The Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge is an in vitro diagnostic test for the quantitative measurement of total testosterone in human serum and plasma on the Dimension Vista® System. Measurements 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.

The Dimension Vista® Testosterone Calibrator is an in vitro diagnostic product for the calibration of the Total Testosterone (TTST) assay on the Dimension Vista® System.

Device Description

The Dimension Vista® LOCI Total Testosterone Flex® Reagent Cartridge (TTST) method is a homogeneous, competitive chemiluminescent immunoassay based on LOCI® technology. LOCI reagents include two synthetic bead reagents and labeled testosterone antibody. The first bead reagent (Chemibeads) is coated with a testosterone analog and contains a chemiluminescent dye. The second bead reagent (Sensibeads) is coated with streptavidin and contains photosensitive dye. Chemibeads and labeled testosterone antibody are added sequentially to the reaction vessel. Testosterone from the patient sample competes with the testosterone-analog-chemibead for a limited amount of labeled testosterone antibody. Sensibeads are then added and bind to the biotinylated portion of the labeled testosterone antibody to form bead pair immunocomplexes. Illumination of the complex by light at 680 nm generates singlet oxygen from the Sensibeads which diffuses to the Chemibeads triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is an inverse function of the concentration of total testosterone in the sample.

Dimension Vista® LOCI Total Testosterone reagents are liquid and contained in reagent wells of a Flex® reagent cartridge. There are twelve (12) wells in each Flex® reagent cartridge. A barcode label on the Flex® reagent cartridge identifies the test method, lot number, expiration date, and fixed number of tests for which the Flex® reagent cartridge can supply reagent. There are eighty (80) tests per Flex® reagent cartridge and four (4) Flex® reagent cartridges per carton.

The Dimension Vista® Testosterone Calibrator (TTST CAL) is a lyophilized human serum based calibrator set containing testosterone and preservatives. Within each set of twelve (12) vials there are two (2) 1.0 mL amber glass vials for each calibrator level. There are six (6) calibrator levels labeled A, B, C, D, E, and F, which span the assay range. Each glass vial is closed with a plug and a color coded plastic cap. Vials are stored at 2-8°C. Lyophilized calibrators are reconstituted with reagent grade water using the steps listed in the instructions for use (IFU).

AI/ML Overview

The provided document describes the Siemens Healthcare Diagnostics Inc. Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge and its associated calibrator, seeking substantial equivalence to predicate devices. The study focuses on the performance characteristics of the new device.

Here's an analysis of the acceptance criteria and study details based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined "acceptance criteria" in a quantitative, pass/fail format for each performance characteristic. Instead, it presents the results of various performance studies and implies that these results demonstrate substantial equivalence to the predicate device. The predicate device itself and recognized CLSI guidelines serve as implicit benchmarks for acceptable performance.

However, based on the provided data, we can infer some targets or observed ranges that indicate acceptable performance. The "Reported Device Performance" column reflects the results of the studies described.

