Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator

Q: Who is the manufacturer of Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator?

Siemens Healthcare Diagnostics, Inc. filed the 510(k) submission for Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator (K151529).

Q: What is the FDA product code for Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator?

CDZ. It is classified under 21 CFR 862.1680 as a Class 1 device in the Clinical Chemistry panel.

Q: What is the regulatory pathway for Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator?

510(k) clearance (submission type: Traditional).

Q: What are the predicate devices for Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator?

Roche Elecsys Testosterone II Assay (k093421); Roche Elecsys Testosterone Calset II (k003411).

Q: Who can help prepare an FDA 510(k) submission like Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA 510(k) submissions. See https://innolitics.com/services/510ks/ or contact https://innolitics.com/contact.

K151529 · Siemens Healthcare Diagnostics, Inc. · CDZ · Feb 11, 2016 · Clinical Chemistry

Device Facts

Record ID	K151529
Device Name	Dimension Vista LOCI Total Testosterone Flex reagent cartridge, Dimension Vista Testosterone Calibrator
Applicant	Siemens Healthcare Diagnostics, Inc.
Product Code	CDZ · Clinical Chemistry
Decision Date	Feb 11, 2016
Decision	SESE
Submission Type	Traditional
Regulation	21 CFR 862.1680
Device Class	Class 1
Attributes	Pediatric

Intended Use

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.

Device Story

The Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge is an in vitro diagnostic immunoassay for use on the Dimension Vista® System. It utilizes LOCI® (Luminescent Oxygen Channeling Immunoassay) technology, a competitive chemiluminescent immunoassay. The device processes human serum or plasma samples by competing patient testosterone with a testosterone-analog-coated chemibead for a limited amount of labeled testosterone antibody. Sensibeads, coated with streptavidin, bind to the biotinylated antibody to form immunocomplexes. Illumination at 680 nm triggers singlet oxygen diffusion from Sensibeads to Chemibeads, inducing chemiluminescence measured at 612 nm. The signal is inversely proportional to testosterone concentration. The system is operated by laboratory personnel in a clinical setting. Results are used by clinicians to diagnose and monitor androgen-related disorders. The device provides quantitative data to assist in clinical decision-making regarding hormonal health.

Clinical Evidence

No clinical diagnostic studies were performed. Evidence consists of analytical bench testing, including precision (n=80 per sample), linearity (R²=0.996-0.999), and interference/cross-reactivity studies. Method comparison against the CDC ID-LC/MS/MS reference method (n=113) yielded a regression slope of 0.93 (95% CI: 0.92-0.95) and r=0.994. Reference intervals were established for adult and pediatric populations (Tanner stages and age-based) following CLSI EP28-A3c.

Technological Characteristics

Competitive chemiluminescent immunoassay (LOCI® technology). Reagents: synthetic beads (Chemibeads with testosterone analog/chemiluminescent dye; Sensibeads with streptavidin/photosensitive dye) and biotinylated sheep monoclonal antibody. Form factor: 12-well Flex® reagent cartridge. Energy source: 680 nm light excitation. Connectivity: Integrated with Dimension Vista® System. Software: Embedded firmware for automated analysis. Standards: CLSI EP05-A2, EP06-A, EP07-A2, EP09-A3, EP17-A2, EP25-A, EP28-A3c, EP32-R.

Indications for Use

Indicated for quantitative measurement of total testosterone in human serum and plasma to aid in diagnosis and treatment of androgen-related disorders, including primary/secondary hypogonadism, delayed/precocious puberty, male impotence, and female hirsutism/virilization due to tumors, polycystic ovaries, or adrenogenital syndromes.

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

Roche Elecsys Testosterone II Assay (k093421)
Roche Elecsys Testosterone Calset II (k003411)

Related Devices

K122793 — LIAISON TESTOSTERONE; LIAISON TESTOSTERONE CONTROL SET · DiaSorin, Inc. · Jan 25, 2013
K101388 — FASTPACK TESTO IMMUNOASSAY · Qualigen, Inc. · Feb 18, 2011
K120009 — TESTOSTERONE TEST SYSTEM; CALIBRATOR; AND QUALITY CONTROL MATERIAL (ASSAYED AND UNASSAYED) · Abbott Laboratories · Sep 11, 2012

Submission Summary (Full Text)

