(33 days)
The ADVIA Centaur® Zika test is for in vitro diagnostic use in the qualitative detection of IgM antibodies to the Zika virus in human serum and plasma (potassium EDTA or lithium heparin) specimens using the ADVIA Centaur XP and ADVIA Centaur XPT systems.
The ADVIA Centaur Zika test is intended for the presumptive clinical laboratory diagnosis of Zika virus infection. The test is intended for use only in individuals (children, adolescents and adults, including pregnant women) with clinical signs and symptoms consistent with Zika virus infection, and/or meeting the CDC Zika virus epidemiological criteria (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). Positive results must be confirmed by following the latest CDC guidelines for the diagnosis of Zika virus infection.
Results of this test are intended to be used in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence to make patient management decisions. Zika IgM levels are variable over the course of the infection, and 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 4 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.
The ADVIA Centaur Zika test is not indicated for testing blood or plasma donors.
The ADVIA Centaur Zika test consists of the components described in the following table: ADVIA Centaur Zika Ab Primary Reagent ReadyPack (included in Zika Ab assay kit), ADVIA Centaur Zika Ab Lite Reagent, ADVIA Centaur Zika Ab Solid Phase Reagent, ADVIA Centaur Zika Ab Ancillary Well Reagent, ADVIA Centaur Zika Ab Calibrators (included in Zika Ab assay kit), ADVIA Centaur Zika Ab High Calibrator, ADVIA Centaur Zika Ab Low Calibrator, ADVIA Centaur Zika Ab Controls (included in Zika Ab QC kit), ADVIA Centaur Zika Ab Negative Control, ADVIA Centaur Zika Ab Low Calibrator, ADVIA Centaur Zika IgM Primary Reagent ReadyPack (included in Zika IgM assay kit), ADVIA Centaur Zika IgM Lite Reagent, ADVIA Centaur Zika IgM Solid Phase Reagent, ADVIA Centaur Zika IgM Ancillary Well Reagent, ADVIA Centaur Zika IgM Calibrators (included in Zika IgM assay kit), ADVIA Centaur Zika IgM High Calibrator, ADVIA Centaur Zika IgM Low Calibrator, ADVIA Centaur Zika IgM Controls (included in Zika IgM QC kit), ADVIA Centaur Zika IgM Negative Control, ADVIA Centaur Zika IgM Low Calibrator. The methodology is an Antibody capture immunoassay using chemiluminescence detection.
Here's an analysis of the provided text, focusing on acceptance criteria and study details for the ADVIA Centaur Zika test:
The document describes the Siemens Healthcare Diagnostics Inc. ADVIA Centaur Zika test, a qualitative assay for IgM antibodies to the Zika virus.
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly present a table of "acceptance criteria" in the format of pass/fail thresholds. However, it presents various performance metrics which can be interpreted as the data used to demonstrate the device's acceptable performance. For clarity, I've extracted the key performance metrics and values from the "Performance Characteristics" section that would typically be evaluated against pre-defined acceptance criteria.
Note: The document itself does not state specific numerical acceptance criteria (e.g., "PPA must be >X%"). Instead, it presents the achieved performance. For biological assays, "acceptance" often implies demonstrating performance comparable to or superior to current standards/predicate devices, and meeting regulatory expectations for diagnostic accuracy.
| Performance Metric | Reported Device Performance (ADVIA Centaur Zika Test) | Relevant Section |
|---|---|---|
| Analytical Sensitivity (Ab Assay) | 23.18 IU/mL (at 0.80 Index cut-off) | 10.4 |
| Analytical Sensitivity (IgM Assay) | 1000 IU/mL (at 1.00 Index cut-off) | 10.4 |
| Cross-Reactivity (Overall) | 1.47% (5/341 samples reactive) | 10.5 |
| Cross-Reactivity (West Nile Virus) | 0.00% (0/11 samples reactive) | 10.7 |
| Cross-Reactivity (Dengue Virus) | 0.00% (0/10 samples reactive) | 10.7 |
| Interference (Hemoglobin) | ≤10% interference at 1000 mg/dL | 10.5 |
| Interference (Triglycerides) | ≤10% interference at 3000 mg/dL | 10.5 |
| Interference (Protein) | ≤10% interference at 12 g/dL | 10.5 |
| Interference (Bilirubin, Conj.) | ≤10% interference at 40 mg/dL | 10.5 |
| Interference (Bilirubin, Unconj.) | ≤10% interference at 60 mg/dL | 10.5 |
| Interference (Biotin) | ≤10% interference at 3500 ng/mL | 10.5 |
| Interference (Cholesterol) | ≤10% interference at 500 mg/dL | 10.5 |
| FDA Panel PPA (Zika Positive) | 87.50% (21/24) | 10.7 |
| FDA Panel NPA (Zika Negative) | 100.00% (12/12) | 10.7 |
| Clinical Study PPA (Zika PCR-positive, single draw) | 95.92% (47/49) | 10.8.2 |
| Clinical Study PPA (Zika PCR-positive, serial bleed, ≥8 days post symptom onset) | 94.14% (225/239) | 10.8.2 |
| Clinical Study PPA (Combined, ≥8 days post symptom onset) | 94.44% (272/288) | 10.8.2 |
| Clinical Study NPA (Endemic, ZIKV Detect 2.0 IgM Capture ELISA negative) | 94.37% (335/355) | 10.8.3 |
| Clinical Study NPA (Non-Endemic, ZIKV Detect 2.0 IgM Capture ELISA negative) | 99.90% (1976/1978) | 10.8.3 |
| Clinical Study NPA (Total Combined) | 99.06% (2311/2333) | 10.8.3 |
Study Details:
Most of the specified details (training set, experts for ground truth, adjudication method, MRMC study, standalone performance) are typically not included in a 510(k) summary for in vitro diagnostic (IVD) devices like this, which primarily focus on analytical and clinical performance compared to a predicate or established standard. This document is for a serological reagent, not an AI/imaging device. However, I will extract what is available from the text.
