The BioGenex Mouse Monoclonal Anti-Progesterone Receptor Antibody (Clone PR88) is an immunohistochemical (IHC) assay and is intended for laboratory use to qualitatively identify by light microscopy human progesterone receptor in normal and/or pathological paraffin-embedded, formalin-fixed tissues. The PR88 antibody specifically binds to antigens located in the nucleus of cell populations that express progesterone receptor in normal and abnormal tissues. This antibody is indicated as an aid in assessing patient response to hormonal therapy and as an aid in the prognosis and management of breast cancer patients. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Device Description

BioGenex PR88 is a monoclonal antibody, which specifically binds to progesterone Dreceptor antigen located in the nuclear region of a variety of normal and abnormal tissues. It is a mouse monoclonal anti-progesterone receptor antibody from mouse ascites fluid diluted in phosphate buffered saline pH 7.6 containing bovine serum albumin as carrier and on and 0.09% sodium azide as preservative. The antibody is available in concentrated proximand 0.5970 bounds ready to use form (AM328-5M and AM328-10M). Refer to package insert for details.

AI/ML Overview

This document appears to be a 510(k) summary for a medical device, the BioGenex Mouse Monoclonal Anti-Progesterone Receptor Antibody (Clone PR88). It does not contain explicit "acceptance criteria" in the format typically used for performance studies with predefined thresholds for success (e.g., a specific sensitivity or specificity target to be met). Instead, it describes a "performance data" section to demonstrate substantial equivalence to a predicate device and a reference method.

Therefore, the response below will present the reported device performance and infer the "acceptance criteria" based on the described concordance and the overall conclusion of substantial equivalence.

Here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

Acceptance Criteria (Inferred)	Reported Device Performance
Substantial equivalence to predicate device (Ventana K990618) and reference DCC technique	Verified by comparison of features and performance study results.
Specificity with normal human tissues	PR88 antibody demonstrated negative immunoreactivity with most normal human tissues. Positive immunoreactivity observed in specific normal tissues (Langerhans islet cells of pancreas, endometrium of uterus, stromal cells of cervix, parenchymal cells of ovary, convoluted and collecting tubes of kidney, epithelial cells of colon, adenohypophysis of pituitary).
Intra-run (within-run) reproducibility	No significant variation among slides of the same tissue stained in a single run.
Inter-run (run-to-run) reproducibility	No significant variation among slides of the same tissue stained in different runs.
Agreement between instrumental vs. manual runs	No significant variation between slides stained manually and by the automated process.
Concordance with reference DCC assay for PR	Overall binary concordance of 74% (99/134) with a 2-sided 95% confidence interval of 66% - 81% (p<0.0001). This level was considered "similar."
Stability	Stable for at least 24 months at 2-8°C. Stable after continuous 48-hour exposure at 45°C.

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

Specificity Test Set: 88 formalin-fixed and paraffin-embedded tissues covering a wide range of normal human tissue types. The document does not specify the country of origin or whether it was retrospective or prospective.
Reproducibility Test Set:
- Intra-run: 10 slides of the same tissues within a single run.
- Inter-run: Slides containing the same tissues over 10 different runs.
- Instrumental vs. manual: 10 slides for each tissue (selected for a wide range of reactivity) stained manually and using BioGenex Automated Stainer.
- The document does not specify the country of origin or whether it was retrospective or prospective.
Sensitivity (DCC Comparison) Test Set: A total of 134 specimens.
- First batch: 41 specimens assayed for DCC at the University of Texas Health Science Center at San Antonio, Texas.
- Second batch: 93 specimens assayed for DCC at Genesee Hospital, Rochester, NY.
- The document does not explicitly state if the data was retrospective or prospective, but the description of "specimens were selected according to ... 1) formalin-fixed and paraffin-embedded tissue sections were available; 2) each tissue was initially assayed for PR by DCC" suggests a retrospective collection of existing samples. The origin appears to be the USA.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

For the Sensitivity (DCC Comparison) Test Set: Each resulting slide was read independently by two pathologists.
Qualifications: The document states they were "pathologists," but does not provide additional details such as years of experience. They reportedly had "no knowledge of any other laboratory or clinical data of the specimens."

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

For the Sensitivity (DCC Comparison) Test Set: The document states "each resulting slide was read independently by two pathologists." It does not describe an adjudication method if there was disagreement between the two pathologists. The scoring was based on percentage of cells with positive nuclear staining, and a cut-off value of >10% of positive tumor cells was used to score a slide as positive or negative. The document reports a single concordance figure, implying agreement or a method not detailed.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not explicitly conducted as described in the context of human readers improving with AI assistance. This device is an immunohistochemical antibody, not an AI software. The study compared the IHC staining (read by pathologists) against a biochemical assay (DCC).

