← Product Code [PCN](/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PCN) · K172613

# Optilite Hevylite IgG Kappa Kit, Optilite Hevylite IgG Lambda Kit (K172613)

_The Binding Site Group , Ltd. · PCN · Feb 15, 2018 · Immunology · SESE_

**Canonical URL:** https://fda.innolitics.com/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PCN/K172613

## Device Facts

- **Applicant:** The Binding Site Group , Ltd.
- **Product Code:** [PCN](/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PCN.md)
- **Decision Date:** Feb 15, 2018
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.5510
- **Device Class:** Class 2
- **Review Panel:** Immunology

## Intended Use

Optilite Hevylite IgG Kappa is a quantitative in vitro assay performed on the Optilite analyser for the measurement of IgG kappa (IgG heavy chain and kappa light chain intact immunoglobulin) in serum. Measurement of Hevylite Human IgG Kappa is used alongside Hevylite Human IgG Lambda to calculate the IgG Kappa / IgG Lambda ratio. The Hevylite Human IgG Kappa / IgG Lambda ratio can be used when monitoring previously diagnosed IgG multiple myeloma and is used in conjunction with other laboratory tests and clinical evaluations. The assignment of complete response is reliant upon other tests including immunofixation, bone marrow and urine assessments. Optilite Hevylite IgG Lambda is a quantitative in vitro assay performed on the Optilite analyser for the measurement of IgG lambda (IgG heavy chain and lambda light chain intact immunoglobulin) in serum. Measurement of Hevylite Human IgG Lambda is used alongside Hevylite Human IgG Kappa to calculate the IgG Kappa / IgG Lambda ratio. The Hevylite Human IgG Kappa / IgG Lambda ratio can be used when monitoring previously diagnosed IgG multiple myeloma and is used in conjunction with other laboratory tests and clinical evaluations. The assignment of complete response is reliant upon other tests including immunofixation, bone marrow and urine assessments.

## Device Story

The Optilite Hevylite IgG Kappa and IgG Lambda kits are in vitro diagnostic assays used on the Binding Site Optilite analyser. The device measures IgG heavy chain and light chain (Kappa or Lambda) concentrations in serum samples via turbidimetry. The system uses polyclonal monospecific sheep anti-human IgG antisera to form insoluble immune complexes with the target antigen; light scatter is measured to determine concentration. The resulting IgG Kappa/IgG Lambda ratio is used by clinicians to monitor disease status in patients previously diagnosed with IgG multiple myeloma. The device is intended for use in clinical laboratories by trained personnel. Results are used in conjunction with other clinical evaluations and laboratory tests (e.g., immunofixation, bone marrow, urine assessments) to assess patient response to therapy. The device provides quantitative data to assist in tracking disease progression or response to treatment, aiding clinical decision-making.

## Clinical Evidence

Clinical validity established via comparison of HLC response categorization between the subject device and predicate. Study used 69 monitoring samples from 22 patients (10 IgG Kappa, 12 IgG Lambda) and mathematical modeling of 437 historical samples. Agreement evaluated using Cohen's Kappa (0.79; 95% CI 0.62–0.96) and weighted Kappa (0.87; 95% CI 0.74–0.98). Analytical performance included precision (total CVs 4.0–9.0%), linearity, and interference testing per CLSI guidelines.

## Technological Characteristics

Turbidimetric immunoassay; reagents contain polyclonal monospecific sheep anti-human IgG antisera and 0.099% sodium azide preservative. Calibrators are single-level, autodiluted by the analyzer. Traceable to ERM-DA470k/IFCC. Designed for use on the Binding Site Optilite analyzer. Open-vial stability: 3 months at 2-8°C. On-board stability: 28 days.

