(251 days)
INNOVANCE Anti-Xa assay in combination with INNOVANCE Heparin Calibrator is an In-vitro diagnostic automated chromogenic assay for the quantitative determination of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) activity in human plasma collected from venous blood samples in 3.2 % sodium citrated tubes in the clinical laboratory. The quantitative determination of UFH and LMWH can be performed on the BCS XP System, CS-2500 System, CS-5100 System and the CA-660 System. For use with plasma from patients undergoing anticoagulant therapy with either UFH or LMWH.
INNOVANCE Anti-Xa assay in combination with INNOVANCE Apixaban Standard provides quantitative determination of the concentration of apixaban in human plasma collected from venous blood samples in 3.2 % sodium citrated tubes in the clinical laboratory. The quantitative determination of apixaban can be performed on CS-2500 System. For use with plasma from patients undergoing anticoagulant therapy with apixaban in situations where quantification of apixaban levels may be indicated:
· Patient with bleeding,
· Patient with risk for bleeding (e.g. during perioperative management),
· Patient with conditions affecting pharmacokinetics (e.g. deteriorating renal function, extremes of body weight, treatment with other drugs known to affect pharmacokinetics of apixaban).
The performance of this device has not been established in neonate and pediatric patient populations.
INNOVANCE Anti-Xa assay is a one stage chromogenic assay. The reagent kit consists of two components. One component (Reagent) contains Xa. the other (Substrate) a chromogenic substrate specific for Xa. Upon mixing of INNOVANCE Anti-Xa Reagent and INNOVANCE Anti-Xa Substrate, Xa converts the chromogenic substrate into two products, one of them is paranitroaniline. The formation of paranitroaniline can be quantified by the coaqulation analyzer employing light absorption at a specific wavelength (405 nm).
In the presence of a heparin containing sample the formation of paranitroaniline will be reduced in a time dependent manner. This is due to inhibition of Xa by the heparin/AT complex is formed in the patient's plasma and competes with the substrate conversion by Xa. The concentration of the complex is not only dependent on the concentration of heparin but also on the availability of the patient's endogenous antithrombin. By comparison to a reference curve the heparin activity of the sample can be quantified.
To reduce the influence from heparin antagonists, such as platelet factor 4 (PF4), dextran sulfate is included in the reaction mixture.
In the presence of an apixaban containing sample factor Xa is inhibited directly by this inhibitor. Comparison to an inhibitor specific reference curve allows quantification of the inhibitor concentration in the sample.
The provided text describes the performance data for the INNOVANCE Anti-Xa assay, a device for quantitative determination of anticoagulants. As the request is about acceptance criteria and study proving it, and this document is an FDA 510(k) summary, specific acceptance criteria would be internal to the manufacturer's validation plan and not explicitly stated as "acceptance criteria" in this public summary. However, the performance data presented (Precision, Reproducibility, LoB, LoD, LoQ, Linearity, Measuring Interval, Interference, and Method Comparison) implicitly demonstrate that the device meets the necessary performance characteristics for its intended use, making it "substantially equivalent" to a predicate device.
Here's an attempt to extract and infer the information based on the provided document:
1. Table of Acceptance Criteria (Inferred from Performance Data) and Reported Device Performance
Since explicit acceptance criteria are not stated as pass/fail thresholds in this summary, they are inferred based on the presented results which led to substantial equivalence. The predicate device's performance often sets the benchmark for substantial equivalence.
| Performance Metric | Implied Acceptance Criteria (Inferred from Industry Standards/Predicate) | Reported Device Performance (INNOVANCE Anti-Xa) |
|---|---|---|
| Precision (Within-Device/Lab CV%) | Generally low CV% (e.g., 0.95) and close to y=x for agreement with predicate. | Overall (n=301): r = 0.989, y = 1.026x - 8.590 ng/mL (across 3 sites) |
2. Sample Size and Data Provenance:
- Test Set Sample Size:
- Precision: 240 measurements for each of the 6 samples (INNOVANCE Apixaban Control 1 & 2, and 4 plasma pools).
- LoB, LoD, LoQ: Not explicitly stated as a single number, but calculation involves measurements of multiple samples (e.g., "samples with an assigned value of 0 ng/mL apixaban" for LoB; "samples with an assigned value of 2, 4, 6, 8 and 10 ng/mL apixaban" for LoD; "samples with an assigned value of 16, 18, 20, 22 and 24 ng/mL apixaban" for LoQ).
- Linearity & Measuring Interval: Not explicitly stated as a single number, but likely involves multiple spike levels and measurements.
- Interference: Not explicitly stated, but involves testing various interfering substances.
- Method Comparison: 301 fresh and frozen plasma samples (multicentric study across 3 sites).
- Data Provenance: The document does not specify the country of origin for the data. It refers to "internally conducted studies" and a "multicentric study" for reproducibility and method comparison, implying clinical laboratories. Since the applicant is Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany, it's highly probable that some or all studies were conducted in Germany or other European countries, though this is not explicitly stated. The studies are described as conforming to CLSI (Clinical and Laboratory Standards Institute) guidelines, which are international standards. The samples for method comparison were "fresh and frozen plasma samples." It is a prospective study in terms of testing the device performance against established samples/methods.
3. Number of Experts and Qualifications for Ground Truth:
This device is an in-vitro diagnostic assay that measures the concentration of substances (heparin, apixaban) in blood plasma directly. Therefore, the "ground truth" is typically defined by:
- Reference Methods: For method comparison, it refers to the results obtained from the predicate device (HemosIL Liquid Anti-Xa) on the ACL TOP system.
