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HER2/ER/PR IHControls® -Level H are peptide based qualitative on-slide controls to monitor the performance of the analytic components (antigen retrieval and immunostaining) of the immunohistochemical (IHC) staining process for certain human epidermal growth factor receptor type II (HER2), estrogen receptor (ER) and progesterone receptor (PR) IHC stains. It is indicated for use with formalin-fixed paraffin-embedded (FFPE) breast turnor samples.

HER2/ER/PR IHControls® -Level H are not intended to be used for scoring HER2, ER, and PR IHC stained slides.

HER2/ER/PR IHControls® -Level H are an additional controls specified in the HER2, ER, or PR IHC device labeling and are not intended to replace the controls approved or cleared as part of an IHC device.

HER2/ER/PR IHControls® -Level M are peptide based qualitative on-slide controls to monitor the performance of the analytic components (antigen retrieval and immunostaining) of the immunohistochemical (IHC) staining process for certain human epidermal growth factor receptor type II (HER2), estrogen receptor (ER) and progesterone receptor type (PR) IHC stains. It is indicated for use with formalin-fixed paraffin-embedded (FFPE) breast turnor samples.

HER2/ER/PR IHControls® -Level M are not intended to be used for scoring HER2, ER, and PR IHC stained slides.

HER2/ER/PR IHControls® -Level M are an additional controls specified in the HER2, ER, or PR IHC device labeling and are not intended to replace the controls approved or cleared as part of an IHC device.

HER2/ER/PR IHControls® -Level L are peptide based qualitative on-slide controls to monitor the performance of the analytic components (antigen retrieval and immunostaining) of the immunohistochemical (IHC) staining process for certain human epidermal growth factor receptor type II (HER2), estrogen receptor (ER) and progesterone receptor (PR) IHC stains. It is indicated for use with formalin-fixed paraffin-embedded (FFPE) breast tumor samples.

HER2/ER/PR IHControls® -Level L are not intended to be used for scoring HER2, ER, and PR IHC stained slides.

HER2/ER/PR IHControls® -Level L are an additional control to the run controls specified in the HER2, ER, or PR IHC device labeling and are not intended to replace the controls approved or cleared as part of an IHC device.

HER2/ER/PR IHControls® - Level H, HER2/ER/PR IHControls® - Level M and HER2/ER/PR IHControls® - Level L (HER2/ER/PR IHControls®) are immunostaining positive controls for diagnostic immunohistochemistry laboratories. The same immunohistochemical reaction that occurs on a tissue or cellular sample also occurs on the HER2/ER/PR IHControls® microbead. As a result of immunostaining, the microbead bearing the analyte turns the same color as cells expressing the analyte.

HER2/ER/PR IHControls® incorporate assay controls for human epidermal growth factor receptor type II (HER-2), estrogen receptor (ER), and progesterone receptor (PR). The HER2/ER/PR panel includes controls at 3 different analyte concentrations, providing users with an opportunity to select the control with an analyte concentration within the dynamic range of their assay.

HER2/ER/PR IHControls® are provided in a small vial containing enough liquid suspension for at least 100 tests. The user is instructed to pipet a one microliter droplet onto the slide that also bears the patient sample. The droplet is a suspension containing microscopic glass microbeads that are approximately the same size as cells. The microbead surface bears the molecule(s) being measured. Peptides representing the epitopes of all of the major commercial HER2. ER. and PR antibodies used by clinical immunohistochemistry laboratories are incorporated into the products.

HER2/ER/PR IHControls® are comprised of two different microbeads: analyte-coated glass test microbeads (7-8 um in diameter) and color standard microbeads (4.5 um in diameter). The latter provide a fixed brown color intensity for use in standardizing stain intensity measurement.

The HER2/ER/PR IHControls® panel is provided at 3 different analyte concentrations. In descending order of concentration, these levels are denoted "H", "M", and "L". These different products allow matching the analyte concentration to the dynamic range of the laboratory's stain.

Level H (high): This product includes analytes for HER2, ER, and PR, at approximately 10^6 molecules per microbead.
Level M (medium): This product includes analytes for HER2, ER, and PR, at approximately 10^5 molecules per microbead.
Level L (low): This product includes analytes for HER2, ER, and PR, at approximately 10^4 molecules per microbead.

These concentrations are approximate; they are not intended as assayed controls.

Three product levels are provided to allow the user to select a control with the lowest analyte concentration that still produces an easily visible immunostain.

The immunoreactivity pattern for product levels H, M, and L is described in Table 1. The table indicates the primary antibodies corresponding with up to 9 separate HER2/ER/PR peptides. (Some peptides are immunoreactive with more than one primary antibody.) Level H has a narrower range of primary antibody immunoreactivity than levels M and L but the concentrations per microbead are higher. Although any individual primary antibody will be listed as potentially immunoreactive with 2 or more levels. IHC laboratories should use the lowest level that provides for an easily visible stain.

Users pipette a droplet onto a microscope slide that also bears a patient's tissue sample. The droplet hardens upon drying, adheres the analyte-coated microbeads to the microscope slide, and is then processed with the patient sample. The hardened droplet is able to pass through dry heat associated with "baking" of slides, organic solvents associated with deparaffinization, boiling associated with antigen retrieval, and repeated rinses associated with immunostaining.

Here's an analysis of the provided text, outlining the acceptance criteria and study details for the HER2/ER/PR IHControls®:

The document describes the Boston Cell Standards HER2/ER/PR IHControls® a class II medical device (Product Code NJW) intended to monitor the performance of immunohistochemical (IHC) staining processes for HER2, ER, and PR in formalin-fixed paraffin-embedded (FFPE) breast tumor samples. These controls are not for scoring stained slides and are meant to be additional controls, not replacements for existing ones.

