(93 days)
The DPP Zika IgM System is intended for the presumptive qualitative detection of Zika virus IgM antibodies in human serum (plain or separation gel), potassium-EDTA plasma, potassium-EDTA venous whole blood, or fingerstick whole blood specimens, collected from individuals meeting the 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 should not be collected prior to 8 days after symptom onset or after potential exposure as a sample collected earlier may return a negative result. If testing is needed after day 8 and results are negative, testing must be repeated one week later. 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 results. Zika IgM levels over the course of illness are not well characterized. Zika IgM levels are variable during the course of 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 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.
The Chembio DPP Zika IgM System is not indicated for testing blood or plasma donors.
The test cannot be visually interpreted by the operator and must be read on the DPP Micro Reader.
DPP Zika IgM System Control Pack
The Chembio DPP Zika IgM System Control Pack is an external quality control kit for use with the DPP Zika IgM System only. The performance characteristics of the DPP Zika IgM System Control Pack have not been established for any other assay or instrument different from the DPP Micro Reader.
DPP Micro Reader
The DPP Micro Reader is a reflectance reader used to obtain test results from DPP Zika IgM System. The DPP Micro Reader is necessary to minimize errors from direct visual interpretation; the results of DPP Zika IgM System cartridges must be read exclusively with the DPP Micro Reader.
Chembio' s DPP Zika IgM System is a qualitative immunochromatographic assay for the presumptive detection of IgM antibodies to Zika virus. The DPP Zika IgM System is composed of:
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A single-use immunochromatographic test for the presumptive detection of ZIK V 1. IgM antibodies in human serum (plain or separation gel), potassium-EDTA plasma, potassium-EDTA venous whole blood, or fingerstick whole blood specimens.
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- The DPP Micro Reader to minimize errors from direct visual interpretation.
The document describes the Chembio DPP Zika IgM System, DPP Zika IgM System Control Pack, and DPP Micro Reader. The system is intended for the presumptive qualitative detection of Zika virus IgM antibodies in human serum, plasma, and whole blood specimens.
Here's a breakdown of the acceptance criteria and study details:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for the DPP Zika IgM System are primarily demonstrated through its Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a predicate EUA or FDA-cleared comparator assay, across various sample types. Analytical performance (precision, cross-reactivity, interference, analytical sensitivity, and stability) also forms part of the acceptance.
| Performance Metric | Acceptance Criteria (Implied by achieved performance) | Reported Device Performance | Comments |
|---|---|---|---|
| Positive Percent Agreement (PPA) | |||
| Serum (Overall) | N/A (Achieved PPA above 95%) | 95.1% (39/41; 95% CI=83.9-98.7%) | Compared to EUA comparator assay. Note: A high percentage of false positive results was observed against the comparator, largely contributed to by the source of the samples, but this metric is for samples expected to be positive. |
| Potassium-EDTA Plasma (Manufacturer Study) | N/A (Achieved PPA 100% for most relevant days post-onset) | 100.0% (288/288) (95% CI 98.7-100.0%) for Days 8-84 post-onset of symptoms. | Data for 0-7 days post-onset excluded from overall PPA due to anticipated false negatives. |
| Potassium-EDTA Plasma (External Sites) | N/A (Achieved PPA 100%) | 100.0% (171/171) (97.8-100.0%) for Days 8-84 post-onset of symptoms. | |
| Potassium-EDTA Venous Whole Blood (Combined Studies) | N/A (Achieved PPA above 92%) | 92.4% (194/210) (88-95.3%) for Days 8-84 post-onset of symptoms. | Note: Data for 0-7 days post-onset excluded. |
| Potassium-EDTA Venous Whole Blood (Contrived) | N/A (Achieved PPA above 99%) | Low Reactive: 99.1% (115/116); Moderate Reactive: 100% (63/63). Combined PPA: 99.4% (178/179) (95% CI 96.9-100%). | Compared against expected results based on spiking level. |
| Fingerstick Whole Blood (Contrived) | N/A (Achieved PPA above 98%) | Low Reactive: 98.0% (146/149); Moderate Reactive: 100.0% (88/88). Combined PPA: 98.7% (234/237) (95% CI 96.4-99.6%). | Compared against predetermined reactivity of spiked sample vials. |
| FDA Plasma Zika Panel (Zika IgM Consensus Positive) | N/A (Achieved PPA 95.8%) | 95.8% (23/24) | PPA for Zika IgM Consensus Positive samples. |
