PART 866—IMMUNOLOGY AND MICROBIOLOGY DEVICES

Chapter I—Food and Drug Administration, Department of Health and Human Services › Subchapter H—Medical Devices

Subpart A—General Provisions

§ 866.1 Scope.

(a) This part sets forth the classification of immunology and microbiology devices intended for human use that are in commercial distribution.

(b) The indentification of a device in a regulation in this part is not a precise description of every device that is, or will be, subject to the regulation. A manufacturer who submits a premarket notification submission for a device under part 807 may not show merely that the device is accurately described by the section title and identification provisions of a regulation in this part, but shall state why the device is substantially equivalent to other devices, as required by § 807.87.

(c) To avoid duplicative listings, an immunology and microbiology device that has two or more types of uses (e.g., used both as a diagnostic device and as a microbiology device) is listed only in one subpart.

(d) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

(e) Guidance documents referenced in this part are available on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm.

§ 866.3 Effective dates of requirement for premarket approval.

A device included in this part that is classified into class III (Premarket approval) shall not be commercially distributed after the date shown in the regulation classifying the device unless the manufacturer has an approval under section 515 of the act (unless an exemption has been granted under section 520(g)(2) of the act). An approval under section 515 of the act consists of FDA's issuance of an order approving an application for premarket approval (PMA) for the device or declaring completed a product development protocol (PDP) for the device.

(a) Before FDA requires that a device commercially distributed before the enactment date of the amendments, or a device that has been found substantially equivalent to such a device, has an approval under section 515 of the act FDA must promulgate a regulation under section 515(b) of the act requiring such approval, except as provided in paragraphs (b) and (c) of this section. Such a regulation under section 515(b) of the act shall not be effective during the grace period ending on the 90th day after its promulgation or on the last day of the 30th full calendar month after the regulation that classifies the device into class III is effective, whichever is later. See section 501(f)(2)(B) of the act. Accordingly, unless an effective date of the requirement for premarket approval is shown in the regulation for a device classified into class III in this part, the device may be commercially distributed without FDA's issuance of an order approving a PMA or declaring completed a PDP for the device. If FDA promulgates a regulation under section 515(b) of the act requiring premarket approval for a device, section 501(f)(1)(A) of the act applies to the device.

(b) Any new, not substantially equivalent, device introduced into commercial distribution on or after May 28, 1976, including a device formerly marketed that has been substantially altered, is classified by statute (section 513(f) of the act) into class III without any grace period and FDA must have issued an order approving a PMA or declaring completed a PDP for the device before the device is commercially distributed unless it is reclassified. If FDA knows that a device being commercially distributed may be a “new” device as defined in this section because of any new intended use or other reasons, FDA may codify the statutory classification of the device into class III for such new use. Accordingly, the regulation for such a class III device states that as of the enactment date of the amendments, May 28, 1976, the device must have an approval under section 515 of the act before commercial distribution.

(c) A device identified in a regulation in this part that is classified into class III and that is subject to the transitional provisions of section 520(l) of the act is automatically classified by statute into class III and must have an approval under section 515 of the act before being commercially distributed. Accordingly, the regulation for such a class III transitional device states that as of the enactment date of the amendments, May 28, 1976, the device must have an approval under section 515 of the act before commercial distribution.

§ 866.9 Limitations of exemptions from section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act).

The exemption from the requirement of premarket notification (section 510(k) of the act) for a generic type of class I or II device is only to the extent that the device has existing or reasonably foreseeable characteristics of commercially distributed devices within that generic type or, in the case of in vitro diagnostic devices, only to the extent that misdiagnosis as a result of using the device would not be associated with high morbidity or mortality. Accordingly, manufacturers of any commercially distributed class I or II device for which FDA has granted an exemption from the requirement of premarket notification must still submit a premarket notification to FDA before introducing or delivering for introduction into interstate commerce for commercial distribution the device when:

(a) The device is intended for a use different from the intended use of a legally marketed device in that generic type of device; e.g., the device is intended for a different medical purpose, or the device is intended for lay use where the former intended use was by health care professionals only;

(b) The modified device operates using a different fundamental scientific technology than a legally marketed device in that generic type of device; e.g., a surgical instrument cuts tissue with a laser beam rather than with a sharpened metal blade, or an in vitro diagnostic device detects or identifies infectious agents by using deoxyribonucleic acid (DNA) probe or nucleic acid hybridization technology rather than culture or immunoassay technology; or

(c) The device is an in vitro device that is intended:

(1) For use in the diagnosis, monitoring, or screening of neoplastic diseases with the exception of immunohistochemical devices;

(2) For use in screening or diagnosis of familial or acquired genetic disorders, including inborn errors of metabolism;

(3) For measuring an analyte that serves as a surrogate marker for screening, diagnosis, or monitoring life-threatening diseases such as acquired immune deficiency syndrome (AIDS), chronic or active hepatitis, tuberculosis, or myocardial infarction or to monitor therapy;

(4) For assessing the risk of cardiovascular diseases;

(5) For use in diabetes management;

(6) For identifying or inferring the identity of a microorganism directly from clinical material;

(7) For detection of antibodies to microorganisms other than immunoglobulin G (IgG) or IgG assays when the results are not qualitative, or are used to determine immunity, or the assay is intended for use in matrices other than serum or plasma;

(8) For noninvasive testing as defined in § 812.3(k) of this chapter; and

(9) For near patient testing (point of care).

Subpart B—Diagnostic Devices

§ 866.1620 Antimicrobial susceptibility test disc.

(a) Identification. An antimicrobial susceptibility test disc is a device that consists of antimicrobic-impregnated paper discs used to measure by a disc-agar diffusion technique or a disc-broth elution technique the in vitro susceptibility of most clinically important bacterial pathogens to antimicrobial agents. In the disc-agar diffusion technique, bacterial susceptibility is ascertained by directly measuring the magnitude of a zone of bacterial inhibition around the disc on an agar surface. The disc-broth elution technique is associated with an automated rapid susceptibility test system and employs a fluid medium in which susceptibility is ascertained by photometrically measuring changes in bacterial growth resulting when antimicrobial material is eluted from the disc into the fluid medium. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

(b) Classification. Class II (performance standards).

§ 866.1640 Antimicrobial susceptibility test powder.

(a) Identification. An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

(b) Classification. Class II (performance standards).

§ 866.1645 Fully automated short-term incubation cycle antimicrobial susceptibility system.

(a) Identification. A fully automated short-term incubation cycle antimicrobial susceptibility system is a device that incorporates concentrations of antimicrobial agents into a system for the purpose of determining in vitro susceptibility of bacterial pathogens isolated from clinical specimens. Test results obtained from short-term (less than 16 hours) incubation are used to determine the antimicrobial agent of choice to treat bacterial diseases.

(b) Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA.”

§ 866.1650 A cellular analysis system for multiplexed antimicrobial susceptibility testing.

(a) Identification. A cellular analysis system for multiplexed antimicrobial susceptibility testing is a multiplex qualitative and/or quantitative in vitro diagnostic device intended for the identification and determination of the antimicrobial susceptibility results of organisms detected in samples from patients with suspected microbial infections. This device is intended to aid in the determination of antimicrobial susceptibility or resistance when used in conjunction with other laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Design verification and validation must include:

(i) Detailed device description documentation, including the device components, ancillary reagents required but not provided, a detailed explanation of the methodology, including primer/probe sequence, design, rationale for sequence selection, and details of the antimicrobial agents, as applicable.

(ii) Detailed documentation from the following analytical and clinical performance studies: limit of detection, inclusivity, precision, reproducibility, interference, cross-reactivity, carryover, and cross-contamination, quality control and additional studies, as applicable to specimen type and assay intended use.

(iii) Detailed documentation from an appropriate clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.

(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) Limitations and protocols regarding the need for correlation of results by standard laboratory procedures, as applicable.

(ii) A detailed explanation of the interpretation of results and acceptance criteria.

(iii) A detailed explanation of the principles of operation and procedures for assay performance and troubleshooting.

§ 866.1655 System for detection of microorganisms and antimicrobial resistance using reporter expression.

(a) Identification. A system for detection of microorganisms and antimicrobial resistance using reporter expression is an in vitro diagnostic device intended for the detection and identification of live microorganisms and the detection of associated antimicrobial drug susceptibility or resistance in specimens from patients at risk of colonization or suspected of infection.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use for the device in the labeling required under § 809.10 of this chapter must include a detailed description of the targets the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.

(2) Any device used for specimen collection and transport must be FDA-cleared, approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of the specimen types claimed by this device and for the maintenance of viability of the targeted microorganisms; alternatively, the specimen collection device must be cleared in a premarket submission as a part of this device.

(3) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed description of the device, including reagents, instruments, ancillary materials, applicable specimen collection and transport device(s) and control elements, and a detailed explanation of the methodology, including all pre-analytical methods for handling and processing of specimens and controls to maintain organism viability;

(ii) Detailed descriptions of the test procedure, including the preparation and maintenance of quality controls and the interpretation of test results;

(iii) Detailed discussion of the performance characteristics of the device for all claimed organisms and specimen types based on analytical studies, including evaluation of analytical sensitivity, inclusivity, cross-reactivity, potentially interfering substances and microorganisms, contamination, specimen stability, precision, and reproducibility;

(iv) Detailed discussion of the performance characteristics of the device observed in a clinical study performed on a population that is consistent with the intended use population in comparison to the results obtained by a reference or comparator method determined to be acceptable by FDA, for microbial detection, identification, and antimicrobial susceptibility testing; and

(v) A limiting statement indicating that a negative test result does not preclude colonization or infection with organisms that do not express detectable levels of the reporter that is identified by the device.

(4) Design verification and validation must include:

(i) A detailed description of the device, including an explanation of the technology, hardware, software, and consumables, as well as an explanation of the result algorithms and method(s) of data processing from signal acquisition to result assignment;

(ii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions;

(iii) Detailed documentation of the analytical and clinical studies required in paragraphs (b)(3)(iii) and (iv) of this section, including the study protocols containing descriptions of the test methods, prescribed methods of data analysis and acceptance criteria, final study reports, and data line listings;

(iv) Detailed documentation of quality control procedures, including an explanation of how quality control materials were selected, the recommended frequency of testing, methods of control preparation, acceptance criteria for performance and the results from quality control testing performed during the analytical and clinical studies required under paragraphs (b)(3)(iii) and (iv) of this section;

(v) Detailed documentation of studies performed to establish onboard and in-use reagent stability, including the test method(s), data analysis plans, acceptance criteria, final study reports, and data line listings;

(vi) Detailed documentation of studies to establish reagent shelf-life for the assay kit and each applicable specimen collection and transport device, including study protocols containing descriptions of the test method(s), data analysis plans, and acceptance criteria; and

(vii) Documentation of an appropriate end user device training program that will be offered as part of efforts to assure appropriate conduct of the assay and to mitigate the risk associated with false results, including failure to use the device correctly or correctly interpret results.

§ 866.1700 Culture medium for antimicrobial susceptibility tests.

(a) Identification. A culture medium for antimicrobial susceptibility tests is a device intended for medical purposes that consists of any medium capable of supporting the growth of many of the bacterial pathogens that are subject to antimicrobial susceptibility tests. The medium should be free of components known to be antagonistic to the common agents for which susceptibility tests are performed in the treatment of disease.

(b) Classification. Class II (performance standards).

Subpart C—Microbiology Devices

§ 866.2050 Staphylococcal typing bacteriophage.

(a) Identification. A staphylococcal typing bacteriophage is a device consisting of a bacterial virus intended for medical purposes to identify pathogenic staphylococcal bacteria through use of the bacteria's susceptibility to destruction by the virus. Test results are used principally for the collection of epidemiological information.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2120 Anaerobic chamber.

(a) Identification. An anaerobic chamber is a device intended for medical purposes to maintain an anaerobic (oxygen free) environment. It is used to isolate and cultivate anaerobic microorganisms.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The device is also exempt from the good manufacturing practice requirements of the quality management system regulation in part 820 of this chapter, except for requirements concerning records and complaint files under § 820.35 of this chapter.

§ 866.2160 Coagulase plasma.

(a) Identification. Coagulase plasma is a device that consists of freeze-dried animal or human plasma that is intended for medical purposes to perform coagulase tests primarily on staphylococcal bacteria. When reconstituted, the fluid plasma is clotted by the action of the enzyme coagulase which is produced by pathogenic staphylococci. Test results are used primarily as an aid in the diagnosis of disease caused by pathogenic bacteria belonging to the genus Staphylococcus and provide epidemiological information on disease caused by these microorganisms.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2170 Automated colony counter.

