The response category assignment of Complete Response for the monitoring of MM is reliant upon the combination of clinical history and other tests including protein electrophoresis, immunofixation and bone marrow, imaging and urine assessments.

Device Description

In-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma by means of particle-enhanced immunonephelometry using the BN Systems. FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and as an aid in the diagnosis of amyloidosis (AL) in conjunction with other laboratory and clinical findings. The response category assignment of Complete Response for the monitoring of MM is reliant upon the combination of clinical history and other tests including protein electrophoresis, immunofixation and bone marrow, imaging and urine assessments,

The 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 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. The devices in this submission have not materially changed since clearance under K171742. The purpose for this submission is to add monitoring of multiple myeloma (MM) to the intended use.

AI/ML Overview

Here's a breakdown of the requested information based on the provided text, focusing on the expanded indication for monitoring Multiple Myeloma (MM) with the N Latex FLC kappa and N Latex FLC lambda assays:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the document beyond the performance metrics themselves. However, the study aims to demonstrate substantial equivalence to the predicate device and satisfactory agreement with clinical status for MM monitoring. The reported performance is as follows:

Performance Metric	Acceptance Criteria (Implied)	Reported Device Performance (N Latex FLC)
Clinical Status Comparison	Demonstrate adequate sensitivity and specificity for progression.	Sensitivity: 26% (12/47) (95% CI: 13.9% – 40.3%) for ProgressionSpecificity: 97% (335/344) (95% CI: 95.1%– 98.8%) for No Progression
Agreement with Clinical Assessment (Good Response)	High agreement with sCR/CR	62%
Agreement with Clinical Assessment (Moderate Response)	High agreement with VGPR/PR	79%
Agreement with Clinical Assessment (Stable Disease)	High agreement with SD	70%
Agreement with Clinical Assessment (Progressive Disease)	High agreement with PD	26%
Overall Agreement to Predicate (Response Category)	Demonstrate high agreement with the predicate device's classifications.	89% agreement across all response categories. Higher for Good Response (100%) and Stable Disease (92%).

Note: The document states "For the predicate device similar data were obtained when compared to clinical status," suggesting the 26% sensitivity for progression is considered acceptable in this context given the device's role as an "aid" in diagnosis and monitoring.

2. Sample Size Used for the Test Set and Data Provenance

Sample Size for Test Set:
- Clinical Status Comparison: 391 patients (divided into 47 with Progression and 344 with No Progression).
- Agreement with Clinical Assessment: 391 patients.
- Comparison to Predicates (Response Category): 391 patients.
- Comparison to Predicates (Follow-up Graphs): 102 patients.
Data Provenance: The study was a "multi-center study." The country of origin is not explicitly stated, but the submission is from Siemens Healthcare Diagnostics Products GmbH, based in Germany. The study appears to be retrospective as it compares results with existing clinical assessments and predicate device results.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications

The document does not specify the number of experts or their qualifications for establishing the ground truth. It mentions "clinical assessment provided by the physician in charge within the Case Report Form (CRF)."

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method. "Clinical assessment provided by the physician in charge" suggests a singular clinical judgment rather than a consensus or adjudicated process among multiple experts for the ground truth.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. This device is an in-vitro diagnostic assay, not an imaging AI system that would typically involve human readers.

6. Standalone Performance

Yes, a standalone performance analysis was done. The N Latex FLC assays were evaluated independently in comparison to clinical status and then compared to the predicate devices. The sensitivity and specificity values are derived from the algorithm's performance in categorizing patient status.

7. Type of Ground Truth Used

The ground truth used was clinical assessment based on IMWG FLC criteria, taking into account IFE (immunofixation electrophoresis) and serum FLC measurements in conjunction with "other clinical findings" and "further information in addition to serum testing" as provided by the treating physician in the Case Report Form.

8. Sample Size for the Training Set

The document does not mention a training set. This is a diagnostic assay, and the study focuses on evaluating its performance (validation) rather than training an algorithm. The "training set" concept is more applicable to machine learning-based AI devices.

9. How the Ground Truth for the Training Set was Established

Not applicable, as no training set is described for this device.

Summary

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Image /page/0/Picture/0 description: The image shows the logos of the Department of Health & Human Services and the Food and Drug Administration (FDA). The Department of Health & Human Services logo is on the left, and the FDA logo is on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.

