(298 days)
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No
The device description and performance studies focus on a standard ELISA immunoassay and spectrophotometric analysis, with no mention of AI or ML algorithms for data interpretation or analysis.
No
{"explanation":"The OSDI HER-2/neu Assay is an in vitro diagnostic device used for the quantitative determination of serum HER-2/neu for monitoring purposes in patients with metastatic breast cancer, not for direct treatment or therapy."}
Yes
The "Intended Use / Indications for Use" section explicitly states, "The OSDI HER-2/neu Assay is an in vitro, diagnostic device intended for use in the quantitative determination of serum HER-2/neu in women with metastatic breast cancer..."
No
The device description clearly outlines a physical ELISA kit with microtiter plates, antibodies, reagents, and a spectrophotometer for quantitative measurement, indicating it is a hardware-based in vitro diagnostic device, not software-only.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The "Intended Use / Indications for Use" section explicitly states that the OSDI HER-2/neu Assay is an "in vitro, diagnostic device".
- Method: The device performs a quantitative determination of a substance (serum HER-2/neu) in a biological sample (serum) outside of the body ("in vitro").
- Purpose: The results are intended to be used in the "follow-up and monitoring of patients with metastatic breast cancer" and "in conjunction with information available from clinical and other diagnostic procedures in the management of breast cancer." This clearly indicates a diagnostic purpose.
N/A
Intended Use / Indications for Use
The OSDI HER-2/neu Assay is an in vitro, diagnostic device intended for use in the quantitative determination of serum HER-2/neu in women with metastatic breast cancer who have an initial value of 15 ng/ml or greater. HER-2/neu values obtained may be used in the follow-up and monitoring of patients with metastatic breast cancer. HER-2/neu values should be used in conjunction with information available from clinical and other diagnostic procedures in the management of breast cancer. The clinical utility of the serum measurement of HER-2/neu as a prognostic indicator for early recurrence and in the management of patients on immunotherapy regiments has not been fully established.
Product codes (comma separated list FDA assigned to the subject device)
NCW
Device Description
The HER-2/neu ELISA is a sandwich enzyme immunoassay which utilizes two monoclonal antibodies to quantitate the extracellular domain (ECD) of the HER-2/neu protein in serum. The capture antibody (NB-3) is immobilized on the interior surface of microtiter plate wells. Serum is incubated in the coated well to allow binding of the antigen by the capture antibody. The captured HER-2/neu ECD is then reacted with a different anti-HER-2/neu antibody designated TA-1, which is biotinylated. The detection of the ECD of HER-2/neu is with a streptavidin horseradish peroxidase conjugate, which catalyzes the conversion of the chromogenic substrate o-phenylenediamine into a colored product. The colored reaction product is quantitated by spectrophotometry (read absorbance at 490 mm) and is related to the amount of the HER-2/neu ECD in the serum sample. Six prepared HER-2/neu standards (0, 2.5, 7.5, 15, 25 and 35 ng/ml) allow construction of a standard curve for subsequent quantification. A set of HER-2/neu controls (10-CVX) at 2.9, 9.1 and 24.0 ng/mL HER-2/neu protein is also available for quality monitoring.
Mentions image processing
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Mentions AI, DNN, or ML
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Input Imaging Modality
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Anatomical Site
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Indicated Patient Age Range
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Intended User / Care Setting
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Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
To assess the safety and effectiveness of the OSDI HER-2/neu Microtiter ELISA, clinical studies were performed at two investigational sites on patient samples from four different locations. All patients were studied retrospectively. Assay values were determined for surplus serum samples which had been collected and stored (-70° C) in specimen banks prior to the study. Studies performed at OSDI have shown no evidence of changes in HER-2/neu concentration in patient samples stored at -80° C for 5 % years.