## Regulatory Identification

An immunoglobulins A, G, M, D, and E immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the immunoglobulins A, G, M, D, an E (serum antibodies) in serum. Measurement of these immunoglobulins aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

## Predicate Devices

- Hevylite® Human IgG Kappa Kit and Hevylite® Human IgG Lambda Kit ([K132555](/device/K132555.md))

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

A. 510(k) Number:
K172613

B. Purpose for Submission:
Modified IVD assay on previously cleared instrument

C. Measurand:
Immunoglobulin IgG Kappa (combined γ heavy and κ light chain) and Immunoglobulin IgG Lambda (combined γ heavy and λ light chain)

D. Type of Test:
Quantitative, Turbidimetry

E. Applicant:
The Binding Site Group, Ltd.

F. Proprietary and Established Names:
Optilite Hevylite IgG Kappa Kit
Optilite Hevylite IgG Lambda Kit

G. Regulatory Information:

1. Regulation section:
21 CFR §866.5510, Immunoglobulins A, G, M, D, and E Immunological Test System

2. Classification:
Class II

3. Product codes:
PCN - IgG Kappa (Heavy and Light chain Combined). Antigen, antiserum, control
PCO - IgG Lambda (Heavy and Light chain Combined). Antigen, antiserum, control

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4. Panel:

Immunology (82)

H. Intended Use:

1. Intended uses:

Optilite Hevylite IgG Kappa is a quantitative in vitro assay performed on the Optilite analyser for the measurement of IgG kappa (IgG heavy chain and kappa light chain intact immunoglobulin) in serum. Measurement of Hevylite Human IgG Kappa is used alongside Hevylite Human IgG Lambda to calculate the IgG Kappa / IgG Lambda ratio. The Hevylite Human IgG Kappa / IgG Lambda ratio can be used when monitoring previously diagnosed IgG multiple myeloma and is used in conjunction with other laboratory tests and clinical evaluations. The assignment of complete response is reliant upon other tests including immunofixation, bone marrow and urine assessments.

Optilite Hevylite IgG Lambda is a quantitative in vitro assay performed on the Optilite analyser for the measurement of IgG lambda (IgG heavy chain and lambda light chain intact immunoglobulin) in serum. Measurement of Hevylite Human IgG Lambda is used alongside Hevylite Human IgG Kappa to calculate the IgG Kappa / IgG Lambda ratio. The Hevylite Human IgG Kappa / IgG Lambda ratio can be used when monitoring previously diagnosed IgG multiple myeloma and is used in conjunction with other laboratory tests and clinical evaluations. The assignment of complete response is reliant upon other tests including immunofixation, bone marrow and urine assessments.

2. Indications for use:

Same as intended use.

3. Special conditions for use statements:

For prescription use only.

Warning: The result of Hevylite IgG Kappa in a given specimen determined with assays with different manufacturers or different instrument platforms can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the Hevylite IgG Kappa assay used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of serially monitoring a patient, the assay method used for determining Hevylite IgG Kappa levels is changed, additional sequential testing should be carried out. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored.

Warning: The result of Hevylite IgG Lambda in a given specimen determined with assays with different manufacturers or different instrument platforms can vary due to differences

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in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the Hevylite IgG Lambda assay used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of serially monitoring a patient, the assay method used for determining Hevylite IgG Lambda levels is changed, additional sequential testing should be carried out. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored.

4. Special instrument requirements:

The Binding Site Optilite analyzer

I. Device Description:

The Hevylite Human IgG Kappa and IgG Lambda Kits contain vials of ready-to-use polyclonal monospecific sheep anti-IgG antisera against combined $\gamma$ heavy and $\kappa$ light chain or combined $\gamma$ heavy and $\lambda$ light chain, calibrators (six levels), controls (low and high) and reaction buffer in liquid form. The reagents contain $0.099\%$ sodium azide as preservative.

J. Substantial Equivalence Information:

1. Predicate device names:

Hevylite® Human IgG Kappa Kit and Hevylite® Human IgG Lambda Kit for use on Siemens BN™ II Systems

2. Predicate 510(k) numbers:

K132555

3. Comparison with predicate:

|  Similarities  |   |   |
| --- | --- | --- |
|  Item | Device
Optilite® Hevylite® IgG Kappa (IgGκ) and IgG Lambda (IgGλ) Kits | Predicate
Hevylite® IgG Kappa (IgGκ) and IgG Lambda (IgGλ) Kits  |
|  Intended Use | Quantitative in vitro assay for the measurement of IgG Kappa (IgG heavy chain and kappa light chain intact immunoglobulin) and IgG Lambda (IgG heavy chain and lambda light chain intact immunoglobulin) in serum. | Same  |

