N Latex FLC kappa assay, N Latex FLC lambda assay

K182098 · Siemens Healthcare Diagnostics Products GmbH · DFH · Nov 1, 2018 · Immunology

Device Facts

• Record ID: K182098
• Device Name: N Latex FLC kappa assay, N Latex FLC lambda assay
• Applicant: Siemens Healthcare Diagnostics Products GmbH
• Product Code: DFH · Immunology
• Decision Date: Nov 1, 2018
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.5550
• Device Class: Class 2

Intended Use

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.

Device Story

In-vitro diagnostic reagents for quantitative determination of free light chains (FLC) in human serum and EDTA-plasma. Principle: particle-enhanced immunonephelometry; polystyrene particles coated with monoclonal antibodies agglutinate with FLC in samples; light scattering intensity proportional to protein concentration. Used on BN II and BN ProSpec systems in clinical laboratory settings. Output: quantitative FLC concentration (mg/L). Healthcare providers use results alongside clinical history, protein electrophoresis, immunofixation, bone marrow, imaging, and urine assessments to monitor multiple myeloma therapy response and aid in amyloidosis diagnosis. Benefits include standardized monitoring of disease progression or response to therapy.

Clinical Evidence

Retrospective clinical study of 98 subjects (104 MM, 21 LCMM) with 391 serum samples. Evaluated performance as an aid in monitoring MM disease status compared to IMWG clinical response criteria. Clinical sensitivity for detecting progressive disease was 26% (95% CI: 13.9%–40.3%) and clinical specificity was 97% (95% CI: 95.1%–98.8%). Comparison with predicate device showed 89% overall agreement in response category assignment.

Technological Characteristics

Particle-enhanced immunonephelometry. Reagents: polystyrene particles coated with mouse monoclonal anti-human FLC kappa or lambda antibodies. Energy source: light beam for nephelometric scattering. Dimensions/form factor: liquid reagents for automated BN II/BN ProSpec systems. Connectivity: standalone/integrated into clinical laboratory instrument workflow.

Indications for Use

Indicated for use as an aid in the diagnosis and monitoring of multiple myeloma (MM) and diagnosis of amyloidosis (AL) in patients, in conjunction with other laboratory and clinical findings. For prescription use only.

Regulatory Classification

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.

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)

Submission Summary (Full Text)

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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 ([e-mail]) or phone [phone] 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)

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.

| 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: | [e-mail] |
| Phone: | 302-631-8811 |
| Fax: | 302-631-6299 |
| Date of Preparation: | August 29, 2018 |

## 2. Device Information

| Trade Name: | N Latex FLC kappa assay<br>N Latex FLC lambda assay |
|-----------------------|---------------------------------------------------------------------------------------|
| Common or Usual Name: | Light Chain immunological test system |
| Classification Name: | Immunoglobulin (light chain specific) immunological<br>test system per 21CFR 866.5550 |
| Product Code: | DFH (kappa)<br>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

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.

