(37 days)
This enzyme-linked immunosorbent assay (ELISA) is indicated for the detection of autoantibodies to the antigens Proteinase 3 (PR-3) and myeloperoxidase (MPA) in human serum. The presence of these antibodies, In combination with clinical observations and other serological tests, can aid in the diagnosis of Wegener's granulomatosis (WG), polyarteritis, necrotizing glomerulonephritis and other conditions associated with elevated anti-neutrophil cytoplasmic antibodies (ANCA). Since a positive test result with this assay does not indicate which ANCA is (are) present, all positives should be confirmed using assays designed for particular ANCA specificities.
An enzyme-linked immunosorbent assay (ELISA) designed for the detection of autoantibodies to the antigens Proteinase 3 and mveloperoxidase in human serum. The ELISA methodology is commonly used for serum antibody evaluations. Purified PR3 and Myeloperoxidase antigens have been attached to the inner surfaces of the microwell plate. During the initial incubation step, antibodies in patient serum bind specifically to the immobilized antigens and remain in place after a wash step. A second antibody which is conjucated to horseradish peroxidase (HRP) is used to recognize the "heavy + light" chain regions of the patient's antibodies remaining after the wash step. In the wells where the second antibody remains bound, the conjugated HRP catalyzes a color change in the substrate, tetramethyl benzidine (TMB). After the reaction is stopped, the color is read in an EIA Plate reader.
The provided text describes the VIRGO® ANCA SCREEN Kit, an enzyme-linked immunosorbent assay (ELISA) for detecting autoantibodies to Proteinase 3 (PR3) and myeloperoxidase (MPO) in human serum.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" with numerical thresholds prior to presenting results, but rather demonstrates performance through comparison to predicate devices and precision studies. Therefore, I will derive the implied acceptance criteria from the context of "Comparison Testing" and "Precision" sections.
| Acceptance Criteria (Implied) | Reported Device Performance (VIRGO® ANCA SCREEN Kit) |
|---|---|
| Relative Sensitivity (against predicate device for positive panels) | 100.0% (35/35, 90.1% to 100% confidence interval) |
| Relative Specificity (against predicate device for normal samples) | 100.0% (66/66, 94.5% to 100% confidence interval) |
| Inter-assay Precision (samples 1-6 %CV) | 9.3% - 12.7% |
| Inter-assay Precision (controls %CV) | 7.5% - 14.9% (for cANCA and pANCA positive controls), 8.5% (for Cutoff Serum) |
| Intra-assay Precision (samples 1-6 %CV) | 4.6% - 14.0% |
| Interfering Substances (Hemoglobin variation) | <15% variation for ≤ 500 mg/dL |
| Interfering Substances (Bilirubin variation) | <15% variation for ≤ 20 mg/dL |
| Interfering Substances (Lipid variation) | <15% variation for ≤ 3000 mg/dL |
| Prozone Effect | Kit gives appropriately high positive results with high titered sera (no prozone effect identified) |
2. Sample Sizes Used for the Test Set and Data Provenance
- Positive Panels: 36 serum specimens. 17 from individuals with Wegener's Granulomatosis, 19 from "pANCA A" (the full context of "A would or 100 Bornh op of our the United States" is unclear, but suggests diverse origins).
- Normal Samples: 73 "normal apparently positive specificals taken from" (This phrase is confusing, but the context of "Normals" table implies healthy controls).
- Precision Studies: 8 serum samples (for both inter-assay and intra-assay studies), plus Negative Control, cANCA Positive Control, pANCA Positive Control, and Cutoff Serum.
- Interfering Substances: Specific samples with varying concentrations of hemoglobin, bilirubin, and lipids.
- Prozone: "several high titered serum samples".
Data Provenance: The text mentions "17 from individuals with Wegners Granulomatosis, 19 pANCA A would or 100 bornh op of our the United States," which suggests some of the data originated from the United States. It's unclear if all data is from the US. The study appears to be retrospective as it uses existing serum specimens for comparison testing.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not explicitly state the number of experts or their qualifications for establishing the initial diagnosis of Wegener's Granulomatosis, pANCA, or normal status.
