The i-STAT® Total Beta-Human Chorionic (B-hCG) test is an in vitro diagnostic test for the quantitative and qualitative determination of ß-hCG in venous whole blood or plasma samples using the i-STAT 1 Analyzer Systems. The test is intended to be used as an aid in the early detection of pregnancy and is for prescription use only.

The i-STAT® Total B-hCG Controls are used to monitor performance of the i-STAT Total β-hCC test.

The i-STAT® Total B-hCG Calibration Verification Materials are used to verify the calibration of the i-STAT Total BhCG test throughout the reportable range.

Device Description

The i-STAT Total ß-hCG test uses a two-site enzyme-linked immunoassay with electrochemical detection of the resulting enzyme signal. Monoclonal antibodies specific for the ß subunit of hCG are localized within a lithographically defined capture region on the surface of a specially designed electrochemical sensor chip. A separate reference sensor of similar construction to the hCG sensor, but without antibodies specific to hCG, is located on the same sensor chip. An alkaline phosphatase-linked monoclonal antibody conjugate specific to a separate epitope on the ß subunit of the hCG molecule is present in a metered amount on the sensor chip.

The i-STAT Total ß-hCG Controls are assayed human serum which are used to monitor the performance of the i-STAT Total ß-hCG test.

The i-STAT Total ß-hCG Calibration Verification materials are assayed human serum used to verify the calibration of the i-STAT Total β-hCG test throughout the reportable range.

AI/ML Overview

This document is a 510(k) premarket notification for the i-STAT® Total β-hCG Test, i-STAT® Total β-hCG Controls, and i-STAT® Total β-hCG Calibration Verification Materials. It aims to demonstrate substantial equivalence to legally marketed predicate devices.

1. Table of Acceptance Criteria and Reported Device Performance:

The document describes various performance characteristics, primarily for the i-STAT Total β-hCG test cartridge. While explicit "acceptance criteria" are not always presented as clear pass/fail thresholds in a dedicated table, the stated "design goals" and "defined as" criteria serve this purpose.

Performance Characteristic	Acceptance Criteria (Design Goal/Defined As)	Reported Device Performance
Blood to Plasma Equivalence	Bias to plasma of no greater than 10%	Bias to plasma of no greater than 10% observed across all blood samples tested.
Precision / Reproducibility	Total imprecision < 10% CV for hCG > 14 IU/L, or SD of 1.4 IU/L for hCG < 14 IU/L	Whole Blood:- At 5 IU/L: highest observed upper (total) imprecision was 0.81 IU/L.- At other levels (25 IU/L, ~800 IU/L, ~1500 IU/L): highest observed (total) imprecision was 7.3 %CV. Plasma:- At 5 IU/L: observed (total) imprecision was 1.03 IU/L.- At other levels (25 IU/L, ~1150 IU/L, ~1875 IU/L): highest observed (total) imprecision was 5.6 %CV.
Linearity / Test Measuring Interval	Not explicitly stated as a single numerical criterion. Evaluated for bias due to non-linearity and percent non-linearity within the reportable range.	- Whole Blood: Bias due to non-linearity was 0.1 IU/L at lowest hCG. Percent non-linearity did not exceed 4.1% across 10 to ~2000 IU/L.- Plasma: Bias due to non-linearity was -0.1 IU/L at lowest hCG. Percent non-linearity did not exceed 2.3% across 10 to ~2000 IU/L.
Limit of Quantitation (LoQ)	Not explicitly stated beyond "LoQ was determined to be < 5.0 IU/L".	LoQ was determined to be < 5.0 IU/L.
Limit of Detection (LoD)	Not explicitly stated beyond "LoD was determined to be ≤ the LoQ".	LoD was determined to be ≤ the LoQ.
Limit of Blank (LoB)	Not explicitly stated beyond "LoB was determined to be < the LoD".	LoB was determined to be < the LoD.
High Dose 'Hook Effect'	No significant hook effect up to 300,000 IU/L	No hook effect observed up to ~450,000 IU/L in plasma and up to ~650,000 IU/L in whole blood.
Analytical Specificity (Interference)	Significant interference defined as recovery within ± 10% compared to reference (for concentrations > 5 IU/L) or within +/- 4 IU/L (for concentrations ~5 IU/L).	- No significant interference observed with various spiked substances (Albumin, Bilirubin, Cholesterol, Hemoglobin, Triglyceride, Uric Acid).- No significant interference observed with TSH, FSH, and LH.- All sample interference from HAMA and/or RF was mitigated.
Recovery	Not explicitly stated as a single numerical criterion, but individual and pooled recovery results are presented and compared to WHO 5th IS.	- Whole Blood (hCG > 5 IU/L): Individual recovery 91.1% to 118.5%; Pooled 95th Percentile: 102.0% - 109.5%.- Whole Blood (hCG ~5 IU/L): Individual bias 0.3 to 1.1 IU/L; Pooled 95th Percentile: 0.7 IU/L.- Plasma (hCG > 5 IU/L): Individual recovery 81.8% to 103.3%; Pooled 95th Percentile: 88.2% - 96.3%.- Plasma (hCG ~5 IU/L): Individual bias -0.2 to -1.2 IU/L; Pooled 95th Percentile: 0.8 IU/L. End-users may obtain individual result > 15% negative bias for plasma samples when hCG concentrations are >5 IU/L.
Method Comparison (with Predicate)	Deming regression slopes between 0.9 and 1.1	- Plasma samples (i-STAT vs ARCHITECT): $y = 1.02x - 0.22, r = 0.99, n = 134$.- Whole blood samples (i-STAT vs ARCHITECT): $y = 0.95x + 2.39, r = 0.99, n = 134$.
Sample Matrix Comparison	Deming regression slopes between 0.9 and 1.1 (compared to Li-Hep plasma)	All Deming regression slopes comparing the sample type investigated with the control (Li-Hep plasma) fell between 0.9 and 1.1.