The clinical utility of the OSDI HER-2/neu Microtiter E.I.ISA in monitoring metastatic breast cancer patients with initial elevated HER-2/neu was evaluated using retrospective serum. Serial serum HER-2/neu values were measured over a 6 to 12 month period in clinically evaluable patients with Stage IV breast cancer undergoing therapy. 33.7 % had initial elevated serum samples (HER-2/neu concentrations equal to or greater than 15 ng/mL). These fifty-six patients were then evaluated for correspondence of changes in their serum HER-2/neu values with changes in their clinical course of disease.
A visit-to-visit analysis of the study results are presented in Table 4.4-1. The changes in serum HER-2/neu values from one visit to the next were calculated for each patient. These changes were separated into 2 groups; Group I had changes in serum HER-2/neu which paralleled the clinical course of disease and Group II had changes in serum HER-2/nen values that did not parallel the clinical course of disease. Clinical course or status was determined by the physician. Correspondence of HER-2/neu changes to clinical status were determined as follows: An increase of 20% or greater from the previous visit was reflective of disease progression. If the change is less than a 20% increase from the previous visit, this was reflective of a lack of disease progression during therapy (including responding or stable disease). Stable and responding were consolidated since both reflect effectiveness of a current therapy. The 20% criterion was derived from the longitudinal variability in normal patients (determined from the HER-2/neu values in six serial samples from each of 38 healthy women).
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Non-Clinical Studies:
Non-clinical studies were carried out to validate the performance of the method according to the protocol entitled "Protocols for Non-Clinical Performance Evaluation of the OSDI HER-2/neu Microtitor ELISA". Protocols were performed at OSDI, Cambridge, Massachusetts. These studies included evaluation of interfering substances, cross-reactivity, heterophilic antibodies, HAMA interference, Herceptin® interference, sample linearity, parallelism (sample dilution), hook effect, reproducibility, spike and recovery, end-to-end variability, plate coating variability and reagent lot-to-lot variation.
Specificity (Interference): The recovery of HER-2/neu from patient samples was studied before and after spiking the serum samples with potentially interfering substances (triglycerides, hemoglobin, immunoglobulin, bilirubin, albumin, heparin, cholesterol, chemotherapeutic drugs, OTC drugs, vitamins, HERCEPTIN®). None of the potential endogenous or exogenous interferents demonstrated any significant interfering effects on HER-2/neu recovery.
Cross-Reactivity: Possible cross-reactions with purified Human Epidermal Growth Factor Receptor (HER-1) showed a maximum effect of ≤1%, which was not significant. No cross-reactivity with HER-3 was observed using cell line lysates.
Heterophilic Antibodies and HAMA Interference: The assay uses Normal Mouse Serum (NMS) in the detector reagent to reduce interference from heterophilic antibodies and Human Anti-Mouse Antibodies (HAMA). With NMS, HAMAs and rheumatoid factors did not cause false negative or false positive results.
Linearity: Two controls with different HER-2/neu levels were combined in discreet proportions to produce five samples. The observed vs. expected concentration plots showed a slope and correlation coefficient close to 1, indicating linearity within the dynamic range.
Spike and Recovery: The total average percent recovery of spiked HER-2/neu in five different patient sera was 103%, indicating no effect of matrix on the ELISA's ability to accurately measure HER-2/neu protein in serum.
Hook Effect (Antigen Excess): A 526 ng/ml stock solution of p105 HER-2/neu was serially diluted. A reportable concentration was obtained only when the expected concentration approached the range of the standard curve (0-35 ng/ml). Separation of sample and reagent addition by washes prevents high-dose hook effect.
Parallelism (Dilution Studies): Five clinical samples and two Bovine Serum-based controls with elevated HER-2/neu were serially diluted two-fold for four dilutions. Recoveries were comparable for all three ELISA kit lots, demonstrating accurate recovery of analyte in human samples.
End-to-End Variation: Varying incubation times of critical reagent steps showed some increase or decrease in recovery (15%) when extended well beyond normal usage. However, normal usage variation should not affect recoveries.