| Negative Percent Agreement (NPA) | |||
| Serum (Endemic Area) | N/A (Achieved NPA above 94%) | 95.7% (202/211) (95%CI 92.1-97.7) | By comparison with both FDA Cleared and EUA tests. |
| Potassium-EDTA Plasma (Endemic Area) | N/A (Achieved NPA above 93%) | 93.8% (198/211) (95%CI 89.8-96.4) | By comparison with both FDA Cleared and EUA tests. |
| Potassium-EDTA Venous Whole Blood (Endemic Area) | N/A (Achieved NPA above 94%) | 94.8% (200/211) (95%CI 90.9-97.1) | By comparison with both FDA Cleared and EUA tests. |
| Capillary Whole Blood (Endemic Area) | N/A (Achieved NPA above 97%) | 97.2% (205/211) (95%CI 93.9-98.7) | By comparison with both FDA Cleared and EUA tests. |
| Serum (Non-Endemic Area) | N/A (Achieved NPA above 98%) | 98.2% (220/224) (95%CI 95.5-99.3) | By comparison with both FDA Cleared and EUA tests. |
| Potassium-EDTA Plasma (Non-Endemic Area) | N/A (Achieved NPA above 97%) | 97.8% (219/224) (95%CI 94.9-99.0) | By comparison with both FDA Cleared and EUA tests. |
| Potassium-EDTA Venous Whole Blood (Non-Endemic Area) | N/A (Achieved NPA above 97%) | 97.3% (218/224) (95%CI 94.3-98.8) | By comparison with both FDA Cleared and EUA tests. |
| Capillary Whole Blood (Non-Endemic Area) | N/A (Achieved NPA above 98%) | 98.7% (221/224) (95%CI 96.1-99.5) | By comparison with both FDA Cleared and EUA tests. |
| FDA Plasma Zika Panel (Zika IgM Consensus Negative) | N/A (Achieved NPA 91.7%) | 91.7% (11/12) | NPA for Zika IgM Consensus Negative samples. |
| Cross-Reactivity | N/A (Evaluated cross-reactivity) | Cytomegalovirus: 5.3%; Dengue Virus: 2.0% | Other tested organisms/conditions (Chikungunya, West Nile, Yellow fever, Malaria, Borrelia, EBV, Hepatitis B/C, HSV-1/2, Leptospira, ANA, Parvovirus B19, Rubella, Rheumatoid Factor, Varicella zoster, HAMA) showed 0% cross-reactivity. |
| Interference | No interference observed | No interference observed for tested substances (Hemoglobin, Bilirubin, Proteins, HAMA, Cholesterol, Rheumatoid Factor, Triglycerides). | |
| Analytical Sensitivity | N/A (Established cut-off values) | Serum: 650 IU/mL; Potassium-EDTA plasma: 700 IU/mL; Potassium-EDTA venous whole blood: 725 IU/mL | Based on WHO 1st International standard for anti-Asian lineage Zika virus antibody (human) (NIBSC 16/352). |
| Precision/Reproducibility | Coefficients of Variation (CV) provided for different components of variability. | Total CV: Moderate Positive (13.7%), Low Positive (19.0%), High Negative (24.5%), Negative (N/A) | For the DPP Zika IgM System. |
| DPP Zika IgM Control Kit Precision | Coefficients of Variation (CV) provided. | Total CV: Moderate Positive Control (17.9%), Low Positive Control (22.7%), Negative Control (N/A) | |
| Assay Cut-off | Established at a specific reader value. | 20 (when analyzed by the DPP Micro Reader) | Based on evaluation using CLSI EP17-A2. |
2. Sample Size Used for the Test Set and Data Provenance
- Serum:
- Positive Predictive Agreement:
- 99 samples from symptomatic individuals in Peru (retrospective).
- 11 samples from individuals in the Dominican Republic (retrospective).
- 32 samples from 26 individuals in Brazil during arbovirus outbreaks (retrospective).
- FDA Plasma Zika Panel: 24 Zika IgM positive, 12 negative.
- Negative Predictive Agreement (Endemic Area): 250 subjects from a Zika endemic area (prospectively collected).
- Negative Predictive Agreement (Non-Endemic Area): 250 subjects from a Zika non-endemic area (prospectively collected).
- Positive Predictive Agreement:
- Potassium-EDTA Plasma:
- Positive Predictive Agreement (Manufacturer Study): 299 IgM antibody samples from 48 individuals (from 50 symptomatic subjects) in the Dominican Republic (archived, confirmed by NAT). Includes 12 pregnant women.
- Positive Predictive Agreement (External Sites): 171 comparator positive IgM antibody samples from 39 individuals in the Dominican Republic (archived). Also, 49 prospectively collected asymptomatic pregnant women from the continental United States (negative by comparator assay) were interspersed.
- Negative Predictive Agreement (Endemic Area): 250 subjects from a Zika endemic area (prospectively collected).
- Negative Predictive Agreement (Non-Endemic Area): 250 subjects from a Zika non-endemic area (prospectively collected).
- Potassium-EDTA Venous Whole Blood:
- Positive Predictive Agreement (Internal/External Sites): 41 plasma samples (from a plasma replacement study) from 6 individuals in the Dominican Republic; 10 frozen natural whole blood samples from individuals in the Dominican Republic; 171 antibody positive plasma specimens (from plasma replacement study) plus 49 antibody negative specimens from asymptomatic pregnant women from the US.
