Optilite Hevylite IgA Kappa Kit, Optilite Hevylite IgA Lambda Kit
Device Facts
| Record ID | K160819 |
|---|---|
| Device Name | Optilite Hevylite IgA Kappa Kit, Optilite Hevylite IgA Lambda Kit |
| Applicant | The Binding Site Group , Ltd. |
| Product Code | OPX · Immunology |
| Decision Date | Jun 16, 2016 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 866.5510 |
| Device Class | Class 2 |
Intended Use
The Optilite Hevylite IgA Kappa kit is a quantitative in vitro assay intended for the measurement of IgA Kappa (IgA heavy chain and Kappa light chain intact immunoglobulin) in serum using the Binding Site Optilite analyser. Measurement of Hevylite IgA Kappa is used alongside Hevylite IgA Lambda to calculate the IgA Lambda ratio. The Hevylite IgA Kappa / IgA Lambda ratio can be used when monitoring previously diagnosed IgA multiple myeloma patients 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. The Optilite Hevylite IgA Lambda kit is a quantitative in vitro assay intended for the measurement of IgA heavy chain and Lambda light chain intact immunoglobulin) in serum using the Binding Site Optilite analyser. Measurement of Hevylite IgA Lambda is used alongside Hevylite IgA Kappa to calculate the IgA Lambda ratio. The Hevylite IgA Kappa / IgA Lambda ratio can be used when monitoring previously diagnosed IgA multiple myeloma patients 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
Device consists of ready-to-use polyclonal monospecific sheep anti-human IgA antisera (combined alpha heavy and kappa/lambda light chains) used on the Binding Site Optilite analyzer. Input is patient serum; device performs turbidimetric analysis where specific antiserum reacts with IgA to form insoluble complexes. Light transmission through the suspension is measured by a photodiode; concentration is calculated via an internal calibration curve. Used in clinical laboratories by trained personnel. Output is quantitative IgA Kappa and IgA Lambda levels, used to calculate the IgA Kappa/IgA Lambda ratio. This ratio assists clinicians in monitoring disease status (CR, VGPR, PR, SD, PD) in IgA multiple myeloma patients. Results are used in conjunction with other clinical evaluations (immunofixation, bone marrow, urine assessments).
Clinical Evidence
No prospective clinical trial performed. Clinical validity established via retrospective data modeling. A comparison study of 33 monitoring samples evaluated agreement between Optilite and predicate response categories. Further validation used 449 patient samples from the predicate submission, applying Passing and Bablok regression equations to transform BN II data to Optilite equivalents. Results showed high concordance with the predicate, with linear weighted Kappa values of 0.94–0.96 and unweighted Kappa values of 0.92–0.93, supporting clinical equivalence in monitoring IgA multiple myeloma.
Technological Characteristics
Turbidimetric assay using polyclonal monospecific sheep anti-human IgA antisera. Reagents include sodium azide, EACA, EDTA, and benzamidine preservatives. Measuring range: IgA Kappa 0.18–11.2 g/L; IgA Lambda 0.16–10.4 g/L (standard 1+9 dilution). Traceable to ERM-DA470k. On-board stability: 14 days. Shelf life: 12 months at 2-8°C. Connectivity: Integrated with Binding Site Optilite analyzer.
Indications for Use
Indicated for the quantitative measurement of IgA Kappa and IgA Lambda in serum to calculate the IgA Kappa/IgA Lambda ratio for monitoring patients with previously diagnosed IgA multiple myeloma. For prescription use only.
Regulatory Classification
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.
