← Product Code [CDZ](/submissions/CH/subpart-b%E2%80%94clinical-chemistry-test-systems/CDZ) · K190121

# IDS SHBG (K190121)

_Immunodiagnostic Systems , Ltd. · CDZ · Jun 17, 2019 · Clinical Chemistry · SESE_

**Canonical URL:** https://fda.innolitics.com/submissions/CH/subpart-b%E2%80%94clinical-chemistry-test-systems/CDZ/K190121

## Device Facts

- **Applicant:** Immunodiagnostic Systems , Ltd.
- **Product Code:** [CDZ](/submissions/CH/subpart-b%E2%80%94clinical-chemistry-test-systems/CDZ.md)
- **Decision Date:** Jun 17, 2019
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 862.1680
- **Device Class:** Class 1
- **Review Panel:** Clinical Chemistry

## Indications for Use

The IDS SHBG assay is an in vitro diagnostic device intended for the quantitative determination of SHBG in human serum or plasma on the IDS System. Results are to be used as an aid in the diagnosis of androgen disorders

## Device Story

IDS SHBG is an in vitro diagnostic chemiluminescent immunoassay for quantitative determination of sex hormone binding globulin (SHBG) in human serum or plasma. The device operates on the IDS-iSYS Multi-Discipline Automated System. Patient samples are incubated with biotinylated monoclonal anti-SHBG antibody, acridinium-labeled monoclonal anti-SHBG conjugate, and streptavidin-labeled magnetic particles. After magnetic capture and washing to remove unbound analyte, trigger reagents are added; emitted light is proportional to SHBG concentration. The system is used in clinical laboratories by trained personnel. Results are interpreted by clinicians alongside other clinical and laboratory data to assist in diagnosing androgen disorders, potentially benefiting patients by providing diagnostic clarity for hormonal conditions.

## Clinical Evidence

Bench testing only. Performance validated via precision (CLSI EP05-A3), linearity (CLSI EP06-A), interference (CLSI EP07-A3), and detection limits (CLSI EP17-A2). Method comparison with predicate (N=136) showed a correlation coefficient (r) of 0.989 and Passing-Bablok slope of 0.9112. Matrix comparison (N=69) confirmed suitability of serum and K2 EDTA plasma. Reference intervals established using 671 healthy adult subjects.

## Technological Characteristics

Chemiluminescent magnetic particle immunoassay. Reagents: streptavidin-coated magnetic particles, biotinylated monoclonal anti-SHBG antibody, acridinium-labeled monoclonal anti-SHBG conjugate. Form factor: ready-to-use reagent cartridge for IDS-iSYS automated system. Connectivity: integrated with IDS-iSYS analyzer. Calibration: 2-point, traceable to WHO 2nd International Standard 08/266.

## Regulatory Identification

A testosterone test system is a device intended to measure testosterone (a male sex hormone) in serum, plasma, and urine. Measurement of testosterone are used in the diagnosis and treatment of disorders involving the male sex hormones (androgens), including primary and secondary hypogonadism, delayed or precocious puberty, impotence in males and, in females hirsutism (excessive hair) and virilization (masculinization) due to tumors, polycystic ovaries, and adrenogenital syndromes.

## Predicate Devices

- Siemens ADVIA Centaur SHBG ([K151986](/device/K151986.md))

## Submission Summary (Full Text)

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>
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1

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION MEMORANDUM
ASSAY ONLY TEMPLATE

A. 510(k) Number:
k190121

B. Purpose for Submission:
New device

C. Measurand:
Sex hormone binding globulin (SHBG)

D. Type of Test:
Quantitative, chemiluminescence immunoassay

E. Applicant:
Immunodiagnostic Systems Ltd.

F. Proprietary and Established Names:
IDS SHBG

G. Regulatory Information:
1. Regulation section:
21 CFR 862.1680 Testosterone test system
2. Classification:
Class I, reserved
3. Product code:
CDZ
4. Panel:
Clinical Chemistry (75)

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H. Intended Use:

1. Intended use(s):

See indication(s) for use below.

2. Indication(s) for use:

The IDS SHBG assay is an *in vitro* diagnostic device intended for the quantitative determination of SHBG in human serum and plasma on the IDS System. Results are to be used as an aid in the diagnosis of androgen disorders.

3. Special conditions for use statement(s):

For prescription use only.

Not for point-of-care use.

