← Product Code [DHR](/submissions/IM/subpart-f%E2%80%94immunological-test-systems/DHR) · K160070

# Rheumatoid Factor (RF) Kit for use on SPAPLUS (K160070)

_The Binding Site Group , Ltd. · DHR · Dec 7, 2016 · Immunology · SESE_

**Canonical URL:** https://fda.innolitics.com/submissions/IM/subpart-f%E2%80%94immunological-test-systems/DHR/K160070

## Device Facts

- **Applicant:** The Binding Site Group , Ltd.
- **Product Code:** [DHR](/submissions/IM/subpart-f%E2%80%94immunological-test-systems/DHR.md)
- **Decision Date:** Dec 7, 2016
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.5775
- **Device Class:** Class 2
- **Review Panel:** Immunology

## Indications for Use

The Rheumatoid Factor (RF) Kit for use on SPAPLUS® is intended for the quantitative in vitro measurement of rheumatoid factor in serum using the Binding Site SPAPLUS® analyser. Measurement of rheumatoid factor may aid in the diagnosis of rheumatoid arthritis. This test should be used in conjunction with other laboratory and clinical findings.

## Device Story

The Rheumatoid Factor (RF) Kit is an in vitro diagnostic reagent system designed for use on the Binding Site SPAPLUS analyzer. It measures rheumatoid factor levels in human serum samples. The device operates via an automated immunoassay process on the SPAPLUS platform. It is intended for use in clinical laboratory settings by trained laboratory personnel. The quantitative output provides clinicians with data to assist in the diagnosis of rheumatoid arthritis, serving as an adjunct to other clinical and laboratory findings.

## Clinical Evidence

No clinical data provided; substantial equivalence is supported by bench testing and performance validation of the assay on the SPAPLUS analyzer.

## Technological Characteristics

Quantitative immunoturbidimetric assay. Reagents include latex particles adsorbed with human IgG, glycine buffer, and sodium azide. Operates on the SPAPLUS® turbidimetric analyzer using optical lens system and photodiode detection. Measuring range 10–1040 IU/mL. Traceable to WHO NIBSC 64/2. Software performs automated calculation of concentrations based on stored calibration curves.

## Regulatory Identification

A rheumatoid factor immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the rheumatoid factor (antibodies to immunoglobulins) in serum, other body fluids, and tissues. Measurement of rheumatoid factor may aid in the diagnosis of rheumatoid arthritis.

## Submission Summary (Full Text)

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>
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION MEMORANDUM

A. 510(k) Number:
K160070

B. Purpose for Submission:
Additional instrument clearance for a previously cleared device

C. Measurand:
Rheumatoid Factor

D. Type of Test:
Quantitative Immunoturbidimetric assay

E. Applicant:
The Binding Site Group, Ltd.

F. Proprietary and Established Names:
Rheumatoid Factor (RF) Kit for use on SPAPLUS®

G. Regulatory Information:

1. Regulation section:
21 CFR § 866.5775, Rheumatoid factor immunological test system

2. Classification:
Class II

3. Product code:
DHR: System, test, Rheumatoid Factor

4. Panel:
Immunology (82)

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H. Intended Use:

1. Intended use(s):

The Rheumatoid Factor (RF) Kit for use on SPAPLUS® is intended for the quantitative in vitro measurement of rheumatoid factor in serum using the Binding Site SPAPLUS® analyser. Measurement of rheumatoid factor may aid in the diagnosis of rheumatoid arthritis. This test should be used in conjunction with other laboratory and clinical findings.

2. Indication(s) for use:

Same as intended use

3. Special conditions for use statement(s):

For prescription use only

4. Special instrument requirements:

SPAPLUS® turbidimetric analyser (K040958)

I. Device Description:

The Rheumatoid Factor Kit for use on SPAPLUS® contains:

Reaction Buffer: Containing glycine buffer (pH 8.3), sodium chloride, sodium ethylenediamine tetra acetic acid disodium salt dehydrate, bovine serum albumin, sodium azide (0.09%, w/v).

Latex Reagent: Containing glycine buffer (pH 7.3), sodium chloride, latex particle adsorbed human IgG, sodium azide (0.09%, w/v)

RF Controls: Supplied at two levels: Low and High. Target values and ranges are supplied in the Quality Control certificate. Supplied ready for use.

RF Calibrator 1–5: Calibration has been carried out and values have been assigned using an immunoturbidimetric method standardised to the international reference preparation, WHO Standard 64/2. Supplied ready for use.