(a) Identification. An automated colony counter is a mechanical device intended for medical purposes to determine the number of bacterial colonies present on a bacteriological culture medium contained in a petri plate. The number of colonies counted is used in the diagnosis of disease as a measure of the degree of bacterial infection.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2180 Manual colony counter.

(a) Identification. A manual colony counter is a device intended for medical purposes that consists of a printed grid system superimposed on an illuminated screen. Petri plates containing bacterial colonies to be counted are placed on the screen for better viewing and ease of counting. The number of colonies counted is used in the diagnosis of disease as a measure of the degree of bacterial infection.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The device is also exempt from the good manufacturing practice requirements of the quality management system regulation in part 820 of this chapter, except for requirements concerning records and complaint files under § 820.35 of this chapter.

§ 866.2190 Automated image assessment system for microbial colonies on solid culture media.

(a) Identification. An automated image assessment system for microbial colonies on solid culture media is a system that is intended to assess the presence or absence of microbial colonies on solid microbiological culture medium, and to interpret their number, and phenotypic and morphologic characteristics through analysis of two dimensional digital images as an aid in diagnosis of infectious disease.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include a detailed description of the device, including the technology employed, components and software modules, as well as a detailed explanation of the result algorithms and any expert rules that are used to assess colony characteristics and enumerate colonies from image capture through end result.

(2) Premarket notification submissions must include detailed documentation of the analytical studies performed to characterize device performance to support the intended use, as appropriate.

(3) Premarket notification submissions must include detailed documentation from clinical studies performed on a population that is consistent with the intended use population.

(i) The clinical studies must establish the device performance based on comparison to results obtained by an acceptable reference method, as appropriate.

(ii) The clinical study documentation must include the study protocol with a predefined statistical analysis plan and the final report documenting support for the Indications for Use and the results of the statistical analysis, as appropriate.

(4) Premarket notification submissions must include detailed documentation for device software, including but not limited to software applications and hardware based components that incorporate software, and any decision-making thresholds used to generate results for the device. If a part of a Total Laboratory Automation System, the premarket notification submission must include detailed documentation addressing the instrument and software system integration.

(5) Premarket notification submissions must include detailed documentation of appropriate instructions for use regarding the intended user's device quality control procedures for the instrument system and components, as appropriate.

(6) The 21 CFR 809.10 compliant device labeling must include:

(i) Detailed user instructions to mitigate the risk of failure to operate the instrument correctly.

(ii) A detailed explanation of the interpretation of results and limitations regarding the need for review of culture plates by a qualified microbiologist, as appropriate.

(iii) A summary of performance data obtained from the analytical studies used to support device performance, as appropriate.

(iv) A summary of performance data obtained from clinical studies performed on a population that is consistent with the intended use population, as appropriate.

(7) Under 21 CFR 820.10(c) design and development, device manufacturers must, as appropriate:

(i) Conduct human factors/usability validation testing with the final version of the labeling and related materials to adequately mitigate the risk of failure to operate the instrument correctly.

(ii) Document a device training program that will be offered to the end user to adequately mitigate the risk of failure to operate the instrument correctly.

§ 866.2300 Multipurpose culture medium.

(a) Identification. A multipurpose culture medium is a device that consists primarily of liquid or solid biological materials intended for medical purposes for the cultivation and identification of several types of pathogenic microorganisms without the need of additional nutritional supplements. Test results aid in the diagnosis of disease and also provide epidemiological information on diseases caused by these microorganisms.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2320 Differential culture medium.

(a) Identification. A differential culture medium is a device that consists primarily of liquid biological materials intended for medical purposes to cultivate and identify different types of pathogenic microorganisms. The identification of these microorganisms is accomplished by the addition of a specific biochemical component(s) to the medium. Microorganisms are identified by a visible change (e.g., a color change) in a specific biochemical component(s) which indicates that specific metabolic reactions have occurred. Test results aid in the diagnosis of disease and also provide epidemiological information on diseases caused by these microorganisms.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2330 Enriched culture medium.

(a) Identification. An enriched culture medium is a device that consists primarily of liquid or solid biological materials intended for medical purposes to cultivate and identify fastidious microorganisms (those having complex nutritional requirements). The device consists of a relatively simple basal medium enriched by the addition of such nutritional components as blood, blood serum, vitamins, and extracts of plant or animal tissues. The device is used in the diagnosis of disease caused by pathogenic microorganisms and also provides epidemiological information on these diseases.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2350 Microbiological assay culture medium.

(a) Identification. A microbiological assay culture medium is a device that consists primarily of liquid or solid biological materials intended for medical purposes to cultivate selected test microorganisms in order to measure by microbiological procedures the concentration in a patient's serum of certain substances, such as amino acids, antimicrobial agents, and vitamins. The concentration of these substances is measured by their ability to promote or inhibit the growth of the test organism in the innoculated medium. Test results aid in the diagnosis of disease resulting from either deficient or excessive amounts of these substances in a patient's serum. Tests results may also be used to monitor the effects of the administration of certain antimicrobial drugs.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2360 Selective culture medium.

(a) Identification. A selective culture medium is a device that consists primarily of liquid or solid biological materials intended for medical purposes to cultivate and identify certain pathogenic microorganisms. The device contains one or more components that suppress the growth of certain microorganisms while either promoting or not affecting the growth of other microorganisms. The device aids in the diagnosis of disease caused by pathogenic microorganisms and also provides epidemiological information on these diseases.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2390 Transport culture medium.

(a) Identification. A transport culture medium is a device that consists of a semisolid, usually non-nutrient, medium that maintains the viability of suspected pathogens contained in patient specimens while in transit from the specimen collection area to the laboratory. The device aids in the diagnosis of disease caused by pathogenic microorganisms and also provides epidemiological information on these diseases.

(b) Classification. Class I (general controls).

§ 866.2410 Culture medium for pathogenic Neisseria spp.

(a) Identification. A culture medium for pathogenic Neisseria spp. is a device that consists primarily of liquid or solid biological materials used to cultivate and identify pathogenic Neisseria spp. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Neisseria, such as epidemic cerebrospinal meningitis, other meningococcal disease, and gonorrhea, and also provides epidemiological information on these microorganisms.

(b) Classification. Class II (performance standards).

§ 866.2420 Oxidase screening test for gonorrhea.

(a) Identification. An oxidase screening test for gonorrhea is an in vitro device that consists of the articles intended to identify by chemical reaction, cytochrome oxidase, an oxidizing enzyme that is associated with certain bacteria including Neisseria gonorrhoeae. A sample of a male's urethral discharge is obtained on a swab which is placed into a wetting agent containing an ingredient that will react with cytochrome oxidase. When cytochrome oxidase is present, the swab turns a dark purple color within 3 minutes. Because it is unlikely that cytochrome oxidase-positive organisms other than Neisseria gonorrhoeae are present in the urethral discharge of males, the identification of cytochrome oxidase with this device indicates presumptive infection of the patient with the causative agent of gonorrhea.

(b) Classification. Class III (premarket approval) (transitional device).

(c) Date PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the act is required before this device may be commercially distributed. See § 866.3.

§ 866.2440 Automated medium dispensing and stacking device.

(a) Identification. An automated medium dispensing and stacking device is a device intended for medical purposes to dispense a microbiological culture medium into petri dishes and then mechanically stack the petri dishes.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The device is also exempt from the good manufacturing practice requirements of the quality management system regulation in part 820 of this chapter, except for requirements concerning records and complaint files under § 820.35 of this chapter.

§ 866.2450 Supplement for culture media.

(a) Identification. A supplement for culture media is a device, such as a vitamin or sugar mixture, that is added to a solid or liquid basal culture medium to produce a desired formulation and that is intended for medical purposes to enhance the growth of fastidious microorganisms (those having complex nutritional requirements). This device aids in the diagnosis of diseases caused by pathogenic microorganisms.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2480 Quality control kit for culture media.

(a) Identification. A quality control kit for culture media is a device that consists of paper discs (or other suitable materials), each impregnated with a specified, freeze-dried, viable microorganism, intended for medical purposes to determine if a given culture medium is able to support the growth of that microorganism. The device aids in the diagnosis of disease caused by pathogenic microorganisms and also provides epidemiological information on these diseases.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2500 Microtiter diluting and dispensing device.

(a) Identification. A microtiter diluting and dispensing device is a mechanical device intended for medical purposes to dispense or serially dilute very small quantities of biological or chemical reagents for use in various diagnostic procedures.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2540 Microbiological incubator.

(a) Identification. A microbiological incubator is a device with various chambers or water-filled compartments in which controlled environmental conditions, particularly temperature, are maintained. It is intended for medical purposes to cultivate microorganisms and aid in the diagnosis of disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The device is also exempt from the good manufacturing practice requirements of the quality management system regulation in part 820 of this chapter, except for requirements concerning records and complaint files under § 820.35 of this chapter.

§ 866.2560 Microbial growth monitor.

(a) Identification. A microbial growth monitor is a device intended for medical purposes that measures the concentration of bacteria suspended in a liquid medium by measuring changes in light scattering properties, optical density, electrical impedance, or by making direct bacterial counts. The device aids in the diagnosis of disease caused by pathogenic microorganisms.

(b) Classification. Class I. With the exception of automated blood culturing system devices that are used in testing for bacteria, fungi, and other microorganisms in blood and other normally sterile body fluids, this device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter.

§ 866.2580 Gas-generating device.

(a) Identification. A gas-generating device is a device intended for medical purposes that produces predetermined amounts of selected gases to be used in a closed chamber in order to establish suitable atmospheric conditions for cultivation of microorganisms with special atmospheric requirements. The device aids in the diagnosis of disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2600 Wood's fluorescent lamp.

(a) Identification. A Wood's fluorescent lamp is a device intended for medical purposes to detect fluorescent materials (e.g., fluorescein pigment produced by certain microorganisms) as an aid in the identification of these microorganisms. The device aids in the diagnosis of disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The device is also exempt from the good manufacturing practice requirements of the quality management system regulation in part 820 of this chapter, except for requirements concerning records and complaint files under § 820.35 of this chapter.

§ 866.2660 Microorganism differentiation and identification device.

(a) Identification. A microorganism differentiation and identification device is a device intended for medical purposes that consists of one or more components, such as differential culture media, biochemical reagents, and paper discs or paper strips impregnated with test reagents, that are usually contained in individual compartments and used to differentiate and identify selected microorganisms. The device aids in the diagnosis of disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.2680 Streptococcus spp. nucleic acid-based assay.

(a) Identification. A Streptococcus spp. nucleic acid-based assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify various Streptococcus spp. nucleic acids extracted directly from clinical specimens. The device detects specific nucleic acid sequences for organism identification. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genus Streptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection.

(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (Limit of Detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, and cross contamination.

(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.

(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.

(5) Premarket notification submissions must include database implementation methodology, construction parameters, and quality assurance protocols, as appropriate.

(6) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate.

(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.

(8) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate.

§ 866.2850 Automated zone reader.

(a) Identification. An automated zone reader is a mechanical device intended for medical purposes to measure zone diameters of microbial growth inhibition (or exhibition), such as those observed on the surface of certain culture media used in disc-agar diffusion antimicrobial susceptibility tests. The device aids in decisionmaking respecting the treatment of disease.

(b) Classification. Class I (general controls).

§ 866.2900 Microbiological specimen collection and transport device.

(a) Identification. A microbiological specimen collection and transport device is a specimen collecting chamber intended for medical purposes to preserve the viability or integrity of microorganisms in specimens during storage of specimens after their collection and during their transport from the collecting area to the laboratory. The device may be labeled or otherwise represented as sterile. The device aids in the diagnosis of disease caused by pathogenic microorganisms.

(b) Classification. Class I (general controls). The device, when solely intended for use in the collection of concentrated parasites from specimens and transport, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.2950 Microbial nucleic acid storage and stabilization device.

(a) Identification. A microbial nucleic acid storage and stabilization device is a device that consists of a container and reagents intended to stabilize microbial nucleic acids in human specimens for subsequent isolation and purification of nucleic acids for further molecular testing. The device is not intended for preserving morphology or viability of microorganisms.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use for the labeling required under § 809.10 of this chapter must include a detailed description of microorganisms and types of human specimens intended to be preserved.

(2) The labeling required under § 809.10(b) of this chapter must include the following:

(i) A detailed device description, including all device components;

(ii) Performance characteristics from applicable analytical studies, including nucleic acid stability and microorganism inactivation;

(iii) A limiting statement that erroneous results may occur when the transport device is not compatible with molecular testing; and

(iv) A limiting statement that the device has only been validated to preserve the representative microorganisms used in the analytical studies.

