The Copalis® Rubella IgM assay uses Coupled Particle Light Scattering (Copalis®) technology in a microparticle aggregation-based immunoassay for the qualitative detection of IgM antibodies to Rubella virus in human serum and EDTA, heparin or sodium citrate plasma using the Copalis® I Immunoassay System. The test is indicated for the presumptive diagnosis of primary rubella infection.

Device Description

KIT DESCRIPTION: Coupled Particle Light Scattering (Copalis®) technology Coupled Particle Light Scattering (Copalis®) technology provides a rapid method for the measurement of antibodies to specific viral or protozoan pathogens.

The Copalis® Rubella IgM Assay is based on the principle of antibody-dependent particle aggregation as detected by measurement of changes in light scattering. The serum or plasma sample is manually pre-diluted in Sample Diluent to remove IgG and IdA antibodies. Polystyrene microparticles present in the Copalis® Test Cup are coated with Rubella viral antigen (HPV 77 strain). These microparticles aggregate in the presence of the pre-diluted human serum/plasma containing IgM antibodies to Rubella virus. After 10 minutes of agitation, the levels of aggregation are determined by measurement of the number of reacted and unreacted particles as they flow past a detector. Reactivity is assessed by the level of aggregation relative to a cutoff value. The Copalis® Rubella IgM Assay detects the presence of Rubella IgM-specific antibodies. Two levels of controls are used to monitor system performance.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the Copalis® Rubella IgM Assay, based on the provided text:

Acceptance Criteria and Device Performance

The core of the performance evaluation rests on the agreement with a predicate device, the Abbott IMx Rubella IgM test. While specific numerical acceptance criteria (e.g., "agreement must be >95%") are not explicitly stated as distinct criteria, the results presented in the tables demonstrate the agreement levels achieved. The study implicitly shows that the observed agreement percentages were deemed sufficient for demonstrating substantial equivalence.

Acceptance Criteria (Implicit)	Reported Device Performance
Overall Agreement with Predicate Device (Abbott IMx Rubella IgM)	Acute Adult Population: 98.2% (108/110) [93.6 - 99.8%]
	Obstetric Adult Population: 100.0% (50/50) [92.9 - 100.0%]
	Seronegative Population: 100.0% (97/97) [96.3 — 100.0%]
	Pediatric Population: 100.0% (20/20) [83.2 - 100.0%]
Reproducibility (Across Sites and Within-Run %CV for Control and Panel Samples)
Neg Control: Low %CV	%CV (Total): 1.7%, %CV (Within Run): na
Pos Control: Moderate %CV	%CV (Total): 8.0%, %CV (Within Run): na
NRM01-01: Low %CV	%CV (Total): 3.0%, %CV (Within Run): 2.2%
NRM01-02: Low %CV	%CV (Total): 2.7%, %CV (Within Run): 1.4%
PRM01-01: Moderate %CV	%CV (Total): 12.4%, %CV (Within Run): 8.9%
PRM01-02: Moderate %CV	%CV (Total): 9.8%, %CV (Within Run): 6.9%
PRM01-03: Low %CV	%CV (Total): 5.1%, %CV (Within Run): 3.8%
PRM01-04: Moderate %CV	%CV (Total): 18.5%, %CV (Within Run): 12.3%
Plasma Reproducibility (Comparison of Serum to EDTA, Heparin, and Citrate Plasma)	Various %CVs reported for Serum, EDTA, Heparin, and Citrate plasma across different sample levels (N1, N2, HP, LP1, LP2). All generally indicate acceptable precision for the different sample types. For example, N1 serum total %CV is 2.57, while N1 EDTA plasma total %CV is 2.43.

