K Number

Device Name

PLATELIA ASPERGILLUS EIA, MODELS 62793 AND 62794

Manufacturer

BIO-RAD

Date Cleared

2003-05-16

(177 days)

Product Code

NOM

Regulation Number

866.3040

Intended Use

The Platelia® Aspergillus EIA is an immunoenzymatic sandwich microplate assay for the detection of Aspergillus galactomannan antigen in serum. The Platelia® Aspergillus EIA is a test which, when used in conjunction with other diagnostic procedures such as microbiological culture, histological examination of biopsy samples and radiographic evidence, can be used as an aid in the diagnosis of invasive aspergillosis.

Device Description

The Platelia Aspergillus EIA is a one-stage immunoenzymatic sandwich microplate assay which detects galactomannan in human serum. The assay uses the rat monoclonal antibody EBA-2, which is directed antibody is used: to coat the wells of the microplate and bind the antigen, and as the detector antibody in the conjugate reagent (peroxidase-linked monoclonal antibody). Serum samples are heat-treated in the presence of EDTA in order to dissociate immune-complexes and to precipitate serum proteins that could possibly interfere with the test. The treated serum samples and conjugate are added to the wells coated with monoclonal antibody, and incubated. A monoclonal antibody - galactomannan - monoclonal antibody / peroxidase complex is formed in the presence of Aspergillus antigen. The strips are washed to remove any unbound material. Next, the substrate solution is added, which will react with the complexes bound to the well to form a blue color reaction. The enzyme reaction is stopped by the addition of acid, which changes the blue color to yellow. The optical absorbance of specimens and controls is determined with a spectrophotometer set at 450 and 620/630 nm wavelength.

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Center

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Device Name

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Third Party Reviewed

Expedited Review

Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description details a standard immunoenzymatic assay process, and there is no mention of AI, ML, or any computational analysis beyond reading optical absorbance values.

Therapeutic

No
The device is an in vitro diagnostic test used as an aid in diagnosing invasive aspergillosis by detecting galactomannan antigen in serum, rather than directly treating or mitigating a disease.

Diagnostic

Yes

The "Intended Use / Indications for Use" section explicitly states that the device "can be used as an aid in the diagnosis of invasive aspergillosis."

SaMD (Software as a Medical Device)

The device description clearly outlines a physical immunoenzymatic assay kit involving reagents, microplates, and a spectrophotometer for analysis, which are hardware components.

IVD (In Vitro Diagnostic)

Based on the provided information, the Platelia® Aspergillus EIA is indeed an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The intended use explicitly states it's an "immunoenzymatic sandwich microplate assay for the detection of Aspergillus galactomannan antigen in serum" and is used "as an aid in the diagnosis of invasive aspergillosis." This clearly indicates it's a test performed in vitro (outside the body) on a biological sample (serum) to provide diagnostic information.
Device Description: The description details a laboratory assay process involving serum samples, reagents, microplates, and a spectrophotometer to detect an analyte (galactomannan antigen). This is characteristic of an in vitro diagnostic test.
Performance Studies: The document describes clinical testing using patient serum samples to evaluate the device's performance (sensitivity, specificity, predictive value) in diagnosing a specific condition (invasive aspergillosis). This is a standard requirement for demonstrating the clinical utility of an IVD.
Predicate Device: The mention of a "Predicate Device" (Meridian Premier Cryptococcal Antigen) is common in regulatory submissions for IVDs, where a new device is compared to a previously cleared device of a similar type.

Therefore, all the key elements point to the Platelia® Aspergillus EIA being an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Platelia® Aspergillus EIA is an immunoenzymatic sandwich microplate assay for the detection of Aspergillus galactomannan antigen in serum.

The Platelia® Aspergillus EIA is a test which, when used in conjunction with other diagnostic procedures such as microbiological culture, histological examination of biopsy samples and radiographic evidence, can be used as an aid in the diagnosis of invasive aspergillosis.

