(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.
§ 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