(167 days)
The LIAISON® Lyme IgM assay uses chemiluminescent immunoassay (CLIA) technology for the qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum and plasma samples (K2-EDTA, Li-heparin). This assay is intended for use on samples from patients with signs and symptoms consistent with or patients suspected of having Lyme disease to assess the presence of antibodies and exposure to Borrelia burgdorferi. In addition, the LIAISON® Lyme IgM assay may be used as a confirmatory test in the modified two-tier test (MTTT) in combination with the DiaSorin LIAISON® Lyme Total Antibody Plus assay.
If used as a first stage test, positive or equivocal results with the LIAISON® Lyme IgM assay should be confirmed through additional testing with a Standard two-tier test (STTT) methodology using an IgM Borrelia burgdorferi Western blot test following current guidelines.
Positive supplemental results are supportive evidence of the presence of antibodies and exposure to Borrelia burgdorferi and may be used along with patient history, symptoms and other laboratory data to support a clinical diagnosis of Lyme disease.
Negative results by the LIAISON® Lyme IgM assay should not be used to exclude Lyme disease.
The test must be performed on the LIAISON® XL Analyzer.
The DiaSorin LIAISON® Lyme IgM Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® Lyme IgM assay. The performance characteristics of LIAISON® Lyme IgM controls have not been established for any other assays or instrument platforms different from the LIAISON® XL.
The LIAISON® Lyme IgM assay is an indirect chemiluminescence immunoassay (CLIA) for the qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum and plasma samples. All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the Analyzer. The principal components of the test are magnetic particles (solid phase) coated with recombinant Borrelia antigens and a conjugate reagent containing an anti-human IgM mouse monoclonal antibody linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, anti-Borrelia burgdorferi antibodies present in calibrators, samples or controls bind to the solid phase. Unbound material is then removed with a wash cycle. During the second incubation, the antibody conjugate reacts with anti-Borrelia burgdorferi IgM antibodies that have bound to the solid phase. Excess antibody conjugate is then removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is 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 Borrelia burgdorferi IgM antibodies present in calibrators, samples or controls.
The provided document describes the LIAISON® Lyme IgM assay, which is a chemiluminescent immunoassay (CLIA) for the qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum and plasma samples. The device performance was evaluated through various studies, including a method comparison with a predicate device, an evaluation using Standard Two-Tier Testing (STTT) and Modified Two-Tier Testing (MTTT) methodologies, testing of a characterized Lyme panel from the CDC, precision and reproducibility studies, a cross-reactivity study, and an interfering substances study.
Here's a breakdown of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria values for agreement percentages (PPA, NPA) or specificity/sensitivity for the method comparison, STTT, or MTTT studies. Instead, it presents the calculated agreement results, implying these are the performance metrics. For precision and reproducibility, specific %CV ranges are not explicitly stated as acceptance criteria, but the calculated %CV values are reported.
| Study Type | Performance Metric | Reported Device Performance |
|---|---|---|
| Method Comparison (vs. Predicate ELISA IgM) | Positive % Agreement (Includes Positive and Equivocal combined) | 56.5% (190/336) [95% CI: 51.2% - 61.7%] |
| Negative % Agreement | 96.5% (2206/2285) [95% CI: 95.7% - 97.2%] | |
| Standard Two-Tier Testing (STTT) with WB IgM | 2nd Tier PPA | 91.6% (109/119) [95% CI: 85.2% - 95.4%] |
| 2nd Tier NPA | 99.4% (2486/2502) [95% CI: 99.0% - 99.6%] | |
| Modified Two-Tier Testing (MTTT) - Prospective | PPA | 93.0% (93/100) [95% CI: 86.3% - 96.6%] |
| NPA | 57.6% (72/225) [95% CI: 48.8% - 65.9%] | |
| Characterized Lyme Panel (CDC) | PPA (Acute) | 71.8% (28/39) [95% CI: 56.2% - 83.5%] |
| PPA (Convalescent) | 87.1% (27/31) [95% CI: 71.1% - 94.9%] | |
| PPA (Late) | 45.0% (9/20) [95% CI: 25.8% - 65.8%] | |
| NPA (Look-alike Diseases) | 88.9% (80/90) [95% CI: 80.7% - 93.9%] | |
| NPA (Healthy controls) | 97.0% (97/100) [95% CI: 91.5% - 99.0%] | |
