(37 days)
This enzyme-linked immunosorbent assay (ELISA) is indicated for the detection of autoantibodies to the antigen Proteinase 3 in human serum. The presence of PR-3 antibodies, in combination with clinical observations and other serological tests, can aid in the diagnosis of Wegener's granulomatosis (WG) and other conditions associated with elevated anti-neutrophil cytoplasmic antibodies (ANCA)
An enzyme-linked immunosorbent assay (ELISA) designed for the detection and measurement of autoantibodies to the antigen Proteinase 3 in human serum. The ELISA methodology is commonly used for serum antibody evaluations. Purified PR3 antigen has been attached to the inner surfaces of the microwell plate. During the initial incubation step, antibodies in patient serum bind specifically to the immobilized antigen and remain in place after a wash step. A second antibody which is conjugated 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 510(k) summary for K973823 describes a VIRGO® cANCA Kit, an enzyme-linked immunosorbent assay (ELISA) designed to detect autoantibodies to Proteinase 3 (PR3) in human serum. This test is intended as an aid in the diagnosis of current or past autoimmune-mediated vasculitides, specifically Wegener's granulomatosis.
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 submission does not explicitly state pre-defined acceptance criteria in terms of specific sensitivity, specificity, or agreement percentages. Instead, the performance is reported as a comparison to a predicate device. The implied acceptance criterion is "substantial equivalence" to the predicate device, which is demonstrated by a high level of agreement.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (VIRGO® cANCA Kit) |
|---|---|---|
| Comparative Testing | Substantial equivalence to the predicate device (Scimedx ANTI-PR3 ANTIBODY EIA), demonstrated by high agreement (sensitivity and specificity). | |
| Relative Sensitivity | N/A (implied high) | 100.0% (28/28) |
| Relative Specificity | N/A (implied high) | 100.0% (80/80) |
| Precision (Inter-assay) | Low coefficient of variation (%CV) | %CV for OD: 6.6% - 11.5%%CV for Units: 7.9% - 12.3% |
| Precision (Intra-assay) | Low coefficient of variation (%CV) | %CV for OD: 3.7% - 6.9%%CV for Units: 3.7% - 6.7% |
| Interfering Substances | No significant interference below specified concentrations | Hemoglobin < 500 mg/dL: No interferenceLipid < 20 mg/dL: No interferenceBilirubin < 3000 mg/dL: No interference |
| Prozone Effect | No unexpectedly low values with high-titered sera | Kit gives appropriately high positive results with high-titered sera. |
2. Sample Size Used for the Test Set and Data Provenance
- Test Set Size (Comparative Testing): A total of 108 serum specimens were used.
- Positive Panel: 28 samples from individuals with Wegener’s Granulomatosis.
- Normal Controls: 80 samples from apparently healthy donors.
- Data Provenance: The document does not explicitly state the country of origin. The study appears to be retrospective, using pre-existing serum specimens. The phrase "samples were used to assay" implies these were collected prior to the study for other purposes or as part of a biobank.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number of experts used to establish the ground truth for the test set, nor does it detail their qualifications. The positive panel samples were "from individuals with Wegener’s Granulomatosis," implying a clinical diagnosis was the ground truth, but the details of this diagnosis (e.g., how many clinicians, their specialties, their experience) are not provided. Similarly, the "normal apparently healthy donors" imply a ground truth of healthy status, but how this was verified is not detailed.
4. Adjudication Method for the Test Set
The document does not mention any adjudication method for establishing the ground truth for the test set. It relies on the pre-existing classification of the samples (e.g., "from individuals with Wegener’s Granulomatosis").
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance
This device is an in-vitro diagnostic (IVD) kit, specifically an ELISA. It does not involve "human readers" or "AI assistance" in the sense of image interpretation or decision support systems. Therefore, an MRMC comparative effectiveness study involving human readers and AI is not applicable to this type of device. The "reading" is an objective optical density measurement by an EIA Plate reader.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, this is essentially a standalone test in the context of IVDs. The "algorithm" is the ELISA assay methodology (binding, washing, enzymatic reaction, color change, OD measurement) and the established cutoff value. The performance metrics (sensitivity, specificity, precision) reflect the algorithm's performance in detecting the target analytes in the absence of human "interpretation" beyond reading the OD value and comparing it to a cutoff. The "human-in-the-loop" would be the clinician interpreting the result in the context of the patient's overall clinical picture, but the performance data presented is for the assay itself.
