IMMULITE BR-MA: For in vitro diagnostic use with IMMULITE analyzer – for the quantitative measurement of CA 15-3 antigen in human serum, as an aid in the detection of recurrence in previously treated stage II and stage III breast cancer patients, and in the management of metastatic breast cancer patients by monitoring disease progression or response to treatment. Serial testing for patient CA 15-3 values should be used in conjunction with other clinical methods used for detecting early recurrence in Stage II and Stage III disease and for monitoring response to treatment in patients with metastatic breast cancer.

IMMULITE 2000 BR-MA: For in vitro diagnostic use with IMMULITE 2000 analyzer – for the quantitative measurement of CA 15-3 antigen in human serum, as an aid in the detection of recurrence in previously treated stage II and stage III breast cancer patients, and in the management of metastatic breast cancer patients by monitoring disease progression or response to treatment. Serial testing for patient CA 15-3 values should be used in conjunction with other clinical methods used for detecting early recurrence in Stage II and Stage III disease and for monitoring response to treatment in patients with metastatic breast cancer.

Device Description

IMMULITE BR-MA and IMMULITE 2000 BR-MA are clinical use devices intended for use with their respective IMMULITE and IMMULITE 2000 Automated Immunoassay Analyzers for the quantitative measurement of CA15-3 antigen in serum.

IMMULITE BR-MA and IMMULITE 2000 BR-MA are two-step sequential chemiluminescent enzyme immunoassays, based on ligand-labeled monoclonal antibody and separation by anti-ligand-coated solid phase.

AI/ML Overview

Here's an analysis of the provided text to extract the acceptance criteria and study details for the IMMULITE® BR-MA and IMMULITE® 2000 BR-MA devices:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in terms of specific thresholds for each characteristic. Instead, it presents performance characteristics for the IMMULITE devices and compares them to a predicate device (Immuno 1 CA 15-3) and other commercially available kits (Kit A, Kit B). The implicit acceptance criteria appear to be substantial equivalence to these existing, legally marketed devices.

Here's a table summarizing the reported performance, with the implicit acceptance criteria being "comparable to or better than" the predicate/comparator devices.

Characteristic	IMMULITE BR-MA (Reported Performance)	IMMULITE 2000 BR-MA (Reported Performance)	Immuno 1 CA 15-3 (Predicate/Comparator)	Implicit Acceptance Criteria (Comparative)
Analytical Performance
Calibration upper limit	300 U/mL	300 U/mL	200 U/mL	Comparable or higher
Analytical Sensitivity	0.2 U/mL	0.2 U/mL	0.2 U/mL	Comparable
Precision (within-run)	CV range: 5.5-8.1%	CV range: 3.7-4.9%	CV range: 1.3-3.4%	Acceptable CV range, ideally comparable.
Precision (total)	CV range: 7.4-8.8%	CV range: 4.5-6.5%	CV range: 3.0-4.0%	Acceptable CV range, ideally comparable.
Specificity	No significant cross-reactivity	No significant cross-reactivity	Data not available	No significant cross-reactivity
Linearity	%Observed/Expected range: 95-105%	%Observed/Expected range: 93-104%	Data not available	Acceptable %Observed/Expected range
Spiking Recovery	%Observed/Expected range: 89-114%	%Observed/Expected range: 92-108%	Data not available	Acceptable %Observed/Expected range
Effect of Bilirubin	No significant effect	No significant effect	No clinically significant effect	No significant effect
Effect of Lipemia	No significant effect	No significant effect	No clinically significant effect	No significant effect
Effect of Hemolysis	No significant effect	No significant effect	No clinically significant effect	No significant effect
High Dose Hook Effect	No effect up to 80,000 U/mL	No effect up to 80,000 U/mL	Data not available	No effect up to high concentrations
Stability	Unopened kits: 2 months (specified conditions), 1 year (long-term storage)	Unopened kits: 2 months (specified conditions), 1 year (long-term storage)	Unopened kits: through last day of month on product label	Comparable or better shelf life
Method Comparison (Qualitative Agreement)
IMMULITE BR-MA vs. Kit A (Positive Agreement)	94.9%	N/A	N/A	High positive agreement
IMMULITE BR-MA vs. Kit A (Negative Agreement)	85.2%	N/A	N/A	High negative agreement
IMMULITE BR-MA vs. Kit B (Positive Agreement)	94.0%	N/A	N/A	High positive agreement
IMMULITE BR-MA vs. Kit B (Negative Agreement)	87.7%	N/A	N/A	High negative agreement
IMMULITE 2000 BR-MA vs. Kit A (Positive Agreement)	N/A	94.1%	N/A	High positive agreement
IMMULITE 2000 BR-MA vs. Kit A (Negative Agreement)	N/A	84.1%	N/A	High negative agreement
Clinical Performance
IMMULITE BR-MA - Recurrence (Agreement with Clinical Status)	81%	N/A	N/A	High agreement (e.g., >80% described as 'accurate')
IMMULITE BR-MA - Recurrence (Sensitivity)	72% (59-83% CI)	N/A	N/A	Clinically acceptable sensitivity
IMMULITE BR-MA - Recurrence (Specificity)	84% (79-88% CI)	N/A	N/A	Clinically acceptable specificity
IMMULITE BR-MA - Treatment Response (Agreement with Clinical Status)	66%	N/A	N/A	Clinically acceptable agreement
IMMULITE BR-MA - Treatment Response (Sensitivity)	74% (68-79% CI)	N/A	N/A	Clinically acceptable sensitivity
IMMULITE BR-MA - Treatment Response (Specificity)	57% (35-77% CI)	N/A	N/A	Clinically acceptable specificity
IMMULITE 2000 BR-MA - Recurrence (Agreement with Clinical Status)	N/A	80%	N/A	High agreement (e.g., >80% described as 'accurate')
IMMULITE 2000 BR-MA - Recurrence (Sensitivity)	N/A	75% (58-88% CI)	N/A	Clinically acceptable sensitivity
IMMULITE 2000 BR-MA - Recurrence (Specificity)	N/A	76% (66-85% CI)	N/A	Clinically acceptable specificity
IMMULITE 2000 BR-MA - Treatment Response (Agreement with Clinical Status)	N/A	80%	N/A	Clinically acceptable agreement
IMMULITE 2000 BR-MA - Treatment Response (Sensitivity)	N/A	85% (74-92% CI)	N/A	Clinically acceptable sensitivity
IMMULITE 2000 BR-MA - Treatment Response (Specificity)	N/A	50% (1-99% CI)	N/A	Clinically acceptable specificity