Acceptance Criteria and Device Performance

The acceptance criteria for this device are implicitly derived from the analytical performance studies demonstrating specificity, shelf life, and reproducibility of pathologist readouts, as well as the clinical performance studies assessing concordance with conventional tissue controls.

Study Details

1. Sample Sizes and Data Provenance

• Test Set (Analytical Studies):
  • Specificity: Tests against 26 antigenically irrelevant primary antibodies + 3 relevant primary antibodies. (Total 29 tests, implied multiple runs for each to confirm results, but specific number of samples/runs per antibody not detailed.)
  • Shelf Life: Real-time testing over approximately 2 years for each of the Level H, M, and L products. (Specific number of samples/tests at different time points not detailed.)
  • Reproducibility of Pathologist Readouts: 30 stained HER2/ER/PR IHControl® slides (10 each for HER2, ER, and PR).
• Test Set (Clinical Performance Studies):
  • Total Slides: 442 tests/slides across three clinical sites.
    • Site 1: 39 (ER) + 39 (PR) + 39 (HER2) = 117 slides
    • Site 2: 172 (PR) + 42 (HER2) = 214 slides (Note: 182 tested initially for PR, 172 informative)
    • Site 3: 37 (ER) + 37 (PR) + 37 (HER2) = 111 slides
  • Data Provenance: The studies were conducted at "three clinical immunohistochemical laboratories." The country of origin is not explicitly stated but is implied to be within the US given the FDA submission. The studies appear to be prospective as the device was "incorporated as on-slide controls... but otherwise followed their typical method for patient testing."

2. Number of Experts and Qualifications for Ground Truth

• Reproducibility of Pathologist Readouts:
  • Number of Experts: Three pathologists.
  • Qualifications: "Pathologists" are mentioned; specific years of experience or board certifications are not provided, but it's implicit they are qualified to interpret IHC staining.
• Clinical Performance Studies:
  • Number of Experts: Not explicitly stated, but "the pathologist interpreted both the conventional (tissue) control and the HER2/ER/PR IHControls®" at each of the three clinical sites. This implies at least one pathologist per site, likely more.
  • Qualifications: "Pathologist" is mentioned; specific qualifications are not detailed.

3. Adjudication Method for the Test Set

• Reproducibility of Pathologist Readouts: No explicit adjudication method (e.g., 2+1, 3+1). The study reports 100% concordance among the three pathologists for all slides, indicating no disagreement required adjudication.
• Clinical Performance Studies: No explicit adjudication method for reconciling discrepancies between the IHControls® and tissue controls. The document states discrepancies were "due to operator error."

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• Was it done?: No, an MRMC comparative effectiveness study in the typical sense (comparing human readers with AI vs. without AI assistance) was not performed.
  • This device is a quality control material, not an AI diagnostic tool. The "readers" here are pathologists interpreting the performance of the IHC staining process using the control material, not interpreting patient cases.
  • The study did involve multiple readers (pathologists) on multiple cases (slides with controls) to assess the reproducibility of the control readout, and compared the control's performance to conventional tissue controls.
• Effect Size: Not applicable, as this was not an AI assistance study.

5. Standalone Performance Study

• Was it done?: Yes, there was an assessment of the device's inherent "standalone" performance in terms of its ability to be correctly recognized as "Pass" or "Fail" by pathologists and its concordance with traditional tissue controls. However, this is "standalone" in the context of a quality control device proving its efficacy, not in the typical AI sense of an algorithm-only performance measurement.
  • The "Reproducibility of Pathologist IHControl® Readouts" section assesses the direct interpretation of the IHControls® by pathologists without direct comparison to patient samples or other controls during the reading.
  • The "Clinical Performance Studies" assess the IHControls® in conjunction with the IHC staining process and compare their outcome to conventional controls.

6. Type of Ground Truth Used

• Specificity: The ground truth for specificity was established by applying the device to antibodies known not to react with HER2, ER, or PR, and confirming the absence of staining. Conversely, ground truth for intended reactivity was established by applying the device to known HER2, ER, and PR antibodies and confirming positive staining. This relies on established knowledge of antibody-antigen reactions and positive tissue controls.
• Reproducibility of Pathologist Readouts: The "Expected Result" (Pass/Fail) for each of the 30 slides was presumably established by the study design (e.g., intentionally diluted primary antibody to create "Fail" results). This is a designed ground truth based on experimental conditions.
• Clinical Performance Studies: The ground truth for the "quality control check" of the IHC stain was the conventional tissue control (scored as "Pass" or "Fail"). The study implicitly uses the established performance of tissue controls as the gold standard against which the new IHControls® are compared for concordance.

7. Sample Size for Training Set

This information is not provided in the document. This device is a control material for IHC staining, not a diagnostic AI algorithm that typically has a "training set." The development of the device (e.g., optimizing peptide concentrations) is a manufacturing and R&D process, not a machine learning training process.

8. How Ground Truth for Training Set Was Established

Not applicable, as a concept of a "training set" in the machine learning sense is not relevant for this device description. The "training" for the device's design would involve material science, peptide chemistry, and immunohistochemistry expertise.

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Ready-to-Use Format

For in vitro diagnostic use.

BOND Ready-to-Use Primary Antibody Progesterone Receptor (16) is a monoclonal antibody intended to the qualitative identification by light microscopy of human progesterone receptor in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining using the automated BOND-III systems. Progesterone Receptor Clone (16) specifically binds to the progesterone receptor antigen located in the nucleus of progesterone receptor positive normal and neoplastic cells.

Progesterone Receptor Clone (16) is indicated as an aid in the management, prognosis and prediction of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Progesterone Receptor Clone (16) is optimized for use on the Leica Biosystems automated BOND-MAX or BOND-III systems using the BOND Polymer Refine Detection kit.

