K Number

Device Name

DAKO MONOCLONAL MOUSE ANTI-HUMAN ESTROGEN RECEPTOR

Manufacturer

DAKO CORP.

Date Cleared

2000-03-03

(102 days)

Product Code

MYA

Regulation Number

864.1860

Intended Use

Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5 may be used in the semi-quantitative detection of human estrogen receptor in tissue sections of human breast cancer by immunohistochemistry. The information gained by this assay can aid in assessing the likelihood of response to therapy as well as in the prognosis and management of breast cancer patients. 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.

Device Description

1) Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5, Device Code No. M7047) is a mouse anti-human monoclonal antibody (Product) produced as a tissue culture supernatant. The antibody is supplied in Description: 0.05M Tris-HCl buffer, pH 7.2, containing fotal bovine serum and 15mM sodium azide. (1mL total volume). 2) Monoclonal Mouse Anti-Human Estrogen Receptor. Clone 105 Ready-to-Use Antibody and Negative Control (Product Code No. N1576) consists of a mouse anti-human monoclonal antibody produced as a tissue culture supernatant and pre-diluted in 0.05M Tris-HCI buffer, pH 7.6, containing fotal bovine serum and 15mM sodium azide (7mL total volume). The primary antibody is packaged with a negative control reagent consisting of a cocktail of purified mouse immunoglobulins (IgG, IgG, IgGz, IgGz, IgGz and IgM) in 0.05M Tris-HCI buffer, pH 7.6 and 15mM sodium azide (5mL total volume).

More Information

Contact

Type

Center

Panel

Date Received

Product Code

Subsequent Product Codes

Applicant Name (Manufacturer)

Device Name

Decision

Street 1

Street 2

City

State

Country Code

ZIP

Postal Code

Class Advise Committee

SSP Indicator

Third Party Reviewed

Expedited Review

Predicate Devices

P880026

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The document describes an antibody for immunohistochemistry and mentions the use of image analysis systems, but there is no indication that these systems incorporate AI or ML. The focus is on the antibody itself and its performance characteristics.

Therapeutic

No
The device is described as an antibody used for the detection of human estrogen receptor in tissue sections. Its purpose is to aid in assessing the likelihood of response to therapy and in prognosis/management, not to provide therapy itself. It is a diagnostic tool, not a therapeutic one.

Diagnostic

Yes

The device aids in assessing the likelihood of response to therapy and in the prognosis and management of breast cancer patients by detecting human estrogen receptor in tissue sections, which directly contributes to clinical interpretation and patient diagnosis/management.

SaMD (Software as a Medical Device)

The device description clearly indicates the device is a monoclonal antibody reagent, which is a biological product used in immunohistochemistry, not a software-only device. While image analysis systems are mentioned as being used in conjunction with the antibody, the device itself is the antibody reagent.

IVD (In Vitro Diagnostic)

Based on the provided information, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The intended use is the "semi-quantitative detection of human estrogen receptor in tissue sections of human breast cancer by immunohistochemistry." This is a diagnostic test performed in vitro (outside the body) on a biological specimen (tissue sections).
Clinical Interpretation: The information gained "can aid in assessing the likelihood of response to therapy as well as in the prognosis and management of breast cancer patients." This clearly indicates a clinical diagnostic purpose.
Device Description: The device is a reagent (monoclonal antibody) used in a laboratory procedure (immunohistochemistry) to analyze a biological sample.
Performance Studies: The document includes detailed performance studies comparing the device to a predicate device (Abbott ER-ICA Monoclonal, Clone H222) and reporting metrics like sensitivity and specificity, which are standard for IVD performance evaluation.
Predicate Device: The mention of a predicate device (P880026 Abbott ER-ICA Monoclonal, Clone H222) which is also an IVD, further supports the classification of this device as an IVD.
Intended User/Care Setting: The intended user is a "qualified individual having knowledge of all the potential antibody reactivities," implying use in a clinical laboratory setting, which is typical for IVDs.

