For the in vitro quantitative determination of human chorionic gonadotropin (hCG) in human serum and plasma. The Elecsys HCG STAT immunoassay is intended for use in the early detection of pregnancy. The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 601 immunoassay analyzer.

Device Description

The Elecsys HCG STAT immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against Human Chorionic Gonadotropin (HCG). The antibodies labeled with ruthenium complex consist of a chimeric construct from human and mouse specific components. The Elecsys HCG STAT immunoassay is used for the in vitro quantitative determination of human chorionic gonadotropin (hCG) in human serum and plasma. It is intended for use on the cobas e 601immunoassay analyzer.

AI/ML Overview

The provided text describes the Elecsys HCG STAT immunoassay, its intended use, technological characteristics, and non-clinical performance evaluations conducted to demonstrate its substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and the study information as requested:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a table of acceptance criteria with corresponding performance, but rather lists the performance data obtained and states that "All performance specifications were met." We can infer the acceptance criteria from the context of typical FDA 510(k) submissions for in vitro diagnostics, where equivalence to the predicate and meeting standard analytical performance metrics are key.

Performance Metric	Acceptance Criteria (Implied / Stated)	Reported Device Performance
Intended Use	Same as predicate device (Elecsys HCG STAT, K002148)	For the in vitro quantitative determination of human chorionic gonadotropin (hCG) in human serum and plasma, for early detection of pregnancy, on the cobas e 601 immunoassay analyzer. (Same as predicate)
Assay Method	Same as predicate device	Sandwich Principle (Same as predicate)
Detection Method	Same as predicate device	Electrochemiluminescence (Same as predicate)
Applications/Test Time	Same as predicate device	9 minutes (Same as predicate)
Instrument Platform	Functionality on cobas e 601	cobas e 601 (Predicate includes cobas e 411, e 601, e 602, e 801. The updated device is specifically for e 601.)
Sample Type/Matrix	Same as predicate device	Human serum, plasma (Same as predicate)
Sample Anticoagulants	Same as predicate device	Li-heparin, K2-EDTA and K3-EDTA plasma (Same as predicate)
Calibrator	Same as predicate device	HCG STAT CalSet (Same as predicate)
Calibration Method	Same as predicate device	Traceability to 4th International Standard for Chorionic Gonadotropin (NIBSC code 75/589); master curve adapted with CalSet. (Same as predicate)
Calibration Interval	Same as predicate device	Once per reagent lot (extended based on verification); renewed after 1 month for same lot or 7 days for same kit. (Same as predicate)
Controls	Same as predicate device	Run individually at least once every 24 hours, once per reagent kit, after each calibration. (Same as predicate)
Traceability/Standardization	Same as predicate device	Standardized against 4th International Standard for Chorionic Gonadotropin (NIBSC code 75/589). (Same as predicate)
Reagent Stability	Same as predicate device	Unopened: 2-8 °C up to expiration date; After opening: 2-8 °C for 12 weeks; On analyzer: 4 weeks. (Same as predicate)
Measuring Range	Values within clinical requirements and comparable to predicate.	1.0 - 10000 mIU/mL (Predicate: 0.500-10000 mIU/mL). Note: The lower limit shifted from 0.500 to 1.0 mIU/mL. The document does not explicitly state this as an issue for substantial equivalence, implying it falls within acceptable clinical utility for its indicated use.
Precision	Meet CLSI EP05-A3 guidelines.	Evaluated using CLSI EP05-A3, producing Repeatability and Intermediate precision (SD and CV values). Specific values are not provided in the summary but were generated.
LoB (Limit of Blank)	Meet CLSI EP17-A2 guidelines.	0.5 mIU/mL (Predicate: 0.500 mIU/mL as lower detection limit)
LoD (Limit of Detection)	Meet CLSI EP17-A2 guidelines.	1.0 mIU/mL (Predicate: 0.500 mIU/mL as lower detection limit)
LoQ (Limit of Quantitation)	Meet CLSI EP17-A2 and EP05-A3 guidelines.	1.0 mIU/mL (Predicate: 0.500 mIU/mL as lower detection limit)
Analytical Specificity/Cross-Reactivity	Acceptable levels of cross-reactivity, comparable to predicate.	FSH 0.007 %, TSH 0.001 % (Predicate: FSH 0.09 %, TSH: no cross-reactivity). This indicates improved specificity for the updated device compared to the predicate's reported FSH cross-reactivity.
Biotin Interference	No significant interference at relevant concentrations, comparable to predicate.	No biotin interference in serum concentrations up to 1200 ng/mL (Predicate: ≤ 164 nmol/L or ≤ 40 ng/mL). This indicates a significantly higher tolerance to biotin for the updated device, which is an improvement.
Hook Effect	No Hook Effect up to a specified high concentration, comparable to predicate.	No Hook Effect up to ≥ 500,000 mIU/mL (Same as predicate)
Method Comparison (vs. Predicate)	Linear regression and Passing/Bablok analysis demonstrating strong correlation and agreement with the predicate device (slope near 1, intercept near 0, high R/T value).	Passing/Bablok: y= 1.012x-0.970, T = 0.996. Linear regression: y = 1.011x + 4.81, r = 1.000. (Predicate's comparison to HCG+ẞ: Passing/Bablok y = 1.0x - 7.38, T = 0.986; Linear regression y = 1.05x - 5.26, r = 0.999). The comparison shows high correlation and close agreement between the updated device and the predicate.
Stability	Meet predetermined stability claims (e.g., shelf-life, on-board stability)	Stability studies "reviewed and found to be acceptable," supporting claims in package labeling. (No specific values provided in summary).
Linearity	Meet CLSI EP6-A guidelines.	Data analysis determined according to CLSI EP6-A. (Specific data not provided in summary).
Endogenous Interferences	Recovery within acceptable limits for various interferents.	Effect on quantitation determined for hemoglobin, intralipid, bilirubin, rheumatoid factor by calculating recovery (absolute deviation or % recovery). (Specific data not provided in summary).
Common Drug Interferences	No significant interference for common pharmaceutical compounds.	Determined by comparing values of spiked samples with reference sample for 17 common pharmaceutical compounds. (Specific data not provided in summary).
Sample Matrix Comparison	Agreement between different anticoagulant plasma types and serum.	Assessed by Passing/Bablok regression analysis for serum vs. Li-Heparin, K2-EDTA, and K3-EDTA plasma. (Specific data not provided in summary).

2. Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

Precision (21-Day): Five human serum samples (HS1-HS5) and two controls (PreciControl Universal level 1 and 2). Replicated twice per run, two runs per day for 21 days (total 84 replicates per sample/control per lot). 1 lot used.
Precision (5-Day): Five human serum samples (HS1-HS5) and two controls (PreciControl Universal level 1 and 2). 5 aliquots per run, 1 run per day for 5 days. 3 lots used.
Reproducibility: Six human serum samples (HSP 1-6) and two controls (CTR 1-2). 5 replicates per run, 1 run per day. 1 lot used.
LoB (Limit of Blank): Five analyte-free samples, measured in two-fold determinations in 6 runs over ≥ 3 days. 2 different lots. Total 60 measured values per lot.
LoD (Limit of Detection): Five low-analyte concentration samples (from LoB up to approx. 4x LoB), measured in two-fold determinations in 6 runs over ≥ 3 days. 2 different lots. Total 60 measured values per lot.
LoQ (Limit of Quantitation): 5 human serum samples covering the range between LoB and 2x LoQ. Measured in 5 replicates, one run per day over 5 days. 2 lots evaluated.
Linearity/Assay Reportable Range: One human serum sample (high analyte), diluted through 21 steps. Assayed in 3-fold determinations. 1 lot tested.
High Dose Hook Effect: Three human serum samples spiked with HCG. Dilution series performed. 1 reagent lot.
Endogenous Interferences: One lot tested on 3 samples of each interfering substance (Hemoglobin, Intralipid, Bilirubin, Rheumatoid Factors). Each HCG sample (low, medium, high) spiked with interferent in 9 dilution steps.
Biotin Interference: Three serum samples (low, medium, high HCG concentration) spiked with biotin up to 3600 ng/mL in 11 dilution steps.
Common Drug Interferences: One human serum sample (HCG conc. near 5 mIU/mL and near 50 mIU/mL), spiked with 17 common pharmaceutical compounds.
Analytical Specificity/Cross-Reactivity: One human serum matrix with HCG level (5 mIU/mL) spiked with LH, FSH, TSH. 1 reagent lot.
Sample Matrix Comparison: At least 40 serum/plasma pairs were tested in one run.
Method Comparison to Predicate: 131 samples covering the measuring range. Tested with 1 run per sample.
Data Provenance (Country of Origin): The document does not explicitly state the country of origin for the data. Given Roche Diagnostics' global presence, the studies could have been conducted in various locations.
Retrospective or Prospective: These studies appear to be prospective analytical performance studies, specifically designed and executed to evaluate the device characteristics described. The phrases "Precision was evaluated...", "LoB ... was determined...", "A method comparison ... was conducted..." all indicate planned experiments.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This section is not applicable as the Elecsys HCG STAT is an in vitro diagnostic (IVD) immunoassay, not an AI or imaging device requiring human expert ground truth for interpretation of images or clinical cases. The "ground truth" for its performance is established through quantitative measurements against known standards, spiked samples, and comparison to a legally marketed predicate device.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This section is not applicable for the same reason as point 3. Adjudication methods like 2+1 or 3+1 are typically used for establishing ground truth in clinical evaluations where there is subjective human interpretation (e.g., radiology reads) and disagreement among readers needs resolution.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This section is not applicable. The Elecsys HCG STAT is an automated immunoassay for quantitative determination of hCG. It does not involve human readers interpreting output that would be improved or supplemented by AI. It is a standalone diagnostic test.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