2. Sample sizes used for the test set and data provenance:
- Analytical Specificity / Cross-Reactivity:
- 341 samples from various disease states (e.g., ANA, Dengue, Malaria, Yellow Fever Immunization). Provenance not specified beyond "specimens containing IgM antibodies against other flavivirus specimens and disease state specimens."
- FDA Zika Performance Panel:
- Test Set (Zika IgM Consensus Positive): 24 samples
- Test Set (Zika IgM Consensus Negative): 12 samples
- Test Set (West Nile Virus): 11 samples
- Test Set (Dengue Virus): 10 samples
- Data Provenance: Samples provided by the FDA, sourced from the Blood Systems Research Institute (BSRI, now Vitalant Research Institute) from a study supported by National Institutes of Health. It appears to be retrospective due to "established consensus of sero-status."
- Clinical Studies (Zika-Positive Populations - Seroconversion Sensitivity):
- 8 serial draws from 36 Zika PCR-positive patients.
- Data Provenance: Dominican Republic. Prospectively collected.
- Clinical Studies (Zika-Positive Populations - Agreement):
- Single draws from 49 Zika PCR-positive patients.
- Data Provenance: Dominican Republic and mainland U.S. Prospectively collected.
- Clinical Studies (Zika-Negative Populations - Endemic Area):
- Residents with symptoms, PCR-negative for Zika: 46 samples
- Asymptomatic residents: 262 samples
- Travelers: 47 samples
- Total Endemic: 355 samples
- Data Provenance: Dominican Republic, Honduras, and Puerto Rico.
- Clinical Studies (Zika-Negative Populations - Non-Endemic Area):
- Apparently healthy male and female blood donors: 1365 samples
- Pregnant females: 485 samples
- Pediatric subjects (2-21 years): 128 samples
- Total Non-Endemic: 1978 samples
- Data Provenance: Mainland U.S.
3. Number of experts used to establish the ground truth for the test set and their qualifications:
- For the FDA Zika Performance Panel: The text states, "Performance was assessed from the subset of panel members for which an established consensus of sero-status was established." It also mentions, "The panel composition and consensus results are the responsibility of the FDA." However, the exact number and qualifications of experts contributing to this "consensus of sero-status" are not specified in this document.
- For Clinical Studies (Zika-Positive): Ground truth was established using Zika PCR-positive status. This is a direct molecular detection, not typically subject to expert consensus interpretation in the same way as imaging.
- For Clinical Studies (Zika-Negative): Ground truth was established by being "negative by the ZIKV Detect 2.0 IgM Capture ELISA" (the predicate device) and/or PCR-negative. Again, this relies on laboratory test results rather than expert interpretation of complex data.
4. Adjudication method for the test set:
- Not applicable or Not specified in the context of expert adjudication for an IVD device like this. The "consensus of sero-status" for the FDA panel implies some form of agreement, but the process is not detailed. For the clinical studies, gold standard laboratory methods (PCR, predicate device results) served as the comparator.
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. This is an in vitro diagnostic (IVD) device, not an AI or imaging device that involves human readers interpreting results. Therefore, an MRMC study is not relevant here. The device automatically generates qualitative results (reactive/non-reactive).
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, implicitly. The ADVIA Centaur Zika test is an automated, qualitative immunoassay. Its performance is entirely standalone; it produces a result (Presumptive Zika Positive or Negative) based on its biochemical reactions and internal algorithm without human interpretation influencing the test result itself. Human involvement is in collecting samples, running the instrument, and interpreting the output for clinical context, but not in establishing the diagnostic result.
7. The type of ground truth used:
- FDA Panel: "Established consensus of sero-status" and "Zika IgM Consensus Result." This implies a combination of serological and potentially molecular data adjudicated to determine true positive/negative status for the panel samples.
- Clinical Studies (Zika-Positive): Primarily Zika PCR-positive status for initial classification.
- Clinical Studies (Zika-Negative): Primarily negative by the ZIKV Detect 2.0 IgM Capture ELISA (predicate device) and in some cases, PCR-negative.
8. The sample size for the training set:
- Not specified as a distinct "training set" in the context of device development (e.g., machine learning). For IVD assays, development involves optimizing reagents and protocols. The "Analytical Sensitivity / Assay Cut-off" section mentions using a WHO International standard for anti-Asian lineage Zika virus antibody to determine cut-off values, which is a form of calibration/optimization rather than training a model. There's no separate section describing a distinct training dataset for an algorithm.
9. How the ground truth for the training set was established:
- Since a "training set" in the machine learning sense is not explicitly identified, the method for establishing its ground truth is not detailed. However, for the analytical sensitivity, the ground truth was based on the WHO 1st International standard for anti-Asian lineage Zika virus antibody (human) (NIBSC 16/352), which is a highly characterized reference material with an assigned concentration.
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Siemens Healthcare Diagnostics Inc. Matthew Gee Senior Manager, Regulatory Affairs 511 Benedict Avenue Tarrytown, New York 10591
July 17, 2019
Re: K191578
Trade/Device Name: ADVIA Centaur Zika test. ADVIA Centaur Zika Ab (100 tests). ADVIA Centaur Zika IgM (50 tests), ADVIA Centaur Zika Ab Quality Control, ADVIA Centaur Zika IgM Quality Control Regulation Number: 21 CFR 866.3935 Regulation Name: Zika Virus Serological Reagents Regulatory Class: Class II Product Code: QFO, QCH Dated: June 12, 2019 Received: June 14, 2019
Dear Matthew Gee:
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
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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 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 (QS) 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 medical devices and radiation-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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Indications for Use
510(k) Number (if known)
Device Name ADVIA Centaur Zika test
Indications for Use (Describe)
The ADVIA Centaur Zika test is for in vitro diagnostic use in the qualitative detection of IgM antibodies to the Zika virus in human serum and plasma (potassium EDTA or lithium heparin) specimens using the ADVIA Centaur XPT systems.