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|  Similarities  |   |   |
| --- | --- | --- |
|  Item | Device
Optilite® Hevylite® IgG Kappa (IgGκ) and IgG Lambda (IgGλ) Kits | Predicate
Hevylite® IgG Kappa (IgGκ) and IgG Lambda (IgGλ) Kits  |
|   | Measurement of Hevylite Human IgG Kappa is used alongside Hevylite Human IgG Lambda to calculate the IgG Kappa/IgG Lambda ratio. The Hevylite Human IgG Kappa/IgG Lambda ratio can be used when monitoring previously diagnosed IgG multiple myeloma and is used in conjunction with other laboratory tests and clinical evaluations. The assignment of complete response is reliant upon other tests including immunofixation, bone marrow and urine assessments. |   |
|  Analyte | IgG Kappa and IgG Lambda | Same  |
|  Antibody | Polyclonal monospecific sheep anti-human combined γ heavy and κ light chain or combined γ heavy and λ light chain | Same  |
|  Control | Binding Site High and Low Controls | Same  |
|  Traceability | ERM-DA470k/IFCC | Same  |
|  Sample Matrix | Serum | Same  |
|  Capture Antibody | Sheep anti-human IgG combined | Same  |
|  Calibrator | Single level Binding Site Hevylite calibrator autodiluted by the analyser to six different concentrations | Same  |
|  Open Vial Stability | Three months | Same  |
|  Reference Interval | IgGκ: 4.03 – 9.78 g/L
IgGλ: 1.97 – 5.71 g/L
IgGκ/IgGλ Ratio: 0.98 – 2.75 | Same  |

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|  Differences  |   |   |
| --- | --- | --- |
|  Item | Device
Optilite® Hevylite® IgG Kappa (IgGκ) and IgG Lambda (IgGλ) Kits | Predicate
Hevylite® IgG Kappa (IgGκ) and IgG Lambda (IgGλ) Kits  |
|  Method | Turbidimetry | Nephelometry  |
|  Instrument | Binding Site Optilite | Siemens BN^{th} II Systems  |
|  On Board Stability | 28 days | Not stated  |
|  Measuring Range | At standard 1/20 dilution:
IgGκ: 2.3 – 30.0 g/L
IgGλ: 1.5 – 17.5 g/L

Extended Range for IgGκ:
1/1 dilution: 0.115 – 1.5 g/L
1/5 dilution: 0.575 – 7.5 g/L
1/80 dilution: 9.2 - 120 g/L

Extended Range for IgGλ:
1/1 dilution: 0.075 – 0.875 g/L
1/5 dilution: 0.375 – 4.375 g/L
1/80 dilution: 6 - 70 g/L
1/120 dilution: 9 – 105 g/L | At standard 1/100 dilution:
IgGκ: 1.72–27.5 g/L
IgGλ: 0.88–14.0 g/L

Extended Range for IgGκ:
1/5 dilution: 0.09–1.38 g/L
1/20 dilution: 0.34–5.50 g/L
1/400 dilution: 6.88–110.0 g/L

1/2000 dilution: 34.4–550 g/L

Extended Range for IgGλ:
1/5 dilution: 0.04–0.70 g/L
1/20 dilution: 0.18–2.80 g/L
1/100 dilution: 0.88–14.0 g/L
1/400 dilution: 3.50–56.0 g/L
1/2000 dilution: 17.5–280 g/L  |

## K. Standard/Guidance Document Referenced (if applicable):

CLSI EP17-A Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline.

CLSI EP07-A2 Interference Testing in Clinical Chemistry, Approved Guideline – Second Edition.

CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach.

CLSI EP05-A2 Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline – Second Edition.

CLSI C28-A3: Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory.

## L. Test Principle:

Evaluating the concentration of a soluble antigen (e.g. IgG Lambda) by turbidimetry involves the addition of the test sample to a solution containing the appropriate antibody (anti-IgG Lambda) in a reaction vessel or cuvette. A beam of light is passed through the cuvette and, as the antigen-antibody reaction proceeds, the light passing through the cuvette is scattered

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increasingly as insoluble immune complexes are formed. Light scatter is monitored by measuring the decrease in intensity of the incident beam of light. The antibody in the cuvette is in excess so the amount of immune complex formed is proportional to the antigen concentration. A series of calibrators of known antigen concentration are assayed initially to produce a calibration curve of measured light scatter versus antigen concentration. Samples of unknown antigen concentration can then be assayed and the results read from the calibration curve.

