K Number

Device Name

RUBELLA IGG ASSAY FOR THE TECHNICON IMMUNO 1 SYSTEM IN-VITRO DIAGNOSTIC DEVICE

Manufacturer

BAYER CORP.

Date Cleared

1996-04-15

(385 days)

Product Code

LFX

Regulation Number

866.3510

Intended Use

This in vitro diagnostic method is intended to quantitatively measure Rubella IgG in human serum on the Technicon Immuno 1® System. Measurements of Rubella IgG are designed to aid in the determination of immune status by detecting IgG class antibodies to rubella virus in human sera. The method is not intended for use on any other system.

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Center

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Expedited Review

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AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a standard in vitro diagnostic assay for measuring Rubella IgG antibodies and does not mention any AI or ML components.

Therapeutic

No
This device is an in vitro diagnostic method designed to measure Rubella IgG in human serum to aid in determining immune status. It does not directly treat or prevent a disease, which is the function of a therapeutic device.

Diagnostic

Yes
The "Intended Use / Indications for Use" section explicitly states, "This in vitro diagnostic method is intended to quantitatively measure Rubella IgG in human serum... Measurements of Rubella IgG are designed to aid in the determination of immune status..." thereby identifying it as a diagnostic device.

SaMD (Software as a Medical Device)

The device is described as an in vitro diagnostic method intended to measure Rubella IgG in human serum on the Technicon Immuno 1® System. This implies the use of reagents and the Technicon Immuno 1® System hardware, which are not software-only components.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

The "Intended Use / Indications for Use" section explicitly states: "This in vitro diagnostic method is intended to quantitatively measure Rubella IgG in human serum..." This clearly identifies the device as an in vitro diagnostic.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

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Mentions AI, DNN, or ML

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Description of the training set, sample size, data source, and annotation protocol

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Description of the test set, sample size, data source, and annotation protocol

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Summary of Performance Studies

Study Type: Method comparison and reproducibility.
Sample Size:
- Method Comparison (Sanofi Platelia): 719 clinical samples (520 from Michigan Department of Public Health and the remaining purchased from an outside vendor, Boston Biomedica).
- Method Comparison (Abbott IMx - Site 1): 296 samples.
- Method Comparison (Abbott IMx - Site 2): 287 samples.
- Reproducibility (In-house): 200 samples.
AUC:
- Unresolved In-house Immuno 1 and Platelia Results (Area = 0.9766)
- HAI Resolved In-house Immuno 1 and Platelia Results (Area = 0.9980)
- Unresolved Immuno 1 versus IMx, NC Baptist Hospital Area = 0.988
- Resolved Immuno 1 versus IMx, NC Baptist Hospital Area = 0.997
- Unresolved Immuno 1 versus IMx, Huntsville Hospital, Area = 0.989
- Resolved Immuno 1 versus IMx, Huntsville Hospital Area = 0.998
MRMC: Not Found
Standalone Performance: Not Found
Key Results:
- Sensitivity and Specificity (relative to Sanofi Platelia, HAI Resolved):
  - Immuno 1 Pos Lot Exp1: Sen = 96.6±1.6
  - Immuno 1 Pos Lot Exp2: Sen = 96.2±1.7
  - Immuno 1 Neg Lot Exp1: Spec = 99.5±0.9
  - Immuno 1 Neg Lot Exp2: Spec = 99.6±0.8
- Sensitivity and Specificity (relative to Abbott IMx, Site 1, HAI Resolved):
  - Immuno 1 Pos Lot RCG: Sen = 94.3±3.1
  - Immuno 1 Pos Lot RDG: Sen = 94.8±3.1
  - Immuno 1 Neg Lot RCG: Spec = 100±2.2
  - Immuno 1 Neg Lot RDG: Spec = 100±2.2
- Sensitivity and Specificity (relative to Abbott IMx, Site 2, HAI Resolved):
  - Immuno 1 Pos Lot RCG: Sen = 98.2±1.8
  - Immuno 1 Pos Lot RDG: Sen = 98.2±1.8
  - Immuno 1 Neg Lot RCG: Spec = 100±2.3
  - Immuno 1 Neg Lot RDG: Spec = 100±2.3
- Overall Agreement (HAI Resolved):
  - Miles Inc. (Platelia): 97.5% (Lot Exp1), 97.2% (Lot Exp2)
  - Site 1 (IMx): 95.6% (Lot RCG), 96.0% (Lot RDG)
  - Site 2 (IMx): 98.6% (Lot RCG), 98.6% (Lot RDG)
- Reproducibility (Overall Agreement %):
  - Miles In House Exp 1 Lot: 99.5
  - Miles In House Exp 2 Lot: 99.5
  - NC Baptist Hospital RCG Lot: 99.0
  - NC Baptist Hospital RDG Lot: 98.7
  - Huntsville Hospital RCG Lot: 99.0
  - Huntsville Hospital RDG Lot: 98.2

