(205 days)
The ADVIA Centaur® Follicle Stimulating Hormone (FSH) Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur FSH assay.
The ADVIA Centaur® Free thyroxine (FT4) Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur FT4 assay.
The ADVIA Centaur® Thyroxine (T4) Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur T4 assay.
The ADVIA Centaur® Triiodothyronine (T3) Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur T3 assay.
ADVIA Centaur® FSH Master Curve Material is an in vitro diagnostic product containing various levels of follicle stimulating hormone spiked in lyophilized equine serum with sodium azide (0.1% after reconstitution) and preservatives. Each set contains eight levels (MCM1–8); with a reconstituted volume of 1.0 mL/vial per level. MCM1contains no analyte. The MCMs assigned values are lot-specific of target values: 0.00, 1.50, 4.50, 12.0, 30.0, 62.5, 130, 225 mIU/mL.
ADVIA Centaur® FT4 Master Curve Material is an in vitro diagnostic product containing various levels of thyroxine in human plasma with sodium azide. Each set contains seven levels; with a reconstituted volume of 1.0 mL/vial per level. MCM1 contains no analyte. The FT4 MCMs assigned values are lot-specific of target values: 0.00, 2.00, 5.00, 10.0, 15.0, 22.0, and 35.0 µg/dL which corresponds to FT4 values of 0.00, 0.42, 0.80, 1.70, 3.0, 5.6, and 13.5 ng/dL.
ADVIA Centaur® T4 Master Curve Material is an in vitro diagnostic product containing various levels of levothyroxine in human plasma with sodium azide and preservatives. Each set contains six levels; with a reconstituted volume of 1.0 mL/vial per level. MCM1 contains no analyte. The T4 MCMs assigned values are lot-specific of target values: 0.00, 2.50, 5.00, 10.0, 15.0. and 35.0 µg/dL.
ADVIA Centaur® T3 Master Curve Material is an in vitro diagnostic product containing various levels of liothyronine in human plasma with sodium azide and preservatives. Each se contains seven levels; with a reconstituted volume of 1.0 mL/vial per level. MCM1 contains no analyte. The T3 MCMs assigned values are lot-specific of target values: 0.00, 0.42, 0.69, 1.11, 1.65, 3.87, and 7.00 ng/mL.
The provided document describes the Siemens Healthcare Diagnostics ADVIA Centaur® Master Curve Materials (MCM) for Follicle Stimulating Hormone (FSH), Free Thyroxine (FT4), Thyroxine (T4), and Triiodothyronine (T3). These devices are quality control materials used for verification of calibration and reportable ranges of their respective ADVIA Centaur assays. The information is presented as a 510(k) Summary, which focuses on demonstrating substantial equivalence to predicate devices, rather than a detailed report of a clinical study for device performance against specific patient outcomes or diagnostic accuracy.
Here's a breakdown of the requested information based on the provided text, with an emphasis on its applicability to in vitro diagnostic quality control materials rather than typical diagnostic imaging AI studies, which often involve human readers and expert consensus.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for these devices are primarily related to stability (shelf-life, open vial, and on-board stability) and value assignment. The reported performance indicates that these criteria were met.