November 1, 2018

Siemens Healthcare Diagnostics Products GmbH Christine Perkins Regulatory Specialist Emil-von-Behring-Str. 76 Marburg, DE 35041

Re: K182098

Trade/Device Name: N Latex FLC kappa assay, N Latex FLC lambda assay Regulation Number: 21 CFR 866.5550 Regulation Name: Immunoglobulin (light chain specific) immunological test system Regulatory Class: Class II Product Code: DFH, DEH Dated: August 2, 2018 Received: August 3, 2018

Dear Christine Perkins:

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/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice

(https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Leonthena R. Carrington -S

Lea Carrington Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K182098

Device Name

N Latex FLC kappa and N Latex FLC lambda

Indications for Use (Describe)

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/0 description: The image shows the Siemens Healthineers logo. The word "SIEMENS" is in teal, and the word "Healthineers" is in orange. To the right of the word "Healthineers" is a graphic of orange dots arranged in a circular pattern.

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: K182098_

1. Submitter

Siemens Healthcare Diagnostics Products GmbH Emil-von-Behring-Str. 76 35041 Marburg, Germany

Contact:	Christine Perkins
Email:	christine.perkins@siemens-healthineers.com
Phone:	302-631-8811
Fax:	302-631-6299
Date of Preparation:	August 29, 2018

2. Device Information

Trade Name:	N Latex FLC kappa assayN Latex FLC lambda assay
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:
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

5. Intended Use / Indications for Use

N Latex FLC kappa and N Latex FLC lambda assays

In-vitro diagnostic reagents for the quantitative determination of free light chains (FLC), type kappa or type lambda in human serum and EDTA-plasma by means of particle-enhanced immunonephelometry using the BN Systems. FLC measurements are used as an aid in the diagnosis and monitoring of multiple myeloma (MM) and as an aid in the diagnosis of amvloidosis (AL) in coniunction with other laboratory and clinical findings. The response category assignment of Complete Response for the monitoring of MM is reliant upon the combination of clinical history and other tests including protein electrophoresis, immunofixation and bone marrow, imaging and urine assessments.

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.

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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 N Latex FLC kappa and N Latex FLC lambda assays versus The Binding Site (TBS) Freelite Human Kappa Free and Lambda Free assays (predicates) is provided in the table below.

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	Proposed Devices	Predicate Devices
	Siemens HealthcareBN Systems	The Binding Site
	N Latex FLC kappaN Latex FLC lambda	Freelite® Human Kappa Free andFreelite® Human Lambda Freekits on the Siemens BN™IIK031016
Indications forUse	In-vitro diagnostic reagents for thequantitative determination of freelight chains (FLC), type kappa ortype lambda in human serum andEDTA-plasma by means of particle-enhanced immunonephelometryusing the BN Systems. FLCmeasurements are used as an aid inthe diagnosis and monitoring ofmultiple myeloma (MM) and as anaid in the diagnosis of amyloidosis(AL) in conjunction with otherlaboratory and clinical findings.The response category assignmentof Complete Response for themonitoring of MM is reliant upon thecombination of clinical history andother tests including proteinelectrophoresis, immunofixationand bone marrow, imaging andurine assessments.	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 chaindeposition disease and connectivetissue diseases such as systemiclupus erythematosus in conjunctionwith other laboratory and clinicalfindings.Lambda: This kit is intended for thequantitation of lambda free lightchains in serum and urine on theSiemens BN™ II. Measurement offree light chains aids in the diagnosisand monitoring of multiple myeloma,lymphocytic neoplasms,Waldenstrom's macroglobulinemia,AL amyloidosis, light chaindeposition disease and connectivetissue diseases such as systemiclupus erythematosus in conjunctionwith other laboratory and clinicalfindings.
Sample Type	Human serum and EDTA plasma	Human serum and urine
Units	mg/L	Same
Technology	Nephelometry	Nephelometry
	Polystyrene particles coated withmonoclonal antibodies	Polystyrene particles coated withpolyclonal monospecific antibodies
Traceability	Internal Reference Plasma Pool	Internal reference preparation
Calibrators	One level	Same
InstrumentSystem	Siemens BN II and BN ProSpecSystems	Siemens BN II
	Proposed Devices	Predicate Devices
	Siemens HealthcareBN Systems	The Binding Site
	N Latex FLC kappaN Latex FLC lambda	Freelite® Human Kappa Free andFreelite® Human Lambda Freekits on the Siemens BN™IIK031016
AnalyticalMeasuring Range(Calibrator lotdependent)	kappa: 3.4 to 110 mg/Llambda: 1.9 to 60 mg/L	Kappa: 5.9 to 190 mg/LLambda: 5.0 to 160 mg/L
ReferenceInterval	kappa: 8.24 – 28.90 mg/Llambda: 9.10 - 32.60 mg/LRatio: 0.53 to 1.51	Kappa: 3.30 to 19.40 mg/LLambda: 5.71 to 26.30 mg/LRatio: 0.26 to 1.65