Study Details

Sample sizes used for the test set and the data provenance:
- Acute Adult Population: 114 samples were analyzed, but agreement was calculated on 110 (excluding 4 EQ results from the IMx Rubella IgM).
- Obstetric Adult Population: 50 samples.
- Seronegative Population: 99 samples were analyzed, but agreement was calculated on 97 (excluding 1 EQ result from the IMx Rubella IgM).
- Pediatric Population: 20 samples.
- Reproducibility Panel: 6 serum samples were tested in duplicate for 5 days (total N=30 per sample ID).
- Plasma Reproducibility: 6 sets of serum/multiple plasma paired samples (EDTA, heparin, sodium citrate) were tested in duplicate for 3 days.
- Data Provenance: The studies were conducted at 3 sites: 1 hospital clinical laboratory, 1 state laboratory, and at DiaSorin itself. The country of origin of the data is not specified but implicitly within the US given the submission to the FDA. The study is prospective in nature as it evaluates the performance of the new device against a predicate.
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):
The ground truth in this study is established by comparison to a legally marketed predicate device, the Abbott IMx Rubella IgM test. Therefore, "experts" in the traditional sense of human readers adjudicating images are not directly applicable. The "ground truth" is the result provided by the established predicate device.
Adjudication method (e.g., 2+1, 3+1, none) for the test set:
Not applicable, as the "ground truth" is determined by a comparative analysis against a predicate device, not by expert human adjudication of discrete findings.
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:
No, a MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) immunoassay, not an AI-assisted diagnostic tool that would involve human readers interpreting results with or without AI. The evaluation focuses on the assay's performance against a predicate device.
If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
Yes, the performance data presented is for the Copalis® Rubella IgM Assay as a standalone device. The results are from the assay directly, without human interpretation influencing the reported agreement percentages. The device's output is compared to the predicate device's output.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The primary "ground truth" used for clinical performance comparison is the results from a legally marketed predicate device (Abbott IMx Rubella IgM test). For reproducibility and plasma studies, internal controls and panel members with known characteristics are used to assess the device's precision.
The sample size for the training set:
The document describes clinical trials for performance evaluation and reproducibility studies. It does not mention a separate "training set" in the context of machine learning. For an immunoassay, the development typically involves assay optimization and validation, rather than a distinct machine learning training phase. Therefore, no specific training set sample size is provided.
How the ground truth for the training set was established:
As there is no explicit mention of a training set in the machine learning context, the method for establishing its "ground truth" is not applicable based on the provided text. The "ground truth" for the overall assay validation is based on the predicate device.

Summary

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FFB 1 0 2000

K993291

January 8, 2000

510(k) Summarv

SUBMITTED BY:

Judith J. Smith DiaSorin, Inc. 9175 Guilford Rd. Suite 100 Columbia, MD 21046

NAME OF DEVICES: Trade Name:

Copalis® Rubella IgM Assay

Common Names/Descriptions:

Immunoassay for the Detection of IgM Antibodies to Rubella virus

Classification Names:

Rubella Serology Test

PREDICATE DEVICES:

Abbott Laboratories IMx Rubella IgM (MEIA)

DEVICE DESCRIPTION: INTENDED USE:

PERFORMANCE DATA:

Clinical Correlation: Clinical trials were conducted at 3 sites (1 hospital clinical laboratory, 1 state laboratory and at DiaSorin) to evaluate the performance of the Copalis® Rubella IgM Assay in detecting IgM antibodies to Rubella antigen on the Copalis® I Immunoassay System. The assay performance was compared to the Abbott IMx Rubella IgM test.

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	Copalis Rubella IgM
IMx Rubella IgM	Pos	Neg	EQ	Grand Total
Pos	70	1	0	71
Neg	1	38	0	39
EQ	1	3	0	4
Grand Total	72	42	0	114

Summary of Acute Adult Population for Copalis® Rubella IgM Assay

Agreement [95% CI]

98.2% (108/110) [93.6 - 99.8%]

Summary of Obstetric Adult Population for Copalis® Rubella IgM Assay

	Copalis Rubella IgM
IMx Rubella IgM	Pos	Neg	EQ	Grand Total
Pos	0	0	0	0
Neg	0	50	0	50
EQ	0	0	0	0
Grand Total	0	50	0	50

Agreement [95% CI]

100.0% (50/50) [92.9 - 100.0%]

Summary of Seronegative Population for Copalis® Rubella IgM Assay

	Copalis Rubella IgM
IMx Rubella IgM	Pos	Neg	EQ	Grand Total
Pos	0	0	0	0
Neg	0	97	1	98
EQ	0	1	0	1
Grand Total	0	98	1	99

Agreement [95% CI]

100.0% (97/97) [96.3 — 100.0%]

Summary of Pediatric Population for Copalis® Rubella IgM Assay

	Copalis Rubella IgM
IMx Rubella IgM	Pos	Neg	EQ	Grand Total
Pos	3	0	0	3
Neg	0	17	0	17
EQ	0	0	0	0
Grand Total	3	17	0	20

Agreement [95% CI]

100.0% (20/20) [83.2 - 100.0%]

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Reproducibility: Reproducibility studies were performed at three sites using one lot of Copalis® Rubella IgM reagents. Assay reproducibility was determined by assaying a reproducibility panel consisting of six serum samples that covered the range of the Copalis® Rubella IgM assay. Panel members were tested in duplicate once a day for five days. Results expressed in Copalis Test Results (CTR) are summarized by combined site results.

