K Number

Device Name

Manufacturer

VYSIS

Date Cleared

1997-10-20

(132 days)

Product Code

Regulation Number

Type

Panel

Reference & Predicate Devices

N/A

Predicate For

N/A

Intended Use

The AneuVysion™ (CEP 18, X, Y-alpha satellite, LSI 13 and 21) Multicolor Probe Panel is intended to use CEP 18/X/Y probe to detect alpha satellite sequences in the centromere regions of chromosomes 18, X, and Y, and LSI 13/21 probe to detect the 13q14 region and the 21q22.13 to 21q22.2 region. The AneuVysion™ kit is indicated for use as an adjunct to standard cytogenetic metaphase analysis for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in metaphase cells and interphase nuclei obtained from amniotic fluid in subjects with presumed high risk pregnancies. It is not intended to be used as a stand alone assay for test reporting. FISH results are intended to be reported and interpreted only in conjunction with results of standard cytogenetic analysis, performed concurrently, utilizing the same patient specimen. FISH results should not be reported prior to standard cytogenetic results except in instances where reporting of FISH results alone is medically indicated or standard cytogenetic results are not available, e.g., culture failure. Reporting and interpretation of FISH should be consistent with professional standards of practice! This device is intended for use only with amniocyte cells; it is not intended for and has not been validated for use with other test matrices. This FISH assay will not detect the presence of structural chromosome abnormalities frequently associated with birth defects. This FISH assay will be performed in cytogenetics laboratories.

Device Description

The AneuVysion™ kit is a combination of two DNA probe mixtures; CEP 18/X/Y and LSI 13/21. The CEP 18/X/Y probe is a mixture of directly labeled fluorescent DNA probes specific for the D18Z1, DXZ1 and DYZ3 regions of chromosomes 18, X, and Y respectively. The LSI 13/21 probe contains a mixture of unique DNA sequences that hybridize in the 13q14 region of chromosome 13, and unique DNA sequences complementary to the D21S259, D21S341, and D21S342 loci contained within the 21q22.13 to 21q22.2 region on the long arm of chromosome 21. The LSI 13 probe was created from a set of overlapping clones which contain the entire RB-1 gene as well as regions extending beyond the gene on both sides. The probe extends beyond the 180 kb RB-1 gene for 110-170 kb in the 5' direction and approximately 120 kb in the 3' direction; the entire probe is 410-470 kb. CEP 18/X/Y is an aqua, green, and orange tri-color probe mixture and LSI 13/21 is a green and orange dual-color probe mixture.

AI/ML Overview

Table of Acceptance Criteria and Reported Device Performance

Performance Metric	Acceptance Criteria	Reported Device Performance
Hybridization Efficiency	<2% cells with no or only one signal for each probe	LSI 13, CEP 18, LSI 21: Average percentage of cells with no hybridization signal was 0.42%. CEP X/Y: Average percentage of cells with only one hybridization Y signal was 0.06%.
Analytical Sensitivity (Limit of Detection)	Not explicitly stated as a fixed acceptance criterion, but implied to be near 3% based on study results.	Estimated to be 3%. 0% XO specimen: Mean 0.04% (±0.20%) X-signaled nuclei, upper 95% CI 0.43%. 10% XO specimen: Mean 9.10% (±1.79%) X-signaled nuclei, lower 95% CI 5.59%.
Analytical Specificity	No cross-hybridization to non-target chromosome loci	No cross-hybridization to other chromosome loci was observed in any of the 705 metaphase cells examined; hybridization was limited to the target regions of chromosomes 13, 18, 21, X, and Y.
Reproducibility (Inter-site, inter-lot, inter-day, inter-observer)	No significant variations observed in ANOVA analysis for percentage of aneuploid cells.	No significant variations were observed in any of the inter-assay reproducibility parameters (inter-site, inter-lot, inter-day, inter-observer) using ANOVA. Intra-assay variability (mean, S.D., C.V.) shown in Table 1 for various mosaicism levels.
Informativeness Rate (Per Specimen)	Not explicitly stated as a fixed acceptance criterion; however, a high rate is implied for device utility.	97.5% (2183/2238)
Informativeness Rate (Per Patient)	Not explicitly stated as a fixed acceptance criterion; however, a high rate is implied for device utility.	99.8% (1503/1516)
Detection of True Aneuploidy	Detect 100% of cases identified by standard cytogenetic analysis.	Detected 99.9% (860/861) of true aneuploid cases identified by standard cytogenetic analysis (one case attributed to long storage).
Detection of Euploidy	Detect 100% of cases identified by standard cytogenetic analysis.	Detected 100% (504/504) of euploid cases identified by standard cytogenetic analysis (FISH showed <10% aneuploid cells).
Correlation of % Aneuploid Cells in Mosaic Cases (FISH vs. Standard Cytogenetics)	Not explicitly stated as a fixed acceptance criterion, but a high correlation indicates good device performance.	0.76
Pseudomosaic Cases (FISH results)	Show less than 10% aneuploid cells, consistent with the euploid state.	FISH assay results showed less than 10% aneuploid cells, which is consistent with the euploid state, across all 76 pseudomosaic cases.
Concordance between Cultured and Uncultured Samples (Aneuploid, Euploid, Pseudomosaic)	Concordant results between cultured and uncultured samples for aneuploid, euploid, and pseudomosaic cases.	The FISH test results in aneuploid, euploid and pseudomosaic cases were concordant between cultured and uncultured samples. (Note: In mosaic cases, varying % aneuploid cells between cultured and uncultured samples led to a few discordances).