The fact that it mentions image processing and image analysis systems does not change its fundamental classification as an IVD. These are tools used to aid in the interpretation of the results obtained from the in vitro diagnostic test.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5 may be used in the semiquantitative detection of human estrogen receptor in tissue sections of human breast cancer by immunohistochemistry. The information gained by this assay can aid in assessing the likelihood of respanse to therapy as well as in the prognosis and management of breast cancer patients.

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.

Product codes

MYA

Device Description

Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5, 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 fotal bovine serum and 15mM sodium azide. (1mL total volume).
Monoclonal Mouse Anti-Human Estrogen Receptor. Clone 105 Ready-to-Use Antibody and Negative Control (Product Code No. N1576) consists of a mouse anti-human monoclonal antibody produced as a tissue culture supernatant and pre-diluted in 0.05M Tris-HCI buffer, pH 7.6, containing fotal bovine serum and 15mM sodium azide (7mL total volume). The primary antibody is packaged with a negative control reagent consisting of a cocktail of purified mouse immunoglobulins (IgG, IgG, IgGz, IgGz, IgGz and IgM) in 0.05M Tris-HCI buffer, pH 7.6 and 15mM sodium azide (5mL total volume).

Mentions image processing

Yes

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

human breast cancer, normal tissue, breast, cervix, uterus

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

Normal Tissue Testing:
The required panel of normal tissues was tested with this antibody as specified in the 6/3/98 final version of Guidance for Submissions of Immunohistochemistry Applications to the FDA. All tissues were formalin fixed and paraffin embedded. Staining was performed using the DAKO LSAB®2 Peroxidase kit system (Code No. K0672).

Reproducibility Testing:
Eight serial sections from each of three different paraffin embedded blocks of human breast carcinoma were collected for testing.

Intra-run reproducibility: Following the standard DAKO LSAB®2 Peroxidase Kit protocol (Code No. K0677), three slides from each tissue block were steined with Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5 Ready-to-Use Antibody and negative control reagent consisting of fatal bovine serum in the equivalent diluent. Concurrently, one slide from each block was stained with the supplied negative control reagent.

Inter-run reproducibility: Staining one slide from each tissue block, the above procedure was repeated on two additional days. Concurrently, one slide from each block was stained with the supplied negative control reagent.

Twenty-six articles published on the characterization or clinical use of estrogen receptor were used in the submission. Twenty-three of those articles reported on studies using anti-ER, 1D5.

Summary of Performance Studies

Functional comparison testing of anti-ER, 1D5 on formalin-fixed paraffin-ambedded specimens and Abbort's ER-ICA using frozen breast cancer specimens is presented in Table 1.

Reproducibility Testing:
Reproducibility experiments with anti-ER. 1DE yielded consistent results with intra- and inter-run testing. Consistent test conditions were maintained throughout the study and reagents were stored at 2-8° C between test runs. (See Section 3 for the Report of the Results of the Reproducibility Testing.)

Published Immunoreactivity:
Twenty-three articles reported on studies using anti-ER, 1D5.
On frozen tissues, anti-ER, 1D6 immunoreacted with 63/93 (67.7%) cases of broast cancer and only 1/30 (3.3%) nonbreast cancers reacted positively. Direct comparison of anti-ER, 1D5 on formalin-fixed, paraffin-embodded (FFPE) specimens with H222 on frozen sections of the same tumors has been completed by 7 different laboratories on more than 1000 specimens. The results are reported in Table 1.

Key Metrics

Mauri, et al.: Specificity = 103/130 = 79.2%; Sensitivity = 231/244 = 94.6%
Goulding, et al.: 1D5 is more sensitive (90%vs 67%) but less specific (51% vs 62%) to H222
Nedergaard et al.: Specificity = 0.75; sensitivity = 0.96
Leong and Milos.: 1D5 specificity = 25/48 (73%); sensitivity = 23/26 (89%); + Predictive value = 23/36 (64%); - Predictive value = 35/38 (92%)
Hopkins et al.: Specificity = 98/151 = 64.90%; Sensitivity = 137/149 = 91.95%; 1D5 had 100% sensitivity and 88% specificity with H222 frozen
Hendricks and Wilkinson: ER 1D5 sensitivity = 93%; Specificity = 50%

Predicate Device(s)

Abbott ER-ICA Monoclonal, Clone H222 approved by the FDA as PM # P880026

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

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.