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

Method Comparison Studies (Test Sets):
- IMMULITE BR-MA vs. Kit A: 1400 specimens (healthy females, pregnant women, and female patients with breast cancer, malignant and nonmalignant diseases).
  - Restricted to working range (1307 specimens): For linear regression.
  - Provenance: Two clinical sites in the northeastern and southern United States. Retrospective (implied, as specimens are "evaluated").
- IMMULITE BR-MA vs. Kit B: 181 specimens (unknown characteristics beyond being used for comparison).
  - Restricted to working range (157 specimens): For linear regression.
  - Provenance: Clinical study conducted in the southern United States. Retrospective (implied).
- IMMULITE 2000 BR-MA vs. Kit A: 500 specimens (healthy females, pregnant women, and female patients with breast cancer, malignant and nonmalignant diseases).
  - Restricted to working range (447 specimens): For linear regression.
  - Provenance: One clinical site in the northeastern United States. Retrospective (implied).
- IMMULITE 2000 BR-MA vs. IMMULITE BR-MA: 466 specimens (subset from the IMMULITE 2000 BR-MA vs. Kit A study, within working range).
  - Provenance: Northeastern United States (same site as IMMULITE 2000 BR-MA vs. Kit A). Retrospective (implied).
Clinical Performance Studies (Test Sets):
- IMMULITE BR-MA:
  - Patients for recurrence: 99 breast cancer patients (serial samples). Total of 294 specimens tested for comparison with clinical status.
  - Patients for response to treatment: 80 breast cancer patients (serial samples). Total of 282 specimens tested for comparison with clinical status.
  - Provenance: Two clinical studies in the northeastern and southern United States. Retrospective (implied, as historical clinical status is compared).
- IMMULITE 2000 BR-MA:
  - Patients for recurrence: 35 breast cancer patients (serial samples). Total of 121 specimens tested for comparison with clinical status.
  - Patients for response to treatment: 15 breast cancer patients (serial samples). Total of 67 specimens tested for comparison with clinical status.
  - Provenance: One clinical study in the northeastern United States. Retrospective (implied).

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

The document does not specify the number of experts or their qualifications for establishing ground truth.

For the method comparison studies, the ground truth for the test set is effectively the measurement obtained from the comparator "Kit A" or "Kit B", which are commercially available and presumably validated immunoassays. No human expert interpretation of the comparator results is explicitly mentioned.

