Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636 is intended for use in the qualititative detection of human progesterone receptor in tissue sections of human breast cancer by immunohistochemistry. The assay is intended for use as an aid in selecting patients most likely to benefit from hormonal therapy as well as an aid in the prognosis and management of breast cancer.

Device Description

Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, (Product Code No. M3569) is a mouse anti-human monoclonal antibody produced as a tissue culture supernatant. The antibody is supplied in 0.05M Tris-HCl buffer, pH 7.2, containing fetal bovine serum and 15mM sodium azide. (0.2 mL and 1 mL total volume).
Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use Antibody (Product Code No. N1630) consists of a mouse anti-human monoclonal antibody produced as a tissue culture supernatant and pre-diluted in 0.05M Tris-HCl buffer, pH 7.6, containing fetal bovine serum and 15mM sodium azide (7mL and 11 mL sizes).
Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use Antibody (Product Code No. NP008) consists of a mouse anti-human monoclonal antibody produced as a tissue culture supernatant and pre-diluted in 0.05M Tris-HCl buffer, pH 7.6, containing fetal bovine serum and 15mM sodium azide (7mL total volume).

AI/ML Overview

Here's an analysis of the provided text, focusing on the acceptance criteria and the study that proves the device meets those criteria:

Device: DAKO Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636 (M3569, N1630, NP008)

Intended Use: Qualitative detection of human progesterone receptor (PgR) in tissue sections of human breast cancer by immunohistochemistry. Aid in selecting patients most likely to benefit from hormonal therapy and in the prognosis and management of breast cancer.

1. Table of Acceptance Criteria and Reported Device Performance:

Acceptance Criteria (Inferred from Predicate Equivalence)	Reported Device Performance (vs. Abbott PR-EIA)
Overall Concordance: High agreement with predicate device (implied by "substantial equivalence")	90.7%
Sensitivity: High detection of positive cases (implied)	87.2%
Specificity: High detection of negative cases (implied)	94%
Kappa Statistic: Strong agreement (implied)	0.8139 (almost perfect correlation)
Tissue Reactivity (Normal Tissues): Specific staining patterns as expected (implied by "Guidance for Submissions of Immunohistochemistry Applications to the FDA")	As per Table 1 (Breast, Cervix, Pituitary, Prostate, Uterus positive; other tissues negative)
Tumor Reactivity: Appropriate staining of known tumor types (implied)	Breast cancer (5/11), uterine (2/2), ovarian (2/6), endometrial (2/2) carcinomas stained strongly; Medullary thyroid (1/2), testicular yolk sac positive; melanoma, lymphoma, neuroendocrine, neural tumors negative.
Western Blot Reactivity: Specific binding to PR-A and PR-B without significant cross-reactivity (implied)	Reacted strongly with PR-A and PR-B from T47D cells; little/no cross-reactivity with other proteins; reacted equally with unliganded and liganded PR; epitope within amino terminal domain (aa 165-533).

Note: The document explicitly states the "Concordance calculation showed concordance = 88 / 97 = 90.7% in this trial. Using the PR-ElA as the predicate device, sensitivity was determined to be 41/47 = 87.2% while specificity was determined to be 47/50, = 94%. The Kappa statistic indicated a 0.8139 kappa, which corresponds to an almost perfect correlation for the qualitative assessment." These values are direct performance metrics against the predicate. The criteria are indirectly inferred as the targets needed to demonstrate substantial equivalence.

2. Sample Size Used for the Test Set and Data Provenance:

Sample Size for Comparison Study: 97 breast carcinoma specimens were successfully evaluated for comparison with the Abbott PR-EIA. (Initially, 106 tests were performed on 101 specimens, but 2 had too little tumor tissue and 2 lacked corresponding PR-EIA results, reducing the comparison set to 97).
Data Provenance: Not explicitly stated, but it's a comparison to the Abbott PR-EIA which is a predicate device, likely indicating retrospective use of existing archived samples with known PR-EIA results. The country of origin is not specified, but given DAKO's location (USA) and the FDA submission, it's reasonable to assume the data is from the US or a region with comparable standards.