Summary

MAR - 3 2000

510{k) Summary

| Submitter: | DAKO Corporation
6392 Via Real
Carpinteria, CA 93013
805-566-6655 |
|---------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Gretchen M. Murray, Ph.D., Regulatory Affairs Manager |
| Date Summary
Prepared: | October 30, 1999 (amended March 2, 2000) |
| Device Name: | 1) DAKO® Monoclonal Mouse Anti-Human Estrogen Receptor, Clone
1D5, Antibody for Immunoenzymatic Staining (Product Code No.
M7047)

DAKO® Monoclonal Mouse Anti-Human Estrogen Receptor, Clone
1D5, Ready-to-Use Antibody and Negative Control Reagent for
Immunoenzymatic Staining (Product Code No.N1575) |
| Device
Classification: | Class II for prognostic immunohistochemical staining reagents (21
CFR 864.1860). |
| Panel: | Hematology and Pathology Devices Panel.
Division of Clinical Laboratory Devices. |
| Predicate Device: | Abbott ER-ICA Monoclonal, Clone H222 approved by the FDA as PM

P880026 and downclassified to class II by 21 CFR 864.1860,

Immunohistochemistry Reagents and Kits on June 3, 1998. Device
package insert from this product is included in Section 2 of this
submission. |

Monocional Mouse Anti-Human Estrogen Receptor, Clone 1D5, Device Code No. M7047) is a mouse anti-human monoclonal antibody (Product) produced as a tissue culture supernatant. The antibody is supplied in Description: 0.05M Tris-HCl buffer, pH 7.2, containing fotal bovine serum and 15mM sodium azide. (1mL total volume).

Monoclonal Mouse Anti-Human Estrogen Receptor. Clone 105 Ready-to-Use Antibody and Negative Control (Product Code No. N1576) consists of a mouse anti-human monoclonal antibody produced as a tissue culture supernatant and pre-diluted in 0.05M Tris-HCI buffer, pH 7.6, containing fotal bovine serum and 15mM sodium azide (7mL total volume). The primary antibody is packaged with a negative control reagent consisting of a cocktail of purified mouse immunoglobulins (IgG, IgG, IgGz, IgGz, IgGz and IgM) in 0.05M Tris-HCI buffer, pH 7.6 and 15mM sodium azide (5mL total volume).

Intended Use: For In Vitro Diagnostic Use

Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5 may be used in the semiquantitative detection of human estrogen receptor in tissue sections of human breast cancer by immunohistochemistry. The information gained by this assay can aid in assessing the likelihood of respanse to therapy as well as in the prognosis and management of breast cancer patients.

Statement of Substantial Equivalence:

DAKO" Monoclonal Mouse Anti-Human Estrogen Receptor, 1D5 (anti-ER, 1D5) is a monoclonal antibody produced as a tissue culture supernatant which is available as a concentrate (Code No. M7047) and a prediluted primary (Code No. N1675),

Anti-ER. 1D5 immunohistochemically demonstrates the presence of estrogen receptor in a variety of normal and pathological tissues. In normal tissue, anti-ER, 1D5 labels estrogen containing cells. Pathological reactivity includes detection of estrogen receptor in breast cancer.

Anti-ER, 1D6 is comparable in use and technology to Abbott ER-ICA Monoclonal, clone H222 which labels cells in tissues and is currently in commercial distribution. Similarities of the anti-ER, 1D5 to the Abbott ER-ICA include that both products are monoclonal antibodies directed against the human Estrogen Receptor (ER). The differences between the two products include that the DAKO anti-ER, 1D5 is directed to the N-terminal end of the ER, while the H222 clone from the Abbott ER-ICA is directed against the functional section of the ER, coded for in exon 5 of the ER DNA. Clone H222 is of rat origin, while anti-ER, 1D5 is of mouse origin. Functionally, anti-ER, 1D5 reacts with an epitope exposed in formalin-fixed, paraffin-embedded tissues by heat induced epitope retrieval. The H222 clone binds to ER found in frozen tissues. When the H222 clone has been tested on formalin-fixed, paraffin-embedded tissues, the specificity was decreased from that seen with frozen tissues.