For the clinical performance studies, the ground truth is "clinical status" and "clinical history." The document states that IMMULITE BR-MA/2000 BR-MA results were "compared with the clinical history of these patients." It does not specify the number of clinicians or the process for determining this "clinical status." The "NED (No Evidence of Disease)" and "Active" status would have been determined by treating physicians based on standard clinical assessments (imaging, physical exams, symptoms, etc.).

4. Adjudication Method for the Test Set

Not applicable. The ground truth for the method comparison studies is the result from the comparator assay; there's no mention of adjudication between multiple assay results. For the clinical performance studies, the ground truth is the "clinical status," which would be a physician's assessment based on multiple factors, but no explicit adjudication process involving multiple independent experts for this clinical status is described.

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

No. This document describes the performance of an in vitro diagnostic immunoassay, not an imaging device or AI-assisted diagnostic tool that would typically involve human readers interpreting cases. Therefore, an MRMC comparative effectiveness study involving human readers with/without AI assistance is not applicable and was not performed.

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

Yes, the entire study is essentially a standalone performance evaluation of the IMMULITE BR-MA and IMMULITE 2000 BR-MA devices (which are immunoassays, not algorithms in the typical AI sense). The device measures CA 15-3 antigen levels quantitatively. Its performance is assessed inherently as a "device only" performance against reference methods or clinical outcomes. There is no human interpretation of the assay result that is then improved or augmented by an algorithm. The device provides a quantitative number, and that number is then used in conjunction with other clinical methods by a human clinician.

7. The Type of Ground Truth Used

Analytical Performance Studies: The ground truth for these characteristics (e.g., precision, sensitivity, linearity) is based on established laboratory testing methodologies and reference materials.
Method Comparison Studies: The ground truth is primarily the results obtained from legally marketed predicate or comparator immunoassays (Kit A, Kit B).
Clinical Performance Studies: The ground truth is the "clinical status" and "clinical history" of breast cancer patients, determined by established clinical diagnostic and monitoring procedures. This would include patient outcomes data (e.g., recurrence, response to treatment) as assessed by treating clinicians.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. These devices are immunoassay kits, not AI algorithms that undergo a distinct training phase. Their development involves R&D and validation but not "training data" in the AI sense.

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

Not applicable, as there is no "training set" in the typical AI sense for these immunoassay devices. The ground truth for their development and validation would be established through standard immunoassay development practices, including analytical characterization against known standards and evaluation against clinical samples with confirmed diagnoses.

Summary

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K013984

510 (k) Summary of Safety and Effectiveness IMMULITE® and IMMULITE® 2000 BR-MA

This summary of 510(k) safety and effectiveness information is being submitted in Inis sammal y of broke visements of SMDA 1990 and 21 CFR Part 807.92.

Name:Address:	Diagnostic Products Corporation5700 West 96th StreetLos Angeles, California 90045
Telephone Number:	(310) 645-8200
Contact Person	Edward M. Levine, Ph.D.
Date of Preparation:	March 22, 2002
Catalog Number:	LKBR1, LKBR5 (100, 500 tests)L2KBR2 (200 tests)
Device NameTrade:	IMMULITE® BR-MA andIMMULITE® 2000 BR-MA
Common:	Reagent system for the determination of CA15-3 antigen inserum.
Classification:	MOI, Class II device
Manufacturer ofIMMULITE BR-MA:	Euro/DPC LimitedGlyn RhonwyLlanberis, Gwynedd LL55 4ELUnited Kingdom(Manufactured under a Quality System-ISO9002/ISO13488/EN46002)
Sole U. S. Importer ofIMMULITE BR-MA:	Diagnostic Products Corporation5700 West 96th StreetLos Angeles, CA 90045-5597
Manufacturer ofIMMULITE 2000 BR-MA:	Diagnostic Products Corporation5700 West 96th StreetLos Angeles, CA 90045-5597(Manufactured under a Quality System-ISO9001/21CFR,Part 820/EN46001)

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Establishment Registration #: Euro/DPC - Not applicable DPC Registration number is 2017183

Substantially Equivalent Predicate Devices:

Baver Immuno 17M CA 15-3TM (K964703) Chiron ACS 180 BR (CA27.29)

Description of Device:

Intended Use of the Device:

IMMULITE BR-MA and IMMULITE 2000 BR-MA are clinical use devices intended for in vitro diagnostic use with IMMULITE analyzer - for the quantitative measurement of CA 15-3 antigen in human serum, as an aid in the detection of recurrence in previously treated stage II and stage III breast cancer patients, and in the management of metastatic breast cancer patients by monitoring disease progression or response to treatment. Serial testing for patient CA 15-3 values should be used in conjunction with other clinical methods used for detecting early recurrence in Stage II and stage IIII disease and for monitoring response to treatment in patients with metastatic breast cancer.

