(14 days)
The DiaSorin ETI-EA-G kit uses Enzyme Linked Immunosorbent Assay (ELISA) technology for the qualitative and/or semi-quantitative detection of IgG antibodies to the EBV Early Antigen Diffuse. The assay is designed for human serum. The presence of EA antibodies is used as an aid in the diagnosis of EBV associated infectious mononucleosis when used in conjunction with other EBV serologies in pediatric, adult, transplant donor and transplant recipient populations. When evaluating properly paired sera, the results of these assays are used to demonstrate seroconversion or significant change in antibody titer as evidence of recent infection. Both specimens should be tested simultaneously.
The method for the determination of specific anti-EA (D) IgG utilizes the enzyme-linked immunosorbent assay (ELISA) technique. Polystyrene microtiter wells are coated with recombinant EA (D) antigen. Diluted patient serum is incubated with the purified antigen bound to the solid surface of a microtiter well. The EA (D) IgG antibodies present in a patient's serum will be captured by the solid phase. After washing, affinity purified polyclonal goat anti-human IgG (Fc) antibodies coniugated to horseradish peroxidase are added to the well. After this incubation, chromogen containing tetramethylbenzidine is added. Enzyme action on the chromogen results in a color reaction. The color can be detected with a photometer at a wavelength of 450 nm. The measured enzyme activity is directly proportional to the concentration of specific anti-EA (D) IgG bound to the solid phase.
This document describes the performance data for the DiaSorin ETI-EA-G Epstein-Barr Viral Early Antigen Diffuse EA (D) IgG ELISA Immunoassay.
1. Table of Acceptance Criteria and Reported Device Performance
For the purpose of this analysis, the "acceptance criteria" are inferred from the Expected Prevalence and the desire for high Sensitivity, Specificity, and Agreement with the predicate device.
| Performance Metric | Expected Pattern (Adult Population) | Adult Population (Reported) | Expected Pattern (Pediatric Population) | Pediatric Population (Reported) |
|---|---|---|---|---|
| Primary Disease State | ||||
| Sensitivity | High (not explicitly defined, but close to 100% ideal) | 97.8% (95% CI: 88.5 - 99.9%) | High (not explicitly defined) | 89.7% (95% CI: 72.6 – 97.8%) |
| Specificity | N/A (not applicable for positive pattern) | N/A | N/A | N/A |
| Agreement | High (not explicitly defined) | 97.8% | High (not explicitly defined) | 89.7% |
| Prevalence ELISA | In range (80-100%) | 97.8% | In range (80-100%) | 89.7% |
| Prevalence IFA (Predicate) | In range (80-100%) | 100% | In range (80-100%) | 100% |
| Seronegative Population | ||||
| Sensitivity | N/A | N/A | N/A | N/A |
| Specificity | High (not explicitly defined, but close to 100% ideal) | 100.0% (95% CI: 59.0 - 100.0%) | High (not explicitly defined) | 96.0% (95% CI: 86.3 - 99.5%) |
| Agreement | High (not explicitly defined) | 100.0% | High (not explicitly defined) | 96.0% |
| Prevalence ELISA | In range (0%) | 0.0% | In range (0%) | 4.0% |
| Prevalence IFA (Predicate) | In range (0%) | 0.0% | In range (0%) | 0.0% |
| Reactivated Population | ||||
| Sensitivity | High (not explicitly defined, but close to 100% ideal) | 96.8% (95% CI: 83.3-99.9%) | High (not explicitly defined) | 100.0% (95% CI: 39.8 - 100.0%) |
| Specificity | N/A | N/A | N/A | N/A |
| Agreement | High (not explicitly defined) | 96.8% | High (not explicitly defined) | 100.0% |
| Prevalence ELISA | In range (90-100%) | 96.8% | In range (90-100%) | 100.0% |
| Prevalence IFA (Predicate) | In range (90-100%) | 100% | In range (90-100%) | 100% |
| Past Infection Population | ||||
| Sensitivity | Varies (36.4% and 66.7% are reported) | 36.4% (95% CI: 20.4 - 54.9%) | Varies | 66.7% (95% CI: 9.0 - 99.9%) |
| Specificity | Varies (75.0% and N/A are reported) | 75.0% (95% CI: 19.4-99.4) | Varies | N/A |
| Agreement | Varies (40.5% and 66.7% are reported) | 40.5% | Varies | 66.7% |
| Prevalence ELISA | In range (10-40%) | 32.4% | In range (10-40%) | 66.7% |
| Prevalence IFA (Predicate) | In range (10-40%) | 89.2% | In range (10-40%) | 100% |
| Transplant Recipient Population | ||||
| Sensitivity | Varies (47.6% and N/A are reported) | 47.6% (95% CI: 25.7 - 70.2%) | Varies | N/A |
