This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Alternatively, electronic comments may be submitted to http://www.regulations.gov . All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this document contact Haja Sittana El Mubarak, Ph.D., Division of Microbiology Devices at 301-796-6193 or by email: HajaSittana.ElMubarak@fda.hhs.gov ,
When final, this document will supersede the document of the same name dated April 3, 2007.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Office of In Vitro Diagnostic Device Evaluation and Safety
Division of Microbiology Devices
Table of Contents
This special controls guidance document was developed to support the reclassification of the herpes simplex virus types 1 and 2(HSV 1 and 2) serological assays into class II. HSV 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.
This document does not address HSV nucleic acid amplification assays. Please contact the Division of Microbiology Devices in the Office of In Vitro Diagnostic Device Evaluation and Safety for further information on HSV 1 and/or 2 nucleic acid amplification assay submissions.
This guidance is issued in conjunction with a Federal Register final rule announcing the reclassification of HSV 1 and 2 serological assays from class III into class II and codifying the classification at 21 CFR 866.3305.
FDA believes that special controls, when combined with the general controls, will be sufficient to provide reasonable assurance of the safety and effectiveness of HSV 1 and 2 serological assays. A manufacturer who intends to market a device of this generic type should (1) conform to the general controls of the Federal Food, Drug, and Cosmetic Act (the Act), including the premarket notification requirements described in 21 CFR 807 Subpart E, (2) address the specific risks to health associated with HSV-specific antibody or antigen assays identified in this guidance, and (3) obtain a substantial equivalence determination from FDA prior to marketing the device.
As explained in “ The New 510(k) Paradigm - Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications; Final Guidance ,” a manufacturer may submit either a Traditional 510(k) or an Abbreviated 510(k). An Abbreviated 510(k) provides a means to streamline the review of data in a 510(k) through a reliance on FDA-recognized consensus standards, special controls, or FDA guidance documents. Guidance on the content and format for abbreviated and traditional 510(k)s is available at Guidance for Industry and FDA Staff: Format for Traditional and Abbreviated 510(k)s . Also, see Section 514(c)(1)(B) of the Act and the FDA guidance, “ Use of Standards in Substantial Equivalence Determinations ”.
The scope of this document is limited to the following devices as described in 21 CFR 866.3305 with the following product codes:
In the companion rule FDA has identified these devices, classified under 21 CFR 866.3305 as follows:
(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. [Ref. 1-4].
The device is classified as class III if the herpes simplex virus serological assay is a type other than types 1 and/or 2.
Failure of HSV 1 and/or 2 type specific serological assays to perform as indicated, or an error in interpretation of results, may lead to misdiagnosis and improper patient management [Ref. 5]. The Centers for Disease Control and Prevention (CDC) reported that this failure is seen with nonglycoprotein G-based HSV antibody assays and recommends that glycoprotein G (gG1 or gG2) -based tests be used for type-specific HSV serologic evaluation [Ref. 6].
We recommend that you include the following in your device description:
In your description of assay components, you should include the antigen source and explain how it was characterized. If a recombinant antigen is used, you should supply specific information concerning the specific HSV 1 or 2 epitopes present on the antigen and specific information for antigen characterization and purification. For monoclonal antibodies, you should give specific information concerning HSV 1 or 2 epitopes that will be detected, and provide appropriate antibody characterization and purification.
General Study Recommendations
We recommend that you provide data and statistical evaluation sufficient to determine if the device is safe and effective for all claimed specimen type(s). You should provide data to substantiate claims of intended use or clinical significance, and to validate use of a new technology, as appropriate [Ref. 11].
In general, testing sites should be representative of where the submitter intends to market the device, e.g., clinical laboratory. If the assay is to be used at a point-of-care (POC) setting, we recommend that the clinical and precision studies be conducted at three POC sites with a sufficient number of specimens at each site so that results will be statistically meaningful.
Please contact the Division of Microbiology Devices in the Office of In Vitro Diagnostic Device Evaluation and Safety for additional information regarding the appropriate data to substantiate claims of intended use or clinical significance of HSV 1 and/or 2 antigen detection assays.Analytical StudiesSpecimen collection and handling conditionsWe recommend that you substantiate statements in your labeling about specimen storage and transport by assessing whether the specimen can maintain acceptable performance with your device (e.g., reproducibility at the cutoff ) over the storage times and temperatures recommended to users. For example, an appropriate study may include an analysis of aliquots stored under the conditions of time, temperature, or number of freeze/thaw cycles that you recommend to users of the device. We recommend that you state the criteria for an acceptable range of recoveries under the recommended storage and handling conditions [Ref. 12].Precision TestingYou should conduct internal precision testing (i.e., at the manufacturer’s site) in accordance with CLSI, EP5-A2 [Ref 13]. Precision testing performed in accordance with CLSI EP15-A2 should be conducted at three external sites [Ref. 14].