Yes, a standalone performance evaluation was completed. The studies described (precision, detection limits, linearity, interference, method comparison) are all evaluations of the Elecsys HCG STAT immunoassay system (reagent + instrument) performance without human intervention in the measurement process. The results generated by the device are quantitative values of hCG concentration.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for this device's performance evaluation typically involves:

Known concentrations: For studies like LoD, LoQ, Linearity, Interference, where samples are prepared with known, precise concentrations of hCG or interfering substances.
Standardized materials: Traceability to the 4th International Standard for Chorionic Gonadotropin from NIBSC code 75/589.
Quantitative measurements by a predicate device: For method comparison studies, the predicate device's results serve as a reference for comparison, establishing "ground truth" for demonstrating substantial equivalence.
Reference measurement procedures: Although not explicitly stated, general analytical performance studies rely on highly accurate reference methods or certified reference materials where available.

8. The sample size for the training set

This section is not applicable. The Elecsys HCG STAT is an immunoassay, not an AI or machine learning algorithm that requires a "training set" in the computational sense. The device's parameters are likely established during development and manufacturing through calibration and optimization procedures, not through a 'training set' of cases as understood in AI studies.

9. How the ground truth for the training set was established

This section is not applicable for the same reason as point 8.

Summary

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

August 18, 2021

Roche Diagnostics Adennis Cora Regulatory Affairs Consultant 9115 Hague Road PO Box 50416 Indianapolis, IN 46250

Re: K203227

Trade/Device Name: Elecsys HCG STAT Regulation Number: 21 CFR 862.1155 Regulation Name: Human chorionic gonadotropin (HCG) test system Regulatory Class: Class II Product Code: DHA Dated: October 31, 2020 Received: November 2, 2020

Dear Adennis Cora:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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.

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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 Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Marianela Perez- Torres, Ph.D. Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K203227

Device Name

Elecsys HCG STAT

Indications for Use (Describe)

on the cobas e 601 immunoassay analyzer.

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)
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Elecsys HCG STAT K203227 Summary

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.

In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).

The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys HCG STAT on the cobas e 601.

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Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457
Contact	Adennis CoraPhone: (317) 521-3915FAX: (317) 521-2324Email: adennis.cora_gress@roche.comTammy DeanPhone: (317) 450-5193FAX: (317) 521-2324Email: tammy.dean@roche.com
Date Prepared	March 17, 2021
Proprietary Name	Elecsys HCG STAT
Common Name	Beta HCG STAT Test
Classification Name	System, Test, Human Chorionic Gonadotropin
Product Codes,Regulation Numbers	DHA21 CFR 862.1155
Predicate Devices	Elecsys HCG STAT (K002148)
Establishment Registration	Roche Diagnostics GmbH Mannheim, Germany: 9610126Roche Diagnostics GmBH Penzberg, Germany: 9610529Roche Diagnostics Indianapolis, IN United States: 1823260.