| Modified Two-Tier Testing (MTTT) - Retrospective (CDC Panel) | PPA (Stage I) | 73.3% |
| PPA (Stage II) | 90.0% | |
| PPA (Stage III) | 45.0% | |
| NPA (Healthy Controls) | 100% | |
| NPA (Disease Controls) | 100% | |
| Precision Study (Within-lot) | Total %CV (Negative Control) | 5.4% |
| Total %CV (Positive Control) | 7.0% | |
| Total %CV (LM-QC3) | 7.8% | |
| Total %CV (LM-QC11) | 6.5% | |
| Total %CV (LM-QC12) | 7.3% | |
| Total %CV (LM-QC13) | 8.9% | |
| Total %CV (LM-QC16) | 8.8% | |
| Total %CV (LM-QC17) | 7.6% | |
| Reproducibility Study (Between-site) | Total %CV (Negative Control) | 26.4% |
| Total %CV (Positive Control) | 6.8% | |
| Total %CV (LM-QC3) | 8.0% | |
| Total %CV (LM-QC11) | 6.5% | |
| Total %CV (LM-QC12) | 4.5% | |
| Total %CV (LM-QC13) | 15.2% | |
| Total %CV (LM-QC16) | 7.7% | |
| Total %CV (LM-QC17) | 9.0% | |
| Cross-Reactivity Study | Number of positive/equivocal results out of 191 samples | 16 (from 19 disease states) |
| Interfering Substances | Assay performance affected | Not affected by specified concentrations |
| Matrix Equivalence Study | Bias (Constant) & Proportional Bias (K2-EDTA, Li-heparin vs. Serum) | Constant: -0.01 to -0.02, Proportional: 1.03 |
2. Sample Size Used for the Test Set and the Data Provenance
- Method Comparison and Prospective MTTT Studies:
- Sample Size: 2621 human serum specimens.
- Data Provenance: Collected in 14 states across five (5) distinct U.S. geographical regions. This indicates prospective data.
- Characterized Lyme Panel and Retrospective MTTT Study:
- Sample Size: 280 samples for the characterized Lyme Panel. For the retrospective MTTT, 279 samples were evaluated after one lacked sufficient volume.
- Data Provenance: Acquired from the CDC. This indicates retrospective (or banked) data.
- Cross-Reactivity Study:
- Sample Size: 191 specimens.
- Data Provenance: From various disease states, implying samples from patients with known conditions, likely retrospective or banked.
- Interfering Substances Study:
- Sample Size: Not explicitly stated, described as "serum specimens containing B. burgdorferi IgM antibodies."
- Data Provenance: Not specified, likely laboratory-prepared samples.
- Matrix Equivalence Study:
- Sample Size: 32 matched patient sets.
- Data Provenance: Not specified, likely laboratory-prepared or procured patient samples, potentially retrospective.
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 or qualifications of experts used to establish the ground truth for the test sets.
4. Adjudication Method for the Test Set
The document does not explicitly describe an adjudication method for the test sets. For the STTT and MTTT, Western blot (WB IgM) is used as a confirmatory test, which acts as a gold standard in the two-tier testing methodology, but it's not described as an "adjudication" in the sense of multiple expert readers resolving discrepancies.
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 document describes an in vitro diagnostic (IVD) device (an immunoassay), not an AI-powered diagnostic imaging or a reader-assisted device. Therefore, a multi-reader multi-case (MRMC) comparative effectiveness study focusing on human reader improvement with or without AI assistance is not applicable and was not performed.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) Was Done
Yes, the studies detailed (Method Comparison, STTT, MTTT, Characterized Lyme Panel, Precision, Reproducibility, Cross-Reactivity, Interfering Substances, Matrix Equivalence) represent the standalone performance of the LIAISON® Lyme IgM assay, which operates as an automated chemiluminescent immunoassay on the LIAISON® XL Analyzer without human interpretation of the primary result (the index value is generated by the machine and then converted to qualitative results). Humans perform the test, but the device provides the result.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)
The type of ground truth used varies:
- Method Comparison: The predicate device, ZEUS ELISA Borrelia burgdorferi IgM Test System, served as a reference for comparison. While not a "ground truth" in terms of pathology, it's a legally marketed device used for establishing substantial equivalence.
- Standard Two-Tier Testing (STTT): IgM Borrelia burgdorferi Western blot (following current guidelines) was used as the second-tier confirmatory test, representing the established serological "gold standard" for Lyme disease diagnosis, especially when combined with a positive first-tier test and clinical context. This is akin to a reference method ground truth.