## M. Performance Characteristics:

### 1. Analytical performance:

The results of all the studies met the Manufacturer's pre-specified acceptance criteria.

#### a. Precision/Reproducibility:

The within-run, between-run, between-day, between-lot and between-instrument imprecision were determined by testing six serum samples over 21 days with two runs per day on three different reagent lots and three different analyzers.

Results are summarised below.

IgGk precision studies:

|  Sample | Mean (g/L) | Within Run |   | Between Run |   | Between Day |   | Between Lot |   | Between Instrument |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV  |
|  1 | 3.148* | 0.048 | 1.5 | 0.104 | 3.3 | 0.124 | 3.9 | 0.098 | 3.1 | 0.036 | 1.1 | 0.169 | 5.4  |
|  2 | 4.260 | 0.184 | 4.3 | 0.209 | 4.9 | 0.162 | 3.8 | 0.14 | 3.3 | 0.033 | 0.8 | 0.323 | 7.6  |
|  3 | 5.601* | 0.145 | 2.6 | 0.263 | 4.7 | 0.308 | 5.5 | 0.205 | 3.7 | 0.099 | 1.8 | 0.430 | 7.7  |
|  4 | 7.621 | 0.178 | 2.3 | 0.263 | 3.5 | 0.413 | 5.4 | 0.426 | 5.6 | 0.216 | 2.8 | 0.521 | 6.8  |
|  5 | 13.574 | 0.218 | 1.6 | 0.385 | 2.8 | 0.879 | 6.5 | 0.851 | 6.3 | 0.253 | 1.9 | 0.984 | 7.2  |
|  6 | 16.824 | 0.383 | 2.3 | 0.352 | 2.1 | 0.992 | 5.9 | 0.991 | 5.9 | 0.608 | 3.6 | 1.120 | 6.7  |

IgGλ precision studies:

|  Sample | Mean (g/L) | Within Run |   | Between Run |   | Between Day |   | Between Lot |   | Between Instrument |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV  |
|  1 | 1.313* | 0.029 | 2.2 | 0.034 | 2.6 | 0.068 | 5.2 | 0.054 | 4.1 | 0.037 | 2.8 | 0.081 | 6.2  |
|  2 | 2.379* | 0.059 | 2.5 | 0.049 | 2.1 | 0.064 | 2.7 | 0.061 | 2.6 | 0.027 | 1.1 | 0.100 | 4.2  |
|  3 | 2.894 | 0.118 | 4.1 | 0.120 | 4.2 | 0.198 | 6.8 | 0.119 | 4.1 | 0.142 | 4.9 | 0.260 | 9.0  |
|  4 | 4.262 | 0.096 | 2.2 | 0.144 | 3.4 | 0.267 | 6.3 | 0.182 | 4.3 | 0.190 | 4.4 | 0.318 | 7.5  |
|  5 | 6.657 | 0.138 | 2.1 | 0.112 | 1.7 | 0.301 | 4.5 | 0.256 | 3.8 | 0.200 | 3.0 | 0.350 | 5.3  |
|  6 | 13.941 | 0.297 | 2.1 | 0.237 | 1.7 | 0.414 | 3.0 | 0.541 | 1.7 | 0.096 | 0.7 | 0.561 | 4.0  |

* samples run at 1/5 dilution

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b. Linearity/assay reportable range:

A linearity study was performed following CLSI guideline EP-6A. The linearity of the IgGκ and IgGλ assays have been confirmed using serially diluted serum samples to cover the standard measuring ranges of 2.3 – 30.0 g/L and 1.5 – 17.5 g/L, respectively. The results demonstrated that the IgGκ and IgGλ assays are linear over the ranges of 1.930 – 33.427 g/L and 1.380 – 19.300 g/L at 1+19 dilution.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Traceability:

An internal reference material was assigned by comparison with the Reference Material ERM-DA470k/IFCC.

Stability:

Open-vial stability was performed on three lots of Optilite Hevylite IgG Kappa and IgG Lambda kits with testing intervals at various time points up to 112 days. Data supports an open vial stability claim of 3 months at 2-8°C.

On-board stability was performed on three lots of Optilite Hevylite IgG Kappa. Open-vial stability was performed on three lots of Optilite Hevylite IgG Kappa and IgG Lambda kits with testing intervals at various time points up to 112 days. Data supports an open vial stability claim of 3 months at 2-8°C.