Summary and Explanation of the Test:

CA 15-3 is a high molecular weight (300 to 450 kDa) polymorphic epithelial mucin. The heterogeneous breast cancer associated mucins consist of a repeated polypeptide core sequence and an outer shell of carbohydrate. Serum CA 15-3 values increase with clinical stage of breast cancer, the highest values occurring in metastatic disease. Serial determinations of CA 15-3 are most useful as an indicator of response to therapy. The measurement of CA 15-3 antigen is more sensitive and specific than the determination of carcinoembryonic antigen (CEA), having a lower percentage positivity with benign breast lesions, liver cirrhosis and other carcinomas -- 99.9% of serum donated by healthy volunteers contained less than 40 U/mL of CA 15-3 is not elevated during pregnancy. The percentage of raised values found in breast cancer can be as high as 98%, but this depends primarily on the tumor stage of the patient population studied. Elevated levels have also been found in patients with lung cancer (63%) and ovarian cancer (80%).

IMMULITE BR-MA and IMMULITE 2000 BR-MA are two-step sequential chemiluminescent enzyme immunoassays, based on ligand-labeled monoclonal antibody and separation by anti-ligand-coated solid phase.

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Performance Equivalence - Technology Comparison:

IMMULITE BR-MA is a chemiluminescent enzyme immunoassay and Immuno 1 CA 15-3 is a magnetic separation assay. The technology in DPC's IMMULITE BR-MA and IMMULITE 2000 BR-MA is identical to technology used in previously cleared and commercially marketed IMMULITE and IMMULITE 2000 products.

IMMULITE BR-MA is a two-step sequential chemiluminescent enzyme-labeled immunometric assay, based on ligand-labeled monoclonal antibody and separation by anti-ligand-coated solid phase. The patient sample and a ligand-labeled anti-CA15-3 monoclonal antibody are simultaneously introduced into the Test Unit, containing immobilized anti-ligand, and incubated for approximately 30 minutes at 37℃ with intermittent agitation. During this time, CA 15-3 antigen in the sample binds to the ligand-labeled monoclonal antibody, which, in turn, binds to the anti-ligand on the solid phase. Unbound serum is then removed by centrifugal wash. An alkaline phosphataselabeled anti-CA 15-3 monoclonal antibody is introduced, and the Test Unit is incubated for another 30-minute cycle. The unbound enzyme conjugate is removed by a centrifugal wash. Substrate is then added, and the Test Unit is incubated for a further 10 minutes.

The chemiluminescent substrate, a phosphate ester of adamantyl dioxetane, undergoes hydrolysis in the presence of alkaline phosphatase to yield an unstable intermediate. The continuous production of this intermediate results in the sustained emission of light, thus improving precision by providing a window for multiple readings. The bound complex and thus also the photon output, as measured by the luminometer - is proportional to the concentration of CA 15-3 in the sample.

IMMULITE 2000 BR-MA is a two-step sequential chemiluminescent enzyme-labeled immunometric assay, based on ligand-labeled monoclonal antibody and separation by anti-ligand-coated solid phase. The patient sample and a ligand-labeled anti-CA15-3 monoclonal antibody are simultaneously introduced into the Reaction Tube, containing immobilized anti-ligand, and incubated for approximately 30 minutes at 37°C with intermittent agitation. During this time, CA 15-3 antigen in the sample binds to the ligand-labeled monoclonal antibody, which, in turn, binds to the anti-ligand on the solid phase. Unbound serum is then removed by centrifugal wash. An alkaline phosphataselabeled anti-CA 15-3 monoclonal antibody is introduced, and the Reaction Tube is incubated for another 30-minute cycle. The unbound enzyme conjugate is removed by a centrifugal wash. Substrate is then added, and the Test Unit is incubated for a further 5 minutes.

The chemiluminescent substrate, a phosphate ester of adamantyl dioxetane, undergoes hydrolysis in the presence of alkaline phosphatase to vield an unstable intermediate. The continuous production of this intermediate results in the sustained emission of light, thus improving precision by providing a window for multiple readings. The bound complex and thus also the photon output, as measured by the luminometer - is proportional to the concentration of CA 15-3 in the sample.