Performance Characteristic	Implicit Acceptance Criteria (Inferred from CLSI Guidelines & Predicate)	Reported Device Performance (Dimension Vista® LOCI Total Testosterone Flex®)
Method Comparison (vs. CDC ID/LC-MS/MS)	High correlation (e.g., r > 0.95), slope near 1, y-intercept near 0, 95% Confidence Interval for slope encompassing 1, for intercept encompassing 0.	N=113 samples. Range: 7.3 - 1033 ng/dL (CDC), 8-949 ng/dL (Vista TTST). Slope: 0.93 y-intercept: 4.0 Correlation coefficient (r): 0.994 95% CI Slope: 0.92 to 0.95 95% CI Intercept: 0.4 to 5.7
Precision (Repeatability %CV)	(Based on CLSI EP05-A2 and typical immunoassay performance expectations, generally <10% for low concentrations, lower for higher concentrations)	Serum Pool 1 (13 ng/dL): 5.2% Serum Pool 2 (75 ng/dL): 1.9% Serum Pool 3 (767 ng/dL): 1.8% Li Heparin Plasma Pool (384 ng/dL): 3.7% Bio-Rad Liquichek™ Level 1 (71 ng/dL): 1.7% Bio-Rad Liquichek™ Level 2 (441 ng/dL): 0.9% Bio-Rad Liquichek™ Level 3 (855 ng/dL): 1.6%
Precision (Within-Lab %CV)	(Based on CLSI EP05-A2 and typical immunoassay performance expectations, generally <15-20% for low concentrations, lower for higher concentrations)	Serum Pool 1 (13 ng/dL): 7.3% Serum Pool 2 (75 ng/dL): 2.1% Serum Pool 3 (767 ng/dL): 2.4% Li Heparin Plasma Pool (384 ng/dL): 4.1% Bio-Rad Liquichek™ Level 1 (71 ng/dL): 2.6% Bio-Rad Liquichek™ Level 2 (441 ng/dL): 1.3% Bio-Rad Liquichek™ Level 3 (855 ng/dL): 2.0%
Analytical Measuring Range/Linearity	Statistically linear across the claimed range (p-value > 0.05 from polynomial regression, high correlation coefficient).	Statistically linear across 8 to 1,000 ng/dL for serum, lithium heparin, sodium heparin, and EDTA plasma. p-values > 0.05. Serum: $0.97x + 0.1$, r=0.999 Sodium Heparin: $0.98x + 0.1$, r=0.998 Lithium Heparin: $0.98x + 0.0$, r=0.999 EDTA: $0.96x + 0.1$, r=0.999
Limit of Blank (LoB)	Stated as 4 ng/dL	4 ng/dL
Limit of Detection (LoD)	Stated as 5 ng/dL	5 ng/dL
Limit of Quantitation (LoQ)	Reproducible measurement with total precision ≤20% (as per CLSI EP05-A2).	8 ng/dL (with total precision ≤20%)
Interferences (Hemoglobin, Bilirubin, Lipemia Bias)	Low bias (e.g., < ±10-15%)	Hemoglobin (1000 mg/dL): 2% bias @ 50 ng/dL, -7% bias @ 300 ng/dL Bilirubin (unconjugated) (60 mg/dL): 2% bias @ 50 ng/dL, -8% bias @ 300 ng/dL Bilirubin (conjugated) (60 mg/dL): -2% bias @ 50 ng/dL, 6% bias @ 300 ng/dL Lipemia (Intralipid) (1000 mg/dL): 2% bias @ 50 ng/dL, 0% bias @ 300 ng/dL
Heterophilic Antibody Interference (HAMA)	Low interference (e.g., < ±10%)	HAMA (1248 ng/mL): -4% @ 149 ng/dL, -6% @ 887 ng/dL HAMA (285 ng/mL): -2% @ 156 ng/dL, -5% @ 746 ng/dL
Cross-reactivity	Low cross-reactivity for structurally similar compounds; no detection (ND) for others.	Varies by substance (e.g., 5α-dihydrotestosterone 0.3%, 17α-methyltestosterone up to 4.2%). Many substances show ND or very low cross-reactivity. Nandrolone decanoate identified as significant cross-reactant (not quantified but a warning is issued).
Serum and Plasma Equivalency (Correlation vs. Serum)	High correlation (e.g., r > 0.95), slope near 1, intercept near 0.	Li Hep Plasma: Slope 0.98, Intercept -1.6 ng/dL, r=0.998 Na Hep Plasma: Slope 0.99, Intercept -1.4 ng/dL, r=0.996 K2 EDTA Plasma: Slope 1.00, Intercept -1.1 ng/dL, r=0.995

2. Sample Size Used for the Test Set and Data Provenance

Method Comparison: 120 serum samples were initially measured. After removing 7 samples (6 below range, 1 above range), 113 samples were used for regression analysis.
- Data Provenance: Not explicitly stated but clinical samples were used, likely from a patient population within the US given the submission to the FDA. The study was performed at Siemens Healthcare Diagnostics' Newark, DE site. This is a retrospective analysis in the sense that samples were collected and then tested.
Precision: Serum pools, a plasma pool, and commercial controls were used.
- Sample Size: Tested in singlicate from two independent cups twice a day for 20 days. This implies 40 measurements per sample type.
- Data Provenance: Not specified, but likely proprietary pools or commercial controls. Study performed at Siemens Healthcare Diagnostics' Newark, DE site.
Analytical Measuring Range/Linearity: High and low pools for serum, lithium heparin, sodium heparin, and EDTA samples.
- Sample Size: Each level was assayed N=5 replicates. The number of distinct pools (high/low) is not specified for each sample type, but implied to be sufficient to cover the range.
- Data Provenance: Not specified, likely internal laboratory prepared pools. Study performed at Siemens Healthcare Diagnostics' Newark, DE site.
Limits of Detection and Quantitation: Testosterone free serum samples and low testosterone serum samples.
- Sample Size: Not explicitly stated for LoB/LoD, but LoQ was determined based on precision data (implied 40 measurements).
- Data Provenance: Not specified, likely internal laboratory prepared samples.
Interferences: Serum samples with various interfering substances spiked in.
- Sample Size: Not specified per substance, typically multiple replicates at each concentration.
- Data Provenance: Not specified, likely internal laboratory prepared samples.
Heterophilic Antibody Interference: Individual human serum samples with low and high endogenous HAMA.
- Sample Size: Not specified, but implied individual samples were tested.
- Data Provenance: Not specified.
Cross-reactivity: Spiked test samples.
- Sample Size: Not specified per cross-reactant, typically multiple replicates at each concentration and testosterone level.
- Data Provenance: Not specified, likely internal laboratory prepared samples.
Serum and Plasma Equivalency: Sixty (60) matched sets of fresh draws.
- Sample Size: 60 matched sets. One sample removed, so 59 sets for regression analysis.
- Data Provenance: Not explicitly stated, but implies prospectively collected clinical samples.
Expected Values (Reference Interval):
- Adult Males ≤50 years old: 174 samples
- Adult Males >50 years old: 174 samples
- Pre-menopausal females: 174 samples
- Post-menopausal females: 174 samples
- Pediatric (various age/gender/Tanner stages): Ranges from 20 to 125 samples per group.
- Data Provenance: Not specified, but likely from healthy volunteers (prospective) or carefully selected retrospective samples to establish reference ranges for different demographics.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