(3) Design verification and validation must include the following:

(i) Overall device design, including all device components and all control elements incorporated into the analytical validation procedures;

(ii) Thorough description of the microorganisms and methodology used in the validation of the device including, extraction platforms and assays used for the detection of preserved nucleic acids; and

(iii) The limit of detection (LoD) of the molecular test used to establish microorganism nucleic acid stability.

§ 866.2952 Device to preserve and stabilize relative abundances of microbial nucleic acids in clinical samples.

(a) Identification. A device to preserve and stabilize relative abundances of microbial nucleic acids in clinical samples is a device that consists of a container and reagents intended to stabilize microbial nucleic acids for the subsequent assessment of the relative abundance of microbial nucleic acids (i.e., microbiome) in human specimens by an assay validated for use with the device. The device may also be indicated for sample collection. The device is not intended for preserving morphology or viability of microorganisms.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use on the device's label and labeling required under § 809.10 of this chapter must include a detailed description of the type(s) of human specimens intended for collection and preservation, and the characteristics of the microbial population intended for subsequent analysis.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed device description, including reagents, ancillary reagents required but not provided, and all other parts that make up the device.

(ii) A warning statement that the device is not for the detection of specific microbial pathogens.

(iii) A warning statement that the device should only be used with legally marketed assays that are indicated for use with the device, including, as appropriate, indicated for the relevant storage and transport conditions.

(iv) Description of the microorganisms used for studies, including the results and performance summaries, required under paragraph (b)(3)(i) of this section.

(3) Design verification and validation must include:

(i) Detailed documentation and results from studies used for device validation. This detailed documentation must include a detailed identification of each of the following (which must be representative of the spectrum of situations in which the device might be used that are within the scope of the device's intended use): the panel of microorganisms, the extraction platforms, the assay protocols used to measure the stabilization of relative ratios (relative abundance) of the microorganisms in the sample, and the bioinformatic pipelines used in the validation studies for the determination of relative abundances of preserved nucleic acids.

(ii) For devices intended for the collection of samples, detailed documentation and results from studies that demonstrate the device's usability, including user collection studies that demonstrate that the user instructions are appropriate for the intended collection methods (e.g., self-collection or clinician/laboratory collection) and users.

Subpart D—Serological Reagents

§ 866.3010 Acinetobacter calcoaceticus serological reagents.

(a) Identification. Acinetobacter calcoaceticus serological reagents are devices that consist of Acinetobacter calcoaceticus antigens and antisera used to identify this bacterium from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by the bacterium Acinetobacter calcoaceticus and provides epidemiological information on disease caused by this microorganism. This organism becomes pathogenic in patients with burns or with immunologic deficiency, and infection can result in sepsis (blood poisoning).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3020 Adenovirus serological reagents.

(a) Identification. Adenovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to adenovirus in serum. Additionally, some of these reagents consist of adenovirus antisera conjugated with a fluorescent dye and are used to identify adenoviruses directly from clinical specimens. The identification aids in the diagnosis of disease caused by adenoviruses and provides epidemiological information on these diseases. Adenovirus infections may cause pharyngitis (inflammation of the throat), acute respiratory diseases, and certain external diseases of the eye (e.g., conjunctivitis).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3035 Arizona spp. serological reagents.

(a) Identification. Arizona spp. serological reagents are devices that consist of antisera and antigens used to identify Arizona spp. in cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Arizona and provides epidemiological information on diseases caused by these microorganisms. Arizona spp. can cause gastroenteritis (food poisoning) and sepsis (blood poisoning).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3040 Aspergillus spp. serological reagents.

(a) Identification. Aspergillus spp. serological reagents are devices that consist of antigens and antisera used in various serological tests to identify antibodies to Aspergillus spp. in serum. The identification aids in the diagnosis of aspergillosis caused by fungi belonging to the genus Aspergillus. Aspergillosis is a disease marked by inflammatory granulomatous (tumor-like) lessions in the skin, ear, eyeball cavity, nasal sinuses, lungs, and occasionally the bones.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3045 In vitro diagnostic device for Bacillus spp. detection.

(a) Identification. An in vitro diagnostic device for Bacillus species (spp.) detection is a prescription device used to detect and differentiate among Bacillus spp. and presumptively identify B. anthracis and other Bacillus spp. from cultured isolates or clinical specimens as an aid in the diagnosis of anthrax and other diseases caused by Bacillus spp. This device may consist of Bacillus spp. antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to presumptively identify bacillus-like organisms in clinical specimens; bacteriophage used for differentiating B. anthracis from other Bacillus spp. based on susceptibility to lysis by the phage; or antigens used to identify antibodies to B. anthracis (anti-toxin and anti-capsular) in serum. Bacillus infections include anthrax (cutaneous, inhalational, or gastrointestinal) caused by B. anthracis, and gastrointestinal disease and non-gastrointestinal infections caused by B. cereus.

(b) Classification. Class II (special controls). The special controls are set forth in FDA's special controls guideline document entitled “In Vitro Diagnostic Devices for Bacillus spp. Detection; Class II Special Controls Guideline for Industry and Food and Drug Administration Staff.” For availability of the guideline document, see § 866.1(e).

(c) Restriction on Distribution. The distribution of these devices is limited to laboratories that follow public health guidelines that address appropriate biosafety conditions, interpretation of test results, and coordination of findings with public health authorities.

(d) Restriction on Use. The use of this device is restricted to prescription use and must comply with the following:

(1) The device must be in the possession of:

(i)(A) A person, or his agents or employees, regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of such device; or

(B) A practitioner, such as a physician, licensed by law to use or order the use of such device; and

(ii) The device must be sold only to or on the prescription or other order of such practitioner for use in the course of his professional practice.

(2) The label of the device shall bear the statement “Caution: Federal law restricts this device to sale by or on the order of a ____”, the blank to be filled with the word “physician” or with the descriptive designation of any other practitioner licensed by the law of the State in which he practices to use or order the use of the device.

(3) Any labeling, as defined in section 201(m) of the Federal Food, Drug, and Cosmetic Act, whether or not it is on or within a package from which the device is to be dispensed, distributed by, or on behalf of the manufacturer, packer, or distributor of the device, that furnishes or purports to furnish information for use of the device contains adequate information for such use, including indications, effects, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to employ the device can use the device safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented. This information will not be required on so-called reminder-piece labeling which calls attention to the name of the device but does not include indications or other use information.

(4) All labeling, except labels and cartons, bearing information for use of the device also bears the date of the issuance or the date of the latest revision of such labeling.

§ 866.3046 Simple in vitro diagnostic device for the detection of secreted proteins from Bacillus species (spp.) in human clinical samples.

(a) Identification. A simple in vitro diagnostic device for the detection of secreted proteins from Bacillus species (spp.) is a prescription in vitro diagnostic device used to detect and presumptively identify B. anthracis and other Bacillus spp. in human clinical samples as an aid in the diagnosis of anthrax and other diseases caused by Bacillus spp. This device is simple to use and does not involve sample manipulation or measurement of an analyte that could be affected by conditions such as sample turbidity or cell lysis. This device may be used to aid in the presumptive diagnosis of anthrax in individuals who have signs and symptoms consistent with anthrax and a likelihood of exposure. Bacillus infections include anthrax (cutaneous, inhalational, or gastrointestinal) caused by B. anthracis, gastrointestinal disease, non-gastrointestinal infections, and an anthrax-like illness caused by B. cereus.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The distribution of these devices is limited to laboratories that follow public health guidelines that address appropriate biosafety conditions, interpretation of test results, and coordination of findings with public health authorities.

(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of the sample types with which this device is intended to be used; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(3) The labeling required under 21 CFR 809.10(b) of this chapter must include:

(i) An intended use statement that includes the following:

(A) A detailed description of targets the device detects and measures;

(B) The results provided to the user (i.e., whether the measurement is qualitative, semi-quantitative, or quantitative);

(C) The clinical indications appropriate for test use (e.g., in conjunction with patient history, epidemiological information, clinical observations, and other laboratory evidence to make patient management decisions);

(D) Sample types with which it is intended for use;

(E) The specific population(s) with which the device is intended to be used;

(F) The testing location(s) where the device is to be used (if not intended for all locations);

(G) A statement that the device results are for the presumptive identification of Bacillus spp., and definitive identification requires additional testing and confirmation procedures in consultation with the appropriate public health authorities;

(H) A statement that negative results do not preclude infection with Bacillus spp. and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions; and

(I) A statement that testing is to be performed and reported in accordance with current guidelines provided by the appropriate public health authorities.

(ii) Detailed instructions for minimizing the risk of user exposure to Bacillus spp. that may be present in test samples and those used as control materials.

(iii) Detailed instructions for minimizing the risk of generating false positive test results due to contamination from positive test samples and/or positive control materials.

(iv) A prominent and conspicuous precaution that interpretation of test results is intended to be performed by experienced healthcare professionals who have training in principles and use of infectious disease diagnostics and the expertise to report results.

(v) A prominent and conspicuous warning statement that the test results alone do not conclusively establish infection and that additional testing and confirmation procedures may be necessary in consultation with the appropriate public health or other authorities to whom reporting is required.

(vi) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of samples.

(vii) Detailed descriptions of the performance characteristics of the device for all claimed sample types as shown by the analytical and clinical studies required under paragraphs (b)(4)(ii) and (b)(4)(iii) of this section, except sample stability performance characteristics.

(viii) For any devices intended for use in a near-patient setting, a brief reference sheet for healthcare professionals that accompanies the device and that includes the name and intended use of the test, step-by-step instructions of all control and sample testing procedures for the claimed sample types, the result(s) interpretation, warning and limitation statements, and information for troubleshooting or technical assistance with the device.

(ix) A statement that a nationally notifiable disease caused by a biothreat microbial agent must be reported to public health authorities in accordance with local, state, and federal law.

(x) Limiting statements indicating, as applicable:

(A) Situations where the device has been demonstrated to fail or may not perform at its expected performance level (e.g., any disease specific circumstances or circumstances identified by human factors or robustness studies);

(B) Any specific circumstances that pose significant risk to public health, and for which the device has not been validated. For example:

(1) Testing of matrices and patient populations that are not identified in the intended use; or

(2) Testing individuals without signs and symptoms of infection, including mass infection screening (such as airport or border screening) that is not limited to individuals who have signs and symptoms and a risk of exposure to biothreat microbial agents.

(4) Design verification and validation must include:

(i) A detailed device description, including all device parts, control elements incorporated into the test procedure, reagents required but not provided, the principle of device operation and test methodology, and the computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).

(ii) Detailed documentation of analytical studies, as applicable, including those demonstrating limit of detection, inclusivity, cross-reactivity, microbial interference, interfering substances, carryover/cross contamination, sample stability, within lab precision, hook effect, reproducibility, and other studies relevant to the technology (e.g., linearity), as determined to be appropriate by FDA.

(iii) Detailed documentation and results from either a clinical study or, when determined to be acceptable by FDA, a study with an equivalent data set. Documentation from this study must include study reports, testing results, and results of all statistical analyses, including line data of all test samples, and an appropriate justification describing how the sample set is representative of the intended use population. This study must compare the device performance to results obtained from a reference or comparator method that FDA has determined to be appropriate. This study must include prospective (sequentially collected) samples for each intended sample type that are representative of the intended use populations and may, when determined to be acceptable by FDA, include additional characterized clinical samples; or, as an alternative, when determined to be acceptable by FDA, an equivalent sample set. This study must include samples spanning all relevant analyte concentrations for all of the indicated sample type(s) and the targeted analyte(s).

(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions, as applicable.

(v) For any devices that detect the presence of an analyte directly from sample, detailed documentation and results from a shelf-life assessment that includes samples formulated in the most complex clinical matrix identified in the device's intended use.

(vi) As part of the risk management activities, if the labeling includes hyperlinks to documents from public health authorities regarding sampling, sample shipment, sample testing, or clinical management of patients suspected of being infected; or if the labeling includes direct contact information for any such public health authority, then the hyperlinks and contact information must be reviewed at least annually and updated to reflect any changes to those hyperlinks or contact information.

§ 866.3050 Beta-glucan serological assays.

(a) Identification. Beta-glucan serological assays are devices that consist of antigens or proteases used in serological assays. The device is intended for use for the presumptive diagnosis of fungal infection. The assay is indicated for use in patients with symptoms of, or medical conditions predisposing the patient to invasive fungal infection. The device can be used as an aid in the diagnosis of deep seated mycoses and fungemias.

