(55 days)
For the qualitative screening of human IgG antibodies to extractable nuclear antigens (ENA) in human serum by indirect enzyme immunoassay as an aid in the diagnosis of certain autoimmune disorders. This test system screens for antibodies to Sm, Sm/RNP, SSA, SSB, Scl-70 and Jo-1 in one well. Positive samples should be evaluated further using tests designed for each ENA antibody. These reagents can be used either manually or in conjunction with the MAGO® or MAGO® PLUS Automated EIA Processors.
The Is-ENA-6 Screen Test Kit System is an enzyme-linked immunosorbent assay (ELISA) for the detection of IgG to six extractable nuclear antigens (ENAs), 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:
Acceptance Criteria and Device Performance
The document does not explicitly state pre-defined "acceptance criteria" in terms of specific thresholds for sensitivity, specificity, or agreement that the device must meet to be considered acceptable. Instead, it presents the performance characteristics of the Is-ENA-6 Screen Test System and compares them to a "comparative method" (a predicate device). The implication is that performance comparable to or better than the predicate device, across multiple testing modalities (manual, MAGO, MAGO PLUS), constitutes acceptable performance.
However, based on the reported performance, we can infer what might be considered acceptable by showing strong correlation and similar diagnostic accuracy to the predicate device.
Inferred Acceptance Criteria & Reported Device Performance Table:
| Performance Metric | Inferred Acceptance Criteria (Implicit: Comparable to Predicate) | Reported Device Performance (Worst Case across Manual, MAGO, MAGO PLUS) |
|---|---|---|
| Relative Sensitivity | High (e.g., >80% and comparable to predicate) | 92.0% (84.3-96.7% CI) |
| Relative Specificity | High (e.g., >90% and comparable to predicate) | 97.2% (93.1-99.2% CI) |
| Overall Agreement | High (e.g., >90% and comparable to predicate) | 95.3% (91.8-97.6% CI) |
| Precision (Intra-assay CV) | Low (e.g., <15% for positive, <50% for negative at low conc.) | 3.0% - 44.8% (See full table in source for detailed breakdown) |
| Precision (Inter-assay CV) | Low (e.g., <20% for positive, <50% for negative at low conc.) | 7.7% - 47.0% (See full table in source for detailed breakdown) |
| Manual vs. MAGO R² | High (strong correlation) | 0.9707 |
| Manual vs. MAGO PLUS R² | High (strong correlation) | 0.9799 |
| MAGO vs. MAGO PLUS R² | High (strong correlation) | 0.988 |
Here's the breakdown of the study details:
2. Sample Size Used for the Test Set and Data Provenance:
- Sample Size:
- 150 sera from normal blood donors
- 88 sera from clinical patients
- Total test samples = 238 (234 for manual/MAGO PLUS, 235 for MAGO after equivocal exclusions)
- Data Provenance: The document states "normal S. Florida blood donor population" for the normal samples and "sera obtained from patients with an autoimmune disease or with a known autoantibody reactivity" for the clinical samples. This implies the data is from the United States (Florida) and is retrospective, as the samples were "obtained" and then subsequently tested.
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 or their qualifications for establishing the initial ground truth for the 88 clinical patient sera.
- For the discordant samples (10-11 samples depending on the test method), the "resolution" involved testing them in "6 specific commercially available ENA test kits for anti-SSA, -SSB, -Sm, -Sm/RNP, Scl-70 and Jo-1." This implies these specific ENA tests were used as the reference standard, not necessarily human expert consensus for the initial classification of all 238 samples.
4. Adjudication Method for the Test Set:
- For the initial classification of the 238 samples, an explicit adjudication method (like 2+1 or 3+1 expert consensus) is not described. The classification of "normal blood donors" and "clinical patients with an autoimmune disease or with a known autoantibody reactivity" likely relied on previous clinical records or diagnostic results.
- For the discordant samples between the Is-ENA-6 Screen Test Kit and the comparative method, the adjudication method involved testing them with "6 specific commercially available ENA test kits." The results from these specific tests were then used to "resolve" the discrepancy (e.g., "POS for anti-SSA"). This is a form of resolution by reference method.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done:
- No, an MRMC comparative effectiveness study was not done. This study focuses on an in vitro diagnostic device (ELISA kit) performance compared to another similar kit, not on human reader performance with or without AI assistance.