| Specificity | Varies (33.3% and 85.7% are reported) | 33.3% (95% CI: 0.8% - 90.6%) | Varies | 85.7% (95% CI: 42.1 - 99.6%) |
| Agreement | Varies (45.8% and 75.0% are reported) | 45.8% | Varies | 75.0% |
| Prevalence ELISA | Not explicitly defined as expected | 50.0% | Not explicitly defined as expected | 12.5% |
| Prevalence IFA (Predicate) | Not explicitly defined as expected | 87.5% | Not explicitly defined as expected | 12.5% |
Summary of Acceptance:
The document states: "The ETI-EA-G ELISA demonstrates good sensitivity and specificity in Primary, Seronegative and Reactivated populations. The prevalence rates were within the expected range for each of these populations." It also provides explanations for the observed differences in Past Infection and Transplant Recipient populations, attributing them to the difference in antigen detection between the predicate and the new device, and concluding that "The results support the Transplant claim in the Intended Use."
2. Sample Size Used for the Test Set and Data Provenance
The provided text only discusses the "clinical trials" which represent the "test set" in this context. There is no mention of a separate training set.
-
Sample Size for Test Set:
- Primary Disease State (Adult): 46 samples (+)
- Primary Disease State (Pediatric): 29 samples (+)
- Seronegative (Adult): 7 samples (-)
- Seronegative (Pediatric): 50 samples (-)
- Reactivated (Adult): 31 samples (+)
- Reactivated (Pediatric): 4 samples (+)
- Past Infection (Adult): 37 samples (-/+) (33 were IFA positive, 4 IFA negative)
- Past Infection (Pediatric): 3 samples (-/+) (3 were IFA positive)
- Transplant Recipient (Adult): 24 samples (21 were IFA positive, 3 IFA negative)
- Transplant Recipient (Pediatric): 8 samples (1 was IFA positive, 7 IFA negative)
- Total Samples (unique cases are not explicit): 235 samples across all categories.
-
Data Provenance: The samples were "patients from the disease states defined below" and "screened" from a clinical laboratory. The data's geographical origin (country) is not explicitly stated. The study is described as "clinical trials," suggesting it was conducted to evaluate the performance of the ETI-EA-G, making it seem prospective for the device's evaluation, although the samples themselves might have been collected retrospectively from existing patient cohorts.
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 specific "qualifications" (e.g., radiologist with X years of experience).
- Method of Ground Truth Establishment (Primary): The ground truth was established by comparing the DiaSorin ETI-EA-G against a "predicate device," the Gull Laboratories, Inc. EA IgG IFA test.
- Method of Ground Truth Establishment (Secondary/Confirmation): Patient samples were "excluded if they failed to fit a recognized EBV marker pattern determined by EBV VCA (IgG, IgM) and EBNA testing." This implies that the initial classification into disease states (Primary, Seronegative, Reactivated, Past Infection) was done based on a combination of EBV serologies (VCA IgG, IgM, and EBNA testing), which would likely have been interpreted by laboratory professionals or clinicians, effectively acting as "experts" in serology.
4. Adjudication Method for the Test Set
The document does not describe an explicit "adjudication method" in the sense of multiple experts reviewing cases and resolving disagreements. The ground truth appears to be based on the results of the predicate IFA test and other established EBV serologies, which function as objective reference standards within the study design.
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 question is not applicable as the device is an immunoassay (ELISA) for detecting antibodies, not an AI-powered diagnostic imaging or analytical tool that involves human readers.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, this study is inherently a standalone performance evaluation. The DiaSorin ETI-EA-G ELISA kit is a laboratory test, and its results are generated directly by the assay without human "reading" in the context of interpretation beyond standard laboratory procedures and result reporting. Its performance (sensitivity, specificity, agreement) is reported for the device itself, comparing its output to a predicate standard.