Product codes (comma separated list FDA assigned to the subject device)

NOM

Device Description

Serum samples are heat-treated in the presence of EDTA in order to dissociate immune-complexes and to precipitate serum proteins that could possibly interfere with the test. The treated serum samples and conjugate are added to the wells coated with monoclonal antibody, and incubated. A monoclonal antibody - galactomannan - monoclonal antibody / peroxidase complex is formed in the presence of Aspergillus antigen. The strips are washed to remove any unbound material. Next, the substrate solution is added, which will react with the complexes bound to the well to form a blue color reaction. The enzyme reaction is stopped by the addition of acid, which changes the blue color to yellow. The optical absorbance of specimens and controls is determined with a spectrophotometer set at 450 and 620/630 nm wavelength.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Not Found

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

Not Found

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

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

A. Reproducibility Studies
Inter-assay and Intra-assay variability for the Platelia® Aspergillus EIA were determined in a study using a panel of 6 pooled patient serum samples (one negative, one low positive, two positive, and two high positive) obtained from actual clinical trial sites. Each of the 6 panel members were tested in triplicate (x3) on 3 different days, on 1 lot, at 2 sites (total number of replicates at each site = 9). Each of the 6 panel members was tested in duplicate (x2) on 3 different days, on I lot, at a third site (total number of replicates at the third site = 6). One (1) operator performed all precision testing at each site.
B. Cross Reactivity
A study to evaluate the effect of potentially interfering medical conditions unrelated to Invasive Aspergillosis was performed with one lot of the Platelia® Aspergillus EIA kit. A total of 151 sera were tested. No positives were found for any of the pathologies tested (Rheumatoid Factor, ANA Positive, IgG Hypergammaglobulinemia, IgM Hypergammaglobulinemia, Cancer, Non-Viral Cirrhosis, Multiple Transfusions, Multiparous Females, HAV, HCV, Rubella, CMV, Syphilis (RPR+), Toxoplasmosis, Mycoplasma).
C. Clinical Testing
Clinical testing to evaluate the sensitivity, specificity, and predictive value of the Platelia® Aspergillus ELA was conducted at three sites located in the U.S. and Canada. The study was conducted retrospectively using a total of 1890 serum samples collected from 179 patients from the following populations:

patients without signs of Invasive Aspergillosis (control patients)
patients with probable Invasive Aspergillosis
patients with proven Invasive Aspergillosis

Sensitivity:

Proven Aspergillosis (N=11 patients, combined sites): Sensitivity: 81.8% (9 / 11).
Probable Aspergillosis (N=20 patients, combined sites): Sensitivity: 80.0% (16 / 20).
Combined Proven and Probable Aspergillosis (N=31 patients, combined sites): Sensitivity: 80.7% (25 / 31). The 95% confidence interval is 64.0 -- 97.3%.

Specificity:
Tested on 1362 samples from 148 Bone Marrow Transplant (BMT) and Leukemia patients without signs of Invasive Aspergillosis.
Site 1 (N=33 patients): Specificity 81.8% (27/33), 95% CI 66.1 – 97.5%. After repeat testing: (31/33).
Site 2 (N=77 patients): Specificity 93.4% (71/77), 95% CI 87.1 – 99.8%. After repeat testing: (74/77).
Site 3 (N=38 patients): Specificity 89.5% (34/38), 95% CI 77.8 – 100%. After repeat testing: (38/38).
Combined Sites (N=148 patients): Specificity 89.2% (132/148), 95% CI 83.8 - 94.6%. After repeat testing: (143/148).

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Sensitivity:
Provenance Aspergillosis (N=11 patients): 81.8% (9/11)
Probable Aspergillosis (N=20 patients): 80.0% (16/20)
Combined Proven and Probable Aspergillosis (N=31 patients): 80.7% (25/31), 95% CI: 64.0 – 97.3%.

Specificity:
Site 1 (N=33 patients): 81.8% (27/33), 95% CI: 66.1 – 97.5%
Site 2 (N=77 patients): 93.4% (71/77), 95% CI: 87.1 – 99.8%
Site 3 (N=38 patients): 89.5% (34/38), 95% CI: 77.8 – 100%
Combined Sites (N=148 patients): 89.2% (132/148), 95% CI: 83.8 – 94.6%

Predictive Value (Actual Prevalence of 14%):
Patient: PPV 54.8 %, NPV 96.6 %
Patient after repeat testing: PPV 68.3 %, NPV 95.5 %

Predictive Value (Calculated Prevalence of 5%):
Patient: PPV 12.5 %, NPV 96.0 %
Patient after repeat testing: PPV 31.3 %, NPV 96.3 %

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

Meridian Premier Cryptococcal Antigen

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 866.3040

Aspergillus spp. serological reagents.(a)
Identification. Aspergillus spp. serological reagents are devices that consist of antigens and antisera used in various serological tests to identify antibodies toAspergillus spp. in serum. The identification aids in the diagnosis of aspergillosis caused by fungi belonging to the genusAspergillus. Aspergillosis is a disease marked by inflammatory granulomatous (tumor-like) lessions in the skin, ear, eyeball cavity, nasal sinuses, lungs, and occasionally the bones.(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 § 866.9.

