This in vitro diagnostic method is intended to quantitatively measure unconjugated estriol (uE¿) in human serum on the Bayer Immuno 1™ system. Measurements of uE, are used in evaluating fetal well-being by monitoring the level of the hormone derived from fetal-placental circulation.

This diagnostic method is not intended for use on any other system.

Device Description

This in vitro diagnostic method is intended to quantitatively measure unconjugated estriol in human serum on the Bayer Immuno 1 System.

AI/ML Overview

Here's an analysis of the provided text regarding the Bayer Immuno 1™ Unconjugated Estriol method, focusing on acceptance criteria and study details:

Device: Bayer Immuno 1™ System Unconjugated Estriol Assay

Predicate Device: Diagnostic Products Corporation (DPC) Coat-a-Count® Free Estriol RIA method

1. Acceptance Criteria and Reported Device Performance

The document presents performance data for the Bayer Immuno 1™ uEstriol method and compares it to the predicate DPC Coat-a-Count® Free Estriol RIA method. While explicit acceptance criteria (e.g., "must be less than X," "must be greater than Y") are not formally listed as such in the provided text, the implied acceptance criteria are that the new device's performance is comparable to or better than the predicate device across various metrics, demonstrating substantial equivalence.

Table of Acceptance Criteria (Implied) and Reported Device Performance:

Performance Metric	Implied Acceptance Criteria (relative to predicate)	Bayer Immuno 1™ uE3 Reported Performance	DPC Coat-a-Count® Free Estriol RIA Reported Performance (Predicate)	Meets Implied Criteria?
Precision (within-run)	Comparable or better %CV at various concentration levels.
- 0.41 ng/mL equiv.	%CV should be similar or lower than predicate.	3.6%	9.1% (for 0.74 ng/mL mean)	Yes
- 3.60 ng/mL equiv.	%CV should be similar or lower than predicate.	3.2%	5.5% (for 2.9 ng/mL mean)	Yes
- 6.49 ng/mL equiv.	%CV should be similar or lower than predicate.	1.5%	3.8% (for 7.9 ng/mL mean)	Yes
- 11.37 ng/mL equiv.	%CV should be similar or lower than predicate.	2.3%	3.8% (for 12.2 ng/mL mean)	Yes
Precision (total)	Comparable or better %CV at various concentration levels.
- 0.41 ng/mL equiv.	%CV should be similar or lower than predicate.	4.9%	21.2% (for 0.74 ng/mL mean)	Yes
- 3.60 ng/mL equiv.	%CV should be similar or lower than predicate.	3.4%	9.3% (for 2.90 ng/mL mean)	Yes
- 6.49 ng/mL equiv.	%CV should be similar or lower than predicate.	2.3%	9.9% (for 7.90 ng/mL mean)	Yes
- 11.37 ng/mL equiv.	%CV should be similar or lower than predicate.	2.7%	8.0% (for 12.20 ng/mL mean)	Yes
Method Comparison	Strong correlation (r close to 1) and linear regression indicating agreement between methods.
- Regression Equation	(No explicit numerical criterion given, but substantial equivalence implies a strong linear relationship with minimal bias)	y = 0.87x + 0.62	N/A (predicate is 'x')	Yes (implied)
- Correlation Coefficient (r)	Close to 1 (e.g., typically > 0.95 for good agreement).	0.98	N/A	Yes
- Sy.x	(No explicit numerical criterion, but a low value indicates good fit).	1.23	N/A	Yes (implied)
Specificity (Cross-reactivity)	Cross-reactivity with common interferents should be low and comparable to the predicate.
- Estriol-3-sulfate	% Cross-reactivity comparable to predicate.	1.70%	0.46%	Comparable*
- Estriol-3-(β-D-glucuronide)	% Cross-reactivity comparable to predicate.	1.60%	0.26%	Comparable*
- Estriol-16-α-(β-D-glucuronide)	% Cross-reactivity comparable to predicate.	0.05%	0.66%	Yes
- Estradiol	% Cross-reactivity comparable to predicate.	0.44%	0.13%	Comparable*
- 16a-Hydroxyestrone	Low cross-reactivity.	7.60%	Not reported	(No direct comparison)
- Other compounds	Low or not detected cross-reactivity.	Generally low or not detected	Generally low or not detected	Yes

*Note on Specificity: For some compounds (e.g., Estriol-3-sulfate, Estriol-3-(β-D-glucuronide), Estradiol), the Bayer Immuno 1™ shows a higher cross-reactivity percentage than the DPC method. However, without explicit acceptance limits, and given that these values are still relatively low (mostly <2%), they are likely considered acceptable in the context of substantial equivalence, particularly if they do not significantly impact the intended use or if the overall profile is favorable. The DPC method did not report 16a-Hydroxyestrone, so direct comparison is not possible for that compound.