2. Sample sizes used for the test set and the data provenance:

Precision / Reproducibility:
- No specific sample size for "test set" is explicitly stated beyond "samples were targeted at four hCG concentrations" and testing at "three external POC sites."
- Provenance: Not specified, but "collected at the POC at four external sites" for method comparison suggests prospective collection in a clinical setting.
Limit of Blank (LoB): 195 replicate measurements in plasma, 144 replicate measurements in blood.
Limit of Detection (LoD): 24 replicate measurements on each of six low-level β-hCG blood samples.
Limit of Quantitation (LoQ): 92 replicate measurements of six low-level β-hCG blood samples.
Analytical Specificity (Interference): "human plasma" with/without specific interferences; "17 human plasma samples" for HAMA/RF.
Recovery: "heparinized whole blood and plasma samples from six donors."
Method Comparison with Predicate Device: 134 samples.
- Provenance: "Blood samples were collected at the POC at four external sites in heparinized evacuated tubes, and analyzed in duplicate on the i-STAT System. The blood tubes were sent to the laboratory and the plasma portion was separated from the red cells. The plasma portion was tested in duplicate on the i-STAT System and the ARCHITECT system within 6 hours of collection." This indicates a prospective collection for comparison.
Sample Matrix Comparison: 40 donor samples, each spiked to create 40 levels of hCG.
Reference Range:
- 123 apparently healthy, non-pregnant females ≥ 18 and < 40 years.
- 125 apparently healthy, non-pregnant females > 40 years.
- Provenance: Specimens from these individuals were "collected and tested at four external sites." This is prospective collection.

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 device is an in vitro diagnostic (IVD) test, not an imaging device that typically requires expert interpretation for ground truth. The "ground truth" for the performance studies is established by the concentration of β-hCG in the samples, either:

Known concentrations: Prepared by spiking samples with WHO 5th IS (Recovery studies).
Reference measurements: From the predicate device (ARCHITECT System) or other reference methods for comparison (Method Comparison, LoB, LoD, LoQ determination using ARCHITECT results for blank plasma/blood), or from CLSI guidelines for establishing reference intervals.
Clinical context: "Early detection of pregnancy consistent with a β-hCG result above 25 IU/L" (referenced from Tietz NW, Clinical Guide to Laboratory Tests, 4th Ed. 2006).