Study Details Proving Device Meets Acceptance Criteria:

The information provided describes several studies that collectively demonstrate the performance of the AneuVysion™ kit.

Sample Size used for the test set and the data provenance:
- Analytical Specificity: 705 metaphase spreads.
- Reproducibility (Pivotal Study): Not explicitly stated how many individual specimens, but 24 measurements were taken for each of the four specimen types (100% XY, 10% X/90% XX, 17% X/47% XX/36% XXX, 50% XY+21/50% XY). The specimens were "cultured human amniocyte specimens."
- Methods Comparison / Clinical Specimens (Pivotal Multi-center Study):
  - Total Patients: 1516 patients.
  - Total Amniocyte Specimens: 2,238 specimens.
  - Aneuploid Cases: 861 cases.
  - Mosaic Cases: 62 cases.
  - Pseudomosaic Cases: 76 cases.
  - Euploid Cases: 504 cases.
  - Pairwise Comparison (Cultured vs. Uncultured): 722 patients.
- Data Provenance: The studies were conducted at "Thirty one investigation sites" in a "multi-center, blinded, controlled, comparative study." The specimens were "human amniotic fluid specimens obtained from a total of 1516 patients." The origin seems to be implicitly from the countries where these investigation sites are located, likely including the USA given the FDA submission. The study is prospective in nature as it involved collecting and analyzing patient samples for the purpose of the study.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The ground truth for the clinical specimens was established by "standard cytogenetic analysis." While the document doesn't explicitly state the number of experts, cytogenetic analysis is a specialized field, and it's implied that qualified cytogeneticists performed this analysis at each of the "Thirty one investigation sites." The qualifications would inherently be those required to perform and interpret standard cytogenetic metaphase analysis.
Adjudication method for the test set:
- The document states that the "results of interphase FISH analysis were compared to standard cytogenetics." Standard cytogenetic analysis served as the gold standard. There is no mention of a specific adjudication method (like 2+1 or 3+1 consensus) for discrepancies between FISH and cytogenetics; rather, standard cytogenetics was the reference.
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:
- This is not an AI-based device. It is a DNA probe kit (FISH assay) for manual interpretation by human cytogeneticists. Therefore, an MRMC study comparing human readers with and without AI assistance is not applicable and was not performed.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- No. The AneuVysion™ kit "is not intended to be used as a stand alone assay for test reporting." FISH results are "intended to be reported and interpreted only in conjunction with results of standard cytogenetic analysis, performed concurrently, utilizing the same patient specimen." The device is a diagnostic reagent, requiring human interpretation of the hybridization signals on cells.
The type of ground truth used:
- The primary ground truth used for the clinical validation was standard cytogenetic analysis (karyotyping of metaphase spreads). This is widely considered the gold standard for detecting chromosomal abnormalities.
The sample size for the training set:
- The document does not explicitly describe a separate "training set" for the AneuVysion™ kit. As this is a probe-based assay that relies on established biological principles of hybridization and is interpreted by human experts, there isn't a machine learning algorithm that requires a traditional training set. The various studies on hybridization efficiency, analytical sensitivity/specificity, and reproducibility likely served to establish and refine the assay's performance characteristics rather than "train" an algorithm.
How the ground truth for the training set was established:
- See point 7. Since a traditional training set for an algorithm is not applicable, the concept of establishing ground truth for it is also not applicable in the context of this device. The performance characteristics were established via validation studies using reference methods (like G-banding for specificity and standard cytogenetics for clinical concordance).

