(511 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 immunoglobulin light-chain amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer.
· as an aid in the monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems.
· 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.
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 EDTAplasma. N Latex FLC kappa and lambda assays are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and immunoglobulin light-chain amyloidosis (AL) and as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS). Monitoring of immunoglobulin light-chain amyloidosis (AL) and evaluation of MGUS are cleared for use only on the BN Systems.
The N Latex FLC test systems are based upon the principles of particle-enhanced immunonephelometry. Polystyrene particles coated with monoclonal antibodies to human free light chains, type kappa or lambda, respectively, are agglutinated when mixed with samples containing free light chains. 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.
This document describes the N Latex FLC kappa and N Latex FLC lambda assays, in vitro diagnostic reagents used for the quantitative determination of free light chains (FLC), type kappa or type lambda, in human serum and EDTA plasma. This submission seeks to add "monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems" to the device's indications for use.
1. Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly derived from the comparative studies presented, aiming to demonstrate substantial equivalence to the predicate device and acceptable concordance with clinical status. The reported performance is summarized in the tables below, using Evaluation Mode 2 as favored by Siemens.
Comparison of N Latex FLC versus Freelite (Predicate Device) - Evaluation Mode 2
| Response Criteria | Acceptance Criteria (Implicit) | Reported Performance (Agreement Rate) | 95% CI Bootstrap |
|---|---|---|---|
| Complete Response | High agreement | 68.1% | 53.6 – 86.3% |
| VGPR | High agreement | 81.8% | 67.4 – 91.1% |
| Partial Response | High agreement | 45.5% | 15.0 – 60.0% |
| Stable Disease | High agreement | 84.4% | 76.5 – 95.4% |
| Progressive Disease | High agreement | 88.2% | 70.0 – 100.0% |
| PPA (Progressive Disease) | High agreement | 88.2% (15/17) | 70.0 – 100.0% |
| NPA (Progressive Disease) | High agreement | 97.8% (219/224) | 95.9 - 99.6% |
Concordance of N Latex FLC versus Clinical Status - Evaluation Mode 2
| Response Criteria | Acceptance Criteria (Implicit) | Reported Performance (Concordance Rate) | 95% CI Bootstrap |
|---|---|---|---|
| Complete Response | High concordance | 52.9% | 25.0 – 74.3% |
| VGPR | High concordance | 71.4% | 56.6 – 88.9% |
| Partial Response | High concordance | 26.8% | 8.0 – 30.3% |
| Stable Disease | High concordance | 57.6% | 38.2 – 72.9% |
| Progressive Disease | High concordance | 70.6% | 47.1 – 88.2% |
| Sensitivity (Progressive Disease) | High sensitivity | 70.6% (12/17) | 47.1 – 88.2% |
| Specificity (Progressive Disease) | High specificity | 96.1% (197/205) | 94.8 - 99.0% |
2. Sample Size Used for the Test Set and Data Provenance
The test set for the comparative effectiveness study included data from a multi-center study on immunoglobulin light-chain amyloidosis (AL) patients.
- Sample Size: The N Latex FLC versus Freelite comparison involves a total of 241 observations based on initial and consecutive blood draws. The comparison to clinical status involves 222 observations.
- Data Provenance: The document does not explicitly state the country of origin. The study is retrospective, comparing changes between an initial sample draw and each consecutive blood draw, and then comparing these results to both a predicate device and clinical response.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The "clinical response" used as ground truth was "provided by the physician taking into account all available clinical and laboratory information."
- Number of Experts: Not explicitly stated, but it implies individual physicians for each patient.
- Qualifications: "Physician" is the qualification mentioned. No specific experience levels (e.g., years of experience or specialization in oncology/hematology) are provided for these physicians.
4. Adjudication Method for the Test Set
The document mentions that clinical response was "provided by the physician taking into account all available clinical and laboratory information." There is no mention of a formal adjudication panel or process (e.g., 2+1, 3+1). The response evaluation criteria are derived from NCCN Response Criteria for serum M protein/IFE and FLC levels/ratios.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC study was conducted. This device is an in-vitro diagnostic assay, not an imaging AI device that would typically involve human readers. The comparative effectiveness assessment focuses on the agreement between the new device and a predicate device, and the concordance of both devices with physician-determined clinical status.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
Yes, the studies presented are standalone performance assessments of the N Latex FLC kappa and lambda assays. The device itself is an automated assay, and its performance is evaluated directly (algorithm only). The comparison to clinical status is essentially an evaluation of the algorithm's output versus an established clinical truth.