Therefore, there were no human experts (like radiologists) establishing ground truth in the way conceptualized for AI in medical imaging. The ground truth is biochemical measurement-based.

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

Not applicable. As an IVD device measuring a biochemical marker, adjudication by experts for discrepancies in qualitative or quantitative assessment is not a standard practice for establishing ground truth in the way it is for image-based diagnostic systems. The "ground truth" relies on the measured concentration by established reference methods or controlled spiking.

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:

Not applicable. This is an in vitro diagnostic test, not an AI-powered image analysis system or a device that directly assists human readers/interpreters. There are no "human readers" in the context of an MRMC study for this type of device.

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

Yes, the studies described are standalone device performance studies. The i-STAT Total β-hCG Test is an automated system that provides quantitative and qualitative results for β-hCG. Its performance characteristics (precision, linearity, limits, specificity, recovery) are evaluated based on its direct output without human intervention for interpretation of the result itself, beyond operating the device and reporting the numerical value. The "algorithm" in this context is the analytical process of the immunoassay and electrochemical detection within the i-STAT system.

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

The ground truth used is primarily biochemical measurement and known concentrations:

Known concentrations: For linearity, recovery, and high dose hook effect studies, samples were spiked to achieve specific, known β-hCG concentrations (often referenced to WHO 5th IS).
Reference device measurements: For method comparison, the predicate device (Abbott ARCHITECT System Total β-hCG) provided the reference measurements. For LoB/LoD/LoQ determinations, the ARCHITECT system was also used to confirm blank samples.
Absence of analyte: For LoB, "blank plasma and fresh whole blood that measured < 1.20 IU/L on the ARCHITECT system."
Clinical criteria/literature: For defining the significance of β-hCG levels (e.g., 25 IU/L for early pregnancy detection, referenced to Tietz NW).
Expected analyte behavior: For analytical specificity, known interfering substances were spiked in at controlled concentrations.

8. The sample size for the training set:

Not explicitly stated. This device is an in vitro diagnostic test, not a machine learning model that typically relies on a distinct "training set" in the same way as AI software. The development of such devices often involves extensive R&D and optimization using various batches and preparations of reagents and samples, which serves an analogous purpose to training, but it's not generally quantified as a "training set" in regulatory submissions for these types of devices.

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

Not applicable in the conventional sense of an AI training set. For the development and optimization of the i-STAT β-hCG test, the ground truth would have been established through:

Chemical and biological characterization: Precisely prepared calibrators and controls with known concentrations of β-hCG (often traceable to international standards like the WHO 5th IS).
Cross-validation with established laboratory methods: Using recognized reference methods or existing FDA-cleared predicate devices to confirm the accuracy and performance of the evolving i-STAT assay during its development.
Internal quality control procedures: Continuous monitoring against known standards and controls during the manufacturing and R&D phases.

Summary

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

April 16, 2015

ABBOTT POINT OF CARE, INC. MELISSA ROBINSON ASSOCIATE DIRECTOR OF REGULATORY AFFAIRS 400 COLLEGE ROAD EAST PRINCETON NJ 08540

Re: K133002 Trade/Device Name: i-STAT® Total B-hCG Test, i-STAT® Total β-hCG Controls, i-STAT® Total ß-hCG Calibration Verification Materials Regulation Number: 21 CFR 862.1155 Regulation Name: Human chorionic gonadotropin (hCG) test system Regulatory Class: II Product Code: DHA, JJX Dated: April 9, 2015 Received: April 13, 2015

Dear Ms. Robinson:

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 (QS) regulation (21 CFR Part 820); and if applicable, the

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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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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Indications for Use

510(k) Number (if known) K133002

Device Name

i-STAT Total ß-hCG test i-STAT Total B-hCG Controls and i-STAT Total ß-hCG Calibration Verification Materials

Indications for Use (Describe)

The i-STAT® Total B-hCG Controls are used to monitor performance of the i-STAT Total β-hCC test.