Concentrated Liquid Antibody Format

For in vitro diagnostic use.

Novocastra Liquid Mouse Monoclonal Antibody Progesterone Receptor Clone (16) (Concentrated Liquid Antibody Format) is intended to be used for the qualitative identification by light microscopy of human progesterone receptor in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining. Progesterone Receptor Clone (10) specifically binds to the progesterone receptor antigen located in the nucleus of progesterone receptor positive normal and neoplastic cells.

Progesterone Receptor Clone (16) Monoclonal Antibody (Concentrated Liquid Antibody Format) is indicated as an aid in the management, prognosis and prediction of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Progesterone Receptor (16) is a mouse anti-human monoclonal antibody produced as a tissue culture supernatant. This antibody is utilized to perform a qualitative immunohistochemical (IHC) assay to identify Progesterone Receptor expression in human breast cancer tissue routinely processed and paraffin-embedded for histological examination.

Progesterone Receptor (PGR) Clone 16 Primary Antibody is provided in a Ready-to-Use (RTU) and a concentrated liquid format. The RTU format is supplied in Tris buffered saline with carrier protein, containing 0.35% ProClin™ 950 as a preservative and is provided in two volumes (7 mL and 30 mL). The total protein concentration is approximately 10 mg/mL and the total antibody concentration is greater than or equal to 1 mg/L as determined by ELISA. The RTU format is optimally diluted for use on the automated BOND-MAX and BOND-III instrument staining platforms in combination with BOND Polymer Refine Detection (DS9800). The concentrated liquid format is provided so that customers may utilize manual staining protocols. The concentrated liquid format is a liquid tissue culture supernatant containing 15 mM sodium azide as a preservative. The total protein concentration is determined on a per batch basis and is described on the vial label, and the antibody concentration is greater than or equal to 324.0 mg/L as determined by ELISA.

The BOND-MAX and BOND-III instruments are fully automated slide stainers that perform automated deparaffinization (dewaxing), antigen retrieval, immunohistochemistry (IHC) staining/in situ hybridization (ISH) staining, and counterstaining. The major components of the BOND staining platforms are the processing module, computer (BOND controller), handheld ID scanner, and slide label printer. The BOND staining platforms are composed of a number of discrete software components including the BOND application software, BOND instrument/processing module software, BOND service software, and Laboratory interface system - integration package (LIS-IP).

Here's a breakdown of the acceptance criteria and study details based on the provided text:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state numerical acceptance criteria for immunoreactivity or stability beyond "met acceptance criteria". However, the repeatability and reproducibility sections do provide numerical agreements and state that they met criteria. The method comparison also provides numerical agreements and states it met acceptance criteria.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Intra-run Repeatability: 6 unique breast tumor tissue cases.
• Inter-day, Inter-instrument, Inter-lot Repeatability: 27 unique breast tumor tissue cases.
• Reproducibility (Inter-laboratory & Inter-pathologist): 135 unique FFPE breast tumor tissue cases.
• Method Comparison: A total of 455 cases (implied from the table total).
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. It only mentions "human progesterone receptor in formalin-fixed, paraffin-embedded tissue" and "breast tumor tissue cases."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

• Reproducibility (Inter-laboratory & Inter-pathologist): 3 pathologists were involved in scoring the slides, one per site. Their qualifications are not specified beyond "pathologist."
• Other studies (Repeatability, Method Comparison): The document does not explicitly state the number of experts used for establishing ground truth or their qualifications for these studies. The scoring for repeatability likely involved expert assessment, and method comparison relied on comparing the subject device to a predicate device, which would also implicitly rely on established expert assessment standards.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

The document does not describe an explicit adjudication method (like 2+1 or 3+1) for resolving discrepancies. For the reproducibility studies, agreements are calculated between observers, suggesting individual pathologist assessments were compared rather than being subjected to a specific adjudication process to establish a single "ground truth" per case.

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

This document describes the performance of an immunohistochemistry reagent/antibody, not an AI-assisted diagnostic device. Therefore, an MRMC comparative effectiveness study involving human readers improving with AI assistance is not applicable and was not performed. The studies focus on the analytical performance and reproducibility of the staining process and the antibody's interpretation by pathologists.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This is an immunohistochemistry reagent, not an algorithm. Therefore, a standalone algorithm-only performance study is not applicable and was not performed. The performance is intrinsically linked to its use in a laboratory setting by human interpretation.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the evaluations appears to be based on pathology assessments by qualified pathologists, specifically following ASCO/CAP guidelines (≥1% cut-off) for determining PR status in breast cancer tissue. This is indicated by phrases like "scored according to ASCO/CAP guidelines" and "clinical interpretation of any staining or its absence should be complemented by morphological studies... by a qualified pathologist."

8. The sample size for the training set

The document describes performance studies, not the development or training of an AI model. Therefore, there is no mention of a "training set" or its sample size.

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

As this is not an AI model, there is no training set and thus no ground truth establishment process described for one. The "training" of the antibody is inherent to its development and optimization for specific antigen binding, which is evaluated through immunoreactivity and analytical performance studies.

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Ready-to-Use Format

Progesterone Receptor (16) monoclonal antibody is intended to be used for the qualitative identification by light microscopy of human progesterone receptor (PR) in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining using the automated BOND-MAX system. Progesterone Receptor Clone (16) [PR (16)] specifically binds to the PR antigen located in the nucleus of PR positive normal and neoplastic cells.

PR (16) is indicated as an aid in the management, prognosis and prediction of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Concentrated Liquid Antibody Format.