7. Type of Ground Truth Used
The ground truth for the clinical comparison was based on clinical status/physician assessment, which encompasses "all available clinical and laboratory information" including NCCN Response Criteria. This is closer to an "outcomes data" or "expert consensus" type of ground truth in a clinical context.
8. Sample Size for the Training Set
The document does not provide information on the training set size. This submission focuses on performance data for an extended indication for monitoring AL. It refers to previous submissions (K171742, K182098, K193047) for established analytical and clinical studies, implying that the device was already developed and validated. The current submission's study used a distinct set of AL patients for evaluating the new monitoring claim.
9. How the Ground Truth for the Training Set Was Established
Not applicable/provided. As this submission is for an extended indication and refers to previous clearances for the device, details on the ground truth establishment for the initial training set (if any for algorithm development) are not included in this document. The focus of the provided text is on demonstrating performance for the new monitoring claim.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health and Human Services logo on the left and the FDA logo on the right. The FDA logo features the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.
October 29, 2021
Siemens Healthcare Diagnostics Products GmbH Kerstin Koenigs Official Correspondent Emil-von-Behring-Str. 76 Marburg, 35041 Germany
Re: K201496
Trade/Device Name: N Latex FLC kappa. N Latex FLC lambda Regulation Number: 21 CFR 866.5550 Regulation Name: Immunoglobulin (Light Chain Specific) Immunological Test System Regulatory Class: Class II Product Code: DFH, DEH Dated: July 29, 2021 Received: August 2, 2021
Dear Kerstin Koenigs:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Ying (Katelin) Mao, Ph.D. Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K201496
Device Name
N Latex FLC kappa and N Latex FLC lambda
Indications for Use (Describe)
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 immunoglobulin light-chain amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer.
· as an aid in the monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems.
· 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.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ------------------------------------------------- | -- |
|X Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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Image /page/3/Picture/1 description: The image shows the logo for Siemens Healthineers. The word "SIEMENS" is written in teal, and the word "Healthineers" is written in orange below it. To the right of the word "Healthineers" is a graphic of orange dots.
510(k) Summary per 21 CFR 807.92
This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K201496
1. Submitter
Siemens Healthcare Diagnostics Products GmbH Emil-von-Behring-Str. 76 35041 Marburg, Germany
| Contact: | Kerstin Koenigs |
|---|---|
| Email: | kerstin.koenigs@siemens-healthineers.com |
| Phone: | +49 (173) 7318139 |
| Fax: | +49 (6421) 394977 |
| Date of Preparation: | October 20, 2021 |
2. Device Information
| Trade Name: | N Latex FLC kappaN Latex FLC lambda |
|---|---|
| Common or Usual Name: | Light Chain immunological test system |
| Classification Name: | Immunoglobulin (light chain specific) immunologicaltest system per 21CFR 866.5550 |
| Product Code: | DFH (kappa)DEH (lambda) |
| Regulatory Class: | II |
| 510(k) Review Panel: | Clinical Immunology (82) |
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3. Predicate Devices
The Binding Site Freelite® Human Kappa Free Kit for use on the Siemens BN II - K031016
The Binding Site Freelite® Human Lambda Free Kit for use on the Siemens BN II - K031016
4. Device Description / Test Principle
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 EDTAplasma. N Latex FLC kappa and lambda assays are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and immunoglobulin light-chain amyloidosis (AL) and as an aid in the evaluation of Monoclonal Gammopathy of Undetermined Significance (MGUS). Monitoring of immunoglobulin light-chain amyloidosis (AL) and evaluation of MGUS are cleared for use only on the BN Systems.
The N Latex FLC test systems are based upon the principles of particle-enhanced immunonephelometry. Polystyrene particles coated with monoclonal antibodies to human free light chains, type kappa or lambda, respectively, are agglutinated when mixed with samples containing free light chains. 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.
The devices in this submission have not materially changed since originally cleared under K171742. The purpose for this submission is to add monitoring of immunoglobulin light-chain amyloidosis (AL), on the BN Systems, to the intended use.
