The PREMIER™ TYPE SPECIFIC HSV-2 IgG ELISA TEST is to be used in the testing of human serum specimens from individuals for whom the qualitative presence of detectable IgG antibody to herpes simplex virus type 2 is warranted; specifically, when used in conjunction with the Premier™ Type Specific HSV-1 IgG ELISA in the screening of sexually active adults. This test is indicated for individuals at risk for a sexually transmitted HSV infection or disease (STD), For example, this test is to be used to screen samples from patients with or without clinical history of herpes and can clarify when an individual with symptoms suggestive of genital herpes has genital HSV-2 infection.

The PREMIER™ TYPE SPECIFIC HSV-2 IgG ELISA TEST is not recommended for use in a pediatric population. The performance characteristics of this device have not been established for prenatal and neonatal screening, the testing of patients with other HSV associated diseases and immunosuppressed patients, or the detection of early stages of HSV seroconversion.

Device Description

The Premier™ Type Specific HSV-2 IgG ELISA Test is an in vitro diagnostic medical device is intended for the qualitative detection of IgG antibody to the herpes simplex virus type 2 in human serum by the enzyme-linked immunosorbent assay (ELISA) method.

The Premier™ Type Specific HSV-2 IgG ELISA Test is comprised of the following items:

Antigen-Coated ELISA Plate: One 96-well plate comprised of twelve 8-well strips with breakaway wells, each well coated with affinity purified HSV-2 glycoprotein G (gG-2).
IgG Specimen Diluent: One bottle containing 30 ml of a lavender colored dilution buffer with sodium azide.
Conjugate: One bottle containing 15 ml of a pink colored solution of alkaline phosphatase-labeled antihuman IgG (Caprine) with sodium azide.
Substrate Buffer: One bottle containing 30 ml of a blue colored buffer solution with sodium azide.
p-NPP Tablets: One foil pack containing 6 tablets of p-nitrophenyl phosphate (p-NPP).
Stopping Reagent: One bottle containing 30 ml of a colorless solution of 1.5 N sodium hydroxide (NaOH).
Positive Control and Negative Control: One vial of each containing 200 ul of serum (human) with sodium azide.
Reference Serum: One vial containing 400 ul of serum (human) with sodium azide.
20X Wash Solution: One bottle containing 60 ml of a green colored solution with detergent and sodium azide.
ELISA Plate Sealer: One acetate sheet with contact adhesive.
Resealable Storage Bag: One plastic sealable bag.
ELISA Worksheet: One worksheet for recording data.

When the Premier™ Type Specific HSV-2 IgG ELISA Test is employed, diluted patient serum is incubated with purified herpes simplex virus type 2 glycoprotein (gG2) bound to the ELISA plate wells. If antibodies to the herpes simplex virus type 2 are present, they bind to the antigen and do not rinse off. Subsequently when enzyme-labeled antihuman IgG is added to the reaction site it binds to the immobilized IgG antibodies. After washing and the addition of a chromogenic substrate and stopping reagent, specimens containing antibodies to the herpes simplex virus type 2 produce a color endpoint reaction which can be read with a standard ELISA plate reader.

AI/ML Overview

The Premier™ Type Specific HSV-2 IgG ELISA Test is an in vitro diagnostic medical device intended for the qualitative detection of IgG antibody to the herpes simplex virus type 2 in human serum.

Here's an analysis of the provided text regarding the acceptance criteria and supporting study:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "The device must achieve a sensitivity of X% and specificity of Y%"). Instead, it presents performance metrics from various studies and implies that these "acceptable agreement" and "relative sensitivity and relative specificity" values demonstrate substantial equivalence to a predicate device, particularly noting "improved specificity" over the predicate.

Given the lack of explicit acceptance criteria, the table below reports the performance metrics achieved in the primary clinical studies.