7. The Type of Ground Truth Used
The primary ground truth for comparison was the Gull Laboratories, Inc. EA IgG IFA test. Additionally, the classification into different disease states (Primary, Seronegative, Reactivated, Past Infection, Transplant Recipient) was based on "a recognized EBV marker pattern determined by EBV VCA (IgG, IgM) and EBNA testing." This indicates a combination of a predicate diagnostic test and clinical/serological consensus based on established EBV marker patterns, representing a form of expert consensus derived from widely accepted EBV serology interpretation guidelines.
8. The Sample Size for the Training Set
The document does not mention a separate training set. The samples described were used for "clinical trials" to evaluate the performance of ETI-EA-G. For immunoassay development, "training" often refers to the optimization phase, which is generally not documented in the same way as clinical validation.
9. How the Ground Truth for the Training Set Was Established
As no separate training set is mentioned, this question is not applicable.
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JUL 12 1560
K992191
510 (k) SUMMARY
SUBMITTED BY:
Judith J. Smith DiaSorin, Inc. 9175 Guilford Rd. Suite 100 Columbia, MD 21046
NAME OF DEVICES: Trade Name:
DiaSorin ETI-EA-G Epstein-Barr Viral Early Antigen Diffuse EA (D) IaG ELISA
Immunoassay for the detection of IgG Common Names/Descriptions: antibodies to the Epstein-Barr Viral (EBV) Early Antigen Diffuse antigen
Classification Names:
EBV Serology Test
PREDICATE DEVICES:
DiaSorin EBV EA (D) IgG Clin-ELISA™ Gull Laboratories EBV EA IgG IFA
DEVICE DESCRIPTION:
INTENDED USE: The DiaSorin ETI-EA-G kit uses Enzyme Linked Immunosorbent Assay (ELISA) technology for the qualitative and/or semi-quantitative detection of IgG antibodies to the EBV Early Antigen Diffuse. The assay is designed for human serum. The presence of EA antibodies is used as an aid in the diagnosis of EBV associated infectious mononucleosis when used in conjunction with other EBV serologies in pediatric, adult, transplant donor and transplant recipient populations. When evaluating properly paired sera, the results of these assays are used to demonstrate seroconversion or significant change in antibody titer as evidence of recent infection. Both specimens should be tested simultaneously.
KIT DESCRIPTION: The method for the determination of specific anti-EA (D) IgG utilizes the enzyme-linked immunosorbent assay (ELISA) technique. Polystyrene microtiter wells are coated with recombinant EA (D) antigen. Diluted patient serum is incubated with the purified antigen bound to the solid surface of a microtiter well. The EA (D) IgG antibodies present in a patient's serum will be captured by the solid phase. After washing, affinity purified polyclonal goat anti-human IgG (Fc) antibodies coniugated to horseradish peroxidase are added to the well. After this incubation, chromogen containing tetramethylbenzidine is added. Enzyme action on the chromogen results in a color reaction. The color can be detected with a photometer at a wavelength of 450 nm. The measured enzyme activity is directly proportional to the concentration of specific anti-EA (D) IgG bound to the solid phase.
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PERFORMANCE DATA:
Comparative Clinical Trials Clinical trials were conducted at 1 clinical laboratory to evaluate the performance of ETI-EA-G in detecting IgG antibodies to EBV EA (D). Assay performance was compared to the Gull Laboratories, Inc. EA IgG IFA test. Patients from the disease states defined below were tested. The screening population is a group of samples from patients suspected of disease. The transplant recipients were patients who had received, or were awaiting, solid organ or bone marrow transplants. Patient samples excluded if they failed to fit a recognized EBV marker pattern determined by EBV VCA (IgG, IgM) and EBNA testing. Results are shown below.