7. The Type of Ground Truth Used
The ground truth used for the comparative testing was clinical diagnosis.
- For the positive panel: "individuals with Wegener's Granulomatosis."
- For the negative/normal panel: "normal apparently healthy donors."
The document does not indicate the use of pathology or specific outcomes data to establish this ground truth, beyond the clinical diagnosis.
8. The Sample Size for the Training Set
The document does not explicitly mention a separate "training set" for the VIRGO® cANCA Kit. For IVD assays, the development process involves optimization and establishment of parameters (like cutoff values), but these are typically part of the assay development phase rather than a formally described "training set" in the context of machine learning. The studies described are performance validation studies.
9. How the Ground Truth for the Training Set Was Established
Since a dedicated "training set" is not explicitly mentioned, the method for establishing its ground truth is not provided. If the question refers to how the assay's cutoff was established, the document does not detail this. It only states that the device "utilizes optical density as a measure of antibody presence, with an established cutoff between a positive and a negative reaction."
{0}------------------------------------------------
K973823
510(k) Summary
NOV 1 3 1997
Submitter's Name/Contact Person 1.
Joseph M. Califano Manager, Regulatory Affairs
Address
Hemagen Diagnostics, Inc. 34-40 Bear Hill Road Waltham, MA, 02154
(617) 890-3766 Phone: (617) 890-3748 Fax: jcalifano@hemagen.com email:
Date Prepared
26 September 1997
Device Name 2.
| Trade Name: | VIRGO® cANCA Kit (EIA method) |
|---|---|
| Common Name: | PR3 Antibody Kit |
| Classification Name: | Antineutrophil Cytoplasmic Antibodies test system |
Predicate Device 3.
Scimedx EIA Kit For the Detection of Anti-PR3 Antibodies
Scimedx Election AN - 16 051105) {510 (k) Docket No. K 954105}
{1}------------------------------------------------
Description of Device 3.
An enzyme-linked immunosorbent assay (ELISA) designed for the detection and measurement of autoantibodies to the antigen Proteinase 3 in human serum.
The ELISA methodology is commonly used for serum antibody evaluations. Purified PR3 antigen has been attached to the inner surfaces of the microwell plate. During the initial incubation step, antibodies in patient serum bind specifically to the immobilized antigen and remain in place after a wash step.
A second antibody which is conjugated 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) designed for the detection and measurement of autoantibodies to the antigen Proteinase 3 in human serum. The test is intended as an aid in the diagnosis of current or past autoimmune mediated vasculitides.
5.(A) Technological Characteristics
Proposed Device
The VIRGO ® cANCA 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 Device
The Scimedx ANTI-PR3 ANTIBODY EIA is also 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.
{2}------------------------------------------------
5.(B) Performance Data
Precision
To evaluate precision, both inter-assay and intra-assay studies were conducted. The results are summarized below:
Eight serum samples were assayed in duplicate twice a day for five different days.
| Sample | Mean OD | Std. Dev. | % CV | Mean Units | Std. Dev | % CV |
|---|---|---|---|---|---|---|
| 1 | 1.444 | 0.112 | 7.8 | 7.3 | 0.6 | 7.9 |
| 2 | 1.060 | 0.070 | 6.6 | 5.3 | 0.4 | 8.0 |
| 3 | 0.128 | 0.020 | N/A | 0.6 | 0.1 | N/A |
| 4 | 0.037 | 0.009 | N/A | 0.2 | 0.04 | N/A |
| 5 | 0.770 | 0.075 | 9.7 | 3.7 | 0.5 | 12.3 |
| 6 | 0.586 | 0.059 | 10.1 | 3.0 | 0.3 | 11.1 |
| 7 | 0.515 | 0.039 | 7.5 | 2.6 | 0.2 | 8.2 |
| 8 | 0.351 | 0.040 | 11.5 | 1.8 | 0.2 | 11.7 |
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 | 0.011 | 0.004 | N/A |
| Positive Control | 0.863 | 0.068 | 7.8 |
| Cutoff Serum | 0.197 | 0.012 | 6.2 |
B. Intra-assay
Eight serum samples were assayed 20 consecutive times in a single run.
