(265 days)
The LIAISON® EA IgG assay and LIAISON® EA IgG Controls use chemiluniescent immunoassay (CLIA) technology on the LIAISON Analyzer for the qualitative determination of IgG antibodies to Epstein-Barr virus early antigen-diffuse [EA(D)] in human serum. This assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM).
The method for qualititative determination of specific IgG to Epstein-Barr virus early antigen-diffuse (EA(D) recombinant polypeptide] is an indirect chemiluminescence immunoassay (CLIA). All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the LIAISON® Analyzer. The principal components of the test are magnetic particles (solid phase) coated with EA(D) recombinant polypeptide and a conjugate of mouse monoclonal antibody to human IgG linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, EA(D) antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with EA(D) antibodies that are already bound to the solid phase. After each incubation, unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of the presence of EA(D) IgG antibodies present in calibrators, samples or controls.
Here's a breakdown of the acceptance criteria and study information for the DiaSorin LIAISON® EA IgG assay, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The provided document does not explicitly state pre-defined "acceptance criteria" as a separate set of pass/fail thresholds. Instead, it presents the performance results of the device and concludes that these results demonstrate "equivalent performance to the corresponding FDA-cleared assay" and "agreement with the comparison method higher then 92% among prospectively collected samples and 100% agreement among retrospective selected samples."
Therefore, the performance of the predicate device (DiaSorin ETI-EA-G ELISA Kit) effectively serves as the benchmark for acceptance.
Inferred Acceptance Criteria (based on predicate device performance and stated conclusions):
| Performance Metric | Acceptance Criteria (Inferred from Predicate Equivalence) | Reported Device Performance (LIAISON® EA IgG) |
|---|---|---|
| Prospective Samples: | ||
| Positive Agreement | Comparable to predicate (DiaSorin ETI-EA-G) | 90.3% (297/329) [Exact 95% CI: 86.6 – 93.3%] |
| Negative Agreement | Comparable to predicate (DiaSorin ETI-EA-G) | 93.5% (462/494) [Exact 95% CI: 91.0 – 95.5%] |
| Overall Agreement | Comparable to predicate (DiaSorin ETI-EA-G) | 92.2% (759/823) [Exact 95% CI: 90.2 – 94.0%] |
| Retrospective Samples (VCA IgM-positive): | ||
| Positive Agreement | Comparable to predicate (DiaSorin ETI-EA-G) | 100.0% (70/70) [Exact 95% CI: 94.9 - 100.0%] |
| Negative Agreement | N/A (no negative samples in this subset) | N.C.* (0/0) |
| Overall Agreement | Comparable to predicate (DiaSorin ETI-EA-G) | 100.0% (70/70) [Exact 95% CI: 94.9 - 100.0%] |
| Reproducibility (Overall %CV) | (Not explicitly stated, but generally expected to be low for diagnostic assays) | Ranged from 9.43% to 15.36% across 9 samples |
| Interference | No significant effect from common interferents | No effect at specified levels of hemoglobin, triglycerides, bilirubin |
| Cross-Reactivity | Limited cross-reactivity with other common infections and autoantibodies | 15/183 specimens showed positive/equivocal results, particularly with Toxoplasma gondii and rubella virus. Conclusion attributes this to performance differences between test methods. |
2. Sample Sizes Used for the Test Set and Data Provenance
- Prospective Samples:
- Sample Size: 823 samples
- Data Provenance: Subjects sent to the laboratory for EBV testing in the US (specifically from two external US laboratories and DiaSorin). The samples were collected prospectively.
- Retrospective Samples:
- Sample Size: 70 samples
- Data Provenance: VCA IgM-positive samples, implying a pre-selected cohort. No specific country of origin is mentioned beyond the US clinical trial sites, but it's likely from the same geographical region. These were retrospective samples from a repository.
- Reproducibility Panel: 9 frozen repository serum samples.
- Interference Samples: Not specified, but involved controlled studies with substances at given concentrations.
- Cross-Reactivity Panel: 183 specimens from various organism/condition categories.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The study uses a comparison assay (DiaSorin ETI-EA-G ELISA Kit) as the "ground truth" or reference method for the clinical trials. This is a common practice for 510(k) submissions of in-vitro diagnostic devices where an existing FDA-cleared predicate device serves as the a reference.
Therefore, there were no human experts establishing ground truth in the way a radiologist might read images. Instead, the ground truth was established by the results of the already-cleared predicate device.
