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510(k) Data Aggregation
(88 days)
The NOVEOS Specific IgE Assay is an in vitro quantitative assay for the measurement of allergen specific IgE in human serum. NOVEOS Specific IgE Assay is to be used with the NOVEOS Immunoassay Analyzer. It is intended for use as an in vitro diagnostic aid in the clinical diagnosis of IgE mediated allergic disorders in conjunction with other clinical findings and is to be used in clinical laboratories.
The NOVEOS Specific IgE Assay is an immunometric, chemilyminescent procedure for the quantitative determination of IgE of known specificity in human serum samples. It employs fluorescent labelled magnetic, streptavidin coated microparticles which are incubated with a biotinylated allergenic capture reagent, patient sample and monoclonal anti-human IgE antibody: horseradish peroxidase conjugate. After a final wash, the resulting complex is incubated with the enzyme substrate and a chemiluminescent signal is generated, the magnitude of which is proportional to the concentration of IgE in the patient sample. The concentration of allergen-specific IgE is determined from a standard curve, which is traceable to the World Health Organization (WHO) reference reagent serum Immunoglobulin E (IqE) 11/234.
This document describes the validation of the NOVEOS Specific IgE (sIgE) assays for Cat Dander (E001, Felis domesticus) and Timothy Grass (G006, Phleum pratense). This is a quantitative in vitro diagnostic device, not an AI/ML powered device. Therefore, many of the typical acceptance criteria for AI models, such as MRMC studies, ground truth establishment by experts, and training set details, are not applicable.
The acceptance criteria for this device are based on its analytical and clinical performance when compared to a legally marketed predicate device (ImmunoCAP Specific IgE Assay) and clinical diagnosis.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally implied by the performance metrics reported and the statistical analysis acceptable for FDA clearance of an in vitro diagnostic device of this type. The key performance indicators for a quantitative assay would typically include linearity, precision (imprecision/reproducibility), agreement with a predicate device, and clinical concordance (sensitivity and specificity).
Performance Table for NOVEOS Specific IgE (sIgE) Assays
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (E001 - Cat Dander) | Reported Device Performance (G006 - Timothy Grass) |
|---|---|---|---|
| Agreement with Predicate | To demonstrate substantial equivalence, percentages should be high (e.g., >90% for PPA and >95% for NPA, or similar ranges). Precision of CI is also important. | PPA: 91.8% (95% CI: 84.6% – 95.8%)NPA: 99.3% (95% CI: 96.1% to 99.9%)(Cut-off: 0.35 kU/L) | PPA: 86.4% (95% CI: 78.5% to 91.7%)NPA: 98.5% (95% CI: 94.6% to 99.6%)(Cut-off: 0.35 kU/L) |
| Clinical Performance | Clinical sensitivity and specificity should demonstrate adequate diagnostic accuracy. Typical acceptance ranges for IVDs might be >70-80% for sensitivity and >90% for specificity, depending on the clinical context. | Sensitivity: 75.7% (95% CI 64.5% to 84.2%)Specificity: 100% (95% CI 97.1% to 100%) | Sensitivity: 76.2% (95% CI 64.4% to 85.0%)Specificity: 99.2% (95% CI 95.6% to 99.9%) |
| Imprecision/Reproducibility | Total CV% should generally be low, typically <10% to 15% across relevant concentrations and study phases (within-run, between-run, between-day, lot-to-lot, site-to-site). Specific ranges depend on the analyte and assay. | Total CV% ranges from 7.0-10.5% (E001, within-lab imprecision)Lot-to-lot CV% ranges from 7.6-9.5%Site-to-site reproducibility CV% ranges from 5.2-13.9% (upper bounds for low concentration samples) | Total CV% ranges from 5.0-11.1% (G006, within-lab imprecision)Lot-to-lot CV% ranges from 5.2-11.2%Site-to-site reproducibility CV% ranges from 6.0-11.1% (upper bounds for low concentration samples) |
| Linearity | R2 value close to 1.0 (e.g., >0.99) and slope close to 1.0 with intercept close to 0, within the claimed measuring interval. | R2: 0.999Slope: 1.00 (95% CI: 0.98 to 1.01)Intercept: -0.37 (95% CI: -0.79 to -0.05)Range: 0.03 - 101.62 kU/L | R2: 0.997Slope: 1.02 (95% CI: 0.99 to 1.05)Intercept: 0.58 (95% CI: -0.36 to 1.51)Range: 0.06 - 104.99 kU/L |
| Detection Limit | LoQ (Limit of Quantitation) should be defined and acceptable for clinical use, typically 0.14 kU/L for specific IgE assays to distinguish very low positive from negative (this is often the action limit for clinical use). LoB and LoD values should be reported. | LoB: 0.02 kU/LLoD: 0.06 kU/LLoQ: 0.14 kU/L | LoB: 0.03 kU/LLoD: 0.06 kU/LLoQ: 0.14 kU/L |
| Interference/Cross-Reactivity | Interference from common endogenous/exogenous substances and cross-reactivity with other related/unrelated allergens or immunoglobulins should be demonstrated to be minimal (e.g., <=15% interference). | Less than or equal to 15% interference for listed substances.Non-detectable cross-reactivity with other human immunoglobulins.<=15% inhibition for related/unrelated allergens. | Less than or equal to 15% interference for listed substances.Non-detectable cross-reactivity with other human immunoglobulins.<=15% inhibition for related/unrelated allergens. |
| Reference Range (Expected Values) | The device should align with established clinical cut-off values (e.g., <0.35 kU/L for negative) and support the verification of expected values in a normal population. | 132 healthy subjects tested <0.35 kU/L (all). | 127 healthy subjects tested <0.35 kU/L (all). |
| Stability | Shelf-life and on-board stability should be demonstrated to support the claimed storage and use conditions. | Shelf-life: 18-48 months (accelerated data). Real-time ongoing, currently supports 16 months.On-board: 48 hours to 28 days depending on component. | Shelf-life: 18-48 months (accelerated data). Real-time ongoing, currently supports 16 months.On-board: 48 hours to 28 days depending on component. |
2. Sample Sizes Used for the Test Set and Data Provenance
The document describes several test sets for different performance evaluations.