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The Bayer Immuno 1 CA 15-3 Assay uses a sandwich immunoassay format. 115D8 Antibody Conjugate (R1) and mIMP® (monoclonal ImmunoMagnetic Particle) Reagent are reacted with patient sample (or calibrator containing CA 15-3 reactive determinants) and incubated on the system at 37°C. The DF3 Enzyme Conjugate (R2) is then added. A second incubation occurs during which the antibody complex is bound. After incubation, the complex is washed and the pNPP (para-nitrophenyl phosphate) substrate is added. The alkaline phosphatase (ALP) in the antibody conjugate reacts with the pNPP to form para-nitrophenoxide and phosphate. Increasing absorbance, due to the formation of paranitrophenoxide, is monitored at 405 nm and 450 nm.

A sample have no CA 15-3 Assay value will have the minimum label bound, while a sample having a high CA 15-3 Assay value will have maximum label bound. Thus, the dose response curve is proportional to the DF3 reactive determinants in the sample.

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Performance Equivalence - Performance Characteristics:

Characteristics	IMMULITE BR-MA	IMMULITE 2000BR-MA	Immuno 1CA 15-3
Calibration upper limit	300 U/mL	300 U/mL	200 U/mL
Analytical Sensitivity	0.2 U/mL	0.2 U/mL	0.2 U/mL
Precision (within-run)	CV range: 5.5-8.1%	CV range: 3.7-4.9%	CV range: 1.3-3.4%
Precision (total)	CV range: 7.4-8.8%	CV range: 4.5-6.5%	CV range: 3.0-4.0%
Specificity	No significant cross-reactivity with thefollowing compounds5-Fluorouracil, AFP,CA 125, CA 19-9,CEA, Cisplatin,Cyclophosphamide,Doxorubicin,hydrochloride,Mitomycin C,Vincristine	No significant cross-reactivity with thefollowing compounds5-Fluorouracil, AFP,CA 125, CA 19-9,CEA, Cisplatin,Cyclophosphamide,Doxorubicin,hydrochloride,Mitomycin C,Vincristine	Data not available
Linearity	%Observed/Expectedrange: 95-105%	%Observed/Expectedrange: 93-104%	Data not available
Spiking Recovery	%Observed/Expectedrange:89-114%	%Observed/Expectedrange:92-108%	Data not available
Effect of Bilirubin(unconjugated)	No significant effect	No significant effect	No clinically significanteffect
Effect of Lipemia	No significant effect	No significant effect	No clinically significanteffect
Effect of Hemolysis	No significant effect	No significant effect	No clinically significanteffect
High Dose Hook Effect	No effect up to 80,000U/mL	No effect up to 80,000U/mL	Data not available
Stability	Unopened kits keptat specifiedconditions are stablefor 2 months. Kitsare stable for oneyear when kept inlong-term storage	Unopened kits kept atspecified conditionsare stable for 2months. Kits arestable for one yearwhen kept in long-term storageconditions.	Unopened kits kept atspecified conditions arestable through the lastday of the month on theproduct label. Long-term stability data notavailable.

The information in the table below provides the performance characteristics of IMMULITE and IMMULITE 2000 BR-MA and Immuno 1 CA 15-3.

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Performance Equivalence - Method Comparison (Breast Cancer Patients and Healthy Subjects):

IMMULITE BR-MA

The IMMULITE BR-MA assay was compared to Kit A, a commercially available immunoassay that also measured CA 15-3, at two clinical sites in the northeastern and southern United States. A total of 1400 specimens from apparently healthy female subjects and pregnant women, and female patients with breast cancer, malignant and nonmalignant diseases, were evaluated at the two clinical sites. Using the 95th percentile of the normal reference ranges of the two assays (38 U/mL for IMMULITE BR-MA and 34.8 U/mL for Kit A), a qualitative comparison of the IMMULITE BR-MA and Kit A yielded the following results.

IMMULITE BR-MA		PositiveAgreement	NegativeAgreement
Kit A	> 38 U/mL ≤ 38 U/mL
> 34.8 U/mL	334 18	94.9%	85.2%
≤ 34.8 U/mL	153 895

Agreement: 87.8%

95% Confidence Limits for positive agreement and negative agreement, respectively: 92.0% - 96.9% and 83.3% - 87.5%.

The CA 15-3 measurements of 1307 specimens that fell within the working range of both assays (300 U/mL for IMMULITE BR-MA and 200 U/mL for Kit A) were compared in a linear regression:

IMMULITE BR-MA = 1.08 (Kit A) + 8.34 r = 0.79

95% Confidence Intervals: Slope: 1.04, 1.13 Intercept: 6.53, 10.2

Means:

39.4 U/mL (IMMULITE BR-MA) 28.7 U/mL (Kit A)

In the clinical study conducted in the southern United States, measurements of CA 15-3 by IMMULITE BR-MA were compared to measurements by Kit B, a commercially available chemiluminescence assay for CA 27-29 on 181 specimens using the respective normal range upper limits of the two assays as the cutoff (38 U/mL for IMMULITE BR-MA and 38.6 U/mL for Kit B).