The i-STAT® Total B-hCG Calibration Verification Materials are used to verify the calibration of the i-STAT Total BhCG test throughout the reportable range.

X Prescription Use (Part 21 CFR 801 Subpart D)

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

CONTINUE ON A SEPARATE PAGE IF NEEDED.

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510(k) Summary i-STAT Total ß-hCG Test

This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1900 and CFR 807.92.

The assigned 510(k) number is: K133002

Date Summary prepared:

1. Submitted by:

Abbott Point of Care Inc. 400 College Road East Princeton, NJ 08540 Phone: 609-454-9000 FAX: 609-419-9370

Establishment Registration Number: 2245578

Contact:

Melissa Robinson 400 College Road East Princeton, NJ 08540 Phone: 609-454-9371 Fax: 609-419-9370

2. Identification of the Device:

Device Classification Name: System, Test, Human Chorionic Gonadotropin Device Name: i-STAT Total ß-hCG Test Classification: Class II (regulation number 862.1155) Classification Product Code: DHA

Device Classification Name: Quality Control Material (Assayed and Unassayed) Device Name: i-STAT Total ß-hCG Control Level 1, 2, 3 Classification:Class I (regulation 862.1660) Product Code: JJX

Regulation Description: Quality Control Material (Assayed and Unassayed) Device Name: i-STAT Total ß-hCG Calibration Verification Levels 1, 2, 3 Classification:Class I (regulation 862.1660) Product Code: JJX

Image /page/3/Picture/16 description: The image shows the logo for Abbott. On the left is a blue symbol that resembles a lowercase "a". To the right of the symbol is the name "Abbott" in bold, black letters. Below the name is the phrase "A Promise for Life" in a smaller font.

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Image /page/4/Picture/0 description: The image shows the logo for Abbott, a healthcare company. The logo is a stylized letter "a" in a sans-serif font. The letter is a solid, light blue color. The logo is simple and modern, and it is easily recognizable.

3. Predicate Device

Predicate Device Name: Abbott ARCHITECT System Total ß-hCG Predicate 510(k) Number: K983424 Regulation Number: Class II (regulation number 862.1155) Classification Product Code: DHA

Predicate Device Name: Cliniqa Beta HCG Control Level 1, 2, 3 Predicate 510(k) Number: K121237 Regulation Description: Quality Control Material (Assayed and Unassayed) Classification: Class 1 (regulation 862.1660) Product Code: JJX

Predicate Device Name: Cliniqa Beta HCG Calibration Verification Control Levels 1, 2, 3 Predicate 510(k) Number: K121237 Regulation Description: Quality Control Material (Assayed and Unassayed) Classification: Class 1 (regulation 862.1660) Product Code: JJX

4. Intended Use/Indications for Use:

The i-STAT® Total Beta-Human Chorionic Gonadotropin (B-hCG) test is an in vitro diagnostic test for the quantitative and qualitative determination of ß-hCG in venous whole blood or plasma samples using i-STAT 1 Analyzer Systems. The test is intended to be used as an aid in the early detection of pregnancy and is for prescription use only.

i-STAT Total ß-hCG Controls are used to monitor the performance of the i-STAT Total ß-hCG test.

i-STAT Total B-hCG Calibration Verification materials are used to verify the calibration of the i-STAT Total B-hCG test throughout the reportable range.

5. Device Description:

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Image /page/5/Picture/0 description: The image shows the logo for Abbott, a healthcare company. The logo is a stylized letter 'a' in a solid blue color. The 'a' is designed with rounded corners and a modern, minimalist aesthetic. The logo is simple and recognizable, representing the company's brand identity.

The i-STAT Total ß-hCG Controls are assayed human serum which are used to monitor the performance of the i-STAT Total ß-hCG test.

The i-STAT Total ß-hCG Calibration Verification materials are assayed human serum used to verify the calibration of the i-STAT Total β-hCG test throughout the reportable range.