Related Devices
- K151759 — Hevylite Human IgA Kappa Kit for use on SPAPLUS, Hevylite Human IgA Lambda Kit for use on SPAPLUS · The Binding Site Group , Ltd. · Nov 6, 2015
Submission Summary (Full Text)
{0}
1
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION MEMORANDUM ASSAY ONLY TEMPLATE
A. 510(k) Number:
K160819
B. Purpose for Submission:
New instrument for a cleared IVD assay
C. Measurand:
Immunoglobulin IgA Kappa (combined α heavy and κ light chain) and Immunoglobulin IgA Lambda (combined α 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® Human IgA Kappa Kit and Optilite Hevylite® Human IgA 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 code:
OPX - IgA Kappa (Heavy and Light chain Combined). Antigen, antiserum, control
OPY - IgA Lambda (Heavy and Light chain Combined). Antigen, antiserum, control
{1}
4. Panel:
Immunology (82)
H. Intended Use:
1. Intended use(s):
The Optilite Hevylite Human IgA Kappa is a quantitative in vitro assay intended for the measurement of IgA Kappa (IgA heavy chain and Kappa light chain intact immunoglobulin) in serum using the Binding Site Optilite analyser. Measurement of Hevylite Human IgA Kappa is used alongside Hevylite Human IgA Lambda to calculate the IgA Kappa/IgA Lambda ratio. The Hevylite Human IgA Kappa/IgA Lambda ratio can be used when monitoring previously diagnosed IgA 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.
The Optilite Hevylite Human IgA Lambda is a quantitative in vitro assay intended for the measurement of IgA Lambda (IgA heavy chain and Lambda light chain intact immunoglobulin) in serum using the Binding Site Optilite analyser. Measurement of Hevylite Human IgA Lambda is used alongside Hevylite Human IgA Kappa to calculate the IgA Kappa/IgA Lambda ratio. The Hevylite Human IgA Kappa/IgA Lambda ratio can be used when monitoring previously diagnosed IgA 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. Indication(s) for use:
Same as intended use.
3. Special conditions for use statement(s):
For prescription use only.
Warning: The result of Hevylite Human IgA Kappa in a given specimen determined with assays with different manufacturers and 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 Human IgA 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 IgA 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.
2
{2}
Warning: The result of Hevylite Human IgA Lambda in a given specimen determined with assays with different manufacturers and 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 Human IgA 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 Human IgA 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 Optilite Hevylite Human IgA Kappa Antiserum and Optilite Hevylite Human IgA Lambda Antiserum contain vials of ready-to-use polyclonal monospecific sheep anti-IgA antisera against combined $\alpha$ heavy and $\kappa$ light chain or combined $\alpha$ heavy and $\lambda$ light chain, one level calibrator, controls (low and high) and Optilite Diluent 2 in liquid form. The reagents contain $0.099\%$ sodium azide, $0.1\%$ E-amino-n-caproic acid (EACA), 1mM ethylenediaminetetraacetic acid (EDTA) and $0.01\%$ benzamidine as preservatives.
## J. Substantial Equivalence Information:
1. Predicate device names and predicate 510(k) number:
Hevylite™ Human IgA Kappa Kit and Hevylite™ Human IgA Lambda Kit for use on Siemens BN™ II Systems (K140105)
2. Comparison with predicate:
| Similarities | | |
| --- | --- | --- |
| Item | Device
Optilite Hevylite® IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits | Predicate
Hevylite™ IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits on Siemens BN™ II |
| Intended Use | Quantitative in vitro assay for the measurement of IgA Kappa (IgA heavy chain and Kappa light chain intact immunoglobulin) and IgA Lambda (IgA heavy chain and Lambda light chain intact immunoglobulin) in serum. | Same |
{3}
| Similarities | | |
| --- | --- | --- |