5. Intended Use / Indications for Use
N Latex FLC kappa and N Latex FLC lambda assays
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 immunoglobulin light-chain amyloidosis (AL) on the BN Systems and Atellica® CH Analyzer.
- . as an aid in the monitoring of immunoglobulin light-chain amyloidosis (AL) on the BN Systems.
- . 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.
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Precaution
- . The performance of N Latex FLC kappa and lambda has not been thoroughly studied in IgM and Light Chain MGUS patients due to the low prevalence of these subtypes.
- . Patients with decreased renal function may have elevated FLC kappa and FLC lambda (Jacobs et al. N Latex FLC serum free light-chain assays in patients with renal impairment. Clin Chem Lab Med 2013, DOI 10.1515/cclm-2013-0864).
- . Sample populations excluded MGUS populations that were further diagnosed with a disease/disorder in subsequent testing with another medical device such as human immunodeficiency virus, hepatitis, and chronic lymphocytic leukemia. Thus, because the samples were enriched the specificity of the test may be inflated.
N FLC Supplementary Reagent
Supplementary reagent for the immunonephelometric determination of free light chains (FLC), type kappa and type lambda on BN Systems. A mixture of both supplementary reagents is used to suppress interference by rheumatoid factors and human anti-mouse antibodies (HAMA).
Special Conditions for Use:
For prescription use only.
Special instrument requirements:
BN II (K943997) and BN ProSpec Systems (K001647)
6. Technical Characteristics
Similarities and Differences to the Predicate
A comparison of the similarities and differences between the proposed Siemens Healthcare Latex FLC kappa and lambda assays versus The Binding Site (TBS) Freelite Human Kappa Free Kit and Lambda Free Kit assays (predicate devices) is provided in the table below.
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| Predicate Devices | Proposed Devices | |
|---|---|---|
| The Binding Site | Siemens HealthcareBN Systems | |
| Freelite® Human Kappa Free Kitand Freelite® Human LambdaFree Kit on the Siemens BN II | N Latex FLC kappaN Latex FLC lambda | |
| K031016 | K171742, K182098, K193047 | |
| Indications forUse | Kappa: This kit is intended for thequantitation of kappa free light chainsin serum and urine on the SiemensBN II. Measurement of free lightchains aids in the diagnosis andmonitoring of multiple myeloma,lymphocytic neoplasms,Waldenstrom's macroglobulinemia,AL amyloidosis, light chain depositiondisease and connective tissuediseases such as systemic lupuserythematosus in conjunction withother laboratory and clinical findings.Lambda: This kit is intended for thequantitation of lambda free lightchains in serum and urine on theSiemens BNTM II. Measurement offree light chains aids in the diagnosisand monitoring of multiple myeloma,lymphocytic neoplasms,Waldenstrom's macroglobulinemia,AL amyloidosis, light chain depositiondisease and connective tissuediseases such as systemic lupuserythematosus in conjunction withother laboratory and clinical findings. | N Latex FLC kappa and lambda are in-vitro diagnostic reagents for thequantitative determination of free lightchains (FLC), type kappa or typelambda in human serum and EDTAplasma.N Latex FLC kappa and lambda assaysare used:• as an aid in the diagnosis andmonitoring of multiple myeloma (MM)on the BN Systems and Atellica® CHAnalyzer.• as an aid in the diagnosis ofimmunoglobulin light-chain amyloidosis(AL) on the BN Systems and Atellica®CH Analyzer.• as an aid in the monitoring ofimmunoglobulin light-chain amyloidosis(AL) on the BN Systems.• as an aid in the evaluation ofMonoclonal Gammopathy ofUndetermined Significance (MGUS) onthe BN Systems.Results of FLC measurements shouldalways be interpreted in conjunctionwith other laboratory and clinicalfindings. |
| Sample Type | Human serum and urine | Human serum and EDTA plasma |
| Units | mg/L | Same |
| Technology | NephelometryPolystyrene particles coated withpolyclonal monospecific antibodies | NephelometryPolystyrene particles coated withmonoclonal antibodies |
| Traceability | Internal reference preparation | Internal Reference Plasma Pool |
