(621 days)
N Latex FLC kappa and lambda are in-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma. N Latex FLC kappa and lambda assays are used:
• as an aid in the diagnosis and monitoring of multiple myeloma (MM) on the BN Systems and Atellica® CH Analyzer,
• as an aid in the diagnosis of amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer,
• as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS) on the BN Systems.
Results of FLC measurements should always be interpreted in conjunction with other laboratory and clinical findings.
The N Latex FLC (free light chain) assays are in vitro diagnostic reagents for the quantitative determination of free light chains, type kappa or type lambda, in human serum and EDTA plasma by means of particle-enhanced immunoassay determination. Used in conjunction with other clinical and laboratory findings, FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM), as an aid in the diagnosis of amyloidosis (AL) and on the BN Systems, as an aid in the evaluation of MGUS.
Polystyrene particles coated with antibodies to human free light chains, type kappa or lambda, are agglutinated when mixed with samples containing FLC. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly defined by the concordance percentages achieved in various patient cohorts. The document does not explicitly state numerical thresholds as "acceptance criteria" but rather presents the performance results.
| Study Endpoint / Criteria | Reported Device Performance |
|---|---|
| MGUS Concordance (Overall): The ability of the device to correctly identify patients with MGUS based on FLC measurements. | 50.4% Concordance across 121 MGUS samples (89 Non-IgM, 21 IgM, 11 LC MGUS). |
| LC MGUS Concordance: The ability of the device to correctly identify patients with Light Chain MGUS (LC MGUS) based on an abnormal FLC-Ratio and elevated iFLC. | 90.9% Concordance across 11 LC MGUS samples when considering both criteria (abnormal FLC-Ratio and positive for iFLC elevation). 10 samples were positive for both criteria, and 1 for one criterion. |
| Polyclonal Immunostimulation Concordance: The ability of the device to correctly differentiate polyclonal immunostimulation from MGUS, yielding a low concordance for MGUS. | 90.2% Concordance across 102 polyclonal immunostimulation samples. (This implies a high agreement that these samples are not MGUS, aligning with the expected performance of a device aiding in MGUS evaluation by not falsely classifying non-MGUS as MGUS). |
| Agreement with Clinical Diagnosis for Stable MGUS: The device's ability to show stability in FLC measurements consistent with clinically stable MGUS. | 98.4% Agreement across 61 stable MGUS patients. Agreement was defined by: 1) κ/λ ratio within the reference interval of 0.53 - 1.51 at the last draw, AND 2) two consecutive assessments not showing a relative change of ≥ 25% for the involved free light chain (iFLC). |
| Agreement with Clinical Diagnosis for Progressive MGUS: The device's ability to show changes in FLC measurements consistent with progression from MGUS to MM. | 75.0% Agreement across 4 progressive MGUS patients. Agreement was defined by: 1) κ/λ ratio outside the reference interval of 0.53 - 1.51 at the time of clinical MM diagnosis, AND 2) two consecutive assessments showing a relative change of ≥ 25% for the involved light chain (iFLC). (Note: The small sample size here for progressive cases should be considered when interpreting this percentage). |
2. Sample Sizes Used for the Test Set and Data Provenance
- MGUS Concordance:
- Test Set Sample Size: 121 MGUS samples (89 Non-IgM, 21 IgM, 11 LC MGUS)
- Data Provenance: Not explicitly stated, but the study was described as a "multi-center study," suggesting samples were collected from various clinical sites. It is implied to be retrospective as they are described as "clinically defined samples" and patients with "diagnosed" MGUS or polyclonal immunostimulation.
- LC MGUS Concordance:
- Test Set Sample Size: 11 LC MGUS samples (subset of the 121 MGUS samples).
- Data Provenance: Same as above (multi-center, implied retrospective).
- Polyclonal Immunostimulation Concordance:
- Test Set Sample Size: 102 specimens.
- Data Provenance: Same as above (multi-center, implied retrospective).
- Evaluation of MGUS Patients (Stable Cohort):
- Test Set Sample Size: 61 patients.
- Data Provenance: Not explicitly stated, but patients were "initially diagnosed for MGUS" and "evaluated over different time periods" with "at least 4 sample draws at various time intervals," indicating a prospective or longitudinal study design over time.
- Evaluation of MGUS Patients (Progressive Cohort):
- Test Set Sample Size: 4 patients.
- Data Provenance: Same as above (prospective/longitudinal).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. It refers to "clinically defined samples" and "clinical diagnosis," implying that the ground truth was based on a comprehensive clinical assessment, likely by medical professionals (e.g., oncologists, hematologists), but the details are not provided.
4. Adjudication Method for the Test Set
The document does not describe an adjudication method for establishing the ground truth of the test set (e.g., 2+1, 3+1). The ground truth appears to be based on pre-existing "clinical diagnosis" or "clinically defined samples."
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic reagent, which provides quantitative measurements, not an imaging device that human readers interpret. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable in this context.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
- Yes, a standalone performance study was done. The studies described (concordance and evaluation of stable/progressive patients) assessed the performance of the N Latex FLC assays (the "device" or "algorithm" in this context) directly against clinical diagnoses and criteria. The results are reported as the "N Latex FLC κ/λ Ratio Concordance" and "N Latex FLC results," indicating an assessment of the device's output without direct human-in-the-loop interpretation of the assay results during the diagnostic process itself (though human interpretation of the FLC results in conjunction with other clinical findings is part of the intended use).
7. Type of Ground Truth Used
The ground truth used was expert consensus / clinical diagnosis / outcomes data.
- "Clinically defined samples" with diagnoses of MGUS or polyclonal immunostimulation.
- "Clinical diagnosis of MGUS" and "change in clinical diagnosis of MGUS to MM" for the stable and progressive cohorts, respectively. This implies that the ground truth was established by medical professionals using a combination of clinical findings, established diagnostic criteria, and other laboratory results, which could be considered a form of expert consensus or clinical outcomes.
8. Sample Size for the Training Set
The document does not report on a separate training set or its sample size. The performance data provided is for the evaluation of the device, implying the device was already developed. For an in-vitro diagnostic assay like this (which is a reagent test and analytical system), the "training" typically refers to the development and optimization of the assay's chemical and biological components, calibration, and establishment of analytical performance characteristics, rather than machine learning model training on a distinct labeled dataset. The document refers to prior submissions (K171742 and K182098) for "previously documented analytical and clinical studies," which likely covered the initial development and analytical validation.
9. How the Ground Truth for the Training Set Was Established
As no explicit "training set" for an AI/ML model is mentioned, this question is not directly applicable. For a traditional diagnostic assay, the "ground truth" during development involves rigorous analytical validation (e.g., using reference materials, spiked samples, and comparison to established methods) and initial clinical studies to define normal ranges and characteristic responses in different disease states. These would have been established through standard laboratory and clinical practices, likely involving certified reference materials, reference methods, and clinical expert assessment of patient samples.
§ 866.5550 Immunoglobulin (light chain specific) immunological test system.
(a)
Identification. An immunoglobulin (light chain specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques both kappa and lambda types of light chain portions of immunoglobulin molecules in serum, other body fluids, and tissues. In some disease states, an excess of light chains are produced by the antibody-forming cells. These free light chains, unassociated with gamma globulin molecules, can be found in a patient's body fluids and tissues. Measurement of the various amounts of the different types of light chains aids in the diagnosis of multiple myeloma (cancer of antibody-forming cells), lymphocytic neoplasms (cancer of lymphoid tissue), Waldenstrom's macroglobulinemia (increased production of large immunoglobulins), and connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus.(b)
Classification. Class II (performance standards).