(280 days)
The VIDAS® RUB IgG (RBG) assay uses Enzyme Linked Fluorescent Assay (ELFA) technology on the VIDAS® automated instruments for the in vitro quantitative and qualitative measurement of IgG antibodies to rubella virus in human serum. The VIDAS® RUB IgG assay is intended as an aid in the determination of immune status to rubella. The performance of this device has not been established for screening of cord blood, or for neonatal samples. Likewise, performance characteristics of the assay have not been established for immunocompromised or immunosuppressed individuals.
The assay principle combines a 2-step enzyme immunoassay sandwich method with a final fluorescent detection (ELFA). The Solid Phase Receptacle (SPR®) serves as the solid phase as well as the pipetting device for the assay. It is coated with Rubella antigen. The other reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips. The individual kit components are described in detail on the following pages.
All of the assay steps are performed automatically by the instrument. The reaction medium is cycled in and out of the SPR several times. This operation enables the Rubella antigen fixed onto the interior wall of the SPR to capture the Rubella antibodies present in the sample. After dilution, the sample is incubated with the SPR. Rubella IgG antibodies present in the specimen bind to the Rubella antigen coating the interior of the SPR. Unbound components are eliminated during the preliminary wash step.
A second incubation step is then performed using alkaline phosphatase labeled monoclonal anti-human IgG antibodies (mouse), followed by a second wash step.
During the final detection step, the substrate (4-Methyl-umbellifery) phosphate) is cycled in and out of the SPR. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone), the fluorescence of which is measured at 450 nm.
The intensity of the fluorescence is proportional to the concentration of antibodies present in the sample. At the end of the assay, results are automatically calculated by the instrument in relation to the calibration curve stored in memory, and then printed out.
This submission describes the VIDAS® RUB IgG Assay, an in vitro diagnostic device for the quantitative and qualitative measurement of IgG antibodies to rubella virus in human serum, intended as an aid in determining immune status to rubella. The study presented aims to demonstrate substantial equivalence to the predicate device, the Abbott's AxSYM Rubella IgG Antibody Assay.
Here's an analysis of the acceptance criteria and study detailed in the provided documentation:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria (e.g., minimum percentage agreement for positive or negative results). Instead, it presents the performance data and implies that these results are considered acceptable for demonstrating substantial equivalence to the predicate device.
For the purpose of this analysis, we will infer the "reported device performance" directly from the clinical performance tables provided. The study compares the VIDAS® RUB IgG assay's results against a "2/3 Consensus" method, which serves as the ground truth.
| Performance Metric | Acceptance Criteria (Inferred Best Case) | Reported Device Performance (Worst Case CI Lower Bound) |
|---|---|---|
| Prospective Pregnant Women | ||
| Positive Agreement | As high as possible (e.g., >95%) | 94.3% (Lower 95% CI for Positive Agreement) |
| Negative Agreement | As high as possible (e.g., >95%) | 9.4% (Lower 95% CI for Negative Agreement) |
| Prospective General Population | ||
| Positive Agreement | As high as possible (e.g., >95%) | 93.5% (Lower 95% CI for Positive Agreement) |
| Negative Agreement | As high as possible (e.g., >95%) | 9.4% (Lower 95% CI for Negative Agreement) |
| Retrospective Pregnant Women | ||
| Positive Agreement | As high as possible (e.g., >95%) | 88.1% (Lower 95% CI for Positive Agreement) |
| Negative Agreement | As high as possible (e.g., >95%) | 29.2% (Lower 95% CI for Negative Agreement) |
| Retrospective General Population | ||
| Positive Agreement | As high as possible (e.g., >95%) | 87.5% (Lower 95% CI for Positive Agreement) |
| Negative Agreement | As high as possible (e.g., >95%) | 96.5% (Lower 95% CI for Negative Agreement) |
| Pre-selected Pregnant Women | ||
| Positive Agreement | As high as possible (e.9., >95%) | 74.0% (Lower 95% CI for Positive Agreement) |
| Negative Agreement | As high as possible (e.9., >95%) | 96.4% (Lower 95% CI for Negative Agreement) |
Note: The wide confidence intervals for negative agreement, especially in prospective populations and retrospective pregnant women, suggest small sample sizes for negative cases in those cohorts. The "Worst Case CI Lower Bound" is used as a conservative measure, as the actual point estimate for agreement is higher in most cases.
2. Sample Sizes and Data Provenance
The study utilized a combination of prospective and retrospective samples from various populations.