| Calibrators | One level | Same |
| Predicate Devices | Proposed Devices | |
| The Binding SiteFreelite® Human Kappa Free Kitand Freelite® Human LambdaFree Kit on the Siemens BN II | Siemens HealthcareBN SystemsN Latex FLC kappaN Latex FLC lambda | |
| K031016 | K171742, K182098, K193047 | |
| InstrumentSystem | Siemens BN II System | Siemens BN II and BN ProSpecSystems |
| AnalyticalMeasuringRange(Calibrator lotdependent) | Kappa: 5.9 to 190 mg/LLambda: 5.0 to 160 mg/L | kappa: 3.4 to 110 mg/Llambda: 1.9 to 60 mg/L |
| ReferenceInterval | Kappa: 3.30 to 19.40 mg/LLambda: 5.71 to 26.30 mg/LRatio: 0.26 to 1.65 | kappa: 8.24 – 28.90 mg/Llambda: 9.10 – 32.60 mg/LRatio: 0.53 to 1.51 |
Comparison of Technological Characteristics
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510(k) Premarket Notification for Addition of immunoglobulin light-chain amyloidosis (AL) Monitoring Claim to N Latex FLC kappa and lambda
The differences between the predicate devices and proposed reagents do not result in a change to the intended use, the indications for use, or the safety and efficacy when used according to the product labeling.
7. Performance Data
Performance Data: Extended indication for monitoring of immunoqlobulin light-chain amyloidosis (AL).
See submissions K171742, K182098 and K193047 for previously documented analytical and clinical studies:
- Precision and Reproducibility ●
- Linearity / Assay Measuring Range ●
- Antigen Excess ●
- Stability ●
- Detection Capabilities ●
- . Analytical Specificity / Interferences
- Expected Values ●
- Clinical Specificity and Sensitivity ●
- Method Comparison to Predicate Devices ●
7.1 Performance data for monitoring of immunoglobulin light-chain amyloidosis (AL) patients
The Latex FLC assays were evaluated on BN II Systems in a multi-center study to evaluate performance in monitoring immunoglobulin light-chain amyloidosis (AL) patients. N Latex FLC kappa and lambda assays were compared to Freelite Kappa and Lambda assays (predicate
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devices) in a method comparison analysis. In addition, both methods were compared to the patient's "clinical response", taking into account all available clinical and laboratory information.
For each of the comparisons these three evaluation modes were applied to all immunoglobulin light-chain amyloidosis (AL) data sets, respectively:
- Evaluation Mode 11 ●
- Evaluation Mode 2² .
- . Evaluation Mode 33-4
Response evaluation was done by comparing changes between the initial sample draw and each consecutive blood draw independently, applying the rules as outlined in the table below.
| NCCN ResponseCriteria | Serum M Protein/ IFE | Evaluation Mode1 | Evaluation Mode2 | Evaluation Mode3 |
|---|---|---|---|---|
| CR(Complete Response) | Serum and UrineIFE negative | FLC levels andratio normal | FLC levels andratio normal | FLC levels andratio normal |
| VGPR(Very Good PartialResponse) | n/a | Reduction in thedFLC to <40 mg/L | Reduction in thedFLC to <40 mg/L | Reduction in thedFLC to <40 mg/L |
| PR(Partial Response) | n/a | dFLC ≥ 50 mg/LA greater than50% reduction inthe initial dFLCvalue | dFLC ≥ 50 mg/LA greater than50% reduction inthe initial dFLCvalue | dFLC ≥ 50 mg/L1. A greater than50% reductionin the initialdFLC value2. For patientswith an initialdFLC value ofless than 50mg/L a low FLCresponse isindicated ifdFLC < 10mg/L* |
| SD(Stable Disease) | n/a | Less than a PR | Less than a PR | Less than a PR |
| PD(ProgressiveDisease) | From CR, anydetectablemonoclonalproteinFrom PR, 50%increase in serumM protein to> 0.5g/dL or 50% | From CR,abnormal FLCratio (light chainmust at leastdouble)From PR, SerumFLC increase of≥ 50% to iFLC | From CR,abnormal FLCratio (light chainmust at leastdouble)From PR, SerumFLC increase of≥ 50% to dFLC | From CR,abnormal FLCratio (light chainmust at leastdouble)From PR, SerumFLC increase of≥ 50% to dFLC |
| increase in urineM protein to > 200mg/dL | > 100 mg/L | > 50 mg/L | > 20 and 20%increase ofbaseline |
Therapy Response Criteria
- Note:-For dFLC <50 it is considered low-dFLC response and based on this citation? the sponsors combined partial response with low-dFLC response.