- Modified Two-Tier Testing (MTTT): For the prospective study, the STTT protocol (LIAISON® Lyme Total Antibody Plus followed by B. burgdorferi IgM Western Blot) was considered the reference to which the MTTT (LIAISON® Lyme Total Antibody Plus followed by LIAISON® Lyme IgM assay) was compared. For the retrospective study using CDC samples, the STTT WB IgM results associated with the characterized panel served as the comparator.
- Characterized Lyme Panel (CDC): The classification of these samples (Acute, Convalescent, Late Lyme disease, Look-alike Diseases, Healthy controls) implies that these samples have a pre-established clinical and/or laboratory diagnosis/classification, representing a form of clinical ground truth.
8. The Sample Size for the Training Set
The document describes studies for substantial equivalence based on performance evaluation. It does not mention a "training set" in the context of machine learning model development. This is an IVD device, not an AI/ML device that requires explicit training data. The "performance data" presented is for evaluation (test sets).
9. How the Ground Truth for the Training Set Was Established
As stated above, this is an IVD device and the document does not refer to a "training set" or "training data" in the typical AI/ML context. The various reference methods (predicate device, Western blot, CDC characterized panels) serve as the comparators or benchmarks for establishing the performance characteristics.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services USA seal. To the right of the seal is the FDA logo in blue, with the words "U.S. FOOD & DRUG" stacked on top of the word "ADMINISTRATION".
February 18, 2021
Carol Depouw Principal Regulatory Affairs Specialist 1951 Northwestern Avenue Stillwater, Minnesota 55082
Re: K202573
Trade/Device Name: LIAISON Lyme IgM, LIAISON Lyme IgM Control Set, LIAISON Lyme Total Antibody Plus Regulation Number: 21 CFR 866.3830 Regulation Name: Treponema Pallidum Treponemal Test Reagents Regulatory Class: Class II Product Code: LSR Dated: September 2, 2020 Received: September 4, 2020
Dear Carol Depouw:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
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
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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Maria Ines Garcia, Ph.D. Branch Chief Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known)
Device Name LIAISON® Lyme IgM assay: LIAISON® Lyme IgM Control Set
Indications for Use (Describe)
The LIAISON® Lyme IgM assay uses chemiluminescent immunoassay (CLIA) technology for the qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum and plasma samples (K2-EDTA, Li-heparin). This assay is intended for use on samples from patients with signs and symptoms consistent with or patients suspected of having Lyme disease to assess the presence of antibodies and exposure to Borrelia burgdorferi. In addition, the LIALSON® Lyme IgM assay may be used as a confirmatory test in the modified two-tier test (MTTT) in combination with the DiaSorin LIAISON® Lyme Total Antibody Plus assay.
If used as a first stage test, positive or equivocal results with the LIAISON® Lyme IgM assay should be confirmed through additional testing with a Standard two-tier test (STT) methodology using an IgM Borrelia burgdorferi Western blot test following current guidelines.
Positive supplemental results are supportive evidence of the presence of antibodies and exposure to Borrelia burgdorferi and may be used along with patient history, symptoms and other laboratory data to support a clinical diagnosis of Lyme disease.
Negative results by the LIAISON® Lyme IgM assay should not be used to exclude Lyme disease.
The test must be performed on the LIAISON® XL Analyzer.
The DiaSorin LIAISON® Lyme IgM Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® Lyme IgM assay. The performance characteristics of LIAISON® Lyme IgM controls have not been established for any other assays or instrument platforms different from the LIAISON® XL.
| Type of Use (Select one or both, as applicable) |
|---|
| Prescription Use (Part 21 CFR 801 Subpart D) |
| Over-The-Counter Use (21 CFR 801 Subpart C) |
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510(k) SUMMARY
| SUBMITTED BY: | Carol A. DePouwDiaSorin Inc.1951 Northwestern AvenueStillwater, MN 55082-0285Phone (651) 439-9710Fax (651) 351-5669Email carol.depouw@diasorin.com |
|---|---|
| DATE PREPARED: | May 05, 2020 |
| NAME OF DEVICE:Trade Name: | LIAISON® Lyme IgMLIAISON® Lyme IgM Control Set |
| Common Names/Descriptions: | Borrelia burgdorferi IgM assay andBorrelia burgdorferi IgM controls |
| Classification Names: | Treponema pallidum; treponemal testreagentsClass II, 21 CFR: 866.3830; Microbiology |
| Product Code: | LSR and QCH |
| Predicate Device: | ZEUS ELISA Borrelia burgdorferi IgM Test System(K900196)/modified (K191240) |
INTENDED USE:
The LIAISON® Lyme IgM assay uses chemiluminescent immunoassay (CLIA) technology for the qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum and plasma samples (K2-EDTA, Li-heparin). This assay is intended for use on samples from patients with signs and symptoms consistent with or patients suspected of having Lyme disease to assess the presence of antibodies and exposure to Borrelia burgdorferi. In addition, the LIAISON® Lyme IgM assay may be used as a confirmatory test in the modified two-tier test (MTT) in combination with the DiaSorin LIAISON® Lyme Total Antibody Plus assay.