4. Adjudication Method for the Test Set
Since the ground truth was established by a comparison assay (DiaSorin ETI-EA-G ELISA Kit), there was no explicit mention of a human expert adjudication method (like 2+1 or 3+1) for the clinical trial results presented. The results of the LIAISON® EA IgG assay were compared directly against the results of the predicate device.
For the cross-reactivity study, some equivocal results were noted, and the document states, "...Since it was not possible to acquire follow-up samples collected one to two weeks later as recommended." This suggests that for discordant or equivocal results, a follow-up sample might typically be used for adjudication or clarification, but this was not feasible in all cases during the cross-reactivity testing.
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 study focuses on the performance of an automated immunoassay device compared to another automated immunoassay device (predicate), not on human reader performance with or without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, this study is a standalone performance evaluation of the DiaSorin LIAISON® EA IgG immunoassay. It measures the device's ability to qualitatively detect specific IgG antibodies to EBV EA(D) in human serum without human intervention in the result interpretation, beyond standard laboratory quality control and reporting procedures. The "algorithm" here refers to the immunoassay's reagents and the LIAISON® Analyzer's automated processing and signal interpretation to yield a positive, equivocal, or negative result.
7. The Type of Ground Truth Used
The primary ground truth used for the comparative clinical trials was the results obtained from an FDA-cleared predicate device, the DiaSorin ETI-EA-G ELISA Kit. This is a form of "reference standard" based on another established diagnostic method.
8. The Sample Size for the Training Set
The document does not provide information on a specific training set for the DiaSorin LIAISON® EA IgG assay. Immunoassays, particularly those developed before the widespread adoption of machine learning in diagnostics, typically do not involve a distinct "training set" in the same way a machine learning algorithm would. The development process would involve reagent optimization, calibration curve establishment, and analytical validation (e.g., specificity, sensitivity, reproducibility) using panels of known samples, but these are not usually referred to as "training sets" in the context of this type of device.
9. How the Ground Truth for the Training Set Was Established
As noted above, there is no explicit mention of a "training set" in the provided text. Therefore, the method for establishing ground truth for a training set is not applicable or not described in this 510(k) submission.
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6.0 510(k) SUMMARY
OCT 1 8 2006
David M. Ikeda Requlatory Affairs/Quality Systems Manager DiaSorin Inc. 1951 Northwestern Avenue P.O. Box 285 Stillwater, MN 55082-0285 Phone (651) 351-5592 Fax (651) 351-5669 E-mail: david.ikeda@diasorin.com
LIAISON® EA IgG / LIAISON® Control EA IgG
Immunoassay for the detection of IgG antibodies to
NAME OF DEVICE: Trade Name:
SUBMITTED BY:
Common Names/Descriptions:
Classification Names:
Product Code:
PREDICATE DEVICE:
EBV early antigen-diffuse [EA(D)]
EPSTEIN-BARR VIRUS, OTHER
DiaSorin ETI-EA-G Kit (K992191)
DEVICE DESCRIPTION:
INTENDED USE: The DiaSorin LIAISON® EA IgG kit uses chemiluminescence immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative detection of specific IgG antibodies to Epstein-Barr virus early antigen-diffuse [EA(D)] in human serum. This assay uses a 47-kDa recombinant antigen expressed in E. coll DH-1 cells. When used in conjunction with other EBV markers, this assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM). LIAISON® Control EA IgG kit is used in conjunction with LIAISON® EA IgG immunoassay for monitoring substantial reagent failure.
LSE
KIT DESCRIPTION: The method for qualititative determination of specific IgG to Epstein-Barr virus early antigen-diffuse (EA(D) recombinant polypeptide] is an indirect chemiluminescence immunoassay (CLIA). All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the LIAISON® Analyzer. The principal components of the test are magnetic particles (solid phase) coated with EA(D) recombinant polypeptide and a conjugate of mouse monoclonal antibody to human IgG linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, EA(D) antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with EA(D) antibodies that are already bound to the solid phase. After each incubation, unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a
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photomultiplier as relative light units (RLU) and is indicative of the presence of EA(D) IgG antibodies present in calibrators, samples or controls.
PERFORMANCE DATA:
COMPARATIVE CLINICAL TRIALS: The clinical trials were conducted at two external US laboratories and at DiaSorin. Testing was performed on repository and prospective samples as defined below. The samples were tested by LIAISON® EA IgG and comparison assay (DiaSorin ETI-EA-G ELISA Kit), at the trial sites per the manufacturers' instructions for use.