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

Not explicitly stated for the comparison study. The ground truth for the comparison study was established by the Abbott PR-EIA, which is itself a laboratory assay. Therefore, the "ground truth" for this specific comparison was the result generated by the predicate device, rather than a panel of human experts reviewing the slides.
For the immunohistochemistry (IHC) on normal and tumor tissues, the evaluation of staining patterns and intensities ("3+ staining intensity," "2+ staining intensity") would have been performed by qualified pathologists or laboratory personnel with expertise in IHC interpretation. However, the exact number and qualifications are not mentioned.

4. Adjudication Method for the Test Set:

Not applicable in the context of the comparison study, as the ground truth was the result from the predicate Abbott PR-EIA assay. The DAKO device's result was compared directly against this predicate result.
For the initial normal and tumor tissue reactivity studies, the evaluation of staining was reported as findings. There is no mention of an adjudication process (e.g., 2+1, 3+1) for interpreting IHC results in the document; typically, this would be handled by a single qualified individual or through internal quality control mechanisms.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Improvement:

No, an MRMC comparative effectiveness study was not done. The study presented is a direct comparison of the DAKO device's output against a predicate device's output (Abbott PR-EIA) on breast cancer specimens. It does not involve human readers' interpretation with and without AI assistance to measure improvement.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

This device is an antibody reagent for immunohistochemistry (IHC). IHC is inherently a "standalone" assay in the sense that the antibody binds to the target protein in the tissue, and the staining is then visually interpreted.
The "performance" described here is the ability of this antibody to produce staining results that correlate with a predicate assay for progesterone receptor. There is no "algorithm" or "AI" involved, nor is there a "human-in-the-loop" component beyond the standard interpretation of an IHC slide by a pathologist. This is a traditional IVD reagent, not an AI-powered diagnostic device.

7. The Type of Ground Truth Used:

For the comparison study: The ground truth was results from the predicate device, Abbott PR-EIA.
For the normal and tumor tissue reactivity studies: The ground truth was based on expected biological expression of progesterone receptor in various normal and tumor tissues, evaluated by presumably qualified laboratory personnel/pathologists through visual interpretation of IHC staining.

8. The Sample Size for the Training Set:

Not applicable / not provided. This is an antibody reagent, not a machine learning algorithm. Therefore, there is no "training set" in the computational sense. The antibody's specificity and reactivity are inherent to its molecular properties and laboratory development, not trained on data.

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

Not applicable. As stated above, there is no training set for this type of device. The development of the antibody (Clone PgR 636) and confirmation of its binding characteristics (e.g., in Western blot described) are part of its development, but not "training" in the context of an AI/ML algorithm.

Summary

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510(k) Summary	DAKO Mouse Anti-HumanProgesterone ReceptorClone PgR 636
Submitter:	K020023DAKO Corporation6392 Via RealCarpinteria, CA 93013805-566-6655	FEB 2 8 2002
Contact:	Gretchen M. Murray, Ph.D., Regulatory and Clinical Affairs Manager
Date SummaryPrepared:	December 18, 2001
Device Name:	1) DAKO® Monoclonal Mouse Anti-Human Progesterone Receptor, ClonePgR 636, Antibody for Immunoenzymatic Staining (Product Code No.M3569)2) DAKO® Monoclonal Mouse Anti-Human Progesterone Receptor, ClonePgR 636, Ready-to-Use Antibody for Immunoenzymatic Staining (ProductCode No. N1630)3) DAKO® Monoclonal Mouse Anti-Human Progesterone Receptor, ClonePgR 636, Ready-to-Use Antibody for Immunoenzymatic Staining (ProductCode No. NP008)
DeviceClassification:	Class II for prognostic immunohistochemical staining reagents (21 CFR864.1860).
Panel:	Hematology and Pathology Devices Panel,Division of Clinical Laboratory Devices.
Predicate Device:	Abbott PR-EIA approved by the FDA as PMA # P900013 anddownclassified to Class II by 21 CFR 864.1860, ImmunohistochemistryReagents and Kits on June 3, 1998. Device package insert from thisproduct is included in Section 2 of this submission.
DeviceDescription:	1) Monoclonal Mouse Anti-Human Progesterone Receptor,Clone PgR 636, (Product Code No. M3569) is a mouse anti-humanmonoclonal antibody produced as a tissue culture supernatant. Theantibody is supplied in 0.05M Tris-HCl buffer, pH 7.2, containing fetalbovine serum and 15mM sodium azide. (0.2 mL and 1 mL total volume).2) Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636,Ready-to-Use Antibody (Product Code No. N1630) consists of a mouseanti-human monoclonal antibody produced as a tissue culture