However, for the discrepant samples in the "Normals" table (one sample where the proposed device was positive, and the predicate device was negative), it states: "The six discrepants were evaluated by a third party IFA assay. All six of the samples were reported to be negative." This implies that the third-party IFA assay served as an arbitration method or a higher-tier "expert" validation for these specific cases, but not for the entire ground truth establishment.
4. Adjudication Method for the Test Set
For the comparison testing, the primary method was direct comparison against the predicate device (Scimedx EIA Kit for Anti-PR3/MPO Antibodies).
For the six discrepant samples, a third-party IFA assay was used. This acts as an adjudication method, providing an independent assessment to resolve differences between the proposed and predicate devices. The rule here seems to imply that the third-party IFA assay was considered the definitive standard for these discrepants.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) assay that produces quantitative results (optical density) and a qualitative interpretation (positive/negative), not an imaging device or AI algorithm requiring human reader interpretation in a clinical setting. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the data presented reflects the standalone performance of the VIRGO® ANCA SCREEN Kit. As an ELISA assay, its performance is evaluated based on its own output (optical density converted to positive/negative) without direct human intervention in the interpretation of each individual test result beyond following the established cutoff.
7. The Type of Ground Truth Used
The ground truth used for the comparison testing was based on:
- Predicate Device Results: For the bulk of the "Comparison Testing," the predicate devices (Scimedx ANTI-PR3 ANTIBODY EIA and Scimedx ANTI-MPO ANTIBODY EIA) served as the primary reference standard to determine relative sensitivity and specificity.
- Clinical Diagnosis/Grouping: For the "Positive Panels," samples were identified based on clinical conditions (e.g., Wegener's Granulomatosis) or prior pANCA classifications, implying a pre-existing clinical or serological diagnosis.
- "Third Party IFA Assay": For the discrepant samples, a third-party IFA assay was used as an independent, higher-tier reference standard, which is often considered a gold standard for ANCA detection.
8. The Sample Size for the Training Set
The document does not mention a training set as this is an ELISA assay, not a machine learning or AI algorithm in the contemporary sense that typically undergoes a distinct training phase. The development of the assay itself would have involved numerous experiments to optimize reagents and establish cutoffs, but these are not referred to as a "training set" in the context of AI regulatory submissions.
9. How the Ground Truth for the Training Set Was Established
Since there is no mention of a "training set" in the context of an AI algorithm, the concept of establishing ground truth for it does not apply here. The "training" for such a device involves biochemical validation, optimization of reagent concentrations, and establishing robust cutoff values through extensive laboratory work and studies similar to those presented (precision, comparison).
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K973822
510(k) Summary
- Submitter's Name/Contact Person 1.
Joseph M. Califano Manager, Regulatory Affairs
Address
Hemagen Diagnostics, Inc. 34-40 Bear Hill Road Waltham, MA, 02154
| Phone: | (781) 890-3766 |
|---|---|
| Fax: | (781) 890-3748 |
| email: | jcalifano@hemagen.com |
Date Prepared
30 September 1997
2. Device Name
| Trade Name: | VIRGO® ANCA SCREEN (EIA method) |
|---|---|
| Common Name: | PR3 and MPO Antibody Kit |
| Classification Name: | Antineutrophil Cytoplasmic Antibodies test system |
3. Predicate Devices
- Scimedx EIA Kit For the Detection of Anti-PR3 Antibodies a. {510 (k) Docket No. K 954105}
- Scimedx EIA Kit For the Detection of Anti-MPO Antibodies b. {510 (k) Docket No. K 954062}
NOV 1 3 1997
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Description of Device 3.
An enzyme-linked immunosorbent assay (ELISA) designed for the detection of autoantibodies to the antigens Proteinase 3 and mveloperoxidase in human serum.
The ELISA methodology is commonly used for serum antibody evaluations. Purified PR3 and Myeloperoxidase antigens have been attached to the inner surfaces of the microwell plate. During the initial incubation step, antibodies in patient serum bind specifically to the immobilized antigens and remain in place after a wash step.