Progesterone Receptor (PGR) Clone 16 monoclonal antibody is intended to be used for the qualitative identification by light microscopy of human progesterone receptor in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining. PGR Clone 16 specifically binds to the PGR antigen located in the nucleus of PGR positive normal and neoplastic cells.

PGR Clone 16 is indicated as an aid in the management, prognosis and prediction of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context's clinical history and other diagnostic tests by a qualified pathologist.

Not Found

I am sorry, but the provided text from the FDA 510(k) summary for the BOND™ Ready-to-Use (RTU) Primary Antibody Progesterone Receptor (16) and Concentrated Liquid Mouse Monoclonal Antibody (Novocastra™) does not contain any information about a study proving the device meets acceptance criteria.

The document is a clearance letter from the FDA, stating that the device is substantially equivalent to legally marketed predicate devices for its intended use. It outlines the regulatory classification, product code, and general controls applicable to the device. The "Indications for Use" section describes what the antibody is intended for (qualitative identification of human progesterone receptor in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining as an aid in the management, prognosis, and prediction of therapy outcome of breast cancer).

However, it does not include:

• A table of acceptance criteria and reported device performance.
• Details about a study design (sample size, data provenance, expert panels, adjudication, MRMC studies, standalone performance).
• Information on ground truth establishment for test or training sets.
• Training set sample size.

This type of detailed study information is typically found in the applicant's 510(k) submission document itself, which is often much more extensive and not usually fully released in the public "summary" letter. The FDA clearance letter primarily confirms the regulatory status and substantial equivalence determination based on the submitted data, but it doesn't present the raw study data or acceptance criteria in the format requested.

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Estrogen Receptor Clone 6F11 (ER 6F11) Mouse Monoclonal antibody is intended for laboratory use to qualitatively identify estrogen receptor (ER) antigen in sections of formalin fixed, paraffin embedded breast cancer tissue by immunohistochemistry methods. Estrogen Receptor Clone 6F11 specifically binds to the ER antigen located in the nucleus of ER positive normal and neoplastic cells.

Estrogen Receptor Clone 6F11 is indicated as an aid in the management, prognosis and predication of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Estrogen Receptor Clone 6F11 Ready-to-Use Primary Antibody for Bond™ and the Estrogen Receptor Clone 6F11 Liquid Concentrate Primary Antibody, Novocastra™ are optimized for use on the Leica Biosystems Bond III staining platform using the Bond Polymer Refine Detection Kit.

Estrogen Receptor Clone 6F11 (ER 6F11) Mouse Monoclonal antibody is intended for laboratory use to qualitatively identify estrogen receptor (ER) antigen in sections of formalin fixed, paraffin embedded breast cancer tissue by immunohistochemistry methods. Estrogen Receptor Clone 6F11 specifically binds to the ER antigen located in the nucleus of ER positive normal and neoplastic cells.

This document is a 510(k) premarket notification decision letter for the Estrogen Receptor Clone 6F11 (ER 6F11) immunohistochemistry reagent. It does not contain information about acceptance criteria or a study proving that a device meets acceptance criteria. The letter primarily states that the FDA has reviewed the submission and found the device substantially equivalent to legally marketed predicate devices.

Therefore, I cannot provide the requested information based on the content of this document.

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For in vitro diagnostic use.

FLEX Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 1294, Ready-to-Use (Dako Omnis), is intended for use in immunohistochemistry with the En Vision FLEX visualization system together with the Dako Omnis instrument to qualitatively detect human progesterone receptor in formalin-fixed, paraffin-embedded tissue sections of human breast cancer. The antibody binds progesterone receptor-expressing cells and is useful in the assessment of progesterone receptor status in human breast carcinomas.

The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist. This antibody is intended to be used after the primary diagnosis of tumor has been made by conventional histopathology using nonimmunologic histochemical stains.

FLEX Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 1294, Readyto-Use (Dako Omnis) is utilized to perform a qualitative immunohistochemical (IHC) assay to identify progesterone receptor (PR) expression in formalin fixed human breast cancer tissues routinely processed and paraffin-embedded for histological examination. The proposed device is a variant of FLEX Monoclonal Mouse Anti-Human Progesterone Receptor intended for use with the automated slide staining instrument Dako Omnis.

The design of the proposed device is developed to provide equivalent performance to its predicate FLEX Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use, (Link) with adaptation of the product configuration, to be used on the Dako Omnis Instrument instead of the Autostainer Link 48 Instrument.

The antibody is provided in liquid form in a buffer containing stabilizing protein and 0.015 mol/L sodium azide. The proposed device is intended for automated immunohistochemical (IHC) slide staining with the Dako Omnis Instrument and the software performing and controlling the automated slide staining process is validated for its intended use.

The provided text is a 510(k) summary for the FLEX Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 1294, Ready-to-Use (Dako Omnis). This document focuses on demonstrating substantial equivalence to a predicate device rather than presenting a detailed clinical study with acceptance criteria for a new AI/software device. Therefore, a direct response to some of the requested points (e.g., human reader improvement with AI, standalone performance, specific ground truth methods with expert numbers) is not fully achievable from this document.

However, I can extract information related to the device's performance evaluation and its acceptance criteria as presented for regulatory approval.

Acceptance Criteria and Reported Device Performance

The document states that "All results from performance studies confirm that the device meets its acceptance criteria and is substantial equivalent to its predicate device." While specific numerical acceptance criteria are not explicitly tabulated, the performance characteristics evaluated were focused on:

• Analytical specificity for normal tissue: This implies the device should not show staining in normal tissues that do not express progesterone receptor, thus minimizing false positives.
• Reproducibility: This measures the consistency of results within a run, between different lots of reagents, across different laboratories, and among different observers.
• Concordance with the predicate device: This is a key acceptance criterion for substantial equivalence, aiming to show that the new device produces results that agree sufficiently with an already approved device.