- Agreement with Predicate Device (Comparative Study):
- E001: 242 clinical samples.
- G006: 238 clinical samples.
- Data Provenance: The document does not explicitly state the country of origin. It refers to "clinical samples" and "patient samples" without further geographical details. The studies are assumed to be retrospective as they involve collecting and testing existing clinical samples.
- Clinical Performance Study:
- E001: 200 samples (70 samples with allergic status confirmed by skin-prick testing and clinical history, and 130 samples from healthy, non-atopic donors with no reported allergy).
- G006: 188 samples (63 samples with allergic status confirmed by skin-prick testing and clinical history, and 125 samples from healthy, non-atopic donors with no reported allergy).
- Data Provenance: Similar to the predicate comparison, the country of origin is not specified, and the studies appear to be retrospective.
- Reference Range Verification:
- E001: 132 apparently healthy subjects.
- G006: 127 apparently healthy subjects.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts
For this type of in vitro diagnostic device, "experts" in the context of AI models (e.g., radiologists interpreting images) are not directly applicable.
- For Agreement with Predicate: The ground truth is the result obtained from the predicate device (ImmunoCAP Specific IgE Assay), which is a previously FDA-cleared and legally marketed device.
- For Clinical Performance: The ground truth for the clinical study was established by "skin-prick testing and clinical history". This implies that clinical professionals (e.g., allergists, physicians) made the diagnosis of "allergic status" or "non-atopic" based on standard medical procedures and patient history, rather than experts reviewing data specifically for the study.
The number and qualifications of these clinical professionals are not specified in the document, as it's a standard clinical diagnostic process rather than a specific panel of experts assembled for ground truth annotation.
4. Adjudication Method for the Test Set
Adjudication methods like 2+1 or 3+1 are typically used for subjective assessments (e.g., image interpretation by multiple human readers). For this quantitative in vitro diagnostic device:
- For Agreement with Predicate: There is no specific "adjudication" in the sense of reconciling differing expert opinions. The comparison is directly between the quantitative results of the new device and the predicate device.
- For Clinical Performance: The "allergic status" or "non-atopic" ground truth was established by clinical diagnosis (skin-prick testing and clinical history). While clinical diagnosis often involves physician judgment, the document does not describe a formal multi-reader adjudication process; it refers to the standard clinical standard of care.
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, an MRMC comparative effectiveness study was not done. This is an in vitro diagnostic assay (a laboratory test) that measures a biomarker (specific IgE) in human serum. It is not an AI-powered image analysis device or a device that directly assists human readers in interpreting complex visual data. Therefore, the concept of human readers improving with AI assistance is not applicable.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the primary performance evaluation of this device is standalone. The NOVEOS Specific IgE assay is an automated in vitro diagnostic test performed on the NOVEOS Immunoassay Analyzer. Its performance (quantitative measurement of IgE) is assessed directly through analytical studies (linearity, imprecision, detection limits, interference, cross-reactivity) and comparison to a predicate device/clinical diagnosis, without human intervention in the measurement process itself. The result is a quantitative value used by clinicians in conjunction with other findings.
7. The Type of Ground Truth Used
- For Agreement with Predicate: The ground truth was based on the results obtained from the legally marketed predicate device (ImmunoCAP Specific IgE Assay). This is a common approach for establishing substantial equivalence for new IVD assays.
- For Clinical Performance: The ground truth for allergic status was established by clinical diagnosis, specifically "skin-prick testing and clinical history." This is considered an objective clinical standard for diagnosing allergic disorders.
8. The Sample Size for the Training Set
This document describes the validation of an immunoassay, not an AI/ML model that requires "training sets" in the conventional sense. The device is a chemical/biological assay system. Therefore, there is no "training set" in the context of machine learning.
The studies described are for validation/testing of the already developed assay.
9. How the Ground Truth for the Training Set Was Established
As stated above, there is no "training set" for an AI/ML model for this type of device. The assay's "performance characteristics" (e.g., reagent formulations, assay parameters) would have been optimized during the device development phase, which is an engineering/chemistry process, not an AI model training process that uses labeled ground truth data.
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