A second antibody which is conjucated to horseradish peroxidase (HRP) is used to recognize the "heavy + light" chain regions of the patient's antibodies remaining after the wash step. In the wells where the second antibody remains bound, the conjugated HRP catalyzes a color change in the substrate, tetramethyl benzidine (TMB). After the reaction is stopped, the color is read in an EIA Plate reader.
4. Intended Use of Device
An enzvme-linked immunosorbent assay (ELISA) intended to determine an individual's serologic status with respect to autoantibodies to the antigens Proteinase 3 and myeloperoxidase in human serum.
5.(A) Technological Characteristics
Proposed Device
The VIRGO ® ANCA SCREEN Kit is an enzyme-linked immunosorbent assay. The device utilizes optical density as a measure of antibody presence, with an established cutoff between a positive and a negative reaction.
Predicate Devices
The Scimedx ANTI-PR3 ANTIBODY EIA and the Scimedx ANTI-MPO ANTIBODY EIA are also an enzyme-linked immunosorbent assays. Both of the devices utilize optical density as a measure of antibody presence, with an established cutoff between a positive and a negative reaction.
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5.(B) Performance Data
Precision
To evaluate precision, both inter-assay and intra-assay studies were conducted. The results are summarized below:
A. Inter-assay
Eight samples were assayed twice a day for five different days.
| Sample | Mean OD | Std. Dev. | % CV |
|---|---|---|---|
| 1 | 1.622 | 0.151 | 9.3 |
| 2 | 0.731 | 0.093 | 12.7 |
| 3 | 0.532 | 0.057 | 10.7 |
| 4 | 0.787 | 0.096 | 12.2 |
| 5 | 0.777 | 0.093 | 12.0 |
| 6 | 1.375 | 0.152 | 11.1 |
| 7 | 0.071 | 0.007 | N/A |
| 8 | 0.040 | 0.007 | N/A |
The assay controls {Positive, Negative, and Cutoff Serum} were assayed concurrently twice a day for each of the five days.
| Sample | Mean OD | Std. Dev. | % CV |
|---|---|---|---|
| Negative Control | 0.009 | 0.003 | N/A |
| cANCA Positive Control | 1.538 | 0.115 | 7.5 |
| pANCA Positive Control | 0.973 | 0.145 | 14.9 |
| Cutoff Serum | 0.224 | 0.019 | 8.5 |
B. Intra-assay
The eight serum samples were assayed 20 consecutive times in a single run.
| Sample | Mean OD | Std. Dev. | % CV |
|---|---|---|---|
| 1 | 1.563 | 0.072 | 4.6 |
| 2 | 0.763 | 0.072 | 9.4 |
| 3 | 0.557 | 0.052 | 9.3 |
| 4 | 0.916 | 0.103 | 11.2 |
| 5 | 0.777 | 0.057 | 7.3 |
| 6 | 1.233 | 0.173 | 14.0 |
| 7 | 0.083 | 0.006 | 7.2 |
| 8 | 0.046 | 0.003 | 6.5 |
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Comparison Testing
A total of 109 serum specimens (17 from individuals with Wegners Granulomatosis, 19 pANCA A would or 100 bornh op of our the United States, and 73 from normal apparently positive specificals taken from ally assayed by both the predicate device and the proposed device. The results are summarized in the tables that follow:
| Table 1.1 Positive Panels, n = 36} | |||
|---|---|---|---|
| Predicate Device | |||
| Positive | Negative | Total | |
| Proposed Device | |||
| Positive | 35 | 0 | 35 |
| Negative | 0 | 1 | 1 |
| Total | 35 | 1 | 36 |
Relative Sensitivity = 100.0 % {35/35}, "gs confidence interval = 90.1 % to 100 %
| Table 1.2 Normals, n = 73 | |||
|---|---|---|---|
| Predicate Device | |||
| Proposed Device | Positive | Negative | Total |
| Positive | 1 | 0 | 1 |
| Negative | 61 | 66 | 72 |
| Total | 7 | 66 | 73 |
Relative Specificity = 100.0 % {66/66}, o.ss confidence interval = 94.5 % to 100 %
- The six discrepants were evaluated by a third party IFA assay. All six of the samples were reported to be negative.