| Sample | Mean OD | Std. Dev. | % CV | Mean Units | Std. Dev. | % CV |
|---|---|---|---|---|---|---|
| 1 | 1.197 | 0.073 | 6.1 | 6.1 | 0.4 | 6.7 |
| 2 | 0.818 | 0.045 | 5.6 | 4.1 | 0.2 | 5.7 |
| 3 | 0.131 | 0.005 | 3.7 | 0.7 | 0.02 | 3.7 |
| 4 | 0.057 | 0.003 | 4.4 | 0.3 | 0.01 | 4.4 |
| 5 | 0.563 | 0.034 | 6.1 | 3.0 | 0.2 | 6.4 |
| 6 | 0.460 | 0.032 | 6.9 | 2.4 | 0.1 | 6.1 |
| 7 | 0.407 | 0.020 | 4.9 | 2.2 | 0.1 | 4.9 |
| 8 | 0.269 | 0.018 | 6.8 | 1.5 | 0.1 | 6.7 |
{3}------------------------------------------------
Comparison Testing
A total of 108 serum specimens (28 from individuals with Wegners Granulomatosis, and 80 includes that follow: Computers.
A total of 108 serum specimens (28 from individuals with Wegners).
from normal apparently donors) were concurrently assayed by both the predice. A total of 108 serum specifieds (2011-11-11).
from normal apparently healthy donors) were concurrently assayed by bom the posses
from normal apparently healthy donors) were p
| Table 1.1 Panel 1, n = 28 { Positive Panel} | Predicate Device |
|---|---|
| --------------------------------------------- | ------------------ |
| Positive | Negative | l olai | |
|---|---|---|---|
| Proposed DevicePositive | 28O | 0O | 28O |
| Negative | 28 | O | 28 |
| Relative Sensitivity = 100.0 % {28/28}, oss confidence interval = 87.9 % to 100 % = 100.0 | |||
| Table 1.2 Normals, n = 80 | Predicate Device | ||
| Positive | Negative | Total | |
| Proposed DevicePositive | 00 | 080 | 080 |
| Negative | 0 | 80 | 80 |
| Total | . | --- confidence interval = 95.4 % to 100 % |
Realive open and and with the assay following the assay following NCCLS
------------------------------------------------------------------------------------------------------Interiog Substances
Interfering Substances were versions the evention in Clinical Chemistry. The Subscription of the Subscription of the Subscription of the Subscription of t more of Gric, and hemolyte samples were Testing in Chincal Onemical onemical of the more
Liberine, icter7-P Proposed Guideline, interence Testing in the assay for samples
res
with:
Hemoglobin concentration: Hemoglobili concentration: Lipid concentration:
< 500 mg/dL < 20 mg/dL < 3000 mg/dL
Prozone
The VIRGO® © eANCA Kit was used to assay several high titered serum samples to doch
if the ViRGO ® cANCA Kit was used to assay several high titered sera. The VIRGO ® CANOT Production of the results with high titered sera.
if the kit would return unexpectedly low values with high titered sera.
kit gives appropriately high posit
Conclusions
Conclusions
The results of the comparative studies support the claim that the proposed device is Ochender
{4}------------------------------------------------
Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized caduceus, which is a symbol often associated with medicine and healthcare. The caduceus is depicted with three intertwined snakes and a staff. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" is arranged in a circular fashion around the caduceus.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
NOV 1 3 1997
Mr. Joseph M. Califano Manager, Regulatory Affairs Hemagen Diagnostics, Inc. 34-40 Bear Hill Road Waltham, Massachusetts 02154
Re : K973823 Trade Name: VIRGO® cANCA Kit (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, Drug, 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, labelinq, 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 Regulations, 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 requlatory 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 obligation 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.
{5}------------------------------------------------
Paqe 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 regulation 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.qov/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 Radioloqical Health
Enclosure
{6}------------------------------------------------
K9738223
Device Name:
VIRGO ® cANCA Kit
Indication(s) For Use
This enzyme-linked immunosorbent assay (ELISA) is indicated for the detection of autoantibodies to the antigen Proteinase 3 in human serum. The presence of PR-3 antibodies, in combination with clinical observations and other serological tests, can aid in the diagnosis of Wegener's granulomatosis (WG) and other conditions associated with elevated anti-neutrophil cytoplasmic antibodies (ANCA)
(PLEASE DO NOT WRITE BELOW THIS LINE)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Peter E. Madem
(Division Sign-Off) Division of Clinical Laboratory Dev 510(k) Number _
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).