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

No, a standalone algorithm-only performance assessment was not performed, as this is not an AI device. The device itself is an antibody reagent, and its performance (IHC staining) is evaluated by human pathologists. The "specificity" and "reproducibility" sections effectively describe the standalone performance of the antibody and staining system.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

For the Sensitivity (DCC Comparison) Test Set: The primary ground truth for comparison was the dextran-coated charcoal (DCC) technique, described as a biochemical assay and "considered the gold standard for PR assay" at the time. Pathologists' readings of IHC slides were then compared against this DCC ground truth.

8. The sample size for the training set

This document does not describe a "training set" in the context of machine learning or AI. This is a traditional IVD device (antibody). The development and optimization of the antibody and staining protocols would have involved various internal tests, but these are not referred to as a "training set" in the provided text.

9. How the ground truth for the training set was established

As there is no mention of a "training set" in the context of an AI/ML algorithm, this question is not applicable to the provided document. The ground truth for the performance evaluation (test set) was established by the DCC assay.

Summary

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Image /page/0/Picture/0 description: The image shows the word "BioGenex" in bold, black font. The letters are slanted to the right, giving the word a dynamic appearance. A thick, black line extends from the right side of the word, adding a visual element to the logo.

Image /page/0/Picture/2 description: The image contains a handwritten string of characters. The string appears to be "K012960". The characters are written in a cursive style, with some connections between the letters and numbers. The writing is in black ink on a white background.

SUMMARY OF SAFETY AND EFFECTIVENESS INFORMATION

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.

GENERAL INFORMATION:

Submitter:	BioGenex Laboratories, Inc.4600 Norris Canyon RoadSan Ramon, CA 94583925-275-0550 (Tel)925-275-0580 (Fax)
Contact Persons:	Gurvinder S. Nanda, Ph.D.Manager, Regulatory Affairs925-543-1336 (Tel)925-866-2525 (Fax)Jintao Chen, Ph.D.Director, Operations925-866-2568 (Tel)925-866-2525 (Fax)
Date of Preparation:	January 30, 2002
Device Generic Name:	Mouse Monoclonal Anti-Progesterone Receptor Antibody
Device Trade Name:	BioGenex Mouse Monoclonal Anti-Progesterone Receptor(Clone PR88)
Device Classification Name:	Immunohistochemistry Reagents and Kits
Assigned 510(k) Number:	K012960

PREDICATE DEVICE:

The device is substantially equivalent to certain well-established, widely accepted reference laboratory methodology dextran-coated charcoal (DCC) technique which were common in use prior to May 28, 1976. The device is substantially equivalent in methodology to similar kits for progesterone receptor (Ventana, K990618).

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DESCRIPTION OF THE DEVICE:

INTENDED USE:

PR88 antibodies have been optimally manufactured for use with BioGenex Super Sensitive MultiLink® Detection Systems with or without BioGenex Automated Staining Systems.

STATEMENT OF HOW TECHNOLOGICAL CHARACTERISTICS COMPARED TO SUBSTANTIAL EQUIVALENT DEVICE:

A table is provided below comparing the similarities and differences between the BioGenex device and the predicate Ventana Device (K990618) to detect progesterone receptors in normal and or pathological tissues.

	BioGenex(New device-K012960)	Ventana(Predicate device K990618)
Clone	PR88	IA6
Antibody	Mouse monoclonal	Mouse monoclonal
Immunoglobulin Class	Mouse IgG1, Kappa	Mouse IgG1, Kappa
Intended Use	Is intended for laboratory useto qualitatively identify bylight microscopy humanprogesterone receptor innormal and/or pathological	Is intended for laboratory usefor the qualitative detectionof progesterone receptor(PGR) antigen in sections offormalin fixed, paraffin

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	paraffin-embedded, formalin-fixed tissues.	embedded normal andneoplastic tissue on aVentana automatedimmunohistochemistry slidestaining device.
Indication	This antibody is indicated asan aid in assessing patientresponse to hormonal therapyand as an aid in the prognosisand management of breastcancer patients.	This antibody is indicated asan aid in the managementprognosis and prediction oftherapy outcome of breastcancer within the context ofpatient's clinical history andother diagnostic testsevaluated by a qualifiedpathologist.
Specificity	Human progesteronereceptor in formalin-fixedparaffin embedded tissues.	Human progesterone receptorin formalin-fixed paraffinembedded tissues.
Total proteinconcentration:	10 mg/ml	10 mg/ml
Storage	2-8°C	2-8°C
Application	For manual and automateduse	For automated use

PERFORMANCE DATA:

1. Specificity of Primary Antibody

A total of 88 formalin-fixed and paraffin-embedded tissues covering a wide range of normal human tissue types were tested with the BioGenex PR88 antibody using BioGenex Super Sensitive HRP Detection System. In normal human tissues PR88 antibody demonstrated negative immunoreactivity with most tissues. However, positive immunoreactivity was observed with some normal tissues like Langerhans islet cells of pancreas, cells of endometrium of uterus, stromal cells of cervix, parenchymal cells of ovary, cells at convoluted and collecting tubes of kidney, epithelial cells of colon, and cells of adenohypophysis of pituitary.