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Interfering Substances
Lipemic, icteric, and hemolytic samples were evaluated with the assay following NCCLS Document EP7-P Proposed Guideline, Interference Testing in Clinical Chemistry. The results indicate that there is no significant effect (<15 % variation) on the assay for samples with:
| Hemoglobin concentration: | ≤ 500 mg/dL |
|---|---|
| Bilirubin concentration: | ≤ 20 mg/dL |
| Lipid concentration: | ≤ 3000 mg/dL |
Prozone
The VIRGO ® ANCA SCREEN Kit was used to assay several high titered serum samples to determine if the kit would return unexpectedly low values. The results of this evaluation indicate that the kit gives appropriately high positive results with high titered sera.
Conclusions
The results of the comparative studies support the claim that the proposed device is substantially equivalent to the predicate devices and performs as an effective screening assay.
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Image /page/5/Picture/1 description: The image contains the text "Public Health Service". The text is in a simple, sans-serif font and is horizontally aligned. The words are stacked on a single line and are easily readable.
Image /page/5/Picture/2 description: The image shows the seal of the U.S. Department of Health & Human Services. The seal features a stylized eagle with its wings spread, and the words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle. The seal is black and white and appears to be a vector graphic.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
NOV 1 3 1997
Mr. Joseph M. Califano Manager, Regulatory Affairs Hemagen Diaqnostics, Inc. 34-40 Bear Hill Road Waltham, Massachusetts 02154
Re : K973822 Trade Name: VIRGO® ANCA Screen (EIA method) Regulatory Class: II Tier: II Product Code: мов Dated: September 30, 1997 Received: October 7, 1997
Dear Mr. Califano:
We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments or to devices that have been reclassified in accordance with the provisions of the Federal Food, Druq, and Cosmetic Act (Act). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the current Good Manufacturing Practice requirement, as set forth in the Quality System Regulation (QS) for Medical Devices: General requlation (21 CFR Part 820) and that, through periodic (QS) inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obliqation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal Laws or Regulations.
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Page 2
Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.
This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the requlation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"
Sincerely yours,
Steven Putman
Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
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Device Name:
VIRGO ® ANCA SCREEN Kit
Indication(s) For Use
This enzyme-linked immunosorbent assay (ELISA) is indicated for the detection of autoantibodies to the antigens Proteinase 3 (PR-3) and myeloperoxidase (MPA) in human serum. The presence of these antibodies, In combination with clinical observations and other serological tests, can aid in the diagnosis of Wegener's granulomatosis (WG), polyarteritis, necrotizing glomerulonephritis and other conditions associated with elevated anti-neutrophil cytoplasmic antibodies (ANCA). Since a positive test result with this assay does not indicate which ANCA is (are) present, all positives should be confirmed using assays designed for particular ANCA specificities.
(PLEASE DO NOT WRITE BELOW THIS LINE)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Greta E. Malm
(Division Sign-Off) Division of Clinical Laboratory Devices 510(k) Number -
ﮯ ﺍﻭﺭ ﺍﺱ ﮐﮯ ﺍﯾﮏ ﺭﮨﺎﺋﺸﯽ ﮨﮯ ﺍﻭﺭ ﺍﺱ ﮐﮯ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﺮﺍﻥ ﮐﮯ ﺷﮩﺮ ﺍﯾﺮﺍﻥ ﮐﮯ ﺷﮩﺮ ﺍﯾﺮﺍﻥ ﮐﮯ ﺷﮩﺮ ﺍﯾﺮﺍﻥ ﮐﮯ ﺷﮩﺮ ﺍ Prescription Use (Per 21 CFR 801.109)
OR
Over-The-Counter-Use__________________________________________________________________________________________________________________________________________________________
§ 866.5660 Multiple autoantibodies immunological test system.
(a)
Identification. A multiple autoantibodies immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when the body's own tissues are injured by autoantibodies).(b)
Classification. Class II (performance standards).