Summary

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K023857

MAY 1 6 2003

ATTACHMENT I 510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is K023857.

DATE:	May 7, 2003
APPLICANT:	Bio-Rad

Boulevard Raymond Poincaré
92430 Marnes-la-Coquette, France |
| OFFICIAL CORRESPONDENT: | Dr. Sylvie Confida |
| TELEPHONE:
FAX: | 33-1-47-95-6138
33-1-47-95-6242 |
| PRODUCT TRADE NAME: | Bio-Rad Laboratories Platelia® Aspergillus EIA |
| COMMON NAME: | Aspergillus Antigen EIA |
| CLASSIFICATION NAME: | Aspergillus spp. serological reagents |
| PREDICATE DEVICE: | Meridian Premier Cryptococcal Antigen |

DEVICE DESCRIPTION

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INTENDED USE

The Platelia® Aspergillus EIA is an immunoenzymatic sandwich microplate assay for the detection of Aspergillus galactomannan antigen in serum.

INDICATIONS FOR USE

TECHNOLOGICAL CHARACTERISTICS

The following tables summarize similarities and differences between the Platelia® Aspergillus EIA and the Premier Cryptococcal Antigen EIA.

| Similarities in
Components / Materials | Platelia® Aspergillus EIA,
Catalog 62793 | Premier Cryptococcal Antigen EIA,
Catalog #602096 |
|-------------------------------------------|-------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|
| Microplate | 96 well microplate - antibody
coated microwells | 96 well microplate - antibody coated
microwells |
| Reagents | Conjugate, Wash Buffer,
Substrate, TMB Chromogen,
Sample Diluent, Positive Control,
Stop Solution. | Conjugate, Wash Buffer, Substrate,
TMB Chromogen, Sample Diluent,
Positive Control, Stop Solution. |

Table 1(a:) Similarities between reagents and materials

Table 1(b): Differences between reagents and materials

| Differences in
Components / Materials | Platelia® Aspergillus EIA,
Catalog 62793 | Premier Cryptococcal Antigen EIA,
Catalog #602096 |
|------------------------------------------|---------------------------------------------------------------|------------------------------------------------------|
| Reagents | Negative and Cut-Off Controls,
Specimen Treatment Solution | N/A |

Table 2(a): Similarities between reagents with regard to function and use

| Similarities in Function
and Use | Platelia® Aspergillus EIA,
Catalog 62793 | Premier Cryptococcal Antigen EIA,
Catalog #602096 |
|-------------------------------------|---------------------------------------------|------------------------------------------------------|
| Intended Use | Antigen detection | Antigen detection |

Table 2(b): Differences between reagents with regard to function and use

| Differences in Function
and Use | Platelia® Aspergillus EIA,
Catalog 62793 | Premier Cryptococcal Antigen EIA,
Catalog #602096 |
|------------------------------------|-------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| Intended Use | Qualitative detection of
Aspergillus galactomannan
antigen. | Qualitative and semi-quantitative
detection of Cryptococcal neoformans
capsular polysaccharide antigens. |
| Matrices | Serum | Serum and cerebrospinal fluid |

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PERFORMANCE SUMMARY

A. Reproducibility Studies

Inter-assay and Intra-assay variability for the Platelia® Aspergillus EIA were determined in a study using a panel of 6 pooled patient serum samples (one negative, one low positive, two positive, and two high positive) obtained from actual clinical trial sites. Each of the 6 panel members were tested in triplicate (x3) on 3 different days, on 1 lot, at 2 sites (total number of replicates at each site = 9). Each of the 6 panel members was tested in duplicate (x2) on 3 different days, on I lot, at a third site (total number of replicates at the third site = 6). One (1) operator performed all precision testing at each site. The data was analyzed according to the National Committee for Clinical Laboratory Standards (NCCLS). The mean optical density (OD) and mean index value, standard deviation (SD), percent coefficient of variation (%CV), within lot precision (intra-assay) and within site (inter-assay) precision for each panel member at each site are illustrated below in the following tables.

