ACCESS SEX HORMONE BINDING GLOBULIN REAGENT, ACCESS SEX HORMONE BINDING GLOBULIN CALIBRATORS AND ACCESS SEX HORMONE BIND

K083867 · Beckman Coulter, Inc. · CDZ · Aug 27, 2009 · Clinical Chemistry

Device Facts

• Record ID: K083867
• Device Name: ACCESS SEX HORMONE BINDING GLOBULIN REAGENT, ACCESS SEX HORMONE BINDING GLOBULIN CALIBRATORS AND ACCESS SEX HORMONE BIND
• Applicant: Beckman Coulter, Inc.
• Product Code: CDZ · Clinical Chemistry
• Decision Date: Aug 27, 2009
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1680
• Device Class: Class 1

Indications for Use

The Access SHBG assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of Sex Hormone Binding Globulin levels in human serum and plasma using the Access Immunoassay Systems. The Access Sex Hormone Binding Globulin assay is indicated for use in the assessment of androgen disorders. The Access SHBG Calibrators are intended to calibrate the Access SHBG assay for the quantitative determination of Sex Hormone Binding Globulin levels in human serum and plasma using the Access Immunoassay Systems. The Access SHBG QC is intended for monitoring system performance of the Access SHBG assay.

Device Story

Access SHBG is a sequential two-step immunoenzymatic (sandwich) assay performed on Access Immunoassay Systems. Input: human serum or plasma sample. Process: sample incubated with paramagnetic particles coated with anti-SHBG antibody; SHBG binds to solid phase; alkaline phosphatase-conjugated anti-SHBG antibody added, binding to a different antigenic site; unbound materials washed away via magnetic field; chemiluminescent substrate (Lumi-Phos 530) added. Output: light production measured by luminometer, proportional to SHBG concentration; concentration determined via stored multi-point calibration curve. Used in clinical laboratory settings by trained personnel. Results aid clinicians in assessing androgen disorders.

Clinical Evidence

Bench testing only. Imprecision study (n=480) showed total CV <7% for concentrations >2 nmol/L. Analytical sensitivity: LoB 0.017 nmol/L, LoD 0.33 nmol/L. Linearity/dilution recovery (100-103%). Interference and cross-reactivity testing per CLSI EP7-A2 showed no significant interference from common endogenous/exogenous substances. Method comparison (n=158) against a commercially available enzyme immunoassay yielded a correlation coefficient of 0.94 (Passing Bablok: slope 1.09, intercept 1.84 nmol/L).

Technological Characteristics

Paramagnetic particle, chemiluminescent two-step sandwich immunoassay. Components: mouse monoclonal anti-SHBG antibodies, alkaline phosphatase conjugate, TRIS buffer, ProClin 300, sodium azide. Energy source: luminometer-based light detection. Form factor: reagent kit for automated immunoassay systems. Connectivity: integrated with Access Immunoassay Systems. Standards: CLSI EP5-A2 (precision), EP7-A2 (interference), EP17-A (LoD/LoB). Traceable to WHO 95/560 reference material.

Indications for Use

Indicated for use in the assessment of androgen disorders in human patients. For prescription use only; for in vitro diagnostic use.

Regulatory Classification

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

• DPC Immulite® SHBG (k941797)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
k083867

B. Purpose for Submission:
New device

C. Measurand:
Sex Hormone Binding Globulin (SHBG)

D. Type of Test:
Quantitative immunoassay

E. Applicant:
Beckman Coulter, Inc.

F. Proprietary and Established Names:
Access Sex Hormone Binding Globulin Reagent
Access Sex Hormone Binding Globulin Calibrators
Access Sex Hormone Binding Globulin Controls

G. Regulatory Information:
| Product Code | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| JIT | Class II | 21 CFR § 862.1150 | Clinical Chemistry (75) |
| CDZ | Class I, reserved | 21 CFR § 862.1680 | Clinical Chemistry (75) |
| JJX | Class I, reserved | 21 CFR § 862.1660 | Clinical Chemistry (75) |

H. Intended Use:

1. Intended use(s):
The Access SHBG assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of Sex Hormone Binding Globulin levels in human serum and plasma using the Access Immunoassay Systems. The Access Sex Hormone Binding Globulin assay is indicated for use in the assessment of androgen disorders.