- Prospective Pregnant Women: 325 samples
- Prospective General Population: 179 samples (1 sample was QNS and excluded from analysis)
- Retrospective Pregnant Women: 200 samples
- Retrospective General Population: 291 samples (5 samples were QNS and excluded from analysis)
- Pre-selected Pregnant Women Population: 127 samples (2 samples were QNS and excluded from analysis)
Data Provenance: The document does not explicitly state the country of origin for the data. Given the submitter's address in Hazelwood, MO, USA, and the FDA's regulatory context, it is highly probable that the studies were conducted in the United States or followed U.S. regulatory guidelines for data collection. The data included both retrospective and prospective samples.
3. Number of Experts and Qualifications for Ground Truth
The document states that the ground truth for the clinical performance evaluation was established using a "2/3 Consensus" method. This implies that at least three reference methods or expert readers were used, and the final classification (Positive, Equivocal, or Negative) was based on agreement from at least two out of three.
Qualifications of Experts: The document does not explicitly state the qualifications of the "experts" or the nature of the "reference methods" used to form the consensus. Typically, for serological assays, this consensus would involve results from established reference assays or expert interpretation of multiple existing test results, rather than human "readers" in the context of imaging.
4. Adjudication Method
The adjudication method used for establishing the ground truth for the test set was a "2/3 Consensus". This means that for a sample to be classified as Positive, Equivocal, or Negative, at least two out of three independent comparators (presumably other rubella IgG assays or a panel with known status) had to agree on that classification.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not explicitly mentioned or presented in the provided text. This type of study typically involves human readers (e.g., radiologists, pathologists) interpreting medical images or data, with and without AI assistance, to measure the impact of AI on their performance. The VIDAS® RUB IgG Assay is an automated immunoassay, designed to directly provide quantitative and qualitative results, rather than assisting human interpretation of complex medical cases. Therefore, an MRMC study is not applicable here.
6. Standalone Performance Study
Yes, a standalone performance study was done. The clinical performance data presented (Prospective, Retrospective, and Pre-selected populations) directly reflects the algorithm's (VIDAS® RUB IgG Assay) performance in classifying samples as Positive, Equivocal, or Negative, compared to the established "2/3 Consensus" ground truth. The tables explicitly show the agreement rates of the VIDAS® assay alone against the consensus.
7. Type of Ground Truth Used
The type of ground truth used for the test set was expert consensus, specifically a "2/3 Consensus" method. While the specifics of what constituted this consensus (e.g., comparison to a gold standard assay, multiple predicate assays, or a well-characterized reference panel) are not detailed, it implies an agreement among a minimum of two out of three established methods or experts.
8. Sample Size for the Training Set
The document does not provide information on the sample size used for the training set. Immunoassays like the VIDAS® system are typically developed and optimized through extensive R&D, including reagent formulation, calibration curve development, and internal validation, rather than "training" in the same sense as machine learning algorithms. If any computational models were involved in the assay's development or calibration, the training data for those are not described. The provided data is for the validation or test sets used to demonstrate clinical performance.
9. How the Ground Truth for the Training Set Was Established
As no training set information is provided, the method for establishing its ground truth is also not described. For laboratory assays, "ground truth" during development often comes from well-characterized reference materials, spiked samples, or comparison to established gold standard methods.
§ 866.3510 Rubella virus serological reagents.
(a)
Identification. Rubella virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubella virus in serum. The identification aids in the diagnosis of rubella (German measles) or confirmation of a person's immune status from past infections or immunizations and provides epidemiological information on German measles. Newborns infected in the uterus with rubella virus may be born with multiple congenital defects (rubella syndrome).(b)
Classification. Class II. The special controls for this device are:(1) National Committee for Clinical Laboratory Standards':
(i) 1/LA6 “Detection and Quantitation of Rubella IgG Antibody: Evaluation and Performance Criteria for Multiple Component Test Products, Speciment Handling, and Use of the Test Products in the Clinical Laboratory, October 1997,”
(ii) 1/LA18 “Specifications for Immunological Testing for Infectious Diseases, December 1994,”
(iii) D13 “Agglutination Characteristics, Methodology, Limitations, and Clinical Validation, October 1993,”
(iv) EP5 “Evaluation of Precision Performance of Clinical Chemistry Devices, February 1999,” and
(v) EP10 “Preliminary Evaluation of the Linearity of Quantitive Clinical Laboratory Methods, May 1998,”
(2) Centers for Disease Control's:
(i) Low Titer Rubella Standard,
(ii) Reference Panel of Well Characterized Rubella Sera, and
(3) World Health Organization's International Rubella Standard.