The ADVIA Centaur Zika test is intended for the presumptive clinical laboratory diagnosis of Zika virus infection. The test is intended for use only in individuals (children, adolescents and adults, including pregnant women) with clinical signs and symptoms consistent with Zika virus infection, and/or meeting the CDC Zika virus epidemiological criteria (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). Positive results must be confirmed by following the latest CDC guidelines for the diagnosis of Zika virus infection.
Results of this test are intended to be used in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence to make patient management decisions. Zika IgM levels are variable over the course of the infection, and 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 4 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.
The ADVIA Centaur Zika test is not indicated for testing blood or plasma donors.
| 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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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.
The assigned 510(k) Number is: K191578
Date Prepared 1.
July 15, 2019
Applicant Information 2.
| Contact: | Matthew Gee, M.Sc.Senior Manager, Regulatory Affairs |
|---|---|
| Address: | Siemens Healthcare Diagnostics Inc.511 Benedict AvenueTarrytown, NY 10591 |
| Phone: | 914-372-9169 |
| Fax: | 914-524-3579 |
Email: matthew.gee@siemens.com
3. Regulatory Information
Table 1. Regulatory Information for ADVIA Centaur Zika Test
| Trade Name | ADVIA Centaur® Zika test |
|---|---|
| Model Numbers | ADVIA Centaur Zika Ab (100 tests): 11202473ADVIA Centaur Zika IgM (50 tests): 11202471ADVIA Centaur Zika Ab Quality Control: 11202474ADVIA Centaur Zika IgM Quality Control: 11202472 |
| Regulation Number | 866.3935 |
| Regulation Name | Zika Virus Serological Reagents |
| Regulation Definition | Zika virus serological reagents are devices that consist ofantigens and antisera for the diagnosis of Zika virus infectionin human clinical specimens from individuals that have signsand symptoms consistent with Zika virus infection and/orepidemiological risk factors. The device aids in thepresumptive clinical diagnosis of Zika virus infection inconjunction with other clinical and laboratory findings. |
| Product Code | QFO |
| Regulatory Class | Class II |
| Review Panel | Microbiology (83) |
4. Predicate Device Information
Predicate Device Name: ZIKV Detect 2.0 IgM Capture ELISA
De Novo Request Number: DEN180069
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Intended Use / Indications for Use 5.
The ADVIA Centaur® Zika test is for in vitro diagnostic use in the qualitative detection of IgM antibodies to the Zika virus in human serum and plasma (potassium EDTA or lithium heparin) specimens using the ADVIA Centaur XP and ADVIA Centaur XPT systems.
The ADVIA Centaur Zika test is intended for the presumptive clinical laboratory diagnosis of Zika virus infection. The test is intended for use only in individuals (children, adolescents and adults, including pregnant women) with clinical signs and symptoms consistent with Zika virus infection, and/or meeting the CDC Zika virus epidemiological criteria (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). Positive results must be confirmed by following the latest CDC guidelines for the diagnosis of Zika virus infection.
Results of this test are intended to be used in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence to make patient management decisions. Zika IgM levels are variable over the course of the infection, and may be detectable near day 4 post onset of symptoms and persist up to approximately 12 weeks following initial infection.
Neqative results may be seen in specimens collected before day 4 post onset of symptoms or after the window of detectable IqM closes, and therefore do not preclude the possibility of Zika virus infection, past or present.
The ADVIA Centaur Zika test is not indicated for testing blood or plasma donors.
6. Device Description
| Component | Volume | Ingredients |
|---|---|---|
| ADVIA Centaur Zika Ab Primary Reagent ReadyPack (included in Zika Ab assay kit) | ||
| ADVIA Centaur Zika Ab Lite Reagent | 5.0 mL/pack (x1) | NS1 Antigen labeled with acridinium ester (0.4 µg/mL) in buffered saline with surfactant, blockers, sodium azide (< 0.1%) and preservatives |
| ADVIA Centaur Zika Ab Solid Phase Reagent | 25.0 mL/pack (x1) | Streptavidin-coated paramagnetic microparticles preformed with biotinylated anti-human IgM antibody (~0.1 mg/mL) in buffered saline with surfactant, blockers, sodium azide (< 0.1%) and preservatives |
| ADVIA Centaur Zika Ab Ancillary Well Reagent | 5.0 mL/pack (x1) | Buffered saline with surfactant, blockers, sodium azide (< 0.1%) and preservatives |
| ADVIA Centaur Zika Ab Calibrators (included in Zika Ab assay kit) | ||
| ADVIA Centaur Zika Ab High Calibrator | 1.0 mL/vial (x1) | Processed human plasma negative for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
| ADVIA Centaur Zika Ab Low Calibrator | 1.0 mL/vial (x1) | Processed human plasma positive for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
The ADVIA Centaur Zika test consists of the components described in the following table.
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| Component | Volume | Ingredients |
|---|---|---|
| ADVIA Centaur Zika Ab Controls (included in Zika Ab QC kit) | ||
| ADVIA Centaur Zika Ab Negative Control | 1.0 mL/vial (x2) | Processed human plasma negative for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
| ADVIA Centaur Zika Ab Low Calibrator | 1.0 mL/vial (x2) | Processed human plasma positive for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
| ADVIA Centaur Zika IgM Primary Reagent ReadyPack (included in Zika IgM assay kit) | ||
| ADVIA Centaur Zika IgM Lite Reagent | 2.5 mL/pack (x1) | NS1 Antigen labeled with acridinium ester (0.4 $ \mu $ g/mL) in buffered saline with surfactant, blockers, sodium azide (<0.1%) and preservatives |
| ADVIA Centaur Zika IgM Solid Phase Reagent | 12.5 mL/pack (x1) | Streptavidin-coated paramagnetic microparticles preformed with biotinylated anti-human IgM antibody (~0.1 mg/mL) in buffered saline with surfactant, blockers, sodium azide (< 0.1%) and preservatives |
| ADVIA Centaur Zika IgM Ancillary Well Reagent | 2.5 mL/pack (x1) | Buffered saline with surfactant, blockers, sodium azide (<0.1%) and preservatives |
| ADVIA Centaur Zika IgM Calibrators (included in Zika IgM assay kit) | ||
| ADVIA Centaur Zika IgM High Calibrator | 1.0 mL/vial (x1) | Processed human plasma negative for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
| ADVIA Centaur Zika IgM Low Calibrator | 1.0 mL/vial (x1) | Processed human plasma positive for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
| ADVIA Centaur Zika IgM Controls (included in Zika IgM QC kit) | ||
| ADVIA Centaur Zika IgM Negative Control | 1.0 mL/vial (x2) | Processed human plasma negative for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
| ADVIA Centaur Zika IgM Low Calibrator | 1.0 mL/vial (x2) | Processed human plasma positive for Zika IgM antibodies with sodium azide (< 0.1%) and preservatives. |
Purpose of the Submission 7.
