
Classification Name	A cervical intraepithelial neoplasia (CIN) test system
Product Codes	PRB, 21 CFR 864.1865
Predicate Devices	CINtec® Histology (DEN160019)
EstablishmentRegistration	Ventana Medical Systems, Inc., 2028492

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1. DEVICE DESCRIPTION

Component	Content
OptiView PeroxidaseInhibitor	3.0% hydrogen peroxide solution
OptiView HQ UniversalLinker	Cocktail of HQ-labeled antibodies (goatanti-mouse IgG, goat anti-mouse IgM, and goat anti-rabbitIgG)
	(<50 µg/mL) in a buffer containing protein with ProClin 300,a preservative
OptiView HRP Multimer	Mouse monoclonal anti-HQ HRP labeled tertiaryantibody (<40 µg/mL) in a buffer containing protein withProClin 300
	OptiView DAB
OptiView H2O2
OptiView Copper	Copper sulfate (5.0 g/L) in an acetate buffer in preservative.

Table 1: OptiView DAB IHC Detection Kit Components

The ancillary reagents required to perform the CINtec Histology assay are provided in Table 2.

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Reagent	Format Provided	Contents	Purpose
EZ Prep	Bulk / 10XConcentrate/ 2 liter	Detergent	Removes paraffinfrom the tissuespecimen
Reaction Buffer	Bulk / 10Concentrate / 2 liter	Tris based buffersolution withdetergent andpreservative	Provides stableenvironment forantibody- antigeninteractions andenzyme reactions.Also used as a rinsesolution to removereagents betweenassay steps.
ULTRA HighTemperature LiquidCoverslip (LCS)	Bulk / 2 liter	Low densityparaffinichydrocarbon andother oils	Functions as a barrierbetween aqueoussolutions and air (i.e.,prevents evaporationof reagents duringincubation periods onthe slide).
ULTRA CellConditioning 1Solution (CC1)	Bulk/Prediluted / 1liter	Tris based buffersolution withdetergent andpreservative	Disrupts covalentbonds at hightemperatures formedby formalin in tissue.Increases antibodyaccessibility.
Hematoxylin IICounterstain	Dispenser/ Prediluted /25 mL	Hematoxylin (≤60%);contains glycol andacetic acid stabilizingsolution	A modified Mayer'shematoxylin usedfor staining cellularnuclei.
Bluing Reagent	Dispenser /Prediluted /25 mL	Solution of 0.1 Mlithium carbonate in0.5 M sodiumcarbonate	Applied afterhematoxylin andchanges the hue of thehematoxylin to a bluecolor.

Table 2: Ancillary Reagents

Controls:

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. Positive and negative control tissue is used to confirm that the assay performed as expected. For optimal quality control, cervical carcinoma, or CIN2/3 cervical tissue positive for CINtec Histology staining is suitable for use as a positive tissue control, and normal cervical tissue is suitable for use as a negative tissue control. Normal human tonsil tissue is also suitable for use as a tissue control, as tonsil contains both positive and

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negative staining elements when stained with CINtec Histology. Within normal tonsil tissue, there is nuclear and/or cytoplasmic staining of scattered squamous epithelial cells primarily in crypt epithelium and scattered follicular dendritic cells in germinal centers and absence of staining in the majority of lymphocytes.

A negative reagent control mouse monoclonal antibody shall be used to evaluate nonspecific staining. This negative reagent control should be used to stain an adjacent section of the patient specimen tissue on a separate slide from the CINtec Histology slide. The staining protocol for the negative reagent control antibody should be the same as that for the primary antibody.

2. INDICATIONS FOR USE

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 p164NK4a 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.

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

TECHNOLOGICAL CHARACTERISTICS 3.

CINtec® Histology is currently manufactured using hybridoma anti-p161NK4a (E6H4) Mouse Monoclonal Primary Antibody (anti-p16 antibody) supplied by Millipore (predicate device). In the subject device, the anti-p16 antibody supplier has been replaced by Roche Penzburg in order to ensure adequate supply continuity. In addition, the hybridoma anti-p16 (E6H4) antibody has been changed to a recombinant anti-p16 (E6H4) antibody. Advantages of recombinant antibodies include high consistency, reproducibility, scalability, and large yield.

4. NON-CLINICAL PERFORMANCE EVALUATION

A summary of non-clinical performance testing is provided in Table 3. The subject recombinant CINtec Histology device performs equivalently to the predicate hybridoma CINtec Histology device and both meet current acceptance criteria.