	IMMULITE BR-MA		PositiveAgreement	NegativeAgreement
Kit B	> 38 U/mL	≤ 38 U/mL
> 38.6 U/mL	63	4	94.0%	87.7%
≤ 38.6 U/mL	14	100

90.1% Agreement:

95% Confidence Limit for positive agreement: 85.4% - 98.4% 95% Confidence Limit for negative agreement: 80.3% - 93.1%

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A subset of the specimens (n=157) within the working ranges of both assays were compared in a linear regression:

IMMULITE BR-MA = 0.86 (Kit B) + 10.4 U/mL r = 0.95 95% Confidence Intervals: 0.82, 0.91 Slope: Slope: Intercept: 7.61. 13.2

Means:

49.1 U/mL (IMMULITE BR-MA) 44.8 U/mL (Kit B)

IMMULITE 2000 BR-MA

The IMMULITE 2000 BR-MA assay was compared to Kit A, a commercially available immunoassay that also measured CA 15-3, at one clinical site in the northeastern United States. A total of 500 specimens from apparently healthy female subjects and pregnant women, and female patients with breast cancer, malignant and nonmalignant dieseases, were evaluated at this clinical site. Using the 95th percentile of the normal reference were cranated at this entired. Cor IMMULITE 2000 BR-MA and 34.8 U/mL for Kit A), a qualitative comparison of the IMMULITE BR-MA and Kit A yielded the following results.

IMMULITE 2000 BR-MA			PositiveAgreement	NegativeAgreement
Kit A	> 38 U/mL	≤ 38 U/mL
> 34.8 U/mL	128	8	94.1%	84.1%
≤ 34.8 U/mL	58	306

Agreement: 86.8%

95% Confidence Limits for positive agreement and negative agreement, respectively: 88.7% - 97.4% and 80.3% - 87.8%.

The CA 15-3 measurements of 447 specimens that fell within the working range of both assays (300 U/mL for IMMULITE 2000 BR-MA and 200 U/mL for Kit A) were compared in a linear regression:

IMMULITE 2000 BR-MA = 1.04 (Kit A) + 7.66 r = 0.85

95% Confidence Intervals: Slope: 0.98. 1.10 Intercept: 5.37, 9.95 Means: 37.2 U/mL (IMMULITE 2000 BR-MA) 28.4 U/mL (Kit A)

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In the same study, IMMULITE 2000 BR-MA was compared to IMMULITE BR-MA in a linear regression for 466 specimens that fell within the working range of both assays:

IMMULITE 2000 BR-MA = 1.02 (IMMULITE BR-MA) + 0.90 r = 0.99

95% Confidence Intervals: Slope: 1.01, 1.04 Intercept: 0.04, 1.76

Means:

42.8 U/mL (IMMULITE BR-MA) 44.7 U/mL (IMMULITE 2000 BR-MA)

Clinical Performance:

In two clinical studies conducted in the northeastern and southern United States, serial samples from 99 breast cancer patients followed for recurrence and 80 patients followed for response to treatment were tested by IMMULITE BR-MA and compared with the clinical history of these patients.

An analysis of these cases considered IMMULITE /IMMULITE 2000 BR-MA as consistent, inconsistent, or equivocal with clinical status if over half, less than half, or exactly half of the specimens tested for a case agreed with the clinical status.

IMMULITE BR-MA measurements accurately reflected the changes in the clinical status in 80 of the 99 (81%) patients followed for recurrence. Of the remainder, 13 (13%) did not parallel the clinical status, and 6 of the 99 (6%) were equivocal as to whether CA 15-3 reflected the clinical status.

For all 294 specimens from patients followed for recurrence, the IMMULITE BR-MA measurements were compared with the clinical status of the breast cancer patients:

ClinicalStatus	IMMULITE>38 U/mL	<=38 U/mL
Active	41	16
NED*	39	198
Agreement 81%
Sensitivity (95% CI): 72% (59-83%)
Specificity (95% CI): 84% (79-88%)
PPV* (95% CI): 51% (40-63%)
NPV* (95% CI): 93% (88-96%)

For patients followed for response to treatment, IMMULITE BR-MA measurements accurately reflected the changes in the clinical status in 53 of the 80 (66%) patients. Of

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the remainder, 19 (24%) did not parallel the clinical status, and 8 (10%) were equivocal as to whether CA 15-3 reflected the clinical status.