The purpose of this premarket notification is to submit a new device (ADVIA Centaur Zika test) to FDA for consideration for clearance.
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8. Comparison of Candidate Device and Predicate Device
Table 2. Comparison of ADVIA Centaur Zika Test to Predicate
| ltem | ADVIA Centaur | ZIKV Detect 2.0 IgM Capture |
|---|---|---|
| Zika Test(Candidate Device) | ELISA(Predicate Device) | |
| Intended Use | The ADVIA Centaur Zika test is for in vitrodiagnostic use in the qualitative detection ofIgM antibodies to the Zika virus in humanserum and plasma (potassium EDTA or lithiumheparin) specimens using the ADVIA CentaurXP and ADVIA Centaur XPT systems.The ADVIA Centaur Zika test is intended for thepresumptive clinical laboratory diagnosis of Zikavirus infection. The test is intended for use onlyin individuals (children, adolescents and adults,including pregnant women) with clinical signsand symptoms consistent with Zika virusinfection, and/or meeting the CDC Zika virusepidemiological criteria (history of residence inor travel to a geographic region with active Zikatransmission at the time of travel, or otherepidemiological criteria for which Zika virustesting may be indicated). Positive results mustbe confirmed by following the latest CDCguidelines for the diagnosis of Zika virusinfection.Results of this test are intended to be used inconjunction with clinical observations, patienthistory, epidemiological information, and otherlaboratory evidence to make patientmanagement decisions. Zika IgM levels arevariable over the course of the infection, andmay be detectable near day 4 post onset ofsymptoms and persist up to approximately 12weeks following initial infection.Negative results may be seen in specimenscollected before day 4 post onset of symptomsor after the window of detectable IgM closes,and therefore do not preclude the possibility ofZika virus infection, past or present.The ADVIA Centaur Zika test is not indicatedfor testing blood or plasma donors. | The ZIKV Detect 2.0 IgM Capture ELISA isintended for the qualitative detection of Zikavirus IgM antibodies in human sera for thepresumptive clinical laboratory diagnosis ofZika virus infection. The assay is intendedfor use only in patients with clinical signsand symptoms consistent with Zika virusinfection, and/or CDC Zika virusepidemiological criteria (e.g., history ofresidence in or travel to a geographic regionwith active Zika transmission at the time oftravel, or other epidemiological criteria forwhich Zika virus testing may be indicated).Assay results are for the presumptivedetection of IgM antibodies to Zika virus(ZIKV). Positive results must be confirmedby following the latest CDC guidelines forthe diagnosis of Zika virus infection. Resultsof this test are intended to be used inconjunction with clinical observations,patient history, epidemiological information,and other laboratory evidence to makepatient management decisions. Zika IgMlevels are variable over the course of theinfection, and may be detectable near dayfour post onset of symptoms and persist upto approximately 12 weeks following initialinfection.Negative results may be seen in specimenscollected before day four post onset ofsymptoms or after the window of detectableIgM closes, and therefore do not precludethe possibility of Zika virus infection, past orpresent.This assay is not indicated for testing bloodor plasma donors. |
| Methodology | Antibody capture immunoassay usingchemiluminescence detection | ELISA |
| Detection Label | Acridinium ester | Horseradish peroxidase |
| Calibration | 2-point calibration | N/A |
| Analyte | Zika virus IgM antibodies | Same |
| Specimen Type | Serum and Plasma (EDTA, LiHep) | Serum |
| Measurement Type | Qualitative | Same |
| Automation | Fully automated | Manual |
| Instruments | ADVIA Centaur XPADVIA Centaur XPT | N/A |
| Incubation Time | ZikaAb Only: 36.25 minutesFull Algorithm: 108.75 minutes | ~200 Minutes |
| Item | ADVIA CentaurZika Test(Candidate Device) | ZIKV Detect 2.0 IgM CaptureELISA(Predicate Device) |
| Required Washes | ZikaAb Only: 2 washesFull Algorithm: 6 washes | 32 (4 x 6) washes |
| Interpretations | ADVIA Centaur ZikaAb < 0.80 Index:Negative for Antibodies to Zika VirusADVIA Centaur ZikaAb ≥ 0.80 Index:Reflex to ADVIA Centaur ZikaM:ADVIA Centaur ZikaM Rep 1 < 1.00 Index:Negative for IgM Antibodies to Zika VirusADVIA Centaur ZikaM Rep 1 ≥ 1.00 Index:Repeat ADVIA Centaur ZikaM in duplicateADVIA Centaur ZikaM Rep 2&3 < 1.00 Index:Negative for IgM Antibodies to Zika VirusADVIA Centaur ZikaM Rep 2or3 ≥ 1.00 Index:Presumptive Zika Positive | Zika Ag OD450 ≥ Threshold Zika Ag OD450AND Zika ISR value > 1.90:Presumptive Zika PositiveInitial: Zika Ag OD450 ≥ Threshold Zika AgOD450 AND 1.50 ≤ Zika ISR ≤ 1.90:Retest in duplicateRetest: Zika Ag OD450 ≥ Threshold Zika AgOD450 AND Zika ISR value ≥ 1.70Presumptive Zika PositiveNot Presumptive Zika Positive & CCA /NCA ratio ≥ 5.00:Presumptive Other Flavivirus PositiveNot Presumptive Zika Positive & CCA /NCA ratio < 5.00:Negative |
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Table 2. Comparison of ADVIA Centaur Zika Test to Predicate
Standard/Guidance Document References 9.