- Positive Predictive Agreement (Contrived): 299 subjects for analysis (from 300 "all comers" at 3 US clinics); samples were contrived by potassium-EDTA plasma replacement.
- Negative Predictive Agreement (Endemic Area): 250 subjects from a Zika endemic area (prospectively collected).
- Negative Predictive Agreement (Non-Endemic Area): 250 subjects from a Zika non-endemic area (prospectively collected).
- Fingerstick Whole Blood:
- Positive Predictive Agreement (Contrived): 372 subjects for analysis (from 375 adult subjects across 4 US near-patient sites, "all comers" basis); samples were pre-spiked to create contrived samples.
- Negative Predictive Agreement (Endemic Area): 250 subjects from a Zika endemic area (prospectively collected).
- Negative Predictive Agreement (Non-Endemic Area): 250 subjects from a Zika non-endemic area (prospectively collected).
- Cross-Reactivity: 329 specimens for various organisms/conditions.
- Interference: Low reactive (n=3) and normal human plasma samples (n=3) for each interfering substance.
- Analytical Sensitivity: Dilution series of WHO 1st International standard.
- Assay Cut-off: 569 natural serum samples (US, Mexico); 184 natural plasma samples (US, Peru); 215 natural venous whole blood samples (US); 102 natural capillary whole blood samples (US).
- Precision/Reproducibility: A blinded panel of four plasma samples (negative, high negative, low positive, moderate positive) tested with 3 lots of the system.
- DPP Zika IgM Control Kit Precision: Moderate positive, low positive, and negative control samples.
Data Provenance: Studies include samples from Peru, Dominican Republic, Brazil, and the United States. Many samples are retrospective (archived, historical data), while some are prospectively collected (e.g., negative predictive agreement studies).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not explicitly state the "number of experts" or their specific "qualifications" used to establish ground truth in the traditional sense of multiple human readers independently adjudicating images/cases.
Instead, the ground truth for clinical performance studies (PPA and NPA) was established by:
- Comparison with an EUA (Emergency Use Authorization) or FDA-cleared comparator assay.
- In some cases, samples were confirmed positive by RT-PCR assay for Zika virus (e.g., Peruvian and Brazilian serum samples).
- Consensus results were provided for the FDA Plasma Zika Panel, and these are stated to be the responsibility of the FDA.
- For contrived samples (venous whole blood, fingerstick whole blood), the "ground truth" was based on expected results from spiking with known positive or negative material, corroborated by comparator testing.
4. Adjudication Method for the Test Set
The primary method for "adjudication" (or reference standard determination) appears to be comparison with another laboratory assay (EUA or FDA-cleared comparator assay). For Negative Percent Agreement, results were compared against an FDA Cleared Comparator and an Additional EUA Test, and "Both FDA Cleared and EUA tests" where results from both were in agreement. There is no mention of a traditional expert consensus or adjudication panel (e.g., 2+1, 3+1) for clinical performance in this document.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The study focuses on the standalone performance of the DPP Zika IgM System against reference methods/comparator assays, not on how human readers improve with or without AI assistance. The DPP Micro Reader is an integral part of the device, reading results from the immunochromatographic assay, and is not an AI tool assisting human interpretation. The document explicitly states the test "cannot be visually interpreted by the operator and must be read on the DPP Micro Reader," meaning it's not a human-in-the-loop scenario.
6. If a Standalone Study Was Done
Yes, a standalone study was done. The document provides extensive data on the performance of the DPP Zika IgM System (algorithm only, as it's an automated reader) in detecting Zika virus IgM antibodies across various sample types and clinical scenarios, independently compared to established reference standards (comparator assays, RT-PCR, or expected reactivity from spiked samples).
7. The Type of Ground Truth Used
The ground truth used various forms:
- Comparator Assay Results: Results from an EUA or FDA-cleared Zika IgM comparator assay.
- RT-PCR Confirmation: For some positive samples, PCR confirmation for Zika virus was used.
- Consensus Data: For the FDA Plasma Zika Panel, consensus results were utilized.
- Expected Reactivity from Spiked Samples: For contrived samples (venous whole blood, fingerstick whole blood), the ground truth was based on the known positive or negative status of the spiked material.
8. The Sample Size for the Training Set
The document does not explicitly specify a "training set" in the context of machine learning. The DPP Micro Reader and assay are likely developed based on extensive R&D and optimization, but the provided performance data relates to validation studies, not an explicit training set for a distinct AI model. The product is an in-vitro diagnostic device that produces quantitative results read by a device, not a machine learning algorithm requiring a separate training dataset in the typical sense.
9. How the Ground Truth for the Training Set Was Established
Since an explicit "training set" for a machine learning model is not described, the method for establishing its ground truth is not applicable or detailed in this document. The development of the assay and the Micro Reader's algorithm would have involved internal validation and optimization using various samples, but these are part of product development rather than a defined, separate "training set" for regulatory evaluation in the context of this 510(k) summary.
§ 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