The Access SHBG Calibrators are intended to calibrate the Access SHBG assay for the quantitative determination of Sex Hormone Binding Globulin levels in human serum and plasma using the Access Immunoassay Systems.

The Access SHBG QC is intended for monitoring system performance of the Access SHBG assay.

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2. Indication(s) for use:
See intended use(s) above.

3. Special conditions for use statement(s):
For prescription use only; For in vitro diagnostic use

4. Special instrument requirements:
Performance characteristics were provided for the Access UniCel Dxl 800 Immunoassay System

I. Device Description:
The kit contains the following components:

| R1a | Paramagnetic particles coated with mouse monoclonal anti-SHBG in a buffered protein (bovine and mouse) matrix with < 0.1% sodium azide and 0.1% ProClin 300. |
| --- | --- |
| R1b | Mouse monoclonal anti-SHBG alkaline phosphatase (bovine) conjugate in a buffered protein (bovine) matrix with < 0.1% sodium azide and 0.1% ProClin 300. |
| R1c | TRIS buffer with < 0.1% sodium azide and 0.1% ProClin 300. |

SHBG calibrators (0, 3, 9, 27, 80 and 200 nmol/L) and SHBG quality controls (10 and 100 nmol/L) are sold separately. All calibrators (except the 0) and controls are prepared from purified human SHBG in a protein (bovine) buffered matrix with &lt; 0.1% sodium azide and 0.1% ProClin 300. All human source materials used in the preparation of the calibrators and controls were tested using FDA-approved methods and found to be non-reactive for the presence of hepatitis B, hepatitis C, HIV-1 and HIV-2.

J. Substantial Equivalence Information:

1. Predicate device name(s):
DPC Immulite® SHBG

2. Predicate K number(s):
k941797

3. Comparison with predicate:

| Item | Device | Predicate |
| --- | --- | --- |
| Similarities | | |
| Intended use | The Access SHBG Assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of SHBG levels in human serum and plasma using the Access Immunoassay Systems. The Access | Immulite SHBG is a solid-phase, two-site chemiluminescent enzyme immunometric assay designed for the quantitative measurement of sex hormone binding globulin (SHBG) in serum. It is intended strictly for in vitro diagnostic use as an aid in the |

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| | SHBG assay is indicated for use in the assessment of androgen disorders. | differential diagnosis of hirsutism. |
| --- | --- | --- |
| Product type | Immunoassay | same |
| Assay format | Chemiluminescent, two-site sandwich immunoassay | same |
| Differences | | |
| Specimens | Serum or plasma (heparin) | serum |
| Components | Mouse monoclonal antibody against SHBG in the capture phase and a mouse monoclonal anti-SHBG antibody conjugated to alkaline phosphatase (bovine) in the signal phase. | Mouse monoclonal antibody against SHBG in the capture phase and a polyclonal rabbit anti SHBG antibody conjugated to alkaline phosphatase (bovine) in the signal phase. |
| Assay range | 0.33 to 200 nmol/L | 0.5 to 180 nmol/L |
| Interference | No interference with acetaminophen (200 mg/L), acetylsalicylic acid (652 mg/L), alpha-fetoprotein (492 μg/L), conjugated bilirubin (300 mg/L), unconjugated bilirubin (200 mg/L), cortisol (100 mg/L), 11-deoxycortisol (4 mg/L), 5α-dihydroxytestosterone (20 mg/L), hemoglobin (4 g/L), heparin (72000 U/L), human serum albumin (60 g/L), ibuprofen (0.5 g/L), estradiol (3.6 μg/L), GAS6 (235 μg/L), laminin (6064 μg/L), multivitamin supplement (0.9% v/v), protein S (26 mg/L), testosterone (20 mg/L), thyroglobulin (300 μg/L), thyroxine-binding globulin (193 mg/L), transferring (4 g/L) and triglycerides/Intralipid (50 g/L) | No interference observed with hemolysis or bilirubin. |
| Cross-reactivity | No cross-reactivity with alpha-fetoprotein (492 μg/L), cortisol (100 mg/L), 5α- dihydroxytestosterone (20 mg/L), 11-deoxycortisol (4 mg/L), estradiol (3.6 μg/L), GAS6 (235 μg/L), laminin (6064 μg/L), protein S (26 mg/L), testosterone (20 mg/L) thyroglobulin (300 μg/L), thyroxine-binding globulin (193 mg/L) and transferring (4 g/L) | No cross-reactivity with alpha-fetoprotein (400 IU/mL), cortisol (100 mg/L), 11-deoxycortisol (4 mg/L), 5α-dihydroxytestosterone (20 mg/L), estradiol (3,600 μg/L), human serum albumin (50 g/L), testosterone (20 mg/L), thyroglobulin (300 μg/L), thyroxine-binding globulin (193 mg/L) and transferring (4 g/L) |
| LoB, LoD (nmol/L) | Limit of Blank (LoB): 0.017 Limit of Detection (LoD): 0.33 | LoD: 0.08 |
| Precision | 6.3 nmol/L, total CV% 5.4 38 nmol/L, total CV% 5.3 80 nmol/L, total CV% 5.5 171 nmol/L, total CV% 5.2 | Within run precision is 8% at > 4.5 nmol/L; between run precision is 10% at > 12 nmol/L. |
| Calibrators and controls | Calibrators (0, 3, 9, 27, 80 and 200 nmol/L) and controls (10 and 100 | Two SHBG Adjustors designated LOW and HIGH, containing different |
| | ng/L) and controls (100 and 1000 | ng/L) and controls (1000 and 10000) |