- Therefore, there is no effect size reported for human readers improving with AI vs. without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, this is a standalone performance study. The device itself (the Is-ENA-6 Screen Test System, operated manually or with automated processors MAGO/MAGO PLUS) is the "algorithm" here, and its performance is evaluated directly against a comparative method. There is no mention of a human-in-the-loop component for the interpretation of the Is-ENA-6 results as part of the study; the device generates a result (positive/negative/equivocal).
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.):
- The ground truth for the 238 test samples primarily relies on pre-existing clinical classification (normal blood donor or patient with autoimmune disease/known autoantibody reactivity).
- For resolving discordant results between the test device and the comparative device, the ground truth was established by results from "6 specific commercially available ENA test kits" for individual ENA antibodies. This represents a reference standard based on other validated diagnostic tests.
8. The Sample Size for the Training Set:
- Not Applicable / Not Provided. This document describes a validation study for an in vitro diagnostic kit, not an AI or machine learning algorithm that requires a separate training set. The "device" itself is a chemical assay kit.
9. How the Ground Truth for the Training Set was Established:
- Not Applicable / Not Provided. As this is not an ML algorithm, there is no training set in the context of machine learning. The "learning" of the device is inherent in its chemical design and manufacturing.
{0}------------------------------------------------
510(k) Summary of Safety and Effectiveness
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K980759
Applicant Information:
| Date Prepared: | April 10, 1998 |
|---|---|
| Name: | Diamedix Corporation |
| Address: | 2140 N. Miami AvenueMiami, FL 33127 |
| Contact Person: | Dr. Lynne Stirling |
|---|---|
| Phone Number: | 305-324-2354 |
| Fax Number: | 305-324-2585 |
Device Information:
| Trade Name: | Is-ENA-6 Screen Test System |
|---|---|
| Common Name: | ENA Screening Test |
| Classification Name: | Antinuclear Antibody Immunological Test System(866.5100), product code LLL |
Equivalent Device:
Zeus Scientific ENA Screen, ELISA Test System
Device Description: The Is-ENA-6 Screen Test Kit System is an enzyme-linked immunosorbent assay (ELISA) for the detection of IgG to six extractable nuclear antigens (ENAs), in human serum.
Intended Use: The assay is intended for use in detecting IgG antibodies to ENA's (SSA, SSB, Sm, Sm/RNP, Scl-70 and Jo-1 in one well) in a single human serum sample. The results of the assay can be used as an aid in the diagnosis of autoimmune disorders.
Principle of the Procedure:
The Is-ENA-6 Screen Test System is an enzyme-linked immunosorbent assay to detect IgG to six ENAs in human serum. Purified antigens are attached to a solid phase microtiter well. Diluted test sera are added to each well. If antibodies which recognize the antigens are present in the patient sample they will bind to the antigens in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human immunoglobulin (conjugate) is added to each test well. If antibody is present the enzyme-linked antibody will bind to it. After incubation, the wells are washed to remove unbound conjugate. A substrate solution is then added to each well. If enzyme is present from prior step, the reaction is stopped and the color intensity is measured photometrically producing an indirect measure of the specific antibodies present in the patient sample.
{1}------------------------------------------------
Performance Characteristics
A. Comparison Testing
The Diamedix Is-ENA-6 Screen Test Kit was evaluated relative to another commercially available ENA Screen test kit. One hundred and fifty sera from normal blood donors and eighty-eight sera from clinical patients were tested by the Is-ENA-6 Screen Test Kit and the comparative method. Testing was performed manually and using the MAGO and MAGO PLUS Automated Processors. The results obtained are shown in Table 1.