Metric (Study 1: STD Clinics)	Reported Device Performance (95% CI)
Relative Agreement	93.1% (704/756)
Relative Sensitivity	80.5% (182/226) (74.1%-85.7%)
Relative Specificity	98.5% (522/530) (96.9%-99.3%)
Predictive Value Positive	95.8% (182/190) (91.6%-98.0%)
Predictive Value Negative	92.2% (522/566) (89.6%-94.2%)

Metric (Study 2: Clinical Laboratory)	Reported Device Performance (95% CI)
Relative Agreement	97.2% (174/179) (93.6%-99.1%)
Relative Sensitivity	98.0% (50/51) (89.5%-99.9%)
Relative Specificity	96.9% (124/128) (92.2%-99.1%)

Metric (CDC Panel)	Reported Device Performance
Total Agreement with CDC	95.0%
Agreement with anti-HSV-2+	86.1%
Agreement with anti-HSV-2-	100.0%

2. Sample Sizes Used for the Test Set and Data Provenance

Study 1 (STD Clinics):
- Sample Size: 756 serum samples.
- Data Provenance: Prospectively collected from unduplicated individuals attending two STD Clinics in the Pacific Northwest Region of the US.
Study 2 (Clinical Laboratory):
- Sample Size: 193 patients (sequential sera), with 179 included in calculations after exclusions.
- Data Provenance: Frozen samples from patients submitted to a clinical laboratory in the Pacific Northwest Region of the US.
Study 3 (CDC Panel):
- Sample Size: 100 clinical specimens (50 paired sera).
- Data Provenance: Serum panel obtained from the Centers for Disease Control (CDC).
Study 4 (Culture Documented HSV-2 Infection):
- Sample Size: 335 archived serum samples.
- Data Provenance: Archived serum samples from patients with culture documented HSV-2 infection (retrospective, pre-selected).
Study 5 (Low Prevalence Populations for Specificity):
- Sample Size:
  - 199 pediatric patients (Northeast Region, US).
  - 209 individuals (University Student Health Clinic, Pacific Northwest Region, US).
  - 100 Blood Bank donors (Northeast Region, US).
- Data Provenance: Prospectively collected (implied by "pediatric patients," "individuals attending," "Blood Bank donors" in specific regions of the US).

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

The ground truth for most studies was established using the Western Blot Method for type specific IgG antibody to HSV-2.

For Study 1 (STD Clinics), it states, "Western Blot results were based on initial testing with the exception of specimens with initial atypical results which were reanalyzed."
For Study 2 (Clinical Laboratory), it states, "Tested for IgG antibodies to HSV-2 using... a Western Blot Method."
For Study 3 (CDC Panel), the specimens were "characterized previously by CDC EIA and Western Blot testing."
For Study 5 (Low Prevalence Populations), the ground truth was also "a Western Blot Method for type specific IgG antibody to HSV-2."

The document does not specify the number of experts or their qualifications who interpreted these Western Blot results. However, Western Blot is typically considered a highly reliable, gold-standard method for HSV-2 serology.

For Study 4 (Culture Documented HSV-2 Infection), the ground truth was prior culture documentation of HSV-2 infection. This does not require expert interpretation of a secondary diagnostic test.

4. Adjudication Method for the Test Set

The document details the following adjudication methods:

Study 1 (STD Clinics) and Study 5 (Low Prevalence Populations):
- Western Blot: Initial atypical results were reanalyzed. Patients not returning for repeat testing were presumed negative.
- Premier™ Type Specific HSV-2 IgG ELISA Test: Specimens initially reported as equivocal were retested, and the second test result was used.
Study 2 (Clinical Laboratory): "There were ten specimens which demonstrated either equivocal ELISA results or atypical Western Blot results and four specimens that could not be typed by Western Blot which were not included in the above calculations." This implies exclusion rather than a specific re-adjudication protocol for these excluded cases.
Study 4 (Culture Documented HSV-2 Infection): "Based on repeat testing of equivocal samples."

No explicit "2+1" or "3+1" expert adjudication scheme is mentioned, but rather a protocol for handling equivocal or atypical results with repeat testing or re-analysis.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done, If So, What was the Effect Size of How Much Human Readers Improve with AI vs without AI Assistance

This is an in vitro diagnostic (IVD) device, specifically an ELISA test, which is read by an automated ELISA plate reader to produce a color endpoint reaction that is then quantitatively measured. It is not an AI-assisted diagnostic imaging or interpretation device that would involve human readers or AI assistance in the way typically discussed in MRMC studies. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance was not applicable and not performed.

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

Yes, the studies presented are standalone performance studies for the Premier™ Type Specific HSV-2 IgG ELISA Test. The device provides a quantitative result (color endpoint) which is then interpreted qualitatively (positive/negative/equivocal) based on pre-defined cut-offs without human interpretive "readings" in the sense of image analysis. The performance metrics (sensitivity, specificity, agreement) directly reflect the algorithm's (the ELISA test's) ability to correctly classify samples against the ground truth.