Site 1

Panel Member	Neg		Low Pos		Pos #1		Pos #2		High Pos#1		High Pos #2		Neg Control		CO Control		Pos Control
	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index
N	9	9	9	9	9	9	9	9	9	9	9	3	3	6	6	3	3
Mean	0.052	0.09	0.445	0.74	0.702	1.17	0.931	1.563	1.227	2.06	2.887	4.83	0.046	0.08	0.606	1.00	2.216	3.67
Within Run
(intra-assay)1 SD	0.002	0.00	0.022	0.03	0.059	0.09	0.044	0.08	0.051	0.09	0.089	0.17	N/A	N/A	0.02	0.03	N/A	N/A
%CV	N/A	N/A	4.8%	4.4%	8.4%	7.6%	4.7%	5.1%	4.2%	4.4%	3.1%	3.6%	N/A	N/A	3.7%	3.4%	N/A	N/A
Total
(inter-assay)2 SD	0.036	0.04	0.051	0.08	0.070	0.14	0.044	0.25	0.058	0.29	0.169	0.58	N/A	N/A	0.102	0.03	0.317	0.12
%CV	N/A	N/A	11.5%	10.4%	10.0%	11.6%	4.7%	15.7%	4.7%	14.3%	5.9%	11.9%	N/A	N/A	16.9%	2.8%	14.3%	3.3%

Site2

Panel Member	Neg		Low Pos		Pos #1		Pos #2		High Pos#1		High Pos #2		Neg Control		CO Control		Pos Control
	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index
N	9	9	9	9	9	9	9	9	9	9	9	9	3	3	6	6	3	3
Mean	0.040	0.10	0.280	0.70	0.364	0.89	0.602	1.49	0.801	2.01	1.361	3.43	0.074	0.18	0.415	1.00	1.197	2.97
Within Run
(intra-assay)1 SD	0.006	0.01	0.041	0.09	0.023	0.07	0.045	0.11	0.046	0.10	0.047	0.11	N/A	N/A	0.00	0.01	N/A	N/A
%CV	N/A	N/A	14.5%	13.0%	6.4%	7.6%	7.5%	7.1%	5.7%	4.8%	3.5%	3.2%	N/A	N/A	1.1%	1.1%	N/A	N/A
Total
(inter-assay)2 SD	0.006	0.03	0.058	0.19	0.083	0.18	0.057	0.28	0.042	0.53	0.079	1.00	N/A	N/A	0.094	0.01	0.068	0.54
%CV	N/A	N/A	20.8%	27.0%	22.7%	19.8%	9.5%	18.7%	5.3%	26.5%	5.8%	29.2%	N/A	N/A	22.7%	0.9%	5.7%	18.2%

Site 3

Panel Member	Neg		Low Pos		Pos #1		Pos #2		High Pos#1		High Pos #2		Neg Control		CO Control		Pos Control
	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index	OD	Index
N	6	6	6	6	6	6	6	6	6	6	6	6	3	3	6	6	3	3
Mean	0.049	0.10	0.388	0.81	0.652	1.36	0.830	1.73	1.158	2.41	2.378	4.96	0.059	0.12	0.480	1.00	1.652	3.45
Within Run
(intra-assay)1 SD	0.003	0.01	0.009	0.02	0.082	0.17	0.068	0.14	0.094	0.20	0.126	0.25	N/A	N/A	0.028	0.06	N/A	N/A
%CV	N/A	N/A	2.4%	2.4%	12.5%	12.2%	8.2%	8.2%	8.1%	8.2%	5.3%	5.1%	N/A	N/A	5.8%	5.8%	N/A	N/A
Total
(inter-assay)2 SD	0.012	0.03	0.078	0.13	0.068	0.15	0.104	0.25	0.082	0.15	0.111	0.34	N/A	N/A	0.028	0.04	0.056	0.23
%CV	N/A	N/A	20.0%	15.8%	10.5%	11.1%	12.5%	14.3%	7.1%	6.2%	4.7%	6.8%	N/A	N/A	5.8%	4.1%	3.4%	6.6%

N/A = not applicable

1NCCLS EP5-A, Vol. 19, No. 2, Page 24, Equation (C2) 2NCCLS EP5-A, Vol. 19, No. 2, Page 25, Equation (C3) and Equation (C4)

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B. Cross Reactivity

A study to evaluate the effect of potentially interfering medical conditions unrelated to Invasive Aspergillosis was performed with one lot of the Platelia® Aspergillus EIA kit. The following serum samples were tested for cross-reactivity with the Platelia® Aspergillus EIA. A total of 151 sera were tested.