The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:
- Evaluation of Precision Performance of Quantitative Measurement Methods: l Approved Guideline - Third Edition (CLSI EP05-A3, 2014; Recognition No. 7-251)
- I Interference Testing in Clinical Chemistry. 3rd Edition (CLSI EP07-A3, 2018; Recognition No. 7-275)
- Supplemental Tables for Interference Testing in Clinical Chemistry. 185 Edition (CLSI I EP37, 2018; Recognition No. 7-284)
- I Medical devices - Application of risk management to medical devices (ANSI/AAMI/ISO 14971:2007/(R)2010; Recognition No. 5-40)
10. Performance Characteristics
Precision/Reproducibility 10.1
Precision of the ADVIA Centaur Zika Ab assay was evaluated according to the CLSI protocol EP05-A3. A two-member panel and controls were assayed in 2 replicates twice a day for 20 days (n = 80 for each sample). The following representative results were obtained:
| Sample | Mean (Index) | Repeatability | Within-Lab | ||
|---|---|---|---|---|---|
| SD | %CV | SD | %CV | ||
| Negative Control | 0.05 | 0.03 | --- | 0.04 | --- |
| Positive Control | 3.26 | 0.06 | 2.0 | 0.13 | 3.9 |
| Plasma Pool 1 | 0.63 | 0.03 | 4.0 | 0.03 | 5.0 |
| Plasma Pool 2 | 1.98 | 0.05 | 2.6 | 0.08 | 4.3 |
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Precision of the ADVIA Centaur Zika IgM assay was evaluated according to the CLSI protocol EP05-A3. A two-member panel and controls were assayed in 2 replicates twice a day for 20 days (n = 80 for each sample). The following representative results were obtained:
| Sample | Mean(Index) | Repeatability | Within-Lab | ||
|---|---|---|---|---|---|
| SD(Index) | %CV | SD(Index) | %CV | ||
| Negative Control | 0.00 | 0.02 | --- | 0.02 | --- |
| Positive Control | 2.92 | 0.06 | 1.9 | 0.13 | 4.6 |
| Plasma Pool 1 | 0.82 | 0.04 | 4.4 | 0.06 | 7.9 |
| Plasma Pool 2 | 2.11 | 0.05 | 2.5 | 0.10 | 4.6 |
Multi-site precision of the ADVIA Centaur Zika Ab assay was evaluated on the ADVIA Centaur XP system. A five-member panel, including negative samples, and low and high positive samples, was assayed in 3 replicates twice a day for 5 days at 3 sites with 3 different lots of ADVIA Centaur Zika Ab reagents (n=270 for each sample). The following results were obtained:
| Sample | Mean(Index) | Repeatability | Between-Run | Between-Day | Between-Lot | Between-Site | Reproducibility | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| Pool 1 | 0.05 | 0.03 | --- | 0.02 | --- | 0.03 | --- | 0.00 | --- | 0.00 | --- | 0.05 | --- |
| Pool 2 | 0.58 | 0.03 | 5.1 | 0.01 | 2.0 | 0.02 | 2.9 | 0.00 | 0.0 | 0.02 | 4.3 | 0.04 | 7.6 |
| Pool 3 | 1.00 | 0.04 | 4.2 | 0.04 | 3.8 | 0.00 | 0.0 | 0.00 | 0.0 | 0.01 | 1.4 | 0.06 | 5.9 |
| Pool 4 | 2.15 | 0.06 | 2.7 | 0.04 | 1.8 | 0.04 | 2.0 | 0.02 | 0.8 | 0.06 | 2.6 | 0.10 | 4.7 |
| Pool 5 | 3.08 | 0.08 | 2.7 | 0.09 | 2.8 | 0.06 | 1.9 | 0.04 | 1.3 | 0.08 | 2.6 | 0.16 | 5.2 |
Multi-site precision of the ADVIA Centaur Zika IgM assay was evaluated on the ADVIA Centaur XP system. A five-member panel, including negative samples, and low and high positive samples, was assayed in 3 replicates twice a day for 5 days at 3 sites with 3 different lots of ADVIA Centaur Zika IgM reagents (n=270 for each sample). The following results were obtained:
| Sample | Mean (Index) | Repeatability | Between-Run | Between-Day | Between-Lot | Between-Site | Reproducibility | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| Pool 1 | 0.09 | 0.07 | --- | 0.04 | --- | 0.02 | --- | 0.04 | --- | 0.04 | --- | 0.10 | --- |
| Pool 2 | 0.67 | 0.05 | 7.3 | 0.00 | 0.0 | 0.00 | 0.0 | 0.01 | 1.0 | 0.05 | 6.9 | 0.07 | 10.1 |
| Pool 3 | 1.08 | 0.04 | 3.8 | 0.02 | 1.9 | 0.00 | 0.0 | 0.00 | 0.0 | 0.05 | 4.4 | 0.07 | 6.1 |
| Pool 4 | 2.40 | 0.05 | 2.2 | 0.04 | 1.5 | 0.03 | 1.3 | 0.04 | 1.8 | 0.09 | 3.9 | 0.13 | 5.2 |
| Pool 5 | 3.53 | 0.08 | 2.3 | 0.02 | 0.7 | 0.06 | 1.6 | 0.06 | 1.8 | 0.14 | 4.0 | 0.19 | 5.3 |
Linearity / Assay Reportable Range 10.2
Linearity is not applicable to the ADVIA Centaur Zika test. The ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM assays are qualitative methods. The reportable range for the assays is 0.00 to 10.00 Index.