J. Substantial Equivalence Information:

1. Predicate device name and 510(k) number:

Roche Tina-Quant RF II assay on Modular P analyzer (K032535)

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2. Comparison with predicate:

|  Similarities  |   |   |
| --- | --- | --- |
|  Item | RF Kit on SPAPLUS® | Roche Tina-Quant RF II on Modular P  |
|  Intended use | Turbidimetric in vitro quantification of rheumatoid factor | Same  |
|  Assay type | Quantitative | Same  |
|  RF Control | Two levels | Same  |
|  Calibration | WHO reference material NIBSC 64/2 | Same  |
|  Differences  |   |   |
| --- | --- | --- |
|  Item | RF Kit on SPAPLUS® | Roche Tina-Quant RF II on Modular P  |
|  Specimen Type | Serum | Serum and plasma  |
|  RF Kit (reagent and buffer), Control and Calibrator packaging | RF Reagent, Buffer, Controls and Calibrators are packaged together as a kit | RF Kit (reagent and buffer), Controls and Calibrators are packaged individually and sold separately  |
|  Antibody | Human IgG anti-human-IgM | Human IgG  |
|  Calibrator | Five levels | Six Levels  |
|  Unopened Kit | 12 months | Not stated  |
|  Open Vial Stability | Three months | 90 days  |
|  On-board stability | 30 days | 90 days  |
|  Instrument | Binding Site SPAPLUS® | Roche Modular P  |
|  Measuring range | 10–104 IU/mL (1/1: Standard Dilution) | 7–130 IU/mL (1/1) Extended range up to 650 IU/mL  |
|   |  70–1040 IU/mL (1/10: Automatic reflex dilution on high results at standard dilution)  |   |
|  Expected value | <12.5 IU/mL | <14 IU/mL  |

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; Approved Guideline

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- 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

# 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.

# M. Performance Characteristics:

# 1. Analytical performance:

All results from all studies met the manufacturer's pre-specified acceptance criteria.

# a. Precision/Reproducibility:

The studies were based on CLSI EP05-A2. Five sample preparations were tested in two runs per day, each of the two runs in duplicate, over 21 days using three analysers and three lots of reagents. A summary of the results is shown below.

|  RF Sample | N | Mean IU/mL | Within-Run |   | Between-Run |   | Between-Day |   | Total Precision  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |   |  SD | %CV | SD | %CV | SD | %CV | SD | %CV  |
|  1 | 84 | 13.8 | 0.37 | 2.7 | 0.44 | 3.2 | 1.16 | 8.4 | 1.29 | 9.3  |
|  2 | 84 | 19.6 | 0.28 | 1.4 | 0.69 | 3.5 | 1.12 | 5.7 | 1.34 | 6.9  |
|  3 | 84 | 39.4 | 0.34 | 0.9 | 0.17 | 0.4 | 1.83 | 4.6 | 1.87 | 4.7  |
|  4 | 84 | 72.4 | 0.82 | 1.1 | 0.00 | 0.0 | 5.77 | 8.0 | 5.83 | 8.0  |
|  5 | 84 | 173.3 | 3.11 | 1.8 | 3.76 | 2.2 | 15.52 | 9.0 | 16.27 | 9.4  |
|  RF Sample | N | Mean IU/mL | Between-lot |   | Between-instrument  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |   |   |  SD | %CV | SD | %CV  |
|  1 | 84 | 13.8 | 1.17 | 8.5 | 0.22 | 1.6  |
|  2 | 84 | 19.6 | 1.08 | 5.5 | 0.40 | 2.0  |
|  3 | 84 | 39.4 | 1.35 | 3.4 | 0.38 | 1.0  |
|  4 | 84 | 72.4 | 6.10 | 8.4 | 0.00 | 0.0  |
|  5 | 84 | 173.3 | 14.57 | 8.4 | 9.81 | 5.7  |

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b. Linearity/assay reportable range:

A linearity study was performed following CLSI guideline EP6-A. The linearity of this assay has been confirmed by dilution of serum samples with analyte-depleted serum to cover the range 10–104 IU/mL at a 1:1 sample dilution (total of 12 dilutions) and 70–1040 IU/mL at a 1:10 sample dilution (total of 13 dilutions). Deviation from linearity calculated according to CLSI guideline EP6-A was ≤ 9.9%. The regression equation for the high linear range (70–1040 IU/mL) was y = 1.02x − 2.84, and for the low linear range (10–104 IU/mL) was y = 1.07x − 1.82.

Antigen Excess:

No antigen excess was observed up to a level of approximately eight times the top of the calibration curve at the standard 1:1 sample dilution. This is equivalent to 8576.8 IU/mL at the 1:10 sample dilution.

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

(i) Traceability: The calibration of the assay is traceable to the WHO International Reference Preparation of Rheumatoid Arthritis Serum NIBSC 64/2.

(ii) Kit Stability:

Unopened kit stability: The manufacturer provided data that support a real-time stability claim of 12 months.

Open-vial stability: The RF Reagent, Calibrator and Controls can be stored opened at 2–8°C for up to three months.

On-board stability: The RF Reagent can be stored on-board the SPAPLUS® Analyzer for at least 30 days.

d. Detection limit:

The analytical sensitivity of both kits was determined in accordance with CLSI guideline EP17-A. The Limit of Blank (LoB) was based on 60 determinations of a blank sample (pool of analyte-depleted samples) and was estimated as the 95% percentile of the distribution. The Limit of Detection (LoD) was calculated according to the equation LoB + 1.645 x SDs where SDs, the standard deviation, was based on 12 determinations of 5 samples with analyte levels near the lower limit of the reportable range. The Limit of Quantitation (LoQ) was calculated from the total error of the LoD study. Total error at LoQ was within the maximum allowable total error for each sample matrix. The bottom of the measuring range, 10 IU/mL is set as the LoQ for this device.