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The following studies were performed in support of an immunoglobulin light-chain amyloidosis (AL) monitoring claim:
Comparison to Predicate Devices
For comparison of the five response criteria (CR (Complete Response), VGPR (Very Good Partial Response), PR (Partial Response), SD (Stable Disease), PD (Progressive Disease)) three evaluation modes were applied to all immunoglobulin light-chain amyloidosis (AL) data sets. Siemens favors using evaluation mode 2.
Response categories were determined for free light chain testing by Siemens Healthcare N Latex FLC and TBS Freelite Kappa Free and Lambda Free. Response evaluation was done by comparing changes between the initial sample draw and each consecutive blood draw independently. The response levels obtained by the two different test systems were compared in 5x5 contingency tables and relative agreement calculated.
| ResponseCriteriabased onN Latex FLCresults | Response Criteria based on Freelite results | |||||
|---|---|---|---|---|---|---|
| CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total | |
| CompleteResponse | 49 | 3 | 1 | 0 | 0 | 53 |
| VGPR | 19 | 48 | 9 | 2 | 0 | 78 |
| PartialResponse | 0 | 5 | 15 | 5 | 1 | 26 |
| StableDisease | 6 | 2 | 1 | 55 | 4 | 68 |
| ProgressiveDisease | 0 | 0 | 1 | 4 | 11 | 16 |
| Total | 74 | 58 | 27 | 66 | 16 | 241 |
Agreement of N Latex FLC versus Freelite (Evaluation Mode 1)
Agreement Rate and 95% Confidence Intervals of N Latex FLC versus Freelite (Evaluation Mode 1)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| AgreementRate | 66.2% | 82.8% | 55.6% | 83.3% | 68.8% |
| 95% CIBootstrap | 51.6 – 83.6% | 70.3 - 92.3% | 21.4 - 71.4% | 77.4 – 96.7% | 47.4 - 92.3% |
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Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) and 95% Confidence Intervals of N Latex FLC versus Freelite (Evaluation Mode 1)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| PPA | 68.8% (11/16) | 47.4 – 92.3% |
| NPA | 97.8% (220/225) | 96.8 - 100.0% |
Agreement of N Latex FLC versus Freelite (Evaluation Mode 2)
| ResponseCriteriabased onN Latex FLCresults | Response Criteria based on Freelite results | |||||
|---|---|---|---|---|---|---|
| CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total | |
| CompleteResponse | 49 | 3 | 0 | 0 | 0 | 52 |
| VGPR | 17 | 45 | 14 | 3 | 0 | 79 |
| PartialResponse | 0 | 5 | 15 | 4 | 1 | 25 |
| StableDisease | 6 | 2 | 2 | 54 | 1 | 65 |
| ProgressiveDisease | 0 | 0 | 2 | 3 | 15 | 20 |
| Total | 72 | 55 | 33 | 64 | 17 | 241 |
Agreement Rate and 95% Confidence Intervals of N Latex FLC versus Freelite (Evaluation Mode 2)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| AgreementRate | 68.1% | 81.8% | 45.5% | 84.4% | 88.2% |
| 95% CIBootstrap | 53.6 – 86.3% | 67.4 – 91.1% | 15.0 – 60.0% | 76.5 – 95.4% | 70.0 – 100.0% |
Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) and 95% Confidence Intervals of N Latex FLC versus Freelite (Evaluation Mode 2)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| PPA | 88.2% (15/17) | 70.0 – 100.0% |
| NPA | 97.8% (219/224) | 95.9 - 99.6% |
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| ResponseCriteria | Response Criteria based on Freelite results | |||||
|---|---|---|---|---|---|---|
| based on NLatex FLCresults | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total |
| CompleteResponse | 50 | 2 | 0 | 0 | 0 | 52 |
| VGPR | 19 | 48 | 7 | 2 | 1 | 77 |
| PartialResponse | 0 | 5 | 15 | 4 | 1 | 25 |
| StableDisease | 6 | 2 | 3 | 54 | 0 | 65 |
| ProgressiveDisease | 0 | 0 | 1 | 3 | 18 | 22 |
| Total | 75 | 57 | 26 | 63 | 20 | 241 |