(b) Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Serological Assays for the Detection of Beta-Glucan.” See § 866.1(e) for the availability of this guidance document.

§ 866.3060 Blastomyces dermatitidis serological reagents.

(a) Identification. Blastomyces dermatitidis serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Blastomyces determatitidis in serum. The identification aids in the diagnosis of blastomycosis caused by the fungus Blastomyces dermatitidis. Blastomycosis is a chronic granulomatous (tumor-like) disease, which may be limited to the skin or lung or may be widely disseminated in the body resulting in lesions of the bones, liver, spleen, and kidneys.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3065 Bordetella spp. serological reagents.

(a) Identification. Bordetella spp. serological reagents are devices that consist of antigens and antisera, including antisera conjugated with a fluorescent dye, used in serological tests to identify Bordetella spp. from cultured isolates or directly from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genus Bordetella and provides epidemiological information on these diseases. Bordetella spp. cause whooping cough (Bordetella pertussis) and other similiarly contagious and acute respiratory infections characterized by pneumonitis (inflammation of the lungs).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3085 Brucella spp. serological reagents.

(a) Identification. Brucella spp. serological reagents are devices that consist of antigens and antisera used for serological identification of Brucella spp. from cultured isolates derived from clinical specimens or to identify antibodies to Brucella spp. in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Brucella spp. directly from clinical specimens or cultured isolates derived from clinical specimens. The identification aids in the diagnosis of brucellosis (e.g., undulant fever, Malta fever) caused by bacteria belonging to the genus Brucella and provides epidemiological information on diseases caused by these microorganisms.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3110 Campylobacter fetus serological reagents.

(a) Identification. Campylobacter fetus serological reagents are devices that consist of antisera conjugated with a fluorescent dye used to identify Campylobacter fetus from clinical specimens or cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by this bacterium and provides epidemiological information on these diseases. Campylobacter fetus is a frequent cause of abortion in sheep and cattle and is sometimes responsible for endocarditis (inflammation of certain membranes of the heart) and enteritis (inflammation of the intestines) in humans.

(b) Classification. Class I (general controls).

§ 866.3120 Chlamydia serological reagents.

(a) Identification. Chlamydia serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to chlamydia in serum. Additionally, some of these reagents consist of chlamydia antisera conjugated with a fluorescent dye used to identify chlamydia directly from clinical specimens or cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Chlamydia and provides epidemiological information on these diseases. Chlamydia are the causative agents of psittacosis (a form of pneumonia), lymphogranuloma venereum (a venereal disease), and trachoma (a chronic disease of the eye and eyelid).

(b) Classification. Class I (general controls).

§ 866.3125 Citrobacter spp. serological reagents.

(a) Identification. Citrobacter spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify Citrobacter spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Citrobacter and provides epidemiological information on diseases caused by these microorganisms. Citrobacter spp. have occasionally been associated with urinary tract infections.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3130 Clostridium difficile toxin gene amplification assay.

(a) Identification. A Clostridium difficile toxin gene amplification assay is a device that consists of reagents for the amplification and detection of target sequences in Clostridium difficile toxin genes in fecal specimens from patients suspected of having Clostridium difficile infection (CDI). The detection of clostridial toxin genes, in conjunction with other laboratory tests, aids in the clinical laboratory diagnosis of CDI caused by Clostridium difficile.

(b) Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Toxin Gene Amplification Assays for the Detection of Clostridium difficile; Guideline for Industry and Food and Drug Administration Staff.” See § 866.1(e) for information on obtaining this document.

§ 866.3135 Coccidioides immitis serological reagents.

(a) Identification. Coccidioides immitis serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Coccidioides immitis in serum. The identification aids in the diagnosis of coccidioidomycosis caused by a fungus belonging to the genus Coccidioides and provides epidemiological information on diseases caused by this microorganism. An infection with Coccidioides immitis produces symptoms varying in severity from those accompanying the common cold to those of influenza.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3140 Corynebacterium spp. serological reagents.

(a) Identification. Corynebacterium spp. serological reagents are devices that consist of antisera conjugated with a fluorescent dye used to identify Corynebacterium spp. from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Corynebacterium and provides epidemiological information on diseases caused by these microorganisms. The principal human pathogen of this genus, Corynebacterium diphtheriae, causes diphtheria. However, many other types of corynebacteria form part of the normal flora of the human respiratory tract, other mucus membranes, and skin, and are either nonpathogenic or have an uncertain role.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3145 Coxsackievirus serological reagents.

(a) Identification. Coxsackievirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to coxsackievirus in serum. Additionally, some of these reagents consist of coxsackievirus antisera conjugated with a fluorescent dye that are used to identify coxsackievirus from clinical specimens or from tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of coxsackievirus infections and provides epidemiological information on diseases caused by these viruses. Coxsackieviruses produce a variety of infections, including common colds, meningitis (inflammation of brain and spinal cord membranes), herpangina (brief fever accompanied by ulcerated lesions of the throat), and myopericarditis (inflammation of heart tissue).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3165 Cryptococcus neoformans serological reagents.

(a) Identification. Cryptococcus neoformans serological reagents are devices that consist of antigens used in serological tests to identify antibodies to Cryptococcus neoformans in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) and are used to identify Cryptococcus neoformans directly from clinical specimens or from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of cryptococcosis and provides epidemiological information on this type of disease. Cryptococcosis infections are found most often as chronic meningitis (inflammation of brain membranes) and, if not treated, are usually fatal.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3169 Hepatitis C virus antibody tests.

(a) Identification. A hepatitis C virus (HCV) antibody test is identified as an in vitro diagnostic device intended for use with human serum, plasma, or other matrices as a prescription device that aids in the diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test is not intended for screening blood, plasma, cell, or tissue donors.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the test is not intended for the screening of blood, plasma, and cell or tissue donors.

(ii) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:

(A) When appropriate, the performance characteristics of the test have not been established in populations of immunocompromised or immunosuppressed patients or, other special populations where test performance may be affected.

(B) The detection of HCV antibodies indicates a present or past infection with hepatitis C virus, but does not differentiate between acute, chronic, or resolved infection.

(C) The specimen types for which the device has been cleared, and that use of the test with specimen types other than those specifically cleared for this device may result in inaccurate test results.

(D) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individual's clinical presentation, history, and other laboratory results.

(E) A non-reactive test result may occur early during acute infection, prior to development of a host antibody response to infection, or when analyte levels are below the limit of detection of the test.

(iii) A detailed explanation of the principles of operation and procedures for performing the test.

(2) Design verification and validation must include the following:

(i) A detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, and design of the antigen(s) and capture antibody(ies) sequences, rationale for the selected epitope(s), degree of amino acid sequence conservation of the target, and the design and nature of all primary, secondary, and subsequent standards used for calibration.

(ii) Documentation and characterization (e.g., supplier, determination of identity, and stability) of all critical reagents (including description of the antigen(s) and capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.

(iii) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.

(iv) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(v) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range.

(vi) All stability protocols, including acceptance criteria.

(vii) Final release test results for each lot used in clinical studies.

(viii) Multisite reproducibility study that includes the testing of three independent production lots.

(ix) Analytical performance studies and results for determining the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility) including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, specimen stability, reagent stability, and cross-genotype antibody detection sensitivity, when appropriate.

(x) Analytical sensitivity of the test is the same or better than that of other cleared or approved tests.

(xi) Detailed documentation of clinical performance testing from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved HCV antibody test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with an acceptable number of HCV positive and negative samples in applicable risk categories. Additional relevant patient groups must be validated as appropriate. The samples may be a combination of fresh and repository samples, sourced from geographically diverse areas. The study designs, including number of samples tested, must be sufficient to meet the following criteria:

(A) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent.

(B) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 96 percent.

(3) For any HCV antibody test intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:

(i) Clinical studies must be conducted at PoC sites.

(ii) Additional labeling must include a brief summary of the instructions for use that are appropriate for use in a PoC environment.

§ 866.3170 Nucleic acid-based hepatitis C virus ribonucleic acid tests.

(a) Identification. A nucleic acid-based hepatitis C virus (HCV) ribonucleic acid (RNA) test is identified as an in vitro diagnostic device intended for prescription use as an aid in the diagnosis of HCV infection in specified populations, and/or as an aid in the management of HCV-infected patients including guiding the selection of genotype-specific treatment in individuals with chronic HCV infection. The test is intended for use with human serum or plasma. The test is not intended for use as a donor screening test for the presence of HCV antibodies in blood, blood products, or tissue donors.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) For all nucleic acid-based HCV RNA tests, the labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the test is not intended for use as a donor screening test for the presence of HCV RNA from human cells, tissues, and cellular and tissue-based products.

(ii) A detailed explanation of the principles of operation and procedures for performing the assay.

(iii) A detailed explanation of the interpretation of results.

(iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. These limitations must include, but are not limited to, statements that indicate:

(A) The specimen types for which the device has been cleared and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.

(B) When applicable, that assay performance characteristics have not been established in populations of immunocompromised or immunosuppressed patients or, other populations where test performance may be affected.

(C) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individual's clinical presentation, history, and other laboratory results.

(2) For all nucleic acid-based HCV RNA tests, the design verification and validation must include:

(i) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included such as design of primers and probes, rationale for the selected gene targets, specifications for amplicon size, and degree of nucleic acid sequence conservation.

(ii) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate (e.g., a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.

(iii) Documentation and characterization (e.g., determination of the identity, supplier, purity, and stability) of all critical reagents (including nucleic acid sequences for primers and probes) and protocols for maintaining product integrity.

(iv) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of detection (LoD), upper and lower limits of quantitation (ULoQ and LLoQ, respectively), linearity, precision, endogenous and exogenous interferences, cross reactivity, carryover, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States. Cross-reactivity studies must include samples from HCV RNA negative subjects with other causes of liver disease, including autoimmune hepatitis, alcoholic liver disease, chronic hepatitis B virus, primary biliary cirrhosis, and nonalcoholic steatohepatitis, when applicable. The effect of each claimed nucleic-acid isolation and purification procedure on detection must be evaluated.

(v) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.

(vi) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(vii) Multisite reproducibility study that includes the testing of three independent production lots.

(viii) All stability protocols, including acceptance criteria.

(ix) Final release test results for each lot used in clinical studies.

(x) Analytical sensitivity and specificity of the test must be the same or better than that of other cleared or approved tests.

(xi) Lot-to-lot precision studies, as appropriate.

(3) For devices intended for the qualitative detection of HCV RNA, in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, the design verification and validation must include detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved qualitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with appropriate numbers of HCV positive and negative samples in applicable risk categories. Additional genotypes must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:

(i) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent.

(ii) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 96 percent.

(4) For devices intended for the quantitative detection of HCV RNA, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:

(i) Labeling required under § 809.10(b) of this chapter must include a prominent statement that the test is not intended as a diagnostic test to confirm the presence of active HCV infection, when applicable.

(ii) Design verification and validation must include the following:

(A) Detailed documentation of the following analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including but not limited to: LoD, ULoQ and LLoQ. LoD, LLoQ, and linearity studies must demonstrate acceptable device performance with all HCV genotypes detected by the device.

(B) Detailed documentation of clinical performance testing from either:

(1) A multisite clinical study with an appropriate number of clinical samples from chronically HCV infected patients in which the results are compared to an FDA-cleared or approved quantitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must include a sufficient number of HCV positive samples containing an analyte concentration near the LLoQ to describe performance at this level. Clinical samples must cover the full range of the device output and must be consistent with the distribution of these genotypes in the U.S. population. Clinical samples may be supplemented with diluted clinical samples for those viral load concentrations that are not sufficiently covered by natural clinical specimens, or

(2) A clinical study with prospectively collected samples demonstrating clinical validity of the device.

(C) Detailed documentation of a qualitative analysis near the lower end of the measuring range demonstrating acceptable performance when used as an aid in diagnosis.

(5) For devices intended for HCV RNA genotyping, in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, design verification and validation must include the following:

(i) Detailed documentation of an analytical performance study demonstrating the LoD for all HCV genotypes detected by the device.

(ii) Detailed documentation, including results, of a multisite clinical study that assesses genotyping accuracy (i.e., the proportion of interpretable results that match with the reference method result) and the genotyping rate (i.e., the proportion of results that were interpretable).

(6) For any nucleic acid-based HCV RNA test intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:

(i) Clinical studies must be conducted at PoC sites.