Pathology	# Samples Tested	# Positives
Rheumatoid Factor	10	0
ANA Positive	10	0
IgG Hypergammaglobulinemia	10	0
IgM Hypergammaglobulinemia	10	0
Cancer*	13	0
Non-Viral Cirrhosis (primary biliary; alcohol induced;
drug induced)	10	0
Multiple Transfusions	10	0
Multiparous Females	10	0
HAV	10	0
HCV	10	0
Rubella	10	0
CMV	10	0
Syphilis (RPR+)	10	0
Toxoplasmosis	10	0
Mycoplasma	10	0

One each of adenocarcinoma, bladder, breast(2), colon, endometrial, lung, melanoma (metastatic), prostate, renal, and squamous(3).

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C. Clinical Testing

Clinical testing to evaluate the sensitivity, specificity, and predictive value of the Platelia® Aspergillus ELA was conducted at three sites located in the U.S. and Canada. The study was conducted retrospectively using a total of 1890 serum samples collected from 179 patients from the following populations*:

. patients without signs of Invasive Aspergillosis (control patients)
. patients with probable Invasive Aspergillosis
. patients with proven Invasive Aspergillosis

The Invasive Fungal Infection Cooperative Group (IFICG) of the European Organization for Research (EORTC) and the Mycosis Study Group (MSG of the National Institute of Allery and Infectious Diseases (NIAID) have defined criteria for diagnosis of Invasive Aspergillosis (IA) in patients with hematologic malignancy or hematopoietic stem cell transplant.

Proven Invasive Aspergillosis is defined by positive microbiological culture obtained by sterile procedure from the site affected, and histopathological demonstration of the appropriate morphological forms in a host with symptoms attributed to the fungal infection.

Probable Invasive Aspergillosis is defined as at least one microbiological criterion, and one major or two minor clinical criteria from a site consistent with infection, in a host with symptoms attributed to the fungal infection.

Possible Invasive Aspergillosis is defined as at least one microbiological criterion, or one major or two minor clinical criteria from a site consistent with infection, in a host with symptoms attributed to the fungal infection

Given the relative rarity of Probable and Proven Invasive Aspergillosis, we offer the following definition of clinical sensitivity and specificity for the purposes of this study.

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SENSITIVITY

Results from this study have been analyzed in terms of patient sensitivity. Sensitivity testing was conducted using the Platelia® Aspergillus EIA at three sites on a combined total of 31 Bone Marrow Transplant (BMT) and Leukemia patients diagnosed with Proven or Probable Invasive Aspergillosis.

1. Proven Aspergillosis (as defined by IFICG / EORTC ; see above)

Combined Sites N = 11 (patients)

l 1 patients: 6 patients diagnosed with Proven Invasive Aspergillosis of the lung 5 patients diagnosed with Proven Invasive Aspergillosis of the sinus

Sensitivity : 81.8% (9 / 11).

Note : The 95% confidence interval could not be calculated due to insufficient sample size.

2. Probable Aspergillosis (as defined by IFICG / EORTC ; see above)

Combined Sites N = 20 (patients)

20 patients : 16 patients diagnosed with Probable Invasive Aspergillosis of the lung 4 patients diagnosed with Probable Invasive Aspergillosis of the sinus

Sensitivity : 80.0% (16 / 20).

Note : The 95% confidence interval could not be calculated due to insufficient sample size.

3. Combined Proven and Probable Aspergillosis (as defined by IFICG / EORTC ; see above)

Combined Sites N = 31 (patients)

31 patients:

22 patients diagnosed with Proven or Probable Invasive Aspergillosis of the lung

9 patients diagnosed with Proven or Probable Invasive Aspergillosis of the sinus

Sensitivity : 80.7% (25 / 31). The 95% confidence interval is 64.0 -- 97.3%.

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SPECIFICITY

Specificity testing was conducted using the Platelia® Aspergillus EIA at three sites on a combined total of 1362 samples obtained from 148 Bone Marrow Transplant (BMT) and Leukemia patients without signs of Invasive Aspergillosis (control patients).