- Assigned Values: For calibrators and controls, the "assigned value" is based on the manufacturer's preparation and testing, often traceable to internal reference preparations or qualified methods like LC-MS/MS for substances like apixaban, as stated in the traceability sections for calibrators and controls.
There is no mention of human "experts" (e.g., radiologists, pathologists) establishing ground truth, as this is a quantitative laboratory assay, not an imaging device requiring expert interpretation.
4. Adjudication Method for the Test Set:
Not applicable. This is a quantitative laboratory assay, not a device where interpretation or human reading requires adjudication. The ground truth for method comparison is the measurement from the predicate device (HemosIL Liquid Anti-Xa).
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
Not applicable. This is an in-vitro diagnostic device for quantitative chemical analysis, not an imaging device or AI algorithm with human-in-the-loop performance component.
6. Standalone (Algorithm Only) Performance:
This device is a standalone diagnostic assay (reagent kit used with specific automated analyzers). Its performance data, as detailed, represents its standalone performance. There is no separate "algorithm" in the sense of AI that needs to be evaluated independently of the assay system.
7. Type of Ground Truth Used:
- Reference Method Comparison: For method comparison, the ground truth was established by the predicate device (HemosIL Liquid Anti-Xa), which is a legally marketed device, providing a comparative ground truth.
- Internal Reference/Assigned Values: For precision, LoB, LoD, LoQ, linearity, and interference studies, the ground truth for samples (e.g., controls, plasma pools, spiked samples) was established by their assigned values, internal reference preparations, or spiked concentrations. The traceability section explicitly mentions that for apixaban, calibration values are "traceable to apixaban supplied by the manufacturer and quantitated in plasmas assayed by Liquid Chromatography - tandem Mass Spectrometry (LC-MS/MS)" for the predicate, and for the subject device, "calibrated against an internal reference preparation."
8. Sample Size for the Training Set:
This document describes the analytical validation of a diagnostic assay (a chemical reagent system) rather than an AI/ML algorithm. Therefore, the concept of a "training set" for an algorithm doesn't directly apply in the traditional sense. The development of such assays involves extensive R&D, formulation, and preliminary testing, but these are not referred to as "training sets" in the context of typical regulatory submissions for IVDs. The closest equivalent would be the R&D samples used during the development and optimization phase of the reagent and its performance on the instruments. No specific numbers are provided for this.
9. How the Ground Truth for the Training Set was Established:
As above, the concept of a "training set" is not relevant here. For the analytical studies presented, "ground truth" (or reference values) for various samples (calibrators, controls, patient samples, spiked samples) were established through recognized methods:
- Predicate Device Measurements: For comparative studies, the measurements from the legally marketed predicate device served as a comparative reference.
- LC-MS/MS (Liquid Chromatography - tandem Mass Spectrometry): This highly accurate analytical technique is explicitly mentioned for establishing traceability and quantifying apixaban in calibrators for the predicate device, and the subject device uses an "internal reference preparation" which would likely also be validated against similar high-accuracy methods.
- Gravimetric/Volumetric Spiking: For linearity, LoD, and LoQ studies, samples are often prepared by precisely adding known concentrations of the analyte (apixaban) to a matrix, making the spiked concentration the ground truth.
§ 864.7295 Heparin and direct oral factor Xa inhibitor drug test system.
(a)
Identification. A heparin and direct oral factor Xa inhibitor drug test system is intended for the detection of heparin and direct oral factor Xa inhibitors in human specimens collected from patients taking heparin or direct oral factor Xa inhibitors. This device is intended to aid in the management of therapy in conjunction with other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include the following:
(i) Detailed documentation of analytical device performance studies and results demonstrating acceptable analytical performance with a sufficient number of specimens tested in order to obtain unbiased estimates of analytical performance. This documentation shall include the following as appropriate to the technology, specimen types tested, and intended use of the device:
(A) Studies and results for that demonstrate device precision including repeatability and reproducibility, using quality controls and clinical samples, when appropriate. Precision studies must assess specimens for each indicated drug at concentrations throughout the measuring range of the device including near clinically relevant levels, as appropriate. The study must evaluate different sources of variability including, as appropriate, between-run, between-operator, between-lot, between-instrument, between-day, and between-site;
(B) Studies and results that demonstrate that the device is free from clinically significant interference, from endogenous and exogenous interferents associated with the target population(s), and interferents that are specific for, or related to, the technology or methodology of the device;
(C) Data to demonstrate appropriate specimen stability for the intended sample matrices under the intended conditions for specimen collection, handling, and storage described in the device labeling;
(D) Studies and results that demonstrate the linear range, limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ), as applicable to the technology of the device; and
(E) For any devices intended for use for near patient testing, studies and results that demonstrate the robustness of the device in the hands of the intended user, including the entire testing procedure, pre-analytical specimen processing steps, and results interpretation.
(ii) Detailed documentation of clinical performance testing in which the performance is analyzed relative to a comparator that FDA has determined is appropriate. Specimens must be representative of the intended use population(s) and must cover the full range of the device output and any clinically relevant decision points as appropriate.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) Identification of any known interferents, including all endogenous, exogenous, technology-specific, and patient population-specific interferents, specific to the test outputs. The information must include the concentration(s) or level(s) of the interferent at which clinically significant interference was found to occur, and the concentration range or levels at which interference was not found to occur;
(ii) A prominent statement that the device is not intended for use in monitoring patients taking heparin or direct oral factor Xa inhibitors; and
(iii) Limiting statements indicating, as applicable:
(A) That the device should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures; and
(B) That the device is not specific to the direct oral factor Xa inhibitor that has been evaluated and may detect the presence of other direct factor Xa inhibitors that have not been evaluated.