Summary

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Page 1 of 4

SUMMARY: SAFETY AND EFFECTIVENESS INFORMATION FOR AneuVysion™ kit

The Aneu Vysion™ (CEP 18, X, Y-alpha satellite, LSI 13 and 21) Multicolor Probe Panel is intended to use CEP 18/X/Y probe to detect alpha satellite sequences in the centromere regions of chromosomes 18, X, and Y, and LSI 13/21 probe to detect the 13g14 region and the 21q22.13 to 21q22.2 region. The Aneu Vysion™ kit is indicated for use as an adjunct to standard cytogenetic metaphase analysis for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in metaphase cells and interphase nuclei obtained from amniotic fluid in subjects with presumed high risk pregnancies. It is not intended to be used as a stand alone assay for test reporting. FISH results are intended to be reported and interpreted only in conjunction with results of standard cytogenetic analysis, performed concurrently, utilizing the same patient specimen. FISH results should not be reported prior to standard cytogenetic results except in instances where reporting of FISH results alone is medically indicated or standard cytogenetic results are not available, e.g., culture failure. Reporting and interpretation of FISH should be consistent with professional standards of practice! This device is intended for use only with amniocyte cells; it is not intended for and has not been validated for use with other test matrices. This FISH assay will not detect the presence of structural chromosome abnormalities frequently associated with birth defects. This FISH assay will be performed in cytogenetics laboratories.

Standard cytogenetic analysis detects cytogenetic abnormalities by karyotyping metaphase spreads after staining the chromosomes with a dye in cultured tissue cells.

Safety and effectiveness issues relevant to FISH assays such as the AneuVysion™ assay may include cross-reactivity, poor sensitivity, poor specificity, or poor reproducibility.

1 American College of Medical Genetics. Prenatal interphase fluorescence in situ hybridization (FISH) policy statement. Am J Hum Genet. 1993;53:526-527.

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Analytical Sensitivity and Specificity

Hybridization Efficiency

In the pivotal study, among the human amniotic fluid specimens, the average percentage of cells with no hybridization signal was 0.42% for LSI 13, CEP 18, and LST 21. The average percentage of cells with only one hybridization Y signal was 0.06% for CEP X/Y. Thus, <2% cells with no or only one signal for each probe is a realistic standard of acceptance.

Analytical Sensitivity

The analytical sensitivity of the AneuVysion™ kit probes was tested in the reproducibility study described below. In that study, the 100% XY (or 0% XO) specimen was estimated with a mean of 0.04% (40.2%), and the 10% XO specimen was estimated with a mean of 9.10% (±1.79%) X-signaled nuclei. The upper 95% CI was 0.43 for the 0% X0 specimen and the lower 95% CI for the 10% XO specimen was 5.59%. Thus, the limit of detection for the AneuVysion™ kit in interphase cells is estimated to be 3%.

Analytical Specificity

Locus specificity studies were performed with metaphase spreads according to standard Vysis QC protocols. A total of 705 metaphase spreads were examined sequentially by G-banding to identify chromosomes 13, 18, 21, X, and Y, followed by FISH. No cross-hybridization to other chromosome loci was observed in any of the 705 cells examined; hybridization was limited to the target regions of chromosomes 13, 18, 21, X, and Y.

Reproducibility

ん

A pivotal study was conducted to assess the reproducibility of the AneuVysion™ assay interphase analysis for the percentage of aneuploid cells. The Aneu Vysion™ assay were assessed for inter-site, inter-lot, inter-day and inter-observer reproducibility. One normal and three mosaic cultured human amniocyte specimens were evaluated for the percentage of aneuploid cells according to the instructions for signal enumeration in the package insert. Using ANOVA, no significant variations were observed in any of the inter-assay reproducibility parameters. The intra-assay mean, S.D., and percent C.V. of the observed percentage of aneuploid nuclei for all samples are shown in Table 1.