| Manual | MAGO | MAGO PLUS | |||||||
|---|---|---|---|---|---|---|---|---|---|
| TABLE 1. | # of Sera | % | 95%CI | # of Sera | % | 95% CI | # of Sera | % | 95% CI |
| Relative Sensitivity | 81/88 | 92.0 | 84.3-96.7 | 82/89 | 92.1 | 84.5-96.8 | 82/89 | 92.1 | 84.5-96.8 |
| Relative Specificity | 143/146 | 97.9 | 94.1-99.6 | 142/146 | 97.2 | 93.1-99.2 | 143/146 | 97.9 | 94.1-99.6 |
| Overall Agreement | 224/234* | 95.7 | 92.3-97.9 | 224/235** | 95.3 | 91.8-97.6 | 225/235** | 95.7 | 92.3-97.9 |
- Four equivocal samples were exluded from calculations; ** Three equivocal samples were excluded from calculations. Ten sera were discordant in the manual and MAGO PLUS testing; an additional sample was discordant in the MAGO testing. All discordant samples were tested in 6 specific commercially available ENA test kits for anti-SSA, -SSB, -Sm, -Sm/RNP, Scl-70 and Jo-1. The resolution of discordant samples is summarized in Table 2.
TABLE 2.
| Sample # | Is-ENA-6 ScreenResult | Other ENA ScreenResult | Resolution |
|---|---|---|---|
| 82-normal | POS | NEG | NEG in all 6 specific ENA tests |
| 84-normal | NEG | POS | NEG in all 6 specific ENA tests |
| 90-normal* | POS | NEG | NEG in all 6 specific ENA tests |
| 91-normal | NEG | POS | NEG in all 6 specific ENA tests |
| 112-clinical | POS | NEG | POS for anti-SSA |
| 128-clinical | NEG | POS | NEG in all 6 specific ENA tests |
| 138-clinical | NEG | POS | POS for anti-Jo-1 |
| 140-clinical | NEG | POS | NEG in all 6 specific ENA tests |
| 173-clinical | POS | NEG | POS for anti-SSA |
| 205-normal | NEG | POS | NEG in all 6 specific ENA tests |
| 225-normal | NEG | POS | NEG in all 6 specific ENA tests |
- This sample was a weak positive (Index 1.2) during MAGO testing only.
B. Precision
The precision of the Is-ENA-6 Screen test kit was determined by testing six different sera (2 negative and 4 positive) and the kit calibrator and controls in triplicate in two different runs on three different days. Precision was evaluated manually and using the MAGO and MAGO PLUS Processors. The intra- and interassay precision is shown in Table3.
| TABLE 3. | Overall | MANUAL | MAGO | MAGO PLUS | |||
|---|---|---|---|---|---|---|---|
| SERUM | Mean Abs. | Intra-CV% | Inter CV% | Intra-CV% | Inter-CV% | Intra-CV% | Inter-CV% |
| A (NEG) | 0.024 | 10.3 | 15.1 | 44.8 | 47.0 | 26.1 | 25.1 |
| B (NEG) | 0.044 | 4.7 | 9.3 | 10.1 | 28.6 | 5.8 | 15.3 |
| C (POS) | 0.600 | 7.0 | 8.4 | 7.3 | 12.0 | 5.9 | 11.6 |
| D (POS) | 0.927 | 4.0 | 10.4 | 7.1 | 11.0 | 6.3 | 8.3 |
| E (POS) | 1.004 | 3.0 | 9.3 | 6.6 | 9.9 | 6.7 | 9.9 |
| F (POS) | 1.488 | 4.9 | 8.5 | 6.7 | 10.4 | 4.9 | 7.9 |
| c/o CAL | 0.368 | 6.6 | 11.2 | 3.7 | 9.2 | 3.3 | 5.0 |
| POS | 0.487 | 3.1 | 7.7 | 5.6 | 9.1 | 3.6 | 7.0 |
| NEG | 0.060 | 9.0 | 12.9 | 18.1 | 23.0 | 10.7 | 13.7 |
{2}------------------------------------------------
C. Expected Values
The expected value for a normal patient is a negative result. However, positive results for autoantibodies may be found in some apparently healthy individuals. Patient sera containing autoantibodies to those antigens represented in the Is-ENA-6 Screen test will give positive results which can be further evaluated in specific tests. The number of positive samples detected is dependent upon the populations being tested. The expected values in a normal S. Florida blood donor population were evaluated by assaying 150 sera both manually and using the MAGO and MAGO PLUS Automated Processors. Figures 1, 3 and 5 show the distribution of results in this normal population. For manual and MAGO PLUS testing 98.6% of the normals gave negative results; for MAGO 98% gave negative results. Two normal samples positive in the Is-ENA-6 Screen were subsequently shown to be strongly positive for SSA antibodies.