If used as a first stage test, positive or equivocal results with the LIAISON® Lyme IgM assay should be confirmed through additional testing with a Standard two-tier test (STTT) methodology using an IgM Borrelia burgdorferi Western blot test following current guidelines.
Positive supplemental results are supportive evidence of the presence of antibodies and exposure to Borrelia burgdorferi and may be used along with patient history, symptoms and other laboratory data to support a clinical diagnosis of Lyme disease.
Negative results by the LIAISON® Lyme IgM assay should not be used to exclude Lyme disease. The test must be performed on the LIAISON® XL Analyzer.
The DiaSorin LIAISON® Lyme IgM Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® Lyme IgM assay. The performance characteristics of LIAISON® Lyme IgM controls have not been established for any other assays or instrument platforms different from the LIAISON® XL.
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KIT DESCRIPTION:
The LIAISON® Lyme IgM assay is an indirect chemiluminescence immunoassay (CLIA) for the qualitative detection of IgM antibodies to Borrelia burgdorferi in human serum and plasma samples. All assay steps (with the exception of magnetic particle resuspension) and incubations are performed by the Analyzer. The principal components of the test are magnetic particles (solid phase) coated with recombinant Borrelia antigens and a conjugate reagent containing an anti-human IgM mouse monoclonal antibody linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation, anti-Borrelia burgdorferi antibodies present in calibrators, samples or controls bind to the solid phase. Unbound material is then removed with a wash cycle. During the second incubation, the antibody conjugate reacts with anti-Borrelia burgdorferi IgM antibodies that have bound to the solid phase. Excess antibody conjugate is then removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is 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 Borrelia burgdorferi IgM antibodies present in calibrators, samples or controls.
| Table 1: Table of Similarities | ||
|---|---|---|
| Characteristic | Candidate DeviceLIAISON® Lyme IgM | Predicate DeviceZEUS ELISABorrelia burgdorferi IgM Test System –K900196/K191240 |
| Intended Use | Qualitative detection of IgM antibodies to Borreliaburgdorferi in human serum and plasma samples.This assay is intended for use on samples frompatients with signs and symptoms consistent with orpatients suspected of having Lyme disease toassess the presence of antibodies and exposure toBorrelia burgdorferi.In addition, the LIAISON® Lyme IgM assay may beused as a confirmatory test in the modified two-tiertest (MTTT) in combination with the DiaSorinLIAISON® Lyme Total Antibody Plus assay.If used as a first stage test, positive or equivocalresults with the LIAISON® Lyme IgM assay shouldbe confirmed through additional testing with aStandard two-tier test (STTT) methodology usingan IgM Borrelia burgdorferi Western blot testfollowing current guidelines.Positive supplemental results are supportiveevidence of the presence of antibodies andexposure to Borrelia burgdorferi and may be usedalong with patient history, symptoms and otherlaboratory data to support a clinical diagnosis ofLyme disease.Negative results by the LIAISON® Lyme IgM assayshould not be used to exclude Lyme disease. | Qualitative detection of IgM class antibody toBorrelia burgdorferi in human serum.The assay is intended for testing serumsamples from symptomatic patients or thosesuspected of Lyme Disease.Positive and equivocal test results with theZEUS ELISA Borrelia burgdorferi IgM TestSystem for the presence of Borreliaburgdorferi antibodies must be confirmedthrough additional testing by one of thefollowing approaches:(1) Standard two-tier test methodology (STTT)using IgM Western blot testing following currentguidelines; or -(2) Modified two-tier test methodology usingthe ZUES ELISA Borrelia VIsE1/pepC10IgG/IgM Test System.Positive test results by either the STTT orMTTT methodology are supportive evidence forthe presence of antibodies and exposure toBorrelia burgdorferi, the cause of Lymedisease.A diagnosis of Lyme disease should be madebased on the presence of Borrelia burgdorferiantibodies history, symptoms and otherlaboratory data. |