## 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 Healthcare<br>BN Systems | The Binding Site | |
| | N Latex FLC kappa<br>N Latex FLC lambda | Freelite® Human Kappa Free and<br>Freelite® Human Lambda Free<br>kits on the Siemens BN™II<br>K031016 | |
| Indications for<br>Use | <i>In-vitro</i> diagnostic reagents for the<br>quantitative determination of free<br>light chains (FLC), type kappa or<br>type lambda in human serum and<br>EDTA-plasma by means of particle-<br>enhanced immunonephelometry<br>using the BN Systems. FLC<br>measurements are used as an aid in<br>the diagnosis and monitoring of<br>multiple myeloma (MM) and as an<br>aid in the diagnosis of amyloidosis<br>(AL) in conjunction with other<br>laboratory and clinical findings.<br>The response category assignment<br>of Complete Response for the<br>monitoring of MM is reliant upon the<br>combination of clinical history and<br>other tests including protein<br>electrophoresis, immunofixation<br>and bone marrow, imaging and<br>urine assessments. | Kappa: This kit is intended for the<br>quantitation of kappa free light chains<br>in serum and urine on the Siemens<br>BN™ II. Measurement of free light<br>chains aids in the diagnosis and<br>monitoring of multiple myeloma,<br>lymphocytic neoplasms,<br>Waldenstrom's macroglobulinemia,<br>AL amyloidosis, light chain<br>deposition disease and connective<br>tissue diseases such as systemic<br>lupus erythematosus in conjunction<br>with other laboratory and clinical<br>findings.<br>Lambda: This kit is intended for the<br>quantitation of lambda free light<br>chains in serum and urine on the<br>Siemens BN™ II. Measurement of<br>free light chains aids in the diagnosis<br>and monitoring of multiple myeloma,<br>lymphocytic neoplasms,<br>Waldenstrom's macroglobulinemia,<br>AL amyloidosis, light chain<br>deposition disease and connective<br>tissue diseases such as systemic<br>lupus erythematosus in conjunction<br>with other laboratory and clinical<br>findings. | |
| Sample Type | Human serum and EDTA plasma | Human serum and urine | |
| Units | mg/L | Same | |
| Technology | Nephelometry | Nephelometry | |
| | Polystyrene particles coated with<br>monoclonal antibodies | Polystyrene particles coated with<br>polyclonal monospecific antibodies | |
| Traceability | Internal Reference Plasma Pool | Internal reference preparation | |
| Calibrators | One level | Same | |
| Instrument<br>System | Siemens BN II and BN ProSpec<br>Systems | Siemens BN II | |
| | Proposed Devices | Predicate Devices | |
| | Siemens Healthcare<br>BN Systems | The Binding Site | |
| | N Latex FLC kappa<br>N Latex FLC lambda | Freelite® Human Kappa Free and<br>Freelite® Human Lambda Free<br>kits on the Siemens BN™II<br>K031016 | |
| Analytical<br>Measuring Range<br>(Calibrator lot<br>dependent) | kappa: 3.4 to 110 mg/L<br>lambda: 1.9 to 60 mg/L | Kappa: 5.9 to 190 mg/L<br>Lambda: 5.0 to 160 mg/L | |
| Reference<br>Interval | kappa: 8.24 – 28.90 mg/L<br>lambda: 9.10 - 32.60 mg/L<br>Ratio: 0.53 to 1.51 | Kappa: 3.30 to 19.40 mg/L<br>Lambda: 5.71 to 26.30 mg/L<br>Ratio: 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 N<br>Latex FLC | Positive* | 12 | 9 | 21 | |
| | Negative** | 35 | 335 | 370 | |
| | Total | 47 | 344 | 391 | |
| Clinical Sensitivity: 26%*** (12/47) (95% CI: 13.9% – 40.3%)<br>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:

| Response<br>Category | Response Criteria based on<br>N Latex FLC and IFE Results | Clinical Assessment<br>based on IMWG |
|------------------------|----------------------------------------------------------------------|--------------------------------------|
| Good Response | FLC ratio normal and IFE<br>negative* | sCR |
| | | CR |
| Moderate<br>Response | ≥ 50 to ≥ 90% reduction of<br>rd_dFLC** | VGPR |
| | | PR |
| Stable Disease | 50% reduction to 25% increase of<br>rd_dFLC | SD |
| Progressive<br>Disease | ≥ 25% increase of rd_dFLC<br>AND increase of d_dFLC***<br>≥ 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 based<br>on N Latex FLC<br>results | Clinical Assessment | | | | |
|---------------------------------------------|---------------------|----------------------|-------------------|------------------------|-------|
| | Good<br>Response | Moderate<br>Response | Stable<br>Disease | Progressive<br>Disease | 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 on<br>N Latex FLC results | Response Based on Freelite Results | | | | |
|------------------------------------------|------------------------------------|----------------------|-------------------|------------------------|-------|
| | Good<br>Response | Moderate<br>Response | Stable<br>Disease | Progressive<br>Disease | 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