4. Special instrument requirements:

IDS-iSYS Multi-Discipline Automated System

I. Device Description:

The IDS SHBG assay is an *in vitro* diagnostic device consisting of ready to use reagents provided in individual compartments within the reagent cartridge.

The kit reagent components are reagent cartridge (one vial each of MPT1, CONJ, Ab-BIOT and DIL), two concentration levels of calibrators (A & B) – one vial of each, and a mini CD.

The reagent cartridge contains:

- MPT1 (Magnetic particles) – Magnetic particles coated with streptavidin in a buffer containing preservative, one bottle, 2.5 mL.
- Ab-BIOT (Biotin antibody) – Mouse monoclonal anti-SHBG labelled with biotin in a buffer containing proteins and preservatives, one bottle, 7.5 mL.
- CONJ (Conjugate) – Mouse monoclonal anti-SHBG antibody labeled with an acridinium ester derivative in a buffer containing proteins and preservatives, one bottle, 7.5 mL.
- DIL (Diluent) – Buffer containing a preservative, one bottle, 18.0 mL.

The calibrators A and B are included in the assay kit. The calibrators consist of a human serum matrix with defined concentrations of SHBG and preservatives. Together with a lot specific master calibration curve, the calibrators are used to perform the adjustment of the master calibration curve.

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J. Substantial Equivalence Information:

1. Predicate device name(s):
ADVIA Centaur SHBG

2. Predicate 510(k) number(s):
k151986

3. Comparison with predicate:
|  Item | IDS SHBG (k190121) (Candidate Device) | ADVIA Centaur SHBG (k151986) (Predicate Device)  |
| --- | --- | --- |
|  Indications for Use | Quantitative determination of SHBG in human serum or plasma. | Same  |
|  Intended Use | Aid in the diagnosis of androgen disorders. | Same  |
|  Intended User | Central Laboratory | Same  |
|  Instrument | IDS-iSYS Multi-Discipline Automated System. | ADVIA Centaur XP system.  |
|  Measurement Methodology | Chemiluminescent Magnetic Latex Particle Immunoassay. | Same  |
|  Sample Volume | 5 μL | 10 μL  |
|  Sample Type | Human serum, K_{2} EDTA plasma. | Human serum, lithium heparin plasma.  |
|  Sample Preparation (pre-treatment) | Performed on-board the analyzer. | Same  |
|  On-board the analyzer reagent stability | 14 days | 60 days  |
|  Automation | Fully automated assay. | Same  |
|  Calibration Procedure | Two point calibration | Same  |
|  Calibration Interval | 10 days | 35 days  |
|  Reportable Range | 1.6 to 180 nmol/L | Same  |
|  Traceability | Standardized to WHO 2nd International Standard (08/266). | Same  |

K. Standard/Guidance Document Referenced (if applicable):
- CLSI EP05-A3: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline-Third Edition.
- CLSI EP06-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A

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Statistical Approach; Approved Guideline-First Edition.

- CLSI EP07-A3: Interference Testing in Clinical Chemistry; Approved Guideline; Approved Guideline-Third Edition.
- CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition
- CLSI EP28-A2: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline-Second Edition

# L. Test Principle:

The IDS SHBG assay is based on chemiluminescence technology. Patient sample or calibrators are incubated with the biotinylated monoclonal anti-SHBG antibody, an acridinium labeled monoclonal anti-SHBG conjugate and streptavidin labeled magnetic particles. The magnetic particles are captured using a magnet and a wash step is performed to remove any unbound analyte. Trigger reagents are added; the resulting light emitted by the acridinium label is directly proportional to the concentration of analyte in the original sample.

# M. Performance Characteristics (if/when applicable):

# 1. Analytical performance:

# a. Precision/Reproducibility:

A precision study was conducted at an internal site by two operators using thirteen serum based samples at concentrations spanning the measuring range, each run on three IDS-iSYS Multi-Discipline Automated System and three reagent cartridge lots for 21 days, with two runs per day in two replicates, for a total of 84 replicates per sample per each of the three kit lots/systems. The study was performed following the CLSI EP05-A3 guideline. The summary result from a representative lot is included in the table below.