| Results | Qualitative | Same |
COMPARISON TO PREDICATE DEVICE
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| Characteristic | Candidate DeviceLIAISON® Lyme IgM | Predicate DeviceZEUS ELISABorrelia burgdorferi IgM Test System –K900196/K191240 |
|---|---|---|
| Measurand | IgM antibodies to Borrelia burgdorferi | Same |
| IntendedPopulation | Patients with signs and symptomsconsistent with Borrelia infection(Lyme disease) | Same |
| AssayPrinciple | Uses Borrelia antigens coated on a solid phaseto capture specific patient IgM antibodies. | Uses B. burgdorferi antigen on coatedsolid phase (wells) to bind withIgM antibodies in patient sample |
| Conjugateantibodyspecificities | Anti-human IgM | Anti-human IgM |
| Assay Output | Index | Same |
| Table 2: Table of Differences | ||
|---|---|---|
| Feature | Candidate DeviceLIAISON® Lyme IgM | Predicate DeviceZEUS ELISABorrelia burgdorferi IgM Test System –K900196/K191240 |
| Test Format | CLIA (indirect chemiluminescent assay) | ELISA |
| Sample Type | Human serum, serum separator tubes, K2-EDTA, lithium heparin plasma | Human serum |
| Reporter Molecule | Isoluminol derivative conjugated to anti-human IgM | TMB (as a substrate for Horseradish peroxidase conjugated to anti-human IgM). |
| Antigen | Recombinant antigens:OspC ( B. afzelii strain pKo).andVlsE ( B. burgdorferi strain B31) | Whole cell antigen fromB. burgdorferi (B31 strain) |
| Assay Procedure | Automated (on the LIAISON® XL Analyzer) | Manual |
| Calibration | Two-point verification (in triplicate) of stored 10 point master curve | Single Cut-off Calibrator assayed in triplicate |
| Output Signal | Flash chemiluminescent response is integrated over a 3 second reading period to generate a relative light unit | Microtiter well O.D. (450 nm) is measured after the enzyme reaction is halted by 1M H2SO4/0.7M HCl. |
| Measurement System | Photomultiplier(flash chemiluminescence reader) | Spectrophotometer(EIA Microtiter plate reader) |
PERFORMANCE DATA:
METHOD COMPARISON:
Two thousand six hundred twenty one (2621) human serum specimens were collected in 14 states which represented five (5) distinct U.S. geographical regions. Of the 2621 samples: 44.1% were male, 55.7% were female, 0.2% gender unknown, the ages ranged from 2 years to 103 years of age.
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Testing with the LIAISON® Lyme IgM assay on the LIAISON® XL was performed in three (3) laboratories (2 external and internally at DiaSorin).
| Predicate Assay (ELISA IgM) | ||||
|---|---|---|---|---|
| LIAISON Lyme IgM | Positive | Equivocal | Negative | Total |
| Positive | 164 | 8 | 51 | 223 |
| Equivocal | 13 | 5 | 28 | 46 |
| Negative | 87 | 59 | 2206 | 2352 |
| Total | 264 | 72 | 2285 | 2621 |
| Table 3: First Tier Percent Agreement with Predicate Device | ||
|---|---|---|
Agreement Results
| Positive % Agreement* | 56.5% (190/336) | 95% CI: 51.2% - 61.7% |
|---|---|---|
| Negative % Agreement | 96.5% (2206/2285) | 95% CI: 95.7% - 97.2% |
| *Includes Positive and Equivocal combined |
Standard Two-Tier Testing Methodology:
Western blot testing was performed on the samples that were positive or equivocal by the test device and the predicate following the current guidelines for Standard Two-Tier testing methodology. The following results were obtained:
| Table 4: Standard Two-Tier Western Blot | |
|---|---|
| ----------------------------------------- | -- |
| Test System | Tier 1 + or Eqv | WB IgM + | WB IgM - |
|---|---|---|---|
| Predicate assay | 336 | 119 | 217 |
| LIAISON® Lyme IgM | 269 | 125 | 144 |
| Predicate assay + LIAISON® Lyme IgM | 190 | 109 | 81 |
Agreement Results:
| 2nd Tier PPA | 91.6% (109/119) | 95% Cl: 85.2% - 95.4% |
|---|---|---|
| 2nd Tier NPA | 99.4% (2486/2502) | 95% Cl: 99.0% - 99.6% |
Modified Two Tier Testing Methodology - Prospective Population
All 2621 prospective (all comer) specimens were tested with the first-tier assay, LIAISON® Lyme Total Antibody Plus. There were 202 positive and 23 equivocal results. In the STTT protocol, the specimens that are positive or equivocal (n=225) are then tested with a B. burgdorferi (IgM) Western Blot.