| Item | Device Optilite Hevylite® IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits | Predicate Hevylite™ IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits on Siemens BN™ II |
| | Measurement of Hevylite Human IgA Kappa is used alongside Hevylite Human IgA Lambda to calculate the IgA Kappa/IgA Lambda ratio. The Hevylite Human IgA kappa/IgA lambda ratio can be used when monitoring previously diagnosed IgA 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. | |
| Method | Nephelometry/ Turbidimetry | Same |
| Analyte | IgA Kappa and IgA Lambda | Same |
| Antibody | Polyclonal monospecific Sheep anti-human combined α heavy and κ light chain or combined α heavy and λ light chain | Same |
| Control | Binding Site High and Low Control | Same |
| Calibrator | Single level Binding Site Hevylite Calibrator auto-diluted to six different concentrations | Same |
| Traceability | ERM-DA470k | Same |
| Sample Matrix | Serum | Same |
| Capture antibody | Sheep anti-human IgA combined | Same |
| Differences | | |
| --- | --- | --- |
| Item | Device Optilite Hevylite® IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits | Predicate Hevylite™ IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits on Siemens BN™ II |
| Instrument | Binding Site Optilite | Siemens BN™ II Systems |
| Method | Turbidimetry | Nephelometry |
| On-board stability | 11 days | Not stated |
| Measuring Range | At standard 1 + 9 dilution: | At standard 1/100 dilution: |
{4}
| Differences | | |
| --- | --- | --- |
| Item | Device
Optilite Hevylite® IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits | Predicate
Hevylite™ IgA Kappa (IgAκ) and IgA Lambda (IgAλ) Kits on Siemens BN™ II |
| | IgAκ: 0.18–11.2 g/L
IgAλ: 0.16–10.4 g/L | IgAκ: 0.35–11.2 g/L
IgAλ: 0.33–10.4 g/L |
| | Extended Range for IgAκ:
1+ 0 dilution: 0.018–1.12 g/L
1+ 59 dilution: 1.08–67.2 g/L
1+ 99 dilution: 1.8–112 g/L | Extended Range for IgAκ:
1/5 dilution: 0.018–0.56 g/L
1/20 dilution: 0.07–2.24 g/L
1/400 dilution: 1.40–44.8 g/L
1/2000 dilution: 7.0–224 g/L |
| | Extended Range for IgAλ:
1+ 0 dilution: 0.016–1.04 g/L
1+ 59 dilution: 0.96–62.4 g/L
1+ 99 dilution: 1.6–104 g/L | Extended Range for IgAλ:
1/5 dilution: 0.016–0.520 g/L
1/20 dilution: 0.065–2.08 g/L
1/400 dilution: 1.40–41.6 g/L
1/2000 dilution: 6.5–208 g/L |
| Reference Interval | IgAκ: 0.588–2.984 g/L
IgAλ: 0.432–2.035 g/L
IgAκ/IgAλ Ratio: 0.911–2.416 | IgAκ: 0.48–2.82 g/L
IgAλ: 0.36–1.98 g/L
IgAκ/IgAλ Ratio: 0.80–2.04 |
## K. Standard/Guidance Document Referenced (if applicable):
CLSI EP05-A2: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline–Second Edition
CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach
CLSI EP07-A2: Interference Testing in Clinical Chemistry
CLSI EP17-A: Protocols for Determination of Limits of Detection and Limits of Quantitation
CLSI C28-A3: Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory
## L. Test Principle:
The determination of soluble antigen concentration by turbidimetric methods involves the reaction with specific antiserum to form insoluble complexes. When light is passed through the suspension formed a portion of the light is transmitted and focused onto a photodiode by an optical lens system. The amount of transmitted light is indirectly proportional to the specific protein concentration in the test sample. Concentrations are automatically calculated by reference to a calibration curve stored within the instrument.
{5}
# M. Performance Characteristics (if/when applicable):
# 1. Analytical performance:
All results met the manufacturer's pre-specified acceptance criteria.
# a. Precision/Reproducibility:
The study design followed the recommendations of CLSI EP05-A2. The within-run, between-run, between-day, between-lot and between-instrument precision were determined by testing six IgA $\kappa$ and five IgA $\lambda$ serum samples over 21 days with two runs per day and two replicates per run on four different reagent lots on six analyzers for IgA $\kappa$ and three different reagent lots on three analyser for IgA $\lambda$ . Results are summarized below.