N = 33 patients Site 1

449 sera obtained from:

16 BMT patients without signs of Invasive Aspergillosis

11 BMT patients colonized with Aspergillus and/or Candida sp.

1 BMT patient diagnosed with Invasive Fusariosis

3 BMT patients diagnosed with Candidemia

1 patient with blood cultures positive for Lecythophora mutabilis

1 patient diagnosed with Invasive Pseudoallescheria boydii

Site 1	Specificity	95% Confidence Interval
Patients (27/33)	81.8%	66.1 – 97.5%
Patients after repeat testing (31/33)

Site 2 N = 77 patients

560 sera obtained from:

67 Leukemic patients without signs of Invasive Aspergillosis

8 Leukemic patients with Fungemia (Candida, Fusarium, Trichosporon, or Aureobasidium)

1 Leukemic patient diagnosed with Probable Fusarium pneumonia

1 Leukemic patient diagnosed with Candida pneumonia

Site 2	Specificity	95% Confidence Interval
Patients (71/77)	93.4%	87.1 – 99.8%
Patients after repeat testing (74/77)

N = 38 patients Site 3

353 sera obtained from :

28 BMT patients without signs of Invasive Aspergillosis

5 Leukemic patients receiving a second course of cytotoxic therapy

5 BMT patients being treated for Graft Versus Host Disease

Site 3	Specificity	95% Confidence Interval
Patients (34/38)	89.5%	77.8 – 100%
Patients after repeat testing (38/38)

Combined Sites N = 148 patients*

Combined Sites	Specificity	95% Confidence Interval
Patients (132/148)	89.2%	83.8 - 94.6%
Patients after repeat testing (143/148)

*Note: A total of 1343 sera obtained from 148 patients were tested. 1343 of the 1362 sera were initially negative, resulting in a sample agreement of 98.6% with a 95% confidence interval of 97.9 - 99.3%. On repeat testing, 1355 of the 1362 sera were negative.

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PREDICTIVE VALUE

Positive and negative predictive values have been analyzed for the patient population in this study, based on the actual average14% prevalence rate observed in this study. Positive and negative predictive values have been calculated for both the initial test result and after repeat testing.

Actual Prevalence of 14%	PPV	NPV
Patient	54.8 %	96.6 %
Patient after repeat testing	68.3 %	95.5 %

The expected prevalence of Invasive Aspergillosis varies with the patient population; rates from 5-20% have been reported 3. For patient populations on the lower end of the published prevalence, the positive and negative prevalence have been re-calculated using a 5% prevalence rate.

Calculated Prevalence of 5%	PPV	NPV
Patient	12.5 %	96.0 %
Patient after repeat testing	31.3 %	96.3 %

A study to evaluate the effect of potentially interfering medical conditions unrelated to invasive Aspergillosis was performed with one lot of the Platelia® Aspergillus EIA kit. The following serum samples were tested for cross-reactivity with the Platelia® Aspergillus EIA. A total of 151 sera were tested.

Pathology	# Samples Tested	# Positives
Rheumatoid Factor	10	0
ANA Positive	10	0
IgG Hypergammaglobulinemia	10	0
IgM Hypergammaglobulinemia	10	0
Cancer*	13	0
Non-Viral Cirrhosis (primary biliary; alcohol induced;
drug induced)	10	0
Multiple Transfusions	10	0
Multiparous Females	10	0
HAV	10	0
HCV	10	0
Rubella	10	0
CMV	10	0
Syphilis (RPR+)	10	0
Toxoplasmosis	10	0
Mycoplasma	10	0

One each of adenocarcinoma, bladder, breast(2), colon, endometrial, lung, melanoma (metastatic), prostate, renal, and squamous(3).

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D. Expected Values

The expected prevalence of Invasive Aspergillosis varies with the patient population; rates from 5-20% have been reported 55. A clinical study was conducted on a total of 1890 serum samples from 179 bone marrow transplant (BMT) and leukemic patients diagnosed with and without Invasive Aspergillosis, at three testing centers in North America to determine the performance characteristics of the Platelia Aspergillus EIA. The average prevalence rate for this study was 14%. The distribution of index values for these populations is represented in the following charts.

Patients diagnosed without Invasive Aspergillosis (control population)

A total of 1362 frozen serum samples obtained from 148 bone marrow transplant (BMT) and leukemic patients at three testing centers in North America were tested with the Platelia® Aspergillus EIA test. The distribution of index values is shown in the following chart.

Image /page/8/Figure/5 description: The image is a bar chart titled "Distribution of Serum Index Value from the Control Patient Population, N=1362". The x-axis represents the index, and the y-axis represents the number of sera. The bar chart shows the distribution of serum index values, with the highest number of sera at index 0.1-0.2, with a value of 709. The number of sera decreases as the index increases, with a value of 4 at index >1.5.

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This scatter plot depicts galactomannan assay results for the 1362 serum samples from 148 control patients in this study diagnosed (patients undergoing immunosuppressive therapy for HSCT, or to treat hematological malignancy).