Ground Truth for Method Comparison: The reference method was the CDC Isotope dilution/liquid chromatographic-tandem mass spectrometry (CDC ID/LC-MS/MS). This is a highly accurate and precise analytical method that by its nature serves as its own "expert" or gold standard. It does not rely on human interpretation or consensus for ground truth.
Ground Truth for Reference Intervals: The reference intervals were established using the "robust" method or non-parametric methods described in CLSI EP28-A3c, applied to samples from healthy individuals. The "ground truth" here is the biological range observed in these populations, rather than an expert interpretation of the result from a single patient. The selection of "healthy" individuals likely involves criteria established by medical professionals, but this is not detailed as a panel of experts.

4. Adjudication Method for the Test Set

This type of in-vitro diagnostic device (immunoassay for a quantitative measurement) does not typically involve an adjudication method in the way medical imaging AI devices do (e.g., 2+1 radiologist review). The output is a quantitative value. Agreement is assessed statistically against a reference method or through precision studies, not through expert consensus on the device's output for individual cases.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic devices where human readers interpret results, and the AI system acts as an aid to improve their performance. This document concerns a fully automated in-vitro diagnostic immunoassay which provides a numerical result directly, rather than an image or complex data needing human interpretation.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, the entire submission and the performance studies detailed (Method Comparison, Precision, Linearity, Limits of Detection/Quantitation, Interferences, Cross-reactivity, Serum/Plasma Equivalency, Reference Intervals) effectively describe the standalone performance of the algorithm, as it's an automated device that provides quantitative results without human interpretation in the determination of the final value. The performance evaluation focuses on the analytical performance of the Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge and system itself.

7. Type of Ground Truth Used

Method Comparison: CDC Isotope dilution/liquid chromatographic-tandem mass spectrometry (CDC ID/LC-MS/MS) (a highly accurate reference analytical method, considered a gold standard).
Precision, Linearity, LoD/LoQ, Interferences, Cross-reactivity, Serum/Plasma Equivalency: These studies rely on known concentrations (e.g., spiked samples, control materials, or reference method values from the method comparison) to establish the accuracy and reliability of the device's measurements.
Expected Values (Reference Interval): Data from well-defined populations of healthy individuals, analyzed using statistical methods (non-parametric or "Robust" method).

8. Sample Size for the Training Set

The provided document does not mention a training set in the context of machine learning or AI algorithms as the primary development method for the immunoassay. This device is based on a "homogeneous, competitive chemiluminescent immunoassay based on LOCI® technology" (a biochemical detection method), not a software algorithm that learns from a training dataset in the typical AI sense. The development of such an assay involves extensive biochemical optimization, reagent formulation, and analytical validation.

9. How the Ground Truth for the Training Set Was Established

As no training set (in the AI/ML context) is discussed, this question is not applicable. The "ground truth" for developing this type of immunoassay would involve precise chemical standards and assays to characterize reagent performance and assay kinetics during R&D.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

SIEMENS HEALTHCARE DIAGNOSTICS, INC. JULIE WARREN REGULATORY TECHNICAL SPECIALIST 500 GBC DR. P.O. BOX 6101 M/S 514 NEWARK DE 19714

February 11, 2016

Re: K151529

Trade/Device Name: Dimension Vista® LOCI Total Testosterone Flex® Reagent Cartridge Dimension Vista® Testosterone Calibrator Regulation Number: 21 CFR 862.1680 Regulation Name: Testosterone test system Regulatory Class: I. Reserved Product Code: CDZ, JIT Dated: February 08, 2016 Received: February 09, 2016

Dear Julie Warren:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Katherine Serrano -S

For : Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

510(k) Number (if known)

K151529

Device Name

Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge

Indications for Use (Describe)

The Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge is an in vitro diagnostic test for the quantitative measurement of total testosterone in human serum and plasma on Vista@ System. Measurements 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, hirsutism (excessive hair), and virilization) due to tumors, polycystic ovaries, and adrenogenital syndromes.

Type of Use (Select one or both, as applicable)
-------------------------------------------------	--

Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

510(k) Number (if known)

K151529

Device Name Dimension Vista® Testosterone Calibrator

Indications for Use (Describe)

The Dimension Vista® Testosterone Calibrator is an in vitro diagnostic product for the calibration of the Total Testosterone (TTST) assay on the Dimension Vista® System.

Type of Use (Select one or both, as applicable)

2 Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

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510(k) Summary

This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and 21 CFR 807.92.