IgA $\kappa$ Precision studies:
| Sample | Mean (g/L) | Within Run | | Between Run | | Between Day | | Between instrument | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 0.298 | 0.01 | 2.1 | 0.01 | 3.1 | 0.02 | 5.7 | 0.01 | 4.3 | 0.02 | 6.9 |
| 2 | 0.853 | 0.01 | 1.7 | 0.02 | 2.2 | 0.02 | 2.7 | 0.01 | 1.1 | 0.03 | 3.9 |
| 3 | 1.650 | 0.05 | 2.8 | 0.04 | 2.2 | 0.09 | 5.4 | 0.04 | 2.3 | 0.11 | 6.5 |
| 4 | 2.449 | 0.05 | 1.9 | 0.07 | 2.9 | 0.09 | 3.9 | 0.04 | 1.5 | 0.13 | 5.2 |
| 5 | 3.379 | 0.11 | 3.1 | 0.12 | 3.4 | 0.14 | 4.0 | 0.08 | 2.4 | 0.22 | 6.1 |
| 6 | 9.115 | 0.12 | 1.4 | 0.15 | 1.7 | 0.41 | 4.5 | 0.25 | 2.7 | 0.45 | 5.0 |
IgA $\lambda$ Precision studies:
| Sample | Mean (g/L) | Within Run | | Between Run | | Between Day | | Between instrument | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 0.301 | 0.00 | 1.3 | 0.01 | 1.8 | 0.02 | 6.5 | 0.01 | 3.0 | 0.02 | 6.9 |
| 2 | 0.935 | 0.02 | 1.7 | 0.01 | 1.1 | 0.04 | 4.3 | 0.02 | 2.4 | 0.04 | 4.7 |
| 3 | 1.633 | 0.04 | 2.3 | 0.03 | 1.8 | 0.15 | 9.0 | 0.08 | 5.7 | 0.15 | 9.5 |
| 4 | 2.317 | 0.04 | 1.9 | 0.06 | 2.5 | 0.20 | 8.7 | 0.15 | 6.5 | 0.21 | 9.3 |
| 5 | 8.582 | 0.11 | 1.3 | 0.14 | 1.6 | 0.26 | 3.0 | 0.07 | 0.8 | 0.31 | 3.7 |
# b. Linearity/assay reportable range:
A linearity study was performed following CLSI EP6-A. The linearity of the IgA $\kappa$ and IgA $\lambda$ assays have been confirmed using serially diluted serum samples (IgA $\kappa$ myeloma sample diluted with IgA $\kappa$ deleted sample and IgA $\lambda$ elevated polyclonal sample diluted with IgA $\lambda$ depleted sample) to cover the standard $(1 + 9)$ dilution measuring range $0.18 - 11.2\mathrm{g / L}$ and $0.16 - 10.4\mathrm{g / L}$ respectively. Deviation from linearity were: $\leq 6.6\%$ and $\leq 4.2\%$ for IgA $\kappa$ and IgA $\lambda$ and the weighted linear
{6}
regression observed versus % high pool were: $y = 12.91x - 0.26$ and $y = 12.33x + 0.00$ , respectively
c. Traceability, Stability, Expected values (controls, calibrators, or methods):
Traceability: An Internal Reference material (IR) was assigned by comparison with the Reference Material DA470K.
Stability: A real-time stability study of unopened kits was performed on three lots of Optilite Hevylite IgA Kappa and Optilite Hevylite IgA Lambda kits with testing time intervals at day 0, 3, 6.5, 10, 13 months. Data support a shelf life claim of 12 months at $2 - 8^{\circ}\mathrm{C}$ .
Open-vial stability was performed on three lots of Optilite IgA Kappa and Optilite IgA Lambda kits with testing time intervals at day 0, and 1, 2, and 3 months. Data support the open vial stability claim of 3 months at $2 - 8^{\circ}\mathrm{C}$ .