Key Metrics

Cut-off Value: 10 IU/mL.
Sensitivity and Specificity:
- Miles Inc. (Platelia, Unresolved):
  - Lot Exp1: Sen = 83.6±3.0, Spec = 98.0±2.3
  - Lot Exp2: Sen = 83.0±3.1, Spec = 98.6±1.9
- Site 1 (IMx, Unresolved):
  - Lot RCG: Sen = 85.7±4.7, Spec = 100±2.2
  - Lot RDG: Sen = 86.5±4.5, Spec = 100±2.2
- Site 2 (IMx, Unresolved):
  - Lot RCG: Sen = 88.2±4.3, Spec = 100±2.3
  - Lot RDG: Sen = 89.0±4.1, Spec = 100±2.3
- Miles Inc. (Platelia, HAI Resolved):
  - Lot Exp1: Sen = 96.6±1.6, Spec = 99.5±0.9
  - Lot Exp2: Sen = 96.2±1.7, Spec = 99.6±0.8
- Site 1 (IMx, HAI Resolved):
  - Lot RCG: Sen = 94.3±3.1, Spec = 100±2.2
  - Lot RDG: Sen = 94.8±3.1, Spec = 100±2.2
- Site 2 (IMx, HAI Resolved):
  - Lot RCG: Sen = 98.2±1.8, Spec = 100±2.3
  - Lot RDG: Sen = 98.2±1.8, Spec = 100±2.3
Overall Agreement (OA):
- Miles Inc. (Platelia, Unresolved): 86.5% (Lot Exp1), 86.4% (Lot Exp2)
- Site 1 (IMx, Unresolved): 87.9% (Lot RCG), 88.6% (Lot RDG)
- Site 2 (IMx, Unresolved): 90.0% (Lot RCG), 90.7% (Lot RDG)
- Miles Inc. (Platelia, HAI Resolved): 97.5% (Lot Exp1), 97.2% (Lot Exp2)
- Site 1 (IMx, HAI Resolved): 95.6% (Lot RCG), 96.0% (Lot RDG)
- Site 2 (IMx, HAI Resolved): 98.6% (Lot RCG), 98.6% (Lot RDG)
Imprecision (CV% TOTAL):
- 10 IU/mL: 7.1%
- 20 IU/mL: 7.5%
- 200 IU/mL: 6.7%
Reproducibility (Overall Agreement %):
- Miles In House Exp 1 Lot: 99.5
- Miles In House Exp 2 Lot: 99.5
- NC Baptist Hospital RCG Lot: 99.0
- NC Baptist Hospital RDG Lot: 98.7
- Huntsville Hospital RCG Lot: 99.0
- Huntsville Hospital RDG Lot: 98.2

Predicate Device(s)

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Reference Device(s)

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Predetermined Change Control Plan (PCCP) - All Relevant Information

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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.

Summary

K951359

APR 1 5 1996

SUMMARY OF SAFETY AND EFFECTIVENESS

RUBELLA IgG METHOD FOR THE IMMUNO 1® SYSTEM

Listed below are comparisons of the performance between the Immuno 1 Rubella IgG method (T01-3547-51) and similar devices that were granted FDA determination of substantial equivalence: the Sanofi Platelia Rubella IgG kit and the Abbott IMx Rubella IgG assay. The comparative data with the Sanofi Platelia assay was collected in-house at Miles Inc. on two manufactured lots of reagents. The comparative data with the Abbott IMx assay was collected at two outside clinical sites using two additional lots of manufactured reagents. All HAI testing was done by a state health agency reference laboratory

The information used in this Summary of Safety and Effectiveness was extracted from the Rubella IgG method sheet and from data on file at Miles Inc. A report provided by the CDC for results obtained with the Immuno 1 Rubella IgG method for the CDC Rubella serum panel is attached as Appendix 1.