Visualization of the primary antibody for the Abbott ER-ICA is achieved using an indirect peroxidase anti-peroxidase (PAP) system. ER-ICA monoclonal is located by a goat anti-rat bridging antibody. Anti-Rat PAP complex is added, which recognizes the bridging antibody. Then a precipitating enzyme generated product (hydrogen peroxide) and a chromogan substrate solution, containing DAB are added. The reaction product produces a reddish brown precipitate at the locations of the primary antibody.

The DAKO anti-estrogen receptor, clone 1D5 is substantially equivalent to the Abbott ER-ICA Monoclonal, clone H222 in that both products specifically bind to estrogen receptor proteins located in the nuclei of cells. Bath products require similar detection chemistry principles for visualization of the product, and both aid in the prognosis of breast carcinoma.

Functional comparison testing of anti-ER, 1D5 on formalin-fixed paraffin-ambedded specimens and Abbort's ER-ICA using frozen breast cancer specimens is presented in Table 1.

Experimental Data 1.

Normal Tissue Testing:

(The negative raagent control for these 2 studies was fetal bovine serum diluted with the same Tris-HCl buffer with 0.015M NaN3 as the primary antibody.)

The required panel of normal tissues was tested with this antibody as specified in the 6/3/98 final version of Guidance for Submissions of Immunohistochemistry Applications to the FDA. All tissues were formalin fixed and paraffin embedded. Staining was performed using the DAKO LSAB®2 Peroxidase kit system (Code No. K0672).

Normal tissues exhibiting positive staining with anti-ER, 1D5 included the following: breast, cervix and uterus. Refer to the package insert Table 2, Normal Tissue Reactivity for additional testing results or to Section 3 of this submission for the Results of the Normal Tissue Reactivity Testing.

Reproducibility Testing:

Eight serial sections from each of three different paraffin embedded blocks of human breast carcinoma were collected for testing. Testing was performed as follows:

Reproducibility experiments with anti-ER. 1DE yielded consistent results with intra- and inter-run testing. Consistent test conditions were maintained throughout the study and reagents were stored at 2-8° C between test runs. (See Section 3 for the Report of the Results of the Reproducibility Testing.)

)). Published Immunoreactivity

Twenty-six articles published on the characterization or clinical use of estrogen receptor were used in the submission. Twenty-three of those articles reported on studies using anti-ER, 1D5. Following is a brief summary of the compiled information.

Estrogen Receptor Characteristics

Steroid receptors exhibit a high affinity and specificity for their ligands. The human estrogen receptor (ER) is a dimeric protein of 65 kDa located primarily on the membrane of cell nuclei and belongs to a class of trans-acting proteins which stimulate transcription by binding to specific DNA elements, also known as hormone response elements. Through binding estrogen, the ER is induced to precisely stimulate gene transcription, hence is also known as an inducible enhancer factor. 1

Measurement of the ER has been shown to be important in the initial evaluation of breast cancer patients, for providing information on the likelihood of a successful endocrine response and for the management of the patiant and the tumor. 2.3

Development of ER-1D5 monoclonal antibody

The monoclonal antibody, anti-ER, 1D6 was produced in BALB/c mice by i.p. injection of recombinant estrogen receptor (RER). * The RER used was obtained by insarting human ER

cDNA into the Ndel-BamHI site of translation vector pETIla and introducing the same into the 5' end of the coding sequence of ER, a fragment of the plasmid pSG5-HGO. This modified cDNA was then inserted into the plasmid expression vector pETIla. E. coli, transformed with pETII-HGO, and produced a protein with molecular mass of 67kD. Clone 1D5 was shown to react with an epitope located in the N-terminal domain of ER.