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| | nmol/L) are sold separately. All calibrators (except the 0) and controls are prepared from purified human SHBG and are traceable to WHO 95/560 | concentrations of SHBG, are provided with the kit. Traceability is not listed. |
| --- | --- | --- |
| Expected values | Males, n=151, median 38.2 nmol/L; 95 percentile, 13.3 - 89.5 nmol/L. Females (nonpregnant) n=141, median 47.2 nmol/L; 95 percentile 18.2-135.5 nmol/L. Female (postmenopausal), n = 131, median 49.6 nmol/L; 95 percentile, 16.8-125.2 nmol/L. | Males, n=122, mean 32 nmol/L; 95 percentile, 13 - 71 nmol/L. Females (nonpregnant), n=111, mean 51 nmol/L; 95 percentile, 18 - 114 nmol/L. |

K. Standard/Guidance Document Referenced (if applicable):
- Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline (EP5-A2)
- Interference Testing in Clinical Chemistry; Approved Guideline (EP7-A2)
- Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline (EP17-A)

L. Test Principle:
The Access SHBG assay is a sequential two-step immunoenzymatic (“sandwich”) assay. A sample is added to a reaction vessel along with paramagnetic particles coated with anti-SHBG antibody. During incubation, the SHBG antigen in the sample binds to the immobilized anti-SHBG antibody on the solid phase. Alkaline phosphatase conjugated anti-SHBG antibody is then added and reacts with a different antigenic site on the SHBG molecule. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then, the chemiluminescent substrate Lumi-Phos 530 is added and the light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of SHBG in the sample. The amount of analyte in the sample is determined from a stored, multi-point calibration curve.

M. Performance Characteristics (if/when applicable):
1. Analytical performance:
All performance characteristics were performed on the UniCel DxI 800 analyzer.

a. Precision/Reproducibility:
The precision of the proposed device was evaluated using a method based on the guideline CLSI EP5-A2 using 4 patient samples. Sample 1 was a serum pool, partly depleted with anti-SHBG paramagnetic particles. Sample 2 and 3 were unaltered serum pools. Sample 4 was pooled serum spiked with human SHBG. The samples were assayed in duplicate, twice

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a day (2 runs per day) for 20 days over a 28 day period for a total of 480 measurements per sample. Three separate pack lots and 2 Access UniCel Dxl 800 instrument were used for the study. The results are summarized below:

| Sample | n | Mean (nmol/L) | Within run | | Between-run | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | CV% | SD | CV% | SD | CV% |
| 1 | 480 | 6.3 | 0.3 | 4.7 | 0.2 | 2.7 | 0.3 | 5.4 |
| 2 | 480 | 38 | 1.8 | 4.6 | 1.1 | 2.8 | 2.0 | 5.3 |
| 3 | 480 | 80 | 3.6 | 4.5 | 2.5 | 3.2 | 4.4 | 5.5 |
| 4 | 480 | 171 | 8.1 | 4.8 | 3.7 | 2.2 | 9.0 | 5.2 |