2. Reproducibility

(a) Intra run (within-run) assay: The reproducibility of staining was determined by staining 10 slides of the same tissues within a single run. All slides were stained by the same individual using the same set of reagents for each of the tissues tested. Evaluation of the results indicates no significant variation among the slides of the same tissue stained in the same run.

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(b) Inter run (run-to-run) assay: The reproducibility between runs was determined Inter Tun (run-to-rul) assame tissues over 10 different runs. Evaluation of by staming sides containing ficant variation among the slides of the same tissue stained in different runs.
(c) Instrumental runs vs. manual runs: Ten slides each were stained with the Instibody manually and using BioGenex Automated Stainer for each of the tissues antioody managing were selected to demonstrate reproducibility over a wide range of reactivity scale. The prediluted form of PR88 antibody was used for this Tange of Teactivity Seale: "The proc. Sensitive MultiLink Detection System with Study along with Dio Ochen Day of the results indicates no significant variation DAD as the same tissue stained manually and in the automated process.

3. Sensitivity

Comparison between PR88 IHC and reference DCC assays. The study was designed Companson between fried the unders to establish the performance characteristics of 10 use mucpendom ennious opennesity the reference methodology, dextran-charcoal I Koo staming and his concerdance is a biochemical assay and has been considered the gold standard for PR assay. More recently, immunohistochemistry (IHC) has the gold standard 101-11€ assays testing (Kell, D et al. 1993, Ferrero-Pous, M et al. 2001, Lohmann, et al. 2001).

A total of 134 specimens were used in this study. All the specimens were selected according to the following criteria: 1) fomalin-fixed and paraffin-embedded tissue sections were available; 2) each tissue was initially assayed for PR by DCC. No other selection criteria were employed. The study was conducted using two different Sciechon of clinical specimens in order to include approximately 50% positive and negative cases.

The first batch of 41 specimens was assayed for DCC in the laboratory of the late Dr. The irrol baten of 11 pp University of Texas Health Science Center at San Antonio, Texas. The DCC results were scored as positive or negative using a cut-off value of ≥10 femtomoles/mg of protein. IHC staining of these slides was done in the laboratory of Dr. Louis P. Pertschuk in the Department of Pathology, King's County Hospital, State University of New York, Health Science Center, Brooklyn, New York using detection reagents provided by BioGenex.

The second batch of 93 specimens was assayed for DCC in the laboratory of Dr. William Fricke (Genesee Hospital, Rochester, NY). The DCC results were scored as positive or negative using a cut-off value of ≥10 femtomoles/mg of protein. The tissue positive of negained as a BioGenex laboratories for slide preparation and IHC staining using BioGenex detection reagents.

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For both the studies, each resulting slide was read independently by two pathologists, who have no knowledge of any other laboratory or clinical data of the specimens. The scoring was based on percentage of cells with positive nuclear staining (Fitzgibbons PL, et al. 2000). Any trace of nuclear staining was counted as positive result (NIH Consensus Statement, 2000). The intensity of staining was not factored into the scoring system. A cut-off value of >10% of positive tumor cells was used to score a slide as positive or negative.

The overall binary concordance of PR88 IHC staining to PR DCC assay was 74% (99/134), with a 2-side 95% confidence interval of 66% - 81% (p<0.0001). This level of concordance indicated that PR88 IHC results and PR DCC results were similar. However, 26% of the results were discordant between these two methods. Reasons for discordance between hormone receptor IHC staining and hormone receptor DCC assays are well known (Ferrero-Poüs, et al. 2001; Kell, et al. 1993). Since DCC requires specimen homogenization, the cellular localization of any detected receptor can not be determined. The receptor might be from either benign epithelium or turnor cells or both sources within the same tissue. With IHC, positive signals from only the tumor areas of the tissue are read by trained pathologists and signals from apparent normal areas from the same tissue are ignored. This would suggest that the IHC method is more specific than the DCC method.

4. Stability:

The objective of this study was to determine the expiration date of the device. The BioGenex PR88 antibody was stored at 2-8°C continuous. Three lots of the device were tested after 24 months of storage following the standard in-house quality control testing procedures. Results of this study indicated that this device was stable for at least 24 months at 2-8°C.

Shipping stress studies were carried out on three lots of the device by continuous exposure to extreme temperature condition 45℃ for 48 hours. Results of this study indicated that this device was stable after continuous 48 hour exposure at 45°C.