In the present studies 88 sera obtained from patients with an autoimmune disease or with a known autoantibody reactivity were evaluated in the Is-ENA-6 Screen. Figures 2, 4 and 6 show the distribution of results for this population.
Image /page/2/Figure/3 description: The image contains six line graphs comparing expected values of normal and clinical samples using different methods: Manual, MAGO, and MAGO PLUS. Figures 1, 3, and 5 show the expected values for normal samples using Manual, MAGO, and MAGO PLUS methods, respectively, with a noticeable spike in index values towards the end of the sample range. Figures 2, 4, and 6 depict the expected values for clinical samples using the same methods, showing a gradual increase in index values as the number of samples increases.
{3}------------------------------------------------
D. Correlation of Manual, MAGO and MAGO PLUS Results
Correlation of manual, MAGO and MAGO PLUS Index Values for the 238 samples tested in the Is-ENA-6 Screen Test Kit is shown in Figures 7, 8 and 9.
Image /page/3/Figure/2 description: This image is a scatter plot titled "Figure 7. Manual vs MAGO Correlation". The x-axis is labeled "Mago" and ranges from 0.0 to 7.0, while the y-axis is labeled "Manual" and ranges from 0.0 to 9.0. A trend line is plotted through the data points, and the R-squared value is 0.9707.
Image /page/3/Figure/3 description: The image is a scatter plot comparing "Manual" and "Mago Plus" measurements. The x-axis represents "Mago Plus" values ranging from 0.0 to 8.0, while the y-axis represents "Manual" values ranging from 0.0 to 10.0. A linear trendline is fitted to the data points, indicating a strong positive correlation between the two measurement methods. The R-squared value is 0.9799, suggesting a high degree of variance explained by the linear model.
Figure 8. Manual vs MAGO PLUS Correlation
Image /page/3/Figure/4 description: The image is a scatter plot titled "Figure 9. MAGO vs MAGO PLUS Correlation". The x-axis represents the MAGO index, and the y-axis represents the MAGO Plus Index. The scatter plot shows a strong positive correlation between the two indices, with an R-squared value of 0.988.
Mago Index
Figure 9. MAGO vs MAGO PLUS Correlation
{4}------------------------------------------------
Image /page/4/Picture/2 description: The image is a black and white seal for the Department of Health & Human Services USA. The seal is circular and contains the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. In the center of the seal is a stylized image of three faces in profile, stacked on top of each other. The faces are connected by a flowing ribbon-like shape.
APR 23 1998
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Lynne Stirling, Ph.D. Diamedix Corporation 2140 N. Miami Avenue Miami, Florida 33127
Re : K980759 Diamedix Is-ENA-6 Screen Test System Trade Name: Regulatory Class: II Product Code: LLL February 26, 1998 Dated: Received: February 27, 1998
Dear Dr. Stirling:
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, 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 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 regulation (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 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}------------------------------------------------
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 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.gov/cdrh/dsmamain.html"
Sincerely yours,
Steven Butman
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 ..... ..............................................................................................................................................................
{6}------------------------------------------------
Appendix G. Indications for Use Statement
INDICATIONS FOR USE STATEMENT
510(K) NUMBER : K980759
DEVICE NAME : Is-ENA-6 Screen Test System
Indications for Use : For the qualitative screening of human IgG antibodies to extractable nuclear antigens (ENA) in human serum by indirect enzyme immunoassay as an aid in the diagnosis of certain autoimmune disorders. This test system screens for antibodies to Sm, Sm/RNP, SSA, SSB, Scl-70 and Jo-1 in one well. Positive samples should be evaluated further using tests designed for each ENA antibody. These reagents can be used either manually or in conjunction with the MAGO® or MAGO® PLUS Automated EIA Processors.
prescription use
✓
in 4/23/98
Peter E. Makison
(Division S... Ort)
Division ...ical Laboratory Devices
510(k) Number K980759
§ 866.5100 Antinuclear antibody immunological test system.
(a)
Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).(b)
Classification. Class II (performance standards).