(ii) Additional labeling must include a brief summary of the instructions for use that are appropriate for use in a PoC environment.

§ 866.3172 Qualitative hepatitis B virus antigen assays.

(a) Identification. A qualitative hepatitis B virus (HBV) antigen assay is identified as an in vitro diagnostic device intended for prescription use for qualitative use with human serum, plasma, or other matrices that aids in the diagnosis of chronic or acute HBV infection. HBV surface antigen (HbsAg) is also used for screening of HBV infection in pregnant women to identify neonates who are at risk of acquiring hepatitis B during perinatal period. The assay is not intended for screening of blood, plasma, cells, or tissue donors.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the assay is not intended for the screening of blood, plasma, cells, or tissue donors.

(ii) A detailed explanation of the principles of operation and procedures for performing the assay.

(iii) A detailed explanation of the interpretation of results.

(iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include statements that indicate:

(A) The specimen types for which the device has been cleared, and that use of this assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results.

(B) When appropriate, performance characteristics of the assay have not been established in populations of immunocompromised or immunosuppressed patients or other populations where assay performance may be affected.

(C) Diagnosis of hepatitis B infection should not be established on the basis of a single assay result but should be determined by a licensed healthcare professional in conjunction with the clinical presentation, history, and other diagnostic procedures.

(D) Detection of HBV antigens indicates a current infection with hepatitis B virus but does not differentiate between acute or chronic infection. False reactive HbsAg result may occur for up to 2 weeks after vaccination with HbsAg containing vaccine.

(E) Current methods for the detection of hepatitis B antigens may not detect all potentially infected individuals. A non-reactive assay result does not exclude the possibility of exposure to or infection with hepatitis B virus. A non-reactive assay result in individuals with prior exposure to hepatitis B may be due to but not limited to antigen levels below the detection limit of this assay or lack of antigen reactivity to the antibodies in this assay. HBV mutants lacking the ability to produce antigens have been reported. These may occur as “escape” mutants in the presence of anti-HBV antibodies and such patients may be infectious.

(F) Results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay.

(2) Design verification and validation must include the following:

(i) A detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, design of the capture antibody(ies), external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design.

(ii) For devices with assay calibrators, the design and composition of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate (e.g., a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.

(iii) Documentation and characterization (e.g., supplier, determination of identity, purity, and stability) of all critical reagents (including description of the capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.

(iv) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on assay performance.

(v) Final release criteria to be used for manufactured assay lots with appropriate evidence that lots released at the extremes of the specifications will meet the identified analytical and clinical performance characteristics as well as stability.

(vi) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range.

(vii) All stability protocols, including acceptance criteria.

(viii) Final release assay results for each lot used in clinical studies.

(ix) Reproducibility study data that includes the testing of three independent production lots.

(x) Detailed documentation of analytical performance studies conducted, as appropriate to the technology, specimen types tested, and intended use of the device, including, the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility) including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, prominent mutants/variants detection (e.g., for HbsAg), specimen stability, reagent stability, and cross-genotype antigen detection sensitivity, when appropriate.

(xi) Analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays.

(xii) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.

(xiii) Detailed documentation and results from a clinical study. Performance must be analyzed relative to an FDA cleared or approved HBV antigen assay or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with an appropriate number of HBV reactive and non-reactive samples in applicable risk and disease categories, and any applicable confirmatory testing. Additional relevant patient groups must be validated as appropriate. The samples must include prospective (sequential) samples for each identified specimen type and, as appropriate, additional characterized clinical samples. Samples must be sourced from geographically diverse areas. This study must be conducted in the appropriate settings by the intended users to demonstrate clinical performance.

§ 866.3173 Hepatitis B virus antibody assays.

(a) Identification. A hepatitis B virus (HBV) antibody assay is identified as an in vitro diagnostic device intended for prescription use in the detection of antibodies to HBV in human serum, plasma, or other matrices, and as a device that aids in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Results from assays may be qualitative or quantitative, such as quantitative anti-HBs. In addition, results from an anti-HBc IgM (IgM antibodies to core antigen) assay indicating the presence of anti-HBc IgM are indicative of recent HBV infection. Anti-HBs (antibodies to surface antigen) assay results may be used as an aid in the determination of susceptibility to HBV infection in individuals prior to or following HBV vaccination or when vaccination status is unknown. The assay is not intended for screening of blood, plasma, cells, or tissue donors. The assay is intended as an aid in diagnosis in conjunction with clinical findings and other diagnostic procedures.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the assay is not intended for the screening of blood, plasma, cells, or tissue donors.

(ii) A detailed explanation of the principles of operation and procedures for performing the assay.

(iii) A detailed explanation of the interpretation of results.

(iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include statements that indicate:

(A) When appropriate, performance characteristics of the assay have not been established in populations of immunocompromised or immunosuppressed patients or other special populations where assay performance may be affected.

(B) Detection of HBV antibodies to a single viral antigen indicates a present or past infection with hepatitis B virus, but does not differentiate between acute, chronic, or resolved infection.

(C) The specimen types for which the device has been cleared, and that use of the assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results.

(D) Diagnosis of hepatitis B infection should not be established on the basis of a single assay result but should be determined by a licensed healthcare professional in conjunction with the clinical presentation, history, and other diagnostic procedures.

(E) A non-reactive assay result may occur early during acute infection, prior to development of a host antibody response to infection, or when analyte levels are below the limit of detection of the assay.

(F) Results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay.

(v) For devices intended for the quantitative detection of HBV antibodies (anti-HBs), in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, labeling required under § 809.10(b) of this chapter must include:

(A) The assay calibrators' traceability to a standardized reference material that FDA has determined is appropriate (e.g., a recognized consensus standard) and the limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ), linearity, and precision to define the analytical measuring interval.

(B) Performance results of the analytical sensitivity study testing a standardized reference material that FDA has determined is appropriate (e.g., a recognized consensus standard).

(2) Design verification and validation must include the following:

(i) Detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, and design of the antigen(s) and capture antibody(ies) sequences, rationale for the selected epitope(s), degree of amino acid sequence conservation of the target, and the design and composition of all primary, secondary and subsequent standards used for calibration.

(ii) Documentation and characterization (e.g., supplier, determination of identity, and stability) of all critical reagents (including description of the antigen(s) and capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.

(iii) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on assay performance.

(iv) Final release criteria to be used for manufactured assay lots with appropriate evidence that lots released at the extremes of the specifications will meet the identified analytical and clinical performance characteristics as well as stability.

(v) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range.

(vi) All stability protocols, including acceptance criteria.

(vii) When applicable, analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays.

(viii) Analytical performance studies and results for determining the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility), including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, specimen stability, reagent stability, and cross-genotype antibody detection sensitivity, when appropriate.

(ix) For devices intended for the detection of antibodies for which a standardized reference material (that FDA has determined is appropriate) is available, the analytical sensitivity study and results testing the standardized reference material. Detailed documentation of that study and its results must be provided, including the study protocol, study report, testing results, and all statistical analyses.

(x) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.

(xi) Detailed documentation of clinical performance testing from a clinical study with an appropriate number of HBV reactive and non-reactive samples in applicable risk categories and conducted in the appropriate settings by the intended users. Performance must be analyzed relative to an FDA cleared or approved HBV antibody assay or a comparator that FDA has determined is appropriate. Additional relevant patient groups must be validated as appropriate. The samples must include prospective (sequential) samples for each identified specimen type and, as appropriate, additional characterized clinical samples. Samples must be sourced from geographically diverse areas.

(3) For any HBV antibody assay intended for quantitative detection of anti-HBV antibodies, the following special controls, in addition to those special controls listed in paragraphs (b)(1) and (2) of this section, also apply:

(i) Detailed documentation of the metrological calibration traceability hierarchy to a standardized reference material that FDA has determined is appropriate.

(ii) Detailed documentation of the following analytical performance studies conducted, as appropriate to the technology, specimen types tested, and intended use of the device, including upper and lower limits of quantitation (UloQ and LloQ, respectively), linearity using clinical samples, and an accuracy study using the recognized international standard material.

§ 866.3174 Hepatitis B virus nucleic acid-based assays.

(a) Identification. A nucleic acid-based hepatitis B virus (HBV) assay is identified as an in vitro diagnostic device intended for prescription use in the detection of HBV nucleic acid in specimens from individuals with antibody evidence of HBV infection. In these devices, the detection of HBV nucleic acid is used as an aid in the management of HBV-infected individuals. The assay is intended for use with human serum or plasma (and other matrices as applicable) from individuals with HBV. The assay is not intended for use as a donor screening assay for the presence of HBV nucleic acids in blood, blood products, plasma, cells, or tissue donors, or as a diagnostic assay to confirm the presence of HBV infection.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the assay is not intended for use as a screening assay for the presence of HBV DNA in blood or blood products, plasma, cells, or tissue donors, or as a diagnostic assay to confirm the presence of HBV infection.

(ii) A detailed explanation of the principles of operation and procedures for performing the assay.

(iii) A detailed explanation of the interpretation of results.

(iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and/or management. These limitations must include statements that indicate:

(A) Management of patients undergoing HBV treatment should not be established on the basis of a single assay result but should be determined by a licensed healthcare professional in conjunction with the clinical presentation, history, and other diagnostic procedures, e.g., HBV serologic testing, liver function assays, liver elastography, etc.

(B) The specimen types for which the device has been cleared, and that use of this assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results.

(C) The results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay.

(2) Design verification and validation must include the following:

(i) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included such as design of primers and probes, rationale for the selected gene targets, specifications for amplicon size, and degree of nucleic acid sequence conservation.

(ii) For devices with assay calibrators, the design and composition of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate (e.g., a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.

(iii) Documentation and characterization (e.g., determination of the identity, supplier, purity, and stability) of all critical reagents (including nucleic acid sequences for primers and probes) and protocols for maintaining product integrity.

(iv) Risk analysis and management strategies demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on assay performance.

(v) Final release criteria to be used for manufactured assay lots with appropriate evidence that lots released at the extremes of the specification will meet the identified analytical and clinical performance characteristics as well as stability.

(vi) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range.

(vii) All stability protocols, including acceptance criteria.

(viii) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including limit of detection (LoD), linearity, precision, endogenous and exogenous interferences, cross-reactivity, carryover, matrix equivalency, sample and reagents stability, and as applicable, upper and lower limits of quantitation (ULoQ and LLoQ, respectively). Samples selected for use must be from subjects with clinically relevant circulating genotypes in the United States. Cross-reactivity studies must include samples from HBV nucleic acid negative subjects with other viral or non-viral causes of liver disease, including autoimmune hepatitis, alcoholic liver disease, chronic hepatitis C virus, primary biliary cirrhosis, and nonalcoholic steatohepatitis, when applicable. The effect of each identified nucleic-acid isolation and purification procedure on detection must be evaluated.

(ix) Analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays.

(x) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.

(xi) Detailed documentation of performance from a clinical study with a design and number of clinical samples (appropriately statistically powered) that is appropriate for the intended use of the device as well as conducted in the appropriate settings by the intended users. The samples must include prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. Samples must be sourced from geographically diverse areas.

§ 866.3175 Cytomegalovirus serological reagents.

(a) Identification. Cytomegalovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to cytomegalovirus in serum. The identification aids in the diagnosis of diseases caused by cytomegaloviruses (principally cytomegalic inclusion disease) and provides epidemiological information on these diseases. Cytomegalic inclusion disease is a generalized infection of infants and is caused by intrauterine or early postnatal infection with the virus. The disease may cause severe congenital abnormalities, such as microcephaly (abnormal smallness of the head), motor disability, and mental retardation. Cytomegalovirus infection has also been associated with acquired hemolytic anemia, acute and chronic hepatitis, and an infectious mononucleosis-like syndrome.

(b) Classification. Class II (performance standards).

§ 866.3180 Quantitative cytomegalovirus nucleic acid tests for transplant patient management.

(a) Identification. A quantitative cytomegalovirus (CMV) nucleic acid test for transplant patient management is identified as a device intended for prescription use in the detection of CMV and as an aid in the management of transplant patients to measure CMV deoxyribonucleic acid (DNA) levels in human plasma and/or whole blood using specified specimen processing, amplification, and detection instrumentation. The test is intended for use as an aid in the management of transplant patients with active CMV infection or at risk for developing CMV infection. The test results are intended to be interpreted by qualified healthcare professionals in conjunction with other relevant clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the device is not intended for use as a donor screening test for the presence of CMV DNA in blood or blood products.