For all 282 specimens from patients followed for response to treatment, the IMMULITE BR-MA measurements were compared with the clinical status of the breast cancer patients:

ClinicalStatus	>38 U/mL	<=38 U/mL
Active	191	68
NED*	10	13
Agreement: 72%
Sensitivity (95% CI): 74% (68-79%)
Specificity (95% CI): 57% (35-77%)
PPV* (95% CI): 95% (91-98%)
NPV* (95% CI): 16% (9-26%)

IMMULITE 2000 BR-MA achieved similar results in one clinical study conducted in the northeastern United States. Serial samples from 35 breast cancer patients followed for recurrence and 15 patients followed for response to treatment were tested by IMMULITE 2000 BR-MA and compared with the clinical history of these patients.

IMMULITE 2000 BR-MA measurements accurately reflected the changes in the clinical status in 28 of the 35 (80%) patients followed for recurrence. Of the remainder, 3 (9%) did not parallel the clinical status, and 4 (11%) were equivocal as to whether CA 15-3 reflected the clinical status.

For all 121 specimens from patients followed for recurrence, the IMMULITE 2000 BR-MA measurements were compared with the clinical status of the breast cancer patients:

ClinicalStatus	IMMULITE 2000>38 U/mL	<=38 U/mL
Active	27	9
NED*	20	65
Agreement: 76%
Sensitivity (95% CI): 75% (58-88%)
Specificity (95% CI): 76% (66-85%)
PPV* (95% CI): 57% (42-72%)
NPV* (95% CI): 88% (78-94%)

For patients followed for response to treatment, IMMULITE 2000 BR-MA measurements accurately reflected the changes in the clinical status in 12 of the 15 (80%)

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patients. Of the remainder, 1 (7%) did not parallel the clinical status, and 2 (13%) were equivocal as to whether CA 15-3 reflected the clinical status.

For all 67 specimens from patients followed for response to treatment, the IMMULITE 2000 BR-MA measurements were compared with the clinical status of the breast cancer patients:

ClinicalStatus	>38 U/mL	<=38 U/mL
Active	55	10
NED*	1	1
Agreement: 84%
Sensitivity (95% CI): 85% (74-92%)
Specificity (95% CI): 50% (1-99%)
PPV* (95% CI):	98% (91-100%)
NPV* (95% CI):	9% (0-41%)
* NED - No Evidence of Disease

PPV - Positive Predictive Value

NPV - Negative Predictive Value

Representative profiles of patients followed for recurrent breast cancer and for response to treatment are shown in the following figures.

Monitoring of a stage II (in May 1988) breast cancer patient with IMMULITE BR-MA (CA 15-3). Longitudinal changes in IMMULITE BR-MA values correlate with changes in disease status.

Image /page/9/Figure/7 description: The figure is a line graph showing the levels of IMMULITE BR-MA (U/mL) over time. The x-axis represents the date, and the y-axis represents the IMMULITE BR-MA levels. The graph shows that the levels were low from 7/27/90 to 7/24/92, and then increased significantly between 7/24/92 and 11/28/94, reaching a level of approximately 1100 U/mL.

Date	U/mL	Disease Status
7/27/90	31.8	CT scan chest - negative, unchanged since 1988.
1/25/91	30.2	Ct scan chest - no evidence of metastasis.
7/24/92	37.7	Total body scan-increased tracer activity, highly suspicious for metastasis.
5/10/94	478	CT abd, pelvis - Multiple fine nodular radiodensities in lungs.
11/28/94	1092	CT chest-small bilateral pleural effusions.

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Monitoring of a stage IV (in December 1989) breast cancer patient with IMMULITE BR-MA (CA 15-3). Longitudinal changes in IMMULITE BR-MA values correlate with changes in disease status and treatment.

Image /page/10/Figure/1 description: The figure shows a line graph of IMMULITE BR-MA/(U/mL) over time. The x-axis shows the date, and the y-axis shows the IMMULITE BR-MA/(U/mL). The graph shows that the IMMULITE BR-MA/(U/mL) starts at around 55 on 4/1/92, decreases to around 30 on 6/3/92, and then increases to around 190 on 12/10/92.

Date	U/mL	Disease Status
4/1/92	55.2	Radiation therapy 4/91 to 10/91.
5/6/92	33.1	CT showed multiple metastasis, decreasing in number and size.
6/3/92	28.0	Chemo-VAT (Virablastin, Adriamycin, Thiotepa).
7/8/92	29.6	Chest X-Ray pos; Abdominal, pelvis areas no change, stable.
10/23/92	111	Bone scan showed bone metastasis. CT scan showed markedincrease in liver metastasis.
12/10/92	185	Terminal breast cancer.