Prospective Samples: Subjects Sent to the Laboratory for EBV Testing:
| LIAISON®EA IgG | DiaSorin ETI-EA-G | Total | |
|---|---|---|---|
| Positive | Negative | ||
| Positive (≥11.0 U/mL) | 297 | 20 | 317 |
| Equivocal (9.0-10.9 U/mL) | 17 | 12 | 29 |
| Negative (<9.0 U/mL) | 15 | 462 | 477 |
| Total | 329 | 494 | 823 |
| Percent Agreement | Exact 95% confidence interval | |
|---|---|---|
| Positive | 90.3% (297/329) | 86.6 – 93.3% |
| Negative | 93.5% (462/494) | 91.0 – 95.5% |
| Overall | 92.2% (759/823) | 90.2 – 94.0% |
Retrospective Samples: VCA IgM-positive Samples
| LIAISON®EA IgG | DiaSorin ETI-EA-G | ||
|---|---|---|---|
| Positive | Negative | Total | |
| Positive (≥11.0U/mL) | 70 | 0 | 70 |
| Equivocal (9.0-10.9 U/mL) | 0 | 0 | 0 |
| Negative (<9.0U/mL) | 0 | 0 | 0 |
| Total | 70 | 0 | 70 |
.
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| Percent Agreement | Exact 95% confidence interval | |
|---|---|---|
| Positive | 100.0% (70/70) | 94.9 - 100.0% |
| Negative | N.C.* (0/0) | N.C.* |
| Overall | 100.0% (70/70) | 94.9 - 100.0% |
REPRODUCIBILITY: Reproducibility studies were performed at 3 sites using a coded panel comprised of 9 frozen repository serum samples. The serum panel was prepared to represent from low- to mid-positive analyte level. The same coded panel was tested at all sites, in three replicates per run for ten runs. Results expressed in U/mL are summarized in the following table.
| ID# | N | mean(U/mL) | withinrunS.D. | withinrun%CV | betweenrunS.D. | betweenrun%CV | betweensiteS.D. | betweensite%CV | overallS.D. | overall%CV |
|---|---|---|---|---|---|---|---|---|---|---|
| EAS1 | 90 | 47.6 | 1.78 | 3.71 | 4.56 | 8.65 | 2.46 | 5.16 | 4.78 | 10.04 |
| EAS2 | 90 | 99.1 | 6.10 | 6.06 | 9.24 | 8.60 | 4.64 | 4.68 | 10.82 | 10.92 |
| EAS3 | 90 | 112.3 | 7.50 | 7.07 | 15.81 | 13.19 | 2.84 | 2.53 | 17.26 | 15.36 |
| EA1 | 90 | 18.2 | 0.93 | 5.17 | 1.56 | 5.50 | 1.37 | 7.52 | 1.85 | 10.15 |
| EA2 | 90 | 20.4 | 0.63 | 3.17 | 2.27 | 5.87 | 2.31 | 11.33 | 2.34 | 11.45 |
| EA3 | 90 | 47.4 | 2.07 | 4.60 | 4.87 | 5.18 | 5.09 | 10.75 | 5.28 | 11.15 |
| EA4 | 90 | 35.9 | 1.58 | 4.60 | 4.02 | 6.02 | 4.08 | 11.35 | 4.30 | 11.99 |
| EA5 | 90 | 52.4 | 2.03 | 3.88 | 4.54 | 3.55 | 5.01 | 9.56 | 4.94 | 9.43 |
| EA6 | 90 | 18.1 | 0.60 | 3.38 | 1.72 | 4.12 | 1.86 | 10.27 | 1.80 | 9.91 |
INTERFERENCE: Controlled studies of potentially interfering substances showed that the assay performance was not affected by hemolysis (at 1000 mg/dL hemoglobin), lipemia (at 3000 mg/dL triglycerides), icterus (at 20 mg/dL bilirubin).
CROSS-REACTIVITY: The cross-reactivity studies for the LIAISON® EA IgG assay were designed to evaluate potential interference from IgG immunoglobulins directed against other Epstein-Barr virus antibodies (VCA, EBNA), closely-related members of the herpes virus family (HSV-1/2, HSV-2, VZV, CMV), from other organisms that may cause symptoms similar to EBV (Toxoplasma gondii, rubella virus) and from other conditions that may result from atypical immune system activity (rheumatoid factor (RF), antinuclear antibodies (ANA)). In addition, potential interference from human anti-mouse antibodies (HAMA) was evaluated.