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1. DEVICE DESCRIPTION

2. INDICATIONS FOR USE

For the in vitro quantitative determination of human chorionic gonadotropin (hCG) in human serum and plasma. The Elecsys HCG STAT immunoassay is intended for use in the early detection of pregnancy.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 601 immunoassay analyzer.

TECHNOLOGICAL CHARACTERISTICS 3.

The reagent working solutions include:

Rack Pack (kit placed on the analyzer).

M Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: Streptavidin-. coated microparticles 0.72 mg/mL; preservative.
R1 Anti-hCG-Ab~biotin (gray cap), 1 bottle, 9 mL: Biotinylated monoclonal anti-hCG . antibody (mouse) 2.3 mg/L; phosphate buffer 40 mmol/L, pH 7.5; preservative.
R2 Anti-hCG-Ab~Ru(bpy)=+ (black cap), 1 bottle, 10 mL:Monoclonal anti-hCG antibody (mouse) labeled with ruthenium complex 6.0 mg/L; phosphate buffer 40 mmol/L, pH 6.5; preservative.

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The following table compares the updated Elecsys HCG STAT with its predicate device, the current Elecsys HCG STAT (K002148).

Feature	Candidate DeviceUpdated Elecsys HCG STAT	Predicate DeviceElecsys HCG STAT (K002148)
Intended Use	For the in vitro quantitativedetermination of human chorionicgonadotropin (hCG) in human serumand plasma. The Elecsys HCG STATimmunoassay is intended for use inthe early detection of pregnancy.The electrochemiluminescenceimmunoassay "ECLIA" is intendedfor use on the cobas e 601immunoassay analyzer.	Same
Assay Method	Sandwich Principle	Same
Detection Method	Electrochemiluminescence	Same
Applications/Test Time	9 minutes	Same
Instrument Platform	cobas e 601	cobas e 411, cobas e 601,cobas e 602, and cobas e 801
Sample Type/Matrix	Human serum, plasma	Same
Sample Anticoagulants	Li-heparin, K2-EDTA andK3-EDTA plasma.	Same
Calibrator	HCG STAT CalSet	Same
Calibration Method	Traceability: This method has beenstandardized against the 4thInternational Standard for ChorionicGonadotropin from the NationalInstitute for Biological Standards andControl (NIBSC) code 75/589.Every Elecsys reagent set has abarcoded label containing specificinformation for calibration of theparticular reagent lot. The predefinedmaster curve is adapted to theanalyzer using the relevant CalSet.	Same
Feature	Candidate DeviceUpdated Elecsys HCG STAT	Predicate DeviceElecsys HCG STAT (K002148)
Calibration Interval	Calibration must be performed onceper reagent lot using fresh reagent(i.e. not more than 24 hours since thereagent kit was registered on theanalyzer).Calibration interval may be extendedbased on acceptable verification ofcalibration by the laboratory.Renewed calibration isrecommended as follows:■ after 1 month (28 days) when usingthe same reagent lot■ after 7 days (when using the samereagent kit on the analyzer)	Same
Controls	Controls for the variousconcentration ranges should be runindividually at least once every 24hours when the test is in use, onceper reagent kit, and following eachcalibration.The control intervals and limitsshould be adapted to eachlaboratory's individual requirements.Values obtained should fall withinthe defined limits. Each laboratoryshould establish corrective measuresto be taken if values fall outside thedefined limits.	Same
Traceability/Standardization	This method has been standardizedagainst the 4th International Standardfor Chorionic Gonadotropin from theNational Institute for BiologicalStandards and Control (NIBSC) code75/589	Same
Reagent Stability	unopened at 2-8 °C up to the statedexpiration dateafter opening at 2-8 °C 12 weekson the analyzer 4 weeks	Same
Measuring Range	1.0-10000 mIU/mL (defined by theLimit of Detection and the maximumof the master curve)	0.500-10000 mIU/mL (defined by thelower detection limit and themaximum of the master curve).
Feature	Candidate DeviceUpdated Elecsys HCG STAT	Predicate DeviceElecsys HCG STAT (K002148)
Precision	Precision was evaluated on onecobas e 601 analyzer according toCLSI guideline EP05-A3. Theprotocol consisted of testing 5Aliquots of each control(PreciControl Universal level 1 andPreciControl Universal level 2) andhuman serum samples (HS1-HS5)per run, 1 run per day for 5 days with3 lots. Repeatability and intermediateprecision (SD and CV values) werecalculated according to CLSI EP05-A3.Precision was determined usingElecsys reagents, pooled human seraand controls in a protocol (EP05-A3)of the CLSI (Clinical and LaboratoryStandards Institute): 2 runs per dayin duplicate each for 21 days (n =84).	Precision was determined usingElecsys reagents, pooled human seraand controls in a modified protocol(EP5-A) of the CLSI (Clinical andLaboratory Standards Institute): 6times daily for 10 days (n = 60).Different Performance Data.Precision was determined usingElecsys reagents, pooled human seraand controls in a separate studyaccording to protocol (EP5-A2) of theCLSI (Clinical and LaboratoryStandards Institute): 2 runs per day induplicate each for 21 days (n = 84).
LoB	0.5 mlU/mL	Lower detection limit: 0.500 mIU/mL
LoD	1.0 mIU/mL	Lower detection limit: 0.500 mIU/mL
LoQ	1.0 mlU/mL	Lower detection limit: 0.500 mIU/mL
Analytical Specificity	FSH 0.007 %, TSH 0.001 %	FSH 0.09 %, TSH: nocross-reactivity
Biotin	This assay has no biotin interferencein serum concentrations up to1200 ng/mL.	≤ 164 nmol/L or ≤ 40 ng/mL
Hook Effect	No Hook Effect up to≥ 500,000 mIU/mL	Same
	Updated Biotin assay (y) compared tocurrent Elecsys HCG STAT assay (x)	Elecsys HCG STAT assay (y) withthe Elecsys HCG+ẞ assay (x)
Method Comparison	Passing/Babloky= 1.012x-0.970T = 0.996Linear regressiony = 1.011x + 4.81r = 1.000	Passing/Babloky = 1.0x - 7.38T = 0.986Linear regressiony = 1.05x - 5.26r = 0.999