ADVIA Centaur® FSH Master Curve Material
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Stability | ||
| Real Time/Shelf Life (Unopened) | The dose recovery for MCM1 (analyte-free) and the % dose recoveries for MCM2-8 met the sponsor's required acceptance criteria. | Current testing meets acceptance criteria up to the 7 months' time point, supporting a 6-month shelf-life claim (storage unopened at 2-8°C). Real-time studies are ongoing. |
| In-Use Open Vial (Reconstituted) | The dose recovery for MCM1 (analyte-free) and the % dose recoveries for MCM2-8 met the sponsor's required acceptance criteria. | Acceptance criteria for open vial (reconstituted) stability study were met up to the 29 days' time point, supporting an open vial claim of 28 days (when properly stored at 2-8°C). |
| On-Board Stability | The dose recovery for MCM1 (analyte-free) and the % dose recoveries for MCM2-8 met the sponsor's required acceptance criteria. | On-board stability study met acceptance criteria at the 5 hours' time point, supporting an on-board stability claim for 4 hours. |
| Value Assignment | The new MCM doses must fall within the final value assignment specification for FSH MCMs. The mean MCM doses of the new MCM lot manufactured must fall within the customer range specifications. MCM1 must measure at or below the FSH assay sensitivity limit. | The document states MCMs are value assigned using assigned reference calibrators and MCMs, and that MCMs are manufactured using qualified materials and measurement procedures. Performance verification runs (6 replicates per level) are conducted to ensure mean MCM doses fall within customer range specifications. No specific values or a pass/fail statement for a particular lot is provided, but implies acceptance criteria were met as part of the overall substantial equivalence. |
| Expected Values | Lot-specific assigned values and customer ranges are established per sponsor's internal procedural specifications. | Example target values (mIU/mL): MCM1: 0.00, MCM2: 1.50, MCM3: 4.50, MCM4: 12.0, MCM5: 30.0, MCM6: 62.5, MCM7: 130, MCM8: 225. Assay Range: 0.3–200 mIU/mL. |
| Traceability | Standardized against WHO 2nd International Standard for human FSH (IS 94/632). | ADVIA Centaur FSH = 0.91 (WHO) - 0.18 mIU/mL (r = 0.999). Assigned values for calibrators/MCMs are traceable to this standardization. |
ADVIA Centaur® FT4 Master Curve Material
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Stability | ||
| Real Time/Shelf Life (Unopened) | The dose recovery for MCM1 and the % dose recoveries for MCM2-7 met the sponsor's required acceptance criteria. | Acceptance criteria met up to the 7 months' time point, supporting a 6-month shelf-life claim (storage unopened at 2-8°C). Real-time studies are ongoing. |
| In-Use Open Vial (Reconstituted) | The dose recovery for MCM1 and the % dose recoveries for MCM2-7 met the sponsor's required acceptance criteria. | Acceptance criteria met, supporting an open vial claim of 14 days (when properly stored at 2–8°C). |
| On-Board Stability | The dose recovery for MCM1 and the % dose recoveries for MCM2-7 met the sponsor's required acceptance criteria. | Acceptance criteria met up to 5 hours, supporting an on-board stability claim for 4 hours. |
| Value Assignment | The new MCM doses must fall within the final value assignment specification for FT4 MCMs. The mean MCM doses must fall within customer range specifications. MCM1 must measure at or below the FT4 assay sensitivity limit. | MCMs are value assigned using assigned reference calibrators and MCMs. Performance verification run (6 replicates per level) ensures mean MCM doses fall within customer range specifications. A nested testing run protocol is used for MCM2-7 value assignment (20 replicates in total). Implies acceptance criteria were met. |
| Expected Values | Lot-specific assigned values and customer ranges are established per sponsor's internal procedural specifications. | Example target values (ng/dL): MCM1: 0.00, MCM2: 0.42, MCM3: 0.80, MCM4: 1.70, MCM5: 3.0, MCM6: 5.6, MCM7: 13.5. Assay Range: 0.1-12.0 ng/dL. |
| Traceability | Standardized to an internal standard manufactured using USP (United States Pharmacopeia) material. | Assigned values for calibrators and MCMs are traceable to this standardization. |
ADVIA Centaur® T4 Master Curve Material
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Stability | ||