Agreement of N Latex FLC versus Freelite (Evaluation Mode 3)
Agreement Rate and 95% Confidence Intervals of N Latex FLC versus Freelite (Evaluation Mode 3)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| AgreementRate | 66.7% | 84.2 | 57.7 | 85.7% | 90.0% |
| 95% CIBootstrap | 52.0 – 83.9% | 71.2 – 93.3% | 23.1 – 76.0% | 77.0 – 96.1% | 77.8 – 100.0% |
Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) and 95% Confidence Intervals of N Latex FLC versus Freelite (Evaluation Mode 3)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| PPA | 90.0% (18/20) | 77.8 – 100.0% |
| NPA | 98.2% (217/221) | 96.3 – 99.6% |
Comparison to Clinical Status
For comparison of the five response criteria (CR (Complete Response), VGPR (Very Good Partial Response), PR (Partial Response), SD (Stable Disease), PD (Progressive Disease)) three evaluation modes were applied to all immunoglobulin light-chain amyloidosis (AL) data sets. Siemens favors using evaluation mode 2.
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Response categories were determined for free light chain testing by Siemens Healthcare N Latex FLC and TBS Freelite Kappa Free and Lambda Free, respectively. Response evaluation was done by comparing changes between the initial sample draw and each consecutive blood draw independently.
The response levels obtained by the two different test systems were compared to the clinical response level provided by the physician taking into account all available clinical and laboratory information. Relative agreement between the clinical response (including further information in addition to serum testing) and the response level applying the clinical response criteria by either using N Latex FLC or the predicate device were calculated, also using 5x5 contingency tables, and compared.
Immunoglobulin light-chain amyloidosis (AL): Concordance Rate N Latex FLC Kappa and Lambda versus Clinical Status
| ResponseCriteria | Response Criteria based on Clinical Status | |||||
|---|---|---|---|---|---|---|
| based onN Latex FLCresults | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total |
| CompleteResponse | 19 | 8 | 10 | 6 | 1 | 44 |
| VGPR | 15 | 40 | 11 | 8 | 1 | 75 |
| PartialResponse | 0 | 4 | 15 | 6 | 1 | 26 |
| StableDisease | 0 | 4 | 17 | 35 | 5 | 61 |
| ProgressiveDisease | 0 | 0 | 3 | 4 | 9 | 16 |
| Total | 34 | 56 | 56 | 59 | 17 | 222 |
Concordance of N Latex FLC versus Clinical Status (Evaluation Mode 1)
Concordance Rate and 95% Confidence Intervals of N Latex FLC versus Clinical Status (Evaluation Mode 1)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| ConcordanceRate | 55.9% | 71.4% | 26.8% | 59.3% | 52.9% |
| 95% CIBootstrap | 28.6 – 75.7% | 56.6 – 88.9% | 7.8 – 30.2% | 39.6 – 75.0% | 28.6 – 78.9% |
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Sensitivity and Specificity and 95% Confidence Intervals of N Latex FLC versus Clinical Status (Evaluation Mode 1)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| Sensitivity | 52.9% (9/17) | 28.6 – 78.9% |
| Specificity | 96.6% (198/205) | 95.2 — 99.5% |
Concordance of N Latex FLC versus Clinical Status (Evaluation Mode 2)
| ResponseCriteriabased onN Latex FLCresults | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total |
|---|---|---|---|---|---|---|
| CompleteResponse | 18 | 8 | 10 | 6 | 1 | 43 |
| VGPR | 16 | 40 | 11 | 8 | 1 | 76 |
| PartialResponse | 0 | 4 | 15 | 6 | 0 | 25 |
| StableDisease | 0 | 4 | 17 | 34 | 3 | 58 |
| ProgressiveDisease | 0 | 0 | 3 | 5 | 12 | 20 |
| Total | 34 | 56 | 56 | 59 | 17 | 222 |
