VENTANA MET (SP44) RxDx Assay

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION Device Generic Name: VENTANA MET (SP44) RxDx Assay Device Trade Name: VENTANA MET (SP44) RxDx Assay Device Procode: SER Applicant’s Name and Address: Ventana Medical Systems, Inc. (Roche Tissue Diagnostics) 1910 E Innovation Park Drive Tucson, AZ 85755 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P240037 Date of FDA Notice of Approval: May 14, 2025 ## II. INDICATIONS FOR USE VENTANA MET (SP44) RxDx Assay is a qualitative immunohistochemical assay using rabbit monoclonal anti-MET, clone SP44, intended for use in the assessment of MET protein in formalin-fixed paraffin embedded (FFPE) non-squamous non-small cell lung cancer (NSCLC) specimens by light microscopy. This assay is for use with OptiView DAB IHC Detection Kit for staining on a BenchMark ULTRA or BenchMark ULTRA PLUS instrument. MET protein expression clinical cut-off is ≥ 50% of tumor cells exhibiting strong membrane and/or cytoplasmic staining (3+) in non-squamous NSCLC. VENTANA MET (SP44) RxDx Assay is indicated as an aid in identifying non-squamous NSCLC patients who may be eligible for treatment with EMRELIS™ (telisotuzumab vedotin-tllv). The results of VENTANA MET (SP44) RxDx Assay should be interpreted by a qualified pathologist in conjunction with histological examination, relevant clinical information and proper controls. This product is intended for in vitro diagnostic (IVD) use. PMA P240037: FDA Summary of Safety and Effectiveness Data {1} III. CONTRAINDICATIONS There are no known contraindications. IV. WARNINGS AND PRECAUTIONS Warnings and precautions can be found in the VENTANA MET (SP44) RxDx Assay labeling (Package Insert/Method Sheet). V. DEVICE DESCRIPTION A. Device Kit Components VENTANA MET (SP44) RxDx Assay contains optimized reagents required to complete the immunohistochemistry (IHC) staining procedure for FFPE specimens on the BenchMark ULTRA or BenchMark ULTRA PLUS automated staining instruments visualized using the OptiView DAB IHC Detection Kit. VENTANA MET (SP44) RxDx Assay recombinant rabbit monoclonal antibody is produced as purified cell culture supernatant. The antibody and detection reagents are provided as ready-to-use dispensers and each VENTANA MET (SP44) RxDx Assay primary antibody dispenser contains sufficient reagent for 50 tests. The VENTANA MET (SP44) RxDx Assay components and their description are provided in Tables 1 and 2, below. PMA P240037: FDA Summary of Safety and Effectiveness Data {2} Table 1. VENTANA MET (SP44) RxDx Assay Components | Components Description | Packaged Form | Description | | --- | --- | --- | | VENTANA MET (SP44) Recombinant Rabbit Monoclonal Primary Antibody | 1 Flo-Lok Dispenser: 50 tests | One 5 mL dispenser of VENTANA MET (SP44) RxDx Assay contains approximately 17.5 μg of recombinant rabbit monoclonal antibody (approximately 3.5 μg/mL). The antibody is diluted in 0.05 M Tris-HCl with carrier protein and 0.10% ProClin 300, a preservative. | | OptiView DAB IHC Detection Kit | Set of 6 Flo-Lok dispensers, packaged in a kit: 250 tests | OptiView Peroxidase Inhibitor contains 3.0% hydrogen peroxide solution. | | | | OptiView HQ Universal Linker contains a cocktail of HQ-labeled (HQ is a proprietary hapten covalently attached to the goat antibodies) antibodies (goat anti-mouse IgG, goat anti-mouse IgM, and goat anti-rabbit) (<50 μg/mL) in a buffer containing protein with ProClin 300, a preservative. | | | | OptiView HRP Multimer contains a mouse monoclonal anti-HQlabeled HRP tertiary antibody (<40 μg/mL) in a buffer containing protein with ProClin 300, a preservative | | | | OptiView H_{2}O_{2} contains 0.04% hydrogen peroxide in a phosphate-buffered saline (PBS) solution | | | | OptiView DAB contains 0.2% 3, 3′-diaminobenzidine tetrahydrochloride (DAB) in a proprietary stabilizer solution with a proprietary preservative. | | | | OptiView Copper contains copper sulfate (5.0 g/L) in an acetate buffer with a proprietary preservative | | BenchMark ULTRA automated staining instrument and Ventana System Software (VSS) software | Instrument installed with the VSS host system software; Version 12.3 to 12.5.4 | A personal computer (PC) that runs on Microsoft Windows controls and monitors the BenchMark ULTRA instrument via the host operating software. | | BenchMark ULTRA PLUS automated staining instrument and VSS software | Instrument installed with the VSS host system software; Version 14.1 | A personal computer (PC) that runs on Microsoft Windows controls and monitors the BenchMark ULTRA PLUS instrument via the host operating software. | | Negative Control (Rabbit Monoclonal Ig) | 1 Flo-Lok dispenser: 250 tests | Intended for laboratory use as a control for non-specific binding of the primary antibody in sections of FFPE tissue. One 25 mL dispenser contains approximately 25 μg (1 ug/mL) of rabbit monoclonal antibody. The antibody is diluted in PBS with 3% carrier protein and 0.05% ProClin 300, a preservative. | PMA P240037: FDA Summary of Safety and Effectiveness Data {3} Table 2: Ancillary Reagents Required for VENTANA MET (SP44) RxDx Assay | Reagent | Description | | --- | --- | | Hematoxylin II counterstain | Modified Mayer's hematoxylin used for staining cellular nuclei on slides containing cells from frozen tissue, FFPE tissue, or cytologic preparations | | Bluing Reagent | Aqueous solution of buffered lithium carbonate used for bluing hematoxylin-stained sections on glass slides | | Reaction Buffer 10x | Tris based buffer solution (pH 7.6 ± 0.1) used to rinse slides between staining steps and provide a stable aqueous environment for reactions carried out on the BenchMark instrument | | EZ Prep 10X | A detergent-containing reagent that removes paraffin from the tissue specimen during the IHC staining to prepare the tissue for antigen retrieval and subsequent reactions | | ULTRA Liquid CoverSlip (LCS), predilute | Pre-diluted coverslip solution used as a barrier between aqueous reagents and air to prevent evaporation | | ULTRA CC1 Cell Conditioning Solution | Pre-diluted solution used as a pretreatment step in the processing of FFPE tissue samples or cytologic on the BenchMark ULTRA and BenchMark ULTRA PLUS instruments | ## B. Device Instrumentation and Software The VENTANA MET (SP44) RxDx Assay is performed on the BenchMark ULTRA automated staining instrument using Ventana System Software (VSS) versions 12.3 to 12.5.4 and the BenchMark ULTRA PLUS automated staining instrument using Ventana System Software (VSS) versions 14.1. ## C. Specimen Preparation Routinely processed FFPE non-squamous NSCLC tissues are suitable for use with this primary antibody when used with OptiView DAB IHC Detection Kit and BenchMark ULTRA and ULTRA PLUS instruments. The recommended tissue fixative is 10% neutral buffered formalin (NBF). The samples should be fixed in NBF for 6-72 hours. Fixation times less than 6 hours are not recommended due to loss of specific MET expression. Zinc formalin fixative may also be used using a fixation time of 6-72 hours. Fixatives such as AFA, PREFER fixative, Z-fix, Alcohol Formalin and 95% ethanol are not recommended for use with this assay and due to significant loss of specific MET protein expression. PMA P240037: FDA Summary of Safety and Effectiveness Data {4} Tissue sections should be cut at approximately 4-5 µm thickness and mounted on positively charged glass slides. Slides should be stained immediately or store at 2-8°C for no more than 45 days before staining, as antigenicity of cut tissue sections may diminish over time. See device labeling for additional details. ## D. Quality Control Procedures Run controls are included in each staining run to establish the validity of the test results. The following controls must be run with VENTANA MET (SP44) RxDx Assay: ### 1. Positive/Negative Tissue Control Gallbladder tissue is used as a positive control for this antibody. Positive and negative staining elements for the MET protein present in gall bladder tissues are used to confirm that the VENTANA MET (SP44) RxDx Assay functioned properly. Positive tissue controls should be utilized only for monitoring performance of reagents and instruments, not as an aid in determining specific diagnosis of test samples. The interpretation of the MET staining in gallbladder tissue when used as a positive/negative tissue control is given in the table below. Table 3: Positive/Negative Control Tissue Evaluation, Gallbladder tissue | Staining Elements | Acceptable | Unacceptable | | --- | --- | --- | | Positive | Presence of Moderate* membrane staining in the epithelium | Absence of Moderate * membrane staining in the epithelium | | Negative | Absence of specific MET staining within cells of stromal tissue | Excessive background staining of the stromal tissue that interferes with interpretation | * Moderate staining intensity is characterized by rich brown thickened membranes that are detectable at low magnifications such as 4x or 10x. Refer to the interpretation guide for additional information. ### 2. Negative Reagent Control (NRC) A matched NRC slide should be run for every specimen to aid in the interpretation of results. Rabbit Monoclonal Negative Control Ig, a negative reagent control antibody, is specifically matched for this VENTANA MET (SP44) RxDx Assay and is used on a separate tissue section from the same patient specimen in place of the primary antibody to evaluate nonspecific staining in the patient tissue that may result from a reaction with the detection chemistry and not the MET (SP44) primary antibody. The incubation period for the negative reagent control should equal the