(89 days)
The DiaSorin LIAISON® XL Zika Capture IgM II assay is intended for the presumptive qualitative detection of Zika virus IgM antibodies in human sera collected from individuals meeting CDC Zika virus clinical criteria (e.g., a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiological criteria for which Zika virus testing may be indicated). Specimens from symptomatic patients or returning travelers from endemic areas must be collected not earlier than day 8 after the onset of symptoms or risk of exposure, respectively. Positive results must be confirmed by following the latest CDC quidelines for the diagnosis of Zika virus infection.
Results of this test are intended to be used in combination with clinical observations, patient history, epidemiological information, and other laboratory evidences. Zika IqM levels over the course of illness are not well characterized. IqM levels are variable, may be detectable near day 4 post onset of symptoms and persist up to approximately 12 weeks following initial infection.
Negative results may be seen in specimens collected before day four post onset of symptoms or after the window of detectable IgM closes, and therefore do not preclude the possibility of Zika virus infection, past or present.
This LIAISON® XL Zika Capture IgM II assay is not indicated for testing blood or plasma donors.
The test has to be performed on the LIAISON® XL Analyzer.
The DiaSorin LIAISON® XL Zika Capture IgM II Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® XL Zika Capture IgM II assay. The performance characteristics of the LIAISON® XL Zika Capture IgM II controls have not been established for any other assay or instrument platforms different from the LIAISON® XL.
The LIAISON® XL Zika Capture IqM II assay is an automated immunoassay utilizing chemiluminescent (CLIA) detection technology for the detection of human IgM antibodies against Zika Virus in patient sera.
The LIAISON® XL Zika Capture IgM II assay consists of the components described in the following tables.
Magnetic Particles (2.4 mL): Magnetic particles coated with a mouse monoclonal antibody to human IgM diluted in phosphate buffer containing BSA, surfactant, and <0.1% sodium azide.
Specimen Diluent (28.0 mL): Buffer containing BSA, surfactant, 0.2% ProClin® 300, and an inert yellow dye.
Assay Buffer (28.0 mL): Buffer containing BSA, surfactant, and 0.2% ProClin® 300
Number of tests: 100
ZIKV-M Reagent Integral Composition:
Calibrator 1 Lyophilized 2 vials: Human serum/defibrinated plasma containing Zika virus IgM, phosphate buffer, BSA, surfactant, 0.18% ProClin® 300, and <0.1% sodium azide. Reconstitute with 2.0 mL of distilled or deionized water.
Calibrator 2 Lyophilized 2 vials: Human serum/defibrinated plasma containing Zika virus IgM, phosphate buffer, BSA, surfactant, 0.18% ProClin® 300, and <0.1% sodium azide. Reconstitute with 2.0 mL of distilled or deionized water.
ZIKV-M Conjugate Lyophilized 1 vial: Recombinant Zika virus NS1 antigen conjugated to an isoluminol derivative diluted in buffer containing BSA, surfactant, and 0.2% ProClin® 300. Reconstitute with 5.0 mL of distilled or deionized water.
Additional components provided not on the ZIKV-M Reagent Integral
ZIKV-C Reagent Integral Composition:
Magnetic Particles (2 X 28.0 mL): Magnetic particles coated with a mouse monoclonal antibody to human IgG diluted in phosphate buffer containing BSA, surfactant, and <0.1% sodium azide.
Specimen Diluent (2 X 28.0 mL): Buffer containing BSA, surfactant, 0.2% ProClin® 300, and an inert yellow dye.
Assay Buffer (28.0 mL): Buffer containing BSA, surfactant, and 0.2% ProClin® 300
Number of tests: 100
Additional components provided, not on the ZIKV-C Reagent Integral:
Calibrator 1 1 vial x 0.9 mL: Human serum/defibrinated plasma containing Zika virus IgG, < 0.3% ProClin® 300, and < 0.1% sodium azide.
Calibrator 2 1 vial x 0.9 mL: Human serum/defibrinated plasma containing Zika virus IgG, < 0.3% ProClin® 300, and < 0.1% sodium azide.
ZIKV-C Conjugate Lyophilized 1 vial: Recombinant Zika virus NS1 antigen conjugated to an isoluminol derivative diluted in buffer containing BSA, surfactant, and 0.2% ProClin® 300. Reconstitute with 5.0 mL of distilled or deionized water.
Materials required but not provided (system related):
LIAISON® XL Analyzer
LIAISON® Wash/System Liquid (REF 319100)
LIAISON® XL Waste Bags (REF X0025)
LIAISON® XL Cuvettes (REF X0016)
LIAISON® XL Starter Kit (REF 319200)
LIAISON® XL Disposable Tips (REF X0015)
LIAISON® XL Zika Capture IgM II Control Set (REF 317151)
Additional required materials (assay related):
LIAISON® XL Zika Capture IgM II Control Set (REF 317151)
The provided text describes the performance characteristics of the DiaSorin LIAISON® XL Zika Capture IgM II assay. However, it does not describe a study comparing the device's performance against human readers or establishing acceptance criteria in the context of an Artificial Intelligence (AI) enabled device. This document is a 510(k) summary for an in-vitro diagnostic (IVD) device, which typically focuses on demonstrating substantial equivalence to a predicate device through analytical and clinical performance studies, not AI-assisted human reading performance.
Therefore, many of the requested points related to AI acceptance criteria, MRMC studies, expert adjudication, and training/test set ground truth establishment for an AI model cannot be extracted from this document.
Here's what can be extracted, interpreted, and what is missing based on the provided text:
Device: LIAISON® XL Zika Capture IgM II Assay
Device Type: In-vitro diagnostic (IVD) immunoassay for the presumptive qualitative detection of Zika virus IgM antibodies. This is not an AI-enabled device.