On-board stability was performed on three lots of Optilite IgA Kappa and Optilite IgA Lambda kits with testing time intervals at 0 and 14 days. Data support the onboard stability claim of 14 days, provided that the power is left switched on as stated in the product insert.
All stability results met the manufacturer's pre-specified acceptance criteria.
d. Detection limit:
The analytical sensitivity was determined in accordance with the non-parametric study design in CLSI EP17-A. The Limits of Blank (LoB) were based on 60 determinations of analyte-depleted sample and was estimated at the $95\%$ percentile of the distribution. The Limits of Detection (LoD) were calculated using the formula $\mathrm{LoD} = \mathrm{LoB} + \mathrm{c}\beta \mathrm{SDs}$ , where $\mathrm{c}\beta$ is 1.645 and SD is the combined standard deviation of five low level samples of serum samples diluted with analyte depleted serum to achieve a concentration close to the bottom of the measuring range. The samples were tested twelve times over five days and the total error $(0.0588~\mathrm{g / L}$ for IgA $\kappa$ and 0.0432 g/L for IgA $\lambda$ ) were within the maximum allowable total error. The Limits of Quantitation (LoQ) were calculated from the total error of the LoD study. The tabulated summary is shown below:
| | LoB | LoD | LoQ |
| --- | --- | --- | --- |
| IgA Kappa | 0.000 g/L | 0.002 g/L | 0.018 g/L |
| IgA Lambda | 0.000 g/L | 0.001 g/L | 0.016 g/ L |
e. Analytical specificity:
Interference:
Interferences were assessed according to CLSI EP07-A2 by testing four serum
{7}
samples with different IgA Kappa and IgA Lambda concentration ranges: (1) within the reference interval serum samples, IgAκ target level: 1.001 g/L and IgAλ target level: 0.847 g/L; (2) close to the lower medical decision point (MDP) serum samples, target levels: 0.539 g/L and 0.316 g/L respectively; (3) close to the higher MDP serum samples, target levels 2.259 g/L and 2.010 g/L respectively; (4) samples above the MDP), target levels 8.363 g/L and 7.997 g/L respectively. Each sample was spiked with interfering substances and tested in replicate. The manufacturer's acceptance criteria were that the mean results from the spiked samples must be within ± 10% of the mean of the control samples.
No significant assay interference effects were observed when the four samples of IgAκ and IgAλ were tested with bilirubin at 200 mg/L, hemoglobin at 5 g/L, triglyceride at 1000 mg/dL or Intralipid at 200 mg/dL and the 15 commonly used drugs at the concentrations given below. However 1000 mg/dL Intralipid showed signs of interference. The Package Insert states: "Lipemic samples are known to interfere with this assay and therefore should not be analysed using this assay". In addition the 'Limitation section' also states that "Turbidimetric assays are not suitable for measurement of highly lipemic or hemolysed samples".
| Drug | Concentration tested |
| --- | --- |
| Acetaminophen | 1324 μmol/L |
| Acetylsalicylic Acid | 3.63 mmol/L |
| Ascorbic Acid | 342 μmol/L |
| Bortezomib | 6 mg/mL |
| Caffeine | 308 μmol/L |
| Cimitidine | 79.2 μmol/mL |
| Cyclophosphamide Monohydrate | 60 μg/L |
| Digoxin | 7.8 nmol/L |
| Furosemide | 90 μmol/L |
| Ibuprofen | 2425 μmol/L |
| Methotrexate | 2 mmol |
| Penicillin | 75 mg/L |
| Phenytoin | 198 μmol/L |
| Pomalidomide | 100 μg/mL |
| Prednisolone | 100 μg/mL |
| Theophylline | 222 μmol/L |
## Cross-reactivity studies:
For IgAκ, the possibility of cross reactivity with other immunoglobulin heavy chain/light chain combinations was assessed by assaying eight IgGK, five IgGL, nine IgMK, five IgML, six IgAλ, one Free Kappa and one Free Lambda myeloma samples. No significant (< 4%) cross reactivity were observed.