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| Organism / condition | Number ofSamples | Positive orequivocalLIAISON® EAIgG Result |
|---|---|---|
| EBV VCA IgG | 3 | (0/3) |
| EBV VCA IgG/EBNAIgG | 4 | (0/4) |
| CMV IgG | 27 | (2/27) |
| VZV IgG | 6 | (0/6) |
| HSV-1/2 IgG | 21 | (1/21) |
| HSV-2 IgG | 1 | (0/1) |
| Toxoplasma gondiiIgG | 17 | (4/17) |
| Rubella virus IgG | 87 | (8/87) |
| RF | 2 | (0/2) |
| ANA | 10 | (0/10) |
| HAMA | 5 | (0/5) |
| Total | 183 | (15/183) |
Fifteen specimens out of 183 total specimens tested from the cross-reaction panel relumed
positive or equivocal results in the LIAISON® EA lgG assay. were-poeitive. There-was somalos the necessionity samples, were aguivanal, by HAIOAN Coannot be excluded. Five of the fifteen discordant included in the colouictions Lion For Locking EA IgG. Equivocal results by LIAISON® EA IgG are semples, sellected and non-agreement since it was not possible to acquire tollow-up samples collected one to two weeks later as recommended. Since the highest rate of the Enclain Ramaines (There with conditions caused by organisms taxonomically unrelated to the Epstein-Barr virus (Toxoplasma gondii and rubella virus), the apparent cross-reactivity may be due to performance differences between the two EA IgG test methods. In fact, the observed that obtained with the presentive with the can inchieds (11.8%) with these samples is similar to that obtained with the prospective clinical samples (93.5% negative sample startenen),
The recombinant EA(D) antigen used in the assay is expressed in E. coli DH-1 cells. The performance characteristics of this device with samples containing antibodies against E. coli have not been established.
WARNING: Assay interference due to circulating antibodies against HIV and Hepatitis A, Hepatitis B and Hepatitis C viruses has not been evaluated. The and repail.ls A, establishing cross-reactivity performance with these infectious agents.
CONCLUSION
The LIAISON® EA IgG assay showed equivalent performance to the corresponding FDAcleared assay. The DiaSorin LIAISON® EA lgG assay demonstrated agreement with the comparison method higher then 92% among prospectively collected samples and 100% agreement among retrospective selected samples. The results demonstrated that LIAISON® EA IgG assay can be used with the LIAISON® Analyzer for the qualitative detection of IGG antibodies to EA(D) recombinant polypeptide and can be intended for use as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM)
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Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three tail feathers, representing the department's commitment to health, human services, and well-being. The eagle is positioned to the right of the department's name, which is arranged in a circular pattern around the logo. The text reads "DEPARTMENT OF HEALTH & HUMAN SERVICES . USA".
Public Health Service
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Mr. Don Kafader Director of Regulatory Affairs DiaSorin Inc. 1951 Northwestern Ave. P.O. Box 285 Stillwater, MN 55082
OCT 1 8 2006
Re: K060204
Trade/Device Name: DiaSorin LIAISON® EA IgG Assay Regulation Number: 21 CFR 866.3235 Regulation Name: Epstein-Barr virus Serological Reagents Regulatory Class: Class I Product Code: LSE Dated: October 6, 2006 Received: October 13, 2006
Dear Mr. Kafader:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and 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) that do not require approval of a premarket approval application (PMA). 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, istis 1.0.1 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 (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Begister.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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This letter will allow you to begin marketing your device as described in your Section 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 information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240)276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Sincerely yours,
Sally, axtom
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known): K060204
LIAISON® EA IgG Assay and LIAISON® EA IgG Controls Device Name:
Indications For Use: The LIAISON® EA IgG assay and LIAISON® EA IgG Controls use chemiluniescent immunoassay (CLIA) technology on the LIAISON Analyzer for the qualitative determination of IgG antibodies to Epstein-Barr virus early antigen-diffuse [EA(D)] in human serum. This assay can be used as an aid in the clinical laboratory diagnosis of Epstein-Barr viral Syndrome in patients with signs and symptoms of EBV infection such as infectious mononucleosis (IM).
Prescription Use × (Part 21 CFR 801 Subpart D)
AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Sali atta
Division Sign
Office of In Vitro Diagnostic D» Evaluation and S & J
10(k)_ KOGO 20 Page 1 of
§ 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).