1. A table of acceptance criteria and the reported device performance
Since this is an IVD device, the "acceptance criteria" are typically defined by performance metrics like positive percent agreement (PPA), negative percent agreement (NPA), precision (reproducibility), analytical specificity (cross-reactivity), and stability. The performance is compared against a comparator assay (predicate device) and clinical observations/nucleic acid testing for ground truth.
| Performance Metric | Acceptance Criteria (Implied/Standard IVD Practice, not explicitly stated as "acceptance criteria") | Reported Device Performance (LIAISON® XL Zika Capture IgM II) |
|---|---|---|
| Positive Agreement (PPA) | High agreement with confirmed positive samples/comparator. | Overall (Day 8-84 post onset of symptoms): 95.6% (174/182) with comparator assay (95%CI 91.6-97.8%) - Day 8-14: 94.6% - Day 15-28: 100% - Day 29-42: 100% - Day 43-56: 82.4% - Day 57-70: 77.8% - Day 71-84: 100%Note: Time frame 0-7 days (35.3%) is outside claimed window of detection. Some samples in the 0-7 day window were only positive by nucleic acid testing, or negative by comparator assay but positive by the device, making direct comparison complex for this early phase. |
| Negative Agreement (NPA) | High agreement with confirmed negative samples/comparator. | Overall: 98.6% (493/500) with comparator assay (95%CI 97.1%-99.3%) - Non-endemic (U.S.): 99.6% (249/250) - Endemic (Dominican Republic): 97.6% (244/250) |
| Percision/Reproducibility | Low %CV for various samples across runs, days, lots, and sites. | Within-laboratory Precision (ZIKV-M): - Neg Ctrl: 15.0% CV - Pos Ctrl: 5.4% CV - Sample #1 (low signal): 15.5% CV - Sample #2: 11.9% CV - Sample #3: 10.6% CV - Sample #4: 9.5% CVBetween-Site Reproducibility (ZIKV-M):- Neg Ctrl: 13.8% CV- Pos Ctrl: 9.7% CV- Sample #1 (low signal): 15.3% CV- Sample #2: 11.1% CV- Sample #3: 7.0% CV- Sample #4: 8.4% CVSimilar comprehensive data provided for ZIKV-C with varying %CVs. |
| Analytical Specificity/Cross-Reactivity | Low reactivity (ideally 0%) to related pathogens or interfering substances. | Cross-Reactivity: - 1/43 (2.33%) Dengue IgM samples reactive (also reactive with comparator). - 1/14 (7.14%) Parvovirus B19 IgM reactive (negative with comparator). - 1/16 (6.25%) Rheumatoid Factor reactive (negative with comparator). - No reactivity for many other tested organisms (Chikungunya, Cytomegalovirus, Epstein Barr, Varicella Zoster, Yellow Fever, West Nile, Malaria, Adenovirus, Enterovirus, Hepatitis (C/B), HSV-1/2, Rubella, Borrelia, Treponema pallidum, HAMA, ANA).Interfering Substances: Hemoglobin (positive interference at 10 mg/mL, minimal at 2 mg/mL). Others (Bilirubin, Triglycerides, Cholesterol, Albumin, HAMA, RF) showed no significant interference. |
2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
-
Positive Agreement Study:
- Sample Size: 244 specimens from 79 subjects.
- Data Provenance: Prospectively collected from the Dominican Republic (endemic region), including 22 pregnant women.
- Nature: Serial serum samples from 46 symptomatic subjects, and 33 single bleeds.
-
Negative Agreement Study:
- Sample Size: 500 serum samples.
- Data Provenance:
- 250 subjects from a non-endemic region (continental United States - Texas and Florida, collected June 2017). Pregnancy status unknown for US subjects.
- 250 subjects from an endemic region (Dominican Republic), including 37 pregnant women.
- Nature: Confirmed negative for Zika IgM by a comparator assay.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
This section is not applicable as the ground truth was established by:
- A "commercially available Zika IgM assay" (predicate device).
- Nucleic acid testing (for positive cases).
- Clinical criteria, patient history, and epidemiological information.
This is a diagnostic kit, not an AI review system, so human expert interpretation (like radiologists) for ground truth is not relevant in this context.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. The ground truth for this IVD device's clinical performance was established by laboratory methods (comparator assay, nucleic acid tests) and patient epidemiology/clinical data, not by human expert review that would require adjudication.
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
No, a multi-reader, multi-case (MRMC) comparative effectiveness study was not conducted. This is an in-vitro diagnostic (IVD) test kit, not an AI-assisted diagnostic tool for human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
This refers to the device itself. The LIAISON® XL Zika Capture IgM II assay is a standalone automated immunoassay. Its performance characteristics (accuracy, precision, etc.) are reported independently of human interpretation in the way an AI algorithm's standalone performance might be. It generates a quantitative "Index value" which is then interpreted as positive, negative, presumptively positive, or presumptively recent based on pre-defined cut-off values.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for the clinical studies was primarily established by:
- Comparator Assay: A "commercially available Zika IgM assay" (the predicate device)
- Nucleic Acid Testing: For confirmation of Zika virus infection in symptomatic subjects.
- Clinical/Epidemiological Data: CDC Zika virus clinical criteria (signs/symptoms) and/or epidemiological criteria (residence/travel to endemic region).
8. The sample size for the training set
The document does not describe a training set as this is a traditional IVD device, not a machine learning/AI model. The "training" of such a device is typically through its chemical and biological formulation and optimization during development, not data-driven model training.
9. How the ground truth for the training set was established
Not applicable as there is no training set mentioned for an AI model.