Monitoring of a stage II (in May 1988) breast cancer patient with IMMULITE 2000 BR-MA (CA 15-3). Longitudinal changes in IMMULITE 2000 BR-MA values correlate with changes in disease status

Image /page/10/Figure/4 description: This image is a line graph showing the levels of IMMULITE 2000 BR-MA (U/mL) over time. The x-axis represents the date, and the y-axis represents the levels of IMMULITE 2000 BR-MA (U/mL). The graph shows that the levels of IMMULITE 2000 BR-MA (U/mL) were relatively low between 7/27/90 and 7/24/92, but then increased significantly between 5/10/94 and 11/28/94, reaching a level of approximately 1400 U/mL.

Date	U/mL	Disease Status
7/27/90	33.1	CT scan chest - negative, unchanged since 1988.
1/25/91	36.5	Ct scan chest - no evidence of metastasis.
7/24/92	38.9	Total body scan-increased tracer activity, highly suspicious for metastasis.
5/10/94	457	CT abd, pelvis - Multiple fine nodular radiodensities in lungs.
11/28/94	1426	CT chest-small bilateral pleural effusions.

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Monitoring of a stage IV (in December 1989) breast cancer patient with IMMULITE 2000 BR-MA (CA 15-3). Longitudinal changes in IMMULITE 2000 BR-MA values correlate with changes in disease status and treatment.

Image /page/11/Figure/1 description: This figure shows a plot of IMMULITE 2000 BR-MA (U/mL) vs. Date. The x-axis shows the date, and the y-axis shows the IMMULITE 2000 BR-MA (U/mL). The plot shows that the IMMULITE 2000 BR-MA (U/mL) decreases from 4/1/92 to 6/3/92, then increases from 7/8/92 to 12/10/92. The values range from approximately 30 to 190 U/mL.

Date	U/mL	Disease Status
4/1/92	58.1	Radiation therapy 4/91 to 10/91.
5/6/92	35.8	CT showed multiple metastasis, decreasing in number and size.
6/3/92	30.3	Chemo-VAT (Virablastin, Adriamycin, Thiotepa).
7/8/92	32.7	Chest X-Ray pos; Abdominal, pelvis areas no change, stable.
10/23/92	115	Bone scan showed bone metastasis. CT scan showed markedincrease in liver metastasis.
12/10/92	189	Terminal breast cancer.

Conclusion:

The conclusions drawn from the clinical and nonclinical studies demonstrate that the device is safe, effective, and is substantially equivalent to the current legally marketed device.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/12/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three heads facing to the right. The eagle is surrounded by a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" written around it.

MAR 2 8 2002

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Edward M. Levine, Ph.D. Director of Clinical Affairs Diagnostic Products Corporation 5700 West 96th Street Los Angeles. California 90045-5597

Re: K013984

Trade/Device Name: IMMULITE® BR-MA and IMMULITE® 2000 BR-MA Regulation Number: 21 CFR § 866.6010 Regulation Name: Tumor Associated Antigen Immunological Test System Regulatory Class: II Product Code: MOI Dated: March 4, 2002 Received: March 5, 2002

Dear Dr. Levine:

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.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), 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 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 Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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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 International and Consumer 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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510(k) Number (if known): K013984 Device Name: IMMULITE® BR-MA IMMULITE® 2000 BR-MA

Indications For Use:

IMMULITE BR-MA

For in vitro diagnostic use with IMMULITE analyzer – for the quantitative measurement of CA 15-3 antigen in human serum, as an aid in the detection of recurrence in previously treated stage II and stage III breast cancer patients, and in the management of metastatic breast cancer patients by monitoring disease progression or response to treatment. Serial testing for patient CA 15-3 values should be used in conjunction with other clinical methods used for detecting early recurrence in Stage II and Stage III disease and for monitoring response to treatment in patients with metastatic breast cancer.

IMMULITE 2000 BR-MA

For in vitro diagnostic use with IMMULITE 2000 analyzer – for the quantitative measurement of CA 15-3 antigen in human serum, as an aid in the detection of recurrence in previously treated stage II and stage III breast cancer patients, and in the management of metastatic breast cancer patients by monitoring disease progression or response to treatment. Serial testing for patient CA 15-3 values should be used in conjunction with other clinical methods used for detecting early recurrence in Stage II and Stage III disease and for monitoring response to treatment in patients with metastatic breast cancer.

Division Sign-Off Division of Clinical Laboratory Devices

510(k) Number Ko 13984

(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

§ 866.6010 Tumor-associated antigen immunological test system.

(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.