6. Substantial Equivalence Information:

Characteristic	Predicate DeviceAbbott ARCHITECT	Proposed DeviceAPOC i-STAT System
Intended Use	The ARCHITECT Total β-hCGAssay is a ChemiluminescentMicroparticle Immunoassay(CMIA) for the quantitative andqualitative determination of beta-human chorionic gonadotropin(β-hCG) in human serum andplasma for the early detection ofpregnancy.	The i-STAT® Total Beta-HumanChorionic Gonadotropin (β-hCG)test is an in vitro diagnostic testfor the quantitative andqualitative determination ofβhCG in venous whole blood orplasma samples. The test isintended to be used as an aid inthe early detection of pregnancy
AssayMethodology	Two site ELISA	Two site ELISA
Capture Site	Heterogenous	Heterogenous
CaptureAntibodies	Monoclonal	Monoclonal
Label Antibody	Monoclonal	Monoclonal
Label	Acridinium	Alkaline Phosphotase
AnalysisSequence	Sequential capture/label	Simultaneous capture/label
Analysis Time	15.6 minutes	10 minutes
Sample Type	Serum or plasma	Whole blood or plasma
EnzymeDetection	Chemiluminescent MicroparticleImmunoassay	Electrochemical

Comparison with predicate (i-STAT Total β-hCG Cartridge):

Image /page/5/Picture/8 description: The image shows the Abbott logo. The logo consists of a blue stylized letter "a" on the left and the word "Abbott" in bold, black font on the right. Below the word "Abbott" is the phrase "A Promise for Life" in a smaller, lighter font.

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Image /page/6/Picture/0 description: The image shows a blue logo of Abbott. The logo is a stylized letter 'a' with rounded corners. The 'a' is formed by a thick line that starts at the top left, curves down and to the right, then curves back up and to the left, forming a closed shape. The logo is simple and modern, and the blue color is clean and professional.

The table below describes the features of the i-STAT Total ß-hCG Cartridge and predicate device that are apparently different.

Analysis of Difference
Detection	The ARCHITECT detects an optical signal from the acridinium label while the i-STAT System detects the enzyme label by reacting with a substrate so as to generate an electrochemically detectable product.
Label	Acridinium is a chemiluminescent label while alkaline phosphatase is an enzyme label.
Analysis Sequence	The ARCHITECT is an ELISA with sequential capture and labeling while the i-STAT System is a simultaneous ELISA with capture and label occurring in parallel.
Sample Type	The ARCHITECT accepts serum or plasma while the i-STAT device is intended for whole blood or plasma specimens. This submission includes a detailed analysis of equivalence between blood and plasma for the i-STAT Total β-hCG test (see section 18.2.4). This data supports the claim of equivalence between blood and plasma.
Reportable Range	The ARCHITECT reports from 1.20 IU/L to 225,000.00 IU/L; the i-STAT Total β-hCG test has a reportable range of 5.0 IU/L to 2000.0 IU/L. These devices are intended for the early detection of pregnancy, consistent with a β-hCG result above 25 IU/L1. The reportable ranges for these devices both exceed that necessary for this intended use.

Image /page/6/Picture/6 description: The image shows the logo for Abbott. The logo consists of a blue stylized letter "a" on the left, followed by the word "Abbott" in bold, black letters. Below the word "Abbott" is the tagline "A Promise for Life" in a smaller, lighter font.

1 Tietz NW, Clinical Guide to Laboratory Tests, 4th Ed. 2006. p. 2160-2161.

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Image /page/7/Picture/0 description: The image shows a blue logo of Abbott. The logo is a stylized letter 'a' with rounded corners. The logo is simple and modern, and it is likely used to represent the company in a variety of contexts.

Comparison with predicate (i-STAT β-hCG Control and Calibration Verification Material):