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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 side of the logo is the seal of the Department of Health & Human Services. To the right of the seal is the FDA logo in blue, with the words "U.S. FOOD & DRUG" on the top line and "ADMINISTRATION" on the bottom line.
October 28, 2019
DiaSorin Inc. Sandra Zimniewicz Senior Regulatory Affairs Specialist 1951 Northwestern Avenue Stillwater, Minnesota 55082-0285
Re: K192046
Trade/Device Name: LIAISON XL Zika Capture IgM II and LIAISON XL Zika Capture IgM II Control Set Regulation Number: 21 CFR 866.3935 Regulation Name: Zika Virus Serological Reagent Regulatory Class: Class II Product Code: QFO, QCH Dated: July 30, 2019 Received: July 31, 2019
Dear Sandra Zimniewicz:
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,
Uwe Scherf, M.Sc., Ph.D. Director 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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510(k) SUMMARY
| 1. DATE PREPARED: | July 30, 2019 |
|---|---|
| 2. APPLICANT INFORMATION: | Sandra ZimniewiczSenior Regulatory Affairs SpecialistDiaSorin Inc.1951 Northwestern Ave.P.O. Box 285Stillwater, MN 55082-0285Phone (651) 351-5711Fax (651) 351-5711Email: sandra.zimniewicz@diasorin.com |
| 3. REGULATORY INFORMATION: | |
| Trade Name: | LIAISON® XL Zika Capture IgM II |
| Common Names/Descriptions: | Zika virus assay |
| Classification Names: | Zika Virus Serological Reagents:Class II, 21 CFR 866.3935; Microbiology (83) |
| Assayed quality control material for clinicalmicrobiology assays: Class II, 21CFR 866.3920;Microbiology (83) | |
| Product Code: | QFO - Zika Virus Serological ReagentsQCH - Assayed quality control material forclinical microbiology assays |
| 4. PREDICATE DEVICE: | InBios ZIKV Detect™ 2.0 IgM Capture ELISA(DEN180069) |
5. INTENDED USE / INDICATIONS FOR USE
LIAISON® XL Zika Capture IqM II
The DiaSorin LIAISON® XL Zika Capture IgM II assay is intended for the presumptive qualitative detection of Zika virus IgM antibodies in human sera collected from individuals meeting CDC Zika virus clinical criteria (e.g., a history of clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiological criteria for which Zika virus testing may be indicated). Specimens from symptomatic patients or returning travelers
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from endemic areas must be collected not earlier than day 8 after the onset of symptoms or risk of exposure, respectively. Positive results must be confirmed by following the latest CDC quidelines for the diagnosis of Zika virus infection.
Results of this test are intended to be used in combination with clinical observations, patient history, epidemiological information, and other laboratory evidences. Zika IqM levels over the course of illness are not well characterized. IqM levels are variable, may be detectable near day 4 post onset of symptoms and persist up to approximately 12 weeks following initial infection.
Negative results may be seen in specimens collected before day four post onset of symptoms or after the window of detectable IgM closes, and therefore do not preclude the possibility of Zika virus infection, past or present.
This LIAISON® XL Zika Capture IgM II assay is not indicated for testing blood or plasma donors.
The test has to be performed on the LIAISON® XL Analyzer.
LIAISON® XL Zika Capture IgM II Control Set
The DiaSorin LIAISON® XL Zika Capture IgM II Control Set is intended for use as assayed quality control samples to monitor the performance of the LIAISON® XL Zika Capture IgM II assay. The performance characteristics of the LIAISON® XL Zika Capture IgM II controls have not been established for any other assay or instrument platforms different from the LIAISON® XL.
6. DEVICE DESCRIPTION
The LIAISON® XL Zika Capture IqM II assay is an automated immunoassay utilizing chemiluminescent (CLIA) detection technology for the detection of human IgM antibodies against Zika Virus in patient sera.
The LIAISON® XL Zika Capture IgM II assay consists of the components described in the following tables.
| Magnetic Particles(2.4 mL) | Magnetic particles coated with a mouse monoclonalantibody to human IgM diluted in phosphate buffercontaining BSA, surfactant, and <0.1% sodium azide. |
|---|---|
| Specimen Diluent(28.0 mL) | Buffer containing BSA, surfactant, 0.2% ProClin® 300, andan inert yellow dye. |
| Assay Buffer(28.0 mL) | Buffer containing BSA, surfactant, and 0.2% ProClin® 300 |
| Number of tests | 100 |
ZIKV-M Reagent Integral Composition
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| Calibrator 1Lyophilized2 vials | Human serum/defibrinated plasma containing Zika virusIgM, phosphate buffer, BSA, surfactant, 0.18% ProClin®300, and <0.1% sodium azide. Reconstitute with 2.0 mL ofdistilled or deionized water. |
|---|---|
| Calibrator 2Lyophilized2 vials | Human serum/defibrinated plasma containing Zika virusIgM, phosphate buffer, BSA, surfactant, 0.18% ProClin®300, and <0.1% sodium azide. Reconstitute with 2.0 mL ofdistilled or deionized water. |
| ZIKV-M ConjugateLyophilized1 vial | Recombinant Zika virus NS1 antigen conjugated to anisoluminol derivative diluted in buffer containing BSA,surfactant, and 0.2% ProClin® 300. Reconstitute with 5.0mL of distilled or deionized water. |
Additional components provided not on the ZIKV-M Reagent Integral
ZIKV-C Reagent Integral Composition
| Magnetic Particles(2.4 mL) | Magnetic particles coated with a mouse monoclonalantibody to human IgG diluted in phosphate buffercontaining BSA, surfactant, and <0.1% sodium azide. |
|---|---|
| Specimen Diluent(2 X 28.0 mL) | Buffer containing BSA, surfactant, 0.2% ProClin® 300, andan inert yellow dye. |
| Assay Buffer(28.0 mL) | Buffer containing BSA, surfactant, and 0.2% ProClin® 300 |
| Number of tests | 100 |
Additional components provided, not on the ZIKV-C Reagent Integral
| Calibrator 11 vial x 0.9 mL | Human serum/defibrinated plasma containing Zika virusIgG, < 0.3% ProClin® 300, and < 0.1% sodium azide. |
|---|---|
| Calibrator 21 vial x 0.9 mL | Human serum/defibrinated plasma containing Zika virusIgG, < 0.3% ProClin® 300, and < 0.1% sodium azide. |
| ZIKV-C ConjugateLyophilized1 vial | Recombinant Zika virus NS1 antigen conjugated to anisoluminol derivative diluted in buffer containing BSA,surfactant, and 0.2% ProClin® 300. Reconstitute with 5.0mL of distilled or deionized water. |
ProClin® is a trademark of the Dow Chemical Company (Dow) or an affiliated company of Dow.