The assigned 510(k) number is: K151529

1. Submitter

Siemens Healthcare Diagnostics, Inc. 500 GBC Dr. Newark, DE 19714

Contact Person: Julie Warren Tel: 302-631-8722 Fax: 302-631-6299 Email: julie.warren@siemens.com

Date of Preparation: February 5, 2016

2. Device Information

Name of Device: Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge Common Name: Testosterone test system Regulatory Class: I (21 CFR §862.1680, Testosterone test system) Product Code: CDZ Panel: Clinical Chemistry

Name of Device: Dimension Vista® Testosterone Calibrator Common Name: Testosterone Calibrator Regulatory Class: II (21 CFR §862.1150, Calibrator) Product Code: JIT Panel: Clinical Chemistry

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3. Predicate Device

Assay: Roche Diagnostics Corp. Device Name: Elecsys® Testosterone II Immunoassay 510(k) Number: K093421 Regulatory Class: I (21 CFR §862.1680, Testosterone test system) Classification Product Code: CDZ Panel: Clinical Chemistry

Calibrator: Roche Diagnostics Corp. Device Name: Elecsys® Testosterone Calset II 510(k) Number: K003411 Regulatory Class: II (21 CFR §862.1150, Calibrator) Classification Product Code: JIT Panel: Clinical Chemistry

4. Device Description

Dimension Vista® LOCI Total Testosterone Flex® Reagent Cartridge

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Example Flex® Reagent Cartridge Well Configuration

1	2	3	4	5	6	7	8	9	10	11	12
---	---	---	---	---	---	---	---	---	----	----	----

Wells	Form	Name	Concentration
1-4	Liquid	Testosterone BiotinylatedAntibody Reagentc, d (Sheepmonoclonal);Displacer	31.3 ng/mL;1200 ng/mL
5-8	Liquid	Testosterone Chemibead Reagentd	100 µg/mL
9-12	Liquid	Testosterone Sensibead Reagentd	400 µg/mL

Wells are numbered consecutively from the wide end of the cartridge. a.

b. Nominal value per well in a cartridge.
Antibody titer and conjugate activity may vary from lot to lot. C.
Contain buffers, stabilizers and preservatives. d.

Calibrator

5. Intended Use/Indications for Use

Assay

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Calibrator

The Dimension Vista® Testosterone Calibrator is an in vitro diagnostic product for the calibration of the Total Testosterone (TTST) assay on the Dimension Vista® System.

7a. Standards Referenced

1. CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents, Approved Guideline; September 23, 2009
1. CLSI EP05-A2 Evaluation of Precision Performance of Clinical Chemistry Devices, Approved Guideline, Second Edition; August 2004
1. CLSI EP6-A: Evaluation of the Linearity of Quantitative Analytical Measurement Procedure: A Statistical Approach, Approved Guideline; April 2003.
1. CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures, Approved Guideline, Second Edition; June 18, 2012
1. CLSI EP07-A2 Interference Testing in Clinical Chemistry, Approved Guideline, Second Edition; November 23, 2005
1. CLSI EP09-A3 Measurement Procedure Comparison and Bias Estimation Using Patient Samples, Approved Guideline, Third Edition; August 30, 2013
1. CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, Approved Guideline, Third Edition; October 19, 2010
1. CLSI EP32-R Metrological Traceability and Its Implementation, A Report, February 17, 2006

7b. Guidance Documents Referenced

. Guidance for Industry and FDA Staff: Bundling Multiple Devices or Multiple Indications in a Single Submission - June 22, 2007
. In Vitro Diagnostic Devices: Guidance for the Preparation of 510(k) Submissions - Jan. 1997
. Format for Traditional and Abbreviated 510(k)'s – Guidance for Industry and Staff - Nov. 17, 2005
Administrative Procedures for CLIA Categorization Guidance for Industry . and Food and Drug Administration Staff - March 12, 2014
Guidance for Industry and Food and Drug Administration Staff eCopy . Program for Medical Device Submissions - October 10, 2013
Refuse to Accept Policy for 510(k)s Guidance for Industry and Food and . Drug Administration Staff - December 31, 2012

8. Medical Device to Which Equivalence is Claimed

The Siemens Healthcare Diagnostics Inc. Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge and the Roche Diagnostics Elecsys Testosterone II Assay (K093421) are in vitro diagnostic devices intended to be used for the quantitation of testosterone in human serum and plasma. The Siemens Healthcare Diagnostics Inc.

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Dimension Vista® Testosterone Calibrator and the Roche Diagnostics Cal II Set (K003411) are in vitro diagnostic devices intended to be used for calibrating quantitative testosterone assays on automated clinical chemistry analyzers. The proposed and predicate devices support the use in quantitating testosterone in human serum and plasma. The proposed devices were compared side by side via the following tables to examine their similarities and differences. The predicate labeling is enclosed in Attachment 12.

The intended usage and observed performance characteristics between the proposed devices and their predicates are substantially equivalent. Any differences in performance based on experimental data do not raise any questions of safety and effectiveness of the assay and calibrator. Siemens Healthcare Diagnostics Inc. claims substantial equivalence to the currently marketed Roche Diagnostics Elecsys® Testosterone II Assay (K093421) and Roche Diagnostics Testosterone CalSet II (K003411).