Technical Characteristics Comparison Table between updated Table 1: Elecsys HCG STAT and current Elecsys HCG STAT

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NON-CLINICAL PERFORMANCE EVALUATION 4.

The non-clinical performance studies for the Elecsys HCG STAT are summarized below. The following performance data are provided in support of the substantial equivalence determination:

Precision (5-Day and 21-Day) according to CLSI EP5-A3 .

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Detection Limit: LoB, LoD and LoO according to CLSI EP17-A2
Linearity according to CLSI EP6-A .
High Dose Hook Effect .
Interferences Hemoglobin, Intralipid, Bilirubin, and Rheumatoid Factors .
Biotin Interference (CLSI EP07-A3) .
Common Drug Interferences .
Analytical Specificity/ Cross Reactivity (CLSI EP17-A2) .
Matrix Comparison Anticoagulants .
Method Comparison to Predicate .
Reagent Stability (CLSI EP25-A) .
Lot Calibration Stability (CLSI EP25-A) .

All performance specifications were met.

4.1. Precision

21 Day Precision (1 lot on 3 sites) 4.1.1. -

Precision was evaluated on one cobas e 601 analyzer according to CLSI guideline EP05-A3. The protocol consisted of testing 2 replicates of each control (PreciControl Universal level 1 and PreciControl Universal level 2) and human serum samples (HS1-HS5) per run, 2 runs per day for 21 days with 1 lot. Repeatability and intermediate precision (SD and CV values) were calculated according to CLSI EP05-A3. Assay calibration was done as specified in the package insert.

4.1.2. 5 Day Precision

Precision was evaluated on one cobas e 601 analyzer according to CLSI guideline EP05-A3. The protocol consisted of testing 5 Aliguots of each control (PreciControl Universal level 1 and PreciControl Universal level 2) and human serum samples (HS1-HS5) per run, 1 run per day for

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5 days with 3 lots. Repeatability and intermediate precision (SD and CV values) were calculated according to CLSI EP05-A3. Assay calibration was done as specified in the package insert.

4.1.3. Reproducibility

Reproducibility of the Elecsys HCG STAT assay was evaluated at three sites (1 internal and 2 external) on the cobas e 601 immunoassay analyzer using one lot of updated assay. The Reproducibility study was performed for a total of 1 run per day with 5 replicates of each human sera (HSP 1-6) and each control (CTR 1-2) per run, 1 run per day. The samples were run in randomized order on the analyzers. Human serum pools (HSP 1-4) and diluted single donor samples (HSP 5-6) were used to calculate Repeatability and Intermediate precision according to EP05-A3.