Materials required but not provided (system related)
| LIAISON® XL Analyzer |
|---|
| LIAISON® Wash/System Liquid (REF 319100) |
| LIAISON® XL Waste Bags (REF X0025) |
| LIAISON® XL Cuvettes (REF X0016) |
| LIAISON® XL Starter Kit (REF 319200) |
| LIAISON® XL Disposable Tips (REF X0015) |
| LIAISON® XL Zika Capture IgM II Control Set (REF 317151) |
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Additional required materials (assay related)
LIAISON® XL Zika Capture IgM II Control Set (REF 317151)
7. PURPOSE OF THE SUBMISSION
The purpose of this premarket notification was to submit a new device (LIAISON® XL Zika Capture IgM II) to FDA for clearance as a 510(k).
8. COMPARISON TO FDA CLEARED METHOD
| Table 1:Table of Similarities | ||
|---|---|---|
| Characteristic | Candidate DeviceLIAISON® XL Zika Capture IgM II | Predicate DeviceInBios ZIKV Detect™ 2.0 IgMCapture ELISADEN180069 |
| Intended Use | Qualitative detection of Zika virusIgM antibodies in human serum | Qualitative detection of Zikavirus IgM antibodies in humanserum |
| Sample Matrix | Serum | Same |
| Reagent Storage | 2-8°C, On-board or in Refrigerator | 2-8°C, Refrigerator only |
| Characteristic | Candidate DeviceLIAISON® XL Zika Capture IgM II | Predicate DeviceInBios ZIKV Detect™ 2.0 IgMCapture ELISADEN180069 |
|---|---|---|
| Type of Assay | Chemiluminescent Immunoassay | Enzyme Immunoassay |
| SampleHandling/Processing | Automated | Manual |
| Interpretation ofResults | Presumptive Zika IgM Positive Presumptive Recent Zika Positive Presumptive Recent Zika Negative Negative | Reactive for Zika IgM Antibodies Reactive for Other Flavivirus IgM Antibodies Negative |
| Calibrators | Two | Three (Antigen reagents) |
| Detector | Zika virus NS1 antigen conjugatedto an Isoluminol derivative | Horseradish peroxidase-labeledanti-mouse antibody |
| Capture Reagent | ZIKV-M: Magnetic particles coatedwith mouse monoclonal to humanIgMZIKV-C: Magnetic particles coatedwith mouse monoclonal to humanIgG | Microwells coated withpolyclonal antibodies to humanIgM |
| Sample Volume | 25 µL w/o dead volume | 50 µL |
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| Table 2 cont.: Table of Differences | ||
|---|---|---|
| MeasurementSystem | Photomultiplier (flashchemiluminescence reader) | ELISA Spectrophotometer |
| Total Incubation | 37 minutes | 3.3 hours (201 minutes) |
| Controls | Provided Separately | Included |
9. PERFORMANCE STANDARDS
The following recognized standards from Clinical Laboratory Standards Institute (CLSI) and special controls were used as a basis of the study procedures described in this submission:
- . Interference Testing in Clinical Chemistry, Approved Guideline. CLSI EP07-A2 Second Edition; November 2005 (Recognition no. 7-127)
- User Verification of Precision and Estimation of Bias, Approved Guideline. . CLSI EP15-A3 Third Edition; September 2014 (Recognition no. 7-253)
- Supplemental Tables for Interference Testing in Clinical Chemistry. 1st ● Edition (CLSI EP37, 2018; Recognition No. 7-284)
- Special controls under 21CFR 866.3935, Zika virus serological reagents, ● Code of Federal Regulation, 2019
10. PERFORMANCE CHARACTERISTICS
10.1 CLINICAL STUDIES
Specimens from patients infected with Zika virus and uninfected individuals were prospectively collected from endemic and non-endemic regions for Zika virus and include pregnant women. Testing was performed at three (3) sites with samples distributed across sites. Samples were tested with the LIAISON® XL Zika Capture IgM II assay and a comercially available Zika IgM assay.
COMPARATIVE AGREEMENT STUDIES
Positive Agreement
Positive agreement was evaluated using 211 serial serum samples prospectively collected from 46 symptomatic subjects. All subjects were confirmed positive for Zika virus by nucleic acid testing and were positive for Zika antibodies in at least one of the serial bleeds by the comparator assay. The analysis also includes 33 single bleeds. Four (4) of them, within the 0-7 day time frame, were only positive by nucleic acid testing. The rest of the 29 single bleeds were positive by the comparator assay and most of them also by nucleic acid testing. The positive population therefore consisted of 244 specimens from 79 subjects from the Dominican Republic, including 22 pregnant women.
The results were calculated to generate positive percent agreement with the comparator assay in the following table.