| Real Time/Shelf Life (Unopened) | The dose recovery for MCM1 and the % dose recoveries for MCM2-6 met the sponsor's required acceptance criteria. | Acceptance criteria met up to the 11 months' time point, supporting a 10-month shelf-life claim (storage unopened at 2-8°C). Real-time studies are ongoing. (No information on open vial or on-board stability for T4 MCM in this summary) |
| Value Assignment | The new MCM doses must fall within the final value assignment specification for T4 MCMs. The mean MCM doses must fall within customer range specifications. MCM1 must measure at or below the T4 assay sensitivity limit. | MCMs are value assigned using assigned reference calibrators and MCMs. Performance verification run (6 replicates per level) ensures mean MCM doses fall within customer range specifications. A nested testing run protocol is used for MCM2-6 value assignment (20 replicates in total). MCM6 is diluted 1:4 before testing to meet reportable range. Implies acceptance criteria were met. |
| Expected Values | Lot-specific assigned values and customer ranges are established per sponsor's internal procedural specifications. | Example target values (µg/dL): MCM1: 0.00, MCM2: 2.50, MCM3: 5.00, MCM4: 10.0, MCM5: 15.0, MCM6: 35.0. Assay Range: 0.3–30.0 µg/dL. |
| Traceability | Standardized to an internal standard manufactured using USP (United States Pharmacopeia) material. | Assigned values for calibrators and MCMs are traceable to this standardization. |
ADVIA Centaur® T3 Master Curve Material
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Stability | ||
| Real Time/Shelf Life (Unopened) | The dose recovery for MCM1 and the % dose recoveries for MCM2-7 met the sponsor's required acceptance criteria. | Acceptance criteria met up to the 11 months' time point, supporting a 10-month shelf-life claim (storage unopened at 2-8°C). Real-time studies are ongoing. |
| In-Use Open Vial (Reconstituted) | The dose recovery for MCM1 and the % dose recoveries for MCM2-7 met the sponsor's required acceptance criteria. | Acceptance criteria met up to the 22 days' time point, supporting an open vial claim of 21 days (when properly stored at 2-8°C). |
| On-Board Stability | The dose recovery for MCM1 and the % dose recoveries for MCM2-7 met the sponsor's required acceptance criteria. | Acceptance criteria met up to 5 hours, supporting an on-board stability claim for 4 hours. |
| Value Assignment | The new MCM doses must fall within the final value assignment specification for T3 MCMs. The mean MCM doses must fall within customer range specifications. MCM1 must measure at or below the T3 assay sensitivity limit. | MCMs are value assigned using assigned reference calibrators and MCMs. Performance verification run (6 replicates per level) ensures mean MCM doses fall within customer range specifications. A nested testing run protocol is used for MCM2-7 value assignment (20 replicates in total). Implies acceptance criteria were met. |
| Expected Values | Lot-specific assigned values and customer ranges are established per sponsor's internal procedural specifications. | Example target values (ng/mL): MCM1: 0.00, MCM2: 0.42, MCM3: 0.69, MCM4: 1.11, MCM5: 1.65, MCM6: 3.87, MCM7: 7.00. Assay Range: 0.1-8 ng/mL. |
| Traceability | Standardized to an internal standard manufactured using USP (United States Pharmacopeia) material. | Assigned values for calibrators and MCMs are traceable to this standardization. |
2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
The document describes several non-clinical performance tests, primarily stability studies and value assignment. These are prospective tests conducted by the sponsor (Siemens Healthcare Diagnostics Inc.).
- Stability Studies (Test Set):
- Real Time/Shelf Life (Unopened): Each MCM (FSH, FT4, T4, T3) was stored unopened at 2-8°C and tested at T=0, 7 months, and 10 or 11 months. Ongoing studies were mentioned at further time points (e.g., 14, 18, 24, 25 months for FSH; 15, 19, 24, 30, 31 months for FT4, T4, T3). The comparison was made against -80°C reference MCMs. No specific number of replicate MCM vials tested at each time point is explicitly stated, other than 'test FSH MCMs were stored'.
- In-Use Open Vial (Reconstituted): Each MCM (FSH, FT4, T3) was reconstituted, pooled, aliquoted, and stored at 2-8°C. They were tested in 5 replicates per level at T=0, 7, 14, 21, 28, and 29 days (for FSH, T3) or T=0, 7, 14, 21, 28, and 29 days (for FT4). T4 MCM summary did not include open vial stability data details.
- On-Board Stability: Pooled aliquots of each MCM (FSH, FT4, T3) in sample cups were stored on the ADVIA Centaur system and measured at T=0, 2, 4, and 5 hours. T4 MCM summary did not include on-board stability data details.