primary antibody incubation period. If the NRC slide is considered not acceptable, the MET (SP44) slide should not be evaluated for scoring purposes, and the assay should be repeated. PMA P240037: FDA Summary of Safety and Effectiveness Data 5 of 58 {5} PMA P240037: FDA Summary of Safety and Effectiveness Data 6 of 58 # E. Principles of Operation The VENTANA MET (SP44) RxDx Assay is fully automated for use on the BenchMark ULTRA and BenchMark ULTRA PLUS automated slide stainers from deparaffinization through counterstaining. Patient FFPE tissue specimens are cut to approximately 4-5µm thickness and mounted on positively charged glass slides. These slides are loaded into the Benchmark ULTRA or BenchMark ULTRA PLUS instrument. This system first removes the paraffin wax from the tissue (deparaffinization), and then subjects the tissue to heated antigen retrieval (cell conditioning). Endogenous peroxidases that could potentially react with the horseradish peroxidase conjugates (HRP) are blocked with OptiView Inhibitor (3% H2O2). After the endogenous peroxidase block, the VENTANA MET (SP44) Rabbit Monoclonal Primary Antibody is dispensed during the antibody incubation step and allowed to bind to its antigen. The slides are then incubated with the reagents in the OptiView DAB IHC Detection Kit, which is an indirect, biotin-free system for detecting mouse IgG, mouse IgM, and rabbit primary antibodies and which produces a visible dark brown precipitate (3,3'-Diaminobenzidine) via a horseradish peroxidase (HRP) enzymatic reaction at the antigen site. Slides are then counterstained using Hematoxylin II and Bluing Reagent to create brown/blue contrast to aid the pathologist when reviewing the slides using bright field microscopy. The VENTANA MET (SP44) RxDx Assay staining protocol is shown in the Table 4 below. Table 4. VENTANA MET (SP44) RxDx Assay Staining Protocol with OptiView DAB Detection Kit on BenchMark ULTRA or Benchmark ULTRA PLUS Instrument | Procedure Type | Protocol Parameter | | --- | --- | | Baking | Optional* | | Deparaffinization | 4 minutes (default), 72°C | | Cell Conditioning (Antigen Unmasking) | ULTRA Cell Conditioning 1 64 minutes, 100°C | | Pre-antibody peroxidase inhibitor | 4 minutes, 36°C | | Antibody (Primary) | 16 minutes, 36°C | | Negative Control | 16 minutes, 36°C | | OptiView HQ Linker | 8 minutes, 36°C | | OptiView HRP Multimer | 8 minutes, 36°C | | Counterstain | Hematoxylin II, 4 minutes | | Post Counterstain | Bluing, 4 minutes | *May be performed on-board the instrument (4-32 minutes, 60°C) or performed offline (up to 60 minutes, 60°C) {6} F. Slide Review and Interpretation of MET Staining The cellular staining pattern for VENTANA MET (SP44) RxDx Assay is membranous and/or cytoplasmic in tumor cells in non-squamous NSCLC tissue with varying ranges of stain intensity. The percentage of tumor cells with strong (3+) membranous and/or cytoplasmic staining will be assessed from for specimens containing a minimum of approximately 100 viable tumor cells. Strong (3+) signal intensity is characterized by dark brown to black hue with saturated DAB. Membranes/cytoplasm exhibiting strong signal are detectable at low power magnifications such as 2x or 4x. 1. Hematoxylin &amp; Eosin (H&amp;E) Slide: The pathologist will determine whether the H&amp;E slide contains sufficient tumor tissue (which is defined as presence of a minimum of approximately 100 viable tumor cells) consistent with non-squamous NSCLC cases to allow interpretation of the case-matched IHC slides. If the H&amp;E is not acceptable, the case-matched NRC and MET (SP44) patient case slides will not be evaluated. 2. System-level Control Slide – Tissue Control Slide(s) One system-level control (SLC) slide containing non-neoplastic gallbladder tissue should be included in each BenchMark ULTRA and Benchmark ULTRA PLUS staining run to confirm the validity of the staining run and should be evaluated by a qualified pathologist. Gallbladder tissue contains positive and negative staining elements for the MET protein and is therefore suitable for use as a tissue control. The positive and negative staining elements should be examined to ascertain that all reagents are functioning properly. If these elements fail to demonstrate appropriate staining, any results with the test specimens included in the same staining run should be considered invalid. Gallbladder tissue demonstrates moderate staining of the membrane in epithelial cells and absence of staining within cells of stromal tissue. The pathologist determined whether the SLC slide was acceptable or unacceptable based on criteria presented in Table 3 above. 3. Negative Reagent Control (NRC) Slide The NRC slide is evaluated based on the level of non-specific staining (background). If the NRC slide is not acceptable, slide will not be evaluated, and the assay should be repeated. 4. Patient Tissue Slide MET IHC status will only be assigned if the H&amp;E slide, the system-level control (SLC) slide, the NRC slide, and the VENTANA MET (SP44) antibody case slide (including background, morphology, and overall staining) are all acceptable. Patient specimens should have a minimum of approximately 100 viable tumor cells identified on the H&amp;E in order to determine MET IHC status. Non- PMA P240037: FDA Summary of Safety and Effectiveness Data 7 of 58 {7} squamous NSCLC tissues stained with the VENTANA MET (SP44) RxDx Assay are scored for percent tumor cell with strong membrane and/or cytoplasmic staining intensity. Non-squamous NSCLC tissue cases are considered positive if ≥ 50% of tumor cells (TC) demonstrate strong membranous and/or cytoplasmic MET (SP44) staining. The scoring algorithm for the VENTANA MET (SP44) RxDx Assay is provided in the Table 5 below along with the staining intensities description. For detailed information on the Assay scoring and algorithm, refer to the device package insert and interpretation guide. Table 5. VENTANA MET (SP44) RxDx Assay Scoring Algorithm for non-squamous NSCLC | MET IHC Status | Staining Description | | --- | --- | | Positive* | ≥ 50% of tumor cells with strong membrane and/or cytoplasmic staining intensity (3+). | | Negative* | < 50% of tumor cells with strong membrane and/or cytoplasmic staining intensity (3+) | | Not Evaluable (N/E) | Interpretation is not possible, e.g., no tissue present, presence of staining artifacts or poor tissue quality | *Re-reading by Additional Pathologists for MET Scoring if borderline staining (%TC or intensity) Re-reading by Additional Pathologists for MET Scoring: To decrease variability of MET results for cases with %TC near the threshold of 50% (40% to 60%) or with staining intensity near the strong versus moderate threshold due to reader variability, re-reading of slides that fall into these categories by a second pathologist is recommended. An initial case result with %TC between 40-60% or borderline strong versus moderate intensity by a pathologist should be reviewed by another independent pathologist and the reported results should be based on a consensus score. VI. ALTERNATIVE PRACTICES AND PROCEDURES There is currently no alternative FDA-cleared or approved assays available for detection of MET protein in FFPE non-squamous non-small cell lung cancer tissue as an aid in identifying patients who may be eligible for treatment with EMRELIS™ (telisotuzumab vedotin-tllv). VII. MARKETING HISTORY The VENTANA MET (SP44) RxDx Assay has not been marketed in the United States or any other foreign country. PMA P240037: FDA Summary of Safety and Effectiveness Data 8 of 58 {8} PMA P240037: FDA Summary of Safety and Effectiveness Data 9 of 58 # VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH VENTANA MET (SP44) RxDx Assay is intended for in vitro diagnostic (IVD) use only. As with any IVD test, the potential risks are associated with an incorrect test result or incorrect interpretation of results. Failure of the device to perform as expected or failure to correctly interpret test results may lead to improper patient management decisions. For the specific adverse events that occurred in the EMRELIST™ clinical studies, please see the EMRELIST™ FDA approved package insert, which is available at Drugs@FDA. # IX. SUMMARY OF NON-CLINICAL STUDIES ## A. Laboratory Studies Non-clinical studies were performed using the VENTANA MET (SP44) RxDx Assay to establish analytical performance of the device in NSCLC. These studies were performed using a BenchMark ULTRA instrument using the VSS software version 12.3 to 12.5.4 or BenchMark ULTRA PLUS instrument using the VSS software version 14.1. These studies were conducted to characterize the VENTANA MET (SP44) RxDx Assay, demonstrate the impact of pre-analytical variables on assay performance, verify precision and robustness of the assay, and establish assay stability. The study results detailed below establish sensitivity, specificity, precision, stability, reproducibility, and other performance characteristics of the device. ## 1. Analytical Sensitivity a. Analytical sensitivity of the VENTANA MET (SP44) RxDx Assay was assessed by evaluating a commercial cohort of 100 unique NSCLC FFPE specimens (resection, core needle biopsy (CNB), and cell block [fine needle aspirate (FNA)]). The slides were read by one pathologist and were scored for the percentage of tumor cells with strong membranous and/or cytoplasmic staining intensity. Of the 100 cases, 91 cases had both membrane and cytoplasmic staining, 8 cases had cytoplasmic staining only, while one case had no staining. The specimens showed a percent tumor cell staining range from 0-95% and a staining intensity range of negative (0) to positive (3+). MET positive status was observed in 12% (12/100) of cases. MET negative status was observed in 88% (88/100) of cases. The results from this study are summarized below. {9} Table 6. Prevalence of MET in NSCLC stained with VENTANA MET (SP44) RxDx Assay | Sample Category | MET IHC % TC Bin (min. to max.) | Resection Samples n (%) | FNA Cell Block Samples n (%) | CNB Samples n (%) | | --- | --- | --- | --- | --- | | Negative | 0 to 49 | 45 (90.0%) | 22 (88.0%) | 21 (84.0%) | | Positive | 50 to 100 | 5 (10.0%) | 3 (12.0%) | 4 (16.0%) | ## 2. Analytical Specificity The antibody used in the VENTANA MET (SP44) RxDx Assay is a rabbit monoclonal antibody, clone SP44, produced against the carboxyl region of the human MET protein. The following studies were conducted with MET (SP44) antibody to establish antibody specificity. ### a. Western Blot Studies Western Blot (WB) analysis was performed on whole cell lysates with varying expression levels of MET. The 6 cell lines were NCI-H441 (Lung Adenocarcinoma), NCI-H596 (Lung Adenosquamous Carcinoma), BC-3C (Bladder Carcinoma), HeLa (Cervix Epithelial Carcinoma), C-33A (Cervix Epithelial Carcinoma), and MET knockout (K/O) from HeLa (Cervix Epithelial Carcinoma). VENTANA MET (SP44) antibody reacted with a ~175kD band corresponding in size to the molecular weight (MW) of the MET precursor protein and a ~145kD band corresponding in size to the MW of the MET β chain in the MET-positive NCI-H596, which expresses high levels of MET protein by IHC staining (3+); NCI-H441 (3+); BC-3C (2.5+); and HeLa (2+) cell lines. MET (SP44) also detected a few additional protein products (40-55kD) that were likely MET protein fragments. Importantly, MET (SP44) did not detect any protein in the MET-negative C-33A cell line or in Hela cells following the knockout of the MET gene. Finally, the MET (SP44) antibody also reacted specifically with a 78 kD-fragment derived from purified recombinant MET (rMET) which includes the antibody immunogen. ### b. Peptide Inhibition Study The specificity of primary antibody binding to MET was assessed by pre-incubating the antibody with four different concentrations of the specific peptide containing the antibody binding epitope, or a non-specific peptide. The antibody was diluted 1:1 with either the peptide solutions under investigation or buffer with no peptide. One lot of antibody was used for this study. In the presence of high molar concentrations of this peptide, the MET (SP44) antibody was completely inhibited from binding to tissue expressing MET protein as determined by the absence of IHC staining. The non-specific peptide had no effect on MET staining. PMA P240037: FDA Summary of Safety and Effectiveness Data {10} # c. Immunoreactivity The purpose of this study was to assess the analytical specificity (Tour of Body and Tour of Tumor) including non-specific staining including background and cross-reactivity of VENTANA MET (SP44) antibody in non-neoplastic (TOB) and neoplastic tissue (TOT) samples. One lot each of VENTANA MET (SP44) RxDx Assay and Rabbit Monoclonal Negative Control Ig were used to stain slides containing tissue micro-arrays (TMA) and uni-blocks of non-neoplastic and neoplastic tissue. For the TOB and TOT TMAs and uni-blocks, there were 610 evaluable test samples. For the TOB and TOT, a positive case is defined as having the presence of any MET staining at any intensity. Of the evaluable test samples, $99.3\%$ (606/610) had acceptable MET background staining. MET (SP44) off target nuclear staining was observed in four test samples out of the 610 evaluable samples $(0.66\%)$ . MET (SP44) staining was observed in 94 non-neoplastic test samples out of 223 evaluable samples. Weak to moderate MET staining can occur in type II pneumocytes and the normal epithelium of bronchi and bronchioles in non-neoplastic lung tissue. MET (SP44) staining was observed in 291 neoplastic test samples out of 386 evaluable samples. Tables containing results for non-neoplastic tissues and results for neoplastic tissues are shown below. Table 7. Specificity of VENTANA MET (SP44) RxDx Assay was Determined by Testing FFPE Non-neoplastic Tissues | Tissue | No. Positive/Total Cases | Tissue | No. Positive/Total Cases | | --- | --- | --- | --- | | Cerebrum | 0/7 | Esophagus c | 3/4 | | Cerebellum | 0/7 | Stomach g,h | 7/7 | | Adrenal gland | 0/7 | Small intestine g | 5/7 | | Ovary | 0/7 | Colon g | 5/6 | | Pancreas a | 1/7 | Liver i | 2/7 | | Parathyroid gland | 0/5 | Salivary gland j | 5/6 | | Pituitary gland | 0/5 | Kidney k | 5/9 | | Testis | 0/7 | Prostate c | 5/7 | | Thyroid b | 3/7 | Cervix c | 3/5 | | Breast c | 2/5 | Skin c | 2/5 | | Spleen | 0/6 | Mesothelium l | 3/4 | | Tonsil d | 5/6 | Appendix g | 3/3 | | Endometrium c | 3/6 | Bladder m | 4/5 | | Skeletal muscle | 0/6 | Fallopian tube c | 4/7 | | Nerve | 0/5 | Rectum g | 3/4 | | Thymus e | 0/6 | Ureter n | 2/2 | | Myeloid (bone marrow) | 0/5 | Lymph node (reactive) | 0/1 | | Lung f,g | 13/16 | Placenta o | 5/6 | | Heart | 0/6 | Spinal cord | 0/2 | a acinar cells (focal staining), b follicular cells, c epithelial cells (weak staining), d germinal center lymphocytes (weak staining), e epithelial cells (focal staining), f type 2 pneumocytes, g epithelial cells, h fundic glands, i focal hepatocyte staining, j serous glands and striated duct epithelium, k renal tubular epithelial cells, l mesothelial cells m urothelial cells, n urothelial cells (weak staining), o cytotrophoblastic and syncytiotrophoblastic cells PMA P240037: FDA Summary of Safety and Effectiveness Data {11} Table 8: Specificity of VENTANA MET (SP44) RxDx Assay of FFPE Neoplastic Tissues | Pathology | No. Positive/Total Cases | | --- | --- | | Adenoma, cortical (Adrenal gland) | 0/1 | | Adrenocortical carcinoma (Adrenal gland) | 0/1 | | Urothelial carcinoma (Bladder) | 2/2 | | Fibroadenoma (Breast) | 0/1 | | Osteosarcoma (Bone) | 0/1 | | Chondrosarcoma (Bone) | 0/1 | | Meningioma (Cerebellum) | 0/2 | | Meningioma (Cerebrum) | 1/1 | | Astrocytoma (Cerebrum) | 0/1 | | Squamous cell carcinoma (Esophagus) | 2/2 | | Adenocarcinoma (Stomach) | 3/3 | | Adenoma (Small intestine) | 1/1 | | Adenocarcinoma (Small intestine) | 1/1 | | Adenoma (Colon) | 1/1 | | Adenocarcinoma (Colon) | 3/3 | | Adenocarcinoma (Rectum) | 3/3 | | Clear cell carcinoma (Kidney) | 2/2 | | Hepatocellular carcinoma (Liver) | 2/4 | | Squamous cell carcinoma (Lung) | 105/145 | | Adenocarcinoma (Lung) | 96/116 | | Small cell carcinoma (Lung) | 0/1 | | Adenosquamous carcinoma (Lung) | 1/1 | | Adenocarcinoma in-situ (Lung) | 12/13 | | Mucinous adenocarcinoma (Lung) | 8/8 | | Papillary carcinoma (Lung) | 5/6 | | Neuroendocrine tumor, typical carcinoid (Lung) | 3/11 | | Neuroendocrine carcinoma (Lung) | 5/5 | | Large cell carcinoma (Lung) | 8/9 | | Large cell neuroendocrine carcinoma (Lung) | 3/3 | | Pleomorphic carcinoma (Lung) | 5/5 | | Mucoepidermoid carcinoma (Lung) | 1/1 | | Hodgkin lymphoma (Lymph node) | 0/1 | | B-cell lymphoma, NOS (Lymph node) | 0/1 | | Anaplastic large cell lymphoma (Lymph node) | 0/1 | | Adenocarcinoma (Oral cavity) | 0/1 | | Squamous cell carcinoma (Oral cavity) | 1/1 | | Nasopharyngeal carcinoma (Nasopharynx) | 1/1 | | Granulosa cell tumor (Ovary) | 0/1 | | Adenocarcinoma (Ovary) | 1/1 | | Endometrioid adenocarcinoma (Ovary) | 0/1 | | Adenocarcinoma (Pancreas) | 0/1 | | Adenocarcinoma (Prostate) | 0/2 | | Pleomorphic adenoma (Salivary gland) | 0/1 | | Adenoid cystic carcinoma (Salivary gland) | 1/1 | PMA P240037: FDA Summary of Safety and Effectiveness Data 12 of 58 {12} | Pathology | No. Positive/Total Cases | | --- | --- | | Squamous cell carcinoma (Skin) | 1/1 | | Melanoma (Nasal cavity) | 1/1 | | Seminoma (Testis) | 0/2 | | Adenoma (Thyroid) | 2/3 | | Follicular carcinoma (Thyroid) | 1/1 | | Papillary carcinoma (Thyroid) | 1/1 | | Squamous cell carcinoma (Cervix) | 2/2 | | Adenocarcinoma (Endometrium) | 2/2 | | Metastatic Colon adenocarcinoma (Liver) | 1/1 | | Metastatic Breast ductal carcinoma (Lymph Node) | 1/1 | | Metastatic Colon signet ring cell carcinoma (Ovary) | 1/1 | | Metastatic Esophageal squamous cell carcinoma (Lymph Node) | 1/1 | ## 3. Precision Precision of the VENTANA MET (SP44) RxDx Assay on BenchMark ULTRA and BenchMark ULTRA PLUS was evaluated follows: Intermediate Precision and Repeatability Studies and Reader (Pathologist) Precision. ### a. Intermediate Precision and Repeatability Studies i. Between MET (SP44) Lot, Between Detection Kit Lot, Day, and ULTRA Instrument Intermediate Precision and Within Run Repeatability Twenty-four NSCLC tissue cases (13 MET positive and 11 MET negative, including 5 borderline samples) that encompassed MET IHC staining status range of positive and negative were used in this study. This study was performed using the following design factors on a BenchMark ULTRA instrument: - Three antibody lots of VENTANA MET (SP44) RxDx Assay - Three lots of OptiView DAB IHC Detection Kits - Three BenchMark ULTRA instruments - Across three days - One pathologist reader - 2 replicates per condition - Across all intermediate precision conditions (within-staining run) All slides were blinded and randomized and evaluated using the VENTANA MET (SP44) RxDx Assay scoring algorithm specified in Table 5, above. Each case had 18 results and a majority MET (SP44) status was assigned based on 18 results. For each case, median %TC and range of %TC of 18 results were calculated. In addition, percent positive (%TC ≥50%, "Eligible" with regard to MET therapy) results were calculated. Results are summarized in the tables below. PMA P240037: FDA Summary of Safety and Effectiveness Data {13} Table 9. Median