Clone 1D5 Positivity in Normal Tissues

In normal frozen and formalin-fixed, paraffin-embedded human tissue, anti-ER, 1D5 reacts with the nuclei of cells known to contain large amounts of ER, including cells of the mammary gland and the uterus. No reactivity was found in tissues normally considered negative for ER. 4 When present, weak cytoplasmic staining was considered nonspecific.

Clone 1D5 Presence in Abnormal Tissues

In pathological tissues, anti-ER, 1D5 was examined for specificity and sensitivity for breast cancer as well as for the evaluation of patients for endocrine therapy. Numerous studies of cases of breast cancer showed anti-ER, 1D5 to be safe and effective in this endoavor. 513 On frozen tissues, anti-ER, 1D6 immunoreacted with 63/93 (67.7%) cases of broast cancer and only 1/30 (3.3%) nonbreast cancers reacted positively. 4 Direct comparison of anti-ER, 1D5 on formalin-fixed, paraffin-embodded (FFPE) specimens with H222 on frozen sections of the same tumors has been completed by 7 different laboratories on more than 1000 specimens. The results are reported in Table 1.

The specificity of anti-ER, 1D5 (aither assessed as compared to H222 or to outcome with tamoxifon) varied from 51% to 79% while sensitivity varied from 89% to 100%. H222 was reported to be less sensitive but more specific in one article. "* Thus, the use of IHC with anti-ER, 1D5 correlates well with a previously approved immunocytochemical assay for ER. However, clinical follow-uns have chown that IHC hu use of anti-FR 105 nrovided

のエロアルバイトのアイテムのアイデントを見つけるときにした。ここでも、この日は、2000年の2000の00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

and and the contribution of the first to the program and comments of the

Definition of positive IHC assay results with anti-ER. 1D5 have ranged somewhat arbitrarily from a minimum of any calls staining positive, to 5% of stained tumor nuclei, 21 to 10% " 11.13.15.18 22 or 20%.18 In over 900 cases of breast cancer, one investigator observed a strong relationship between staining intensity and the number of positive cells (g 0.001).ª Because of the above arbitrary limits of positivity, these authors and others 4, 20, 22-28 designed a semiguantitative "score" from the percentage of stained cells and the nuclear staining intensity (e.g. 0-3 or negative, weak, moderate, and strong). This scoring system is adopted for anti-ER, 1D5. Howaver, Pertchuck et al (1996) found little support for the use of such scores. 13

lmage analysis systems 7,8,19 and automated stainers 5 were used in an effort to obtain greater objectivity in assessing positive expressions but have yet to be validated in the literature.

In 105 cases of node-negative primary breast cancer, anti-ER, 105-positivity made no significant difference in predicting overall survival, whereas in 152 node-positive casas, anti-ER, 1D5-positivity was found to be prognostically relevant for predicting overall survival and predicting relapse-free survival.11 Staining with anti-ER, 106 provided predictive information for the selection of patients who may benefit by hormonal treatment. 1 Image analysis of stained tissues from 250 cases of breast cancer showed disease progression to be 1.7 times and death rate to be 2.5 times higher in anti-ER, 1D5negative cases than in 1D5-positive cases if the cut-off value was "optimally" salected. 4 Of 36 Anti-ER, 1 D5-positive cases, 23 (64%) showed favorable responses to therapy, whereas 35/38 (92%) 1D5-negative cases showed disease progression. 13 Others 19 have reported that 1D5-positivity was a strong prodictor of favorable primary response to tamoxifen in 89% of 72 cases and that treatment did not impede the detection of ER by anti-ER, 1D5.