Analytical Sensitivity 4.2.

4.2.1. Limit of Blank (LoB)

LoB of the Elecsys HCG STAT on the cobas e 601 analyzer was determined according to CLSI EP17-A2. Limit of Blank determines the highest observed measurement values for samples free of analyte. The Limit of Blank was determined as the 95th percentile of measurements of blank samples. For determination of LoB five analyte free samples were measured in two-fold determinations in 6 runs, distributed over ≥ 3 days, with 2 different lots on one cobas e 601 analyzer. In total 60 measured values of analyte free samples were obtained per lot. As the analyzers do not report negative sample concentrations the data set is truncated and the data were evaluated according to EP17-A2, chapter 5.3.3.1 as the linear interpolation of the 57th and 58th ranked observation.

Limit of Detection (LoD) 4.2.2.

The LoD determines the lower limit for samples with analyte. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability. For determination of LoD five samples with low-analyte concentration (from LoB up to approx. 4 times the LoB) were measured in 2-fold determination in 6 runs, distributed over ≥ 3 days, with 2 different lots on one cobas e 601 analyzer. In total 60 measured values of samples with low

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analyte concentrations were obtained per lot. Data analysis was based on determination of the 60 measured values of the 5 low analyte samples (according to CLSI EP17-A2, chapter 5.3.3.2).

Limit of Quantitation (LoQ) 4.2.3.

For the determination of LoO. 2 lots were evaluated, each with 5 human serum samples covering the range between LoB and 2x LoQ. Each sample was measured in 5 replicates (single determination of each replicate) with one run per day over 5 days on one cobas e 601 analyzer. Assay calibration was performed as specified in the package insert. Analyte-low samples or sample pools were used for the determination of LoQ.

The mean value and the intermediate precision as coefficient of variation (CV) and standard deviation (SD) were calculated for each LoQ sample. Data Analysis was determined according to CLSI EP17-A2.

4.3. Linearity/Assay Reportable Range

For linearity, one lot was tested on one cobas e 601 with one run. One human serum sample with high analyte content above the measuring range was diluted to the lower end of the measuring range with various amounts of human serum sample without analyte content. The dilution series contained 21 steps. Samples were assayed in 3-fold determinations. Data Analysis was determined according to CLSI EP6-A.

4.4. High Dose Hook Effect

The high-dose hook effect of the Elecsys HCG STAT assay was assessed with one reagent lot on one cobas e 601 analyzer in one-fold determination. Three human serum samples were spiked with analyte (HCG) to achieve high HCG concentrations. For each sample, a dilution series was performed using serum. The hook concentration reported corresponds to the highest analyte concentration that generates a signal ≥ 10% above the upper limit of the measuring range.

Endogenous Interferences 4.5.

Hemoglobin/Intralipid/Bilirubin/Rheumatoid Factor 4.5.1. -

The effect on quantitation of analyte in the presence of endogenous interfering substances using the Elecsys HCG immunoassay was determined on one cobas e 601 analyzer for the following

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four interfering substances: hemoglobin, intralipid, bilirubin and rheumatoid factor. The effect on quantitation of analyte in the presence of endogenous interfering substances was determined for HCG concentrations and a dilution set of the added interfering substances. For the sample with highest HCG concentration, spiked samples were used. One reagent lot was tested on 3 samples of each interfering substance.

One aliquot of each HCG sample (low, medium, high) was spiked with the interfering endogenous substance and used as "interference pool". Another aliquot of the sample was spiked with the same volume of the solvent of the interfering endogenous substance (without interfering substance) and used as the related "dilution pool". A series of at least 9 dilution steps were prepared by mixing the interference pools and the related dilution pools in 10 % increments.

The recovery (absolute deviation or % recovery) was calculated for each sample compared to the reference (unspiked) sample.