Since the document concludes that the device meets its acceptance criteria, the reported device performance is implicitly that these aspects were successfully demonstrated.

Study Details from the Document:

1. Sample size used for the test set and the data provenance: The document mentions a "concordance study" but does not specify the sample size for the test set (number of cases or tissue sections) or the data provenance (e.g., country of origin, retrospective/prospective).
2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: The document states that "The clinical interpretation of any staining or its absence... should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist." This indicates that pathologists are involved in interpretation but does not specify the number or specific qualifications (e.g., years of experience) of experts used to establish the ground truth for the test set in the analytical or concordance studies mentioned.
3. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not specified in the provided text.
4. 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: This is not an AI/software device. It is an immunohistochemistry (IHC) reagent used with an automated staining instrument. Therefore, an MRMC study comparing human readers with and without AI assistance is not applicable and was not performed. The study evaluates the performance of the IHC reagent itself.
5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: This question is not directly applicable as the device is an IHC reagent and an automated staining platform, not an AI algorithm. The performance evaluation is inherently "standalone" in terms of the reagent's analytical performance, but its interpretation requires a "human-in-the-loop" (a pathologist).
6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.): The ground truth for this type of device, aimed at detecting progesterone receptor expression, is typically established by pathological assessment of the stained tissue sections, often comparing the new device's staining patterns and intensity against a gold standard or the predicate device's results. The interpretation is done by "qualified pathologists."
7. The sample size for the training set: The document does not describe a "training set" in the context of machine learning. For an IHC reagent, "training" would refer to internal development and optimization, not a distinct dataset for algorithm training.
8. How the ground truth for the training set was established: As above, the concept of a "training set" and its ground truth in the AI/ML sense is not applicable to this device. Quality control and optimization during the development of the reagent and staining protocol would rely on expert pathological evaluation.

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For in vitro diagnostic use.

FLEX Monoclonal Rabbit Anti-Human Estrogen Receptor a, Clone EP1, Ready-to-Use (Dako Omnis), is intended for use in immunohistochemistry with the EnVision FLEX visualization system together with the Dako Omnis instrument to qualitatively detect human estrogen receptor in formalin-fixed, paraffin-embedded tissue sections of human breast cancer. The antibody binds estrogen receptor a expressing cells and is useful in the assessment of estrogen receptor status in human breast carcinomas.

The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist. This antibody is intended to be used after the primary diagnosis of tumor has been made by conventional histopathology using nonimmunologic histochemical stains.

The FLEX Monoclonal Rabbit Anti-Human Estrogen Receptor a, Clone EP1, Ready-to-Use (Dako Omnis) antibody is utilized to perform a qualitative immunohistochemical (IHC) assay to identify estrogen receptor (ER) expression in fixed human breast cancer tissues routinely processed and paraffin-embedded for histological examination.

The design of the proposed device is based on the design of its predicate FLEX Monoclonal Rabbit Anti-Human Estrogen Receptor α. Clone EP1, Ready-to-Use (Link) with adaptation of the product configuration, to be used on the Dako Omnis Instrument instead of the Autostainer Link 48 Instrument.

The antibody is provided in liquid form in a buffer containing stabilizing protein and 0.015 mol/L sodium azide. The antibody is intended for automated immunohistochemical (IHC) slide staining with the Dako Omnis Instrument and the software performing and controlling the automated slide staining process is validated for its intended use.

This document describes the Dako FLEX Monoclonal Rabbit Anti-Human Estrogen Receptor α, Clone EP1, Ready-to-Use (Dako Omnis) Immunohistochemistry (IHC) reagent system, referred to as GA084, and its equivalence to a predicate device (IR084).

Here's an analysis of the acceptance criteria and study findings based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document states that "All results from performance studies confirm that GA084 meets its acceptance criteria and is substantial equivalent to its predicate device IR084." However, it does not explicitly list the numerical acceptance criteria for each performance characteristic. Instead, it broadly indicates that the device met these criteria. The performance characteristics evaluated were:

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

The document does not specify the exact sample size used for the test set in the performance studies. It mentions that concordance studies were performed to establish equivalence.

The data provenance is not explicitly stated regarding country of origin or whether it was retrospective or prospective.

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

The document does not specify the number of experts used or their qualifications for establishing ground truth specifically for the test set. It mentions that clinical interpretation "should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist." This implies that qualified pathologists are involved in interpretation but doesn't detail their role in establishing ground truth for the study.

4. Adjudication Method for the Test Set

The document does not specify the adjudication method used for the test set.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance.

This device is an immunohistochemistry (IHC) reagent system, not an AI or imaging device. Therefore, an MRMC comparative effectiveness study involving AI assistance for human readers is not applicable and was not reported. The focus is on the performance of the staining reagent itself.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done.

As stated above, this is an IHC reagent system. There is no algorithm involved that operates in a standalone manner. The device's performance is inherently tied to the staining process and subsequent human interpretation by a pathologist.

7. The Type of Ground Truth Used

The type of ground truth used is expert evaluation by qualified pathologists of the stained tissue sections. The clinical interpretation of any staining or its absence "should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist." The antibody is intended to be used "after the primary diagnosis of tumor has been made by conventional histopathology using nonimmunologic histochemical stains." This implies that the 'ground truth' for whether a tumor is present and for the ER status would ultimately rely on comprehensive pathological assessment.

8. The Sample Size for the Training Set

The document does not mention a training set as this is not an algorithm-based device.

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

As there is no training set for this type of device, this question is not applicable.