Concordance Rate and 95% Confidence Intervals of N Latex FLC versus Clinical Status (Evaluation Mode 2)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| ConcordanceRate | 52.9% | 71.4% | 26.8% | 57.6% | 70.6% |
| 95% CIBootstrap | 25.0 – 74.3% | 56.6 – 88.9% | 8.0 – 30.3% | 38.2 – 72.9% | 47.1 – 88.2% |
Sensitivity and Specificity and 95% Confidence Intervals of N Latex FLC versus Clinical Status (Evaluation Mode 2)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| Sensitivity | 70.6% (12/17) | 47.1 – 88.2% |
| Specificity | 96.1% (197/205) | 94.8 - 99.0% |
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| ResponseCriteria | Response Criteria based on Clinical Status | |||||
|---|---|---|---|---|---|---|
| based onN Latex FLCresults | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total |
| CompleteResponse | 18 | 8 | 10 | 6 | 1 | 43 |
| VGPR | 16 | 40 | 10 | 7 | 1 | 74 |
| PartialResponse | 0 | 4 | 15 | 6 | 0 | 25 |
| StableDisease | 0 | 4 | 18 | 34 | 2 | 58 |
| ProgressiveDisease | 0 | 0 | 3 | 6 | 13 | 22 |
| Total | 34 | 56 | 56 | 59 | 17 | 222 |
Concordance of N Latex FLC versus Clinical Status (Evaluation Mode 3)
Concordance Rate and 95% Confidence Intervals of N Latex FLC versus Clinical Status (Evaluation Mode 3)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| ConcordanceRate | 52.9% | 71.4% | 26.8% | 57.6% | 76.5% |
| 95% CIBootstrap | 24.0 – 74.2% | 56.4 – 89.1% | 7.9 – 30.3% | 37.5 – 72.3% | 52.9 – 93.8% |
Sensitivity and Specificity and 95% Confidence Intervals of N Latex FLC versus Clinical Status (Evaluation Mode 3)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| Sensitivity | 76.5% (13/17) | 52.9 – 93.8% |
| Specificity | 95.6% (196/205) | 93.3 – 99.0% |
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immunoglobulin light-chain amyloidosis (AL): Agreement Rate Freelite Kappa and Lambda versus Clinical Status
| ResponseCriteriabased onFreeliteresults | Response Criteria based on Clinical Status | |||||
|---|---|---|---|---|---|---|
| CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total | |
| CompleteResponse | 21 | 14 | 12 | 13 | 1 | 61 |
| VGPR | 11 | 37 | 5 | 3 | 1 | 57 |
| PartialResponse | 2 | 2 | 15 | 7 | 0 | 26 |
| StableDisease | 0 | 3 | 23 | 32 | 4 | 62 |
| ProgressiveDisease | 0 | 0 | 1 | 4 | 11 | 16 |
| Total | 34 | 56 | 56 | 59 | 17 | 222 |
Concordance of Freelite versus Clinical Status (Evaluation Mode 1)
Concordance Rate and 95% Confidence Intervals of Freelite versus Clinical Status (Evaluation Mode 1)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| ConcordanceRate | 61.8% | 66.1% | 26.8% | 54.2% | 64.7% |
| 95% CIBootstrap | 40.7 – 87.0% | 54.9 – 85.4% | 6.2 – 29.2% | 34.2 – 70.7% | 38.9 – 82.4% |
Sensitivity and Specificity and 95% Confidence Intervals of Freelite versus Clinical Status (Evaluation Mode 1)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| Sensitivity | 64.7% (11/17) | 38.9 - 82.4% |
| Specificity | 97.6% (200/205) | 94.8 - 99.5% |
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| ResponseCriteria | Response Criteria based on Clinical Status | |||||
|---|---|---|---|---|---|---|
| based onFreeliteresults | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total |
| CompleteResponse | 20 | 14 | 12 | 13 | 1 | 60 |
| VGPR | 12 | 34 | 5 | 3 | 0 | 54 |
| PartialResponse | 2 | 5 | 16 | 7 | 2 | 32 |
| StableDisease | 0 | 3 | 21 | 31 | 4 | 59 |
| ProgressiveDisease | 0 | 0 | 2 | 5 | 10 | 17 |
| Total | 34 | 56 | 56 | 59 | 17 | 222 |
Concordance of Freelite versus Clinical Status (Evaluation Mode 2)
Concordance Rate and 95% Confidence Intervals of Freelite versus Clinical Status (Evaluation Mode 2)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| ConcordanceRate | 58.8% | 60.7% | 28.6% | 52.5% | 58.8% |
