(207 days)
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.
| Acceptance Criteria Category | Specific Criteria (Implicit/Explicit) | Reported Device Performance |
|---|---|---|
| Specificity | No cross-reactivity with antigenically irrelevant primary antibodies. Immunoreactivity with appropriate ER, HER2, and PR primary antibodies. | No cross-reactivity detected with 26 antigenically irrelevant, commonly used primary antibodies. Positive reactivity demonstrated with appropriate ER, HER2, and PR primary antibodies. |
| Shelf Life | Maintain performance for a specified duration when stored appropriately (2-8°C). | All three levels (H, M, L) demonstrated a shelf life of 392 days when stored at 2-8°C. |
| Reproducibility of Readouts | Pathologists should be able to visually interpret the controls and reproducibly render "Pass" or "Fail" scores. | Overall agreement among three pathologists for the interpretation of HER2/ER/PR IHControls® was 100% across all 30 blinded slides (10 for each marker: HER2, ER, PR). This indicates highly reproducible "Pass" or "Fail" scoring. |
| Clinical Concordance | Performance of IHControls® should be highly concordant with conventional tissue controls in assessing IHC test quality in clinical laboratory settings. | Overall concordance rate of 99.5% (440 out of 442 tests) across three clinical sites for combined ER, PR, and HER2 tests. Individual site concordances were 100%, 99.5%, and 99.1%. Two discrepancies were attributed to operator error; one site had a technologist error in pipetting. The device provides "an equally accurate assessment of IHC test quality" compared to 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."
- Total Slides: 442 tests/slides across three clinical sites.
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.
§ 864.1860 Immunohistochemistry reagents and kits.
(a)
Identification. Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.(b)
Classification of immunohistochemistry devices. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter. This exemption applies to IHC's that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding. These IHC's are used after the primary diagnosis of tumor (neoplasm) has been made by conventional histopathology using nonimmunologic histochemical stains, such as hematoxylin and eosin. Examples of class I IHC's are differentiation markers that are used as adjunctive tests to subclassify tumors, such as keratin.(2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.
(3) Class III (premarket approval). IHC's intended for any use not described in paragraphs (b)(1) or (b)(2) of this section.
(c)
Date of PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the Federal Food, Drug, and Cosmetic Act is required for any device described in paragraph (b)(3) of this section before this device may be commercially distributed. See § 864.3.