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Ready-to-Use Format: Progesterone Receptor (16) monoclonal antibody is intended to be used for the qualitative identification by light microscopy of human progesterone receptor (PR) in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining using the automated BONDMAX system. Progesterone Receptor Clone (16) [PR (16)] specifically binds to the PR antigen located in the nucleus of PR positive normal and neoplastic cells. PR (16) is indicated as an aid in the management, prognosis and prediction of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Concentrated Liquid Antibody Format: Progesterone Receptor (PGR) Clone 16 monoclonal antibody is intended to be used for the qualitative identification by light microscopy of human progesterone receptor in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining. PGR Clone 16 specifically binds to the PGR antigen located in the nucleus of PGR positive normal and neoplastic cells. PGR Clone 16 is indicated as an aid in the management, prognosis and prediction of therapy outcome of breast cancer. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Not Found

I apologize, but the document you provided does not contain information about acceptance criteria, device performance, sample sizes for test or training sets, data provenance, expert qualifications, adjudication methods, multi-reader multi-case studies, standalone performance, or the type of ground truth used.

The document is a 510(k) premarket notification letter from the FDA to Leica Biosystems, Inc. regarding their BOND Ready-to-Use (RTU) Primary Antibody Progesterone Receptor (16) and Novocastra Liquid Mouse Monoclonal Antibody Progesterone Receptor Clone 16. It focuses on:

• FDA's substantial equivalence determination: Stating the device is substantially equivalent to legally marketed predicate devices.
• Regulatory information: Listing regulation numbers, names, and class.
• General controls and additional controls: Informing the manufacturer about applicable FDA regulations.
• Indications for Use: Describing the intended use of the devices for qualitative identification of human progesterone receptor in formalin-fixed, paraffin-embedded tissue by immunohistochemical staining, primarily as an aid in breast cancer management, prognosis, and prediction of therapy outcome.

To provide the information you requested, I would need a different document, such as a study report, clinical trial summary, or a more detailed technical submission that includes performance data and methodology.

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For in vitro diagnostic use.

FLEX Monoclonal Rabbit Anti-Human Estrogen Receptor α, Clone EP1, Ready-to-Use, (LINK), is intended for use in immunohistochemistry with EnVision FLEX, High pH visualization kit together with Autostainer Link 48 to semiquantitatively detect human estrogen in formalin-fixed, paraffin-embedded tissue sections of human breast cancer. The antibody labels estrogen receptor a-positive cells and is useful in the assessment of estrogen receptor status in human breast carcinomas.

The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

For in vitro diagnostic use.

FLEX Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use, (Link), is intended for use in immunohistochemistry together with EnVision FLEX+, High pH visualization kit together with Autostainer Link 48 instrument to semi-quantitatively detect human progesterone receptor in formalin-fixed, paraffin-embedded human breast carcinoma. This antibody labels progesterone receptor-positive cells and is useful in the assessment of progesterone receptor status in human breast carcinomas.

The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Not Found

The provided document is a 510(k) premarket notification for a modification to two existing immunohistochemistry reagents: FLEX Monoclonal Rabbit Anti-Human Estrogen Receptor α, Clone EP1, Ready-to-Use (Link) and FLEX Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use (Link).

The modification is specifically for the addition of the new Dako PT Link PT200 as recommended equipment for automated epitope retrieval pre-treatment. This is a special 510(k) submission, meaning it's for modifications to the submitter's own cleared devices where the intended use has not changed, and the fundamental scientific technology remains the same.

Therefore, the document does not contain a performance study designed to establish new acceptance criteria or demonstrate the performance of the device against new criteria. Instead, it relies on the predicate devices' prior clearances and focuses on demonstrating that the modification does not negatively impact the device's functionality or intended use.

Here's an breakdown of why the requested information isn't directly available in this document:

1. A table of acceptance criteria and the reported device performance:

   • This document is a modification submission, not an initial clearance. It doesn't present new performance data against specific acceptance criteria for the modified device itself. It hinges on the fact that the intended use has not changed and the fundamental scientific technology has not changed.
   • The "acceptance criteria" here relate to the design control activities for the modification, ensuring that the change (adding a new pre-treatment instrument) does not alter the device's fundamental performance. The document only mentions that the submitter identified "verification and/or validation activities required, including methods or tests used and acceptance criteria to be applied" based on a risk analysis, but it does not provide the actual table of those criteria or the results.

2. Sample size used for the test set and the data provenance:

   • No new test set data is presented for performance evaluation because the modification does not warrant it in a Special 510(k) (where the fundamental scientific technology and intended use are unchanged).
   • The original clearance (K120663 and K130861) for the predicate devices would contain this information.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • Not applicable to this modification document for the reasons stated above.

4. Adjudication method:

   • Not applicable to this modification document.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:

   • Not applicable to this modification document. These are reagents, not AI-powered diagnostic devices.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • Not applicable. These are reagents for immunohistochemistry, which require human interpretation by a pathologist.

7. The type of ground truth used:

   • Not applicable to this modification document. For the original clearances, the ground truth for IHC reagents typically involves expert consensus (pathology review), often comparing staining results to established clinical outcomes or other validated methods.

8. The sample size for the training set:

   • Not applicable. These are reagents, not AI algorithms requiring training sets.

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

   • Not applicable. These are reagents, not AI algorithms.

In summary, this 510(k) is a "Special 510(k)" for a device modification (adding a new recommended pre-treatment instrument to already cleared IHC reagents). It explicitly states that the "INDICATION/INTENDED USE...HAS NOT CHANGED" and the "FUNDAMENTAL SCIENTIFIC TECHNOLOGY...has not changed." Therefore, it does not present new performance data or acceptance criteria for the device itself but rather demonstrates that the modification does not alter the device's previously established performance or intended use.