Precision of % Aneuploid Cells by Level of Mosaicism
Specimen	N	SummaryStatistics	%X	%XX	%XXX	%XY	+ 21	%2-sigCH-21	%2-sigCH-18	%2-sigCH-13
100% XY	24	meanS.D.C.V. (%)	0.040.20--	0.040.20--	0.000.00--	98.881.141.2	0.790.77--	96.71.011.0	94.61.982.1	97.11.531.6
10% X/90% XX	24	meanS.D.C.V. (%)	9.101.5116.6	88.171.611.8	0.850.67--	0.000.00--	1.250.69--	94.81.441.5	94.91.621.7	95.61.691.8
17% X/47% XX/36% XXX	24	meanS.D.C.V. (%)	19.484.0620.8	42.563.658.6	36.683.7410.2	0.000.00--	1.160.72--	96.11.721.8	95.71.161.2	97.31.031.1
50% XY+21/50% XY	24	meanS.D.C.V. (%)	0.040.12--	0.000.00--	0.000.00--	98.131.341.4	52.033.256.2	45.983.698.0	96.10.900.9	97.11.331.4

Table 1 Precision of % Aneuploid Cells by Lavel of Mossicism

Property of Vysis Inc.

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Methods Comparison; Clinical Specimens

A multi-center, blinded, controlled, comparative study was conducted to further define A multi-center, onnoon, contronou, ochipe in relative to standard cytogenetic analysis, the standard of care, in cultured and uncultured amniotic fluid speciments. Thirty one investigation sites analyzed amniotic fluid specimens obtained from a total of 1516 patients.

All study sites conducted the trial according to the prescribed assay procedures and signal enumeration guides.

A total of 2,238 amniocyte specimens were obtained and analyzed from 1,516 patients. Of these 2,238 specimens, 55 were deemed uninformative. These 55 uninformative specimens included three due to maternal cell contamination, four due to FISH assay specificals included unce date to machine (c40) number of nucles for analysis. Thus on per specimen basis, the rate of informativeness is 97.5% (2183/2238). Note that among the Specifich basis, the rate of insufficient (<40) number of nuclei available for one of both of the probes, 31 were partially uninformative for either the CEP 18/X/Y (22) or the LSI 13/21 (9).

Of the 1516 patients, thirteen patients with either cultured or uncultured speciments were included in the 55 uninformative specimens. Thus on per patient basis, the rate of informativeness is 99.8% (1503/1516). One species per patient was included in the miorinativeness is 97.0% (1958) 1939) were cultured and 927 were uncultured specimens.

The maternal age ranged from 13 to 52 years, with a mean (±S.D.) age of 33.2 years The matchial age ranged from 11 to 38 weeks, with a mean (tS.D.) of (10.6 years). The gestarional age varied age varied among study sites, while the mean gestational age did not.

Each site performed FISH analyses according to the instructions in the Ane Vysion™ kit package insert. The percentage of aneuploid cells was determined by FISH after enumerating a minimum of 50 interphase nuclei per target; a minimum of 40 evaluable nuclei was deemed informative.

From this pivotal multi-center comparative study described above, the results of interphase FISH analysis were compared to standard cytogenetics.

True Aneuploid Cases

Among the 861 aneuploid cases, there were 75 +13; 192 +18; 322 +21; 107 45,X;
Among the 861 aneuploid cases, there were 75 +13; 192 +18; 322 +21; 107 45,X; 44 47,XXX; 57 47,XXY, 24 47,XYY; one -21; one XXY +18; one XXX +18; 44 47,XXXXY; one 48,XXYY; one tetraploid, 92,XXYY; and 33 triploids (19 69,XXXX and 14 69,XXY) and one 46,XXX idic(18). Of which, 860 had % 09,AXA and 14 07,AXX / and one 35%, which was due to long storage of prepared slide. Thus, under the worst case scenario, for determination of true aneuploidy, FISH is able to detect 99.9% (860/861) of cases identified by or true and cytogenetic analysis. Note also that one male and one female trisomy 21 Standard Cycligencie analysis. - Il contamination were deemed informative.

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Mosaic Cases

There were 62 true mosaic cases, as identified by standard cytogenetic analysis. There were 23 cases associated with X0, 10 with XXX, 8 with XXY, 7 with +21, 4 with +18, 2 with -18, 3 with +13, and 5 with X0 complexes. Even though aneuploid cell lines were detected in 60 cases, twelve of the 62 mosaic cases showed less than 10% % aneuploid cells by FISH, and 15, showed greater than 60%. The correlation of the % aneuploid cells is 0.76, between FISH assay and standard cytogenetic analysis.

Pseudomosaic Cases

There were 76 pseudomosaic cases, as identified by standard cytogenetic analysis. Among these 76 cases, 7 +13, 9 -13, one +18, 24 -18, 11 +21, 19 -21, 25 X0, one XXX, one XXY, one XYY, and 6 XXYY were observed. FISH assay results showed less than 10% aneuploid cells which is consistent with the euploid state.