and Range of %TC for Samples in the Intermediate Precision Study (ULTRA) | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results %, (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | | | | | | | Percent Agreement with Majority MET Status %, (n/N) | 95% CI* | | 1 | Negative | 1 | 1, 2 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 2 | Negative | 10 | 5, 15 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 3 | Negative | 15 | 10, 30 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 4 | Negative | 20 | 15, 30 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 5 | Negative | 25 | 20, 40 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 6 | Negative | 30 | 10, 45 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 7 | Negative | 30 | 20, 35 | 0 (0/16) | 100.0 (16/16) | 80.6, 100.0 | | 8 | Negative | 30 | 25, 45 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 9 | Negative | 35 | 30, 40 | 0 (0/18) | 100.0 (18/18) | 82.4, 100.0 | | 10 | Negative | 45 | 40, 60 | 27.8 (5/18) | 72.2 (13/18) | 49.1, 87.5 | | 11 | Negative | 45 | 40, 50 | 5.6 (1/18) | 94.4 (17/18) | 74.2, 99.0 | | 12 | Positive | 55 | 50, 60 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 13 | Positive | 55 | 50, 60 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 14 | Positive | 55 | 45, 65 | 88.9 (16/18) | 88.9 (16/18) | 67.2, 96.9 | | 15 | Positive | 65 | 40, 70 | 83.3 (15/18) | 83.3 (15/18) | 60.8, 94.2 | | 16 | Positive | 70 | 50, 75 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 17 | Positive | 70 | 65, 75 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 18 | Positive | 70 | 50, 75 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 19 | Positive | 75 | 30, 85 | 88.9 (16/18) | 88.8 (16/18) | 67.2, 96.9 | | 20 | Positive | 80 | 40, 85 | 94.4 (17/18) | 94.4 (17/18) | 74.2, 99.0 | | 21 | Positive | 85 | 65, 90 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 22 | Positive | 90 | 55, 95 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 23 | Positive | 90 | 80, 90 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | | 24 | Positive | 95 | 80, 100 | 100.0 (18/18) | 100.0 (18/18) | 82.4, 100.0 | *2-sided 95% CIs were calculated using Wilson score method. PMA P240037: FDA Summary of Safety and Effectiveness Data 14 of 58 {14} Table 10. Precision Components for Samples in the Intermediate Precision Study (ULTRA) | | | | | Standard Deviation | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Case ID | Majority Call MET Result | Number of Results | Median %TC | Within Run | Between Day | Between Antibody Lot | Between Detection Kit | Between Instrument | Total | | 1 | Negative | 18 | 1 | 0.24 | 0.55 | 0 | 0 | 0 | 0.6 | | 2 | Negative | 18 | 10 | 1.18 | 5.71 | 0 | 0 | 0 | 5.83 | | 3 | Negative | 18 | 15 | 4.08 | 4.33 | 0 | 0 | 0 | 5.95 | | 4 | Negative | 18 | 20 | 2.36 | 2.36 | 4.08 | 0 | 4.08 | 6.67 | | 5 | Negative | 18 | 25 | 5.14 | 2.36 | 2.89 | 0 | 3.82 | 7.41 | | 6 | Negative | 18 | 30 | 6.97 | 0 | 3.91 | 4.41 | 0 | 9.13 | | 7 | Negative | 16 | 30 | 2.67 | 4.63 | 0 | 0 | 0 | 5.35 | | 8 | Negative | 18 | 30 | 7.17 | 0 | 6.24 | 5.71 | 3.73 | 11.7 | | 9 | Negative | 18 | 35 | 3.12 | 0 | 0 | 0 | 0 | 3.12 | | 10 | Negative | 18 | 45 | 2.89 | 7.77 | 0 | 0 | 0 | 8.29 | | 11 | Negative | 18 | 45 | 1.18 | 0 | 2.76 | 1.18 | 2.76 | 4.25 | | 12 | Positive | 18 | 55 | 1.67 | 0.83 | 0 | 0 | 0 | 1.86 | | 13 | Positive | 18 | 55 | 1.18 | 2.36 | 3.54 | 2.89 | 2.89 | 6.01 | | 14 | Positive | 18 | 55 | 2.64 | 2.2 | 7.07 | 0 | 4.08 | 8.86 | | 15 | Positive | 18 | 65 | 7.82 | 6.82 | 0 | 8.66 | 0 | 13.51 | | 16 | Positive | 18 | 70 | 6.87 | 0 | 4 | 0 | 0 | 7.95 | | 17 | Positive | 18 | 70 | 2.04 | 0 | 3.54 | 0 | 3.54 | 5.4 | | 18 | Positive | 18 | 70 | 5.53 | 0 | 9.32 | 0 | 0 | 10.83 | | 19 | Positive | 18 | 75 | 5.77 | 21.26 | 0 | 0 | 0 | 22.03 | | 20 | Positive | 18 | 80 | 6.97 | 0 | 0 | 15.63 | 0.83 | 17.14 | | 21 | Positive | 18 | 85 | 5 | 0 | 0 | 5.2 | 0 | 7.22 | | 22 | Positive | 18 | 90 | 10.21 | 6.12 | 0 | 0 | 0 | 11.9 | | 23 | Positive | 18 | 90 | 1.18 | 0 | 3.73 | 4.93 | 0 | 6.29 | | 24 | Positive | 18 | 95 | 3.91 | 5.07 | 0 | 0 | 0 | 6.4 | In addition, a qualitative analysis of different components was performed. Results are summarized in the table below. Table 11. Intermediate Precision of VENTANA MET (SP44) RxDx Assay | Repeatability/ Precision | Agreement | | | | | --- | --- | --- | --- | --- | | | Type | n/N | % | 95% CI* | | Between- Antibody Lots | PPA | 76/78 | 97.4 | 91.7, 100.0 | | | NPA | 64/64 | 100.0 | 94.3, 100.0 | | | OPA | 140/142 | 98.6 | 95.7, 100.0 | | Between-Instruments (BenchMark ULTRA) | PPA | 78/78 | 100.0 | 95.3, 100.0 | | | NPA | 65/65 | 100.0 | 94.4, 100.0 | | | OPA | 143/143 | 100.0 | 97.4, 100.0 | PMA P240037: FDA Summary of Safety and Effectiveness Data {15} | Repeatability/ Precision | Agreement | | | | | --- | --- | --- | --- | --- | | | Type | n/N | % | 95% CI* | | Between-Detection Kits | PPA | 75/78 | 96.2 | 90.3, 100.0 | | | NPA | 61/65 | 93.8 | 83.3, 100.0 | | | OPA | 136/143 | 95.1 | 89.5, 99.3 | | Between-Day | PPA | 75/78 | 96.2 | 89.7, 100.0 | | | NPA | 63/65 | 96.9 | 89.8, 100.0 | | | OPA | 138/143 | 96.5 | 91.7, 100.0 | | Within-Run | PPA | 230/232 | 99.1 | 97.9, 100.0 | | | NPA | 196/198 | 99.0 | 97.5, 100.0 | | | OPA | 426/430 | 99.1 | 98.1, 99.8 | *2-sided 95% confidence intervals were calculated using the percentile bootstrap method from 2,000 bootstrap samples except that the CIs for 100% PPA, NPA and OPA were calculated using Wilson score method. ii. Between Day and Between ULTRA PLUS Instrument Intermediate Precision and Within Run Repeatability Twenty-eight unique NSCLC tissue cases (12 MET positive and 16 MET negative) that encompassed the MET IHC staining status range of positive and negative, using the following design factors on a BenchMark ULTRA PLUS: - Three BenchMark ULTRA PLUS instruments - Across three days - Across all intermediate precision conditions (within-staining run) - One pathologist reader - 2 replicates per condition Table 12. Median and Range of %TC for Samples in the Intermediate Precision Study (ULTRA PLUS) | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results % (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | | | | | | | Percent Agreement with Majority MET Status % (n/N) | 95% CI* | | 1 | Negative | 0 | 0, 1 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 2 | Negative | 0 | 0, 0 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 3 | Negative | 0 | 0, 0 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 4 | Negative | 0 | 0, 1 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 5 | Negative | 0 | 0, 1 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 6 | Negative | 0 | 0, 0 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 7 | Negative | 0.5 | 0, 2 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 8 | Negative | 1 | 0, 1 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 9 | Negative | 2 | 1, 5 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 10 | Negative | 5 | 1, 10 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 11 | Negative | 5 | 2, 10 | 0 | 100.0 (10/10) | 72.2, 100.0 | PMA P240037: FDA Summary of Safety and Effectiveness Data {16} | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results % (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | | | | | | | Percent Agreement with Majority MET Status % (n/N) | 95% CI* | | 12 | Negative | 17.5 | 10, 20 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 13 | Negative | 17.5 | 5, 40 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 14 | Negative | 17.5 | 15, 30 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 15 | Negative | 20 | 20, 20 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 16 | Negative | 25 | 25, 35 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 17 | Negative | 30 | 25, 35 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 18 | Negative | 35 | 30, 40 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 19 | Negative | 35 | 25, 45 | 0 | 100.0 (10/10) | 72.2, 100.0 | | 20 | Positive | 70 | 50, 95 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 21 | Positive | 80 | 70, 85 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 22 | Positive | 80 | 70, 85 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 23 | Positive | 80 | 70, 90 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 24 | Positive | 85 | 75, 90 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 25 | Positive | 87.5 | 70, 95 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 26 | Positive | 96.5 | 75, 100 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 27 | Positive | 98 | 90, 100 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | | 28 | Positive | 100 | 70, 100 | 100.0 (10/10) | 100.0 (10/10) | 72.2, 100.0 | *2-sided 95% CIs were calculated using Wilson score method. Table 13. Precision Components for Samples in the Intermediate Precision Study (ULTRA PLUS) | | | | | Standard Deviation | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | Case ID | Majority Call MET Result | Number of Results | Median %TC | Within Run | Between Day | Between Instrument | Total | | 1 | Negative | 10 | 0.0 | 0.32 | 0.00 | 0.18 | 0.37 | | 2 | Negative | 10 | 0.0 | 0.00 | 0.00 | 0.00 | 0.00 | | 3 | Negative | 10 | 0.0 | 0.00 | 0.00 | 0.00 | 0.00 | | 4 | Negative | 10 | 0.0 | 0.32 | 0.18 | 0.00 | 0.37 | | 5 | Negative | 10 | 0.0 | 0.32 | 0.00 | 0.18 | 0.37 | | 6 | Negative | 10 | 0.0 | 0.00 | 0.00 | 0.00 | 0.00 | | 7 | Negative | 10 | 0.5 | 0.45 | 0.39 | 0.58 | 0.83 | | 8 | Negative | 10 | 1.0 | 0.45 | 0.00 | 0.39 | 0.59 | | 9 | Negative | 10 | 2.0 | 0.00 | 0.58 | 2.00 | 2.08 | | 10 | Negative | 10 | 5.0 | 2.53 | 4.14 | 0.00 | 4.85 | | 11 | Negative | 10 | 5.0 | 0.95 | 2.81 | 1.80 | 3.47 | | 12 | Positive | 10 | 17.5 | 3.16 | 1.83 | 5.00 | 6.19 | | 13 | Positive | 10 | 17.5 | 11.51 | 0.00 | 0.00 | 11.51 | PMA P240037: FDA Summary of Safety and Effectiveness Data {17} | | | | | Standard Deviation | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | Case ID | Majority Call MET Result | Number of Results | Median %TC | Within Run | Between Day | Between Instrument | Total | | 14 | Positive | 10 | 17.5 | 5.70 | 0.00 | 2.96 | 6.42 | | 15 | Positive | 10 | 20.0 | 0.00 | 0.00 | 0.00 | 0.00 | | 16 | Positive | 10 | 25.0 | 4.47 | 0.00 | 0.00 | 4.47 | | 17 | Positive | 10 | 30.0 | 4.18 | 0.00 | 0.00 | 4.18 | | 18 | Positive | 10 | 35.0 | 1.58 | 0.91 | 4.79 | 5.12 | | 19 | Positive | 10 | 35.0 | 3.87 | 5.66 | 0.00 | 6.86 | | 20 | Positive | 10 | 70.0 | 11.07 | 0.00 | 6.86 | 13.02 | | 21 | Positive | 10 | 80.0 | 4.47 | 3.87 | 0.00 | 5.92 | | 22 | Positive | 10 | 80.0 | 3.16 | 1.83 | 7.07 | 7.96 | | 23 | Positive | 10 | 80.0 | 4.47 | 0.00 | 4.83 | 6.58 | | 24 | Positive | 10 | 85.0 | 4.74 | 1.83 | 0.00 | 5.08 | Table 14. Intermediate Precision of VENTANA MET (SP44) RxDx Assay | Repeatability/ Precision | Agreement | | | | | --- | --- | --- | --- | --- | | | Type | n/N | % | 95% CI* | | Between-Instruments (BenchMark ULTRA PLUS) | PPA | 54/54 | 100.0 | 93.4, 100.0 | | | NPA | 114/114 | 100.0 | 96.7, 100.0 | | | OPA | 168/168 | 100.0 | 97.8, 100.0 | | Between-Day | PPA | 54/54 | 100.0 | 93.4, 100.0 | | | NPA | 114/114 | 100.0 | 96.7, 100.0 | | | OPA | 168/168 | 100.0 | 97.8, 100.0 | | Within-Run | PPA | 45/45 | 100.0 | 92.1, 100.0 | | | NPA | 95/95 | 100.0 | 96.1, 100.0 | | | OPA | 140/140 | 100.0 | 97.3, 100.0 | *2-sided 95% confidence intervals were calculated using the Wilson score method. iii. BenchMark ULTRA and BenchMark ULTRA PLUS Between Day, and Between Platform Precision Twenty-eight unique NSCLC tissue cases (16 MET positive, 12 MET negative, including 4 borderline samples) that encompassed the MET IHC staining status range of positive and negative, using the following design factors on a BenchMark ULTRA and BenchMark ULTRA PLUS. - Across five days - One pathologist reader - 2 replicates per condition PMA P240037: FDA Summary of Safety and Effectiveness Data {18} Table 15. Median and Range of %TC for Samples in the Intermediate Precision Study (ULTRA &amp; ULTRA PLUS) | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results %, (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | | | | | | | Percent Agreement with Majority MET Status %, (n/N) | 95% CI* | | 1 | Negative | 0 | 0, 0 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 2 | Negative | 0 | 0, 0 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 3 | Negative | 0 | 0, 0 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 4 | Negative | 0 | 0, 1 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 5 | Negative | 1 | 0, 1 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 6 | Negative | 1 | 1, 2 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 7 | Negative | 5 | 0, 10 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 8 | Negative | 5 | 0, 20 | 0 | 100.0 (19/19) | 83.2, 100.0 | | 9 | Negative | 5 | 0, 20 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 10 | Negative | 15 | 10, 20 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 11 | Negative | 15 | 10, 20 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 12 | Negative | 20 | 10, 40 | 0 | 100.0 (18/18) | 82.4, 100.0 | | 13 | Negative | 20 | 0, 20 | 0 | 100.0 (20/20) | 83.9, 100.0 | | 14 | Negative | 30 | 10, 65 | 15.8 (3/19) | 84.2 (16/19) | 62.4, 94.5 | | 15 | Negative | 40 | 25, 55 | 5.0 (1/20) | 95.0 (19/20) | 76.4, 99.1 | | 16 | Positive | 50 | 50, 60 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 17 | Positive | 55 | 15, 75 | 85.0 (17/20) | 85.0 (17/20) | 64.0, 94.8 | | 18 | Positive | 60 | 20, 75 | 85.0 (17/20) | 85.0 (17/20) | 64.0, 94.8 | | 19 | Positive | 65 | 55, 80 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 20 | Positive | 65 | 10, 90 | 85.0 (17/20) | 85.0 (17/20) | 64.0, 94.8 | | 21 | Positive | 70 | 60, 95 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 22 | Positive | 72.5 | 30, 90 | 95.0 (19/20) | 95.0 (19/20) | 76.4, 99.1 | | 23 | Positive | 87.5 | 75, 95 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 24 | Positive | 90 | 75, 100 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 25 | Positive | 95 | 50, 99 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 26 | Positive | 95 | 80, 100 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | | 27 | Positive | 98 | 10, 99 | 95.0 (19/20) | 95.0 (19/20) | 76.4, 99.1 | | 28 | Positive | 100 | 100, 100 | 100.0 (20/20) | 100.0 (20/20) | 83.9, 100.0 | *95% CIs were calculated using Wilson score method. PMA P240037: FDA Summary of Safety and Effectiveness Data 19 of 58 {19} Table 16. Precision Components for Samples in the Intermediate Precision Study (ULTRA &amp; ULTRA PLUS) | | | | | | Standard Deviation | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Case ID | Majority Call MET Result | Number of Results | Median %TC | Range %TC (Min to Max) | Within Run | Between Day | Between Platform | Total | | 1 | Negative | 20 | 0 | 0, 0 | 0 | 0 | 0 | 0 | | 2 | Negative | 20 | 0 | 0, 0 | 0 | 0 | 0 | 0 | | 3 | Negative | 20 | 0 | 0, 0 | 0 | 0 | 0 | 0 | | 4 | Negative | 20 | 0 | 0, 1 | 0.22 | 0 | 0 | 0.22 | | 5 | Negative | 20 | 1 | 0, 1 | 0.32 | 0.21 | 0.37 | 0.53 | | 6 | Negative | 20 | 1 | 1, 2 | 0.22 | 0 | 0 | 0.22 | | 7 | Negative | 20 | 5 | 0, 10 | 2.55 | 0 | 2.19 | 3.36 | | 8 | Negative | 19 | 5 | 0, 20 | 4.29 | 0.31 | 0.66 | 4.35 | | 9 | Negative | 20 | 5 | 0, 20 | 3.04 | 2.97 | 5.7 | 7.11 | | 10 | Negative | 20 | 15 | 10, 20 | 2.24 | 1.94 | 1.12 | 3.16 | | 11 | Negative | 20 | 15 | 10, 20 | 2.5 | 0 | 2.5 | 3.54 | | 12 | Negative | 18 | 20 | 10, 40 | 5.45 | 0 | 2.89 | 6.17 | | 13 | Negative | 20 | 20 | 0, 20 | 4.74 | 0 | 2.02 | 5.15 | | 14 | Negative | 19 | 30 | 10, 65 | 7.82 | 0 | 16.65 | 18.4 | | 15 | Negative | 20 | 40 | 25, 55 | 4.33 | 0 | 5.56 | 7.05 | | 16 | Positive | 20 | 50 | 50, 60 | 2.96 | 0 | 2.68 | 3.99 | | 17 | Positive | 20 | 55 | 15, 75 | 7.98 | 6.44 | 14.72 | 17.94 | | 18 | Positive | 20 | 60 | 20, 75 | 5.36 | 10.78 | 13.03 | 17.74 | | 19 | Positive | 20 | 65 | 55, 80 | 6.71 | 0 | 6.3 | 9.2 | | 20 | Positive | 20 | 65 | 10, 90 | 12.65 | 0 | 16.59 | 20.86 | | 21 | Positive | 20 | 70 | 60, 95 | 6.8 | 1.37 | 4.26 | 8.14 | | 22 | Positive | 20 | 72.5 | 30, 90 | 8.94 | 13.28 | 8.86 | 18.3 | | 23 | Positive | 20 | 87.5 | 75, 95 | 5.81 | 0 | 3.83 | 6.96 | | 24 | Positive | 20 | 90 | 75, 100 | 7.17 | 0 | 3.61 | 8.03 | | 25 | Positive | 20 | 95 | 50, 99 | 5.2 | 0 | 10.87 | 12.05 | | 26 | Positive | 20 | 95 | 80, 100 | 4.28 | 1.63 | 0 | 4.58 | | 27 | Positive | 20 | 98 | 10, 99 | 20.12 | 2.74 | 0 | 20.31 | | 28 | Positive | 20 | 100 | 100, 100 | 0 | 0 | 0 | 0 | PMA P240037: FDA Summary of Safety and Effectiveness Data 20 of 58 {20} Table 17. Intermediate Precision of VENTANA MET (SP44) RxDx Assay | Repeatability/ Precision | Agreement | | | | | --- | --- | --- | --- | --- | | | Type | n/N | % | 95% CI* | | Between-Platform | PPA | 249/260 | 95.8 | 92.1, 100.0 | | | NPA | 292/296 | 98.6 | 96.3, 100.0 | | | OPA | 541/556 | 97.3 | 95.1, 99.1 | | Between-Day (ULTRA) | PPA | 120/130 | 92.3 | 85.5, 98.0 | | | NPA | 144/147 | 98.0 | 94.7, 100.0 | | | OPA | 264/277 | 95.3 | 91.8, 98.2 | | Between-Day (ULTRA PLUS) | PPA | 129/130 | 99.2 | 97.7, 100.0 | | | NPA | 148/149 | 99.3 | 97.8, 100.0 | | | OPA | 277/279 | 99.3 | 98.2, 100.0 | *2-sided 95% confidence intervals were calculated using the percentile bootstrap method from 2,000 bootstrap samples. iv. Between Day Intermediate Precision – Biopsy Sample Type Twenty unique NSCLC biopsy cases (9 MET positive, 11 MET negative, including 3 borderline samples) that encompassed the MET IHC staining status range of positive and negative, using the following design factors on a BenchMark ULTRA. - Across three days - One pathologist reader - 2 replicates per condition Table 18. Median and Range of %TC for Samples in the Between Day Intermediate Precision Study for Biopsy Sample Types | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results, % (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | | | | | | | Percent Agreement with Majority MET Status, % (n/N) | 95% CI* | | 1 | Negative | 0.0 | (0, 0) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 2 | Negative | 0.0 | (0, 1) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 3 | Negative | 0.0 | (0, 0) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 4 | Negative | 1.0 | (1, 2) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 5 | Negative | 1.5 | (0, 5) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 6 | Negative | 5.0 | (2, 5) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 7 | Negative | 5.0 | (5, 10) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 8 | Negative | 5.0 | (5, 5) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 9 | Negative | 10.0 | (2, 25) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 10 | Negative | 15.0 | (10, 25) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 11 | Negative | 17.5 | (10, 25) | 0 | 100.0 (6/6) | 61.0, 100.0 | PMA P240037: FDA Summary of Safety and Effectiveness Data {21} | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results, % (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | | | | | | | Percent Agreement with Majority MET Status, % (n/N) | 95% CI* | | 12 | Negative | 20.0 | (15, 20) | 0 | 100.0 (6/6) | 61.0, 100.0 | | 13 | Negative | 35.0 | (30, 