INTENDED USE

CHARACTERISTICS

The assay has a range of 0 to 500 IU/mL Six calibrators are used with values of 0, 10, 20, 50, 200, 500 IU/mL, traceable to the WHO 2nd International Standard for Anti-Rubella Serum. Agreement between Immuno 1® Rubella IgG Calibrators and a set of calibrators prepared with the WHO Standard is shown in Figure 1 with regression analysis.

IMMUNO 1 vs WHO Rubella IgG Calibrators

Image /page/1/Figure/1 description: This image is a scatter plot comparing WHO calibrators to IMMUNO 1 calibrators, both measured in IU/mL. The main plot shows a linear relationship between the two calibrators, with values ranging from 0 to 600 IU/mL. An inset plot provides a closer view of the relationship at lower concentrations, ranging from 0 to 30 IU/mL for both calibrators.

Image /page/1/Figure/2 description: Figure 1 shows the correlation between Immuno 1 Rubella IgG calibrators and the WHO International Standard. Ten replicate measurements were made at each calibrator level. The figure is labeled as Figure 1.

Linear regression analysis yielded the following results:

Y = 1.020 X + 2.984 R = 0.9989 95% CI intercept = 2.984 ± 3.781 95% CI slope = 1.020 ± 0.017

Cut-off Value Selection

The cutoff value is 10 IU/mL. based on recommendations of the NCCLS and the CDC. Accordingly, the NCCLS subcommittee ".... recommends the use of 10 IU/mL as an indicator of immune status. This breakpoint detects most seropositive persons. Because detection of nonimmune status is clinically more important, selecting 10 IU/mL as the indicator of immune status favors immunization." The assay is calibrated against the WHO 2nd International Rubella IgG standard. The validity of using 10 IU/mL as the cut-off in the Immuno 1 Rubella IgG assay is demonstrated by the comparative clinical performance, Table 3, and summarized by the receiver-operator-curve analysis (ROC) shown in Figures 2a thru 2f and Table 4 of this report. A report provided by Dr. John Stewart. VEH Branch of the CDC in Atlanta, shows that the Immuno-1 Rubella IgG method correctly classified all of the CDC Rubella proficiency panel samples (Appendix 1).

IMPRECISION

Imprecision claims for the IMMUNO 1® Rubella IgG method are based on data collected at two independent clinical site studies. Results are summarized in Table 1. These estimates of imprecision were obtained from replicate assays of human serum pools, controls, and calibrators. Imprecision estimates were collected and computed according to NCCLS document EP5-T2, User Evaluation of Precision Performance of Clinical Chemistry Devices; Tentative Guideline. On-board reagent and calibration stability claims are 60 and 30 days, respectively. Calibration stability requires recovery of target values within ± 2 standard deviations of the claimed level specific total standard deviations.

Table 1. Imprecision of Immuno 1 Rubella IgG Method
-----------------------------------------------------	--	--

| LEVEL
(IU/mL) | SD
TOTAL
(IU/mL) | CV
TOTAL
(%) | SD
WITHIN-RUN
(IU/mL) | CV
WITHIN-RUN
(%) |
|------------------|------------------------|--------------------|-----------------------------|-------------------------|
| 10 | 0.7 | 7.1 | 0.5 | 5.5 |
| 20 | 1.5 | 7.5 | 1.4 | 7.2 |
| 200 | 13.4 | 6.7 | 10.1 | 5.0 |

METHOD COMPARISONS

Comparative results to the Abbott IMx were collected from two clinical sites. each using two lots of Immuno 1 Rubella IgG manufactured reagents. The Pasteur Diagnostics Platelia results were obtained in-house also, using two lots of manufactured reagents different from those used at the clinical sites. Thus a total of four manufactured reagent lots are represented in the method comparisons.

Sensitivity and Specificity

Sensitivity and specificity results, relative to the Sanofi Platelia and the Abbott IMx Rubella IgG assays, are presented in Table 2. The Platelia results were generated on 719 clinical samples (520 from Michigan Department of Public Health and the remaining purchased from an outside vendor, Boston Biomedica, in order to increase the number of negative samples). The sample IU/mL distributions for the in-house and two clinical sites analyses are given in Table 2. The additional negative samples were supplied to the clinical sites as masked specimens.

| IU/mL Range | IN-HOUSE
No. Smpls | % Total | SITE 1
No. Smpls | % Total | SITE 2
No. Smpls | % Total |
|--------------|-----------------------|---------|---------------------|---------|---------------------|---------|
| 0 to