7. The Type of Ground Truth Used

The primary type of ground truth used across most studies was:

Expertly Interpreted Gold Standard Test: The Western Blot Method for type specific IgG antibody to HSV-2. This is considered the reference standard for HSV type-specific serology.
Outcomes Data/Validated Diagnosis: For one study (Study 4), culture documented HSV-2 infection was used as the ground truth.

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" for the Premier™ Type Specific HSV-2 IgG ELISA Test. The studies described are performance evaluations of the completed device. For IVDs like ELISA tests, the "training" analogous to machine learning often involves optimizing reagent concentrations, incubation times, and optical density cut-offs during product development, typically using characterized clinical samples (development panels), but this is not typically referred to as a "training set" in the same way as for AI/ML models. No sample size for such a set is provided.

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

Since no explicit training set is mentioned, this information is not provided. If the question implies how the inherent parameters (like cut-offs) of the ELISA test were established during development, it would have been based on characterized samples, likely against a gold standard like Western Blot or culture results, but the document does not detail this process or the ground truth establishment for such a developmental phase.

Summary

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510(k) SUMMARY FOR PREMIER™ TYPE SPECIFIC HSV-2 IgG ELISA TEST

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SUBMITTER: Gull Laboratories, Inc. 1011 Murray Holladay Road Salt Lake City, UT 84117 (801) 263-3524

CONTACT PERSON: Fred W. Rachford

DATE: June 22, 1999

DEVICE NAME:

Trade/Proprietary Name:	Premier™ Type SpecificHSV-2 IgG ELISA Test
Common/Usual Name:	Anti-HSV-2 IgG Antibody Test
Classification Name:	Herpes Simplex Virus Type 2 SerologicalReagent

HSV-2 IgG ELISA Test / Gull Laboratories, Inc. PREDICATE DEVICE:

DEVICE DESCRIPTION:

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The Premier™ Type Specific HSV-2 IgG ELISA Test is comprised of the following items:

Antigen-Coated ELISA Plate: One 96-well plate comprised of twelve 1. 8-well strips with breakaway wells, each well coated with affinity purified HSV-2 glycoprotein G (gG-2).
1. IgG Specimen Diluent: One bottle containing 30 ml of a lavender colored dilution buffer with sodium azide.
Conjugate: One bottle containing 15 ml of a pink colored solution of 3. alkaline phosphatase-labeled antihuman IgG (Caprine) with sodium azide.
1. Substrate Buffer: One bottle containing 30 ml of a blue colored buffer solution with sodium azide.
న్. p-NPP Tablets: One foil pack containing 6 tablets of p-nitrophenyl phosphate (p-NPP).
1. Stopping Reagent: One bottle containing 30 ml of a colorless solution of 1.5 N sodium hydroxide (NaOH).

Positive Control and Negative Control: One vial of each containing 200 ul of serum (human) with sodium azide.

1. Reference Serum: One vial containing 400 ul of serum (human) with sodium azide.
1. 20X Wash Solution: One bottle containing 60 ml of a green colored solution with detergent and sodium azide.
ELISA Plate Sealer: One acetate sheet with contact adhesive. 10.
1. Resealable Storage Bag: One plastic sealable bag.
1. ELISA Worksheet: One worksheet for recording data.

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INTENDED USE:

The Premier™ Type Specific HSV-2 IgG ELISA Test is intended for the qualitative detection of IgG antibody to herpes simplex virus type 2 in human serum by the enzyme-linked immunosorbent assay (ELISA) method. When performed according to instructions, the Premier™ Type Specific HSV-2 IgG ELISA Test is of value in the determination of immunological experience pertaining to infection with HSV-2 and as an aid in the diagnosis of herpes simplex virus-associated disease.

The Premier™ Type Specific HSV-2 IgG ELISA Test is not recommended for use in a pediatric population. The performance characteristics of this device have not been established for testing patients with other HSV associated disease. prenatal and neonatal screening, the testing of immunosuppressed patients, or the detection of early stages of HSV seroconversion.

TECHNOLOGICAL COMPARISON TO PREDICATE DEVICE:

The Premier™ Type Specific HSV-2 IgG ELISA Test and the HSV-2 IgG ELISA Test both are technologically based on the enzyme-linked immunosorbent assay (ELISA) method.