Plate Coating Variations: Antibody coating was consistent throughout plates and kit lots, with 4.7-7.6% CV.
Reproducibility:
Intra- and inter-assay reproducibility were evaluated at OSDI and two clinical trial sites.
OSDI Site, All Microtiter ELISA Lots Combined (45 runs, 134-135 replicates per control):
- Control 1 (Mean 24.2 ng/mL): Within Run %CV 3.8, Total %CV 7.8
- Control 2 (Mean 9.5 ng/mL): Within Run %CV 4.7, Total %CV 9.1
- Control 3 (Mean 2.9 ng/mL): Within Run %CV 7.8, Total %CV 10.6
- Control 4 (Mean 9.2 ng/mL): Within Run %CV 4.5, Total %CV 8.3
Three Sites and Three Kit Lots Combined (130-131 runs, 385-390 replicates per control):
- Control 1 (Mean 24.5 ng/mL): Within Run %CV 6.0, Total %CV 10.7
- Control 2 (Mean 9.8 ng/mL): Within Run %CV 7.0, Total %CV 10.4
- Control 3 (Mean 3.3 ng/mL): Within Run %CV 10.2, Total %CV 17.7
- Control 4 (Mean 9.5 ng/mL): Within Run %CV 6.9, Total %CV 10.8
Imprecision data showed within run CV's of 6-7% and total CV's of 10-11% for clinically relevant controls. A low control (3 ng/ml) had higher CV's of 10.2% within run and 17.7% total, which is within acceptable limits.
Sensitivity (Detection Limit): The Minimum Detectable Dose (MDD) was 1.5 ng/mL when assaying 232 replicates of Sample Diluent alone across three kit lots. This is acceptable for the intended use, given that the lowest normal patient value was 4.23 ng/ml and the cutoff for elevated HER-2/neu was 1.5 ng/ml.
Clinical Studies (Retrospective):
The OSDI HER-2/neu ELISA was evaluated as an aid in the management of metastatic breast cancer patients with elevated serum HER-2/neu values during the course of disease and therapy. The study was conducted at two US clinical trial sites.
Metastatic Patient Serial Monitoring: Fifty-six clinically evaluable patients with Stage IV breast cancer undergoing therapy, whose initial serum HER-2/neu levels were ≥15 ng/mL (33.7% of total), were evaluated for correspondence of changes in serum HER-2/neu values with changes in their clinical course of disease over 6-12 months.
Correspondence of Metastatic Breast Cancer Patient Disease Status with Changes in Serum HER-2/neu: Visit-by-Visit (Total 236 observations):
- Change In HER-2/neu ≥20% ↑: 52 (Progression), 33 (No Progression), TOTAL 85
- Change In HER-2/neu
§ 866.6010 Tumor-associated antigen immunological test system.
(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.
0
SEP 2 9 2000 510(k) SUMMARY FOR THE ONCOGENE SCIENCE DIAGNOSTICS, INC. MANUAL HER-2/NEU MICROTITER ELISA
This summary of 510(k) safety and cffectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K994112 - 11 - 11 - 1
During the period since the original submission, Oncogene Science Diagnostics, Inc. was acquired by Bayer Diagnostics, Tarrytown, NY (12/1/99) and became Oncogene Science, a part of Bayer Diagnostics. Throughout this document, Oncogene Science will be referred to as Oncogene Science Diagnostics,
GENERAL INFORMATION 1.