On-board stability was performed on three lots of Optilite Hevylite IgG Kappa and IgG Lambda kits with testing intervals at various time points up to 37 days for IgGκ and 49 days for IgGλ. Data supports an on-board stability claim of 28 days, provided that the power is left switched on as stated in the product insert.

d. Detection limit:

The analytical sensitivity was determined in accordance with CLSI EP17-A. The Limit of Blank was based on 60 determinations of analyte depleted sample and was calculated as the 95th percentile of the distribution. The Limit of Detection was calculated from the LoB and the combined SD of the five LoQ samples. The LoQ was calculated from five independent samples (serum samples diluted with analyte depleted serum to achieve a concentration close to the bottom of the measuring range) tested 12 times over five days. The tabulated summary of results is shown below:

|   | LoB | LoD | LoQ  |
| --- | --- | --- | --- |
|  IgG Kappa | 0.000 g/L | 0.009 g/L | 0.115 g/L  |
|  IgG Lambda | 0.000 g/L | 0.005 g/L | 0.075 g/L  |

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e. Analytical specificity:

Interference:

Interferences were assessed according to CLSI guideline EP07-A2 by testing three serum samples with different IgG Kappa and IgG Lambda concentration ranges, including a sample close to the lower limit of the reference interval, a sample within the reference interval and an elevated serum sample. Each sample was spiked with interfering substances and tested in multiple replicates. No significant assay interference effects were observed when the samples were tested with bilirubin at 200mg/L, hemoglobin at 5g/L, triglyceride at 1000mg/dL, intralipid at 125mg/dL or the 16 commonly used drugs at the concentrations given below.

|  Substance | Concentration  |
| --- | --- |
|  Acetaminophen | 1324μmol/L  |
|  Acetylsalicylic Acid | 3.63mmol/L  |
|  Ascorbic Acid | 342μmol/L  |
|  Bortezomib | 6mg/mL  |
|  Caffeine | 308μmol/L  |
|  Cimetidine | 79.2μmol/L  |
|  Cyclophosphamide Monohydrate | 60μg/mL  |
|  Digoxin | 3.9nmol/L (IgGK)
7.8nmol/L (IgGL)  |
|  Furosemide | 181μmol/L  |
|  Ibuprofen | 2425μmol/L  |
|  Methotrexate | 2mmol/L  |
|  Penicillin | 75mg/L  |
|  Phenytoin | 198μmol/L  |
|  Pomalidomide | 100μg/mL  |
|  Prednisolone | 100μg/mL  |
|  Theophylline | 222μmol/L  |

Cross-reactivity:

No significant cross reaction was observed during testing for the predicate device. The specificity of the antisera is unchanged.

Antigen Excess:

The possibility of antigen excess occurring when using the device on the Binding Site Optilite was evaluated with eight monoclonal IgG Kappa and six monoclonal IgG Lambda samples with concentrations above the respective standard measuring ranges. No antigen excess was observed up to 100.5g/L and 102.5g/L for IgG Kappa and IgG Lambda respectively.

f. Assay cut-off:

Refer to Expected values

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# 2. Comparison studies:

a. Method comparison with predicate device:

# IgG Kappa:

A comparison study was performed by analysing 284 serum samples (including 135 IgG Kappa paraprotein and 60 IgG Lambda paraprotein samples, 60 donor samples and 29 other samples, covering the range  $0.2 - 47.69\mathrm{g / L}$ ) using the Optilite Hevylite IgG Kappa kit and an alternative commercially available assay. Passing-Bablok regression analysis generated the results below.

# IgG Lambda:

A comparison study was performed by analysing 172 serum samples (including 42 IgG Kappa paraprotein and 59 IgG Lambda paraprotein samples, 59 donor samples and one AL Amyloidosis sample, covering the range  $0.09 - 40.65\mathrm{g / L}$ ) using the Optilite Hevylite IgG Lambda kit and an alternative commercially available assay. Passing-Bablok regression analysis generated the results below.