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Table 3: Summary of Performance Testing

Test	StudyDesign	AcceptanceCriteria	Result
Western Blot	Recombinant anti-p16 antibody+ hybridoma anti-p16antibody/ cell lines with various expression of p16protein and recombinant p16 protein	Single band between 15-20 kDa (~16 kDa) must be detectedon the Western blot membrane for those lanes loaded withrecombinant p16INK4a protein or with lysates from p16INK4a -expressing cell lines and consequently probed withrecombinant anti- p16INK4a antibody orhybridoma anti- p16INK4a antibody.	Pass
Peptide Inhibition	Recombinant CINtec® Histology / multi-tissueblock (MTB) containing tissues with variouscervical diagnosis stained with recombinantCINtec® Histology reagent diluted 1:1 withdifferent concentrations of p16-specific peptide(3x10-6 - 3x10-8 M), non- specific peptide (3x10-6- 3x10-8 M) or diluent only (no-peptide control).	Decreased staining in the tissues stained with recombinantCINtec Histology reagent containing p16 epitope-specificpeptide when compared to the tissues stained withrecombinant CINtec Histology reagent containing diluentor non-specific peptide.The tissues stained with recombinant CINtec Histologyreagent containing highest concentration (3x10-6 M) of p16specific-peptide must show significant p16 signal reductioncompared to the tissues stained with recombinant CINtec®Histology reagent containing a non-specific- peptide or onlydiluent. A significant reduction in staining intensity indicatesthat the peptide is able to inhibit antibody binding to the targettissue. The tissues stained with the recombinant CINtecHistology reagent containing only diluent must demonstrateappropriate specific staining. The tissues stained with therecombinant CINtec Histology reagent containing middle andlowest concentrations of p16-specific- peptide should scorebetween 0 and the score obtained on the control slides stainedwith recombinant CINtec Histology containing only diluent.Duplicate samples tested must stain equivalently (within 0.5point). Background must be less than or equal to 0.5 point forat least 90% of samples tested.The negative control MTB slide should not have any specificstaining present.	Pass
Between Lotsprecision	3 lots of recombinant CINtec® Histology/ 26cervical cases with various diagnosis	Stain intensity shall not vary more than 0.5 point from themedian score on a 0-4 scale of each sample on greater than orequal to 85% between lots; All samples shall show equal to orhigher than 90% positive/negative agreement for CINtec®Histology status; the antibody shall demonstratebackground/cross-reactivity less than or equal to 0.5 points ona 0-4 scale in 90% or greater of the tissue samples stained.	Pass
Immunoreactivity	1 lot of recombinant CINtec® Histology + currenthybridoma CINtec® Histology /Tour of Body (TOB),Tour of Tumor (TOT), 20 additional cases	Background/cross-reactivity less than or equal to 0.5points on a 0-4 scale in 90% or greater of the tissuesamples stained. The recommended staining protocolshall preserve tissue morphology as noted by thequalified reader in a minimum of 90% of interpretablesamples stained.	Pass
Equivalency/MethodComparison	1 lot of recombinant CINtec® Histology + currenthybridoma CINtec® Histology/249 cervical cases withvarious diagnosis	Overall percent agreement (OPA) shall demonstrate a lowerbound for the two-sided 95% confidence interval (LBCI) ofgreater than or equal to 85%. Background should be (lessthan or equal to 0.5 points (on a 0-4 scale) in 90% or greaterof the tissue samples stained. Tissue morphology should bepreserved as noted by the qualified reader in a minimum of90% of interpretable samples stained.	Pass
Stability	3 lots of recombinant CINtec® Histology /normalcervix, cervical squamous cell carcinoma (SCC), tonsil	Stain intensity for all tissue slides stored at 45°C for at least227 hours or at 37°C for at least 493 hours shall not vary morethan 1.0 point in stain intensity as compared to the respectivereference tissue slides stained at 0 hour; background for alltissue slides stored at 45°C for at least 227 hours or 37°C for atleast 493 hours shall not exceed 0.5 points as compared to therespective Time 0 reference slides for 24 months' expirationdating.	Pass

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5. CLINICAL PERFORMANCE EVALUATION

The substantial equivalence is not based on an assessment of clinical performance data.

CONCLUSIONS 6.

The subject recombinant CINtec Histology performs equivalently to the predicate hybridoma CINtec Histology and both meet current acceptance criteria.

Regulation Number and Section

§ 864.1865 Cervical intraepithelial neoplasia (CIN) test system.