{8}
For $\mathrm{IgA}\lambda$ , the possibility of cross reactivity with other immunoglobulin heavy chain/light chain combinations was assessed by assaying eight $\mathrm{IgG}\kappa$ , five $\mathrm{IgG}\lambda$ , seven $\mathrm{IgM}\kappa$ , four $\mathrm{IgM}\lambda$ , six $\mathrm{IgA}\kappa$ , one Free Kappa and one Free Lambda myeloma samples. No significant ( $< 1\%$ ) cross reactivity were observed.
# Antigen Excess Detection
The possibility of antigen excess occurring when using the device on The Binding Site SPAPLUS was evaluated with nine monoclonal IgA Kappa and six monoclonal IgA Lambda samples with concentrations above the $0.18 - 11.2\mathrm{g / L}$ and $0.16 - 10.4\mathrm{g / L}$ standard measuring ranges respectively. No antigen excess effect up to $81.1\mathrm{g / L}$ of $\mathrm{IgA}\kappa$ and $101.3\mathrm{g / L}$ of $\mathrm{IgA}\lambda$ concentration levels were observed at $1 + 9$ dilution.
f. Assay cut-off:
Refer to Expected values
# 2. Comparison studies:
a. Method comparison with predicate device:
IgA Kappa:
A comparison study was performed by analysing 259 samples (including 63 IgA Kappa paraprotein and 41 IgA Lambda paraprotein samples, 29 donor samples and 127 other clinical samples, covering the range $0.02 - 64.4\mathrm{g / L}$ ) using the Optilite IgA Kappa Kit and an alternative commercially available assay. Passing Bablok regression analysis generated the results below.
IgA Lambda:
A comparison study was performed by analysing 217 samples (including 38 IgA Kappa paraprotein and 41 IgA Lambda paraprotein samples, 29 donor samples and 109 other clinical samples, covering the range $0.07 - 31.8\mathrm{g / L}$ ) using the Optilite IgA Lambda Kit and an alternative commercially available assay.
Passing Bablok regression analysis generated the following results:
| Assay | N | Sample Range | Passing & Bablok | Slope 95% CI | Intercept 95% CI |
| --- | --- | --- | --- | --- | --- |
| IgA Kappa | 259 | 0.02–64.4 g/L | y = 1.09x + 0.03 g/L | 1.07 to 1.11 | -0.01 to 0.07 |
| IgA Lambda | 217 | 0.07–31.8 g/L | y = 1.09x–0.02 g/L | 1.06 to 1.12 | -0.04 to -0.01 |
| IgAκ/IgAλ ratio | 211 | 0.001–273.1 | y= 1.01x + 0.09 | 0.97 to 1.07 | 0.04 to 0.14 |
{9}
The following regression equation based on the study above was used for the transformation in the data modeling described below.