4.6. Biotin

The effect on quantitation of analyte in the presence of biotin using the Elecsys HCG STAT assay was determined on a cobas e 601 analyzer using three serum samples (low, medium, and high) concentration of HCG according to CLSI EP07-A3. One aliquot of each sample (low, medium, high) was spiked with biotin up to 3600 ng/mL and used as "interference pool". Another aliquot of the sample was spiked with the same volume of the interfering endogenous substance (without interfering substance) and used as the related "dilution pool". A series of 11 dilution steps were prepared by mixing the interference pools and the related dilution pools. The recovery (absolute deviation or % recovery) were calculated for each sample compared to the reference (unspiked) sample. For the sample with highest HCG concentration, spiked samples were used.

Common druq Interferences 4.7.

The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 17 common pharmaceutical compounds with the reference sample. One human serum sample was used and tested on the cobas e 601 immunoassay analyzer. Samples (with HCG concentrations near 5 mIU/mL

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and near 50 mIU/mL) were divided into aliquots and spiked with the common drug interferents. The reference sample without drug was spiked with the respective amount of solvent.

Analytical Specificity/Cross-Reactivity 4.8.

The analytical specificity of the Elecsys HCG STAT assay was determined with one reagent lot on one cobas e 601 analyzer using a human serum matrix with one HCG level (5 mIU/mL). The sample was spiked with the following potential cross-reactants: LH, FSH, and TSH. The sample was measured in presence and absence of the potential cross-reactants and cross reactivity was calculated using the following % Cross-reactivity formula:

mean analyte conc. of spiked sample — mean analyte conc. of unspiked sample x 100% = spiked concentration of cross — reactant

4.9. Sample Matrix Comparison

The effect on quantitation of analyte in the presence of anticoagulants on the Elecsys HCG STAT assay. Values obtained from serum samples drawn into serum primary tubes (reference) were compared to Li-Heparin, K2-EDTA and K3-EDTA plasma. At least 40 serum/plasma pairs were tested in one run on one cobas e 601 analyzer. Data was assessed by Passing/Bablok regression analysis. Spiked samples were used when necessary for reaching high HCG concentrations but allotted for less than 10 % of all samples.

4.10. Method Comparison to Predicate

A method comparison (MC) study of the updated Elecsys HCG STAT assay (candidate device, Y) versus the predicate device, Elecsys HCG STAT current assay (X) was conducted on the cobas e 601 analyzer according to CLSI Guideline EP09-A3. Serum samples were measured internally using both the current and updated reagent formulations. One hundred thirty one (131) samples that span the measuring range were tested with 1 run per sample (no replicates). To sufficiently cover the measuring range, samples were spiked with recombinant HCG to cover the upper end of the measuring range, or diluted to cover the lower end of the measuring range.

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Equivalence of the current Elecsys HCG STAT (K002148) assay and the updated Elecsys HCG STAT assay were evaluated as described below.

· Samples without further clinical or demographic information were used. Samples were distributed to span the reportable range.

• Calculation: Scatter-plot of numerical values of the current assay (x-axis) versus the updated assay (y-axis).

• Passing-Bablok analysis for slope and intercept was performed for the updated lot against the current lot.

4.11. Stability

The stability studies and acceptance criteria have been reviewed and found to be acceptable. The stability data supports Roche Diagnostic's claims as reported in the package labeling.

4.12. Substantial Equivalence

The Elecsys HCG STAT immunoassay (updated assay, Mat. No. 08890587190) is substantially equivalent to the Elecsys HCG STAT immunoassay (current assay, Mat. No. 03300811190).

Regulation Number and Section

§ 862.1155 Human chorionic gonadotropin (HCG) test system.

(a)
Human chorionic gonadotropin (HCG) test system intended for the early detection of pregnancy —(1)Identification. A human chorionic gonadotropin (HCG) test system is a device intended for the early detection of pregnancy is intended to measure HCG, a placental hormone, in plasma or urine.(2)
Classification. Class II.(b)
Human chorionic gonadotropin (HCG) test system intended for any uses other than early detection of pregnancy —(1)Identification. A human chorionic goadotropin (HCG) test system is a device intended for any uses other than early detection of pregnancy (such as an aid in the diagnosis, prognosis, and management of treatment of persons with certain tumors or carcinomas) is intended to measure HCG, a placental hormone, in plasma or urine.(2)
Classification. Class III.(3)
Date PMA or notice of completion of a PDP is required. As of the enactment date of the amendments, May 28, 1976, an approval under section 515 of the act is required before the device described in paragraph (b)(1) may be commercially distributed. See § 862.3.