(ii) Limitations, which must be updated to reflect current clinical practice. The limitations must include, but are not limited to, statements that indicate:

(A) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with clinical signs and symptoms and other relevant laboratory results;

(B) Negative test results do not preclude CMV infection or tissue invasive CMV disease, and that CMV test results must not be the sole basis for patient management decisions.

(iii) A detailed explanation of the interpretation of results and acceptance criteria must be provided and include specific warnings regarding the potential for variability in CMV viral load measurement when samples are measured by different devices. Warnings must include the following statement, where applicable: “Due to the potential for variability in CMV viral load measurements across different CMV assays, it is recommended that the same device be used for the quantitation of CMV viral load when managing CMV infection in individual patients.”

(iv) A detailed explanation of the principles of operation and procedures for assay performance.

(2) Design verification and validation must include the following:

(i) Detailed documentation of the device description, including all parts that make up the device, reagents required for use with the CMV assay but not provided, an explanation of the methodology, design of the primer/probe sequences, rationale for the selected gene target, and specifications for amplicon size, guanine-cytosine content, and degree of nucleic acid sequence conservation. The design and nature of all primary, secondary, and tertiary quantitation standards used for calibration must also be described.

(ii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's function.

(iii) Documentation and characterization of all critical reagents (e.g., determination of the identity, supplier, purity, and stability) and protocols for maintaining product integrity throughout its labeled shelf life.

(iv) Stability data for reagents provided with the device and indicated specimen types, in addition to the basis for the stability acceptance criteria at all time points chosen across the spectrum of the device's indicated life cycle, which must include a time point at the end of shelf life.

(v) All stability protocols, including acceptance criteria.

(vi) Final lot release criteria, along with documentation of an appropriate justification that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(vii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel CMV stains (e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible primer or probe mismatches). All results of this protocol, including any findings, must be documented.

(viii) Analytical performance testing that includes:

(A) Detailed documentation of the following analytical performance studies: Limit of detection, upper and lower limits of quantitation, inclusivity, precision, reproducibility, interference, cross reactivity, carryover, quality control, specimen stability studies, and additional studies as applicable to specimen type and intended use for the device.

(B) Identification of the CMV strains selected for use in analytical studies, which must be representative of clinically relevant circulating strains.

(C) Inclusivity study results obtained with a variety of CMV genotypes as applicable to the specific assay target and supplemented by in silico analysis.

(D) Reproducibility studies that include the testing of three independent production lots.

(E) Documentation of calibration to a standardized reference material that FDA has determined is appropriate for the quantification of CMV DNA (e.g., a recognized consensus standard).

(F) Documentation of traceability performed each time a new lot of the standardized reference material to which the device is traceable is released, or when the field transitions to a new standardized reference material.

(ix) Clinical performance testing that includes:

(A) Detailed documentation of device performance data from either a method comparison study with a comparator that FDA has determined is appropriate, or results from a prospective clinical study demonstrating clinical validity of the device.

(B) Data from patient samples, with an acceptable number of the CMV positive samples containing an analyte concentration near the lower limit of quantitation and any clinically relevant decision points.

(C) The method comparison study must include predefined maximum acceptable differences between the test and comparator method across all primary outcome measures in the clinical study protocol.

(D) The final release test results for each lot used in the clinical study.

§ 866.3181 Cytomegalovirus nucleic acid detection device for congenital cytomegalovirus infection.

(a) Identification. A cytomegalovirus nucleic acid detection device for congenital cytomegalovirus infection is an in vitro diagnostic device intended for the qualitative detection of cytomegalovirus DNA in clinical samples from newborn babies to aid in the diagnosis of congenital cytomegalovirus infection. Negative results do not preclude infection and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results should be interpreted with consideration of other clinical information and laboratory findings and should not be used as the sole basis for treatment or other patient management decisions.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) An intended use with a detailed description of what the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) to be tested.

(ii) A detailed device description, including all device components, instrument requirements, ancillary reagents required but not provided, and an explanation of the methodology, including all pre-analytical methods for specimen processing.

(iii) Performance characteristics from analytical and clinical studies required under paragraphs (b)(2)(ii) and (iii) of this section.

(iv) A detailed explanation of the interpretation of results and criteria for validity of results.

(v) A limiting statement that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.

(vi) As applicable, a limiting statement and specific sample collection recommendations to indicate that breast milk can result in false positive results for saliva samples if samples are collected less than 1 hour after breastfeeding. Sample collection a minimum of 1 hour from breastfeeding must be recommended.

(vii) Detailed instructions for use that minimize the risk of generating a false result.

(2) Design verification and validation must include:

(i) Detailed device description documentation, including methodology from obtaining sample to result, design of primer/probe sequences, rationale for sequence selection, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).

(ii) Detailed documentation of analytical studies including characterization of the cutoff, analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, instrument and method carryover/cross contamination, and sample stability and handling.

(iii) Detailed documentation from a clinical study documenting sensitivity and specificity of the device; if the number of positive samples in the clinical study is insufficient to properly estimate device sensitivity, additional pre-selected positive samples must be evaluated to supplement the study. Clinical study subjects must be consistent with the intended use population (i.e., infants younger than 21 days of age), and device results must be compared to FDA-accepted comparator methods. Documentation from the clinical study must include the clinical study protocol, the clinical study report, testing results, and results of all statistical analyses.

(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.

§ 866.3183 Quantitative viral nucleic acid test for transplant patient management.

(a) Identification. A quantitative viral nucleic acid test for transplant patient management is identified as a device intended for prescription use in the detection of viral pathogens by measurement of viral DNA or RNA using specified specimen processing, amplification, and detection instrumentation. The test is intended for use as an aid in the management of transplant patients with active viral infection or at risk for developing viral infections. The test results are intended to be interpreted by qualified healthcare professionals in conjunction with other relevant clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) A prominent statement that the device is not intended for use as a donor screening test for the presence of viral nucleic acid in blood or blood products.

(ii) Limitations which must be updated to reflect current clinical practice. These limitations must include, but are not limited to, statements that indicate:

(A) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with clinical signs and symptoms and other relevant laboratory results; and

(B) Negative test results do not preclude viral infection or tissue invasive viral disease and that test results must not be the sole basis for patient management decisions.

(iii) A detailed explanation of the interpretation of results and acceptance criteria must be provided and include specific warnings regarding the potential for variability in viral load measurement when samples are measured by different devices. Warnings must include the following statement, where applicable: “Due to the potential for variability in [analyte] measurements across different [analyte] assays, it is recommended that the same device be used for the quantitation of [analyte] when managing individual patients.”

(iv) A detailed explanation of the principles of operation and procedures for assay performance.

(2) Design verification and validation must include the following:

(i) Detailed documentation of the device description, including all parts that make up the device, ancillary reagents required for use with the assay but not provided, an explanation of the methodology, design of the primer/probe sequences, rationale for the selected gene target, and specifications for amplicon size, guanine-cytosine content, and degree of nucleic acid sequence conservation. The design and nature of all primary, secondary and tertiary quantitation standards used for calibration must also be described.

(ii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions;

(iii) Documentation and characterization (e.g., determination of the identity, supplier, purity, and stability) of all critical reagents and protocols for maintaining product integrity throughout its labeled shelf-life.

(iv) Stability data for reagents provided with the device and indicated specimen types, in addition to the basis for the stability acceptance criteria at all time points chosen across the spectrum of the device's indicated life cycle, which must include a time point at the end of shelf life.

(v) All stability protocols, including acceptance criteria.

(vi) Final lot release criteria along with documentation of an appropriate justification that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(vii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Mode Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel viral stains (e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible primer or probe mismatches). All results of this protocol, including any findings, must be documented.

(viii) Analytical performance testing that includes:

(A) Detailed documentation of the following analytical performance studies: limit of detection, upper and lower limits of quantitation, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, quality control, specimen stability studies, and additional studies as applicable to specimen type and intended use for the device;

(B) Identification of the viral strains selected for use in analytical studies, which must be representative of clinically relevant circulating strains;

(C) Inclusivity study results obtained with a variety of viral genotypes as applicable to the specific assay target and supplemented by in silico analysis;

(D) Reproducibility studies that include the testing of three independent production lots;

(E) Documentation of calibration to a reference standard that FDA has determined is appropriate for the quantification of viral DNA or RNA (e.g., a recognized consensus standard); and

(F) Documentation of traceability performed each time a new lot of the standardized reference material to which the device is traceable is released, or when the field transitions to a new standardized reference material.

(ix) Clinical performance testing that includes:

(A) Detailed documentation from either a method comparison study with a comparator that FDA has determined is appropriate, or results from a prospective clinical study demonstrating clinical validity of the device;

(B) Data from patient samples, with an acceptable number of the virus-positive samples containing an analyte concentration near the lower limit of quantitation and any clinically relevant decision points. If an acceptable number of virus-positive samples containing an analyte concentration near the lower limit of quantitation and any clinically relevant decision cannot be obtained, contrived samples may be used to supplement sample numbers when appropriate, as determined by FDA;

(C) The method comparison study must include predefined maximum acceptable differences between the test and comparator method across all primary outcome measures in the clinical study protocol; and

(D) The final release test results for each lot used in the clinical study.

§ 866.3200 Echinococcus spp. serological reagents.

(a) Identification. Echinococcus spp. serological reagents are devices that consist of Echinococcus spp. antigens and antisera used in serological tests to identify antibodies to Echinococcus spp. in serum. The identification aids in the diagnosis of echinococcosis, caused by parasitic tapeworms belonging to the genus Echinococcus and provides epidemiological information on this disease. Echinococcosis is characterized by the development of cysts in the liver, lung, kidneys, and other organs formed by the larva of the infecting organisms.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3205 Echovirus serological reagents.

(a) Identification. Echovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to echovirus in serum. Additionally, some of these reagents consist of echovirus antisera conjugated with a fluorescent dye used to identify echoviruses from clinical specimens or from tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of echovirus infections and provides epidemiological information on diseases caused by these viruses. Echoviruses cause illnesses such as meningitis (inflammation of the brain and spinal cord membranes), febrile illnesses (accompanied by fever) with or without rash, and the common cold.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3210 Endotoxin assay.

(a) Identification. An endotoxin assay is a device that uses serological techniques in whole blood. The device is intended for use in conjunction with other laboratory findings and clinical assessment of the patient to aid in the risk assessment of critically ill patients for progression to severe sepsis.

(b) Classification. Class II (special controls). The special control for this device is the FDA guidance entitled “Class II Special Controls Guidance Document: Endotoxin Assay.” See § 866.1(e) for the availability of this guidance document.

§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.

(a) Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.

(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.

(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.

(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:

(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.

(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.

(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.

(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.

(6) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.

(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.

§ 866.3220 Entamoeba histolytica serological reagents.

(a) Identification. Entamoeba histolytica serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Entamoeba histolytica in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Entamoeba histolytica directly from clinical specimens. The identification aids in the diagnosis of amebiasis caused by the microscopic protozoan parasite Entamoeba histolytica and provides epidemiological information on diseases caused by this parasite. The parasite may invade the skin, liver, intestines, lungs, and diaphragm, causing disease conditions such as indolent ulcers, an amebic hepatitis, amebic dysentery, and pulmonary lesions.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3225 Enterovirus nucleic acid assay.

(a) Identification. An enterovirus nucleic acid assay is a device that consists of primers, probes, enzymes, and controls for the amplification and detection of enterovirus ribonucleic acid (RNA) in cerebrospinal fluid (CSF) from individuals who have signs and symptoms consistent with meningitis or meningoencephalitis. The detection of enterovirus RNA, in conjunction with other laboratory tests, aids in the clinical laboratory diagnosis of viral meningitis caused by enterovirus.

(b) Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Nucleic Acid Amplification Assay for the Detection of Enterovirus RNA.” See § 866.1(e) for the availability of this guidance document.

§ 866.3230 Device to detect and measure non-microbial analytes to aid in the detection and identification of localized human infections.

(a) Identification. A device to detect and measure non-microbial analytes to aid in the detection and identification of localized human infections is identified as an in vitro diagnostic device intended for the detection and qualitative measurement, quantitative measurement, or both of one or more non-microbial analytes in human clinical specimens to aid in the assessment, identification, or both of a localized microbial infection when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of human specimens; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) An intended use with a detailed description of what the device detects and measures, the type of results provided to the user, the sample type, whether the measure is qualitative and/or quantitative, the clinical indications for the test use, and the specific population(s) for which the device is intended.

(ii) A detailed description of the performance characteristics of the device for all intended specimen types from the analytical and clinical studies (as applicable) required under paragraphs (b)(3)(ii) and (iii) of this section.