Characteristic	Predicate Device	Proposed Device
	Cliniqa Beta HCG Control Level1, 2, 3 and Cliniqa Beta HCGCalibration Verification ControlsLevel 1, 2, 3(K121237)	i-STAT Total β-hCG Controlsand Calibration VerificationMaterial
Intended Use	Cliniqa Beta HCG Control Level1, Cliniqa Beta HCG ControlLevel 2, Cliniqa Beta HCGControl Level 3 are assayedquality control material used tomonitor the precision Beta HCGassays.	i-STAT Total β-hCG Controlsare used to monitor theperformance of the i-STATTotal β-hCG test.
	Cliniqa Beta HCG CalibrationVerification Controls, level 1, 2,and 3 are assayed quality controlmaterials used to monitor theprecision of Beta HCG assays.	i-STAT Total β-hCGCalibration Verificationmaterials are used to verify thecalibration of the i-STAT Totalβ-hCG test throughout thereportable range.
Matrix	Human serum with added bufferstabilizers, and purified humanhormones.	Human serum with addedbuffer stabilizers, and purifiedhuman hormones.
Form	Liquid	Liquid
Open VialStability	30 days	30 days
Caution	Human Source Material	Human Source Material
Values	Specific for each lot	Specific for each lot
Stability	Opened: 30 days at 2-8 °CShelf Life: 3 years at 2-8 °C	Opened: 30 days at 2-8 °CShelf Life: 3 years at 2-8 °C

Image /page/7/Picture/5 description: The image shows the logo for Abbott. The logo consists of a blue stylized "a" on the left, followed by the word "Abbott" in a bold, dark font. Below "Abbott" is the tagline "A Promise for Life" in a smaller, lighter font. The logo is clean and professional, conveying a sense of trust and reliability.

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7. Standard/Guidance Documents

CLSI EP05-A2: Evaluation of Precision Performance of Quantitative Measurement Methods

CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures CLSI EP07-A2: Interference Testing in Clinical Chemistry

CLSI EP09-A2: Method Comparison and Bias Estimation Using Patient Samples CLSI EP12-A2: User Protocol for Evaluation of Qualitative Test Performance CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures

CLSI C28-A3c: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory

CLSI I/LA30-A: Immunoassay Interference by Endogenous Antibodies ISO 14971: Medical Devices – Application of Risk Management to Medical Devices

i-STAT Total ß-hCG Cartridge Performance Characteristics: 8.

i-STAT Total ß-hCG test cartridge:

Blood to Plasma Equivalence a)

The i-STAT Total B-hCG test is designed to function using whole blood or plasma at the point of care. To support equivalence to our predicate device the estimated bias between blood and plasma was determined. A bias to plasma of no greater than 10% was observed across all blood samples tested. This data supports the claim of equivalence between the two sample types and equivalence to our predicate device.

b) Precision / Reproducibility

The test is designed to have total imprecision < 10% CV for concetrations of hCG above 14 IU/L, or a standard deviation (SD) of 1.4 IU/L for concentrations of hCG < 14 IU/L in blood and plasma. Precision of the i-STAT Total ß-hCG test was evaluated in whole blood and plasma. The precision in blood and plasma was demonstrated at three external POC sites.

In whole blood, samples were targeted at four hCG concentrations: 5 IU/L, 25 IU/L, Mid level (~800 IU/L) and High level (~1500 IU/L). The highest observed upper (total) imprecision at 5 IU/L was 0.81 IU/L. The highest observed (total) imprecision was 7.3 %CV at all other levels.

In plasma, samples were targeted at four hCG concentrations: 5 IU/L, 25 IU/L, mid level (~1150 IU/L) and high level (~1875 IU/L). The observed (total) imprecision at 5 IU/L was 1.03 IU/L. The highest observed (total) imprecision was 5.6 %CV at all other levels.

Image /page/8/Picture/17 description: The image shows the logo for Abbott. On the left is a blue symbol that resembles a stylized letter 'a'. To the right of the symbol is the word "Abbott" in bold, black letters. Below the word "Abbott" is the phrase "A Promise for Life" in a smaller font size.

