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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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For in Vitro Diagnostic Use:
QCS HER2 ImmunoControls, are intended for a laboratory to control semi-quantitative immunohistochemistry using different HER2/neu antibodies. Each QCS HER2 control slide contains four control sections prepared from breast cancer ccll lines that represent different levels of Her-2/neu protein expression. The cells are formalin-fixed and paraffin-embedded. These controls ensure that performance of immunohistochemical staining is consistent in one laboratory over time and also aids in correlation with the results of other laboratories.

QCS HER2 ImmunoControls: This product provides appropriate control for semi-quantitative immunohistochemistry using polyclonal or monoclonal HER2/neu antibodies. Each slide contains four control sections prepared from breast cancer cell lines that represent different levels of Her-2/neu protein expression (-, 1+, 2+, 3+). These cells are formalin-fixed and paraffin-embedded, the slide is positively charged.

Here's a breakdown of the acceptance criteria and study information for the QCS HER2 ImmunoControls, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance:

The document describes the device as a control with expected staining levels for different cell lines when tested with specific HER2 antibodies. The acceptance criteria are implicit in the "expected results" for the QCS HER2 Controls as presented in Table 1, which are compared directly to the predicate device, DAKO HER2 Controls.

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

• Sample Size for Test Set: Not explicitly stated. The "Multiple studies" sentence suggests more than one evaluation, but no specific number of samples or experiments is provided beyond the cell lines themselves.
• Data Provenance: Not explicitly stated for the specific comparison shown in Table 1. However, the cell lines (MDA-361, MDA-453, MDA-175, MCF-7) are human breast cancer cell lines. The referenced studies (Rhodes et al., Taylor CR, Ruby SG & McNally AC) are published scientific articles, implying a general scientific/medical community provenance. The context of a 510(k) summary implies the data was generated or compiled for regulatory submission. It is retrospective in the sense that the data in Table 1 represents established characteristics of these cell lines, likely from previous research, rather than a new prospective clinical trial.

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

• Number of Experts: Not specified.
• Qualifications of Experts: Not specified. The data in Table 1 reflects "expected results" which are typically established through extensive research by pathologists and other specialists skilled in immunohistochemistry. The external references imply a basis in published, peer-reviewed scientific literature, often involving expert consensus or established laboratory practices.

4. Adjudication Method for the Test Set:

• Adjudication Method: Not specified. The "expected results" suggest a prior determination of the staining levels, likely based on established laboratory protocols and expert evaluation, rather than an explicit adjudication process for this specific submission.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done:

• No, an MRMC comparative effectiveness study was NOT done. This device is a control slide for immunohistochemistry, not an AI diagnostic tool for interpreting images. The study focuses on demonstrating the control's intended performance (i.e., showing specific staining patterns) with standard antibodies, not on reader performance with or without AI assistance.

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

• Not applicable. This device is a physical control slide, not an algorithm. Therefore, "standalone performance" in the context of an algorithm is not relevant.

7. The Type of Ground Truth Used:

• Ground Truth Type: Expert consensus/established biological characteristics. The "expected level of staining" for the cell lines, as recognized in the scientific community and presumably confirmed by the manufacturer's testing, serves as the ground truth. This is supported by the direct comparison to the "Expected level of staining for valid results on the DAKO cell line control slide, as given in the HercepTest protocol." This indicates that the ground truth is based on established, conventional laboratory understanding of these cell lines' HER2 expression.

8. The Sample Size for the Training Set:

• Not applicable. This product is a control device, not an AI algorithm that requires a training set. The cell lines themselves are the "samples" whose characteristics are being confirmed.

9. How the Ground Truth for the Training Set was Established:

• Not applicable. As this is not an AI algorithm, there is no "training set" in the conventional sense. The "ground truth" for the cell lines' HER2 expression levels would have been established through extensive research, molecular characterization, and immunhistochemical testing over time in research and diagnostic laboratories. The references provided (e.g., Rhodes et al.) highlight studies that contribute to establishing such control materials and their expected performance.

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