| 95% CIBootstrap | 33.3 – 84.0% | 49.1 – 82.6% | 6.9 – 30.4% | 32.7 – 68.8% | 28.6 – 80.0% |
Sensitivity and Specificity and 95% Confidence Intervals of Freelite versus Clinical Status (Evaluation Mode 2)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| Sensitivity | 58.8% (10/17) | 28.6 – 80.0% |
| Specificity | 96.6% (198/205) | 94.2 - 99.5% |
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| ResponseCriteriabased onFreeliteresults | Response Criteria based on Clinical Status | |||||
|---|---|---|---|---|---|---|
| CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease | Total | |
| CompleteResponse | 22 | 14 | 12 | 13 | 1 | 62 |
| VGPR | 11 | 36 | 5 | 3 | 1 | 56 |
| PartialResponse | 1 | 2 | 15 | 7 | 0 | 25 |
| StableDisease | 0 | 3 | 22 | 30 | 4 | 59 |
| ProgressiveDisease | 0 | 1 | 2 | 6 | 11 | 20 |
| Total | 34 | 56 | 56 | 59 | 17 | 222 |
Concordance of Freelite versus Clinical Status (Evaluation Mode 3)
Concordance Rate and 95% Confidence Intervals of Freelite versus Clinical Status (Evaluation Mode 3)
| ResponseCriteria | CompleteResponse | VGPR | PartialResponse | StableDisease | ProgressiveDisease |
|---|---|---|---|---|---|
| ConcordanceRate | 64.7% | 64.3% | 26.8% | 50.8% | 64.7% |
| 95% CIBootstrap | 44.4 – 91.3% | 52.6 – 84.6% | 6.4 – 29.3% | 31.7 – 66.7% | 38.9 – 83.3% |
Sensitivity and Specificity and 95% Confidence Intervals of Freelite versus Clinical Status (Evaluation Mode 3)
| Result(n / Total) | 95% CI Bootstrap | |
|---|---|---|
| Sensitivity | 64.7% (11/17) | 38.9 – 83.3% |
| Specificity | 95.6% (196/205) | 93.4 - 99.0% |
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Comparison to Predicate Devices using Follow-up Graphs
Patients were monitored and tested using N Latex FLC kappa and lambda and Freelite Kappa and Lambda after initiation of the first therapy phase and at intervals of ≥ one week with a total of at least three collections. Two graphs each were established for the 72 patients included in the study, one using involved free light chain (iFLC) and one using the difference between the two free light chain concentrations (dFLC).
While N Latex FLC kappa and lambda and Freelite Kappa and Lambda assays react in the same manner and follow a parallel response, they do not always agree in the magnitude of concentration. For this reason, different free light assays cannot be used interchangeably (as stated in the sponsor's package insert). They do, for the most part, follow a parallel path.
References
- National Comprehensive Cancer Network. "NCCN clinical practice guidelines in oncology 1) (NCCN guidelines)." Systemic Light Chain Amyloidosis Version 1 (2022): 1-27.
-
- Peter Mollee, Jill Tate and Carel J. Pretorius, "Evaluation of the N Latex light chain assay in the diagnosis and monitoring of AL amyloidosis", in Clin Chem Lab Med 2013.
-
- Paolo Milani, Giampaolo Merlini and Giovanni Palladini, "Novel Therapies in Light Chain Amyloidosis", in Kidney International Reports (2018) 3, 530-541.
- Giovanni Palladini and Giampaolo Merlini. "When should treatment of AL amyloidosis start 4) at relapse? Early, to prevent organ progression", in Blood Advances, Point Counterpoint, Jan 2019, Vol 3, No. 2.
8. Proposed Labeling
The labeling is adequate and satisfies requirements of 21 CFR Part 809.10.
9. Conclusion
The N Latex FLC kappa and lambda reagents with the expanded intended use to include monitoring of immunodlobulin light-chain amyloidosis (AL) patients are substantially equivalent to the legally marketed predicate devices FDA cleared under K031016.
END OF SUMMARY
§ 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).