CONCLUSION:

The results indicate that BioGenex Mouse Monoclonal Anti-Progesterone Receptor antibody (Clone PR88) is substantially equivalent to dextran-coated charcoal (DCC) technique and Ventana PGR primary antibody (K990618).

BIBLIOGRAPHY:

Ferrero-Poüs, M., Trassard, M. . Le Doussal, V. Hacène, K Tubiana-Hulin, M., Spyratos, F., Comparison of enzyme immunoassay and immunohistochemical measurements of estrogen and progesterone receptors in breast cancer patients. Appl. Immunohistochem. & Mol. Mor. 2001;9:267-275.

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Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O'Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000 Jul;124(7):966-78.]

Kell D, Kamel O, Rouse R, Immunohistochemical analysis of breast carcinoma estrogen and progesterone receptors in paraffin embedded tissue. Appl. Immunohistochem. 1993;1(4):275-281.

Lohmann C, Gibney E, Cotsonis G, Lawson D, Cohen C. Progesterone receptor immunohistochemical quantitation compared with cytosolic assay: correlation with prognosis in breast cancer. Appl Immunohistochem Molecul Morphol 2001 Mar;9(1):49-રૂડે :

NIH Consensus Statement. Adjuvant Therapy for Breast Cancer, Volume 17, Number. 4, November 1-3, 2000. National Institutes of Health, Office of the Director, pg. 8.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three swooping lines representing its wings. The eagle is positioned to the right of a circular border containing the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA". The text is arranged around the circle, with "DEPARTMENT OF HEALTH & HUMAN SERVICES" on the left side and "USA" on the top right.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Gurvinder S. Nanda, Ph.D. Manager. Regulatory Affairs BioGenex Laboratories, Inc. 4600 Norris Canyon Road San Ramon, CA 94583

MAR 8 2002

Re: K012960

Trade/Device Name: BioGenex Mouse Monoclonal Anti-Progesterone Receptor Antibody (Clone PR88); BioGenex Super Sensitive (SS) Secondary Immunodetection System (Manual and Automated) Regulation Number: 21 CFR 864.1860; 21 CFR 866.5550 Regulation Name: Immunohistochemistry reagents and kits; Immunoglobulin (light chain specific) immunological test system Regulatory Class: Class II; Class II Product Code: DEH: MXZ Dated: December 18, 2001 Received: December 20, 2001

Dear Dr. Nanda:

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 hourication. The I'DA iniding of successification 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 1 II you desire specific active for your as ic devices), please contact the Office of Compliance at additionally 809.10 for in True diagnestions on the promotion and advertising of your device, (301) 394-4588. Additionally, for question of (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 Information on your responsionals and Consumer Assistance at its toll-free number (800) 638-2041 or Manufacturers International and Collass "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Butman

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

Enclosure

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INDICATIONS FOR USE STATEMENT

K012960 510(k) Number (if known):

Device Name:

BioGenex Mouse Monoclonal Anti-Progesterone Receptor Antibody (Clone PR88).

The BioGenex Mouse Monoclonal Anti-Progesterone Indications for Use: (Clone PR88) is an Antibody Receptor immunohistochemical (IHC) assay and is intended for laboratory use to qualitatively identify by light microscopy human progesterone receptor in normal and/or pathological paraffin-embedded, formalin-fixed tissues. The PR88 antibody specifically binds to antigens located in the nucleus of cell populations that express progesterone receptor in normal and abnormal tissues. This antibody is indicated as an aid in assessing patient response to hormonal therapy and as an aid in the prognosis and management of breast cancer patients. The clinical interpretation of any staining or its absence should be complemented by morphological studies using proper controls and should be evaluated within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

PR88 antibodies have been optimally manufactured for use with BioGenex Super Sensitive MultiLink® Detection Systems with or without BioGenex Automated Staining Systems.

Susan S. Altare

I I ahoratory Devices

510(k) Number K012960

Prescription Use

Regulation Number and Section

§ 864.1860 Immunohistochemistry reagents and kits.

(a)
Identification. Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.(b)
Classification of immunohistochemistry devices. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter. This exemption applies to IHC's that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding. These IHC's are used after the primary diagnosis of tumor (neoplasm) has been made by conventional histopathology using nonimmunologic histochemical stains, such as hematoxylin and eosin. Examples of class I IHC's are differentiation markers that are used as adjunctive tests to subclassify tumors, such as keratin.(2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.
(3) Class III (premarket approval). IHC's intended for any use not described in paragraphs (b)(1) or (b)(2) of this section.
(c)
Date of PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the Federal Food, Drug, and Cosmetic Act is required for any device described in paragraph (b)(3) of this section before this device may be commercially distributed. See § 864.3.