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10.3 Detection Limits
Detection Limits (Limit of Blank, Limit of Detection, Limit of Quantitative) are not applicable to the ADVIA Centaur Zika test. The ADVIA Centaur Zika Ab and ADVIA Centaur Zika IqM assays are qualitative methods.
Analytical Sensitivity / Assay Cut-off 10.4
The analytical sensitivity at the cut-off values for the ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM assays was determined using WHO 1® International standard for anti-Asian lineage Zika virus antibody (human) (NIBSC 16/352). This preparation contains antibodies reactive to Dengue virus. The standard was used to prepare a dilution series which was tested using linear regression. The concentration of the reference reagent that corresponds to the cut-off value of 0.80 Index for ADVIA Centaur Zika Ab is 23.18 IU/mL. The concentration of the reference reagent that corresponds to the cut-off value of 1.00 Index for ADVIA Centaur Zika IgM is 1000 IU/mL.
10.5 Analytical Specificity / Cross-Reactivity and Interference
The ADVIA Centaur Zika test was evaluated for potential cross-reactivity with specimens containing IgM antibodies against other flavivirus specimens and disease state specimens. The following results were obtained using the ADVIA Centaur Zika test.
| Disease State | Number ofSamples Tested | ADVIA CentaurZika TestNonreactiveSamples | ADVIA CentaurZika TestReactiveSamples | Cross-Reactivity |
|---|---|---|---|---|
| ANA | 19 | 19 | 0 | 0.00% |
| Adenovirus | 1 | 1 | 0 | 0.00% |
| Borrelia sp. (Lyme) | 11 | 11 | 0 | 0.00% |
| Chikungunya Virus | 21 | 21 | 0 | 0.00% |
| CMV | 12 | 12 | 0 | 0.00% |
| Dengue Virus | 41 | 39 | 2 | 4.88% |
| EBV | 11 | 11 | 0 | 0.00% |
| HAMA | 15 | 15 | 0 | 0.00% |
| HBV | 11 | 11 | 0 | 0.00% |
| HCV | 15 | 15 | 0 | 0.00% |
| HSV-1/2 | 26 | 26 | 0 | 0.00% |
| Leptospira | 16 | 16 | 0 | 0.00% |
| Malaria | 10 | 8 | 2 | 20.00% |
| Parvovirus B19 | 16 | 16 | 0 | 0.00% |
| RF | 21 | 21 | 0 | 0.00% |
| Rubella Virus | 10 | 10 | 0 | 0.00% |
| Toxoplasma gondii | 16 | 16 | 0 | 0.00% |
| Syphilis | 10 | 10 | 0 | 0.00% |
| VZV | 15 | 15 | 0 | 0.00% |
| WNV | 23 | 23 | 0 | 0.00% |
| Yellow Fever Immunization | 21 | 20 | 1 | 4.76% |
| Total | 341 | 336 | 5 | 1.47% |
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The ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM assays were evaluated for potential interference with endogenous substances Testing was performed separately with both the ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM assays in accordance with CLSI Documents EP07-A3 and EP37.
| Endogenous Substance | Highest Concentration Testedwith ≤10% Interference |
|---|---|
| Hemoglobin | 1000 mg/dL |
| Triglycerides (Intralipid) | 3000 mg/dL |
| Protein | 12 g/dL |
| Conjugated Bilirubin | 40 mg/dL |
| Unconjugated Bilirubin | 60 mg/dL |
| Biotin | 3500 ng/mL |
| Cholesterol | 500 mg/dL |
Comparison Studies 10.6
10.6.1 Method Comparison with Predicate Device
See Clinical Studies section.
10.6.2 Matrix Comparison
Specimen equivalency was determined using the Deming linear regression model in accordance with CLSI Document EP09-A3. No significant difference was observed between tube types.
The following results were obtained using the ADVIA Centaur Zika Ab assay:
| Specimen (y) | ReferenceSpecimen (x) | Regression Equation | SampleInterval | N | CorrelationCoefficient |
|---|---|---|---|---|---|
| LiHep Plasma | Serum | y = 1.02x - 0.04 | 0.00-3.86 | 20 | 1.00 |
| EDTA Plasma | Serum | y = 0.98x - 0.01 | 0.00-3.67 | 20 | 1.00 |
The following results were obtained using the ADVIA Centaur Zika IgM assay:
| Specimen (y) | ReferenceSpecimen (x) | Regression Equation | SampleInterval | N | CorrelationCoefficient |
|---|---|---|---|---|---|
| LiHep Plasma | Serum | $y = 1.06x + 0.00$ | 0.00-5.44 | 20 | 1.00 |
| EDTA Plasma | Serum | $y = 1.06x - 0.00$ | 0.00-5.78 | 20 | 1.00 |
10.7 FDA Zika Performance Panel
Performance of the ADVIA Centaur Zika test was evaluated by testing a panel of samples provided by the FDA. The FDA's panel consists of plasma samples from individuals infected with Zika, West Nile or Dengue viruses at various stages of infection. Sample demographics and results were randomized and blinded to diagnostic developers to assess the proficiency of their tests. Performance was assessed from the subset of panel members for which an established consensus of sero-status was established:
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| Zika IgMConsensusResult | Total Samples | ADVIA CentaurZika TestPresumptiveZika Positive | ADVIA CentaurZika TestNegative* | % Agreement |
|---|---|---|---|---|
| Positive | 24 | 21 | 3 | PPA = 87.50% (21/24) |
| Negative | 12 | 0 | 12 | NPA = 100.00% (12/12) |
- Includes samples that were nonreactive with either ADVIA Centaur Zika Ab or ADVIA Centaur Zika IgM.
Results from the cross-reactivity evaluation are shown below:
| DiseaseState* | Total Samples | ADVIA CentaurZika TestPresumptiveZika Positive | ADVIA CentaurZika TestNegative* | % Cross-Reactivity |
|---|---|---|---|---|
| West Nile Virus | 11 | 0 | 11 | 0.00% (0/11) |
| Dengue Virus | 10 | 0 | 10 | 0.00% (0/10) |
- These were single bleeds that were positive for West Nile Virus or Denque virus and negative for Zika virus.