60) | 16.7 (1/6) | 83.3, (5/6) | 43.6, 97.0 | | 14 | Positive | 55.0 | (50, 65) | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | 15 | Positive | 55.0 | (15, 75) | 66.7 (4/6) | 66.7 (4/6) | 30.0, 90.3 | | 16 | Positive | 60.0 | (55, 75) | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | 17 | Positive | 75.0 | (65, 75) | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | 18 | Positive | 80.0 | (75, 85) | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | 19 | Positive | 82.5 | (65, 90) | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | 20 | Positive | 92.5 | (50, 100) | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | *95% CIs were calculated using Wilson score method. PMA P240037: FDA Summary of Safety and Effectiveness Data 22 of 58 {22} Table 19. Components for Samples in Between Day Intermediate Precision Study for Biopsy Sample Types | | | | | Standard Deviation | | | --- | --- | --- | --- | --- | --- | | Case ID | Majority MET (SP44) Status | Number of Results | Median %TC | Between Day | Total | | 1 | Negative | 6 | 0.0 | 0.00 | 0.00 | | 2 | Negative | 6 | 0.0 | 0.00 | 0.41 | | 3 | Negative | 6 | 0.0 | 0.00 | 0.00 | | 4 | Negative | 6 | 1.0 | 0.00 | 0.58 | | 5 | Negative | 6 | 1.5 | 2.55 | 2.58 | | 6 | Negative | 6 | 5.0 | 1.73 | 1.73 | | 7 | Negative | 6 | 5.0 | 0.00 | 2.89 | | 8 | Negative | 6 | 5.0 | 0.00 | 0.00 | | 9 | Negative | 6 | 10.0 | 10.23 | 10.43 | | 10 | Negative | 6 | 15.0 | 2.89 | 6.77 | | 11 | Negative | 6 | 17.5 | 0.00 | 6.45 | | 12 | Negative | 6 | 20.0 | 0.00 | 2.04 | | 13 | Negative | 6 | 35.0 | 9.90 | 11.81 | | 14 | Positive | 6 | 55.0 | 6.45 | 6.77 | | 15 | Positive | 6 | 55.0 | 20.10 | 22.91 | | 16 | Positive | 6 | 60.0 | 10.41 | 10.41 | | 17 | Positive | 6 | 75.0 | 0.00 | 4.08 | | 18 | Positive | 6 | 80.0 | 3.54 | 4.08 | | 19 | Positive | 6 | 82.5 | 7.64 | 9.57 | | 20 | Positive | 6 | 92.5 | 5.00 | 19.04 | Table 20. VENTANA MET (SP44) RxDx Assay Between Day Biopsy Intermediate Precision | Agreement Rate | n/N (Sample) | Percentage (95% Confidence Interval*) | | --- | --- | --- | | PPA | 40/42 | 95.2 (85.2, 100.0) | | NPA | 77/78 | 98.7 (95.8, 100.0) | | OPA | 117/120 | 97.5 (93.3, 100.0) | *2-sided 95% confidence intervals were calculated using the percentile bootstrap method from 2,000 bootstrap samples. 1. Between Day Intermediate Precision - Cell Block Sample Type Twenty-one unique NSCLC cell block (FNA) cases (10 MET positive, 11 MET negative) that encompassed the MET IHC staining status range of positive and negative, using the following design factor on a BenchMark ULTRA. PMA P240037: FDA Summary of Safety and Effectiveness Data {23} - Across three days Sixteen unique NSCLC cell block (pleural effusion) (2 MET positive, 14 MET negative, including 1 borderline sample) cases that encompassed the MET IHC staining status range of positive and negative, using the following design factor on a BenchMark ULTRA. - Across three days Table 21. Median and Range of %TC for Samples in the Between Day Intermediate Precision Study for Cell Block Samples | Cell Block Type | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results, % (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | | Percent Agreement with Majority MET Status, % (n/N) | 95% CI* | | FNA | 1 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 2 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 3 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 4 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 5 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 6 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 7 | Negative | 1.5 | 1, 2 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 8 | Negative | 10.0 | 1, 15 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 9 | Negative | 10.0 | 10, 15 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 10 | Negative | 15.0 | 5, 20 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 11 | Negative | 25.0 | 20, 30 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 12 | Negative | 30.0 | 30, 40 | 0 | 100.0 (6/6) | 61.0, 100.0 | | FNA | 13 | Positive | 72.5 | 70, 75 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 14 | Positive | 75.0 | 60, 80 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 15 | Positive | 85.0 | 85, 90 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 16 | Positive | 85.0 | 80, 85 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 17 | Positive | 87.5 | 85, 90 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 18 | Positive | 95.0 | 95, 95 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 19 | Positive | 95.0 | 90, 95 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 20 | Positive | 95.0 | 95, 95 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | FNA | 21 | Positive | 95.0 | 90, 95 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 22 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 23 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 24 | Negative | 0.0 | 0, 0 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 25 | Negative | 1.0 | 1, 2 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 26 | Negative | 1.0 | 1, 1 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 27 | Negative | 1.5 | 1, 2 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 28 | Negative | 2.0 | 2, 5 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 29 | Negative | 5.0 | 2, 10 | 0 | 100.0 (6/6) | 61.0, 100.0 | PMA P240037: FDA Summary of Safety and Effectiveness Data {24} PMA P240037: FDA Summary of Safety and Effectiveness Data 25 of 58 Table 22. Precision Components for Samples in Between Day Intermediate Precision Study for Cell Block Samples | Cell Block Type | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong Tumor Cell (Min., Max.) | Percent Positive Results, % (n/N) | Agreement | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | | Percent Agreement with Majority MET Status, % (n/N) | 95% CI* | | Pleural effusion | 30 | Negative | 10.0 | 10, 20 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 31 | Negative | 15.0 | 10, 20 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 32 | Negative | 17.5 | 15, 20 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 33 | Negative | 20.0 | 15, 20 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 34 | Negative | 37.5 | 35, 40 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 35 | Negative | 45.0 | 40, 45 | 0 | 100.0 (6/6) | 61.0, 100.0 | | Pleural effusion | 36 | Positive | 75.0 | 65, 75 | 100.0 (5/5) | 100.0 (5/5) | 56.6, 100.0 | | Pleural effusion | 37 | Positive | 95.0 | 95, 95 | 100.0 (6/6) | 100.0 (6/6) | 61.0, 100.0 | *2-sided 95% confidence intervals were calculated using the Wilson score method. | | | | | | Standard Deviation | | | --- | --- | --- | --- | --- | --- | --- | | Cell Block Type | Case ID | Majority MET (SP44) Status | Number of Results | Median %TC | Between Day | Total | | FNA | 1 | Negative | 6 | 0.0 | 0.00 | 0.00 | | FNA | 2 | Negative | 6 | 0.0 | 0.00 | 0.00 | | FNA | 3 | Negative | 6 | 0.0 | 0.00 | 0.00 | | FNA | 4 | Negative | 6 | 0.0 | 0.00 | 0.00 | | FNA | 5 | Negative | 6 | 0.0 | 0.00 | 0.00 | | FNA | 6 | Negative | 6 | 0.0 | 0.00 | 0.00 | | FNA | 7 | Negative | 6 | 1.5 | 0.41 | 0.58 | | FNA | 8 | Negative | 6 | 10.0 | 4.96 | 5.97 | | FNA | 9 | Negative | 6 | 10.0 | 0.00 | 2.89 | | FNA | 10 | Negative | 6 | 15.0 | 5.40 | 7.07 | | FNA | 11 | Negative | 6 | 25.0 | 1.44 | 3.23 | | FNA | 12 | Negative | 6 | 30.0 | 0.00 | 4.56 | | FNA | 13 | Positive | 6 | 72.5 | 2.04 | 2.89 | | FNA | 14 | Positive | 6 | 75.0 | 0.00 | 8.42 | | FNA | 15 | Positive | 6 | 85.0 | 2.89 | 2.89 | | FNA | 16 | Positive | 6 | 85.0 | 2.89 | 2.89 | | FNA | 17 | Positive | 6 | 87.5 | 2.04 | 2.89 | | FNA | 18 | Positive | 6 | 95.0 | 0.00 | 0.00 | | FNA | 19 | Positive | 6 | 95.0 | 2.89 | 2.89 | | FNA | 20 | Positive | 6 | 95.0 | 0.00 | 0.00 | | FNA | 21 | Positive | 6 | 95.0 | 2.89 | 2.89 | {25} | | | | | | Standard Deviation | | | --- | --- | --- | --- | --- | --- | --- | | Cell Block Type | Case ID | Majority MET (SP44) Status | Number of Results | Median %TC | Between Day | Total | | Pleural effusion | 22 | Negative | 6 | 0.0 | 0.00 | 0.00 | | Pleural effusion | 23 | Negative | 6 | 0.0 | 0.00 | 0.00 | | Pleural effusion | 24 | Negative | 6 | 0.0 | 0.00 | 0.00 | | Pleural effusion | 25 | Negative | 6 | 1.0 | 0.58 | 0.58 | | Pleural effusion | 26 | Negative | 6 | 1.0 | 0.00 | 0.00 | | Pleural effusion | 27 | Negative | 6 | 1.5 | 0.41 | 0.58 | | Pleural effusion | 28 | Negative | 6 | 2.0 | 0.00 | 1.22 | | Pleural effusion | 29 | Negative | 6 | 5.0 | 1.12 | 2.63 | | Pleural effusion | 30 | Negative | 6 | 10.0 | 0.00 | 4.56 | | Pleural effusion | 31 | Negative | 6 | 15.0 | 3.54 | 4.08 | | Pleural effusion | 32 | Negative | 6 | 17.5 | 2.04 | 2.89 | | Pleural effusion | 33 | Negative | 6 | 20.0 | 0.00 | 2.89 | | Pleural effusion | 34 | Negative | 6 | 37.5 | 2.04 | 2.89 | | Pleural effusion | 35 | Negative | 6 | 45.0 | 0.00 | 2.89 | | Pleural effusion | 36 | Positive | 5 | 75.0 | 5.77 | 5.77 | | Pleural effusion | 37 | Positive | 6 | 95.0 | 0.00 | 0.00 | Table 23. VENTANA MET (SP44) RxDx Assay Between Day Biopsy Intermediate Precision for Cell Block Samples | Precision | Agreement Rate | n/N (Sample) | Percentage (95% Confidence Interval*) | | --- | --- | --- | --- | | Between Day - FNA | PPA | 54/54 | 100.0 (93.4, 100.0) | | | NPA | 72/72 | 100.0 (94.9, 100.0) | | | OPA | 126/126 | 100.0 (97.0, 100.0) | | Between Day – Pleural Effusion | PPA | 11/11 | 100.0 (74.1, 100.0) | | | NPA | 84/84 | 100.0 (95.6, 100.0) | | | OPA | 95/95 | 100.0 (96.1, 100.0) | *2-sided 95% confidence intervals were calculated using the Wilson