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| Days post onset of symptoms | Comparator Assay: Zika IgM Reactive# | Comparator Assay: Zika IgM Non-Reactive## | ||||
|---|---|---|---|---|---|---|
| LIAISON® XL Zika Capture IgM II Assay Positive (P)& | LIAISON® XL Zika Capture IgM II Assay Negative (N)&& | LIAISON® XL Zika Capture IgM II Assay Positive (P)& | LIAISON® XL Zika Capture IgM II Assay Negative (N)&& | Total (n) | ||
| 0-7* | 6 | 11 | 1 | 32** | 50 | |
| 8-14 | 53 | 3 | 0 | 0 | 56 | |
| 15-28 | 62 | 0 | 2 | 0 | 64 | |
| 29-42 | 33 | 0 | 3 | 0 | 36 | |
| 43-56 | 14 | 3 | 4 | 1 | 22 | |
| 57-70 | 7 | 2 | 2 | 0 | 11 | |
| 71-84 | 5 | 0 | 0 | 0 | 5 | |
| Total | 180 | 19 | 12 | 33 | 244 |
*This time frame is outside the claimed window of detection.
**Four (4) single bleeds were positive only by nucleic acid testing.
*Comparator assay positive samples include Possible and Presumptive Zika Positive specimens.
##Comparator assay negative samples include Negative and Presumptive Other Flavivirus Positive specimens.
8Positive samples include presumptive recent Zika positive and presumptive Zika IqM positiye specimens based on a similar required clinical follow-up.
&&Negative samples include presumptive recent Zika negative specimens as presumptive samples are considered negative until re-testing results are obtained.
| Days post onset ofsymptoms | Comparator Assay:Zika IgM ReactivePositive Percent Agreement | Comparator Assay:Zika IgM NonreactiveNegative Percent Agreement |
|---|---|---|
| 0-7* | 6/17=35.3%* | 32/33=97.0% |
| 8-14 | 53/56=94.6% | N/A |
| 15-28 | 62/62=100% | 0/2=0% |
| 29-42 | 33/33=100% | 0/3=0% |
| 43-56 | 14/17=82.4% | 1/5=20% |
| 57-70 | 7/9=77.8% | 0/2=0% |
| 71-84 | 5/5=100% | N/A |
| Total(Day 8-84) | 174/182=95.6%(%CI 91.6-97.8%) | 1/12=8.3% |
*This time frame is outside the claimed window of detection. N/A: Not Applicable dvision by 0.
Among the 174 LIAISON® positive samples, there were 136 (78.2%) that were presumptive Zika IgM positive (PlgM-pos) and 38 (21.8%) that were presumptive recent Zika positive (PR-pos).
Among the 8 LIAISON® negative samples, there were 4 (50%) that were negative (neg) and 4 (50%) that were presumptive recent Zika negative (PR-neg).
Negative Agreement
Negative percent agreement testing included 500 serum samples confirmed negative for Zika IqM by a comparator assay. These specimens consisted of 250 subjects from an
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area non-endemic for Zika virus (continental United States) and 250 subjects from an area endemic for Zika virus (Dominican Republic). Of the 250 subjects from the Dominican Republic, 37 were pregnant women. Pregnancy status for the U.S. subjects is unknown. The results are shown in the following table.
| LIAISON® XL Zika Capture IgM II Assay | |||||
|---|---|---|---|---|---|
| Negative Agreement | 95% Confidence Intervals | ||||
| Population | Negative# | Positive## | Total | ||
| Non-endemic (U.S)^ | 249 | 1* | 250 | 99.6% | 97.8 - 99.9% |
| Endemic (Dominican Republic)^^ | 244 | 6* | 250 | 97.6% | 94.9 - 98.9% |
| Total | 493 | 7 | 500 | 98.6% | 97.1% - 99.3% |
#Negative samples include presumptive recent Zika negative specimens as presumptive samples are considered negative until re-testing results are obtained.
##Positive samples include presumptive recent Zika positive Zika IgM positive specimens based on a similar required clinical follow up.
*Samples were negative for Zika IgM by the comparator assay.
^Includes samples from Texas (83) and Florida (87). These samples were collected in June 2017 when very few cases of locally acquired Zika were reported.
^^37 pregnant subjects were included in the normal subject population and were negative.
Among 493 LIAISON® negative samples, there were 436 (87.2%) that were negative (neg) and 57 (11.4%) that were presumptive recent Zika negative (PR-neg).
Among 7 LIAISON® positive samples, there were 2 (0.4%) that were presumptive Zika lgM positive (PlgM-pos) and 5 (1%) that were presumptive recent Zika positive (PR-pos).
10.2 PRECISION/REPRODUCIBILITY
A within-laboratory precision study was performed consulting CLSI document EP15-A3 in the preparation of the testing protocol. Four samples with negative, high negative, low positive and moderate positive levels of Zika IgG and IgM antibodies and kit controls (negative and positive) were assayed with their respective reagent packs (ZIKV-C and ZIKV-M). Each sample was tested in triplicate, in 2 runs per day over 5 operating days with multiple technicians. The following within-laboratory precision results were obtained from samples tested internally at DiaSorin Inc. using 3 kit lots.