|  Sample | Mean (nmol/L) | Within-Run |   | Between Run |   | Between Day |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  SD | % CV | SD | % CV | SD | % CV | SD | % CV  |
|  CALB | 124.95 | 3.93 | 3.1% | 1.64 | 1.3% | 2.02 | 1.6% | 4.71 | 3.8%  |
|  CTL1 | 9.08 | 0.20 | 2.2% | 0.12 | 1.3% | 0.33 | 3.6% | 0.40 | 4.4%  |
|  CTL2 | 36.54 | 1.03 | 2.8% | 0.00 | 0.0% | 1.32 | 3.6% | 1.67 | 4.6%  |
|  CTL3 | 93.43 | 2.93 | 3.1% | 3.61 | 3.9% | 0.00 | 0.0% | 4.65 | 5.0%  |
|  CV 1 | 8.96 | 0.20 | 2.2% | 0.12 | 1.4% | 0.29 | 3.3% | 0.37 | 4.2%  |
|  CV 2 | 90.58 | 2.68 | 3.0% | 2.86 | 3.2% | 0.37 | 0.4% | 3.94 | 4.3%  |
|  CV 3 | 201.67 | 7.49 | 3.7% | 4.90 | 2.4% | 2.56 | 1.3% | 9.31 | 4.6%  |
|  IQC 1 | 5.57 | 0.09 | 1.7% | 0.06 | 1.1% | 0.20 | 3.5% | 0.23 | 4.1%  |
|  IQC 2 | 52.45 | 1.24 | 2.4% | 0.92 | 1.8% | 0.87 | 1.7% | 1.77 | 3.4%  |
|  IQC 3 | 96.82 | 2.76 | 2.8% | 0.43 | 0.4% | 1.26 | 1.3% | 3.06 | 3.2%  |
|  Patient 1 | 16.56 | 0.28 | 1.7% | 0.14 | 0.9% | 0.51 | 3.1% | 0.60 | 3.6%  |
|  Patient 2 | 85.46 | 2.15 | 2.5% | 0.00 | 0.0% | 1.63 | 1.9% | 2.70 | 3.2%  |

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|  Sample | Mean (nmol/L) | Within-Run |   | Between Run |   | Between Day |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  SD | % CV | SD | % CV | SD | % CV | SD | % CV  |
|  Patient 3 | 38.81 | 0.69 | 1.8% | 0.40 | 1.0% | 0.93 | 2.4% | 1.22 | 3.2%  |

# b. Linearity/assay reportable range:

A linearity study was conducted for the serum and the  $\mathrm{K}_2$  EDTA plasma matrices following the CLSI EP06-A guideline. A dilution series of sixteen levels per matrix type were prepared using a high-SHBG sample (above the upper limit of the assay,  $180\mathrm{nmol / L}$ ) and a low SHBG sample (close to the LoQ, +/- 0.30 nmol/L). Each level was assayed in quadruplicate. The summary results are shown below.

Serum: Concentration range assayed: 0.013 to 185.803 nmol/L.

$$
y = 1. 0 0 0 x - 0. 5 4 3; R ^ {2}: 0. 9 9 9
$$

$\mathrm{K}_2$  EDTA plasma: Concentration range assayed: 0.022 to 180.921 nmol/L.

$$
y = 0. 9 6 7 x - 0. 4 6 4; R ^ {2}: 0. 9 9 8
$$

Based on the study results, the IDS SHBG assay is linear over the claimed measuring range of 1.60 to  $180.00\mathrm{nmol / L}$ .

Dilution Recovery Study: The sponsor conducted a recovery study to support an extended reportable range up to  $720\mathrm{nmol / L}$ .

The recovery study was conducted using nine native samples spanning SHBG concentrations from 310.24 to  $726.84\mathrm{nmol / L}$  (as measured by the predicate device). The samples were automatically diluted 1:4 onboard of the IDS-iSYS Multi-Discipline Automated System and measured by the candidate device in singlicate. The percent recovery ranged from  $87\%$  to  $100\%$  compared to the expected concentration. The results of the dilution study support the sponsor's claims that samples with SHBG concentrations above the  $180\mathrm{nmol / L}$  may be diluted 1:4 on-onboard the analyzer to obtain results up to  $720\mathrm{nmol / L}$ .

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

The IDS SHBG assay is traceable to the WHO  $2^{\mathrm{nd}}$  international standard 08/266.

d. Detection limit:

The limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) studies were conducted per CLSI EP17-A guideline.

The LoB blank sample was run in twelve replicates for each of five runs over three days, by one operator for each kit lot/analyzer for a total of sixty replicates per lot

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with at least two hours interval between runs. The study was conducted using three device lots on three analyzers. Data was analyzed using the non-parametric approach and LoB was calculated based on type I alpha error of 0.05 (5%).