Using the MTTT algorithm, the positive/equivocal specimens (n=225) were tested on the LIAISON® Lyme IgM assay. The second-tier LIAISON® Lyme IgM equivocal and positive results were considered positive. The equivocal and positive results were added together, and the results compared with the STTT positive results. The results obtained are shown in Table 5.
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| WB-STTT (IgM) | ||||
|---|---|---|---|---|
| + | Total | |||
| XL -MTTT (IgM) | t | ત્વે ઉત્પત્તર તે જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામમાં પ્રાથમિક શાળા, પંચાયતઘર, આંગણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામમાં પ્રાથમિક શાળા, પંચાયતઘર, આંગણ | ર્દિર | 146 |
| 7 | 72 | 79 | ||
| Total | 100 | 125 | 225 |
Table 5: MTTT LIAISON Lyme IgM compared to STTT WB IgM
Agreement Results
| PPA: | 93.0% (93/100) | 95% CI: 86.3% - 96.6% |
|---|---|---|
| NPA: | 57.6% (72/225) | 95% CI: 48.8% - 65.9% |
Characterized Lyme Panel:
Two hundred eighty samples of various reactivity were acquired from the CDC and evaluated internally at the manufacture's site. The results of the testing are presented here as a means of conveying further information on the performance of the LIAISON® Lyme IqM assay with a characterized serum panel. This does not imply an endorsement of the assay by the CDC.
Table 6: Testing of CDC Lyme Reference Sera
| CDC Reference Classification | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Sample Category | N | LIAISON Lyme IgM | PPA 95% Wilson CI | Predicate IgM | PPA 95% Wilson CI | ||||
| Pos | Neg | Eqv | Pos | Neg | Eqv | ||||
| Acute | 39 | 27 | 11 | 1 | 71.8% (28/39)56.2% - 83.5% | 28 | 10 | 1 | 74.4% (29/39)(58.9% - 85.4%) |
| Convalescent | 31 | 26 | 4 | 1 | 87.1% (27/31)71.1% - 94.9% | 25 | 6 | 0 | 80.6% (25/31)(63.7% - 90.8%) |
| Late | 20 | 9 | 11 | 0 | 45.0% (9/20)25.8% - 65.8% | 17 | 2 | 1 | 90.0% (18/20)(69.9% - 97.2%) |
| Look-alike Diseases | 90 | 6 | 80 | 4 | 88.9% (80/90)80.7% - 93.9% | 8 | 79 | 3 | 87.8% (79/90)(79.4% - 93.0%) |
| Healthy controls | 100 | 2 | 97 | 1 | 97.0% (97/100)91.5% - 99.0% | 2 | 97 | 1 | 97.0% (97/100)(91.5% - 99.0%) |
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Modified Two Tier Testing Methodology-Retrospective population
The 280 retrospective samples from the CDC were first tested with the LIAISON® Lyme Total Antibody Plus. One (1) sample, belonging to endemic negative control group, did not have sufficient volume for testing; therefore 279 retrospective samples were evaluated. The LIAISON® Lyme Total Antibody Plus assay vielded 82 positive and equivocal samples. The 82 positive and equivocal samples were then tested by the IgM Western Blot (STTT) or the LIAISON® Lyme IgM assay (MTT). The results of MTTT-IgM compared to WB-STTT (IgM).
| Stage I(n=60) | Stage II(n=10) | Stage III(n=20) | Healthy Controls(n=99) | Disease Controls(n=90) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| STTTWB IgM | MTTTXL IgM | STTTWB IgM | MTTTXL IgM | STTTWB IgM | MTTTXL IgM | STTTWB IgM | MTTTXL IgM | STTTWB IgM | MTTTXL IgM | |
| Positive | 30 | 44 | 9 | 9 | 7 | 9 | 0 | 0 | 0 | 0 |
| Negative | 30 | 16 | 1 | 1 | 13 | 11 | 99 | 99 | 90 | 90 |
| Sensitivity orPPA | 50.0% | 73.3% | 90.0% | 90.0% | 35.0% | 45.0% | N/A | N/A | N/A | N/A |
| Specificity orNPA | N/A | N/A | N/A | N/A | N/A | N/A | 100% | 100% | 100% | 100% |
PRECISION STUDY
A 12 day precision/repeatability was conducted at DiaSorin Inc. on 2 lots of the LIAISON® Lyme IgM assay. Six (6) serum samples and two (2) lots of LIAISON® Lyme IgM Controls were tested for 12 days, 2 runs/day, and 2 reps per run by multiple technicians for a total of 48 replicates per lot spanning 2 calibration cycles. One (1) lot is presented below.