Euploid Cases

Among 504 euploid cases identified by standard cytogenetic analysis, FISH also found each to have % aneuploid cells less than 10%. Thus, for determination of euploidy, FISH is able to detect 100% (504/504) of cases identified by standard cytogenetic analysis. Note also that all four male fetal cases with mild maternal cell contamination were deemed informative.

Pairwise Comparison between Cultured and Uncultured Specimens There were 722 patients in the pivotal study with FISH assay performed on both uncultured and cultured samples of the same specimen. In mosaic cases, the aneuploid cell lines were detected by FISH with varying %aneuploid cells between cultured and uncultured samples, leading to a few discordance. The FISH test results in aneuploid, euploid and pseudomosaic cases were concordant between cultured and uncultued samples.

Conclusions

Performance of Aneu Vysion™ is supported by the Vysis Quality Control Procedures and is demonstrated in the clinical studies. When the AneuVysion™ DNA Probe Kit is used as instructed in the package insert, the above statements describe its performance.

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Image /page/4/Picture/2 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" arranged around it. Inside the circle is an abstract symbol that resembles a stylized human figure or a bird in flight, composed of curved lines.

JAN 2 5 2012

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993

Vysis c/o Dr. Russel K. Enns Vice President, Regulatory Affairs 3100 Woodcreek Dr. Downers Grove, IL 60515

Re: K972200

Trade/Device Name: AneuVysion (CEP 18, X, Y-alpha satellite, LSI 13 and 21) Multicolor Probe Panel Regulation Number: 21 CFR §866.4700 Regulation Name: Automated fluorescence in situ hybridization (FISH) enumeration systems. Regulatory Class: Class II Product Code: OYU, KIR Dated: September 18, 1997 Received: September 19, 1997

Dear Dr. Enns:

This letter corrects our substantially equivalent letter of October 20, 1997.

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 class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807);

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Page 2 – Dr. Russel K. Enns

labeling (21 CFR Parts 801 and 809); medical device reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), 11 Jou active of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 Fires, part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of

Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Maria M Clan

Maria M. Chan, Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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510(k) Number (if known): K972200

Device Name: Aneu Vysion™ Multicolor DNA Probe Kit CEP® 18/X/Y-alpha satellite, LSI® 13/21

Indications For Use:

The AneuVysion™ (CEP 18, X, Y-alpha satellite, LSI 13 and 21) Multicolor Probe Panel is intended to use CEP 18/X/X probe to detect alpha satellite sequences in the centromere regions of chromosomes 18, X, and Y, and LSI 13/21 probe to detect the 13q14 region and the 21q22.13 to 21q22.2 region. The AneuVysion™ kit is indicated for use as an adjunct to standard cytogenetic metaphase analysis for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in metaphase cells and interphase nuclei obtained from uncultured amniotic fluid in subjects with presumed high risk pregnancies. It is not intended to be used as a stand alone grossy for test reporting. FISH results are intended to be reported and interpreted only in conjunction with results of standard cytogenetic analysis, performed concurrently utilizing the same patient specimen. FISH results should not be reported prior to standard cytogenetic results except in instances where reporting of FISH results alone is medically indicated or standard cycogenetic results are not available, e.g., culture failure. Reporting and interpretation of FISH should be consistent with professional standards of propotice [1] ] This device is intended for use only with amniocyte cells; it is not intended for and has not been validated for use with other test matrices. This FISH assay will not dee the presence of structural chromosome abnormalities frequently associated with birth defects. This FISH assay will be performed in cytogenetics laboratories.

Tita E. Masini

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number 1972200

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use

Over-The-Counter Use_

Regulation Number and Section

§ 866.4700 Automated fluorescence

in situ hybridization (FISH) enumeration systems.(a)
Identification. An automated FISH enumeration system is a device that consists of an automated scanning microscope, image analysis system, and customized software applications for FISH assays. This device is intended for in vitro diagnostic use with FISH assays as an aid in the detection, counting and classification of cells based on recognition of cellular color, size, and shape, and in the detection and enumeration of FISH signals in interphase nuclei of formalin-fixed, paraffin-embedded human tissue specimens.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Automated Fluorescencein situ Hybridization (FISH) Enumeration Systems.” See § 866.1(e) for the availability of this guidance document.