Attribute	Predicate DeviceRoche Elecsys®Testosterone II Assay(K093421)	Proposed DeviceDimension Vista® LOCITotal Testosterone Flex®reagent cartridge
Similarities
Intended Use	Immunoassay for the in vitroquantitative determination oftestosterone in human serumand plasma.	The TTST assay is an in vitro diagnostic test for thequantitative measurementof total testosterone inhuman serum and plasma.
Indications for Use	Measurements of testosteroneare used in the diagnosis andtreatment of disordersinvolving the male sexhormones (androgens),including primary andsecondary hypogonadism,delayed or precociouspuberty, impotence in malesand, in females hirsutism(excessive hair) andvirilization (masculinization)due to tumors, polycysticovaries, and adrenogenitalsyndromes.	Same
Measurand	Testosterone	Same

Substantial Equivalence Comparison of Technological Characteristics with the Predicate Device

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Attribute	Predicate DeviceRoche Elecsys®Testosterone II Assay(K093421)	Proposed DeviceDimension Vista® LOCITotal Testosterone Flex®reagent cartridge
Similarities
Measurement Method	Immunoassay	Same
Test Principle	Competitive assay with sheepmonoclonal antibody	Same
Reagent Form	Ready to use, in a unit thatcannot be separated	Same
Differences
Technology	electrochemiluminescence"ECLIA"	chemiluminescent "LOCI®"
Instrument	Elecsys® 2010 and Cobas eImmunoassay analyzers	Dimension Vista® System
Sample Size	20 µL	10 µL
Sample Type	Human Serum and Li-heparin,K2- and K3-EDTA plasma.	Human Serum, Li and NaHeparin, K2 EDTA
Detection	Electrochemiluminescence(ECLIA)	ChemiluminescenceLOCI® technology
Measuring Range	2.5 -1500 ng/dL(0.087 – 52.0 nmol/L)	8-1000 ng/dL(0.278 – 34.7 nmol/L)
High Samples	Generally not necessary dueto the broad measuring range.	Samples outside the assayrange are diluted withMULTI 2 SDIL 1:2 dilution
Limits of Detection	Limit of Blank: 1.2 ng/dLLimit of Detection: 2.5 ng/dL	Limit of Blank: 4 ng/dLLimit of Detection: 5 ng/dL
Limit of Quantitation	12.0 ng/dL	8 ng/dL

Attribute	Roche ElecsysTestosterone Calset II(K003411)	Dimension Vista®Testosterone Calibrator
Similarities
Intended Use	Elecsys TestosteroneCalSet II is used forcalibrating the quantitativeTestosterone assay.	The TTST CAL is an in vitro diagnostic productfor the calibration of theTotal Testosterone(TTST) assay.
Measurand	Testosterone	Same
Calibrator Form	Lyophilized	Same
Calibrator Matrix	Human Serum	Same

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Attribute	Roche ElecsysTestosterone Calset II(K003411)	Dimension Vista®Testosterone Calibrator
Differences
Instrument	Elecsys and Cobas eimmunoassay analyzers	Dimension Vista®System
Traceability/Standardization	ID-GC/MS (Isotope DilutionGasChromatography/MassSpectrometry)	ID-LC/MS/MS(Isotope dilution liquidchromatography/tandemmass spectrometry)
Calibrator	Two levelsCal 1: <1.0 ng/mLCal 2: 13.0 ng/mL	Six levels at theapproximateconcentrations listedbelow.Calibrator A: 0 ng/dLCalibrator B: 20 ng/dLCalibrator C: 50 ng/dLCalibrator D: 100 ng/dLCalibrator E: 200 ng/dLCalibrator F: 1100 ng/dL

9. Performance Characteristics

The Siemens Healthcare Diagnostics Inc. Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge calibrated with Dimension Vista® Testosterone Calibrator and the predicate Roche Testosterone II Assay calibrated with Roche Testosterone CalSet II are in vitro diagnostic immunoassay systems intended for the measurement of Testosterone in human serum and plasma. Performance of the Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge was evaluated at Siemens Healthcare Diagnostics' Newark, DE site on the Dimension Vista® 1500 System.

a. Method Comparison
A method comparison study was performed to demonstrate the accuracy of the Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge following CLSI EP09-A3 Measurement Procedure Comparison and Bias Estimation Using Patient Samples, Approved Guideline, Third Edition.

Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge was tested versus the reference method, CDC Isotope dilution/liquid chromatographic-tandem mass spectrometry (CDC ID/LC-MS/MS).

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One hundred twenty (120) serum samples across the assay range were measured. Six (6) samples were removed because they measured below the Dimension Vista® TTST assay range and one (1) sample was removed for being above the assay range. A Passing & Bablok regression analysis was done on results within the reportable range of 8 ng/dL to 1000 ng/dL, for a total of 113 samples. Correlation coefficient is based on least squares regression statistics.

N	113
Range	7.3 -1033 ng/dL CDC ID-LC-MS/MS8-949 ng/dL Vista TTST
Slope	0.93
y-intercept	4.0
Correlation coefficient (r)	0.994
95% confidence interval	Slope: 0.92 to 0.95Intercept: 0.4 to 5.7

Regression Summary

b. Precision

Reproducibility testing was conducted in accordance with CLSI EP05-A2 Evaluation of Precision Performance of Clinical Chemistry Devices, Approved Guideline, Second Edition. Serum pools, a plasma pool, and commercial controls were run in singlicate from two independent cups twice a day for twenty (20) days. The repeatability and within lab standard deviation and %CV were calculated by analysis of variance method.