Each of the seven LoD samples was measured in duplicate for a total of five assays run over three days by one operator on each kit lot/analyzer, for a total of seventy replicates per lot with at least two hours interval between runs. The study was conducted using three device lots on three analyzers. Data was analyzed using the parametric approach. LoD was determined using the formula  $\mathrm{LoD} = \mathrm{LoB} + 1.645 \times$  pooled SD based on the lowest amount of analyte in a sample that can be detected with type II beta error of 0.05 (5%).

For calculation of the LoQ, a panel of nine samples were measured in singlicate two times per day for a total of ten assays run over five days by one operator on each kit lot/analyzer, for a total of ninety replicates per lot with at least two hours interval between runs. The study was conducted using three device lots on three analyzers. LoQ was calculated from the regression curve of the plot of  $\% \mathrm{CV}$  of measured concentration versus sample concentration as determined from the candidate device. The LoQ is the concentration interpolated from the regression curve at the  $20\%$  CV level.

The summary results for LoB, LoD and LoQ are shown below.

|  Limits of Detection | SHBG Concentration  |
| --- | --- |
|  LoB | 0.01 nmol/L  |
|  LoD | 0.15 nmol/L  |
|  LoQ | 0.30 nmol/L  |

The claimed measuring range of the IDS SHBG assay is from 1.60 to  $180.00\mathrm{nmol / L}$

# e. Analytical specificity:

Interference and cross-reactivity studies were conducted following the CLSI EP7-A2 guideline.

Interference Study: Twenty potential interfering substances were tested at two SHBG concentrations (approximately 25-30 nmol/L and 100-120 nmol/L). Control samples (blank) for each of the two SHBG samples were spiked with a volume of relevant diluent equal to that of the spiked interferent. The samples were assayed in 26 replicates. Non-significant interference is defined as bias  $\leq \pm 10\%$ . The summary results are shown below.

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|  Potential interferents | Highest concentration tested that demonstrated no significant interference  |
| --- | --- |
|  Triglycerides | 3000 mg/dL  |
|  Hemoglobin | 500 mg/dL  |
|  Bilirubin, conjugated | 40 mg/dL  |
|  Bilirubin, unconjugated | 40 mg/dL  |
|  Total Protein | 12 g/dL  |
|  Biotin | 1200 ng/mL  |
|  Rheumatoid Factor | 7000 IU/mL  |
|  Human Anti Mouse Antibody (HAMA) | 3000 ng/mL  |
|  Cholesterol, total | 456 mg/dL  |
|  Acetaminophen | 1324 μmol/L  |
|  Acetylsalicylic acid | 3.62 nmol/L  |
|  Salicylic acid | 4.34 mmol/L  |
|  Ibuprofen | 2425 μmol/L  |
|  Ascorbic acid (Vit C) | 1700 μmol/L  |
|  Creatinine | 2.65 mmol/L  |
|  Dopamine | 850 μmol/L  |
|  Tetracycline | 90 μmol/L  |
|  Tolbutamide | 3.7 mmol/L  |
|  Tolazamide | 3.21 mmol/L  |
|  Uric Acid | 1.4 mmol/L  |

Cross-Reactivity Study: Fifteen cross-reactants were evaluated in the study. Cross-reactant solutions were prepared by manufacturing a 'top dose' of the relevant analyte which was then diluted down to a range of stock concentrations in undetectable SHBG matrix (serum based zero matrix). The stock cross reactant or zero matrix was spiked directly into a low SHBG sample and a high SHBG sample. The cross reactivity was determined using the below equation,

$$
\% \text{ cross reactivity} = \left[\frac{\text{Mean SHBG conc. of spiked sample} - \text{mean SHBG conc. of un-spiked sample}}{\text{×100\%}}\right] / \text{Cross-reactant spiked concentration}
$$

The summary results are shown below.

|  Potential Cross Reactant | Concentration tested | % Cross-reactivity  |
| --- | --- | --- |
|  AFP | 5000 ng/mL | 0.5 %  |
|  Thyroglobulin | 3000 ng/mL | 90.2 %  |
|  Thyroxin binding globulin | 200 μg/mL | -0.1 %  |
|  Transferrin | 4 mg/mL | 0.0 %  |
|  Cortisol | 1,00,000 ng/mL | 0.0 %  |
|  11-deoxycortisol | 4000 ng/mL | -0.1 %  |