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c) Linearity / Test Measuring Interval

The linearity of the i-STAT Total B-hCG test was evaluated on the i-STAT System by creating a series of concentration levels in both whole blood and plasma through a process of mixing different proportions of low and high positive ß-hCG samples. The samples tested ranged in concentration from 5 IU/L to >2000 IU/L. In whole blood, the bias due to non-linearity was found to be 0.1 IU/L at the lowest hCG concentration. The percent non-linearity measured in whole blood did not exceed 4.1% across all levels between 10 and ~2000 IU/L. In plasma, the bias due to nonlinearity was found to be -0.1 IU/L at the lowest hCG concentration. The percent non-linearity measured in plasma did not exceed 2.3% across all levels between 10 and ~2000 IU/L.

d) Limit of Blank (LoB), Limit of Detection (LoD) and Limit of Quantitation (LoQ)

The Limit of Blank (LoB) was determined using blank plasma and fresh whole blood that measured < 1.20 IU/L on the ARCHITECT system. One hundred and ninety five (195) replicate measurements in plasma and 144 replicate measurements in blood were used for this determination. Testing was completed over five days using two unique lots of i-STAT Total ß-hCG cartridges from two unique ß-hCG reagent sets.

The Limit of Detection (LoD) determination was based on 24 replicate measurements on each of six low level ß-hCG blood samples. This study included the use of 29 i-STAT 1 Analyzers and spanned five testing days and two unique i-STAT Total ß-hCG cartridge lots using two unique ß-hCG reagent sets.

The Limit of Quantitation (LoQ) determination was based on 92 replicate measurements of six low level ß-hCG blood samples. This study included the use of 13 i-STAT Analyzers and spanned six testing days using two unique i-STAT Total B-hCG cartridge lots from two unique ß-hCG reagent sets.

The LoQ was determined to be < 5.0 IU/L, the LoD was determined to be ≤ the LoQ and the LoB was determined to be < the LoD.

e) High dose 'Hook Effect'

The i-STAT Total B-hCG test has a reportable range of 5.0 IU/L to 2000.0 IU/L. In an in-house study, no hook effect was observed up to ~450,000 IU/L in plasma and

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up to ~650,000 IU/L in whole blood. These results support the design goal of no significant hook effect up to 300,000 IU/L.

f) Analytical Specificity

Three studies for analytical specificity were performed following CLSI guideline EP07-02. The first study used human plasma with ~ 50 IU/L and ~1500 IU/L hCG that was spiked with known interference substances. No significant interference, defined as recovery within ± 10% compared to reference without any interfering substance, was observed. The second study used human plasma with ~50 IU/L and ~1500 IU/L hCG that was spiked with the following interferents: Albumin, Bilirubin, Cholesterol, Hemoglobin, Triglyceride and Uric Acid. No significant interference, defined as recovery within ± 10% compared to reference without any interfering substance, was observed. The third study used human whole blood and plasma with ~5 IU/L hCG that was spiked with the same known interference substances as in previous studies. No significant interference, defined as recovery within +/- 4 IU/L compared to reference without interfering substance, was observed.

The cross-reactivity of the i-STAT Total ß-hCG test with glycoproteins of similar structure, namely Thyroid Stimulating Hormone (TSH), Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) was evaluated. The following levels were tested: 100 mIU/L TSH, 300 IU/L FSH and 450 IU/L LH. No significant interference, defined as recovery within ± 10% compared to reference without any interfering substance, was observed with the test.

Potential interference from human anti-mouse antibody (HAMA) and Rheumatoid factor (RF) was evaluated using 17 human plasma samples that had been prescreened as interferents to our test (each containing HAMA and/or RF). All sample interference was mitigated using the i-STAT Total ß-hCG test.

g) Recovery

A dilution recovery study was performed using heparinized whole blood and plasma samples from six donors. For each donor, the original negative sample and ß-hCG spiked samples were prepared with WHO 5th IS (07/364) in either heparinized whole blood or heparinized plasma to approximately 2000 IU/L. The spiked samples were diluted using unspiked whole blood or plasma and tested in a minimum of ten cartridges. A series of nine levels were generated for each donor. For samples with hcg concentrations >5 IU/L, the individual recovery results for whole blood ranged from 91.1% to 118.5%, and for plasma samples from 81.8% to 103.3% when compared to WHO hCG 5th IS. For whole blood samples with hCG at a concentration of ~5 IU/L, the individual bias ranged from 0.3 to 1.1 IU/L, and for plasma samples from -0.2 to -1.2 IU/L when compared to WHO hCG 5th IS. End-

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users may obtain individual result > 15% negative bias for plasma samples when hCG concentrations are >5 IU/L.