Observed performance on the Dimension Vista® LOCI Total Testosterone assay is summarized below.

		Repeatability		Within-Lab
Sample	Mean VistaTTST (ng/dL)	StandardDeviation	%CV	StandardDeviation	%CV
Serum Pool 1	13	0.7	5.2	1.0	7.3
Serum Pool 2	75	1.4	1.9	1.6	2.1
Serum Pool 3	767	13.8	1.8	18.2	2.4
Li Heparin Plasma Pool	384	14.3	3.7	15.8	4.1
Bio-Rad Liquichek™Level 1*	71	1.2	1.7	1.8	2.6
Bio-Rad Liquichek™Level 2*	441	4.1	0.9	5.6	1.3
Bio-Rad Liquichek™Level 3*	855	13.2	1.6	16.9	2.0

*Bio-Rad® is a registered trademark of Bio-Rad Laboratories, Irvine, CA 92618, USA. Liquichek™ is a trademark of Bio-Rad Laboratories, Irvine, CA 92618, USA. Bio-Rad Liquichek™ Immunoassay Plus Controls, Bio-Rad Laboratories, Irvine, CA.

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c. Analytical Measuring Range/Linearity
Linearity was evaluated to determine the upper limit of the assay range according to CLSI EP6-A: Evaluation of the Linearity of Quantitative Analytical Measurement Procedure: A Statistical Approved Guideline. For each sample type tested, a high pool (greater than the assay range) and low pool were combined in varying ratios to produce dilutions covering the measuring interval, 8 to 1,000 ng/dL. Each level was assayed N=5 replicates.

Polynomial regression analysis was performed for the mean observed value vs. the expected value. The method is statistically linear across the analytical measuring range (AMR) of 8 to 1,000 ng/dL for serum and the following plasma sample types: lithium heparin, sodium heparin, and EDTA. The p-values observed were not significant; all sample types tested have p value >0.05.

Sample Type	DemingRegression	CorrelationCoefficient	R2
Serum	$0.97x + 0.1$	0.999	0.998
Sodium Heparin	$0.98x + 0.1$	0.998	0.996
Lithium Heparin	$0.98x + 0.0$	0.999	0.999
EDTA	$0.96x + 0.1$	0.999	0.999

d. Limits of Detection and Quantitation
Limits of Blank (LoB) and Limit of Detection (LoD) were determined experimentally following CLSI EP 17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline; Second Edition. The limit of blank was claimed as 4 ng/dL based on data using testosterone free serum samples. The limit of detection was claimed as 5 ng/dL based on data obtained from low testosterone serum samples.

Limit of Quantitation (LoQ) was determined experimentally following CLSI EP05-A2 Evaluation of Precision Performance of Clinical Chemistry Devices; Approved Guideline; Second Edition. The limit of quantitation, 8 ng/dL, is based on the lowest analyte concentration that can be reproducibly measured with a total precision of ≤20%.

e. Interferences
Interference testing was evaluated according to CLSI EP07-A2 Interference Testing in Clinical Chemistry, Approved Guideline, Second Edition. Hemolysate, Icterus, Bilirubin and Lipemia and several method specific interferents were tested using a paired-difference approach. Results are summarized below.

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Substance	SubstanceConcentration	TTSTBias (%)@ 50 ng/dL	TTSTBias (%)@ 300 ng/dL
Hemoglobin	1000 mg/dL	2%	-7%
Bilirubin(unconjugated)	60 mg/dL	2%	-8%
Bilirubin(conjugated)	60 mg/dL	-2%	6%
Lipemia(Intralipid)	1000 mg/dL	2%	0%

Non-Interfering substances were tested according to CLSI EP07-A2 Interference Testing in Clinical Chemistry, Approved Guideline, Second Edition. Results are as follows. Albumin at 6 g/dL increases TTST results by 19% at a testosterone concentration of 50 ng/dL. Immunoglobulin G at 5 g/dL decreases TTST results 27% at a testosterone concentration of 300 ng/dL. Nandrolone decanoate (19-nortestosterone) shows significant cross-reactivity with the TTST assay at 1,000 ng/mL. Do not use samples from patients under Nandrolone treatment. The following compounds at the specified concentrations tested did not show significant interference.

