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510(k) Data Aggregation
(88 days)
For the quantitative determination of free protein S antigen in human plasma collected from venous blood samples in 3.2% sodium citrate tubes on the Sysmex® CS-5100 analyzer.
As an aid in the diagnosis of protein S deficiency in patients who are suspected of free protein S deficiency. The performance of this device has not been established in neonate and pediatric patient populations.
The INNOVANCE® Free PS Ag assay is an immunoturbidimetric assay. The reagent kit consists of two components. One component (Reagent) contains polystyrene particles coated with two different monoclonal antibodies both specific for free protein S. This latex reagent aggregates when mixed with samples containing free protein S. The degree of aggregation is directly proportional to the concentration of free protein S in the test sample and is detected turbidimetrically via the increase in turbidity.
The provided document describes the Siemens Healthcare Diagnostics Products GmbH's INNOVANCE Free PS Ag device (K181525) and its performance data in support of its substantial equivalence to a predicate device.
Here's a breakdown of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly present a single table of "acceptance criteria" against which all performance metrics are directly compared. Instead, it discusses various studies with implicit acceptance criteria (e.g., successful verification of LoQ, fulfillment of predetermined criteria for Passing-Bablok regression). I'll compile a table based on what can be inferred for key performance characteristics.
| Performance Metric | Acceptance Criteria (Inferred from study description) | Reported Device Performance |
|---|---|---|
| Measuring Interval (Limit of Quantitation - LoQ) | Lower limit of 10% of norm must be accurately measurable with Total Error ≤ 4.0% of norm. | Successfully verified. Study confirms lower limit of 10% of norm can be accurately measured. |
| Measuring Interval (Linearity) | Maximal deviation from theoretical ideal linearity: ± 3.2% of norm for < 40% of norm, and ± 8.0% relative for ≥ 40 to 150% of norm. | Study supports linearity across the measuring range (10 to 150% of norm). |
| Specificity (Interference) | "No interference up to" indicated concentrations for various endogenous and exogenous substances. | Observed no interference up to the indicated concentrations for a wide range of substances (see detailed list in source text). Minimal interference from heterophile antibodies by added blocking reagent; however, complete elimination cannot be guaranteed. |
| Frozen vs. Fresh Samples (Bridging Study) | Predetermined acceptance criteria for Passing-Bablok regression and predicated bias from medical decision points (MDPs) were fulfilled. | Slope: 0.98, Intercept: 1.50, r: 0.999. Bias at MDPs: Combined 0.65%, Female 0.72%, Male 0.51%. |
| Precision (Single Site) | (Implicit: Acceptable CV values within common laboratory standards) | Within-Run CV: 0.47 - 5.29%, Between-Run CV: 0.00 - 2.09%, Between-Day CV: 0.00 - 1.40%, Total (Within-Site) CV: 0.76 - 5.48%. |
| Precision (Multi-Lot Single Site) | (Implicit: Acceptable CV values within common laboratory standards) | Within-Run CV: 0.54 - 2.63%, Between-Run CV: 0.00 - 1.47%, Between-Day CV: 0.00 - 0.50%, Between-Lot CV: 0.62 - 1.36%, Total (Combined Lots) CV: 1.05 - 2.82%. |
| Reproducibility (Multi-Site, One Lot) | (Implicit: Acceptable CV values within common laboratory standards) | Within-Run CV: 0.72 - 3.74%, Between-Run CV: 0.00 - 1.18%, Between-Day CV: 0.00 - 0.89%, Between-Site CV: 1.24 - 1.89%, Total (Combined Sites) CV: 2.10 - 4.08%. |
| Precision (Internal Site, 3 Analyzer/Operator) | (Implicit: Acceptable CV values within common laboratory standards) | Within-Run CV: 0.79 - 1.69%, Between-Run CV: 0.39 - 1.92%, Between-Day CV: 0.00 - 0.36%, Between-Instrument CV: 0.00 - 4.13%, Total (Combined Instruments) CV: 1.15 - 4.86%. |
| Method Comparison | Results from each application met the predetermined acceptance criteria (for Passing-Bablok regression and Bland-Altman plots). Device should perform comparably to predicate. | Combined Sites (N=350): $y = 0.95x + 4.92$, $r = 0.940$, $r^2 = 0.883$. Individual sites also showed strong correlation. |
2. Sample Size Used for the Test Set and the Data Provenance
The document describes several non-clinical and clinical studies, each with its own sample size and provenance.
- Measuring Interval (LoQ): Five independent low-analyte plasma pools.
- Measuring Interval (Linearity): Not explicitly stated as a number of individual samples, but involved a dilution series prepared from a high pool and a low pool to create 11 different dilutions.
- Specificity (Interference):
- Dose-response experiments: Used samples prepared with native plasma. Specific number of samples not given for each interferent.