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Percent recovery results were pooled across each hCG concentration.

Level	ExpectedMean (IU/L)	ObservedMean (IU/L)	% Recovery orAbsolute Bias
1	1936.4	1974.6	102.0 %
2	972.7	989.3	101.7 %
3	644.8	677.4	105.1 %
4	484.2	509.5	105.2 %
5	242.2	261.4	107.9 %
6	121.3	128.2	105.7 %
7	60.6	62.9	103.8 %
8	24.3	26.6	109.5 %
9	5.1	5.8	0.7 IU/L

Summary Recovery Performance. Whole Blood

Summary Recovery Performance, Plasma

Level	ExpectedMean (IU/L)	ObservedMean (IU/L)	% Recovery orAbsolute Bias
1	1972.6	1811.5	91.8 %
2	986.5	895.5	90.8 %
3	657.5	622.1	94.6 %
4	493.3	475.0	96.3 %
5	246.9	234.1	94.8 %
6	123.5	109.2	88.4 %
7	61.8	54.5	88.2 %
8	24.8	22.6	91.0 %
9	5.3	4.5	0.8 IU/L

9. i-STAT Total β-hCG Controls and Calibration Verification Performance Characteristics:

The i-STAT Total ß-hCG Control and Calibration Verification materials are manufactured by Cliniqa (K121237). The materials were evaluated and cleared for market use in k12137.

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10. Comparison Studies:

Method Comparison with Predicate Device a)

Method comparison data were collected following CLSI guideline EP9-A2. Blood samples were collected at the POC at four external sites in heparinized evacuated tubes, and analyzed in duplicate on the i-STAT System. The blood tubes were sent to the laboratory and the plasma portion was separated from the red cells. The plasma portion was tested in duplicate on the i-STAT System and the ARCHITECT system within 6 hours of collection. A total of 134 samples spanning the measuring interval of the i-STAT Total ß-hCG test were collected. The data was evaluated by weighted Deming regression analysis, using the first result of each duplicate measurement, and the results were as follows:

Plasma samples:	$y = 1.02x - 0.22, r = 0.99, n = 134$
Whole blood samples:	$y = 0.95x + 2.39, r = 0.99, n = 134$

b) Sample Matrix Comparison

Sample matrix comparison was conducted based on the recommendations of CLSI guideline EP9-A2. Forty levels of hCG across and beyond the intended measurement interval of the i-STAT Total ß-hCG test were prepared using 40 donor samples and spiking each with a stock solution containing hCG antigen. The study took place over 12 testing days and the samples were run in random order across the measurement interval. Four sample types were investigated; lithium-heparin (Li-Hep) whole blood and plasma and sodium-heparin (Na-Hep) whole blood and plasma. Results of each sample type against the control (Li-Hep plasma) were analyzed. All Deming regression slopes comparing the sample type investigated with the control fell between 0.9 and 1.1.

11. Reference Range:

Lithium heparin whole blood and plasma specimens from 123 apparently healthy. non-pregnant females ≥ 18 and < 40 years and from 125 apparently healthy, nonpregnant females > 40 years were collected and tested at four external sites. Subjects self-reported their menopausal status, which was defined as 12 months since last menses.

The 95th percentile and 95% confidence interval were calculated non-parametrically based on CLSI EP28-A3c.

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ReferencePopulationage (years)	NSubjects	NWholebloodresults	NPlasmaresults	Median(IU/L)	Range(IU/L)	95th Percentile(IU/L), [95% CI]
≥ 18 and < 40	123	122	120	0	0 – 3.9	0.7 [0.3, 1.6]
≥ 40 y	125	125	124	0	0 – 9.6	4.5 [4.0 , 5.4]
≥ 40 y, pre-menopausal	68	68	68	0	0 - 2.5	--
≥ 40 y post-menopausal	57	57	56	1.5	0 – 9.6	--

12. Proposed Labeling:

The labeling is sufficient and satisfies the requirements of 21 CFR Part 809.10.

13. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision to the predicate devices.

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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.