Comparison of Technological Characteristics

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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 MM. See original submission (K171742) 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 MM patients

The Latex FLC assays were evaluated on BN II Systems in a multi-center study to evaluate performance in monitoring multiple myeloma (MM) patients. The following studies were performed in support of an MM monitoring claim:

Comparison to Clinical Status

Therapy response was evaluated according to IMWG FLC criteria considering IFE and serum FLC measurements. Response categories were determined for FLC testing by N Latex FLC and Freelite, respectively. The response levels obtained by the two different test systems were compared to the clinical response level provided by the physician in charge within the Case Report Form (CRF). Relative agreement between the clinical responses (including further

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information in addition to serum testing) and the response level applying the IMWG FLC response scheme by either using N Latex FLC or the predicate device were calculated and compared.

		Clinical Status
		Progression	No Progression	Total
Change in NLatex FLC	Positive*	12	9	21
	Negative**	35	335	370
	Total	47	344	391
Clinical Sensitivity: 26%*** (12/47) (95% CI: 13.9% – 40.3%)Clinical Specificity: 97% (335/344) (95% CI: 95.1%– 98.8%)

*Positive: ≥25% rd dFLC and d dFLC ≥100 mg/L

**Negative: <25% rd dFLC and d dFLC FLC <100 mg/L

*** For the predicate device similar data were obtained when compared to clinical status.

Results of N Latex FLC Kappa and N Latex FLC Lambda assays in combination with IFE results were used to assign a response category and compared to the clinical assessment according to the table below:

ResponseCategory	Response Criteria based onN Latex FLC and IFE Results	Clinical Assessmentbased on IMWG
Good Response	FLC ratio normal and IFEnegative*	sCR
		CR
ModerateResponse	≥ 50 to ≥ 90% reduction ofrd_dFLC**	VGPR
		PR
Stable Disease	50% reduction to 25% increase ofrd_dFLC	SD
ProgressiveDisease	≥ 25% increase of rd_dFLCAND increase of d_dFLC***≥ 100 mg/L	PD

*Applies only to MM population

**rd_dFLC = (dFLC t2 - dFLC t1)/ dFLC t1

***d_dFLC = dFLC t2 = dFLC t1 (with 'dFLC = iFLC = ni FLC')

Definitions:

t1 = time point 1; t2 = time point 2 ●
rd = relative difference ●
iFLC = involved FLC; niFLC = not involved FLC; ●
. Relative change of involved FLC: rd_iFLC = (iFLC t2 = iFLC t1)/ iFLC t1
Relative change of difference between both FLC: dFLC = iFLC = niFLC

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The performance of N Latex FLC kappa and FLC lambda in combination with IFE compared to the clinical assessment is summarized in the following table:

Response basedon N Latex FLCresults	Clinical Assessment
	GoodResponse	ModerateResponse	StableDisease	ProgressiveDisease	Total
Good Response	21	3	6	1	31
Moderate Response	10	104	38	16	168
Stable Disease	3	24	126	18	171
Progressive Disease	0	0	9	12	21
Total	34	131	179	47	391
Agreement	62%	79%	70%	26%	67%

Discordance results:

The response criteria established by clinicians are often based on multiple factors ● besides FLC results, therefore FLC results alone might lead to a different classification.

Comparison to Predicates

Therapy response was evaluated according to the International Myeloma Working Group (IMWG) FLC criteria considering IFE and serum FLC measurements alone.

The performance of N Latex FLC kappa and FLC lambda assays were also compared to the predicate devices based on the disease response categories describe above.

In this retrospective clinical study, all samples were tested with the N Latex FLC kappa and lambda assays and with the predicate device. The performance of N Latex FLC kappa and N Latex FLC lambda assays compared to the predicate devices based on the same disease response category is summarized as follows:

Response based onN Latex FLC results	Response Based on Freelite Results
	GoodResponse	ModerateResponse	StableDisease	ProgressiveDisease	Total
Good Response	27	2	0	1	31
Moderate Response	0	66	15	0	81
Stable Disease	0	13	238	7	258
Progressive Disease	0	0	5	16	21

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Total	27	81	259	24	391
Agreement	100%	81%	92%	67%	89%

Comparison to Predicates 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 ≥ three weeks with a total of at least four collections. Two graphs each were established for the 102 patients included in the study, one using lin/lin and one using log/log scaling.

While N Latex FLC assays 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 FLC assays cannot be used interchangeably (as stated in the sponsor's package insert).

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 assays with the expanded intended use to include monitoring of multiple myeloma patients are substantially equivalent to the legally marketed predicate devices FDA cleared under K031016.

END OF SUMMARY

Regulation Number and Section

§ 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).