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510(k) Summary	DAKO Mouse Anti-HumanProgesterone ReceptorClone PgR 636
supernatant and pre-diluted in 0.05M Tris-HCl buffer, pH 7.6, containingfetal bovine serum and 15mM sodium azide (7mL and 11 mL sizes).
3) Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636,Ready-to-Use Antibody (Product Code No. NP008) consists of a mouseanti-human monoclonal antibody produced as a tissue culturesupernatant and pre-diluted in 0.05M Tris-HCl buffer, pH 7.6, containingfetal bovine serum and 15mM sodium azide (7mL total volume).
Intended Use:	For In Vitro Diagnostic Use
	Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636 isused in the qualitative detection of human progesterone receptor intissue sections of human breast cancer by immunohistochemistry using amanual or automated procedure. This antibody is indicated for use as anaid in selecting patients most likely to benefit from hormonal therapy aswell as an aid in the prognosis and management of breast cancer.
ExperimentalData:		Distribution of PgR throughout normal tissue has been reported in avariety of studies. The nuclei of uterine gland cells were found to bestrongly immunoreactive. Weaker immunostaining was observed in thenuclei of endometrial and prostatic stromal cells.
	Immunoreactivity in a panel of normal tissues:
	The required panel of normal tissues was tested with this antibody asspecified in the 6/3/98 final version of Guidance for Submissions ofImmunohistochemistry Applications to the FDA. All tissues were formalinfixed and paraffin embedded. Staining was performed using the DAKOLSAB®2 Peroxidase kit system (Code No. K0672).
	Table 1 contains a list of positive tissues with PgR immunoreactivity. Alltissues were formalin-fixed and paraffin embedded and stained with Anti-PgR, 636 according to the instructions in the package insert.

and the commend of the comments of

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TABLE 1: Summary of PgR Normal Tissue Reactivity
TISSUE TYPE(# tested)	POSITIVE TISSUE ELEMENTSTAINING AND STAINING PATTERN
Breast (3)	Ductal epithelial cells (3+ staining intensity, 3/3 tissues)
Cervix uteri (3)	Glandular epithelial cells (2+ staining intensity, 1/3 tissues); Stromal fibroblasts(2+ staining intensity, 2/3 tissues)
Pituitary (3)	Pituicytes (2+ staining intensity, 1/3 tissues)
Prostate (3)	Stromal fibroblasts (2+ staining intensity, 1/3 tissues)
Uterus (3)	Endometrial stroma (2+ staining intensity 3/3 tissues)Myometrium (2+ staining intensity, 3/3 tissues)Endometrial glands (2+ staining intensity, 2/3 tissues)

Negative tissues included adrenal (4), bone marrow (2,) brain/cerebellum (4), brain/cerebrum (3), colon (3), esophagus (3), heart (3), kidney (3), liver (3), lung (3), mesothelial cells (3), ovary (3), pancreas (3), parathyroid (3), peripheral nerve (3), salivary gland (3), skeletal muscle (3), skin (3), small intestine (3), spleen (4), stomach (3), testis (3), thymus (3), thyroid (3), and tonsil (3).