{0}------------------------------------------------ Image /page/0/Picture/1 description: The image is a black and white logo for the U.S. Department of Health & Human Services. The logo features a stylized design of three human profiles facing to the right. The profiles are stacked on top of each other, creating a sense of depth and unity. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the central design. 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. {1}------------------------------------------------ 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 {2}------------------------------------------------ #### 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." {3}------------------------------------------------ #### 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.* 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." {4}------------------------------------------------ ## 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 {5}------------------------------------------------ #### 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 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 reagents for this assay are assigned to wells as per the table below. {6}------------------------------------------------ #### 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 Biotinylated Antibody Reagentc, d (Sheep monoclonal); 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 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). #### 5. Intended Use/Indications for Use #### Assay 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. {7}------------------------------------------------ ## 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 - 2. CLSI EP05-A2 Evaluation of Precision Performance of Clinical Chemistry Devices, Approved Guideline, Second Edition; August 2004 - 3. CLSI EP6-A: Evaluation of the Linearity of Quantitative Analytical Measurement Procedure: A Statistical Approach, Approved Guideline; April 2003. - 4. CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures, Approved Guideline, Second Edition; June 18, 2012 - 5. CLSI EP07-A2 Interference Testing in Clinical Chemistry, Approved Guideline, Second Edition; November 23, 2005 - 6. CLSI EP09-A3 Measurement Procedure Comparison and Bias Estimation Using Patient Samples, Approved Guideline, Third Edition; August 30, 2013 - 7. CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, Approved Guideline, Third Edition; October 19, 2010 - 8. 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. {8}------------------------------------------------ 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 Device Roche Elecsys® Testosterone II Assay (K093421) | Proposed Device Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge | |---------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------| | Similarities | | | | Intended Use | Immunoassay for the in vitro quantitative determination of testosterone in human serum and plasma. | The TTST assay is an in vitro diagnostic test for the quantitative measurement of total testosterone in human serum and plasma. | | Indications for Use | 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. | Same | | Measurand | Testosterone | Same | Substantial Equivalence Comparison of Technological Characteristics with the Predicate Device {9}------------------------------------------------ | Attribute | Predicate Device Roche Elecsys® Testosterone II Assay (K093421) | Proposed Device Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge | |-----------------------|--------------------------------------------------------------------------|-------------------------------------------------------------------------------------------| | Similarities | | | | Measurement Method | Immunoassay | Same | | Test Principle | Competitive assay with sheep monoclonal antibody | Same | | Reagent Form | Ready to use, in a unit that cannot be separated | Same | | Differences | | | | Technology | electrochemiluminescence "ECLIA" | chemiluminescent "LOCI®" | | Instrument | Elecsys® 2010 and Cobas e Immunoassay 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 Na Heparin, K2 EDTA | | Detection | Electrochemiluminescence (ECLIA) | Chemiluminescence LOCI® 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 due to the broad measuring range. | Samples outside the assay range are diluted with MULTI 2 SDIL 1:2 dilution | | Limits of Detection | Limit of Blank: 1.2 ng/dL Limit of Detection: 2.5 ng/dL | Limit of Blank: 4 ng/dL Limit of Detection: 5 ng/dL | | Limit of Quantitation | 12.0 ng/dL | 8 ng/dL | | Attribute | Roche Elecsys Testosterone Calset II (K003411) | Dimension Vista® Testosterone Calibrator | |-------------------|------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------| | Similarities | | | | Intended Use | Elecsys Testosterone CalSet II is used for calibrating the quantitative Testosterone assay. | The TTST CAL is an in vitro diagnostic product for the calibration of the Total Testosterone (TTST) assay. | | Measurand | Testosterone | Same | | Calibrator Form | Lyophilized | Same | | Calibrator Matrix | Human Serum | Same | {10}------------------------------------------------ | Attribute | Roche Elecsys Testosterone Calset II (K003411) | Dimension Vista® Testosterone Calibrator | |------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Differences | | | | Instrument | Elecsys and Cobas e immunoassay analyzers | Dimension Vista® System | | Traceability/Standardization | ID-GC/MS (Isotope Dilution Gas Chromatography/Mass Spectrometry) | ID-LC/MS/MS (Isotope dilution liquid chromatography/tandem mass spectrometry) | | Calibrator | Two levels Cal 1: <1.0 ng/mL Cal 2: 13.0 ng/mL | Six levels at the approximate concentrations listed below. Calibrator A: 0 ng/dL Calibrator B: 20 ng/dL Calibrator C: 50 ng/dL Calibrator D: 100 ng/dL Calibrator E: 200 ng/dL Calibrator 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). {11}------------------------------------------------ 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/MS 8-949 ng/dL Vista TTST | | Slope | 0.93 | | y-intercept | 4.0 | | Correlation coefficient (r) | 0.994 | | 95% confidence interval | Slope: 0.92 to 0.95 Intercept: 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 Vista TTST (ng/dL) | Standard Deviation | %CV | Standard Deviation | %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. {12}------------------------------------------------ - 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 | Deming Regression | Correlation Coefficient | 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. {13}------------------------------------------------ | | Substance | Substance Concentration | TTST Bias (%) @ 50 ng/dL | TTST Bias (%) @ 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 | {14}------------------------------------------------ | Substance | Concentration Tested | |-------------------|-------------------------| | 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. {15}------------------------------------------------ | HAMA Concentration | Testosterone Level | % 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% | | Dehydroepiandrosterone sulfate (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% | {16}------------------------------------------------ ## 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 Range Category | Observed TTST Value (ng/dL) | Sample Range TTST (ng/dL) | Number of Samples | |------------------------------|-----------------------------------------|---------------------------------------|-------------------------| | Adult Males ≤50 years old | 2.5% = 113 ng/dL; 97.5% = 1065 ng/dL | 41-1465 ng/dL | 174 | | | Adult Males >50 years old | 2.5% = 95 ng/dL; 97.5% = 948 ng/dL | 24-1053 ng/dL | | Pre-menopausal females | | 2.5% = 9 ng/dL; 97.5% = 53 ng/dL | 3-64 ng/dL | | | Post-menopausal females | 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. {17}------------------------------------------------ | 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 of Horn & 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) | Lower Limit (ng/dL) | Upper Limit (ng/dL) | Lower Limit (nmol/L) | Upper Limit (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 | {18}------------------------------------------------ | Stages/Age | Gender | N | Median (ng/dL) | Median (nmol/L) | Lower Limit (ng/dL) | Upper Limit (ng/dL) | Lower Limit (nmol/L) | Upper Limit (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