Trade Name:
Oncogene Science Diagnostics, Inc. (OSDI) Manual HER-2/neu Microtiter ELISA
Classification Name: Tumor-Associated Antigen Immunological Test Systems
Walter P. Carney, Ph.D. President 80 Rogers Street Cambridge, MA 02142 Phone # 617-492-7289 Fax # 617-492-8438
Date
1
0000003
In this 510(k) promarket application and notification, the performance and clinical safety and effectiveness of the Oncogcne Science Diagnostics Inc. (OSDI) HER-2/nou ELISA for the management and monitoring of metastatic breast cancer patients with initial elevated HER-2/neu has been established by extcrnal clinical studies in the target population of longitudinal metastatic breast cancer patients and by comparison to accepted diagnostic procedures in accordance with the "Guidance Document For Submission of Tumor Associated Antigen Premarket Notifications, 510(k), to the FDA". Clinical evaluations of the HER-2/neu ELISA at two US clinical trial sites demonstrated clinical safety and cffectiveness. Non-clinical studies indicate this assay is a stable, reproducible, highly specific and sensitive assay in which serum components and therapeutic agents do not interfere. Together these studies validated clinical performance characteristics and the comparison to accepted diagnostic procedures.
The HER-2/neu growth factor receptor encodes a full length HER-2/neu protcin (p185) that is overexpressed in breast cancer cells. The extracellular domain (ECD) of this receptor (p97-115kDa) is shed into the serum of healthy women and is elevated above normal levels in women with metastatic breast cancer. Many reports indicate that monitoring the HER-2/neu serum levels has clinical utility in the management of women with metastatic breast cancer. The OSDI HER-2/neu Manual Microtiter ELISA accurately measures HER-2/neu ECD in serum.
2. INDICATIONS FOR USE
The OSDI HER-2/nou ELISA is an in vitro diagnostic assay intended to quantitalively measure the extraccllular domain of HER-2/nou protein in human serum. HER-2/ncu values obtained may be used in the follow-up and monitoring of patients with metastatic breast cancer whose initial serum level of HER-2/neu is 15 ng/ml or greater. HF/R-2/neu values should be used in conjunction with information available from clinical and other
2
0300004
510(k) Notification Safety and Effectiveness
diagnostic proccdures in the management of breast cancer. The clinical utility of serum measurement of HER-2/neu as a prognostic indicator for early detection of recurrence and in the management of patients on immunotherapy regimens has not been fully established.
DEVICE DESCRIPTION 3.
Description of the Method: The HER-2/neu ELISA is a sandwich cnzyme immunoassay. which utilizes two monoclonal antibodies to quantitate the extraccllular domain (ECD) of the HER-2/neu protein in scrum. The initial report describing the assay was published in 1991 (Carney, W. P., et al., Journal of Tumor Marker Oncology, 6(2): p. 53-72). Both the capture and detector anti-HER-2/neu monoclonal antibodies specifically bind the ECD of the HER-2/neu protein. The capture antibody (NB-3) has been immobilized on the interior surface of the microtiter plate wells. To perform the assay, an appropriate volume of serum is incubated in the coated well to allow binding of the antigen by the capture antibody. The captured HER-2/neu ECD is then reacted with a different anti-HER-2/neu antibody designated TA-1. The TA-1 antibody is biotinylated. The detection of the ECD of HER-2/neu is with a streptavidin horseradish peroxidase conjugate, which then catalyzes the conversion of the chromogenic substrate o-phenylenediamine into a colored product. The colored reaction product is quantitated by spectrophotometry (read absorbance at 490 mm) and is related to the amount of the HER-2/neu ECD in the serum sample. Six propared HER-2/neu standards (0, 2.5, 7.5, 15, 25 and 35 ng/ml) allow construction of a standard curve for subsequent quantification of HER-2/neu in servin samples. Also available from OSDI is a sct of HER-2/neu controls (10-CVX) designed to be used in conjunction with the ELISA for quality monitoring of assay performance. This control set consists of three (3) control levels at 2.9, 9.1 and 24.0 ng/mL HER-2/ncu protein.
3
000005 510(k) Notification Safcty and Effectiveness
SUMMARY OF STUDIES 4.