| | Slope | Intercept |
| --- | --- | --- |
| IgA Kappa | 1.09 | 0.03 |
| IgA Lambda | 1.09 | -0.02 |
The slope and the intercept were applied to the previous data using the following equation: (Original result $\times$ Slope) + Intercept
As the intercepts were negative, data that were already close to LoQ are transformed into negative values by the formula; however, negative IgA Kappa and IgA Lambda results are not possible. Therefore, results that were transformed were capped at LoQ (IgA Kappa: 0.018 g/L and IgA Lambda: 0.016 g/L).-Passing Bablok regression equations were generated with the 3000 bootstrapped patient data points with the following results:
| Assay | N | Sample Range | Regression Equation | Slope 95% CIs | Intercept 95% Cis |
| --- | --- | --- | --- | --- | --- |
| IgA Kappa | 2817 | 0.02 to 64.4 g/L | 1.09 + 0.02 | 1.079 to 1.091 | 0.001 to 0.028 |
| IgA Lambda | 2759 | 0.02 to 47.3 g/L | 1.09 + 0.04 | 1.084 to 1.098 | 0.011 to 0.056 |
| IgA Kappa / IgA Lambda | 2803 | 0.00 to 273.08 | 1.01 + 0.10 | 0.999 to 1.029 | 0.079 to 0.111 |
b. Matrix comparison:
Not applicable
# 3. Clinical studies:
a. Clinical Sensitivity/ clinical specificity:
Not applicable
b. Other clinical supportive data (when a. is not applicable):
Transformation of the BN II Study onto Optilite Study
# Purpose of the study
The purpose of this study was to compare the clinical HLC Response categorization of the predicate and from the Optilite Hevylite IgA Kappa and Optilite Hevylite IgA
{10}
Lambda Kit results obtained from samples taken at multiple time points from IgA Kappa and IgA Lambda multiple myeloma patients during the course of their disease. The Sponsor generated Passing and Bablok regression equations for the comparison study of the Optilite kits against the predicate kits. The regression equation was then modelled with the existing 449 monitoring sample results from the original BNII submission to evaluate the clinical validity of the new device.
Table 1: HLC Monitoring Response Category
| Complete Response (CR) | HLC ratio within the normal range, negative urine immunofixation (where available) and ≤ 5% plasma cells in bone marrow. |
| --- | --- |
| Very Good Partial Response (VGPR) | >94% reduction of HLC ratio from baseline and urine M-immunoglobulin level < 100 mg/24hrs. |
| Partial Response (PR) | Reduction of HLC ratio from baseline between 60–94% and reduction in 24hr urinary M-immunoglobulin by ≥90% from baseline or ≤ 200 mg/24hrs. |
| Stable Disease (SD) | A change in HLC ratio from baseline < 24% increase but < 60% reduction |
| Progressive Disease (PD) | ≥ 24% increase in HLC ratio from baseline (the absolute increase in involved IgA must be ≥ 5 g/L) or ≥ 25% increase in urine M-immunoglobulin from baseline (the absolute increase must be ≥ 200 mg/24hrs). |
# Optilite HLC Response Category Study
Assignment of classification was based on the HLC Monitoring Response Category detailed in Table 1, using all assay data available. Responses were categorized in accordance with NCCN Guidelines v.1.2011 by using the percentage (\%) change in SPEP or total IgA from baseline. Responses were characterized as progressive disease (PD), stable disease (SD), partial response (PR), very good partial response (VGPR) and complete response (CR). Kappa Statistics was used to evaluate the agreement between test and the clinical status as determined by clinical evaluation combined with either the test or predicate device.
# Optilite Monitoring Study Design
A comparison study using 33 monitoring samples from 20 patients (10 IgA Kappa and 10 IgA Lambda) was performed to compare the BN II HLC response category assigned to those observed with the Optilite Hevylite IgA Kappa and IgA Lambda Kits. (Note: The Optilite HLC monitoring response categories were based on NCCN v1.2011 Treatment Response Classification category. The Optilite HLC monitoring response category is not to be used interchangeably with other manufacturer's assays or with any other instrument platform monitoring response category.) The results of comparison study using 33 monitoring samples are shown in the table below:
| Observed | BN II HLC response | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | CR | VGPR | PR | SD | PD | Total |
| Optilite HLC Response | CR | 0 | 0 | 0 | 0 | 0 | 0 |
| | VGPR | 0 | 2 | 0 | 0 | 0 | 2 |
| | PR | 0 | 0 | 1 | 0 | 0 | 1 |
{11}
These monitoring data were also supported by additional statistical regression equation modelling data.