(iii) A detailed explanation of the interpretation of results, including acceptance criteria for evaluating the validity of individual runs (e.g., assessment of internal and/or external quality controls, as applicable).

(iv) The following limiting statements:

(A) A statement that a negative test result does not preclude the possibility of infection;

(B) A statement that the test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;

(C) A statement that consistent device performance is dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and

(D) A statement that details any limitations associated with the samples, as appropriate (e.g., collected on the day of admission to the intensive care unit).

(3) Design verification and validation must include the following:

(i) A detailed device description, including as appropriate, all device parts; control elements incorporated into the test procedure; instrument requirements; reagents required but not provided; and the principle of device operation and test methodology, including all preanalytical methods for the processing of specimens and the methodology from obtaining a sample to the result; design of primer/probe sequences; rationale for target analyte selection; and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).

(ii) Detailed documentation of analytical studies including analytical sensitivity (Limit of Detection, Limit of Quantitation, and Limit of Blank), inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross-contamination, specimen stability, within-lab precision, reproducibility, and linearity, as applicable.

(iii) Detailed documentation and results either from a clinical study, that includes prospective (sequentially collected) samples for each intended specimen type that are representative of the intended use populations and, when determined to be acceptable by FDA, additional characterized clinical samples; or, when determined to be acceptable by FDA, an equivalent sample set. The clinical study must compare the device performance to results obtained from an FDA-accepted reference method and/or FDA-accepted comparator method, as appropriate. Documentation from the clinical studies must include the clinical study protocol (e.g., the predefined statistical analysis plan), clinical study report, testing results, and results of all statistical analyses.

(iv) An evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (e.g., age, racial, ethnic, and sex distribution) similar to the intended use population of the device.

(v) Documentation of an appropriate end user device training program that will be offered as part of efforts to mitigate the risks of false results, failure to operate the device correctly, and failure to interpret test results correctly.

(vi) An appropriate risk mitigation strategy to ensure that the device does not prevent any other device(s) with which it is indicated for use, including incorporated device(s), from achieving their intended use (e.g., safety and effectiveness of the functions of the indicated device(s) remain unaffected).

(vii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.

§ 866.3231 Device to detect bacterial protease activity in chronic wound fluid.

(a) Identification. A device to detect bacterial protease activity in chronic wound fluid is a lateral flow prescription in vitro diagnostic device that may include a sterile swab. The device is intended for use in patients as an aid in assessing the risk for non-healing of chronic venous, diabetic foot, and pressure ulcers associated with wounds where there are no signs of wound infection and where patients are asymptomatic for clinical signs of infection.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Any swab used to collect a patient specimen must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of wound fluid specimens; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) An intended use that includes the following statements:

(A) A statement that the device detects and measures bacterial proteases from a swab saturated with wound fluid.

(B) A statement that the device provides a qualitative output to aid the user in assessing the risk for non-healing of wounds (e.g., chronic venous, diabetic foot and pressure ulcers).

(C) A description of the clinical indications for test use.

(D) The specific population(s) for which the device is intended.

(E) A description of the recommended training (e.g., knowledge and experience) for safe and effective use of the device and to minimize the risks of incorrect results and misinterpretation.

(ii) A detailed description of the performance characteristics of the device from the analytical and clinical studies required under paragraphs (b)(3)(ii) and (iii) of this section.

(iii) A detailed explanation of the interpretation of results.

(iv) A warning statement describing situations where the device has not been validated or may not perform as identified in the labeling (e.g., not for use with wounds which are ≥6 months of age and ≥1 cm 2 in size).

(v) The following limiting statements:

(A) That the device is not intended to provide a risk assessment of chronic wound infection status or aid in the diagnosis of infection in chronic wounds, nor is the device intended for monitoring the effectiveness of anti-infective therapy.

(B) That a negative result does not exclude the presence of bacterial proteases. Therefore, the results should be used in conjunction with clinical findings to make an accurate assessment of risk of nonhealing. The test result should be interpreted in conjunction with other risk factors, along with clinical and laboratory data available to the clinician.

(C) That the device has been validated using wound fluid samples only. Other sample types (e.g., whole blood from venous or capillary draws, other body fluids) have not been evaluated.

(D) That skin flora may secrete bacterial proteases therefore, swab contact with intact skin should be avoided as this may yield false positive results.

(vi) Labeling must include a brief reference sheet for healthcare professionals that includes the intended use, summary of clinical performance, results from analytical testing on normal skin and human proteases, and warning and limiting statements.

(3) Design verification and validation must include the following:

(i) A detailed device description (e.g., all device parts, control elements incorporated into the test procedure, reagents required but not provided, and the principle of device operation and test methodology).

(ii) Detailed documentation and results from analytical studies, including the limit of detection, inclusivity, cross-reactivity, microbial interference, analytical sensitivity for normal skin flora and human proteases, interfering substances, specimen stability, within-lab precision, and reproducibility.

(iii) Detailed documentation and results from a clinical study that includes prospective (sequentially collected) samples for the intended specimen type that are representative of the intended use population(s). The clinical study must compare the device performance to results obtained from a reference or comparator method that FDA has determined is appropriate.

§ 866.3235 Epstein-Barr virus serological reagents.

(a) Identification. Epstein-Barr virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Epstein-Barr virus in serum. The identification aids in the diagnosis of Epstein-Barr virus infections and provides epidemiological information on diseases caused by these viruses. Epstein-Barr viruses are thought to cause infectious mononucleosis and have been associated with Burkitt's lymphoma (a tumor of the jaw in African children and young adults) and postnasal carcinoma (cancer).

(b) Classification. Class I (general controls).

§ 866.3236 Device to detect or measure nucleic acid from viruses associated with head and neck cancers.

(a) Identification. A device to detect or measure nucleic acid from viruses associated with head and neck cancers is an in vitro diagnostic test for prescription use in the detection of viral nucleic acid in nasopharyngeal or oropharyngeal cellular specimens from patients with signs and symptoms of head and neck cancer. The test result is intended to be used in conjunction with other clinical information to aid in assessing the clinical status of virus-associated head and neck cancers and/or the likelihood that head and neck cancer is present.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Any device used for specimen collection and transport must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of human specimens; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(2) The labeling required under § 809.10(b) of this chapter must include, as determined to be appropriate by FDA:

(i) An intended use statement that includes the following:

(A) The analyte(s) detected by the device;

(B) Data output of the device (qualitative, semiquantitative, or quantitative);

(C) The specimen types with which the device is intended for use;

(D) The clinical indications appropriate for test use (e.g., in conjunction with endoscopy);

(E) The intended use populations (e.g., signs and symptoms, ethnicity); and

(F) The intended use location(s) (e.g., specific name and location of testing facility or facilities).

(ii) A detailed device description, including reagents, instruments, ancillary materials, specimen collection and transport devices, controls, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.

(iii) A detailed explanation of the interpretation of results.

(iv) Limiting statements indicating:

(A) The device is not intended for use in screening for head and neck cancer in asymptomatic populations.

(B) Results of the device are not predictive of a patient's future risk of head and neck cancer.

(C) Patients who test negative for the virus should be managed in accordance with the standard of care, based on the assessment of endoscopy and/or other clinical information by a licensed healthcare professional.

(D) Results of the device are not intended to be used as the sole basis for determining the need for biopsy or for any other patient management decision.

(3) Design verification and validation must include the following:

(i) A detailed device description including pre-analytical specimen processing, assay technology, target region, primer/probe sequences, reagents, controls, instrument requirements, and the computational path from collected raw data to reported result.

(ii) Detailed documentation and results from analytical performance studies, including characterization of the cutoff(s), limit of detection, limit of quantitation, precision (including multisite reproducibility, if applicable), inclusivity, cross-reactivity, interference, carryover/cross-contamination, reagent stability, and specimen/sample stability, as determined to be appropriate by FDA.

(iii) Detailed documentation of a clinical performance study that includes patients from the intended use population, including the clinical study protocol, with a predefined statistical analysis plan, and a clinical study report with testing results and results of all statistical analyses.

(iv) A detailed description of the impact of any software, including software applications and software incorporated in hardware-based devices, on the device's functions.

§ 866.3240 Equine encephalomyelitis virus serological reagents.

(a) Identification. Equine encephalomyelitis virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antobodies to equine encephalomyelitis virus in serum. The identification aids in the diagnosis of diseases caused by equine encephalomyelitis viruses and provides epidemiological information on these viruses. Equine encephalomyelitis viruses are transmitted to humans by the bite of insects, such as mosquitos and ticks, and may cause encephalitis (inflammation of the brain), rash, acute arthritis, or hepatitis.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3250 Erysipelothrix rhusiopathiae serological reagents.

(a) Identification. Erysipelothrix rhusiopathiae serological reagents are devices that consist of antigens and antisera used in serological tests to identify Erysipelothrix rhusiopathiae from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by this bacterium belonging to the genus Erysipelothrix. This organism is responsible for a variety of inflammations of the skin following skin abrasions from contact with fish, shellfish, or poultry.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3255 Escherichia coli serological reagents.

(a) Identification. Escherichia coli serological reagents are devices that consist of antigens and antisera used in serological tests to identify Escherichia coli from cultured isolates derived from clinical specimens. Additionally, some of these reagents consist of Escherichia coli antisera conjugated with a fluorescent dye used to identify Escherichia coli directly from clinical specimens or cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by this bacterium belonging to the genus Escherichia, and provides epidemiological information on diseases caused by this microorganism. Although Escherichia coli constitutes the greater part of the microorganisms found in the intestinal tract in humans and is usually nonpathogenic, those strains which are pathogenic may cause urinary tract infections or epidemic diarrheal disease, especially in children.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3270 Flavobacterium spp. serological reagents.

(a) Identification. Flavobacterium spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify Flavobacteriuim spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Flavobacterium and provides epidemiological information on diseases caused by these microorganisms. Most members of this genus are found in soil and water and, under certain conditions, may become pathogenic to humans. Flavobacterium meningosepticum is highly virulent for the newborn, in whom it may cause epidemics of septicemia (blood poisoning) and meningitis (inflammation of the membranes of the brain) and is usually attributable to contaminated hospital equipment.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3280 Francisella tularensis serological reagents.

(a) Identification. Francisella tularensis serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Francisella tularensis in serum or to identify Francisella tularensis in cultured isolates derived from clinical specimens. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Francisella tularensis directly from clinical specimens. The identification aids in the diagnosis of tularemia caused by Francisella tularensis and provides epidemiological information on this disease. Tularemia is a desease principally of rodents, but may be transmitted to humans through handling of infected animals, animal products, or by the bites of fleas and ticks. The disease takes on several forms depending upon the site of infection, such as skin lesions, lymph node enlargements, or pulmonary infection.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3290 Gonococcal antibody test (GAT).

(a) Identification. A gonococcal antibody test (GAT) is an in vitro device that consists of the reagents intended to identify by immunochemical techniques, such as latex agglutination, indirect fluorescent antibody, or radioimmunoassay, antibodies to Neisseria gonorrhoeae in sera of asymptomatic females at low risk of infection. Identification of antibodies with this device may indicate past or present infection of the patient with Neisseria gonorrhoeae.

(b) Classification. Class III (premarket approval) (transitional device).

(c) Date PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the act is required before this device may be commercially distributed. See § 866.3.

§ 866.3300 Haemophilus spp. serological reagents.

(a) Identification. Haemophilus spp. serological reagents are devices that consist of antigens and antisera, including antisera conjugated with a fluorescent dye, that are used in serological tests to identify Haemophilus spp. directly from clinical specimens or tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genus Haemophilus and provides epidemiological information on diseases cause by these microorganisms. Diseases most often caused by Haemophilus spp. include pneumonia, pharyngitis, sinusitis, vaginitis, chancroid venereal disease, and a contagious form of conjunctivitis (inflammation of eyelid membranes).

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 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).

§ 866.3307 Herpes simplex virus nucleic acid-based assay for central nervous system infections.

(a) Identification. A herpes simplex virus nucleic acid-based assay for central nervous system infections is a qualitative in vitro diagnostic device intended for the detection and differentiation of HSV-1 and HSV-2 in cerebrospinal fluid (CSF) samples from patients suspected of Herpes Simplex Virus (HSV) infections of the central nervous system (CNS). This test is intended as an aid in the diagnosis of HSV-1 and HSV-2 infections of the CNS. Negative results do not preclude HSV-1 or HSV-2 infection and should not be used as the sole basis for treatment or other patient management decisions.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Design verification and validation must include:

(i) Detailed documentation for the device description, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer design and selection.