Non-clinical studies were carried out to validate the performance of the mcthod according to the protocol cntitled "Protocols for Non-Clinical Performance Evaluation of the OSI)I HER-2/neu Microtitor ELISA". Protocols were performed at OSDI, Cambridge, Massachusetts. These studies included evaluation of interfering substances, crossreactivity, hctcrophilic antibodies, HAMA interference, Herceptin® interference, sample linearity, parallelism (sample dilution), hook cffect, reproducibility, spike and recovery, end-10-end variability, plate coating variability and reagent lot-10-lot variation.
The OSDI HER-2/neu EIJSA was cvaluated as an aid in the management of metastatic breast cancer patients with elevated scrum HER-2/neu values during the course of disease and therapy. This clinical cvaluation was conducted at two US clinical trial sites.
Characterization of the Antigen, 4.1
The standard antigen used in the OSDI HER-2/neu ELISA is the extracellular domain (ECD) of HRR-2/nou, p105. It is derived from a recombinant NIII 3T3 mouse ccll line designated 3-30. HER-2/neu p105 antigen is harvested from the cell culture serum-free conditioned medium and concentrated 10-fold. Western blot analysis shows a glycoprotein with a molccular wcight range between 97 and l 15 kd.
4.2 Characterization of the Antibodies
The NB-3 monoclonal antibody is used to capture the ECD and is therefore coated onto the surface of the microtiter well. The TA-1 monoclonal anti-HER-2/neu is used as the reagent to detect the HER-2/neu ECD. NB-3 is purified from tissue culture supernatant, produced in bioreactors, using Protein G+ affinity chromatography. The TA-1 antibody is purified from mouse ascites using Protein
4
A + affinity chromatography. Production and purification of antibodies utilize standard protocols and the antibodies are manufactured in Cambridge, MA. I All lots arc isotyped and characterized by SDS-PAGE, isoelectric focusing and Coomassie Blue staining prior to functional testing.
Assay Performance 4.3
Specificity: Interference 4.3.1
The recovery of HER-2/neu from patient samples was studied before and after spiking the serum samples with the potentially interfering substance, Each potential interforent was tested at concentrations that were higher than the recommended dietary or therapeutic doses. Endogenous compounds (common serum constituents) were tested at concentrations greater than those normally observed during routine clinical testing.
The OSDI HER-2/neu ELISA was performed on serum samples or pools of serum to which were added various concentrations of either triglycerides, hemoglobin, immunoglobulin, bilirubin, albumin, heparin or cholesterol. HER-2/neu values were also measured in serum samples after spiking with either an individual chemotherapeutic drug, "Over the Counter" (OTC) drug, vitamin or IIERCEPTIN® (Trastuzumab), trademark of Genentech BioOncology, South San Francisco, CA. Nonc of the potential endogenous or exogenous interferents demonstrated any significant interfering effects on HER-2/neu recovery.
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510(k) Notification 0000007 Safety and Effectiveness
Cross-Reactivity 4.3.2
Possible cross-reactions in the OSDI HER-2/ncu EI.JSA wcrc studied by assaying purified Human Epidermal Growth Factor Reccptor (HER-1) spiked into Sample Diluent . The maximum effect seen with this cross-reactant was not significant (≤1%). Assays with cell line lysatcs have indicated that there is also no cross-reactivity with HER-3.
Heterophilic Antibodies and HAMA Interference 4.3.3
Hetcrophile antibodies possess a broad range of non-specific reactivities with other species of immunoglobulins. They include human anti-mousc antibodies (HAMA) and rheumatoid factors (RF). Thesc antibodies may interfere with immunoassays and cause false positive or negative results. The OSDI HER-2/ncu ELISA uses two mouse monoclonal antibodics, for capture and detection, but has Normal Mouse Serum (NMS) in the detector reagent to reducc this interference. A number of IJAMA and rhoumatoid factor positive serum samples were assayed in the HER-2/neu ELISA with significant interference for a small percentage of specimens without NMS in the detector diluent, but none when detector diluent contained NMS. HAMA and rhcumatoid factors do not cause false negative or false positive results in the present assay format.