# IgG Kappa/Lambda Ratio:

A comparison study was performed by analysing 143 serum samples (including 39 IgG Kappa paraprotein and 44 IgG Lambda paraprotein samples, 59 donor samples and one AL Amyloidosis sample, covering the range  $0.01 - 277.50\mathrm{g / L}$ ) using the Optilite Hevylite IgG Kappa and IgG Lambda kits and alternative commercially available assays. Passing-Bablok regression analysis generated the results below.

|   | N | Sample Range | Passing & Bablok | Slope 95% CI | Intercept 95% CI  |
| --- | --- | --- | --- | --- | --- |
|  IgG Kappa | 284 | 0.200-47.69 g/L | y = 1.100x - 0.68 | 1.05 to 1.15 | -1.05 to -0.43  |
|  IgG Lambda | 172 | 0.090-40.65 g/L | y = 0.950x + 0.00 | 0.88 to 1.01 | -0.18 to 0.14  |
|  IgGκ/IgGλ ratio | 143 | 0.014-277.5 | y = 1.124x - 0.17 | 1.07 to 1.21 | -0.30 to -0.10  |

b. Matrix comparison:

Not applicable

# 3. Clinical studies:

a. Clinical Sensitivity and clinical specificity:

Not applicable

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# b. Other clinical supportive data:

Transformation of the BNII Study onto the Optilite

The purpose of this study was to compare the clinical Heavy+Light Chain (HLC) Response categorization of the predicate and the Optilite Hevylite IgG Kappa and Lambda Kits obtained from samples taken at multiple time points from patients with IgG Kappa and IgG Lambda multiple myeloma during the course of their disease. Passing-Bablok regression equations were generated for the comparison study of the Optilite kits against the predicate kits. The regression equation was then modeled with the existing 437 monitoring sample results from the original BNII submission to evaluate the clinical validity of the new device.

|  HLC Monitoring Response Categories  |   |
| --- | --- |
|  Complete Response (CR) | HLC ratio within the normal range and negative urine immunofixation.  |
|  Very Good Partial Response (VGPR) | >91% reduction of HLC ratio from baseline and reduction in 24 hour urinary M-protein to ≤100mg per 24 hours  |
|  Partial Response (PR) | Reduction of HLC ratio from baseline between 47 - 91% and reduction in 24 hours urinary M-protein by ≥90% or to ≤200mg/24 hours.  |
|  Stable Disease (SD) | A change in HLC ratio from baseline < 32% increase but < 47%  |
|  Progressive Disease (PD) | >32% increase in HLC ratio from baseline (the absolute increase in involved IgG must be ≥5g/L) or a ≥25% increase in urine M-protein from baseline (the absolute increase must be ≥200mg/24 hours)  |
|  Relapse from CR | >32% increase in HLC ratio from baseline (the absolute increase in involved IgG must be ≥5g/L)  |

# Optilite HLC Response Category Study

Assignment of classification was based on the HLC Monitoring Response Category detailed in the above table, using all assay data available. Responses were categorized in accordance with NCCN Guidelines v1.2011 by using the percentage change from baseline. Responses were characterised as progressive disease (PD), stable disease (SD), partial response (PR), very good partial response (VGPR), and complete response (CR). Kappa statistics were used to evaluate agreement between the test and predicate devices.

# Optilite Monitoring Study Design

A comparison of 69 monitoring samples from 10 IgG Kappa patients and 12 IgG Lambda patients was performed to compare the BNII HLC response category assigned to those observed with the Optilite Hevylite IgG Kappa and Lambda kits (Note: The Optilite monitoring response category is not to be used interchangeably with other manufacturer's assays or with any other instrument platform monitoring

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response category). The results of the comparison study using 69 monitoring samples yielding 43 response classifications are shown in the table below:

|  Observed | Predicate HLC response  |   |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  CR | VGPR | PR | SD | PD | Total  |
|  Optilite HLC Response | CR | 0 | 0 | 0 | 0 | 0 | 0  |
|   |  VGPR | 0 | 1 | 0 | 0 | 0 | 1  |
|   |  PR | 0 | 0 | 11 | 1 | 0 | 12  |
|   |  SD | 0 | 0 | 1 | 23 | 1 | 25  |
|   |  PD | 0 | 0 | 0 | 2 | 3 | 5  |
|   |  Total | 0 | 1 | 12 | 26 | 4 | 43  |
|  Kappa (95% CIs) |   | 0.79 (0.62 – 0.96)  |   |   |   |   |   |
|  Weighted Kappa (95% CIs) |   | 0.87 (0.74 – 0.98)  |   |   |   |   |   |

These monitoring data were also supported by additional statistical regression equation modelling data.