Bibliography:

1. Kurnar V, Green S, Stack G, Berry M, Jin J-R, Chambon P. Functional domains of the human estrogen receptor. Cell 1987; 51: 941
1. Glick JH, Abeloff MD, Brown BW jr, Cobau CD, Johnson BL, Lichter AS, O'Bannon HB, Ottman R, Russo J, Singer K, Trafford A, Wood WC. Adjuvant chemotherapy for breast cancer. J Am Med Assn 1986; 264(24): 3461

Pertschuk LP, Kim Y-D, Axiotis CA, Braverman AS, Carter AC, Eisenberg KB, Braithwaite 3. LV. Estrogen receptor immunocytochemistry: The promise and the perils. J Cell Biochem 1994: Suppl 19: 134.
Al Saati T, Clamons S, Cohen-Knafo E, Faye JC, Prats H, Coindre JM, Wafflart J, 4. Caveriviere P, Bayard F, Dasol G. Production of monoclonal antibodies to human estrogen receptor protein (EA) using recombinant ER (RER). Int J Cancer 1993; 56: 661
1. Esteban JM, Ahn C, Battifora H, Felder B. Quantitative immunohistochemical assay for hormonal receptors: Technical aspects and biological significance. J Cell Biochem, 1994; Suppl 19: 138
Esteban JM, Felder B, Ahn C, Simpson JF, Battifora H, Shively JE. Prognostic relevance of 6. carcinoembryonic antigen and estrogen receptor status in breast cancer patients. Cancer 1994; 74(6): 1576
Esteban JM, Ahn C, Mehta P, Battifora H. Biologic significance of quantitative estrogen 7. receptor immunohistochemical assay by image analysis in breast cancer. Am J Clin Pathol 1994; 102(2): 158
1. Esteban JM, Ahn C, Battifora H, Felder B. Predictive value of estrogen receptors evaluated by quantitative immunohistochemical analysis in breast cancer. Am J Clin Pathol 1994; 102(4) Syppl 1: S9
1. de Mascarel I, Soubevran I, MacGrogan G, Wafflart J, Bonichon F, Durand M, Avril A, Mauriac L. Troiani M. Coindre JM. Immunohistochemical analysis of estrogen receptors in 938 breast carcinomas: Concordance with biochemical assay and prognostic significance. Appl Immunohistochem 1995; 3(4): 222
Johnston SRD, Sacanni-Jotti G. Smith IE, Salter J. Newby J. Coppen M, Ebbs SR, Dowsett 10. M. Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifenresistant human breast cancer. Cancer Res 1996; 56; 3331
1. Veronese SM, Barbareschi M, Morelli L, Aldovini D, Mauri FA, Caffo O, Gambacorta M, Dalla Palma P. Predictive value of ER1D5 antibody immunostaining in breast cancer. Appl Immunohistochem 1996; 3(2): 86
1. Pellicer EM, Sundblad A. Evaluation antibodies to estrogen receptors. Appl Immunahistachem 1994 ; 2(2); 141
1. Pertschuk LP, Feldman JG, Kin Y-D, Braithwaite L, Schneider F, Braverman AS Axiotis C. Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D6 predicts breast cancer endocrine response more accurately than H222Spy in frozen sections or cytosol-based ligand-binding assays. Cancer 1996; 77(12): 2514
1. Goulding H, Pinder S, Cannon P, Pearson D, Nicholson R, Snead D, Bell J, Elston CWE, Robertson JF, Blamey RW, Ellis IO. A new immunohistochemical antibody for the assessment of estrogen receptor status on routine formalin-fixed tissue samples. Hum Pathol 1995; 26: 291
1. Mauri FA, Veronese S, Frigo B, Girlando S, Losi L, Gambacorta M, Palma PD, Barbareschi M. ER1D5 and H222 (ER-ICA) antibodias to human estrogen receptor protein in breast carcinomas. Appl Immunohistochem 1994; 2(3):167
Barnes DM, Harris WH, Smith P, Millis RR, Rubens RD. Immunohistochemical determination 16. of oestrogen receptor: Comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 1996; 74: 1446
1. Hopkins CA, McNeill WF, Walker GH. Comparison of antibodies for estrogen and progesterone receptors using paraffin-embedded tissues and frozen sections. Am J Clin Pathol 1996; 103(4) 603
1. Nedergaard L. Haerslev T, Jacobsen GK, Immunohistochemical study of estrogen receptors in primary breast carcinomas and their lymph node metastases including comparison of two monoclonal antibodies. APMIS 1996; 103; 20
1. Hendricks JB, Wilkerson EJ. Comparison of two antibodies for evaluation of estrogen receptors in paraffin-embedded turnors. Modern Pathol 1993; 6(6): 766