** Includes samples that were nonreactive with either ADVIA Centaur Zika Ab or ADVIA Centaur Zika IqM.
This evaluation was performed using samples provided by Blood Systems Research Institute (BSRI, now Vitalant Research Institute) from a study supported by National Institutes of Health. The panel composition and consensus results are the responsibility of the FDA and do not necessarily represent the official views of BSRI, the NHLBI, or the National Institutes of Health.
10.8 Clinical Studies
Specimens from patients infected with Zika virus and uninfected individuals were collected from areas of low and high Zika virus prevalence. Testing was performed at 3 sites, with samples distributed approximately evenly across sites. Samples were tested with the ADVIA Centaur Zika test and a commercially-available Zika IgM assay.
10.8.1 Seroconversion Sensitivity
Eight (8) serial draws from 36 Zika PCR-positive patients from the Dominican Republic were prospectively collected and evaluated using the ADVIA Centaur Zika test and the ZIKV Detect 2.0 IgM Capture ELISA. The following seroconversion sensitivity results were obtained:
| First Reactive(Presumptive Zika Positive)Bleed Number* | Number of Reactive(Presumptive Zika Positive)Bleeds | ||||
|---|---|---|---|---|---|
| Series ID | ZIKV Detect2.0 IgMCapture ELISA | ADVIACentaur ZikaTest | Differencein BleedNumbers** | ZIKV Detect2.0 IgMCapture ELISA | ADVIACentaur ZikaTest |
| TDS0067 | 1 (Day 3) | 2 (Day 27) | -1 | 8 | 4 |
| TDS0123*** | 3 (Day 13) | 3 (Day 13) | 0 | 6 | 6 |
| TDS0173 | 2 (Day 10) | 2 (Day 10) | 0 | 7 | 7 |
| TDS0220 | 1 (Day 6) | 1 (Day 6) | 0 | 8 | 8 |
| TDS0246 | 2 (Day 19) | 1 (Day 5) | +1 | 7 | 8 |
| First Reactive(Presumptive Zika Positive)Bleed Number* | Number of Reactive(Presumptive Zika Positive)Bleeds | ||||
| Series ID | ZIKV Detect2.0 IgMCapture ELISA | ADVIACentaur ZikaTest | Differencein BleedNumbers** | ZIKV Detect2.0 IgMCapture ELISA | ADVIACentaur ZikaTest |
| TDS0249 | 2 (Day 20) | 1 (Day 5) | +1 | 7 | 8 |
| TDS0257 | 2 (Day 19) | 2 (Day 19) | 0 | 6 | 7 |
| TDS0263 | 2 (Day 18) | 2 (Day 18) | 0 | 7 | 7 |
| TDS0271 | 1 (Day 4) | 2 (Day 10) | -1 | 8 | 4 |
| TDS0279 | 2 (Day 11) | 2 (Day 11) | 0 | 7 | 7 |
| TDS0281 | 2 (Day 14) | 2 (Day 14) | 0 | 7 | 7 |
| TDS0282 | 1 (Day 2) | 2 (Day 13) | -1 | 8 | 7 |
| TDS0284 | 2 (Day 17) | 2 (Day 17) | 0 | 7 | 7 |
| TDS0292 | 2 (Day 13) | 1 (Day 4) | +1 | 6 | 8 |
| TDS0296 | 2 (Day 9) | 2 (Day 9) | 0 | 7 | 7 |
| TDS0306 | 1 (Day 4) | 1 (Day 4) | 0 | 8 | 8 |
| TDS0310 | 2 (Day 8) | 2 (Day 8) | 0 | 7 | 7 |
| TDS0314 | 1 (Day 6) | 1 (Day 6) | 0 | 8 | 8 |
| TDS0322 | 1 (Day 5) | 1 (Day 5) | 0 | 8 | 8 |
| TDS0328 | 2 (Day 10) | 2 (Day 10) | 0 | 7 | 2 |
| TDS0341 | 2 (Day 10) | 2 (Day 10) | 0 | 7 | 5 |
| TDS0343 | 2 (Day 18) | 2 (Day 18) | 0 | 7 | 7 |
| TDS0345 | 2 (Day 10) | 2 (Day 10) | 0 | 5 | 7 |
| TDS0362 | 2 (Day 25) | 2 (Day 25) | 0 | 2 | 7 |
| TDS0372 | 2 (Day 9) | 2 (Day 9) | 0 | 7 | 7 |
| TDS0376 | 2 (Day 14) | 2 (Day 14) | 0 | 7 | 7 |
| TDS0379 | 1 (Day 6) | 1 (Day 6) | 0 | 8 | 7 |
| TDS0396 | 1 (Day 2) | 1 (Day 2) | 0 | 8 | 8 |
| TDS0421 | 2 (Day 9) | 1 (Day 2) | +1 | 7 | 8 |
| TDS0422 | 1 (Day 8) | 1 (Day 8) | 0 | 7 | 8 |
| TDS0437 | 2 (Day 12) | 2 (Day 12) | 0 | 7 | 7 |
| TDS0440 | 2 (Day 12) | 2 (Day 12) | 0 | 7 | 7 |
| TDS0458 | 2 (Day 12) | 2 (Day 12) | 0 | 7 | 7 |
| TDS0468 | 2 (Day 14) | 1 (Day 6) | +1 | 5 | 8 |
| TDS0480 | 2 (Day 12) | 2 (Day 12) | 0 | 7 | 7 |
| TDS0499 | 1 (Day 5) | 2 (Day 12) | -1 | 8 | 7 |
| Total Reactive Bleeds | 250 | 249 |
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- The number of days is in relation to the initial draw date.
** The difference in bleed numbers is relative to the comparator assay. For example, a +1 means that the comparator assay required 1 additional bleed before reactivity was determined as compared to the timepoint when the ADVIA Centaur assay confirmed positive.