- Paired-difference experiments: Used individual native samples with and without interferent. Panel of exogenous substances.
- Reference Interval: 300 ostensibly healthy subjects (149 males, 151 females). Provenance: Three clinical study sites in the United States. Prospective/Retrospective: The guidance followed (CLSI EP28-A3c) suggests a prospective collection for establishing reference intervals.
- Frozen versus Fresh Samples (Bridging Study): A minimum of 60 fresh individual plasma samples. Provenance: One external site in Germany. Prospective/Retrospective: Seems prospective for the sample collection and immediate testing, followed by freezing and re-testing.
- Precision / Reproducibility:
- Three plasma pools (Low, MDL, High) and two control materials (Control Plasma N, Control Plasma P).
- External Reproducibility (multi-site): Used these plasma pools/controls. Overall study involved 20 days, 2 runs/day, 2 replicates/run. Provenance: Two study sites in the U.S. (Site 1, Site 2) and one study site in Germany (Site 3).
- Internal Precision: Same plasma pools/controls. 5 days, 2 runs/day, 4 replicates/run. Provenance: Siemens company site in Germany (Site 4).
- Method Comparison: Total N = 350 patient samples.
- Distribution: 304 samples with clinical demand for protein S testing (137 suspected thrombophilia, 1 congenital protein S deficiency, 166 other reasons), 31 samples from patients with congenital Protein S deficiency (from commercial vendor), and 15 samples without clinical demand for Protein S testing.
- Provenance: Three external sites in the United States.
- Prospective/Retrospective: Used "fresh and frozen samples from patients ≥ 18 years of age," implying a mix or at least collection over time. The nature of "samples with clinical demand" and "samples from commercial vendor" suggests a mix, likely retrospective within patient cohorts or collected specifically for the study.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
The document does not describe the use of "experts" to establish ground truth for the test set in the traditional sense of medical image or diagnostic interpretation. The device is an in-vitro diagnostic (IVD) for quantitative measurement of free protein S antigen. The "ground truth" for these types of devices is based on established laboratory methods, reference materials, or clinical diagnosis.
For the Method Comparison study, the predicate device (STA-Liatest Free Protein S) served as the comparator, with its results being the benchmark. The reference interval study established normal ranges based on testing ostensibly healthy subjects, not expert consensus on individual cases.
4. Adjudication Method for the Test Set
Not applicable. This is an IVD device for quantitative measurement, not a diagnostic imaging or clinical decision-making algorithm that typically involves adjudication of expert interpretations for ground truth. The "adjudication" is inherent in the laboratory testing and statistical analysis methods (e.g., CLSI guidelines).
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
Not applicable. This is an IVD device for quantifiable laboratory measurements and does not involve "human readers" or AI assistance in the interpretation of complex data (like medical images) that would require an MRMC study.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) Was Done
Yes. All presented performance studies (Measuring Interval, Specificity, Frozen vs. Fresh Samples, Precision/Reproducibility, Method Comparison) represent the standalone performance of the INNOVANCE Free PS Ag assay on the Sysmex CS-5100 analyzer. The device provides a quantitative measurement, and its output is then interpreted by clinicians, but the device's performance itself is evaluated in isolation.
7. The Type of Ground Truth Used
The type of "ground truth" varies by study:
- Measuring Interval (LoQ & Linearity): Established by demonstrating accurate measurement across known concentrations (dilutions or spiked samples).
- Specificity (Interference): Lack of interference at known concentrations of interfering substances.
- Reference Interval: Determined by measuring ostensibly healthy subjects and calculating statistical percentiles (2.5th – 97.5th percentile).
- Frozen versus Fresh Samples (Bridging Study): Comparison against results from the same samples tested fresh, serving as the immediate "truth."
- Precision / Reproducibility: Intrinsic variability of the assay measured by statistical methods like Coefficient of Variation (CV).
- Method Comparison: The results obtained from the legally marketed predicate device (STA-Liatest Free Protein S) served as the comparative "truth" or reference standard to establish substantial equivalence.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" sample size. For IVD devices, a "training set" typically refers to the samples used during the development and optimization of the assay itself. This document focuses on the validation and verification of the finalized device's performance. The studies detailed are performance evaluations, not descriptions of the assay's developmental phase.
9. How the Ground Truth for the Training Set Was Established
As mentioned above, a "training set" is not explicitly defined or detailed in this submission. For an IVD like this, the "ground truth" during development would be established through a combination of:
- Reference materials: Known concentrations of free protein S.
- Clinical samples: Samples from patients with known protein S levels or deficiencies (diagnosed through other means, e.g., clinical presentation, other laboratory tests).
- Pathology/Biochemistry: Using established gold-standard biochemical assays or methods to determine free protein S concentrations in development samples.
The document implicitly relies on the established understanding of protein S biology and its measurement principles for its development and the subsequent performance validation against a predicate device.
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