The CLSI Document EP5-A3 was consulted in the preparation of the testing protocol.
| Sample ID | N | Mean | Within Run | Between Run | Between Day | TOTAL(Within-lot) | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Negative Control Lot 1 | 48 | 2550* | 84.7 | 3.3% | 95.6 | 3.8% | 53.1 | 2.1% | 138.4 | 5.4% |
| Positive Control Lot 1 | 48 | 2.39 | 0.06 | 2.3% | 0.07 | 2.8% | 0.14 | 6.0% | 0.17 | 7.0% |
| Negative Control Lot 2 | 48 | 1500* | 50.9 | 3.4% | 50.7 | 3.4% | 39.4 | 2.6% | 81.9 | 5.5% |
| Positive Control Lot 2 | 48 | 2.33 | 0.08 | 3.5% | 0.00 | 0.0% | 0.13 | 5.5% | 0.15 | 6.3% |
| LM-QC3 | 48 | 1.54 | 0.06 | 3.8% | 0.00 | 0.0% | 0.1 | 6.8% | 0.12 | 7.8% |
| LM-QC11 | 48 | 1.51 | 0.03 | 2.3% | 0.06 | 3.7% | 0.07 | 4.9% | 0.1 | 6.5% |
| LM-QC12 | 48 | 4.65 | 0.12 | 2.7% | 0.08 | 1.8% | 0.31 | 6.6% | 0.34 | 7.3% |
| LM-QC13 | 48 | 0.29 | 0.01 | 2.9% | 0.01 | 4.5% | 0.02 | 7.1% | 0.03 | 8.9% |
| LM-QC16 | 48 | 0.8 | 0.04 | 4.5% | 0.01 | 1.8% | 0.06 | 7.4% | 0.07 | 8.8% |
| LM-QC17 | 48 | 0.78 | 0.02 | 3.0% | 0.01 | 1.3% | 0.05 | 6.9% | 0.06 | 7.6% |
*RLU - Index was below measuring range of assay
REPRODUCIBILITY STUDY
A five (5) day precision/reproducibility study was performed internally at DiaSorin Inc. and at two (2) external U.S. laboratories with one (1) lot of the LIAISON® Lyme IgM assay.
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The study was performed for 5 days, 2 runs/day, and 3 replicates/run. Each day, two operators, at each testing site performed the testing for a total of 30 replicates at each site. CLSI document EP15-A3 was consulted in the preparation of the testing protocol.
| Sample ID | Within Run | Between Day | Between Run | Between Site | TOTAL | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |
| Negative Control | 90 | 1277* | 56.99 | 4.5% | 29.39 | 2.3% | 0.000 | 0.0% | 331.56 | 26.0% | 337.7 | 26.4% |
| Positive Control | 90 | 2.74 | 0.104 | 3.8% | 0.082 | 3.0% | 0.077 | 2.8% | 0.104 | 3.8% | 0.185 | 6.8% |
| LM-QC3 | 90 | 1.62 | 0.050 | 3.1% | 0.047 | 2.9% | 0.036 | 2.2% | 0.103 | 6.4% | 0.129 | 8.0% |
| LM-QC11 | 90 | 1.50 | 0.048 | 3.2% | 0.056 | 3.8% | 0.020 | 1.4% | 0.061 | 4.1% | 0.098 | 6.5% |
| LM-QC12 | 90 | 4.40 | 0.105 | 2.4% | 0.047 | 1.1% | 0.078 | 1.8% | 0.139 | 3.2% | 0.197 | 4.5% |
| LM-QC13 | 90 | 0.312 | 0.012 | 3.8% | 0.015 | 4.8% | 0.000 | 0.0% | 0.043 | 13.9% | 0.047 | 15.2% |
| LM-QC16 | 90 | 0.791 | 0.028 | 3.6% | 0.029 | 3.7% | 0.011 | 1.4% | 0.045 | 5.6% | 0.061 | 7.7% |
| LM-QC17 | 90 | 0.774 | 0.024 | 3.1% | 0.03 | 3.9% | 0.013 | 1.7% | 0.056 | 7.2% | 0.069 | 9.0% |
*RLU - Index was below measuring range of assay
CROSS-REACTIVITY STUDY
The cross-reactivity study was designed to evaluate 191 specimens from nineteen (19) disease states either known to contain potentially cross reactive antibodies to B. burgdorferi or from patients with diagnoses that can exhibit signs and symptoms similar to Lyme disease and cause false positive results.