Linearity 4.3.4
To evaluate the linearity of recovered values, two controls containing different levels of HER-2/neu were combined in discreet proportions to produce five samples of defined concentrations for assay. When observed HER-2/neu concentration was plotted versus expected concentration, the slope and correlation coefficient of each data set were close to the optimum of 1, indicating lincarity within the dynamic range of the assay.
6
Spike and Recovery 4.3.5
In order to determine the cffect of sample matrix on the ability of the HER-2/neu ELISA to detect HER-2/neu, recovered dosages of spiked analyte in Sample Diluent (ideal matrix) were compared to recovered dosages of spiked analyte into five different patient sera. The total average percent recovery of all spiked serum samples in all three kit lots was 103%, indicating no effect of matrix on the ability of the ELISA to accurately measure HER-2/ncu protein in serum.
4.3.6 Hook Effect (Antigen Excess)
Extremely high concentrations of HER-2/neu seen in some malignant conditions may cause a "hook cffcct" in certain assay formats. An excess of analyte saturates both label and capture antibody and causes the reported concentration to "hook" back into the assay range rather than be flagged as above range. A 526 ng/ml stock solution of p105 HER-2/neu was serially diluted six times at 1:2 and assayed. A reportable concentration was obtained only when the expected concentration of the diluted sample approaches the range of the standard curve (0-35 ng/ml). Separation of sample and reagent addition by washes prevents high-dose hook effect in this device.
Parallelism (Dilution Studies) 4.3.7
Five scparate clinical samples containing elevated levels of HER-2/ncu, and two Boving Serum-based controls containing spiked HFR-2/neu were serially diluted two-fold for four dilutions. Recoveries were evaluated at cach of the dilution points for mean and standard deviation and were comparable for all three ELISA kit lots. Scrum samples diluted in kit Sample Dilucnt result in accurate recovery of analyte at a range of concentrations in human samples.
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510(k) Notification Safety and Effectiveness
4.3.8 End-to-End Variation
The effect on HER-2/neu recovery when incubation times of critical reagent steps were varied from sample to sample within a single assay run was evaluated. When times extended well beyond normal usage, some increase or decrease in recovery was observed (15%). However, the expected variance in timing during normal use by skilled individuals should fall well short of these extended times tested and recoveries should be unaffected.
4.3.9 Plate Coating Variations
In order to evaluate antibody coaling variations, a human serum sample was assayed over entire plates. Serum sample recovery, and therefore antibody coating, is consistent throughout plates and kit lots with 4.7-7.6 % CV.
4.3.10 Reproducibility
Intra- and inter-assay reproducibility were evaluated at OSDI and at two clinical trial sites. Three controls and a human scrum pool were assayed for reproducibility and results are shown in Tables 4.3-1 and 4.3-2. Imprecision data pooled across HER-2/neu ELISA kit lots and across assay sites showed within run CV's of 6-7% and total CV's of 10-11% for clinically relevant controls. A low control (3 ng/ml), below the lowest normal patient sample, gave higher within run and total % CV's of 10.2 and 17.7, respectively. This is well within acceptable limits for an assay of this type and for its intended use.