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Detection Limit Summary:

$\mathrm{LoB} = 0.475 \mathrm{IU} / \mathrm{mL}$

$\mathrm{LoD} = 1.174 \mathrm{IU} / \mathrm{mL}$

$\mathrm{LoQ} = 10 \mathrm{IU} / \mathrm{mL}$

# e. Analytical specificity:

Interferences were assessed according to CLSI EP07-A2 by testing samples at different RF concentrations. Each sample was spiked with interfering substances and tested and compared with results from non-spiked samples. The data demonstrated that the assay was not affected by the following substances at the concentrations given below.

|  Interferent | Concentration | Interferent | Concentration  |
| --- | --- | --- | --- |
|  Ascorbic Acid | 342 μmol/L | Acetylsalicylic | 1.815 mmol/L  |
|  Bilirubin, Conjugated | 200 mg/L | Penicillin | 75 mg/L  |
|  Hemoglobin | 4 g/L | Caffeine | 308 μmol/L  |
|  Intralipid | 500 mg/dL | Prednisolone | 100 μg/mL  |
|  Triglyceride | 500 mg/dL | Digoxin | 7.8 nmol/L  |
|  Acetaminophen | 1324 μmol/L | Cimetidine | 79.2 μmol/L  |
|  Ibuprofen | 2425 μmol/L | Theophylline | 222 μmol/L  |
|  Methotrexate | 2 mmol | Phenytoin | 198 μmol/L  |

# f. Assay cut-off:

12.5 IU/mL

# 2. Comparison studies:

# a. Method comparison with comparator device:

A comparison study was performed by analysing 324 samples (including 51 Rheumatoid Arthritis, 9 Osteoarthritis, 10 Psoriatic arthritis, 1 Juvenile Arthritis, 1 Spondyloarthritis, 17 SLE, 11 Sjögrens Syndrome, 2 Mixed Connective Tissue disease, 5 Lyme disease, 9 HCV, 5 Ulcerative Colitis, 5 Crohn's disease, 4 Celiac disease, 10 Syphilis, 5 Systemic Sclerosis, 4 Cirrhosis, 99 other clinical conditions, and 76 apparently healthy donor samples, covering the range  $10.1 - 666\mathrm{IU / mL}$ ) using the RF Kit on SPAPLUS® and a comparator assay. Passing Bablok regression analysis generated the following results:

$$
y = 0.93x + 2.30 IU/mL \quad (y = SPAPLUS^{®}; x = comparator assay)
$$

(95% CI: Intercept = 1.25 – 3.12; Slope = 0.90 – 0.97)

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Correlation coefficient r = 0.98

The same comparison study was also analyzed with by calculating the % Positive Agreement, % Negative Agreement and % Overall Agreement calculations with the following results:

|   | Comparator Assay  |   |   |   |
| --- | --- | --- | --- | --- |
|   |   |  Positive | Negative | Total  |
|  RF Kit on SPAplus | Positive | 134 | 10* | 144  |
|   |  Negative | 7** | 173 | 180  |
|   |  Total | 141 | 183 | 324  |

* These ten samples had the following diseases/ conditions: four RA, one syphilis, one healthy donor and four other clinical conditions.
** These seven samples had the following diseases/ conditions: one RA, one osteoarthritis, one Sjögren's, one celiac, one ulcerative colitis, one Crohn's disease, and one donor.

Positive Percent Agreement: 95.0% (134/141) (95% CI: 90.2% – 97.0%)

Negative Percent Agreement: 95.0% (173/183) (95% CI: 90.1% – 97.6%)

Overall Percent Agreement: 95.0% (307/324) (95% CI: 91.8% – 96.7%)

b. Matrix comparison:

Not applicable

3. Clinical studies:

a. Clinical Sensitivity and specificity:

Not applicable.

b. Other clinical supportive data:

Not applicable

4. Clinical cut-off:

See assay cut-off above.

5. Expected value:

The values provided are intended for guidance purposes only. Expected values may vary with age, sex, sample type, diet and geographical location. Each laboratory should verify the transferability of the expected value to its own population and, if necessary, determine its own value.

The value was transferred from a comparator assay by ROC analysis with an AUC of 0.9.

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Wherever possible it is strongly recommended that local values are generated.

|   | Expected value (IU/mL)  |
| --- | --- |
|  Rheumatoid factor | < 12.5  |

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.

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**Source:** [https://fda.innolitics.com/submissions/IM/subpart-f%E2%80%94immunological-test-systems/DHR/K160070](https://fda.innolitics.com/submissions/IM/subpart-f%E2%80%94immunological-test-systems/DHR/K160070)

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