*** There was insufficient volume for testing with ZIKV Detect 2.0 IgM Capture ELISA for Bleed 3 of TDS0123. This analysis assumes that ZIKV Detect 2.0 IgM Capture ELISA was Presumptive Zika Positive at this Bleed.
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10.8.2 Agreement in Zika-Positive Populations
Single draws from 49 Zika PCR-positive patients from the Dominican Republic and mainland U.S. were prospectively collected and evaluated using the ADVIA Centaur Zika test and the ZIKV Detect 2.0 IgM Capture ELISA. The positive percent agreement of the ADVIA Centaur Zika test in this population was 95.92% (47/49).
Eight (8) serial draws from 36 Zika PCR-positive patients from the Dominican Republic were prospectively collected and evaluated using the ADVIA Centaur Zika test and the ZIKV Detect 2.0 IgM Capture ELISA. The positive percent agreement of the ADVIA Centaur Zika test in this population for specimens collected at 8 days or later after symptom onset was 94.14% (225/239).
The positive percent agreement of the ADVIA Centaur Zika test in the combined single draw and serial bleed population for specimens collected at 8 days or later after symptom onset was 94.44% (272/288).
| ZIKV Detect 2.0 IgM Capture ELISANegative | ZIKV Detect 2.0 IgM Capture ELISAPositive | |||||
|---|---|---|---|---|---|---|
| Days AfterSymptom Onset | ADVIACentaurZika TestReactive | ADVIACentaurZika TestNonreactive | Negative %Agreement | ADVIACentaurZika TestReactive | ADVIACentaurZika TestNonreactive | Positive %Agreement |
| 0-7* | 5 | 21 | 80.77% | 7 | 4 | 63.64% |
| 8-14 | 0 | 0 | --- | 45 | 2 | 95.74% |
| 15-28 | 1 | 0 | 0.00% | 71 | 1 | 98.61% |
| 29-42 | 3 | 0 | 0.00% | 64 | 2 | 96.97% |
| 43-56 | 3 | 0 | 0.00% | 60 | 4 | 93.75% |
| 57-70 | 5 | 0 | 0.00% | 18 | 4 | 81.82% |
| ≥71 | 0 | 0 | --- | 5 | 3 | 62.50% |
| Variable** | 0 | 0 | --- | 9 | 0 | 100.00% |
| Total | 17 | 21 | 55.26% | 279 | 20 | 93.31% |
| Total (≥ Day 8) | 12 | 0 | 0.00% | 272 | 16 | 94.44% |
This timeframe is not supported. IgM antibodies to Zika virus develop during the first week of illness.
** Specimens were collected between 4 to 8 weeks after symptom onset. However, the exact date of symptom onset is unknown.
10.8.3 Agreement in Zika-Negative Populations
A population of residents and travelers to areas of high prevalence for Zika virus infection (Dominican Republic, Honduras and Puerto Rico) that were negative by the ZIKV Detect 2.0 IgM Capture ELISA were tested using the ADVIA Centaur Zika test. The categories included residents with symptoms associated with Zika infection but were PCR-negative for Zika virus (N = 46), asymptomatic residents (N = 262) and travelers (N = 47).
The negative percent agreement of the ADVIA Centaur Zika test in this population was 94.37% (335/355).
A population of residents from an area of low prevalence of Zika virus infection (mainland U.S.) that were negative by the ZIKV Detect 2.0 IgM Capture ELISA were tested using the ADVIA Centaur Zika test. The categories included apparently healthy male and female blood donors (N = 1365), pregnant females (N = 485), and pediatric subjects 2 to 21 years
{14}------------------------------------------------
of age (N = 128). The negative percent agreement of the ADVIA Centaur Zika test in this population was 99.90% (1976/1978).
The negative percent agreement of the ADVIA Centaur Zika test in the combined nonendemic and endemic population was 99.06% (2311/2333).
| Category | ADVIA CentaurZika Test Result | Total | Negative PercentAgreement | |
|---|---|---|---|---|
| Nonreactive | Reactive | |||
| Endemic Area Travelers | 47 | 0 | 47 | 100.00% (47/47) |
| Endemic Area Symptomatic Residents | 45 | 1 | 46 | 97.83% (45/46) |
| Endemic Area Asymptomatic Residents | 243 | 19 | 262 | 92.75% (243/262) |
| Non-Endemic Healthy Blood Donors | 1365 | 0 | 1365 | 100.00% (1365/1365) |
| Non-Endemic Pregnant Women | 483 | 2 | 485 | 99.59% (483/485) |
| Non-Endemic Pediatrics (2-21 years) | 128 | 0 | 128 | 100.00% (128/128) |
| Total Endemic Population | 335 | 20 | 355 | 94.37% (335/355) |
| Total Non-Endemic Population | 1976 | 2 | 1978 | 99.90% (1976/1978) |
| Total | 2311 | 22 | 2333 | 99.06% (2311/2333) |
10.9 Traceability
The assay standardization for the ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM assays is based on agreement with known Zika positive samples. Assigned values of calibrators and controls are traceable to this standardization.
10.10 Stability
The onboard stability of the ADVIA Centaur ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM reagents on ADVIA Centaur XP and ADVIA Centaur XPT systems is 28 days with a calibration interval of 14 days.
The onboard stability of the ADVIA Centaur ADVIA Centaur Zika Ab and ADVIA Centaur Zika IgM calibrators and controls on ADVIA Centaur XP and ADVIA Centaur XPT systems is 8 hours.
The open vial stability of the ADVIA Centaur ADVIA Centaur Zika Ab and ADVIA Centaur Zika IqM calibrators and controls is 60 days.
The reagents, calibrators and controls are stable until the date printed on the box label when stored at 2-8°C.
Conclusions 11.
The ADVIA Centaur Zika test is substantially equivalent in principle and performance to the currently-marketed predicate device, the ZIKV Detect 2.0 IgM Capture ELISA, granted De Novo classification under DEN180069.
§ 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