# b. Linearity/assay reportable range:

Linearity studies were performed using 3 serum samples. Sample 1 was spiked with human SHBG to approximately $200\mathrm{nM}$ . Sample 2 was an unaltered sample with approximately $35\mathrm{nM}$ SHBG. Sample 3 was partly depleted with anti-SHBG paramagnetic particles to approximately $3\mathrm{nM}$ SHBG. At least 6 serial dilutions were prepared from each sample using Access Wash Buffer II. Each dilution was tested in 4 replicates; neat sample concentrations were determined as the mean of 8 replicates. The data was analyzed using linear and quadratic models. The quadratic fit was found to be significant. Therefore, the degree of non linearity was assessed by calculating the $\%$ difference between the linear and non-linear model at each concentration. The results are summarized below:

| Linear fit | Non-Linear fit | Nonlinearity | Nonlinearity % | Expected |
| --- | --- | --- | --- | --- |
| 0.0000 | 0.0004 | 0.0004 | +∞ | 0.000 |
| 0.1068 | 0.1190 | 0.0121 | 11.4% | 0.087 |
| 0.3350 | 0.3310 | -0.0041 | -1.2% | 0.290 |
| 1.0669 | 0.9952 | -0.0717 | -6.7% | 0.968 |
| 1.1798 | 1.0981 | -0.0817 | -6.9% | 1.074 |
| 1.5802 | 1.4645 | -0.1157 | -7.3% | 1.452 |
| 2.0896 | 1.9344 | -0.1552 | -7.4% | 1.936 |
| 2.5953 | 2.4050 | -0.1903 | -7.3% | 2.419 |
| 3.1010 | 2.8793 | -0.2218 | -7.2% | 2.904 |
| 3.8037 | 3.5438 | -0.2599 | -6.8% | 3.581 |
| 6.5037 | 6.1464 | -0.3573 | -5.5% | 6.197 |
| 12.3677 | 11.9778 | -0.3899 | -3.2% | 11.935 |
| 18.4248 | 18.1541 | -0.2708 | -1.5% | 17.903 |
| 21.2128 | 21.0296 | -0.1833 | -0.9% | 20.658 |
| 24.4570 | 24.3937 | -0.0633 | -0.3% | 23.870 |
| 30.4600 | 30.6556 | 0.1956 | 0.6% | 29.826 |
| 36.4742 | 36.9592 | 0.4850 | 1.3% | 35.805 |
| 69.5758 | 71.6816 | 2.1058 | 3.0% | 68.861 |
| 103.9005 | 107.0587 | 3.1583 | 3.0% | 103.291 |
| 138.1333 | 141.3100 | 3.1767 | 2.3% | 137.721 |

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| 172.2347 | 174.2660 | 2.0314 | 1.2% | 172.083 |
| --- | --- | --- | --- | --- |
| 206.4251 | 206.0959 | -0.3292 | -0.2% | 206.582 |

Based upon the linearity study and the limits of detection, the claimed measuring range is 0.33 to 200 nmol/L.

The package insert states:

- Samples can be accurately measured within the analytical range of the lower limit of detection (0.33 nmol/L) and the highest calibrator value (approximately 200 nmol/L).
- If a sample contains less than the lower limit of detection for the assay, report the results as less than that value (i.e., &lt; 0.33 nmol/L).
- If a sample contains more than the stated value of the highest Access SHBG Calibrator (S5), report the result as greater than the value of the highest calibrator. Alternatively, dilute one volume of sample with 9 volumes of Wash Buffer II.

High-dose hook effect: The potential for a high-dose hook effect was evaluated using one patient sample spiked to approximately 49,500 nmol/L SHBG and a second sample obtained by dilution an SHBG stock solution in serum to create a sample with approximately 1000 nmol/L SHBG. The relative light units at 49,500 nmol/L and at 863 nmol/L did not fall below the relative light units generated by the highest SHGB calibrator (S5).