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|  Potential Cross Reactant | Concentration tested | % Cross-reactivity  |
| --- | --- | --- |
|  5α-dihydroxytestosterone | 20,000 ng/mL | 0.0 %  |
|  Estradiol | 3600 pg/mL | -7.3 %  |
|  Testosterone | 20,000 ng/mL | 0.0 %  |
|  Fibrinogen | 4.5 g/L | 0.0 %  |
|  Corticosteroid binding globulin | 35 mg/dL | 0.0 %  |
|  Thyrotropin (TSH) | 180 mIU/mL | 0.0 %  |
|  Plasminogen | 250 mg/L | 0.0 %  |
|  Human IgA | 367 mg/dL | 0.0 %  |
|  Human IgG | 335 mg/dL | 0.0 %  |

High-dose Hook Effect: A hook effect study was conducted using five SHBG levels ranging from 150 to 1500 nmol/L. Each level was tested in quadruplicate to establish if any hook effect is present between 180 to 1500 nmol/L. Results were analyzed by plotting the SHBG concentration (nmol/L) versus the obtained signal (RLU). No hook effect was observed up to 1125 nmol/L SHBG.

f. Assay cut-off:

Not applicable.

2. Comparison studies:

a. Method comparison with predicate device:

A method comparison study was conducted using 136 serum samples (approximately 5% samples tested were contrived) by two operators and three lots of candidate device. Results obtained from the candidate device were compared to the predicate device. The Passing-Bablok regression analysis was performed on the comparative data. The summary result from a representative reagent lot is shown below.

|  N | SHBG Range nmol/L | Slope | 95% CI | Intercept nmol/L | 95% CI nmol/L | Correlation Coefficient (r)  |
| --- | --- | --- | --- | --- | --- | --- |
|  136 | 2.54 to 172.12 | 0.9112 | 0.88 to 0.94 | 0.1556 | -0.35 to 0.9 | 0.989  |

b. Matrix comparison:

A matrix comparison study was conducted using 69 matched serum (without additives), serum gel separator tubes and K2 EDTA plasma samples. The samples

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were tested in duplicate using one device lot. The Passing-Bablok regression analysis was performed on the comparative data. The summary result from one singlicate data set is shown below.

|  Tube type | N | Slope | Intercept | Correlation coefficient r  |
| --- | --- | --- | --- | --- |
|  Serum gel separator tube | 69 | 1.019 | 0.4897 | 0.999  |
|  K2 EDTA plasma | 69 | 0.9854 | 0.0308 | 0.998  |

The study results support the sponsor's claim that human serum and K2 EDTA plasma are acceptable sample types to be used with this assay.

# 3. Clinical studies:

a. Clinical Sensitivity:

Not applicable.

b. Clinical specificity:

Not applicable.

c. Other clinical supportive data (when a. and b. are not applicable):

Not applicable.

# 4. Clinical cut-off:

Not applicable.

# 5. Expected values/Reference range:

A reference range study was conducted according to the CLSI C28-A3c guideline. The expected values were assessed by using 671 serum samples from the United States in which the subjects were apparently healthy adults and aged between 21 and 77 years old. The data were analysed to generate a nonparametric  $95\%$  reference interval using the  $2.5^{\text{th}}$  and  $97.5^{\text{th}}$  percentiles as reference limits. The observed ranges were established is summarised in the table below:

|  Parameters | Males 21 to 49 years | Males >50 years | Females premenopausal | Females postmenopausal  |
| --- | --- | --- | --- | --- |
|  Number of subjects | 165 | 180 | 206 | 120  |
|  Mean nmol/L | 29.74 | 35.32 | 54.37 | 52.11  |
|  Median nmol/L | 28.39 | 33.92 | 46.35 | 48.48  |
|  2.5thto 97.5th percentile nmol/L | 11.47 - 58.07 | 14.85 - 65.21 | 20.30 - 140.18 | 11.30 - 127.31  |

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The package insert recommends “above ranges should be considered as guidelines only; it is recommended that each laboratory establish its own expected range based upon its own patient population.”

N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809, as applicable.

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/CH/subpart-b%E2%80%94clinical-chemistry-test-systems/CDZ/K190121](https://fda.innolitics.com/submissions/CH/subpart-b%E2%80%94clinical-chemistry-test-systems/CDZ/K190121)

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