(a)
Identification. A cervical intraepithelial neoplasia (CIN) test system is a device used to detect a biomarker associated with CIN in human tissues. The device is indicated as an adjunct test and not to be used as a stand-alone device. The test results must be interpreted in the context of the patient's clinical history including, but not limited to, prior and current cervical biopsy results, Papanicolaou (Pap) test results, human papillomavirus (HPV) test results, and morphology on hematoxylin and eosin (H&E) stained sections. This device is not intended to detect the presence of HPV.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information:
(i) The indications for use must specify the biomarker that is intended to be identified and its adjunct use (
e.g., adjunct to examination of H&E stained slides) to improve consistency in the diagnosis of CIN.(ii) Summary of professional society recommendations, as applicable.
(iii) A detailed device description including:
(A) A detailed description of all test components, including all provided reagents and required, but not provided, ancillary reagents.
(B) A detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals.
(C) If applicable, detailed documentation of the device software, including, but not limited to, stand-alone software applications and hardware-based devices that incorporate software.
(D) A detailed description of appropriate positive and negative controls that are recommended or provided.
(E) Detailed specifications for sample collection, processing, and storage.
(F) A detailed description of methodology and assay procedure.
(G) A description of the assay cutoff (the medical decision point between positive and negative) or other relevant criteria that distinguishes positive and negative results, including the rationale for the chosen cutoff or other relevant criteria and results supporting validation of the cutoff.
(H) Detailed specification of the criteria for test results interpretation and reporting.
(iv) Detailed information demonstrating the performance characteristics of the device, including:
(A) Analytical specificity studies such as, but not limited to, antibody characterization (
e.g., Western Blot, peptide inhibition analysis), studies conducted on panels of normal tissues and neoplastic tissues, interference by endogenous and exogenous substances as well as cross-reactivity, as applicable.(B) Device analytical sensitivity data generated by testing an adequate number of samples from individuals with the target condition including limit of blank, limit of detection, and limit of quantification, as applicable.
(C) Device precision/reproducibility data to evaluate within-run, between-run, between-day, between-lot, between-site, between-reader, within-reader and total precision, as applicable, using a panel of samples covering the device measuring range and/or the relevant disease categories (
e.g. No CIN, CIN1, CIN2, CIN3, cervical cancer) and testing in replicates across multiple, nonconsecutive days.(D) Device robustness/guardbanding studies to assess the tolerance ranges for various critical test and specimen parameters.
(E) Device stability data, including real-time stability and shipping stability under various storage times, temperatures, and freeze-thaw conditions.
(F) Data from a clinical study demonstrating clinical validity using well-characterized prospectively or retrospectively obtained clinical specimens, as appropriate, representative of the intended use population. The study must evaluate the consistency of the diagnosis of CIN, for example, by comparing the levels of agreements of diagnoses rendered by community pathologists to those rendered by a panel of expert pathologists. Agreement for each CIN diagnostic category (
e.g., No CIN, CIN1, CIN2, CIN3, cancer) and for alternate diagnostic categories (e.g., No CIN, low grade squamous intraepithelial lesion (LSIL)-histology, high grade squamous intraepithelial lesion (HSIL)-histology, cancer) between reference diagnosis by expert pathologist and community pathologist must be evaluated, as applicable. In addition, agreements for CIN binary categories as ≥CIN2 (i.e., CIN2 or CIN3 or cancer) and ≤CIN1 (i.e., No CIN or CIN1) between reference diagnosis by expert pathologist with H&E staining and community pathologist with H&E staining and agreements for alternate CIN binary categories as ≥HSIL-histology (i.e., HSIL-histology or cancer) and ≤LSIL-histology (i.e., No CIN or LSIL-histology) between reference diagnosis by an expert pathologist with H&E + [biomarker specified in paragraph (b)(1)(i) of this section] and a community pathologist with H&E + [biomarker specified in paragraph (b)(1)(i) of this section] must be evaluated and compared, as applicable.(G) The staining performance of the device as determined by the community pathologists during review of the study slides must be evaluated. The staining performance criteria assessed must include overall staining acceptability, background staining acceptability, and morphology acceptability, as applicable.
(H) Appropriate training requirements for users, including interpretation manual, as applicable.
(I) Identification of risk mitigation elements used by the device, including a description of all additional procedures, methods, and practices incorporated into the instructions for use that mitigate risks associated with testing.
(2) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol, including the information described in paragraph (b)(1)(ii) of this section, as applicable, and a detailed description of the performance studies performed and the summary of the results, including those that relate to paragraph (b)(1)(ii) of this section, as applicable.