Leong AS-Y, Milios J. Comparison of antibodies to estrogen and progesterone receptors 20. and the influence of microwave-antigen retrieval. Appl Immunohistochem 1993 ; 144: 282
Kell DL, Kamel OW, Rouse RV. Immunohistochamical analysis of broast carcinoma estrogen 21. and progesterone receptors in paraffin-ambedded tissue: Correlation of clones ER1D5 and 1 A6 with cytosol-based hormone receptor assay. Appl Immunohistochem 1993; 114): 276
Bier B, Bankfalvi A, Grote L, Blasius S, Ofner D, Bōcker W, Jasani B, Schmid KW. Wet 22. autoclave pretreatment for immunohistochemical demonstration of oestrogen receptors in routinely processed breast carcinoma tissue. Histochem J 1996; 27: 148
Sannino P, Shousha S. Demonstration of oestrogen receptors in paraffin wax sections of 23. breast carcinoma using the monoclonal antibody 105 and microwave oven processing. J Clin Pathol 1994; 47: 90 1994
1. Sacanni Jotti G, Johnston SRD, Salter J, Detre S, Dowsett M. Comparison of new immunohistochemical assay for cestrogen receptor in paraffin wax embedded breast carcinoma tissue with quantitative enzyme immunoassay. J Clin Path 1994; 47: 900
1. Balaton AJ, Mathieu M-C, Le Doussal V. Optimizaiton of heat-induced epitope retrieval for estrogen receptor determination by immunohistochemistry on paraffin sections. Appl Immunohistochem 1996; 4(4): 259
1. Barnes DM, Millis RR. Oestrogen receptors: the history, the relevance and the mathods of evaluation. In Kirkham N, Lamoine NR, eds. Progress in Pathology 2, Edinburgh, Churchill Livingstone, 1995, 89

TABLE 1

: 上

A-014-088	1
	ﮐ
	able	1

| Author/Journal | Study
comparison | Number
of
samples | Scoring system | 2x2 | | Relationship to outcome |
|----------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|----------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | | | | + | H222 | |
| Mauri, et al. Appl
Immunohistochem 2(3) 1994;
15715 | 1D5 (DAKO)
to H222
(frozen) | 374 | All cells with stained
nuclei were counted
as positive. 7.2%
(1D5+/H222-) and
3.5% 1D5-/H222+. | 231 + 231
1D5 - 13
Total 244 | 27
103
130 | Specificity = 103/130 = 79.2
Sensitivity = 231/244 = 94.6 |
| Goulding, et al.
Human Pathol
1995; 26:29114 | 1D5 (DAKO)
paraffin to
H222, frozen | 90 | H scores 1D5
correlation with
H222 frozen R=
0.7, with
p Trade Name: DAKO® Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5, Antibody for Immunoenzymatic Staining (Product Code No. M7047) and DAKO® Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5, Ready-to-Use Antibody and Negative Control Reagent for Immunoenzymatic Staining (Product Code No. N1575)

Regulatory Class: II Product Code: MYA Dated: February 4, 2000 Received: February 17, 2000

Dear Dr. Murray:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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 (Premarket Approval), 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 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic OS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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 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

Page

510(k) Number (if known): K993957

Device Name: Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5 Antibody for Immunoenzymatic Staining (DAKO Code No. M7047)

Monoclonal Mouse Anti-Human Estrogen Receptor, Clone 1D5 Ready-to-Use Antibody and Negative Control for Immunoenzymatic Staining (DAKO Code No. N1575)

Indications For Use:

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

inn of Clinical Laboratory Devi

Prescription Use V (Per 21 CFR 801.109)

IVD Use V (Per 21 CFR 801.119 Over-The-Counter Use (Per 21 CFR 801.110

(Optional Format 1-2-96)

19 18

AP
11-17-