# Data Modeling
Data modeling procedure was carried out in the remaining patient samples which were not being included in the Optilite Response Category study. The Passing and Bablok regression equations derived from the previously cleared 449 BN II data set was mathematically transformed using the Optilite regression equation. The statistical regression equation modelling results are summarized in the tables below.
A summary of the Cohen's Kappa results are provided below:
| Observed | BN II Assigned HLC* response | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | CR | VGPR | PR | SD | PD | Total |
| Optilite H/L** transformed data | CR | 18 | 0 | 0 | 0 | 0 | 18 |
| | VGPR | 9 | 151 | 3 | 0 | 0 | 164 |
| | PR | 1 | 4 | 117 | 8 | 0 | 128 |
| | SD | 0 | 0 | 2 | 115 | 1 | 118 |
| | PD | 0 | 0 | 0 | 0 | 20 | 21 |
| | Total | 28 | 155 | 122 | 123 | 21 | 449 |
| Linear Weighted Kappa (95% CIs) | | 0.94 (95% CIs: 0.92–0.96) | | | | | |
| Unweighted Kappa (95%CIs) | | 0.92 (95% Cis: 0.90–0.93) | | | | | |
*HLC: HevyLite Chain Response
**H/L: H: highest kappa; L: lowest lambda; For H/L - applied the imprecision values to generate the highest kappa and the lowest lambda possible.
| Observed | BN II Assigned HLC* response | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | CR | VGPR | PR | SD | PD | Total |
| Optilite L/H*** transformed data | CR | 21 | 0 | 0 | 0 | 0 | 21 |
| | VGPR | 7 | 152 | 3 | 0 | 0 | 162 |
| | PR | 0 | 3 | 117 | 7 | 0 | 127 |
| | SD | 0 | 0 | 2 | 116 | 0 | 118 |
| | PD | 0 | 0 | 0 | 0 | 21 | 21 |
{12}
| | Total | 28 | 155 | 122 | 123 | 21 | 449 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Linear Weighted Kappa (95% CIs) | | 0.96 (95% CI: 0.94–0.97) | | | | | |
| Unweighted Kappa (95%CIs) | | 0.93 (95% CI: 0.92–0.95) | | | | | |
* HLC: HevyLite Chain Response
***For L/H - applied the imprecision values to generate the lowest kappa and highest lambda results possible.
The HLC Optilite IgA Monitoring Response Category in the two Tables above were derived from the NCCN v1.2011 Guidelines on Treatment Response Classification as shown in Table below.
Table: Comparison of Treatment Response Classification-NCCN v1.2011 and Hevylite IgA kappa/lambda ratio (HLC ratio)
| Response | NCCN v1.2011 | Disease Monitoring Using HLC Optilite IgA |
| --- | --- | --- |
| 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 (Optilite IgAκ/IgAλ Ratio 0.911–2.416 and negative urine immunofixation and ≤ 5% plasma cells in bone marrow (where available) |
| 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 | >94% 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 60–94% 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 < 24% increase but < 60% reduction. |
{13}
| Response | NCCN v1.2011 | Disease Monitoring Using HLC Optilite IgA |
| --- | --- | --- |
| 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 ≥ 200mg/24hr) • 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 | ≥ 24% increase in HLC ratio from baseline (the absolute increase in involved IgA must be ≥ 5 g/L) or a ≥ 25% increase in urine M-component from baseline (the absolute increase must be ≥ 200mg/24hr) |
4. Clinical cut-off:
Refer to discussion above.
5. Expected values/Reference range:
| Reference Adult Serum | Mean | Median | 95th Percentile Range |
| --- | --- | --- | --- |
| IgA Kappa (g/L) | 1.441 | 1.292 | 0.588–2.984 |
| IgA Lambda (g/L) | 1.013 | 0.915 | 0.432–2.035 |
| IgA Kappa/IgA Lambda Ratio | 1.451 | 1.401 | 0.911–2.416 |
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 a substantial equivalence decision.