| Expected Pattern | + |
|---|---|
| Sensitivity | 45/46 = 97.8% |
| (95% CI) | (88.5 - 99.9%) |
| Specificity | N/A |
| (95% CI) | |
| Agreement | 45/46 = 97.8% |
| Prevalence ELISA | 45/46 = 97.8% |
| Prevalence IFA | 46/46 = 100% |
| Expected Prevalence | 80-100% |
Primary Disease State: Adult Population
Primary Disease State; Pediatric Population
| Expected Pattern | + |
|---|---|
| Sensitivity | 26/29 = 89.7% |
| (95% CI) | (72.6 – 97.8%) |
| Specificity | N/A |
| (95% CI) | |
| Agreement | 26/29 = 89.7% |
| Prevalence ELISA | 26/29 = 89.7% |
| Prevalence IFA | 29/29 = 100% |
| Expected Prevalence | 80-100% |
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Seronegative; Adult Population
| Expected Pattern | - |
|---|---|
| Sensitivity | N/A |
| (95% CI) | |
| Specificity | 7/7 = 100.0% |
| (95% CI) | (59.0 - 100.0%) |
| Agreement | 7/7 = 100.0% |
| Prevalence ELISA | 0/7 = 0.0% |
| Prevalence IFA | 0/7 = 0.0% |
| Expected Prevalence | 0% |
:
:
Seronegative; Pediatric Population
| Expected Pattern | - |
|---|---|
| Sensitivity | N/A |
| (95% CI) | |
| Specificity | 48/50 = 96.0% |
| (95% CI) | (86.3 - 99.5%) |
| Agreement | 48/50 = 96.0% |
| Prevalence ELISA | 2/50 = 4.0% |
| Prevalence IFA | 0/50 = 0.0% |
| Expected Prevalence | 0% |
Reactivated; Adult Population
| Expected Pattern | + |
|---|---|
| Sensitivity | 30/31 = 96.8% |
| (95% CI) | (83.3-99.9%) |
| Specificity | N/A |
| (95% Cl) | N/A |
| Agreement | 30/31 = 96.8% |
| Prevalence ELISA | 30/31 = 96.8% |
| Prevalence IFA | 31/31 = 100% |
| Expected Prevalence | 90-100% |
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Reactivated; Pediatric Population
| Expected Pattern | + |
|---|---|
| Sensitivity | 4/4 = 100.0% |
| (95% CI) | (39.8 - 100.0%) |
| Specificity | N/A |
| (95% CI) | |
| Agreement | 4/4 = 100.0% |
| Prevalence ELISA | 4/4 = 100.0% |
| Prevalence IFA | 4/4 = 100.0% |
| Expected Prevalence | 90-100% |
. .
Past Infection; Adult Population
:
| Expected Pattern | -/+ |
|---|---|
| Sensitivity | 12/33 = 36.4% |
| (95% CI) | (20.4 - 54.9%) |
| Specificity | 3/4= 75.0% |
| (95% CI) | (19.4-99.4) |
| Agreement | 15/37 = 40.5% |
| Prevalence ELISA | 13/37 = 32.4% |
| Prevalence IFA | 33/37 = 89.2% |
| Expected Prevalence | 10-40% |
Past Infection; Pediatric Population
| Expected Pattern | -/+ |
|---|---|
| Sensitivity | 2/3 = 66.7% |
| (95% CI) | (9.0 - 99.9) |
| Specificity | N/A |
| (95% CI) | |
| Agreement | 2/3 = 66.7% |
| Prevalence ELISA | 2/3 = 66.7% |
| Prevalence IFA | 3/3 = 100.0% |
| Expected Prevalence | 10-40% |
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| ELISA Result | EA (D) IgG |
|---|---|
| Sensitivity | 10/21 = 47.6% |
| (95% CI) | (25.7 - 70.2%) |
| Specificity | 1/3 = 33.3% |
| (95% CI) | (0.8% - 90.6%) |
| Agreement | 11/24 = 45.8% |
| Prevalence ELISA | 12/24 = 50.0% |
| Prevalence IFA | 21/24 = 87.5% |
Transplant Recipient patients: Adult Population
Transplant Recipient patients; Pediatric Population
| ELISA Result | EA (D) IgG |
|---|---|
| Sensitivity(95% CI) | N/A |
| Specificity(95% CI) | 6/7 = 85.7%(42.1 - 99.6%) |
| Agreement | 6/8 = 75.0% |
| Prevalence ELISA | 1/8 = 12.5% |
| Prevalence IFA | 1/8 = 12.5% |
The ETI-EA-G ELISA demonstrates good sensitivity and specificity in Primary. Seronegative and Reactivated populations, The prevalence rates were within the expected range for each of these populations.