Substance	Concentration Tested
Acetaminophen	20 mg/dL
Acetylcysteine	150 mg/L
Amikacin	8 mg/dL
Ampicillin	5.3 mg/dL
Ascorbic Acid	6 mg/dL
Biotin	100 ng/mL
Calcium Dobesilate	200 mg/L
Caffeine	6 mg/dL
Carbamazepine	3 mg/dL
Cefoxitin	2500 mg/L
Chloramphenicol	5 mg/dL
Chlordiazepoxide	1 mg/dL
Chlorpromazine	0.2 mg/dL
Cholesterol	503 mg/dL
Cimetidine	2 mg/dL
Creatinine	30 mg/dL
Cyclosporine	5 mg/L
Dextran 40	5000 mg/dL
Diazepam	0.51 mg/dL
Digoxin	6.1 ng/mL
Doxycycline	50 mg/L
Enoxaparin Sodium	60 mg/L
Erythromycin	6 mg/dL
Ethanol	400 mg/dL

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Substance	ConcentrationTested
Ethosuximide	25 mg/dL
Furosemide	6 mg/dL
Gentamicin	1 mg/dL
Heparin	3 U/mL
Ibuprofen	50 mg/dL
Immunoglobulin G	4 g/dL
Levodopa	20 mg/L
Lidocaine	1.2 mg/dL
Lithium	2.2 mg/dL
Leuprolide	200 ng/mL
Methyldopa	20 mg/L
Metronidazole	200 mg/L
Nicotine	0.1 mg/dL
Penicillin G	25 U/mL
Pentobarbital	10 mg/dL
Phenobarbital	15 mg/dL
Phenylbutazone	400 mg/L
Phenytoin	5 mg/dL
Primidone	4 mg/dL
Propoxyphene	0.16 mg/dL
Protein: Albumin	5 g/dL
Protein: Total	10.5 g/dL
Rheumatoid Factor	1110 IU/mL
Rifampicin	60 mg/L
Salicylic Acid	60 mg/dL
Theophylline	4 mg/dL
Triglycerides	900 mg/dL
Urea	500 mg/dL
Uric Acid	20 mg/dL
Valproic Acid	50 mg/dL
Vancomycin	10 mg/dL

f. Heterophilic Antibody Interference
Heterophilic antibody interference was evaluated and reagent was designed with blockers based on the efficacy in minimizing the extent of potential interference. Human anti-mouse antibodies (HAMA) interference was evaluated according to CLSI EP07-A2 Interference Testing in Clinical Chemistry, Approved Guideline, Second Edition. Samples were individual human serum samples with low and high endogenous HAMA. Two levels of testosterone were tested, approximately 150 ng/dL testosterone and ~700-800 ng/dL. Less than 10% interference was observed for HAMA at 285ng/mL and 1248 ng/mL in the presence of ~150 ng/dL and ~700-800 ng/dL testosterone.

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HAMA Concentration	TestosteroneLevel	% Interference
1248 ng/mL	149 ng/dL	-4%
285 ng/mL	156 ng/dL	-2%
1248 ng/mL	887 ng/dL	-6%
285 ng/mL	746 ng/dL	-5%

g. Cross-reactivity
Cross-reactivity of multiple compounds was evaluated in two concentrations of testosterone, at a 0 ng/mL and 300 ng/mL. Spiked test samples were assayed and compared to control samples. Percent cross-reactivity was calculated between the means, where ND denotes not detected. Observed results are shown below.

Cross Reactant	Conc. Tested	Testosterone 0 ng/dL	Testosterone 300 ng/dL
5α-dihydrotestosterone	500 ng/mL	0.3%	-0.1%
5α-androstane-3-beta,17-beta-diol	1000 ng/mL	0.02%	-0.03%
5-androstene-3b,17b-diol	1000 ng/mL	0.2%	0.1%
5β-androstane-3b,17b-diol	100 ng/mL	ND	-0.2%
11b-hydroxytestosterone	100 ng/mL	1.9%	1.0%
11-deoxycortisol	1000 ng/mL	ND	0.01%
11-ketotestosterone	1000 ng/mL	0.2%	1.6%
17α-methyltestosterone	100 ng/mL	4.2%	1.7%
17β-Estradiol	1000 ng/mL	0.01%	-0.02%
Androstenedione	100 ng/mL	0.2%	-0.1%
Androsterone	1000 ng/mL	ND	0.004%
Corticosterone	1000 ng/mL	ND	0.001%
Cortisol	1000 ng/mL	ND	0.01%
Danazol	1000 ng/mL	0.1%	0.04%
Dehydroepiandrosterone(DHEA)	1000 ng/mL	ND	-0.01%
Dehydroepiandrosteronesulfate (DHEA-S)	50,000 ng/mL	0.02%	0.03%
Dexamethasone	2000 ng/mL	ND	0%
Estrone	1000 ng/mL	ND	-0.01%
Ethisterone	1000 ng/mL	0.1%	-0.003%
Norethindrone	50 ng/mL	0.4%	0.5%
Norgestrel	1000 ng/mL	0.1%	-0.02%
Oxymetholone	100 ng/mL	ND	0.02%
Progesterone	1000 ng/mL	ND	0%
Testosterone Propionate	100 ng/mL	ND	0%
Prednisone	1000 ng/mL	ND	0.01%
Prednisolone	1000 ng/mL	ND	-0.002%
Cortisone	2000 ng/mL	ND	0.003%

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h. Serum and Plasma Equivalency

The recommended tube types for use with the Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge are serum, lithium heparin plasma, sodium heparin plasma, and K2 EDTA. Sixty (60) matched sets were freshly drawn and tested. Samples included in the regression spanned the assay range. One sample was removed from analysis because it quantitated below the assay range. Regression analysis was performed on each sample type versus serum.