score method. Results from above studies (4.a.i. - 4.a.v.) are summarized in the table below. PMA P240037: FDA Summary of Safety and Effectiveness Data {26} Table 24. Summary of VENTANA MET (SP44) RxDx Assay Intermediate Precision and Repeatability | Repeatability/Precision | Agreement | | | | --- | --- | --- | --- | | | Type | n/N | Percentage (95% Confidence Interval) | | Between-Antibody Lots | PPA | 76/78 | 97.4% (91.7, 100.0) | | | NPA | 64/64 | 100.0% (94.3, 100.0) | | | OPA | 140/142 | 98.6% (95.7, 100.0) | | Between-Detection Kit Lots | PPA | 75/78 | 96.2% (90.3, 100.0) | | | NPA | 61/65 | 93.8% (83.3, 100.0) | | | OPA | 136/143 | 95.1% (89.5, 99.3) | | Between-Instruments (BenchMark ULTRA) | PPA | 78/78 | 100.0% (95.3, 100.0) | | | NPA | 65/65 | 100.0% (94.4, 100.0) | | | OPA | 143/143 | 100.0% (97.4, 100.0) | | Between-3 non-consecutive Day (BenchMark ULTRA) | PPA | 75/78 | 96.2% (89.7, 100.0) | | | NPA | 63/65 | 96.9% (89.8, 100.0) | | | OPA | 138/143 | 96.5% (91.7, 100.0) | | Within-Run (BenchMark ULTRA) | PPA | 230/232 | 99.1 (97.9, 100.0) | | | NPA | 196/198 | 99.0 (97.5, 100.0) | | | OPA | 426/430 | 99.1 (98.1, 99.8) | | Between-Instruments (BenchMark ULTRA PLUS) | PPA | 54/54 | 100.0% (93.4, 100.0) | | | NPA | 114/114 | 100.0% (96.7, 100.0) | | | OPA | 168/168 | 100.0% (97.8, 100.0) | | Between-3 non-consecutive Day (BenchMark ULTRA PLUS) | PPA | 54/54 | 100.0% (93.4, 100.0) | | | NPA | 114/114 | 100.0% (96.7, 100.0) | | | OPA | 168/168 | 100.0% (97.8, 100.0) | | Within-Run (BenchMark ULTRA PLUS) | PPA | 45/45 | 100.0% (92.1, 100.0) | | | NPA | 95/95 | 100.0% (96.1, 100.0) | | | OPA | 140/140 | 100.0% (97.3, 100.0) | | Between-5 non-consecutive Day (BenchMark ULTRA) | PPA | 120/130 | 92.3% (85.5, 98.0) | | | NPA | 144/147 | 98.0% (94.7, 100.0) | | | OPA | 264/277 | 95.3% (91.8, 98.2) | | Between-5 non-consecutive Day (BenchMark ULTRA PLUS) | PPA | 129/130 | 99.2% (97.7, 100.0) | | | NPA | 148/149 | 99.3% (97.8, 100.0) | | | OPA | 277/279 | 99.3% (98.2, 100.0) | | Between-Platform | PPA | 249/260 | 95.8% (92.1, 100.0) | | | NPA | 292/296 | 98.6% (96.3, 100.0) | | | OPA | 541/556 | 97.3% (95.1, 99.1) | | Between-Day – Biopsy (BenchMark ULTRA) | PPA | 40/42 | 95.2% (85.2, 100.0) | | | NPA | 77/78 | 98.7% (95.8, 100.0) | | | OPA | 117/120 | 97.5% (93.3, 100.0) | | Between Day – Cell Block; FNA (BenchMark ULTRA) | PPA | 54/54 | 100.0% (93.4, 100.0) | | | NPA | 72/72 | 100.0% (94.9, 100.0) | | | OPA | 126/126 | 100.0% (97.0, 100.0) | PMA P240037: FDA Summary of Safety and Effectiveness Data 27 of 58 {27} | Repeatability/ Precision | Agreement | | | | --- | --- | --- | --- | | | Type | n/N | Percentage (95% Confidence Interval) | | Between Day – Cell Block; Pleural Effusion (BenchMark ULTRA) | PPA | 11/11 | 100.0% (74.1, 100.0) | | | NPA | 84/84 | 100.0% (95.6, 100.0) | | | OPA | 95/95 | 100.0% (96.1, 100.0) | ## b. Reader Precision ### i. Between and Within Reader Precision In the Reader Precision study for VENTANA MET (SP44) RxDx Assay, Within-Reader and Between-Reader components of precision for NSCLC tissue reads were evaluated. The study included 100 unique NSCLC specimens (50 MET positive and 50 MET negative, including 12 borderline samples) that were stained with VENTANA MET (SP44) RxDx Assay. Specimens were blinded and randomized prior to evaluation for MET status using the VENTANA MET (SP44) RxDx Assay scoring algorithm specified in Table 5, above. The study included three readers (pathologists). Readers scored all specimens twice, with a minimum of two-week wash-out period between reads. Each case had 6 reads (2 reads by each of three readers). Variability of %TC values for 100 cases was evaluated and the following precision components were calculated: within-reader, between-reader, and total. Data of the Reader Precision study is presented in Table 25, below. Table 25. Precision Components for Samples in Reader Precision of VENTANA MET (SP44) RxDx Assay | | | | | | Standard Deviation | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Sample Category | MET IHC %TC Bin (min. to max.) | n of Samples | n of reads | Range of Median %TC | Within Reader | Between Reader | Total | Percent Positive Results, % (n/N) | | Negative | 0 to 39 | 47 | 282 | 0.0 - 37.5 | 5.02 | 9.8 | 11.01 | 0.7 (2/282) | | Borderline Negative | 40 to 49 | 4 | 24 | 40.0 - 47.5 | 1.84 | 10.05 | 10.21 | 20.8 (5/24) | | Borderline Positive | 50 to 60 | 8 | 48 | 50.0 - 60.0 | 7.37 | 3.5 | 8.16 | 93.8 (45/48) | | Positive | 61 to 100 | 41 | 246 | 65.0 - 99.5 | 6.8 | 10.27 | 12.32 | 98.0 (241/246) | In addition, within-reader and between-reader precision was determined with average positive agreement (APA), average negative agreement (ANA), and overall percent agreement (OPA) across all observations. This data is summarized in Table 26, below. PMA P240037: FDA Summary of Safety and Effectiveness Data {28} Table 26. Within-Reader and Between Reader Precision of VENTANA MET (SP44) RxDx Assay | Precision | Agreement | | | | | --- | --- | --- | --- | --- | | | Type | n/N | % | 95% CI* | | Within-Reader | APA | 288/293 | 98.3 | 91.3, 98.2 | | | ANA | 302/307 | 98.4 | 91.9, 98.4 | | | OPA | 295/300 | 98.3 | 92.0, 98.0 | | Between-Reader | APA | 278/292 | 95.2 | 96.6, 99.6 | | | ANA | 294/308 | 95.5 | 96.6, 99.7 | | | OPA | 286/300 | 95.3 | 96.7, 99.7 | Average Positive Agreement (APA), Average Negative Agreement (ANA), Overall Percent Agreement (OPA) *2-sided 95% confidence intervals were calculated using the percentile bootstrap method from 2,000 bootstrap samples. ii. Between and Within Reader Precision in Cell Block Sample Types In the Reader Precision study for VENTANA MET (SP44) RxDx Assay, Within-Reader and Between-Reader components of precision for NSCLC cell block reads were evaluated. The study included 40 unique NSCLC cell block cases (38 FNA and 2 pleural effusion; 20 MET positive, 20 MET negative, including 3 borderline samples) that were stained with VENTANA MET (SP44) RxDx Assay. Specimens were blinded and randomized prior to evaluation for MET status using the VENTANA MET (SP44) RxDx Assay scoring algorithm specified in Table 5, above. The study included four readers (pathologists). Readers scored all specimens twice, with a minimum of two-week wash-out period between reads. Each case had 8 reads (2 reads by each of four readers). Variability of %TC values for 40 cases was evaluated and the following precision components were calculated: within-reader, between-reader, and total. Data of the Reader Precision study is presented in Table 27, below. Table 27. Precision Components for Samples in Reader Precision Study of VENTANA MET (SP44) RxDx Assay in Cell Block Sample Types | | | | | | Standard Deviation | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Sample Category | MET IHC %TC Bin (min. to max.) | n of Samples | n of reads | Range of Median %TC | Within Reader | Between Reader | Total | Percent Positive Results, % (n/N) | | Negative | 0 to 39 | 17 | 136 | 0.0 - 35.0 | 4.38 | 9.45 | 10.41 | 1.5 (2/136) | | Borderline Negative | 40 to 49 | 3 | 24 | 42.5 - 45.0 | 13.32 | 15.13 | 20.16 | 20.8 (5/24) | | Borderline Positive | 50 to 60 | 0 | 0 | N/A | N/A | N/A | N/A | N/A | | Positive | 61 to 100 | 20 | 160 | 70.0 - 100.0 | 5.88 | 7.29 | 9.37 | 98.8 (158/160) | PMA P240037: FDA Summary of Safety and Effectiveness Data 29 of 58 {29} Table 28. Within-Reader and Between Reader Precision of VENTANA MET (SP44) RxDx Assay in Cell Block Sample Types | Precision | Agreement | | | | | --- | --- | --- | --- | --- | | | Type | n/N | % | 95% CI* | | Within-Reader | APA | 164/165 | 99.4 | 98.1, 100.0 | | | ANA | 154/155 | 99.4 | 98.1, 100.0 | | | OPA | 159/160 | 99.4 | 98.0, 100.0 | | Between-Reader | APA | 222/234 | 94.9 | 89.5, 98.8 | | | ANA | 228/240 | 95.0 | 90.0, 98.8 | | | OPA | 2334/246 | 95.1 | 90.5, 98.8 | Average Positive Agreement (APA), Average Negative Agreement (ANA), Overall Percent Agreement (OPA) *2-sided 95% confidence intervals were calculated using the percentile bootstrap method from 2,000 bootstrap samples. ## 4. Inter-Laboratory Reproducibility and Method Comparison Studies ### Inter-laboratory Reproducibility (ILR) The Inter-laboratory Reproducibility (ILR) and Method Comparison (MC) study for the VENTANA MET (SP44) RxDx Assay was conducted to evaluate the reproducibility of the VENTANA MET (SP44) RxDx Assay on the BenchMark ULTRA and the BenchMark ULTRA PLUS platforms independently. Additionally, a method comparison between the BenchMark ULTRA and BenchMark ULTRA PLUS was performed to determine if the performance of the VENTANA MET (SP44) RxDx Assay is equivalent on both BenchMark platforms. The ILR study included 60 NSCLC specimens (30 MET Positive and 30 MET Negative, including several cases which exhibited borderline/challenging staining relative to the diagnostic cutoff) run across three BenchMark ULTRA and three BenchMark ULTRA PLUS instruments on 3 non-consecutive days at three external laboratories. For each BenchMark platform a set of 3 stained slides per sample per staining day was randomized and evaluated by a total of 6 readers (2 readers per site). Each case had 6 results per site per BenchMark platform (18 results per platform, 36 results in total for two platforms). Performance was evaluated and the following precision components were calculated: between-reader, between-site and total. The ILR study results are presented in the tables below. PMA P240037: FDA Summary of Safety and Effectiveness Data 30 of 58 {30} Table 29. Results of the Inter-Laboratory Reproducibility Study (ULTRA) | | Standard Deviation | Percent Positive Results | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | n/N (%) | | | | | | | | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong TC (Min., Max.) | Between Reader | Between Day | Between Site | Total | Site A | Site B | Site C | Total | | 1 | Negative | 0 | 0, 0 | 0 | 0 | 0 | 0 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 2 | Negative | 0 | 0, 1 | 0 | 0 | 0 | 0.24 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 3 | Negative | 0 | 0, 2 | 0.41 | 0.33 | 0.1 | 0.63 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 4 | Negative | 2.5 | 0, 15 | 0.58 | 0.85 | 2.72 | 3.97 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 5 | Negative | 2.5 | 0, 5 | 1.33 | 0 | 1.65 | 2.26 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 6 | Negative | 2.5 | 0, 20 | 1.84 | 2.27 | 2.34 | 5.74 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 7 | Negative | 3.5 | 0, 15 | 2.67 | 1.67 | 2.61 | 4.79 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 8 | Negative | 4.5 | 0, 35 | 5.33 | 3.81 | 7.44 | 10.97 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 9 | Negative | 5 | 0, 15 | 1.08 | 0 | 4.08 | 5.14 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 10 | Negative | 5 | 0, 15 | 2.01 | 0 | 3.06 | 5.42 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 11 | Negative | 7.5 | 0, 20 | 1.99 | 2.79 | 5.32 | 6.8 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 12 | Negative | 7.5 | 0, 20 | 3.19 | 2.79 | 5.84 | 8 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 13 | Negative | 7.5 | 0, 35 | 4.58 | 6 | 6.21 | 10.2 | 0/4 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/16 (0.0) | | 14 | Negative | 7.5 | 0, 65 | 20.24 | 4.65 | 8.98 | 23.24 | 2/6 (33.3) | 0/6 (0.0) | 0/4 (0.0) | 2/16 (12.5) | | 15 | Negative | 10 | 1, 20 | 3.55 | 3.7 | 3.42 | 7.02 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 16 | Negative | 10 | 0, 20 | 0 | 0 | 7.34 | 9.07 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 17 | Negative | 12.5 | 0, 40 | 6.28 | 3.73 | 12.46 | 15.41 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | PMA P240037: FDA Summary of Safety and Effectiveness Data {31} | | Standard Deviation | Percent Positive Results | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | n/N (%) | | | | | | | | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong TC (Min., Max.) | Between Reader | Between Day | Between Site | Total | Site A | Site B | Site C | Total | | 18 | Negative | 17.5 | 5, 25 | 2.47 | 0 | 6.25 | 8.11 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 19 | Negative | 17.5 | 0, 50 | 9.94 | 0 | 12.73 | 18.06 | 0/6 (0.0) | 0/6 (0.0) | 1/6 (16.7) | 1/18 (5.6) | | 20 | Negative | 20 | 0, 40 | 7.83 | 0 | 14.16 | 16.4 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 21 | Negative | 22.5 | 0, 45 | 6 | 5.41 | 9.67 | 15.66 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 22 | Negative | 25 | 0, 50 | 12.08 | 5.77 | 0 | 16.16 | 1/6 (16.7) | 1/6 (16.7) | 0/6 (0.0) | 2/18 (11.1) | | 23 | Negative | 27.5 | 10, 50 | 8.58 | 0 | 5 | 12.25 | 1/6 (16.7) | 0/6 (0.0) | 0/6 (0.0) | 1/18 (5.6) | | 24 | Negative | 27.5 | 5, 60 | 15.94 | 5.53 | 0 | 18.18 | 0/6 (0.0) | 0/6 (0.0) | 3/6 (50.0) | 3/18 (16.7) | | 25 | Negative | 27.5 | 1, 60 | 0 | 0 | 7.68 | 22.28 | 2/6 (33.3) | 1/6 (16.7) | 2/6 (33.3) | 5/18 (27.8) | | 26 | Negative | 30 | 5, 60 | 6.12 | 6.67 | 10.65 | 17.02 | 1/6 (16.7) | 0/6 (0.0) | 1/6 (16.7) | 2/18 (11.1) | | 27 | Negative | 40 | 20, 55 | 7.99 | 5.53 | 0 | 11.96 | 2/6 (33.3) | 0/6 (0.0) | 1/6 (16.7) | 3/18 (16.7) | | 28 | Negative | 40 | 20, 50 | 12.58 | 4.25 | 0 | 13.99 | 1/6 (16.7) | 1/6 (16.7) | 2/6 (33.3) | 4/18 (22.2) | | 29 | Negative | 40 | 5, 70 | 12.47 | 7.55 | 14.73 | 22.7 | 4/6 (66.7) | 0/6 (0.0) | 3/6 (50.0) | 7/18 (38.9) | | 30 | Negative | 40 | 5, 70 | 15.86 | 0 | 0 | 19.86 | 3/6 (50.0) | 3/6 (50.0) | 2/6 (33.3) | 8/18 (44.4) | | 31 | Negative | 45 | 5, 75 | 12.75 | 8.25 | 13.39 | 22.64 | 3/6 (50.0) | 1/6 (16.7) | 3/6 (50.0) | 7/18 (38.9) | | 32 | Positive | 50 | 10, 70 | 4.08 | 6.87 | 10.18 | 15.17 | 6/6 (100.0) | 2/6 (33.3) | 3/6 (50.0) | 11/18 (61.1) | | 33 | Positive | 50 | 5, 90 | 9.43 | 14.85 | 11.67 | 25.33 | 6/6 (100.0) | 3/6 (50.0) | 5/6 (83.3) | 14/18 (77.8) | | 34 | Positive | 50 | 0, 70 | 9.99 | 15.85 | 0 | 20.27 | 5/6 (83.3) | 3/6 (50.0) | 2/6 (33.3) | 10/18 (55.6) | | 35 | Positive | 50 | 10, 70 | 8.38 | 0 | 9.57 | 20.94 | 5/6 (83.3) | 2/6 (33.3) | 2/5 (40.0) | 9/17 (52.9) | PMA P240037: FDA Summary of Safety and Effectiveness Data {32} | | Standard Deviation | Percent Positive Results | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | n/N (%) | | | | | | | | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong TC (Min., Max.) | Between Reader | Between Day | Between Site | Total | Site A | Site B | Site C | Total | | 36 | Positive | 50 | 25, 90 | 22.82 | 6.97 | 0 | 25.9 | 4/6 (66.7) | 3/6 (50.0) | 4/6 (66.7) | 11/18 (61.1) | | 37 | Positive | 50 | 1, 90 | 17.91 | 0 | 0 | 35.25 | 4/6 (66.7) | 2/6 (33.3) | 4/6 (66.7) | 10/18 (55.6) | | 38 | Positive | 50 | 25, 75 | 9.35 | 6.01 | 4.71 | 13.39 | 6/6 (100.0) | 1/6 (16.7) | 4/6 (66.7) | 11/18 (61.1) | | 39 | Positive | 50 | 1, 90 | 20.13 | 0 | 18.73 | 29.47 | 5/6 (83.3) | 1/6 (16.7) | 5/6 (83.3) | 11/18 (61.1) | | 40 | Positive | 50 | 5, 80 | 22.42 | 4.08 | 0 | 23.66 | 5/6 (83.3) | 3/6 (50.0) | 5/6 (83.3) | 13/18 (72.2) | | 41 | Positive | 57.5 | 20, 80 | 12.19 | 9.28 | 6.4 | 19.98 | 6/6 (100.0) | 3/6 (50.0) | 3/6 (50.0) | 12/18 (66.7) | | 42 | Positive | 62.5 | 10, 90 | 17.32 | 0 | 6.22 | 23.27 | 6/6 (100.0) | 3/6 (50.0) | 5/6 (83.3) | 14/18 (77.8) | | 43 | Positive | 65 | 25, 98 | 13.47 | 0 | 3.55 | 20.84 | 6/6 (100.0) | 4/6 (66.7) | 5/6 (83.3) | 15/18 (83.3) | | 44 | Positive | 72.5 | 1, 95 | 11.53 | 9.4 | 17.36 | 28.86 | 6/6 (100.0) | 3/6 (50.0) | 6/6 (100.0) | 15/18 (83.3) | | 45 | Positive | 82.5 | 20, 100 | 20.96 | 7.17 | 8.04 | 25.28 | 6/6 (100.0) | 4/6 (66.7) | 6/6 (100.0) | 16/18 (88.9) | | 46 | Positive | 85 | 5, 99 | 15.65 | 11.9 | 0 | 23.25 | 6/6 (100.0) | 5/6 (83.3) | 6/6 (100.0) | 17/18 (94.4) | | 47 | Positive | 90 | 10, 100 | 0 | 5.11 | 11.94 | 22.38 | 6/6 (100.0) | 5/6 (83.3) | 6/6 (100.0) | 17/18 (94.4) | | 48 | Positive | 92.5 | 5, 100 | 15.86 | 6.95 | 6.9 | 24.98 | 6/6 (100.0) | 4/6 (66.7) | 6/6 (100.0) | 16/18 (88.9) | | 49 | Positive | 95 | 70, 100 | 3.81 | 3.33 | 2.06 | 7.22 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 50 | Positive | 95 | 65, 100 | 8.23 | 2.79 | 0 | 10.13 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 51 | Positive | 95 | 80, 100 | 5.68 | 0 | 0 | 8.8 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 52 | Positive | 95 | 70, 100 | 8.64 | 0 | 0 | 9.92 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 53 | Positive | 97.5 | 90, 100 | 4.56 | 1.67 | 0 | 5.4 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | PMA P240037: FDA Summary of Safety and Effectiveness Data {33} | | Standard Deviation | Percent Positive Results | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | n/N (%) | | | | | | | | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong TC (Min., Max.) | Between Reader | Between Day | Between Site | Total | Site A | Site B | Site C | Total | | 54 | Positive | 97.5 | 85, 100 | 6.01 | 0 | 0 | 6.67 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 55 | Positive | 97.5 | 80, 100 | 5.89 | 0 | 0 | 6.87 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 56 | Positive | 100 | 90, 100 | 2.53 | 0.75 | 0 | 3.04 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 57 | Positive | 100 | 90, 100 | 2.64 | 0 | 0 | 3.73 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 58 | Positive | 100 | 90, 100 | 3.91 | 0 | 0 | 4.56 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 59 | Positive | 100 | 90, 100 | 2.64 | 0 | 0 | 3.33 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | | 60 | Positive | 100 | 65, 100 | 5.89 | 6.24 | 0 | 10.74 | 6/6 (100.0) | 6/6 (100.0) | 6/6 (100.0) | 18/18 (100.0) | Table 30. Results of the Inter-Laboratory Reproducibility Study (ULTRA PLUS) | | Standard Deviation | Percent Positive Results | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | n/N (%) | | | | | | | | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong TC (Min., Max.) | Between Reader | Between Day | Between Site | Total | Site A | Site B | Site C | Total | | 1 | Negative | 0 | 0, 0 | 0 | 0 | 0 | 0 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 2 | Negative | 0 | 0, 1 | 0 | 0 | 0 | 0.24 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 3 | Negative | 0 | 0, 5 | 0.67 | 0.58 | 0 | 1.22 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 4 | Negative | 1 | 0, 15 | 3.82 | 1.91 | 0 | 4.66 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 5 | Negative | 1 | 0, 15 | 4.62 | 0.53 | 0 | 4.92 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 6 | Negative | 1.5 | 0, 15 | 3.82 | 1.13 | 1.32 | 4.81 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | PMA P240037: FDA Summary of Safety and Effectiveness Data {34} | | Standard Deviation | Percent Positive Results | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | n/N (%) | | | | | | | | Case ID | Majority MET (SP44) Status | Median % Strong TC | Range of % Strong TC (Min., Max.) | Between Reader | Between Day | Between Site | Total | Site A | Site B | Site C | Total | | 7 | Negative | 5 | 0, 15 | 4.49 | 1.05 | 4.53 | 7.01 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 8 | Negative | 5 | 0, 25 | 6.77 | 1.05 | 0 | 7.63 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 9 | Negative | 5 | 0, 25 | 6.14 | 0 | 3.69 | 7.86 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 10 | Negative | 5 | 0, 40 | 9.96 | 0 | 4.31 | 12 | 0/6 (0.0) | 0/6 (0.0) | 0/6 (0.0) | 0/18 (0.0) | | 11 |…