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0000010
Oncogene Science Diagnostics, Inc. Manual HER-2/neu Microtiter ELISA
510(k) Notification Safety and Effectiveness
| | Number of
Runs | Number of
Replicates | Mean
(ng/mL) | Within Run | | Total | |
|-----------|-------------------|-------------------------|-----------------|------------|-----|---------|------|
| | | | | STD DEV | %CV | STD DEV | %CV |
| Control 1 | 45 | 135 | 24.2 | 0.91 | 3.8 | 1.90 | 7.8 |
| Control 2 | 45 | 135 | 9.5 | 0.45 | 4.7 | 0.86 | 9.1 |
| Control 3 | 45 | 134 | 2.9 | 0.22 | 7.8 | 0.30 | 10.6 |
| Control 4 | 45 | 135 | 9.2 | 0.42 | 4.5 | 0.77 | 8.3 |
Table 4 3-J Junecision for OSDI Site, All Microtiter ELISA Lots Combined
Table 4.3-2 Imprecision for Three Sites and Three Kit Lots Combined
| | Number of
Runs | Number of
Replicates | Mean
(ng/mL) | Within Run | | Total | |
|-----------|-------------------|-------------------------|-----------------|------------|------|---------|------|
| | | | | STD DEV | %CV | STD DEV | %CV |
| Control 1 | 130 | 385 | 24.5 | 1.46 | 6.0 | 2.62 | 10.7 |
| Control 2 | 131 | 390 | 9.8 | 0.69 | 7.0 | 1.03 | 10.4 |
| Control 3 | 131 | 386 | 3.3 | 0.34 | 10.2 | 0.59 | 17.7 |
| Control 4 | 130 | 385 | 9.5 | 0.65 | 6.9 | 1.02 | 10.8 |
4.3.11 Sensitivity (Detection Limit)
Sensitivity of the HER-2/neu Microtiter ELISA was evaluated at OSDI and at two clinical trial sites by determining the Minimum Detectable Dose (MDD). An MDI> of 1.5 ng/mL was observed when assaying 232 replicates of Sample Diluent alone in three HER-2/new ELISA kit lots. This MDD is acceptable for the intended use of this assay, where the lowest normal pationt was 4.23 ng/ml and the cutoff determined in this study for elevated HER-2/neu values was 1.5 ng/ml.
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4.4 CLINICAL STUDIES
4.4.1 Introduction
To assess the safety and effectivencss of the OSDI HER-2/neu Microtiter ELISA, clinical studies were performed at two investigational sites on pationt samples from four different locations. All patients were studied retrospectively. Assay values were determined for surplus scrum samples which had been collected and stored (-70° C) in specimen banks prior to the study. Studies performed at OSDI have shown no evidence of changes in HER-2/neu concentration in patient samples stored at -80° C for 5 % years.
4.4.2 Metastatic Patient Serial Monitoring - HER-2/neu Management Value
The clinical utility of the OSDI HER-2/neu Microtiter E.I.ISA in monitoring metastatic breast cancer patients with initial elevated HER-2/neu was evaluated using retrospective scrum. Scrial serum HER-2/neu values were measured over a 6 to 12 month period in clinically evaluable patients with Stage IV breast cancer undergoing therapy. 33.7 % had initial clevated serum samples (HER-2/neu concentrations cqual to or greater than 15 ng/mL). These fifty-six patients were then evaluated for correspondence of changes in their serum HER-2/neu values with changes in their clinical course of disease.
A visit-to-visit analysis of the study results are presented in Table 4.4-1. The changes in serum HER-2/neu values from one visit to the next were calculated for cach patient. These changes were scparated into 2 groups; Group I had changes in serum HER-2/neu which paralleled the clinical course of discase and Group II had changes in scrum HER-2/nen values that did not parallel the clinical course of discase. Clinical course or status was determined by the physician. Correspondence of HER-2/neu changes
10
0300012
to clinical status were determined as follows: An increase of 20% or greater from the previous visit was reflective of disease progression. If the change is less than a 20% increase from the previous visit, this was reflective of a lack of discase progression during therapy (including responding or stable discase). Stable and responding were consolidated since both reflect effectiveness of a current therapy. The 20% critcrion was derived from the longitudinal variability in normal patients (determined from the HER-2/neu values in six serial samples from cach of 38 healthy women).
Table 4.4-1: Correspondence of Metastatic Breast Cancer Patient Disease Status with Changes in Serum HER-2/neu: Visit-by-Visit
| | | Pro-
gression | No Pro-
gression | TOTAL |
|------------------------|--------|------------------|---------------------|-------|
| Change
In HER-2/neu | ≥20% ↑ | 52 | 33 | 85 |
| Change
In HER-2/neu |