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

Sample Size for Method Comparison (Regression Equation): n = 249 (samples were compared between Immuno 1 uE3 Assay and DPC Coat-a-Count Free Estriol RIA).
Sample Size for Precision (within-run & total): n = 20 samples measured over 10 days for each concentration level.
Sample Size for Specificity (Cross-Reactants): Cross-reactants were "spiked into Normal Human Serum Pools." The number of individual samples within these pools or the number of pools tested isn't specified, but it implies a controlled experiment using pooled human serum.
Data Provenance: The document does not explicitly state the country of origin for the data or whether it was retrospective or prospective. It presents laboratory performance data. Given it's a submission to the FDA, it would typically be derived from studies conducted in a controlled lab environment, likely from a prospective study design to evaluate the new device. The phrase "Normal Human Serum Pools" suggests controlled sample procurement.

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

This document describes the performance characteristics of an in vitro diagnostic assay for measuring unconjugated estriol. For such assays, "ground truth" is typically established by:

Reference Methods: Comparison to a legally marketed predicate device (as done here with the DPC RIA method) is a common way to establish agreement and "truth" in terms of clinical utility relative to existing methods.
Analytical Standards: Known concentrations of analytes (e.g., purified unconjugated estriol) are used to calibrate the assay and determine its accuracy, linearity, and precision.

Therefore, the concept of "experts establishing ground truth" in the sense of clinical specialists reviewing cases (like radiologists for imaging studies) is not directly applicable here. The "ground truth" in this context is the accuracy and reliability of the measurement itself, validated against established analytical principles and a predicate device.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used in clinical studies, especially those involving subjective interpretation of data (e.g., imaging, pathology slides) by multiple human experts.

Since this is an analytical performance study for an in vitro diagnostic assay, there is no adjudication method described or relevant in this context. The comparisons are quantitative measurements between the new device and the predicate device, or between multiple runs of the same device.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.

MRMC studies are relevant for evaluating the impact of AI systems, particularly in diagnostic imaging or pathology, on the performance of human readers. This document describes an in vitro diagnostic assay for measuring a specific hormone level in serum, which is an automated, quantitative measurement. It does not involve human "readers" interpreting output in a comparative effectiveness setting.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the provided study assesses standalone performance.

The Bayer Immuno 1™ Unconjugated Estriol method is an automated in vitro diagnostic system, meaning it operates as an "algorithm only" (or rather, an automated instrument and reagent system) without human interpretation as part of its core function, other than loading samples and reviewing results. The reported precision, method comparison, and specificity data all represent the standalone analytical performance of the device.

7. The Type of Ground Truth Used

The "ground truth" for this study is established by:

Comparison to a Legally Marketed Predicate Device: The DPC Coat-a-Count® Free Estriol RIA method served as the reference for method comparison, implying its accepted performance defines the "ground truth" for clinical utility in that context.
Analytical Standards/Known Concentrations: For precision and specificity, the ground truth is based on known concentrations of unconjugated estriol and other compounds used in spiked samples and controls. This ensures the device accurately measures what it's supposed to measure and doesn't react significantly with other substances.

In essence, the ground truth is analytical accuracy and precision relative to established methods and known chemical standards, rather than expert consensus on a clinical outcome or pathology.

8. The Sample Size for the Training Set

This document describes a pre-market submission for a medical device (an in vitro diagnostic assay). The concept of a "training set" is primarily associated with machine learning or AI models. This device is a traditional analytical instrument system.

Therefore, there is no "training set" in the machine learning sense for this type of device. The system's "training" involves its chemical and mechanical design, calibration procedures using known standards, and validation processes described in the performance studies.

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

As noted above, the concept of a "training set" and associated "ground truth" in the machine learning context does not apply to this traditional in vitro diagnostic assay.

Instead, the device's accuracy and reliability are ensured through:

Calibration: Using reference materials with defined, known concentrations of unconjugated estriol.
Quality Control: Regular testing with control samples to ensure the assay is performing within expected parameters.
Development and Validation: Extensive lab testing during the device's development to optimize its chemical reactions, optical/detection system, and software algorithms to accurately quantify unconjugated estriol. These processes inherently rely on established chemical and physiological principles and analytical standards.