A second survey of normal tissues demonstrated positivity in endometrium and weak positivity in prostate after heat-induced epitope retrieval. Negative tissues included esophagus, testes, breast liver, kidney, skeletal muscle, placenta, adrenal, tonsil, lung, colon, skin, pancreas, spleen, thyroid, stomach and cardiac muscle. (See Press article)

Other testing with PgR 636 clone

Western blot

PgR 636 was tested in Western blots using whole cell extracts from 2 cell lines, MDA-MB-231 (PR negative) and T47D (PR A and PR B positive). PgR 636 reacted strongly with both PR-A and PR-B bands from T47D cells, and gave little or no cross reactivity with other proteins in the T47D cell extracts. PgR 636 reacted equally with unliganded and liganded PR. The domain mapping experiments demonstrated that PgR 636 reacted with amino terminal domain (AN) and the amino terminal domain linked to DBD, but not with any of the C-terminal tail (aa 919-933) of human PR. Thus, the PgR 636 epitope is contained within the amino termal domain common to the A and B receptors in a region between an 165 and 533. (See Press article)

Immunohistochemistry of tumors

PR 636 was used to immunostain a variety of 60 different tumor types. Breast cancer (5/11), uterine (2/2), ovarian (2/6), and endometrial (2/2) carcinomas stained strongly. Medullary carcinoma of the thyroid (1/2) and testicular yolk sac tumor were positive. Other tumors including

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melanoma, lymphoma and neuroendocrine and neural turnors were negative for PR expression. (See Press article)

Comparison testing to Abbott PR-EIA

Substantial equivalence to the Abbott PR-EIA was demonstrated in a comparison study of breast carcinomas. One hundred six tests were performed on 101 specimens previously evaluated for PR presence using the Abbott PR-EIA. Two specimens had too little tumor tissue for evaluation. Two specimens had no corresponding PR-EIA results for the 97 specimens indicated 53 as negative for PR by IHC, and 44 positive. Correlation with the PR-EIA is presented in Table 2.

Concordance of DAKO Monoclonal Mouse anti-human Progesterone Table2:

	Abbott Result
DAKO Result	Negative	Positive	Total
Negative	47	6	53
Positive	3	41	44
Total	50	47	97

Receptor clone PgR 636 with Abbott PR-EIA

Concordance calculation showed concordance = 88 / 97 = 90.7% in this trial. Using the PR-ElA as the predicate device, sensitivity was determined to be 41/47 = 87.2% while specificity was determined to be 47/50, = 94%. The Kappa statistic indicated a 0.8139 kappa, which corresponds to an almost perfect correlation for the qualitative assessment.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo features a stylized eagle with three wings, representing health, services, and people. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle.

Gretchen M. Murray, Ph.D. Regulatory and Clinical Affairs Manager DAKO Corporation 6392 Via Real Carpinteria, California 93013

FEB 2 8 2002

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

FEB 2 8 2002

Re: K020023

Trade/Device Name: DAKO Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636 Antibody for Immunoenzymatic Staining available in three different iterations:

1. (Product Code No. M3569),
1. Ready-to-use (Product Code No. N1630),
1. Ready-to-use (Product Code No. NP008)

Regulation Number: 21 CFR § 864.1860 Regulation Name: Immunohistochemistry Reagents and Kits Regulatory Class: II Product Code: MXZ Dated: December 31, 2001 Received: January 3, 2002

Dear Dr. Murray:

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 Putman

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

510(k) Number (if known):_____________________________________________________________________________________________________________________________________________________

Device Name: Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636 Antibody for Immunoenzymatic Staining available in three different iterations:

DAKO Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Antibody for Immunoenzymatic Staining (Product Code No. M3569)

DAKO® Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use Antibody for Immunoenzymatic Staining (Product Code No. N1630)
DAKO® Monoclonal Mouse Anti-Human Progesterone Receptor, Clone PgR 636, Ready-to-Use Antibody for Immunoenzymatic Staining (Product Code No. NP008)

Indications For Use:

The clinical interpretation of any positive staining or its absence should be complemented by morphological and histological studies with proper controls. Evaluations should be made within the context of the patient's clinical history and other diagnostic tests by a qualified individual having knowledge of all the potential antibody reactivities.

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)

IVD Use (Per 21 CFR 801.119) OR

Over-The-Counter Use (Per 21 CFR 801.110

Sousan S. Altaie

(Division Sign-Off) Division of Clinical Laboratory Devices Division of Chilegi __________________________________________________________________________________________________________________________________________________________

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.