We recommend that you characterize samples used for intra- and inter-assay precision testing according to guidelines provided in CLSI, EP12-A [Ref. 15].
We recommend that you use patient samples, your assay calibrator(s), and the quality control materials that you supply or recommend for your device for this characterization. We recommend that you evaluate precision at relevant measurements, including levels near medical decision points and measurements near the limits of the reportable range.
We recommend that you include the following items in your 510(k):
We recommend that you include the following items:
You may not need to perform additional interference testing with potential interferents of your assay that have already been identified in literature or by other sources. However, you may address additional potential interferents with appropriate citations in the labeling. Cross-reactivityWe recommend that you include data on assay specificity by measuring the cross‑reactivity of your device with antigens of, or antibodies to, other relevant microorganisms. In particular, studies should be performed to characterize performance in the presence of antigens of, or antibodies to, other agents that may clinically be confused with herpes simplex, e.g., Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-zoster Virus (VZV), Chlamydia trachomatis, Treponema pallidum, human papilloma virus (HPV), rubella virus, Toxoplasma gondii,Candida albicans, Neisseria gonorrhea, and organisms associated with bacterial vaginosis, e.g., Bacteroides species, Gardnerella vaginalis, Mobiluncus species. If your antigen and/or antisera are recombinant, we recommend that you provide cross-reactivity studies against the recombinant vector. For HSV 1 and/or 2 IgM assays, we recommend that you include performance in the presence of such factors as rheumatoid factor, anti-nuclear antibodies, and human anti-mouse antibodies [Ref. 11].Cut-off pointsWe recommend that you provide data to explain how your clinically relevant cut-off point was selected and established. Your cut-off point should distinguish between positive (infected and previously exposed or infected) and negative (non-infected) individuals [Ref. 17]. You should provide information on the use of an equivocal zone for testing. If you believe an equivocal zone is inappropriate, you should explain this carefully.Other analytical studiesWe recommend that you test seroconversion serum panels consisting of well- characterized HSV 1 and 2 samples, which can be obtained from the CDC [Ref.18].
If a matrix other than serum is recommended, e.g., EDTA or sodium heparin anticoagulated plasma, provide information demonstrating that there is no or minimal assay effect when these anticoagulants are compared to serum.
Performance of the assay may be demonstrated with multiple matrices by using the most current version of CLSI, EP9A2 [Ref. 19].
8. Prevalence (Expected Values)
We recommend that you establish the prevalence of HSV 1 and/or 2 antibodies and antigen in a population with symptoms consistent with HSV infections or individuals who would be tested for anti-HSV 1 and/or 2 using the new device. You should assay a statistically determined number of samples that are representative of the intended use, clinical utility, and matrix of the samples. You should provide these results based on your new device (rather than a predicate device). We recommend that you summarize the distribution of the population according to age groups (in decades), gender, geographical area, and the number of positive, negative, and equivocal results. We recommend that blood donors not be used for this study.
We recommend that you evaluate your assay at three sites, one of which may be the manufacturer's site. We recommend that you assess performance in the testing environment where the device will ultimately be used (i.e., clinical laboratory or point-of-care) by individuals who will use the test in clinical practice (e.g., trained technologists). We recommend that you initially analyze data from each study site separately to evaluate any inter-site variation and include results of the analysis in the 510(k) summary report. It may be possible to pool clinical study results from the individual sites in the package insert if you can demonstrate that there are no significant statistical or clinical differences in the results or populations among sites. Before initiating any clinical study, we suggest you contact the Division of Microbiology Devices.
Detectability and Comparative Performance
We recommend that you determine the detectability of HSV antibody, by devices that do not differentiate HSV 1 or 2 by comparing test performance with a legally marketed device or by testing against an appropriate algorithm that will diagnose HSV acute and past infections. To determine seroconversion, acute and convalescent serum should be collected during the acute stage of infection and by collecting a second sample 10-14 days later.
Sample Selection, Inclusion, and Exclusion Criteria
We recommend that you evaluate specimens from the intended use population in a prospective study, and provide a clear description of how the samples were selected, including reasons that samples were excluded. Target populations include individuals with signs and symptoms of HSV 1 and/or 2 infections, pregnant women and sexually active adults at risk for sexually transmitted diseases.
Low prevalence populations are not a target population for HSV testing, as the public health benefit of screening for HSV in low prevalence populations has not been determined [Ref. 5].
Presentation of Results
We recommend that you provide line data for all studies. You may supply this information electronically using Microsoft EXCEL, delimited text files, or SAS files.
The premarket notification should include labeling in sufficient detail to satisfy the requirements of 21 CFR 807.87(e). Although final labeling is not required for 510(k) clearance, final labeling must comply with the applicable requirements of 21 CFR 801 and 21 CFR 809.10 before a medical device is introduced into interstate commerce. The following suggestions are aimed at assisting you in preparing labeling that satisfies these requirements.