Image /page/9/Figure/2 description: The image shows a scatter plot titled "CONTROL POPULATION: DISTRIBUTION OF INDEX / PATIENT (N=148)". The x-axis represents the patient number, ranging from 0 to 140. The y-axis represents the index, ranging from 0.00 to 2.00. Most of the data points are clustered between 0.00 and 0.40, with a few outliers above 0.50.

This scatter plot depicts galactomannan assay results for the 528 serum samples from 31 patients in this study diagnosed with proven or probable Invasive Aspergillosis as defined by EORTC/NIAID definitions. Not every serum sample from each patient is expected to be positive. The expected prevalence of Invasive Aspergillosis varies with the population; rates from 5-20% have been reported 35. The prevalence rate for this study was 14%.

Image /page/9/Figure/4 description: This image is a scatter plot titled "Proven Aspergillosis: Distribution of Index / Patient (N=31)". The x-axis is labeled "Patient Number" and ranges from 0 to 31. The y-axis is labeled "Index" and ranges from 0.00 to 2.00. There is a horizontal line at the index value of 0.50.

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The following graphs represent examples of a patient without clinical signs or symptoms of Invasive Aspergillosis (negative for Aspergillus) and a patient with proven or probable Invasive Aspergillosis (positive for Aspergillus) respectively.

Negative Patient

Positive Patient

Image /page/10/Figure/5 description: The image is a line graph titled "Proven or Probable Invasive Aspergillosis Patient". The x-axis is labeled "Days" and ranges from 0 to 60, while the y-axis is labeled "Index". A horizontal line is labeled "Cut-off". The line graph shows an index that is relatively flat from day 0 to day 40, and then increases sharply from day 40 to day 60.

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E. Bibliography

de Repentigny, L., L. Kaufman, G. T. Cole, D. Kruse, J. P. Latge, and R. C. Matthews. 1994. 1. Immunodiagnosis of Invasive fungal infections. J Med Vet Mycol 32:239-252.
Denning, D. W. 1998. Invasive Aspergillosis. Clin Infect.Dis. 26:781-803. 2.
Erjavec, Z. and P. E. Verweij. 2002. Recent progress in the diagnosis of fungal infections in the 3. immunocompromised host. Drug Resist.Updat. 5:3-10.
Herbrecht, R., V. Letscher-Bru, C. Oprea, B. Lioure, J. Waller, F. Campos, O. Villard, K. L. 4. Liu, S. Natarajan-Ame, P. Lutz, P. Dufour, J. P. Bergerat, and E. Candolfi. 2002. Aspergillus galactomannan detection in the diagnosis of Invasive Aspergillosis in cancer patients. J Clin.Oncol. 20:1898-1906.
1. Herbrecht, R., D. Denning, T. Patterson, J. Bennett, R. Greene, J. Oestmann, W. Kern, K. Marr, P. Ribaud, O. Lortholary, R. Sylvester, R. Rubin, J. Wingard, P. Stark, C. Durand, D. Caillot, E. Thiel, P. Chandrasekar, M. Hodges, H. Schlamm, P. Troke, B. DePauw. 2002. Voriconazole Versus Amphotericin B for Primary Therapy of Invasive Aspergillosis. N Engl J Med. 347, 6:408-415.
Latee, J. P. 1995. Tools and trends in the detection of Aspergillus fumigatus. Curr Top Med Mycol 6. 6:245-281.
1. Latge, J. P. Aspergillus fumigatus and Aspergillosis. Clin Microbiol Rev 12/2], 310-50. 1999.
Latge, J. P., H. Kobayashi, J. P. Debeaupuis, M. Diaquin, J. Sarfati, J. M. Wieruszeski, E. 8. Parra, J. P. Bouchara, and B. Fournet. 1994. Chemical and immunological characterization of the extracellular galactomannan of Aspergillus fumigatus. Infect.Immun. 62:5424-5433.
Maertens, J., J. Verhaegen, H. Demuynck, P. Brock, G. Verhoef, P. Vandenberghe, J. Van ﮨ Eldere, L. Verbist, and M. Boogaerts. 1999. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for Invasive Aspergillosis, J.Clin.Microbiol. 37:3223-3228.
1. Maertens, J., J. Verhaegen, K. Lagrou, J. Van Eldere, and M. Boogaerts. 2001. Screening for circulating galactomannan as a noninyasive diagnostic tool for Invasive Aspergillosis in proloneed neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 97:1604-1610.
1. Stynen, D., A. Goris, J. Sarfati, and J. P. Latge. 1995. A new sensitive sandwich enzyme-linked immunosorbent assay to detect galactofuran in patients with Invasive Aspergillosis. J.Clin.Microbiol. 33:497-500.
1. Stynen, D., J. Sarfati, A. Goris, M. C. Prevost, M. Lesourd, H. Kamphuis, V. Darras, and J. P. Latge. 1992. Rat monoclonal antibodies against Aspergillus galactomannan. Infect.Immun. 60:2237-2245.
1. Sulahian, A., F. Boutboul, P. Ribaud, T. Leblanc, C. Lacroix, and F. Derouin. 2001. Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of Invasive Aspergillosis in two adult and pediatric hematology units during a 4-year prospective study. Cancer 91:311-318.