The product insert states:

- The access SHBG assay does not demonstrate any “hook” effect up to 49,500 nmol/L.

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

The Access SHBG calibrators (0, 3, 9, 27, 80 and 200 nmol/L) and controls (10 and 100 nmol/L) are traceable to WHO 95/560 reference material. They are sold separately.

Real-time stability including shelf-life and open vial stability studies were performed for the controls and calibrators. The study protocols and statistically calculated acceptance limits were reviewed and found to be acceptable. At the time of submission, the sponsor has demonstrated acceptable unopened shelf life of 12 months for the controls and calibrators when stored at 2 to 8 °C. The sponsor has demonstrated acceptable open vial stability of 28 days for the calibrators and controls when stored at 2 to 8 °C.

Calibration Frequency: The calibration curve is stable for 28 days.

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d. Detection limit:

The Limit of Blank (LoB) and the Limit of Detection (LoD) studies were performed in accordance to CLSI EP17-A. For LoB, 156 replicates of the S0 calibrator were measured. The $95^{\text{th}}$ percentile of the replicates was estimated using a non-parametric approach and the $97.5\%$ upper confidence limit of this estimate was used to estimate the LoB. For LoD, 180 replicates of 5 low level samples were measured.

The LoB was estimated to be $0.017\mathrm{nmol / L}$ The LoD was estimated to be $0.33\mathrm{nmol / L}$

e. Analytical specificity:

Interference from various compounds was evaluated on serum samples containing approximately $13\mathrm{nmol / L}$ and $140\mathrm{nmol / L}$ SHBG. The sponsor defined noninterference as $&lt; 10\%$ deviation from the un-spiked samples. Based on data, the sponsor claims no interference for the substances and concentrations listed in the table below:

| Compound | Concentration added to samples | |
| --- | --- | --- |
| | Low | High |
| Acetaminophen | 30 mg/L | 200 mg/L |
| Acetylsalicylic acid | 390 mg/L | 652 mg/L |
| Alpha-Fetoprotein (AFP) | 74.9 μg/L | 492 μg/L |
| Bilirubin (conjugated) | 2.98 mg/L | 300 mg/L |
| Bilirubin (unconjugated) | 12.2 mg/dL | 200 mg/L |
| Cortisol | 16 μg/L | 100 mg/L |
| 11-deoxycortisol | 1.58 mg/L | 4 mg/L |
| 5α-dihydroxytestosterone | 0.85 μg/L | 20 mg/L |
| Hemoglobin | 2 g/L | 4 g/L |
| Heparin | 1000 U/L | 72000 U/L |
| Human serum albumin (HAS) | 51 g/L | 60 g/L |
| Ibuprofen | 0.07 g/L | 0.5 g/L |
| Estradiol | 750 ng/L | 3.6 μg/L |
| GAS6 | 63 μg/L | 235 μg/L |
| Laminin | 520 μg/L | 6064 μg/L |
| Multivitamin Supplement | 0.3 % (v/v) | 0.9 % (v/v) |
| Protein S | 3.6 mg/L | 26 mg/L |
| Testosterone | 210 ng/L | 20 mg/L |
| Thyroglobulin (Tg) | 40 μg/L | 300 μg/L |
| Thyroxine-binding Globulin (TBG) | 55 mg/L | 193 mg/L |
| Transferrin | 1.3 g/L | 4 g/L |
| Triglycerides (Intralipid) | 3.29 g/L | 50 g/L |

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To evaluate the potential cross-reactivity of various compounds whose structure is similar to SHBG the substances were spiked in the Access SHBG calibrator S0. % cross reactivity was calculated as follows:

[(mean test value-mean control value) x 100]/concentration of compound tested.