| ZIKV-C | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample IDN=90 | MeanIndex | Within Run | Between-Run | Between-Day | Between-Lot/Instrument | Total* | |||||
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| Neg Ctrl | 0.392 | 0.009 | 2.2 | 0.005 | 1.4 | 0.031 | 7.9 | 0.073 | 18.5 | 0.080 | 20.3 |
| Pos Ctrl | 9.71 | 0.135 | 1.4 | 0.082 | 0.8 | 0.375 | 3.9 | 0.435 | 4.5 | 0.596 | 6.1 |
| Sample #1 | 0.775 | 0.013 | 1.6 | 0.000 | 0.0 | 0.037 | 4.8 | 0.156 | 20.1 | 0.160 | 20.7 |
| Sample #2 | 3.19 | 0.034 | 1.1 | 0.042 | 1.3 | 0.120 | 3.8 | 0.157 | 4.9 | 0.205 | 6.4 |
| Sample #3 | 5.68 | 0.073 | 1.3 | 0.020 | 0.3 | 0.212 | 3.7 | 0.501 | 8.8 | 0.549 | 9.7 |
| Sample #4 | 11.1 | 0.181 | 1.6 | 0.067 | 0.6 | 0.399 | 3.6 | 0.793 | 7.2 | 0.909 | 8.2 |
7IKV-C
*Total = Within-Run + Between-Run + Between-Day + Between-Lot/Instrument
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| Sample IDN=90 | MeanIndex | Within Run | Between-Run | Between-Day | Between-Lot/Instrument | Total* | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| Neg Ctrl | 0.523 | 0.032 | 6.1 | 0.022 | 4.2 | 0.045 | 8.7 | 0.051 | 9.7 | 0.078 | 15.0 |
| Pos Ctrl | 5.82 | 0.124 | 2.1 | 0.111 | 1.9 | 0.236 | 4.1 | 0.118 | 2.0 | 0.312 | 5.4 |
| Sample #1 | 0.578 | 0.053 | 9.2 | 0.035 | 6.1 | 0.062 | 10.7 | 0.012 | 2.1 | 0.090 | 15.5 |
| Sample #2 | 0.841 | 0.048 | 5.8 | 0.057 | 6.8 | 0.067 | 7.9 | 0.000 | 0.0 | 0.100 | 11.9 |
| Sample #3 | 2.69 | 0.078 | 2.9 | 0.090 | 3.3 | 0.16 | 5.9 | 0.204 | 7.6 | 0.285 | 10.6 |
| Sample #4 | 6.25 | 0.172 | 2.8 | 0.224 | 3.6 | 0.326 | 5.2 | 0.412 | 6.6 | 0.596 | 9.5 |
ZIKV-M
*Total = Within-Run + Between-Run + Between-Day + Between-Lot/Instrument
A reproducibility/precision study was performed at 2 US external sites and internally at DiaSorin Inc. consulting CLSI document EP15-A3 in the preparation of the testing protocol. Four samples with negative, high negative, low positive and moderate positive levels of Zika IgG and IgM antibodies and kit controls (negative and positive) were assayed with their respective reagent packs (ZIKV-C and ZIKV-M). Each sample was tested in triplicate, in 2 runs per day over 5 operating days with multiple technicians. The following reproducibility/precision results were obtained from samples tested at the 3 sites with 1 kit lot.
ZIKV-C
| Sample IDN=90 | MeanIndex Value | Within Run | Between-Run | Between-Day | Between-Site | Total* | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| Neg Ctrl | 0.409 | 0.015 | 3.6 | 0.013 | 3.1 | 0.018 | 4.5 | 0.028 | 6.9 | 0.039 | 9.5 |
| Pos Ctrl | 10.1 | 0.181 | 1.8 | 0.418 | 4.1 | 0.422 | 4.2 | 0.519 | 5.1 | 0.809 | 8.0 |
| Sample #1 | 0.656 | 0.019 | 2.9 | 0.022 | 3.4 | 0.032 | 4.9 | 0.064 | 9.8 | 0.077 | 11.8 |
| Sample #2 | 3.27 | 0.082 | 2.5 | 0.137 | 4.2 | 0.115 | 3.5 | 0.071 | 2.2 | 0.209 | 6.4 |
| Sample #3 | 5.54 | 0.091 | 1.6 | 0.229 | 4.1 | 0.239 | 4.3 | 0.033 | 0.6 | 0.345 | 6.2 |
| Sample #4 | 12.2 | 0.215 | 1.8 | 0.580 | 4.8 | 0.656 | 5.4 | 0.356 | 2.9 | 0.969 | 8.0 |
*Total = Within-Run + Between-Run + Between-Day + Between-Site
ZIKV-M
| Sample ID | Mean | Within Run | Between-Run | Between-Day | Between-Site | Total* | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| N=90 | IndexValue | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Neg Ctrl | 0.496 | 0.027 | 5.4 | 0.023 | 4.6 | 0.042 | 8.4 | 0.042 | 8.4 | 0.069 | 13.8 |
| Pos Ctrl | 5.48 | 0.160 | 2.9 | 0.072 | 1.3 | 0.323 | 5.9 | 0.388 | 7.1 | 0.534 | 9.7 |
| Sample #1 | 0.624 | 0.049 | 7.9 | 0.011 | 1.7 | 0.061 | 9.8 | 0.053 | 8.5 | 0.095 | 15.3 |
| Sample #2 | 0.881 | 0.048 | 5.4 | 0.042 | 4.8 | 0.074 | 8.4 | 0.000 | 0.0 | 0.098 | 11.1 |
| Sample #3 | 2.87 | 0.117 | 4.1 | 0.082 | 2.8 | 0.141 | 4.9 | 0.000 | 0.0 | 0.200 | 7.0 |
| Sample #4 | 6.48 | 0.306 | 4.7 | 0.203 | 3.1 | 0.398 | 6.1 | 0.000 | 0.0 | 0.542 | 8.4 |
*Total = Within-Run + Between-Run + Between-Day + Between-Site
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10.3 ASSAY REPORTABLE RANGE
The ZIKV-M reagent pack measures between 0.1 and 29 Index value. The lowest reportable value is 0.1 Index. Values below 0.1 Index should be reported as < 0.1 Index. Values above 29 Index should be reported as > 29 Index.