Copalis CTR
Sample ID	Mean	%CV	Within Run%CV
Neg Control	100	1.7%	na
Pos Control	136	8.0%	na
NRM01-01	102	3.0%	2.2%
NRM01-02	102	2.7%	1.4%
PRM01-01	156	12.4%	8.9%
PRM01-02	142	9.8%	6.9%
PRM01-03	117	5.1%	3.8%
PRM01-04	364	18.5%	12.3%
Sample N	30	30	30

Copalis CTR Results Sites Combined - Copalis Rubella IgM Assay

Plasma reproducibility studies were performed at DiaSorin using one lot of Copalis® Rubella IgM. Six sets of serum/ multiple plasma paired samples were prepared using EDTA. heparin and sodium citrate plasma and spanned the range of the assay. The samples were tested in duplicate once a day for 3 days.

CTR	serum			EDTA plasma			HEPARIN plasma			CITRATE plasma
	total	within run		total	within run		total	within run		total	within run
	mean	%CV	%CV	mean	%CV	%CV	mean	%CV	%CV	mean	%CV	%CV
N1	102	2.57	1.37	102	2.43	1.37	106	1.48	0.67	102	1.20	0.35
N2	100	2.36	1.41	105	2.25	1.02	100	2.16	1.07	92	31.54	1.39
HP	200	6.23	3.54	196	8.01	4.41	176	5.71	2.39	191	10.07	2.53
LP1	130	4.32	1.66	131	5.13	1.39	125	2.90	1.17	124	3.49	0.57
LP2	139	4.90	1.31	144	5.73	3.28	145	4.10	1.94	143	3.92	1.22

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Image /page/3/Picture/1 description: The image is a black and white logo for the Department of Health & Human Services USA. The logo consists of a stylized eagle with three curved lines representing its wings and body. The eagle is enclosed within a circular border, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is written around the border of the circle.

FEB 1 0 2000

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Ms. Judith J. Smith Process Owner, Worldwide Regulatory Affairs and Quality System DiaSorin, Inc. 9175 Guilford Road, Suite 100 Columbia, Maryland 21046

Re: K993291 Trade Name: Copalis® Rubella IgM Assay Regulatory Class: III Product Code: LFX Dated: December 13, 1999 Received: December 14, 1999

Dear Ms. Smith:

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 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). 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 Regulations, Title 21, Parts 800 to 895. A 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 regulations.

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Page 2

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" (21CFR 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/dsma/dsmamain.html".

Sincerely yours,

Steven Butman

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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INDICATIONS FOR USE

510(k) Number (if known): K993291

Copalis® Rubella IgM Assay Device Name:

Indications For Use: The Copalis® Rubella IgM assay uses Coupled Particle Light Scattering (Copalis®) technology in a microparticle aggregation-based immunoassay for the qualitative detection of IgM antibodies to rubella virus in human serum and EDTA, heparin or sodium citrate plasma using the Copalis® I Immunoassay System. The test is indicated for the presumptive diagnosis of primary rubella infection.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Woody Duboe

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number K993291

Prescription Use _ (Per 21 CFR 801.109)

Over-The-Counter Use __

(Optional Format 1-2-96)

Regulation Number and Section

§ 866.3510 Rubella virus serological reagents.

(a)
Identification. Rubella virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubella virus in serum. The identification aids in the diagnosis of rubella (German measles) or confirmation of a person's immune status from past infections or immunizations and provides epidemiological information on German measles. Newborns infected in the uterus with rubella virus may be born with multiple congenital defects (rubella syndrome).(b)
Classification. Class II. The special controls for this device are:(1) National Committee for Clinical Laboratory Standards':
(i) 1/LA6 “Detection and Quantitation of Rubella IgG Antibody: Evaluation and Performance Criteria for Multiple Component Test Products, Speciment Handling, and Use of the Test Products in the Clinical Laboratory, October 1997,”
(ii) 1/LA18 “Specifications for Immunological Testing for Infectious Diseases, December 1994,”
(iii) D13 “Agglutination Characteristics, Methodology, Limitations, and Clinical Validation, October 1993,”
(iv) EP5 “Evaluation of Precision Performance of Clinical Chemistry Devices, February 1999,” and
(v) EP10 “Preliminary Evaluation of the Linearity of Quantitive Clinical Laboratory Methods, May 1998,”
(2) Centers for Disease Control's:
(i) Low Titer Rubella Standard,
(ii) Reference Panel of Well Characterized Rubella Sera, and
(3) World Health Organization's International Rubella Standard.