Comparative			Correlation	Number of
Specimen	Slope	Intercept	Coefficient	Samples
Li Hep Plasma	0.98	-1.6 ng/dL	0.998	59
Na Hep Plasma	0.99	-1.4 ng/dL	0.996	59
K2 EDTA Plasma	1.00	-1.1 ng/dL	0.995	59

i. Expected Values (Reference Interval)
The following patient populations were tested to determine the reference interval for the Dimension Vista® Testosterone Assay following CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, Approved Guideline, Third Edition.

The reference intervals were calculated non-parametrically and represent the central 95% of results determined from healthy males ≤50 years old, males >50 years of, normal cycling females and postmenopausal females.

Reference RangeCategory	Observed TTST Value(ng/dL)	Sample RangeTTST (ng/dL)	NumberofSamples
Adult Males ≤50years old	2.5% = 113 ng/dL;97.5% = 1065 ng/dL	41-1465 ng/dL	174
	Adult Males >50years old	2.5% = 95 ng/dL;97.5% = 948 ng/dL	24-1053 ng/dL
Pre-menopausalfemales		2.5% = 9 ng/dL;97.5% = 53 ng/dL	3-64 ng/dL
	Post-menopausalfemales	2.5% = <8 ng/dL;97.5% = 48 ng/dL	0-61 ng/dL

The reference intervals for pediatric ranges were calcualted either non-parametrically or using the "Robust" method of Horn & Pesce, depending on the number of samples per age group.

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Number of Samples	Percentile Reported	Calculation Method
$19 \le N \le 38$	5th and 95th (Central 90th)	Non-parametric
$N = 39$	2.5th and 97.5th (Central 95th)	Non-parametric
$40 \le N \le 119$	2.5th and 97.5th (Central 95th)	"Robust" method ofHorn & Pesce
$N \ge 120$	2.5th and 97.5th (Central 95th)	Non-parametric

The reference intervals represent females ages 2-10 years, 11-15 years, and 16-21 years and males 2-10 years, 16-21 years, and individual ages 11,12,13, 14, and 15. In addition, the Tanner stages I-V were evaluated for both males and females.

Stages/Age	Gender	N	Median(ng/dL)	Median(nmol/L)	LowerLimit(ng/dL)	UpperLimit(ng/dL)	LowerLimit(nmol/L)	UpperLimit(nmol/L)
Ages 2-10	Male	44	< 8	< 0.278	< 8	31	< 0.278	1.08
Ages 11	Male	21	12	0.416	< 8	321	< 0.278	11.1
Ages 12	Male	24	84	2.91	< 8	531	< 0.278	18.4
Ages 13	Male	20	107	3.71	< 8	609	< 0.278	21.1
Ages 14	Male	30	275	9.54	23	652	0.798	22.6
Ages 15	Male	20	298	10.3	126	792	4.37	27.5
Ages 16-21	Male	44	424	14.7	116	779	4.03	27.0
Ages 2-10	Female	40	< 8	< 0.278	< 8	80	< 0.278	2.78
Ages 11-15	Female	125	21	0.729	< 8	49	< 0.278	1.70
Ages 16-21	Female	35	34	1.18	20	56	0.694	1.94

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Stages/Age	Gender	N	Median(ng/dL)	Median(nmol/L)	LowerLimit(ng/dL)	UpperLimit(ng/dL)	LowerLimit(nmol/L)	UpperLimit(nmol/L)
Tanner Stage I	Male	39	< 8	< 0.278	< 8	64	< 0.278	2.22
Tanner Stage II	Male	41	13	0.451	< 8	166	< 0.278	5.76
Tanner Stage III	Male	42	208	7.22	< 8	609	< 0.278	21.1
Tanner Stage IV	Male	42	308	10.7	43	756	1.49	26.2
Tanner Stage V	Male	42	422	14.6	66	841	2.29	29.2
Tanner Stage I	Female	45	< 8	< 0.278	< 8	79	< 0.278	2.74
Tanner Stage II	Female	41	17	0.59	< 8	45	< 0.278	1.56
Tanner Stage III	Female	39	23	0.798	< 8	49	< 0.278	1.70
Tanner Stage IV	Female	40	25	0.868	8	54	0.278	1.87
Tanner Stage V	Female	41	30	1.04	14	71	0.486	2.46

10. Conclusion

The Siemens Healthcare Diagnostics Inc. Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge is considered substantially equivalent to the Roche Diagnostics Elecsys® Testosterone II Assay (K093421) based on their substantially equivalent intended use. Feature comparison and assay comparative testing described in the submission demonstrates substantially equivalent performance.

Dimension Vista® Testosterone Calibrator is considered substantially equivalent to the Roche Diagnostics Testosterone Cal II Set (K003411) based on their substantially equivalent intended use. Feature comparison and comparative testing described in the submission demonstrates substantially equivalent performance.

Julie Warren

Regulatory Technical Specialist

Regulation Number and Section

§ 862.1680 Testosterone test system.

(a)
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.(b)
Classification. Class I.