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The Virtuoso TM 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 IHC PR (1E2) using the VENTANA iScan HT is for the digital read application. This particular Virtuoso system is intended for use as an aid to the pathologist in the qualitative detection of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

Note: The IHC PR (1E2) Digital Read application is an adjunctive computer-assisted methodology for the qualified pathologist in the acquisition and interpretation of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The accuracy of the test results depends on the quality of the immunohistochemical 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-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the Virtuoso System for IHC PR Digital Read scores. The actual correlation of CONFIRM™ anti-PR antibody to clinical outcome has not been established. This device is intended for IHC slides stained on the BenchMark ULTRA stainers. For prescription use only.

The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, paraffinembedded normal and neoplastic tissues. The system consists of a slide scanner, computer, monitor, keyboard, and mouse for specific immunohistochemical markers, and software with a Windows web browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations and generate reports.

Hardware: The iScan HT scanning device captures digital images of formalinfixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide scanner, a carousel for loading glass slides, computer, scanner software, keyboard, mouse and monitor.

Software: The Virtuoso software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the process.

Acceptance Criteria and Device Performance for Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT

This response summarizes the acceptance criteria and study findings for the Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT, based on the provided FDA 510(k) summary (K142965).

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the reported agreement rates. For the purpose of this table, we will highlight the reported agreement rates as the measure of meeting the acceptance of substantial equivalence.

Note: The document states that the test system was shown to be "as safe and effective (therefore substantially equivalent) as the predicate devices". The provided agreement rates are the key metrics demonstrating this substantial equivalence. Specific predefined numerical acceptance criteria are not explicitly stated as distinct thresholds in the provided text but are implicitly met by achieving high concordance with manual methods and good reproducibility, consistent with existing legally marketed devices.

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

• Sample Size for Method Comparison Test Set:
  • Site 1: 159 cases
  • Site 2: 162 cases
  • Site 3: 156 cases
  • Overall: 477 cases (sum of evaluable cases from the three sites)
• Sample Size for Reproducibility Test Set: 39 cases (for intra-pathologist reproducibility)
• Sample Size for Scanner Precision Test Set: 40 cases
• Data Provenance: The document does not explicitly state the country of origin. However, the study involved three different "sites", implying a multi-center study possibly within the US, but this is not explicitly confirmed. The study appears to be retrospective in nature, using existing formalin-fixed, paraffin-embedded tissue blocks that were then stained and digitally scanned.

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

• Number of Experts: 3 pathologists (referred to as "Readers" or "Investigators"). The method comparison study involved each of these 3 pathologists providing both manual and digital reads. The reproducibility studies also involved these 3 pathologists.
• Qualifications of Experts: The document refers to them as "qualified pathologists" or "investigators." Specific details regarding their years of experience or sub-specialty (e.g., radiologist, breast pathologist) are not provided.

4. Adjudication Method for the Test Set

• Method Comparison: The ground truth for the device's performance was established using the manual read (MR) by the same pathologist as the reference for the digital read (DR) evaluation. Each pathologist's DR results were compared to their own MR results. There is no explicit mention of an independent adjudication committee or consensus among multiple experts for the ground truth itself.
• Reproducibility: For intra-pathologist reproducibility, the comparison was between the same pathologist across three different reading sessions. For inter-pathologist reproducibility, the comparison was between pairs of pathologists.
• Scanner Precision: The comparison was between clinical scoring categories agreed upon at different sites/days for the same FOVs.
• It appears no formal "N+1" or similar adjudication method was employed to establish a single, definitive ground truth independent of the readers whose digital reads were being assessed. Instead, the agreement between the digital read and a human's manual read served as the primary performance indicator, and reproducibility between humans (both manual and digital) was also evaluated.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

• Yes, a form of MRMC study was implicitly done. The method comparison study involved 3 pathologists (multi-reader) evaluating multiple cases (multi-case), where their digital reads were compared to their manual reads. The reproducibility studies also involved multiple readers and multiple cases.
• Effect Size (Human Reader Improvement with AI vs. without AI): The document does not report an effect size for human readers improving with AI assistance. The study design is primarily focused on demonstrating the substantial equivalence of the digital read system to the manual read, rather than measuring the improvement in human performance when assisted by the AI. The Virtuoso™ System is described as an "aid to the pathologist" and an "adjunctive computer-assisted methodology," but the study evaluates its standalone performance against manual reading, and its reproducibility, not its comparative effectiveness in improving reader accuracy or efficiency.

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

• No, a standalone (algorithm only) performance study was not done or reported. The device is described as an "aid to the pathologist" and the software explicitly "makes no independent interpretations of the data and requires competent human intervention for all steps in the process."
• The Digital Read (DR) method involves the pathologist reviewing the digital images. The performance metrics (OPA, PPA, NPA) are based on the pathologist's interpretation using the digital system, not an automated algorithm's output directly.

7. The Type of Ground Truth Used

• The primary ground truth used for the method comparison study was the expert's own manual microscopic assessment of the formalin-fixed, paraffin-embedded tissue slides, using a traditional microscope. This acts as the "reference manual method."
• For the reproducibility and precision studies, the ground truth for comparison was the clinical score assigned by pathologists (either their own previous scores for intra-reader, or other pathologists' scores for inter-reader/inter-scanner).
• The ground truth categories were defined as:
  • Negative: PR score of 0 to 0.99% positive staining
  • Positive: PR score of ≥1% positive staining
  • For scanner precision: 0 – 0.99%, 1–10%, and ≥ 10% positive staining.
• There is no mention of pathology or outcomes data being used as an independent, external ground truth beyond expert consensus.

8. The Sample Size for the Training Set

• The document does not provide information on the sample size used for the training set for the Virtuoso™ System's software. The study focuses on the clinical validation of the device, implying that the algorithm development (training) phase was completed prior to these validation studies.