- Value Assignment (Test Set):
- For each new MCM lot, MCM1 (analyte-free) was run in 5 replicates on two separate runs.
- Other MCM levels (MCM2-8 for FSH, MCM2-7 for FT4/T3, MCM2-6 for T4) were tested using a nested testing run protocol with alternating samples of reference and new MCM, totaling 20 replicates.
- A performance verification run consisted of 6 replicates of each MCM level.
- Data Provenance: The studies were conducted by Siemens Healthcare Diagnostics Inc., likely in the USA. The data is prospective, generated specifically for this 510(k) submission.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
This type of in vitro diagnostic quality control material does not rely on "expert" interpretation in the same way as, for example, an imaging device. The "ground truth" for these materials is established through a process of:
- Traceability: Standardization to internationally recognized reference materials (e.g., WHO 2nd International Standard for human FSH) or internal standards traceable to official pharmacopeia (USP T4, T3 stock).
- Assigned Values: The values of the MCMs are assigned by the manufacturer based on these traceable standards and validated measurement procedures.
- Internal Protocols: The "sponsor's internal procedural specifications" and "qualified materials and measurement procedures" form the basis for establishing the expected values and ranges.
Therefore, there are no "experts" (like radiologists) establishing ground truth in terms of diagnostic interpretation from patient data. The ground truth is analytical and based on metrological traceability and rigorous laboratory procedures.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
Adjudication methods like 2+1 or 3+1 (where multiple experts independently assess and then resolve discrepancies) are not applicable here. These methods are used in scenarios involving subjective expert interpretation, often for imaging or clinical diagnosis. For these quality control materials, "ground truth" and performance are determined through quantitative analytical measurements against established reference values and statistical methods to ensure measurements fall within specified limits.
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
MRMC studies are typically performed for diagnostic imaging devices where human readers (e.g., radiologists) interpret cases, sometimes with AI assistance. This document describes in vitro diagnostic quality control materials, not a diagnostic AI device that involves human interpretation of cases. Therefore, no MRMC comparative effectiveness study was performed, and thus no effect size for human reader improvement with AI assistance is mentioned.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the studies described are standalone in the sense that they evaluate the performance of the quality control materials themselves (stability, value assignment) within the ADVIA Centaur assay system, without direct human cognitive input being part of the 'device's' analytical function during testing. The "algorithm" here is the underlying immunoassay technology, and the MCM's performance is tested analytically.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The ground truth used for these quality control materials is analytical traceability to recognized international standards (WHO) or national pharmacopeia (USP) for the respective analytes. It also includes reliance on the sponsor's "qualified materials and measurement procedures" and internal procedural specifications for value assignment. This is an objective, quantitative ground truth, not derived from expert consensus, pathology, or outcomes data.
8. The sample size for the training set
The concept of a "training set" is relevant for machine learning algorithms. These devices are chemical/biological reagents designed as quality control materials for immunoassays, not AI algorithms. Therefore, there is no "training set" as understood in machine learning. The manufacturing processes and associated testing are quality control steps, not a machine learning training phase.
9. How the ground truth for the training set was established
As there is no "training set" in the machine learning sense for these devices, this question is not applicable. The establishment of ground truth for the performance evaluation (test set, as discussed in point 7) is through analytical traceability to standards.
§ 862.1660 Quality control material (assayed and unassayed).
(a)
Identification. A quality control material (assayed and unassayed) for clinical chemistry is a device intended for medical purposes for use in a test system to estimate test precision and to detect systematic analytical deviations that may arise from reagent or analytical instrument variation. A quality control material (assayed and unassayed) may be used for proficiency testing in interlaboratory surveys. This generic type of device includes controls (assayed and unassayed) for blood gases, electrolytes, enzymes, multianalytes (all kinds), single (specified) analytes, or urinalysis controls.(b)
Classification. Class I (general controls). Except when intended for use in donor screening tests, quality control materials (assayed and unassayed) are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.