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1. Sulahian, A., M. Tabouret, P. Ribaud, J. Sarfati, E. Gluckman, J. P. Latge, and F. Derouin. 1996. Comparison of an enzyme immunoassay and latex agglutination test for detection of galactomannan in the diagnosis of Invasive Aspergillosis. Eur.J Clin.Microbiol.Infect.Dis. 15:139-145.
1. Swanink, C. M., J. F. Meis, A. J. Rijs, J. P. Donnelly, and P. E. Verweij, 1997. Specificity of a sandwich enzyme-linked immunosorbent assay for detecting Aspergillus galactomannan. J Clin.Microbiol. 35:257-260.
1. Verweij, P. E., E. C. Dompeling, J. P. Donnelly, A. V. Schattenberg, and J. F. Meis. 1997. Serial monitoring of Aspergillus antigen in the early diagnosis of Invasive Aspergillosis. Preliminary investigations with two examples. Infection 25:86-89.
1. Verweii, P. E. and J. F. Meis. 2000. Microbiological diagnosis of invasive fungal infections in transplant recipients. Transpl.Infect.Dis. 2:80-87.
1. Verweij, P. E., D. Stynen, A. J. Rijs, B. E. de Pauw, J. A. Hoogkamp-Korstanje, and J. F. Meis. 1995. Sandwich enzyme-linked immunosorbent assay compared with Pastorex latex agglutination test for diagnosing Invasive Aspergillosis in immunocompromised patients. J Clin.Microbiol. 33:1912-1914.
1. Verweij, P. E., C. M. Weemaes, J. H. Curfs, S. Bretagne, J. F. Meis. 2000. Failure to detect circulating Aspergillus markers in a patient with chronic granulomatous disease and Invasive Aspergillosis. J Clin.Microbiol. 38:3900-3901.
1. Walsh T. J., R.L. Schaufele, T. Sein, J. Gea-Banacloche, M. Bishop, N. Young, R. Childs, J. Barrett. H. L. Malech, and S.M. Holland. 2002. Reduced expression of galactomannan antigenemia in patients with Invasive Aspergillosis and chronic granulomatous disease or Job's syndrome. Abstracts of the 40th Annual Meeting of the Infectious Diseases Society of America. Arlington, VA. P. 105 ; Abstr. 345.
1. Yeo, S. F. and B. Wong. 2002. Current Status of Nonculture Methods for Diagnosis of Invasive Fungal Infections. Clin.Microbiol.Rev. 15:465-484

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

MAY 1 6 2003

Mr. David Bhend Regulatory Affairs Associate Bio-Rad Laboratories 6565 185th Avenue NE Redmond, WA 98052

Re: K023857

Trade/Device Name: Platelia® Aspergillus EIA Regulation Number: 21 CFR 866.3040 Regulation Name: Aspergillus Spp. Serological Reagents Regulatory Class: Class I Product Code: NOM Dated: March 17, 2003 Received: March 18, 2003

Dear Mr. Bhend:

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 vour 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 Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

Page 2 -

This letter will allow you to begin marketing your device as described in your Section 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 information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 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 Sutman

Steven I. Gutman, M.D., M.B.A. Director Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

Premarket 510(k) Notification April, 2003 (Revised)

ATTACHMENT G INDICATIONS FOR USE STATEMENT

510(k) Number (if known): K023857

Device Name: Platelia® Aspergillus EIA

Indications for Use:

The Platelia® Aspergillus EIA is an immunoenzymatic sandwich microplate assay for the detection of Aspergillus galactomannan antigen in serum.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Professional Use:	/
-------------------	---

Prescription Use:	/
(Per 21 CFR 801.109)

	Over-The-Counter Use:
	(Optional Format 1-2-96)

Signature
Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K02.3857