Summary

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Attachment 3

Summary of Safety and Effectiveness

1114121

ുവള

Unconjugated Estriol Method for the Bayer Immuno 1" System

Listed below is a comparison of the performance of the Bayer Immuno 1™ Unconjugated Estriol method and a similar device granted clearance of substantial equivalence (Diagnostic Products Corporation Coat-a-Count Free Estriol RIA method). The information below was extracted from the Bayer Immuno 1 Unconjugated Estriol method sheet and the DPC Free Estriol RIA Package Insert.

Intended Use

This in vitro diagnostic method is intended to quantitatively measure unconjugated estriol in human serum on the Bayer Immuno 1 System. Measurements of unconjugated estriol are used to evaluate fetal well-being by monitoring the level of the hormone derived from fetal-placental circulation.

uEstriol Method:	Bayer Immuno 1™		DPC Coat-a-Count®
Part Number:	Reagents	T01-3987-51	kit(s)	TKEF1 (100)TKEF5 (500)
	Calibrators	T03-3986-01
Expected Values:	<2.0 to 42.0 ng/mL		graphical
Precision (within-run):	mean	% CV	mean	% CV
(n = 20 over 10 days)	0.41	3.6%	0.74	9.1
	3.60	3.2%	2.9	5.5
	6.49	1.5%	7.9	3.8
	11.37	2.3%	12.2	3.8
Precision (total):	(inter-assay only presented)
(n = 20 over 10 days)	0.41	4.9%	0.74	21.2
	3.60	3.4%	2.90	9.3
	6.49	2.3%	7.90	9.9
	11.37	2.7%	12.20	8.0
Regression Equation:	y = 0.87x + 0.62
where:	y	=	Immuno 1 uE3 Assay
	x	=	DPC Coat-a-Count Free Estriol RIA
	n	=	249
	r	=	0.98
	Sy.x	=	1.23
	range	=	0 to 30 ng/ml

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Specificity: Cross Reactants Spiked into Normal Human Serum Pools

Compound	DPC Free Estriol% Crossreactivity	Bayer Immuno 1 uE3% Crossreactivity
Estriol-3-sulfate	0.46%	1.70%
Estriol-3-(β-D-glucuronide)	0.26%	1.60%
Estriol-16-α-(β-D-glucuronide)	0.66%	0.05%
Estriol-17-β-(β-D-glucuronide)	not detected	0.08%
Estradiol	0.13%	0.44%
Estrone	0.05%	0.06%
Estrone-β-D-glucuronide	not detected	0.07%
Estrone-3-sulfate	not detected	0.06%
16-Epiestriol	0.26%	0.30%
17-Epiestriol	0.10%	1.00%
Cortisol	not detected	not detected
11-deoxycortisol	not detected	not detected
5α-Dihydroxytestosterone	not detected	not detected
Testosterone	0.003%	not detected
16a-Hydroxyestrone	not reported	7.60%

Gabriel J. Munaco Jr.

Gabriel J. Muraca, Jr. Manager Regulatory Affairs Bayer Corporation 511 Benedict Avenue Tarrytown, New York 10591-5097

12/11/97

Date

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Gabriel Muraca, Jr. Manager Requlatory Affairs Bayer Corporation 511 Benedict Avenue Tarrytown, New York 10591-5097

MAR - 3 1998

K974721 Re : Unconjugated Estriol Assay for the Bayer Immuno 1™ System Requlatory Class: I Product Code: CGI Dated: December 18, 1997 Received: December 18, 1997

Dear Mr. Muraca:

We have reviewed your Section 510 (k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to 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). 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.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. ਬ substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note:

this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic -------Product Radiation Control provisions, or other Federal laws or requlations.

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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655.

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".

sincerely yours,
Steven Gutman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Attachment 7

Page 1 of 1

974721

510(k) Number (if known):

Device Name: Bayer Immuno 1TM System Unconjugated Estriol

Indications For Use:

This diagnostic method is not intended for use on any other system.

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number. K974721

(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use (Per 21 CFR 801.109)

Over-The-Counter Use

Optional Format 1-2-96)

Regulation Number and Section

§ 862.1265 Estriol test system.

(a)
Identification. An estriol test system is a device intended to measure estriol, an estrogenic steroid, in plasma, serum, and urine of pregnant females. Estriol measurements are used in the diagnosis and treatment of fetoplacental distress in certain cases of high-risk pregnancy.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.