| Organism Infected or Disease State | SamplesTested (n) | Pos or Eqv |
|---|---|---|
| Tick Borne Diseases | ||
| Anaplasmosis IgM | 1 | 1 |
| Babesiosis IgM | 10 | 4^ |
| Autoimmune Disorders | ||
| Anti-Nuclear Antibodies (ANA) | 10 | 0 |
| Multiple Sclerosis | 10 | 0 |
| Viral Diseases | ||
| Cytomegalovirus (CMV) IgM | 10 | 1^ |
| Epstein-Barr Virus (EBV) | 10 | 0 |
| VCA and/or heterophile Ab IgM | 10 | 0 |
| Epstein-Barr Virus (EBV) VCA IgM | 10 | 2$ |
| Herpes Simplex Virus (HSV) IgM | 10 | 1^ |
| Human Immunodeficiency Virus (HIV) | 10 | 0 |
| Influenza Virus | 10 | 0 |
| Parvovirus IgM | 10 | 1 |
| Varicella Zoster Virus (VZV) IgM | 10 | 1^ |
| Bacterial Diseases | ||
| H. pylori | 10 | 0 |
| Syphilis | 10 | 2 |
| Rheumatic Diseases | ||
| Fibromyalgia | 10 | 0 |
| Rheumatoid Arthritis | 10 | 0 |
| Rheumatoid Factor | 10 | 1^ |
| Systemic Lupus Erythematosus (SLE) | 10 | 1 |
| Additional Markers | ||
| Chronic Fatigue Syndrome | 10 | 0 |
| Human Anti-mouse Antibodies (HAMA) | 10 | 1 |
| Total | 191 | 16 |
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INTERFERING SUBSTANCES
"Controlled studies of potentially interfering substances from endogenous interferents spiked into serum specimens containing B. burgdorferi IgM antibodies at levels near the cut-off showed that assay performance was not affected at the concentration for each substance listed below. The testing was based on CLSI-EP7-A3.
| Substances | TestedConcentrations |
|---|---|
| Hemoglobin | 1000 mg/dL |
| Triglycerides | 1500 mg/dL |
| Bilirubin | 40 mg/dL |
| Total protein | 12 g/dL |
| Cholesterol | 400 mg/dL |
| Biotin | 3600 ng/mL |
MATRIX EQUIVALENCE STUDY:
Thirty-two (32) matched patient sets of serum, K2-EDTA plasma and lithium heparin plasma samples were tested to determine if these sample types provide equivalent results. Sample regression analysis was done by Passing & Bablok regression. All sample types met acceptance criteria for use in the LIAISON® Lyme IgM assay. A summary of the results are shown in the following table.
| Comparison to Serum | Bias | 95% Cl | |
|---|---|---|---|
| Serum SST | Constant | -0.01 | -0.03 to 0.00 |
| Proportional | 1.03 | 1.00 to 1.06 | |
| EDTA Plasma | Constant | -0.02 | -0.05 to 0.03 |
| Proportional | 1.03 | 0.97 to 1.08 | |
| Lithium Heparin Plasma | Constant | -0.02 | -0.05 to -0.00 |
| Proportional | 1.03 | 1.00 to 1.07 |
CONCLUSION:
The material submitted in this premarket notification supports a substantial equivalence decision. The labelling satisfies the requirements of 21CFR 809.10.
§ 866.3830
Treponema pallidum treponemal test reagents.(a)
Identification. Treponema pallidum treponemal test reagents are devices that consist of the antigens, antisera and all control reagents (standardized reagents with which test results are compared) which are derived from treponemal sources and that are used in the fluorescent treponemal antibody absorption test (FTA-ABS), theTreponema pallidum immobilization test (T.P.I.), and other treponemal tests used to identify antibodies toTreponema pallidum directly from infecting treponemal organisms in serum. The identification aids in the diagnosis of syphilis caused by bacteria belonging to the genusTreponema and provides epidemiological information on syphilis.(b)
Classification. Class II (performance standards).