BIOGENEX MONOCLONAL ANTI-PROGESTERONE RECEPTOR

K012960 · Biogenex Laboratories · MXZ · Mar 8, 2002 · Hematology

Device Facts

• Record ID: K012960
• Device Name: BIOGENEX MONOCLONAL ANTI-PROGESTERONE RECEPTOR
• Applicant: Biogenex Laboratories
• Product Code: MXZ · Hematology
• Decision Date: Mar 8, 2002
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.1860
• Device Class: Class 2

Indications for Use

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

Device Story

BioGenex PR88 is a mouse monoclonal antibody (Clone PR88) used in immunohistochemical (IHC) assays. It binds to progesterone receptor antigens in the nuclei of normal and abnormal tissue cells. The device is used in clinical laboratories by pathologists to process paraffin-embedded, formalin-fixed tissue sections. The antibody is applied manually or via BioGenex Automated Staining Systems using the Super Sensitive MultiLink Detection System. Pathologists examine the resulting stained slides under light microscopy to identify nuclear staining. The presence or absence of staining, evaluated alongside clinical history and other diagnostic tests, assists in assessing hormonal therapy response and managing breast cancer patients. The device provides a qualitative assessment of receptor status, offering a more localized analysis of tumor cells compared to traditional biochemical assays.

Clinical Evidence

Bench testing only. Study compared PR88 IHC to gold-standard DCC biochemical assay using 134 clinical specimens. Concordance was 74% (95% CI: 66%-81%, p<0.0001). Discordance (26%) attributed to IHC's ability to specifically target tumor cells versus DCC's homogenization of whole tissue. Reproducibility studies (intra-run, inter-run, and manual vs. automated) showed no significant variation. Stability testing confirmed 24-month shelf life at 2-8°C.

Technological Characteristics

Mouse monoclonal antibody (Clone PR88, IgG1, Kappa) in phosphate buffered saline (pH 7.6) with bovine serum albumin and 0.09% sodium azide. Formulated as concentrate or ready-to-use. Compatible with BioGenex Super Sensitive MultiLink Detection Systems and automated staining platforms. Storage at 2-8°C.

Indications for Use

Indicated for use as an aid in assessing patient response to hormonal therapy and as an aid in the prognosis and management of breast cancer patients. Used for qualitative identification of progesterone receptor in normal and pathological paraffin-embedded, formalin-fixed tissues.

Regulatory Classification

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.

Special Controls

(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.

Predicate Devices

• Ventana PGR primary antibody (K990618)

Submission Summary (Full Text)

{0}------------------------------------------------

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.<br>4600 Norris Canyon Road<br>San Ramon, CA 94583<br>925-275-0550 (Tel)<br>925-275-0580 (Fax) |
|-----------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact Persons: | Gurvinder S. Nanda, Ph.D.<br>Manager, Regulatory Affairs<br>925-543-1336 (Tel)<br>925-866-2525 (Fax)<br>Jintao Chen, Ph.D.<br>Director, Operations<br>925-866-2568 (Tel)<br>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<br>(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).

{1}------------------------------------------------

### DESCRIPTION OF THE DEVICE:

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.

### INTENDED USE:

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.

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<br>(New device-K012960) | Ventana<br>(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 use<br>to qualitatively identify by<br>light microscopy human<br>progesterone receptor in<br>normal and/or pathological | Is intended for laboratory use<br>for the qualitative detection<br>of progesterone receptor<br>(PGR) antigen in sections of<br>formalin fixed, paraffin |

{2}------------------------------------------------

| | paraffin-embedded, formalin-fixed tissues. | embedded normal and<br>neoplastic tissue on a<br>Ventana automated<br>immunohistochemistry slide<br>staining device. |
|---------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Indication | This antibody is indicated as<br>an aid in assessing patient<br>response to hormonal therapy<br>and as an aid in the prognosis<br>and management of breast<br>cancer patients. | This antibody is indicated as<br>an aid in the management<br>prognosis and prediction of<br>therapy outcome of breast<br>cancer within the context of<br>patient's clinical history and<br>other diagnostic tests<br>evaluated by a qualified<br>pathologist. |
| Specificity | Human progesterone<br>receptor in formalin-fixed<br>paraffin embedded tissues. | Human progesterone receptor<br>in formalin-fixed paraffin<br>embedded tissues. |
| Total protein<br>concentration: | 10 mg/ml | 10 mg/ml |
| Storage | 2-8°C | 2-8°C |
| Application | For manual and automated<br>use | 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.

{3}------------------------------------------------

- (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.

{4}------------------------------------------------

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.

{5}------------------------------------------------

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.

{6}------------------------------------------------

## 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.

{7}------------------------------------------------

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, [phone]. Additionally, for question of [phone]. 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 [phone] 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

{8}------------------------------------------------

# 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