Directions for Use
You should provide clear and concise instructions that delineate the technological features of the specific device and how the device is to be used for testing patients. Instructions should encourage local/institutional training programs designed to familiarize users with the features of the device and how to use it in a safe and effective manner.
We recommend that you provide a description of quality control recommendations in the labeling and specify what your quality control material will measure.
Precautions for Use
We recommend that you address issues concerning safe use of your assay with statements in the labeling, such as the following:
Assay results should be interpreted only in the context of other laboratory findings and the overall clinical status of the individual. Timing of specimen collection for paired or non paired sera may be critical. In some patients, antibody titers may rise to significant levels and fall again to lower or undetectable levels within a month. Other patients may not develop significant antibody levels.
We also recommend that you discuss issues concerning interpretation of a nonreactive result in the labeling.
1. Arvin, A.M., Prober, C.G., 1995. Herpes Simplex Viruses, in Manual of Clinical Microbiology, 6th Ed., Baron, E.J., et al., eds. ASM Press, Washington, D.C., 876-883.
2. Screening for Genital Herpes Simplex, Brief Update, Guide to Clinical Preventive Services, 2nd Ed., Report of the U.S. Preventive Services Task Force, 2005. Glass, N., Nelson, H. D., Huffman, L., eds. International Medical Publishing, Alexandria, VA, 1-17.
3. Whitley, R.J., 1996. Herpes Simplex Viruses, Fields Virology, 3rd Ed., Fields, B.N., et al., eds. Lippincott-Raven, Philadelphia, P.A., 2297-2333.
4. Nahmias, A.J., et al. 1991. Herpes Simplex Viruses 1 and 2, in Viral Infections of Humans - Epidemiology and Control, 3rd Ed., Evans, A.S., ed. Plenum Medical Book Company, New York, 393-417.
5. Ashley, R., 2001. Sorting out the New HSV Type Specific Antibody Tests, Sexually Transmitted Infections, 77:232-237.
6. Centers for Disease Control and Prevention (CDC), 2002. Sexually Transmitted Diseases Guidelines, Genital Herpes Simplex Virus Infections, http://www.cdc.gov/std/treatment/default.htm .
7. Prober, C.G., et al. 1992. The Management of Pregnancies Complicated by Genital Infections with Herpes Simplex Virus, Clinical Infectious Diseases, 15:1031-1038.
8. Prober, C.G., et al. 1987. Low Risk of Herpes Simplex Virus Infections in Neonates Exposed to the Virus at the Time of Vaginal Delivery to Mothers with Recurrent Genital Herpes Simplex Virus Infections, New England Journal of Medicine. 316(5):240-244.
9. Brown, ZA, et al. 2003. Effect of Serologic Status and Cesarean Delivery on Transmission Rates of Herpes Simplex Virus From Mother to Infant, JAMA 289: 203-209.
10. De Tiege, X, et al. 2003. Limits of Early Diagnosis of Herpes Simplex Encephalitis in Children: A Retrospective Study of 38 Cases, Brief Report, CID, 36:1335-1339.
11. OIVD Guidance Document - Review Criteria for In Vitro Diagnostic Devices for Detection of IgM Antibodies to Viral Agents, http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/UCM094261.pdf
12. Clinical Laboratory Standards Institute (CLSI). Procedures for Handling and Processing of Blood Specimens; Approved Guideline, CLSI Document H18-A3 (ISBN 1-56238-555-0) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2004.
13. Clinical Laboratory Standards Institute (CLSI). Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline, CLSI document EP5-A2 (ISBN 1-56238-542-9) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2004.
14. Clinical Laboratory Standards Institute (CLSI). User Verification of Performance for Precision and Trueness; Approved Guideline, CLSI document EP15-A2 (ISBN 1-56238-574-7) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2005.
15. Clinical Laboratory Standards Institute (CLSI). User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline, CLSI document EP12-A (ISBN 1-56238-468-6) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2002.
16. Clinical Laboratory Standards Institute (CLSI). Interference Testing in Clinical Chemistry; Approved Guideline, CLSI document EP7-A (ISBN 1-56238-480-5) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2004.
17. Clinical Laboratory Standards Institute (CLSI). Specifications for Immunological Testing for Infectious Diseases; Approved Guideline, CLSI document I/LA18-A2 (ISBN 1-56238-445-7) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2001.
18. Centers for Disease Control and Prevention, HSV IgG Panel [well characterized sera for device validation].
19. Clinical Laboratory Standards Institute (CLSI). Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline, CLSI document EP9-A2 (ISBN 1-56238-472-4) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2002.
20. Clinical Laboratory Standards Institute (CLSI). User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline. CLSI document EP12-A (ISBN 1-56238-468-6) CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2002.
This guidance document addresses assays that detect HSV 1, HSV 2, or both.