The ZIKV-C reagent pack measures between 0.01 and 35 Index value. The lowest reportable value is 0.01 Index. Values below 0.01 Index should be reported as < 0.01 Index. Values above 35 Index should be reported as > 35 Index.
10.4 DETECTION LIMITS
Detection Limits (Limit of Blank, Limit of Detection, Limit of Quantitation) are not applicable to the LIAISON® XL Zika Capture IgM II assay.
10.5 ANALYTICAL SENSITIVITY/ ASSAY CUT-OFFs
Analytical sensitivity was evaluated using the WHO 1st International Standard for anti-Asian lineage Zika virus antibody (human) (NIBSC 16/352). This preparation is composed of pooled serum obtained from six individuals who tested positive for Zika infection. The undiluted standard (1000 IU/mL) returned a positive result in the LIAISON® XL Zika Capture IgM II assay with Index values just above the ZIKV-M and ZIKV-C cutoff values of 1 and 4, respectively. The standard tested at a 1:3 dilution returned a negative result in the assay.
10.6 ANALYTICAL SPECIFICITY/CROSS-REACTIVITY and INTERFERENCE
The cross reactivity study for the LIAISON® XL Zika Capture IgM II assay was designed to evaluate potential interference from antibodies against other closely related viruses as well as organisms whose infection produces symptoms similar to those observed during Zika virus infection. Samples containing IgM and IgG antibodies against other flavivirus specimens and disease state specimens were used to test for potentially cross-reactive antibodies.
One Dengue IgM sample (1/43) was reactive in the LIAISON® XL Zika Capture IgM II assay although this sample was also reactive with the comparator method. Additionally, one Parvovirus B19 IgM (1/14) and one rheumatoid factor (1/16) samples were reactive in the LIAISON® XL Zika Capture IgM II assay. There is a possibility of cross-reactivity to Chikungunya IgM in the assay as a sample cross-reactive in the first version of the assay was not available for repeat measurements with the LIAISON® XL Zika Capture IqM II assay.
| Organism/Condition | Samplestested | Number Reactivewith LIAISON® XLZika Capture IgMII Assay | % Reactive |
|---|---|---|---|
| Anti-Chikungunya virus (IgM) | 17 | 0 | 0 |
| Anti-Chikungunya virus (IgG) | 14 | 0 | 0 |
| Anti-Cytomegalovirus (IgM) | 11 | 0 | 0 |
| Anti-Cytomegalovirus (IgG) | 11 | 0 | 0 |
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| Anti-Dengue virus (IgM) | 43 | 1^ | 2.33% |
|---|---|---|---|
| Anti-Dengue virus (IgG) | 53 | 0 | 0 |
| Anti-Epstein Barr Virus (IgM) | 11 | 0 | 0 |
| Anti-Epstein Barr Virus (IgG) | 10 | 0 | 0 |
| Anti-Parvovirus B19 (IgM) | 14 | 1& | 7.14% |
| Anti-Parvovirus B19 (IgG) | 13 | 0 | 0 |
| Anti-Varicella zoster virus (IgM) | 11 | 0 | 0 |
| Anti-Varicella zoster virus (IgG) | 14 | 0 | 0 |
| Yellow fever virus post-immunization | 17 | 0 | 0 |
| Anti-West Nile Virus (IgM) | 15 | 0 | 0 |
| Anti-West Nile Virus (IgG) | 19 | 0 | 0 |
| Anti- Malaria/anti-plasmodium falciparum* | 10 | 0 | 0 |
| Adenovirus** | 10 | 0 | 0 |
| Enterovirus*** | 10 | 0 | 0 |
| Anti-Hepatitis (C) virus (Total IgG) | 10 | 0 | 0 |
| Anti-Hepatitis (B) virus (IgM) | 10 | 0 | 0 |
| Anti-Hepatitis (B) virus (Total Antibodies) | 10 | 0 | 0 |
| Anti-Herpes simplex virus 1 (HSV-1) (IgM) | 10 | 0 | 0 |
| Anti-Herpes simplex virus 1 (HSV-1) (IgG) | 10 | 0 | 0 |
| Anti-Herpes simplex virus 2 (HSV-2) (IgM) | 10 | 0 | 0 |
| Anti-Herpes simplex virus 2 (HSV-2) (IgG) | 10 | 0 | 0 |
| Anti-Rubella virus (IgM) | 10 | 0 | 0 |
| Anti-Rubella virus (IgG) | 10 | 0 | 0 |
| Anti-Borrelia sp.(Lyme Disease) (IgM) | 10 | 0 | 0 |
| Anti-Borrelia sp.(Lyme Disease) (Total Ig) | 12 | 0 | 0 |
| Anti-Treponema pallidum.(Syphilis)(Total Antibodies) | 20 | 0 | 0 |
| Human Anti-mouse Antibody (HAMA) | 11 | 0 | 0 |
| Anti-nuclear antibodies (ANA) | 29 | 0 | 0 |
| Rheumatoid Factor | 16 | 1& | 6.25% |
*Specimens were confirmed positive for Malaria infection, but serological status is not known.
**Presence of antibodies was assumed from the results of culture and complement fixation in 3/10 samples; 4/10 showed IgA and IgG presence by ELISA; 3/10 were not characterized.
***Presence of antibodies was assumed from the results of culture and complement fixation.
^This sample was Zika IgM positive by a comparator assay.
&This sample was Zika IgM negative by a comparator assay.