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

• The document does not provide information on how the ground truth for the training set was established. This information is typically part of the device development process and is not always included in the 510(k) summary for validation studies.

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The GenASIs HiPath IHC Family provides image capture, management, analysis, and viewing of specific immunohistochemically stained slides. 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:

1. The GenASIs HiPath IHC Family for HER2 (4B5) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/ neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

NOTE: The GenASIs HiPath IHC Family for HER2 (4BS) image capture and analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and semi-quantitative measurement of images from microscope glass slides of breast cancer specimens stained for the presence of HER-2/neu receptor protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results on the quality of the immuchistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the PATHWAY® anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the GenASIs HiPath IHC Family for HER2 (4B5) image capture and analysis scores. The actual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not been established.

2. The GenASIs HiPath IHC Family for PR (1E2) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC for PR (1E2) image capture and analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the GenASIs HiPath IHC Family for PR (1E2) image capture and analysis scores. The actual correlation of CONFIRMTM anti-PR antibody to clinical outcome has not been established.

3. The GenASIs HiPath IHC Family for ER (SP1) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of ER (SP1): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody. The Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of ER status in breast cancer patients (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC Family for ER (SP1) image capture and analysis applications are adjunctive computerassisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer specimens stained for the protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the immuohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to assure the validity of the GenASIs HiPath IHC Family for ER (SP1) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to clinical outcome has not been established.

4. The GenASIs HiPath IHC Family for Ki67 (30-9) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of Ki67 (30-9): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) assay is indicated for use in assessing the activity of breast cancer tissue. When used with this assay, the GenASIs HiPath IHC Family for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis applications are adjunctive computerassisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer stained for the presence of Ki67 protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

The GenASIs HiPath IHC Family, including software is designed to assist the qualified pathologist in the consistent assessment in inmmohistochemnically stained histologic sections from formalin-fixed, paraffin-embedded breast cancer tissues. The device consists of a slide capture camera, Microscope, computer, monitor, keyboard, mouse, image analysis algorithms for specific immunohistochemical markers, and software with a Graphic User Interface (GUI).

The GenASIs HiPath IHC Family is an intranet-based, end-to-end, digital pathology software solution that allows pathology laboratories, to acquire, manage, view, analyze, share, and report test results of pathology specimens. Using the GenASIs HiPath IHC Family software the pathologist can view captured images, add annotations, make measurements, perform image analysis and generate reports.

Hardware: A camera based acquisition device designed to captures bright-field microscope digital images of formalin-fixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide acquisition camera, X-Y Stage with holder adaptor for loading glass slides on a microscope and a workstation including a computer, keyboard, mouse and monitor.

Software: The GenASIs HiPath IHC Family software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

Here's a breakdown of the acceptance criteria and the study details for the GenASIs HiPath IHC Family device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the "Overall Agreement," "Positive Agreement," and "Negative Agreement" percentages. These percentages represent the agreement between the device's analysis and manual pathological analysis.

HER2/neu (4B5)

PR (1E2)

ER (SP1)

Ki67 (30-9)

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

The study was conducted across three clinical sites. The data provenance is not explicitly stated (e.g., country of origin), nor is it specified whether the data was retrospective or prospective. However, it involved "stained samples," implying real patient data.

• HER2/neu (4B5): 357 stained samples
• PR (1E2): 385 stained samples
• ER (SP1): 427 stained samples
• Ki67 (30-9): 373 stained samples

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

• Number of Experts: Three (3) pathologists.
• Qualifications: "Pathologist that followed the recommendations of the Ventana user insertions for the different panel antibodies." This implies they are qualified experts in immunohistochemical analysis. Specific experience levels (e.g., years of experience) are not provided.

4. Adjudication Method for the Test Set

The ground truth was established by manual evaluation through microscope eyepieces performed by three different pathologists. The document refers to "comparison to the measures of agreement test of conventional manual evaluation through the microscope eyepieces, performed by pathologist." It then presents "Pooled Results; Frequency distribution of agreement of Manual versus GenASIs HiPath IHC Family." This indicates that the manual reads by the three pathologists were likely combined to form a consensus or reference standard, against which the device's results were compared. An explicit adjudication method like "2+1" or "3+1" is not detailed, but the pooling of results suggests a form of consensus was used to derive the "Manual analysis" column in the tables.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

The document describes a comparison study where "manual evaluation through the microscope eyepieces, performed by pathologist" was compared to the device's analysis. However, it does not present a MRMC comparative effectiveness study in the sense of evaluating how much human readers improve with AI vs without AI assistance. Instead, it evaluates the agreement between the standalone AI device and the human readers' manual interpretations. There is no mention of human readers using the AI as assistance and then assessing their improved performance.

6. Standalone Performance Study

Yes, a standalone performance study was conducted. The "Analytical Performance" section details the "agreement rates of the comparison between manual and GenASIs HiPath IHC Family system statistical test results." This directly presents the device's performance in categorizing samples (Negative/Positive) against the ground truth established by manual pathological analysis, without human-in-the-loop during the device's diagnostic output generation.

7. Type of Ground Truth Used

Expert Consensus: The ground truth for the test set was established through "conventional manual evaluation through the microscope eyepieces, performed by pathologist that followed the recommendations of the Ventana user insertions for the different panel antibodies." This indicates that the ground truth was based on the consensus or established interpretations of qualified pathologists.

8. Sample Size for the Training Set

The document does not explicitly state the sample size used for the training set. The "Analytical Performance" section focuses on the validation study (test set).

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

As the training set sample size is not specified, neither is the method for establishing its ground truth. However, given the context of a medical device submission, it would be expected that if a machine learning model was developed, the training data would also be expert-annotated.

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