The following compounds at the listed concentrations were tested:

| Substance | Concentration added to samples | |
| --- | --- | --- |
| | Low | High |
| Alpha-fetoprotein (AFP) | 74.9 μg/L | 492 μg/L |
| Cortisol | 16 μg/L | 100 mg/L |
| 5α-dihydroxytestosterone | 0.85 μg/L | 20 mg/L |
| 11-Deoxycortisol | 1.58 mg/L | 4 mg/L |
| Estradiol | 750 ng/L | 3.6 μg/L |
| GAS6 | 63 μg/L | 235 μg/L |
| Laminin | 520 μg/L | 6064 μg/L |
| Protein S | 3.6 mg/L | 26 mg/L |
| Testosterone | 210 ng/L | 20 mg/L |
| Thyroglobulin (Tg) | 40 μg/L | 300 μg/L |
| TBG | 55 mg/L | 193 mg/L |
| Transferrin | 1.3 g/L | 4 g/L |

The sponsor provided data to support the claim that no significant cross-reactivity (defined as $\leq 1.3\%$ ) was observed when the calibrator S0 was spiked with the compounds listed above.

f. Assay cut-off: Not applicable.

# 2. Comparison studies:

a. Method comparison with predicate device:

To compare the performance of the Access SHBG assay to the predicate device, a total of 158 unaltered serum samples ranging from 5.7 to 184.5 nmol/L SHBG were assayed on both devices. The slope, intercept and confidence interval (CI) were determined using Deming regression; the correlation coefficient $(\mathrm{r}^2)$ was determined by linear regression. The results are summarized in the table below:

| n | Slope (95% CI) | Intercept (nmol/L) (95% CI) | r2 |
| --- | --- | --- | --- |
| 158 | 1.09 (1.06 to 1.12) | 1.84 (0.54 to 3.00) | 0.94 |

b. Matrix comparison:

A comparison study was performed following the recommendations in CLSI EP14-A2 with a total of 61 matched serum and plasma (heparin)

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samples. All samples were unaltered and ranged from approximately 10 to 200 nmol/L SHBG. Serum samples were collected in plain and gel (SST) tubes. Samples were assayed in 3 replicates on one Access UniCel Dxl 800 instrument. The slope, bias, y-intercept and confidence intervals (CI) were determined using a Deming regression and the correlation coefficient (r²) was determined by linear regression. The results are summarized in the tables below:

| | Slope (95% CI) | Intercept (nmol/L) (95% CI) | r² |
| --- | --- | --- | --- |
| Serum gel vs. serum | 1.00 (0.97 to 1.063) | -0.84 (-3.04 to -1.36) | 0.994 |
| Plasma (heparin) vs. serum | 0.99 (0.97 to 1.01) | -0.48 (-2.17 to 1.21) | 0.996 |

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: Samples from males, females, and postmenopausal females from the United States were assayed using the proposed device. The inclusion/exclusion criteria are summarized below:

| Males | Females | Postmenopausal women |
| --- | --- | --- |
| • “Apparently healthy”
• No known endocrine disorder
• Access testosterone >1.75 ng/mL
• Access human thyroid stimulating hormone (hTSH) 0.34 – 6.60 μIU/mL | • “Apparently healthy”
• No known endocrine or reproductive disorder
• Not pregnant with regular menstrual cycle
• Access beta human chorionic gonadotropin < 2.9 IU/mL
• Access estradiol values >20 pg/mL
• No steroid based contraceptives
• Access hTSH 0.34 – | • “Apparently healthy”
• No known endocrine or reproductive disorder
• No menstrual period for at least 12 months
• For women < 55 years; Access human luteinizing hormone, Access human follicle stimulating hormone levels consistent with postmenopausal status, and Access estradiol levels < 88 pg/mL. |

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| | 6.60 μIU/mL | • No hormone replacement therapy
• No osteoporosis medication with estrogen analog (e.g. Evista).
• Access hTSH between 0.34 – 6.60 μIU/mL |
| --- | --- | --- |

Analysis was performed including a non-parametric determination of the 95% reference range and a bootstrap estimation of the 95% confidence interval (CI) of each of the range estimates. The Access SHBG reference range is summarized below:

| | n | Median age | Median | 95% CI |
| --- | --- | --- | --- | --- |
| Males (20 – 50 yrs) | 151 | 37 | 38.2 nmol/L | 13.3 – 89.5 nmol/L |
| Females (20 – 46 yrs) | 141 | 34 | 47.2 nmol/L | 18.2 – 135.5 nmol/L |
| Post-menopausal females (47 – 91 yrs) | 131 | 59 | 49.6 nmol/L | 16.8 – 125.2 nmol/L |

The product insert states:
- Each laboratory should establish its own reference ranges to assure proper representation of specific populations.

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.