Controlled studies of potentially interfering substances performed on 3 negative and 3 positive serum samples near the clinical decision points showed only interference in the LIAISON® XL Zika Capture IgM II assay for hemoglobin. The positive interference for hemoglobin at 10 mg/mL was significant while at 2 mg/mL interference was minimal with no change in the final call. The testing was based on CLSI-EP7-A2.
| Endogenous Substance | Concentration Tested |
|---|---|
| Hemoglobin | 10 mg/mL and 2 mg/mL |
| Bilirubin (conjugated) | 0.4 mg/mL |
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| Bilirubin (unconjugated) | 0.4 mg/mL |
|---|---|
| Triglycerides | 30 mg/mL |
| Cholesterol | 5 mg/mL |
| Albumin | 60 mg/mL |
| HAMA | 800-1380 ng/mL |
| Rheumatoid Factor | 3500-17800 IU/mL |
10.7 CLASS SPECIFICITY
Antibody class specificity was evaluated on each of the ZIKV-M (anti-IgM antibody) and ZIKC-C (anti-IgG antibody) reagent packs. Six (6) specimens containing various levels of Zika virus IgM antibodies and high levels of Zika virus IgG antibodies were used for this testing. DTT was used to specifically inactivate IgM antibodies without affecting IgG antibodies.
Class specificity for the LIAISON® XL Zika Capture IgM II assay was demostrated as all IgM positive samples dropped below the assay cut-off value after treatment with DTT while the IgG positive samples demonstrated ≤ 10% change in Index value.
10.8 CARRY-OVER
Sample carry-over testing was performed independently for the ZIKV-M and ZIKV-C reagent packs on the LIAISON® XL to determine if there is potential instrument carryover. The study was designed to demonstrate that a sample containing a high level of analyte which preceded a sample containing no analyte will not cause an inappropriate elevation of the subsequent negative sample signal. Carry-over was not observed in either the ZIKV-M or the ZIKV-C reagent pack under the specific testing conditions. For each run, the average of the negative sample replicates following the high sample showed ≤ 10% difference from the average of the negative sample replicates which were tested prior to the high sample. Additionally, the percent of negative results of the negative sample following the high sample was 100% for each reagent pack.
| LIAISON® XL Zika Capture IgM II Reagents | |
|---|---|
| Study | Stability |
| Kit Shelf-Life at 2-8 °C | 9 months |
| ZIKV-M Reagent Integral Shelf-Life at 2-8 °C | 9 months |
| ZIKV-C Reagent Integral Shelf-Life at 2-8 °C | 18 months |
| Calibration Curve | 14 days |
| Reagent Integrals Open Use Storage On-board Analyzerat 11-15 °C | 14 days |
| Reagent Integrals Open Use Storage at 2-8 °C | 14 days |
| Reconstituted Conjugates Open Use Storage at 2-8 °C | 14 days |
| ZIKV-M Reconstituted Calibrator Open Use at RoomTemperature (18-25°C) | 6 hours |
| ZIKV-M Reconstituted Calibrator Open Use at 2-8 °C | 24 hours |
| ZIKV-C Calibrator Open Use at 2-8 °C | 14 days |
11.0 STABILITY
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| LIAISON® XL Zika Capture IgM II Control Set | |
|---|---|
| Study | Stability |
| ZIKV-M Controls Shelf-Life at 2-8 °C | 10 months |
| ZIKV-C Controls Shelf-Life at 2-8 °C | 10 months |
| Control Open Use Storage On-board Analyzer at 18-25 °C | 24 hours |
| Control Open Use Storage at 2-8°C | 56 days |
SPECIMEN STABILITY
Studies were performed to determine the stability of human serum samples at storage temperatures of 2-8°C, and 18-25°C. A multiple freeze/thaw (F/T) study was also performed. Testing was performed with both the ZIKV-M and ZIKV-C reagent packs using a minimum of five (5) serum samples having index values below, near and above the respective reagent pack cut-off values. Stability of human serum samples was determined to be 7 days at 2- 8 °C and 24 hours at room temperature (18 – 25 °C). Serum samples are stable through 3 freeze/thaw cycles.
12. CONCLUSION:
The material submitted in this premarket notification is complete and supports a substantial equivalence decision. The labelling is sufficient and it satisfies the requirements of 21CFR 809.10.
§ 866.3935 Zika virus serological reagents.
(a)
Identification. Zika virus serological reagents arein vitro diagnostic devices that consist of antigens or antibodies for the detection of Zika virus or Zika antibodies in human specimens from individuals who have signs and symptoms consistent with Zika virus infection and/or epidemiological risk factors. The detection aids in the diagnosis of current or recent Zika virus infection or serological status. Negative results obtained with this test do not preclude the possibility of Zika virus infection, past or present. Positive results should be interpreted with consideration of other clinical information and laboratory findings and should not be used as the sole basis for treatment or other patient management decisions.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10(b) of this chapter must include:
(i) An intended use with a detailed description of what the device detects (Zika IgM antibodies, other Zika antibodies, or Zika antigens), the type of results provided to the user, the specimen type for which testing is indicated (
e.g., serum, whole blood), the clinical indications appropriate for test use, and the specific population(s) for which the test is intended.(ii) Performance characteristics from analytical and clinical studies required under paragraphs (b)(2)(ii) and (iii) of this section.
(iii) A detailed explanation of the interpretation of results and criteria for validity of results (
e.g., criteria that internal or external quality controls must meet in order for a test/test run to be valid, minimum signal strength that the sample has to yield to be interpretable as a valid result).(iv) Limiting statements indicating that:
(A) Results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. The test results should be interpreted in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence.
(B) Device results are intended to be followed up according to the latest professional guidelines (
e.g., recommendations from the Centers for Disease Control and Prevention) for the diagnosis of Zika virus infection.(C) Negative test results do not preclude the possibility of Zika virus infection, past or present.
(D) Specimens can result in false negative results on the device if collected outside of the appropriate response window for specific Zika virus antigens or antibodies, as determined by scientific evidence (
e.g., for IgM