SUBSTANTIAL EQUIVALENCE PERFORMANCE DATA:

Seven hundred fifty six serum samples prospectively collected from unduplicated individuals attending two STD Clinics in the Pacific Northwest Region of the US were tested with the Premier™ Type Specific HSV-2 IgG ELISA Test and a Western Blot Method for type specific IgG antibody to HSV-2. Western Blot results were based on initial testing with the exception of specimens with initial atypical results which were reanalyzed. These repeat Western Blot results were used for patients returning for repeat analysis. Patients not returning for repeat testing were presumed to be negative. Specimens initially reported as equivocal with the Premier™ Type Specific HSV-2 IgG ELISA Test were retested with the second test result used. The relative agreement between the two methods was 93.1% (704/756). The relative sensitivity and relative specificity of the Premier™ Type Specific HSV-2 IgG ELISA Test were 80.5% (182/226) with a 95% confidence interval of 74.1%-85.7% and 98.5% (522/530) with a 95% confidence interval of 96.9%-99.3% respectively when compared with the Western Blot results. The predictive value positive and predictive value negative were 95.8% (182/190) with a 95% confidence interval of 91.6%-98.0% and 92.2% (522/566) and a 95% confidence interval of 89.6%-94.2% respectively.

Frozen samples of sequential sera from 193 patients were submitted to a clinical laboratory in the Pacific Northwest Region of the US for HSV antibody detection and typing. These specimens were tested for IgG antibodies to HSV-2 using the

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Premier™ Type Specific HSV-2 IgG ELISA Test and a Western Blot Method for detection of HSV type specific antibody. The relative agreement between the two test systems was 97.2% (174/179) with a 95% confidence interval of 93.6%-99.1%. The relative sensitivity and relative specificity of the Premier™ Type Specific HSV-2 IgG ELISA Test were 98.0% (50/51) with a 95% confidence interval of 89.5%-99.9% and 96.9% (124/128) with a 95% confidence interval of 92.2%-99.1% respectively when compared with the Western Blot results. There were ten specimens which demonstrated either equivocal ELISA results or atypical Western Blot results and four specimens that could not be typed by Western Blot which were not included in the above calculations. The calculations for the 95% confidence interval were made by the Exact Method.

The following information is from a serum panel obtained from the Centers for Disease Control (CDC) and tested by Gull Laboratories. Inc. The results are presented as a means to convey further information on the performance of this assay with a masked, characterized serum panel. This does not imply an endorsement of the assay by the CDC.

A serum panel comprised of one hundred clinical specimens (50 paired sera) was tested using the Premier™ Type Specific HSV-2 IgG ELISA Test. These specimens were characterized previously by CDC EIA and Western Blot testing. The panel of 100 samples contains more than 30% positive anti-HSV-2 samples. The Premier™ Type Specific HSV-2 IgG ELISA Test demonstrated 95.0% total agreement with the CDC results. Of the results obtained with the Premier™ Type Specific HSV-2 IgG ELISA Test there was 86.1% agreement with the anti-HSV-2 positive specimens and 100.0% agreement with the anti-HSV-2 negative specimens.

Three hundred thirty five archived serum samples from patients with culture documented HSV-2 infection were tested with the Premier™ Type Specific HSV-2 IgG ELISA Test. Based on repeat testing of equivocal samples 89.3% (299/335) of the serum samples from culture positive patients tested positive in the Premier™ Type Specific HSV-2 IgG ELISA Test. Since the above study was performed on pre-selected retrospective specimens, the assay's positive and negative predictive values could not be calculated or inferred.

The Premier™ Type Specific HSV-2 IgG ELISA Test also was used to test serum samples from individuals in low prevalence populations to determine the specificity of the assay. Serum samples from (a) one hundred ninety nine pediatric patients, one to twelve years of age, in the Northeast Region of the US, (b) two hundred nine individuals attending a University Student Health Clinic in the Pacific Northwest Region of the US, and (c) one hundred Blood Bank donors in the Northeast Region of the US were tested with the Premier™ Type Specific HSV-2 IgG ELISA Test and a Western Blot Method for type specific IgG antibody to HSV-2. Western Blot results were based on initial testing with the exception of specimens with initial atypical results which were reanalyzed. These repeat Western Blot results were used for analysis. Specimens initially reported as

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equivocal with the Premier™ Type Specific HSV-2 IgG ELISA Test were retested with the second test result used.