In the Past Infection population the prevalence rate for ETI-EA-G was consistent with published rates of 10-40%, while IFA rates were 90%. This appears to reflect the fact that the IFA detects both the Restricted and the Diffuse EA antigen, while ETI-EA-G detects only the Diffuse antigen. The Restricted antigen is only occasionally seen in acute IM cases, and then only late in the acute phase. Following IM, however, the Restricted antigen persists in a substantial number of patients for at least 10-104 months. In light of this, it is predictable that the Gull IFA would detect Early Antigen at a much higher rate in a Past Infection population than would the ETI-EA-G ELISA. The same situation appears to account for the results seen in the Transplant Recipients who included a high percentage of samples with EBV markers consistent with Past Infection. The results support the Transplant claim in the Intended Use.
Within each of the defined disease states, results were similar across the adult and pediatric populations, supporting the separate adult and pediatric claims in the Intended Use for ETI-EA-G.
Reproducibility: Reproducibility studies were performed at 3 sites using one lot of ETI-EA-G reagents. Assay reproducibility was determined using 6 samples that spanned
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the range of the assay. Samples were tested in triplicate once a day for 3 days. Combined results are summarized below.
| Within-run | Between day | Between site | Total | ||
|---|---|---|---|---|---|
| Sample | Mean (AU) | %CV | %CV | %CV | %CV |
| Negative | 7.6 | 12.14 | 22.02 | 14.77 | 21.63 |
| Negative | 9.2 | 14.24 | 24.19 | 20.01 | 19.61 |
| low pos | 29.4 | 7.57 | 4.97 | 11.37 | 8.18 |
| low pos | 26.0 | 13.47 | 12.32 | 9.59 | 15.88 |
| mid pos | 74.5 | 9.71 | 2.68 | 3.36 | 10.12 |
| high pos | 122.4 | 6.74 | 3.06 | 0.98 | 6.64 |
Reproducibility for ETI-EA-G based on Arbitrary Units (AU)
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Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an abstract symbol resembling a stylized human figure or a bird in flight, composed of three curved lines.
Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850
JUL 1.2 1999
DiaSorin, Inc. c/o Ms. Carole Stamp TÜV Product Service, Inc. 1775 Old Highway 8 NW Suite 104 New Brighton, MN 55112-1891
Re: K992191 Trade Name: DiaSorin ETI-EA-G Regulatory Class: I Product Code: LSE Dated: June 25, 1999 Received: June 28, 1999
Dear Ms. Stamp:
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 legally marketed predicate 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 requirements, 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.
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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 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 Sutman
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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INDICATIONS FOR USE
510(k) Number (if known): Not known
Device Name: DiaSorin ETI-EA-G
Indications For Use:
The DiaSorin ETI-EA-G kit uses Enzyme Linked Immunosorbent Assay (ELISA) technology for the qualitative and/or semi-quantitative detection of IgG antibodies to the EBV Early Antigen Diffuse. The assay is designed for human serum. The presence of EA antibodies is used as an aid in the diagnosis of EBV associated infectious mononucleosis when used in conjunction with other EBV serologies in pediatric, adult, transplant donor and transplant recipient populations. When evaluating properly paired sera, the results of these assays are used to demonstrate seroconversion or significant change in antibody titer as evidence of recent infection. Both specimens should be tested simultaneously.
(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Woody Dubois
ical I aboratory Devices 510(k) Number
Prescription Use (Per 21 CFR 801.109) OR
Over-The-Counter Use
(Optional Format 1-2-96)
§ 866.3235 Epstein-Barr virus serological reagents.
(a)
Identification. Epstein-Barr virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Epstein-Barr virus in serum. The identification aids in the diagnosis of Epstein-Barr virus infections and provides epidemiological information on diseases caused by these viruses. Epstein-Barr viruses are thought to cause infectious mononucleosis and have been associated with Burkitt's lymphoma (a tumor of the jaw in African children and young adults) and postnasal carcinoma (cancer).(b)
Classification. Class I (general controls).