# Data Modelling

A data modelling procedure was carried out on monitoring sample results from the original BNII submission. The Passing-Bablok regression equations derived from the previously cleared 437 BNII data set were mathematically transformed using the Optilite regression equation. The statistical regression equation modeling (Cohen's Kappa) results are summarized in the tables below.

|  H/L* | Predicate Assigned Response  |   |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  CR | VGPR | PR | SD | PD | Total  |
|  Transformed Data Response | CR | 29 | 5 | 2 | 0 | 0 | 36  |
|   |  VGPR | 24 | 72 | 27 | 0 | 0 | 123  |
|   |  PR | 7 | 4 | 165 | 4 | 0 | 180  |
|   |  SD | 0 | 1 | 4 | 92 | 0 | 97  |
|   |  PD | 0 | 0 | 0 | 0 | 1 | 1  |
|   |  Total | 60 | 82 | 198 | 96 | 1 | 437  |
|  Kappa (95% CIs) |   | 0.75 (0.70 – 0.80)  |   |   |   |   |   |
|  Weighted Kappa (95% CIs) |   | 0.86 (0.82 – 0.89)  |   |   |   |   |   |

* H/L: H = highest kappa, L = lowest lambda; the imprecision values were applied to generate the highest possible kappa and the lowest possible lambda results.

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The Otpilite HLC Monitoring Response Category in the two Tables above were modified from the NCCN v1.2011 Guidelines on Treatment Response Classification as shown in the Table below.

|  Response |   | NCCN v1.2011 | Disease Monitoring Using HLC Optilite IgG  |
| --- | --- | --- | --- |
|  Complete Response (CR) | Negative IFE on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow | HLC ratio within the normal range (SPAPLUS® IgGκ/IgGλ Ratio 0.98–2.75) and negative urine immunofixation  |   |
|  Very Good Partial Response (VGPR) | Serum and urine M protein detectable by IFE but not SPEP or ≥ 90% reduction in serum M protein level plus urine M protein level < 100 mg per 24 hours | > 91% reduction of HLC ratio from baseline and urine M protein level < 100 mg per 24 hours  |   |
|  Partial Response (PR) | ≥ 50% reduction of serum M protein and reduction in 24 hour urinary M protein by ≥ 90% or to < 200 mg per 24 hours. | Reduction of HLC ratio from baseline between 47–91% and reduction in 24 hour urinary M protein by ≥ 90% or to < 200 mg per 24 hours.  |   |
|  Stable Disease (SD) | Not meeting criteria for CR, VGPR, PR or progressive disease | A change in HLC ratio from baseline < 32% increase but < 47% reduction.  |   |

{12}

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|  Response | NCCN v1.2011 | Disease Monitoring Using HLC Optilite IgG  |
| --- | --- | --- |
|  Progressive Disease (PD) | Increase of ≥ 25% from baseline in 1 or more:
• Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL)
• Urine M component and/or (the absolute increase must be ≥ 200 mg per 24 hours)
• Bone marrow plasma cell percentage: the absolute percentage must be ≥ 10%
• Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
• Development of hypercalcemia | ≥ 32% increase in HLC ratio from baseline (the absolute increase in involved IgG must be ≥ 5 g/L) or a ≥ 25% increase in urine M-component from baseline (the absolute increase must be ≥ 200 mg per 24 hours)  |
|  Relapse from CR |  | > 32% increase in HLC ratio from baseline (the absolute increase in involved IgG must be ≥5g/L)  |

4. Clinical cut-off:

Refer to discussion above.

5. Expected values/Reference range:

The reference intervals were transferred from the predicate devices and were verified by testing 50 normal adult donor samples.

|   | 95 Percentile Range  |
| --- | --- |
|  IgG kappa (g/L) | 4.03 – 9.78 g/L  |
|  IgG lambda (g/L) | 1.97 – 5.71 g/L  |
|  IgG kappa/ IgG lambda ratio | 0.98 – 2.75  |

{13}

N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion:

The submitted information in this premarket notification is complete and supports substantial equivalence decision.

14

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**Source:** [https://fda.innolitics.com/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PCN/K172613](https://fda.innolitics.com/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PCN/K172613)

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