For the pediatric patient specimens the relative agreement between the two methods was 78.9% (157/199). The relative sensitivity and relative specificity of the Premier™ Type Specific HSV-2 IgG ELISA Test were 100.0% (2/2) with a 95% confidence interval of 1.6%-100.0% and 78.7% (155/197) with a 95% confidence interval of 73.0%-84.4% respectively when compared to the Western Blot results. The predictive value positive and predictive value negative were 4.5% (2/44) with a 95% confidence interval of 0.6%-15.5% and 100.0% (155/155) and a 95% confidence interval of 97.6%-100.0% respectively.

For the University Student Health Clinic specimens the relative agreement between the two methods was 96.6% (198/205). The relative sensitivity and relative specificity of the Premier™ Type Specific HSV-2 IgG ELISA Test were 60.0% (3/5) with a 95% confidence interval of 14.7%-94.7% and 97.5% (195/200) with a 95% confidence interval of 94.3%-99.2% respectively when compared to the Western Blot results. The predictive value positive and predictive value negative were 37.5% (3/8) with a 95% confidence interval of 8.5%-75.5% and 99.0% (195/197) and a 95% confidence interval of 96.4%-99.9% respectively. There were four specimens which either demonstrated equivocal ELISA or atypical Western Blot results which were not included in the calculations.

For the Blood Bank specimens the relative agreement between the two methods was 91.0% (91/100). The relative sensitivity and relative specificity of the Premier™ Type Specific HSV-2 IgG ELISA Test were 76.5% (13/17) with a 95% confidence interval of 49.8.3%-92.2% and 94.0% (78/83) with a 95% confidence interval of 85.9%-97.8% respectively when compared with the Western Blot results. The predictive value positive and predictive value negative were 72.2% (13/18) with a 95% confidence interval of 46.9%-89.3% and 95.1% (78/82) with a 95% confidence interval of 87.3%-98.4% respectively.

CONCLUSIONS:

The Premier™ Type Specific HSV-2 IgG ELISA Test is believed to be substantially equivalent to the HSV-2 IgG ELISA Test. This assessment is based on (1) the two tests are technologically equivalent, both being based on the enzyme-linked immunosorbent assay methods. (2) the intended use of each test is comparable with both being used for the qualitative determination of antibody to HSV-2 with the Premier™ Type Specific HSV-2 IgG ELISA Test having improved specificity, and (3) the data from clinical studies conducted at Gull Laboratories, Inc. and two outside clinical institutions demonstrated acceptable agreement and the relative sensitivity and relative specificity when test results were compared with the expected specimen reactivity showed the Premier™ Type Specific HSV-2 IgG ELISA Test to demonstrate superior specificity for IgG antibody to HSV-2.

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Public Health Service

JUN 25 1999

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

Alan Nickol, Ph.D. Director of Clinical and Regulatory Affairs Meridian Diagnostics, Inc. 3471 River Hills Drive Cincinnati, OH 45244

Re: K984346

Trade Name: Premier™ Type Specific HSV-2 IgG ELISA Test Regulatory Class: III Product Code: LGC Dated: April 4, 1999 Received: April 6, 1999

Dear Dr. Nickol:

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 QS 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.

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Page 2

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.

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" (21 CFR 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 at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely yours,

Steven Sutman

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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EXHIBIT F - REVISED 06/22/99

INDICATIONS FOR USE STATEMENT

510(k) Number (if known): K984346

PREMIER™ TYPE SPECIFIC HSV-2 IgG ELISA TEST Device Name:

Product Number: H2S100

Indications For Use:

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

	Woody Dubois
(Division Sign/Off)
Division of Clinical Laboratory Devices
510(k) Number	K984346

Regulation Number and Section

§ 866.3305 Herpes simplex virus serological assays.

(a)
Identification. Herpes simplex virus serological assays are devices that consist of antigens and antisera used in various serological tests to identify antibodies to herpes simplex virus in serum. Additionally, some of the assays consist of herpes simplex virus antisera conjugated with a fluorescent dye (immunofluorescent assays) used to identify herpes simplex virus directly from clinical specimens or tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by herpes simplex viruses and provides epidemiological information on these diseases. Herpes simplex viral infections range from common and mild lesions of the skin and mucous membranes to a severe form of encephalitis (inflammation of the brain). Neonatal herpes virus infections range from a mild infection to a severe generalized disease with a fatal outcome.(b)
Classification. Class II (special controls). The device is classified as class II (special controls). The special control for the device is FDA's revised guidance document entitled “Class II Special Controls Guidance Document: Herpes Simplex Virus Types 1 and 2 Serological Assays.” For availability of the guidance revised document, see § 866.1(e).