(ii) Detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (limit of detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carryover, and cross contamination. Documentation must include reagent and sample stability recommendations.

(iii) Detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to the results of two polymerase chain reaction methods followed by bidirectional sequencing.

(iv) Documentation of an appropriate end user device training program that will be offered as part of efforts to mitigate the risk of failure to correctly operate the instrument.

(v) Quality assurance protocols and detailed documentation for device software, including standalone software applications and hardware-based devices that incorporate software.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed explanation of the interpretation of results and acceptance criteria.

(ii) A limiting statement indicating that negative results do not preclude HSV-1 or HSV-2 infection and should not be used as the sole basis for treatment or other patient management decisions.

§ 866.3309 Herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel.

(a) Identification. A herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel is a qualitative in vitro diagnostic device intended for the simultaneous detection and differentiation of different herpes viruses in cutaneous and mucocutaneous lesion samples from symptomatic patients suspected of Herpetic infections. Negative results do not preclude infection and should not be used as the sole basis for treatment or other patient management decisions. The assay is not intended for use in cerebrospinal fluid samples.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include detailed documentation for the device description, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology including primer design and selection.

(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (Limit of Detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, and cross contamination.

(3) Premarket notification submissions must include detailed documentation of a clinical study using lesion samples in which Herpes Simplex Virus 1, Herpes Simplex Virus 2, or Varicella Zoster Virus DNA detection was requested. The study must compare the device performance to an appropriate well established reference method.

(4) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.

(5) The device labeling must include a limitation statement that reads: “The device is not intended for use with cerebrospinal fluid or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS).”

(6) Premarket notification submissions must include quality assurance protocols and a detailed documentation for device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.

(7) The risk management activities performed as part of the manufacturer's 21 CFR 820.10(c) design and development activities must document an appropriate end user device training program that will be offered as part of efforts to mitigate the risk of failure to correctly operate the instrument.

§ 866.3310 Hepatitis A virus (HAV) serological assays.

(a) Identification. HAV serological assays are devices that consist of antigens and antisera for the detection of hepatitis A virus-specific IgM, IgG, or total antibodies (IgM and IgG), in human serum or plasma. These devices are used for testing specimens from individuals who have signs and symptoms consistent with acute hepatitis to determine if an individual has been previously infected with HAV, or as an aid to identify HAV-susceptible individuals. The detection of these antibodies aids in the clinical laboratory diagnosis of an acute or past infection by HAV in conjunction with other clinical laboratory findings. These devices are not intended for screening blood or solid or soft tissue donors.

(b) Classification. Class II (special controls). The special control is “Guidance for Industry and FDA Staff: Class II Special Controls Guidance Document: Hepatitis A Virus Serological Assays.” See § 866.1(e) for the availability of this guidance document.

§ 866.3320 Histoplasma capsulatum serological reagents.

(a) Identification. Histoplasma capsulatum serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Histoplasma capsulatum in serum. Additionally, some of these reagents consist of Histoplasma capsulatum antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Histoplasma capsulatum from clinical specimens or cultured isolates derived from clinical specimens. The identification aids in the diagnosis of histoplasmosis caused by this fungus belonging to the genus Histoplasma and provides epidemiological information on the diseases caused by this fungus. Histoplasmosis usually is a mild and often asymptomatic respiratory infection, but in a small number of infected individuals the lesions may spread to practically all tissues and organs.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3328 Influenza virus antigen detection test system.

(a) Identification. An influenza virus antigen detection test system is a device intended for the qualitative detection of influenza viral antigens directly from clinical specimens in patients with signs and symptoms of respiratory infection. The test aids in the diagnosis of influenza infection and provides epidemiological information on influenza. Due to the propensity of the virus to mutate, new strains emerge over time which may potentially affect the performance of these devices. Because influenza is highly contagious and may lead to an acute respiratory tract infection causing severe illness and even death, the accuracy of these devices has serious public health implications.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The device's sensitivity and specificity performance characteristics or positive percent agreement and negative percent agreement, for each specimen type claimed in the intended use of the device, must meet one of the following two minimum clinical performance criteria:

(i) For devices evaluated as compared to an FDA-cleared nucleic acid based-test or other currently appropriate and FDA accepted comparator method other than correctly performed viral culture method:

(A) The positive percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.

(B) The negative percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.

(ii) For devices evaluated as compared to correctly performed viral culture method as the comparator method:

(A) The sensitivity estimate for the device when testing for influenza A must be at the point estimate of at least 90 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 80 percent. The sensitivity estimate for the device when testing for influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.

(B) The specificity estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.

(2) When performing testing to demonstrate the device meets the requirements in paragraph (b)(1) of this section, a currently appropriate and FDA accepted comparator method must be used to establish assay performance in clinical studies.

(3) Annual analytical reactivity testing of the device must be performed with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:

(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA-designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.

(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.

(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:

(A) Placing the results directly in the device's § 809.10(b) of this chapter compliant labeling that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or

(B) In the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.

(4) If one of the actions listed at section 564(b)(1)(A)-(D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:

(A) Placing the results directly in the device's § 809.10(b) of this chapter compliant labeling that physically accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or

(B) In a section of the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.

§ 866.3330 Influenza virus serological reagents.

(a) Identification. Influenza virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to influenza in serum. The identification aids in the diagnosis of influenza (flu) and provides epidemiological information on influenza. Influenza is an acute respiratory tract disease, which is often epidemic.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3332 Reagents for detection of specific novel influenza A viruses.

(a) Identification. Reagents for detection of specific novel influenza A viruses are devices that are intended for use in a nucleic acid amplification test to directly detect specific virus RNA in human respiratory specimens or viral cultures. Detection of specific virus RNA aids in the diagnosis of influenza caused by specific novel influenza A viruses in patients with clinical risk of infection with these viruses, and also aids in the presumptive laboratory identification of specific novel influenza A viruses to provide epidemiological information on influenza. These reagents include primers, probes, and specific influenza A virus controls.

(b) Classification. Class II (special controls). The special controls are:

(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Reagents for Detection of Specific Novel Influenza A Viruses.” See § 866.1(e) for information on obtaining this document.

(2) The distribution of these devices is limited to laboratories with experienced personnel who have training in standardized molecular testing procedures and expertise in viral diagnosis, and appropriate biosafety equipment and containment.

§ 866.3336 John Cunningham Virus serological reagents.

(a) Identification. John Cunningham Virus serological reagents are devices that consist of antigens and antisera used in serological assays to identify antibodies to John Cunningham Virus in serum and plasma. The identification aids in the risk stratification for the development of progressive multifocal leukoencephalopathy in multiple sclerosis and Crohn's disease patients undergoing natalizumab therapy. These devices are for adjunctive use, in the context of other clinical risk factors for the development of progressive multifocal leukoencephalopathy.

(b) Classification. Class II (special controls). The special control for this device is the FDA guideline document entitled “Class II Special Controls Guideline: John Cunningham Virus Serological Reagents.” For availability of the guideline document, see § 866.1(e).

§ 866.3340 Klebsiella spp. serological reagents.

(a) Identification. Klebsiella spp. serological reagents are devices that consist of antigens and antisera, including antisera conjugated with a fluorescent dye (immunofluorescent reagents), that are used in serological tests to identify Klebsiella spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genus Klebsiella and provides epidemiological information on these diseases. These organisms can cause serious urinary tract and pulmonary infections, particularly in hospitalized patients.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3350 Leptospira spp. serological reagents.

(a) Identification. Leptospira spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Leptospira spp. in serum or identify Leptospira spp. from cultured isolates derived from clinical specimens. Additionally, some of these antisera are conjugated with a fluorescent dye (immunofluorescent reagents) and used to identify Leptospira spp. directly from clinical specimens. The identification aids in the diagnosis of leptospirosis caused by bacteria belonging to the genus Leptospira and provides epidemiological information on this disease. Leptospira infections range from mild fever-producing illnesses to severe liver and kidney involvement producing hemorrhage and dysfunction of these organs.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3355 Listeria spp. serological reagents.

(a) Identification. Listeria spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify Listeria spp. from cultured isolates derived from clinical specimens. Additionally, some of these reagents consist of Listeria spp. antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Listeria spp. directly from clinical specimens. The identification aids in the diagnosis of listeriosis, a disease caused by bacteria belonging to the genus Listeria, and provides epidemiological information on diseases caused by these microorganisms. Listeria monocytogenes, the most common human pathogen of this genus, causes meningitis (inflammation of the brain membranes) and meningoencephalitis (inflammation of the brain and brain membranes) and is often fatal if untreated. A second form of human listeriosis is an intrauterine infection in pregnant women that results in a high mortality rate for infants before or after birth.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3360 Lymphocytic choriomeningitis virus serological reagents.

(a) Identification. Lymphocytic choriomeningitis virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to lymphocytic choriomeningitis virus in serum. The identification aids in the diagnosis of lymphocytic choriomeningitis virus infections and provides epidemiological information on diseases caused by these viruses. Lymphocytic choriomeningitis viruses usually cause a mild cerebral meningitis (inflammation of membranes that envelop the brain) and occasionally a mild pneumonia, but in rare instances may produce severe and even fatal illnesses due to complications from cerebral meningitis and pneumonia.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3361 Mass spectrometer system for clinical use for the identification of microorganisms.

(a) Identification. A mass spectrometer system for clinical use for the identification of microorganisms is a qualitative in vitro diagnostic device intended for the identification of microorganisms cultured from human specimens. The device is comprised of an ionization source, a mass analyzer, and a spectral database. The device is indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infections.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.

(2) Premarket notification submissions must include database implementation methodology, construction parameters, and quality assurance protocols.

(3) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.

(4) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.

(5) Premarket notification submissions must include details on the appropriate end user device training program that will be offered while marketing the device.

§ 866.3365 Multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures.

(a) Identification. A multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures is a qualitative in vitro device intended to simultaneously detect and identify microorganism nucleic acids from blood cultures that test positive by Gram stain or other microbiological stains. The device detects specific nucleic acid sequences for microorganism identification as well as for antimicrobial resistance. This device aids in the diagnosis of bloodstream infections when used in conjunction with other clinical and laboratory findings. However, the device does not replace traditional methods for culture and susceptibility testing.

(b) Classification. Class II (special controls). The special control for this device is FDA's guideline document entitled “Class II Special Controls Guideline: Multiplex Nucleic Acid Assay for Identification of Microorganisms and Resistance Markers from Positive Blood Cultures.” For availability of the guideline document, see § 866.1(e).

§ 866.3367 Device to detect and identify microbial nucleic acids by FISH in clinical specimens.

(a) Identification. A device to detect and identify microbial nucleic acids by fluorescence in situ hybridization (FISH) in clinical specimens is an in vitro diagnostic device intended for the detection and identification of microbial pathogens in specimens collected from patients with signs and symptoms of infection. The device is intended to aid in the diagnosis of human disease in conjunction with clinical signs and symptoms and other laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Design verification and validation must include the following:

(i) Detailed device description documentation, including the device components, instrument requirements, ancillary reagents required but not provided, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens, probe sequences, and rationale for probe sequence selection;

(ii) Detailed description of the fluorophores, signal source, detection mechanism, and method of result interpretation;

(iii) Detailed documentation from the following analytical studies: analytical sensitivity (Limit of Detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability; and

(iv) Detailed documentation from a clinical study that includes prospective (sequential) samples. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from appropriate and well-accepted comparator methods.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) A statement that the device is intended to be used in conjunction with clinical history, signs, symptoms, and the results of other diagnostic testing;

(ii) A detailed explanation of the interpretation of results and acceptance criteria for any quality control testing; and

(iii) A limitation that negative results do not preclude the possibility of infection.

§ 866.3370 Mycobacterium tuberculosis immunofluorescent reagents.

(a) Identification. Mycobacterium tuberculosis immunofluorescent reagents are devices that consist of antisera conjugated with a fluorescent dye used to identify Mycobacterium tuberculosis directly from clinical specimens. The identification aids in the diagnosis of tuberculosis and provides epidemiological information on this disease. Mycobacterium tuberculosis is the common causative organism in human tuberculosis, a chronic infectious disease characterized by formation of tubercles (small rounded nodules) and tissue necrosis (destruction), usually occurring in the lung.

(b) Classification. Class I (general controls).

§ 866.3372 Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex in respiratory specimens.

(a) Identification. Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex in respiratory specimens are qualitative nucleic acid-based in vitro diagnostic devices intended to detect Mycobacterium tuberculosis complex nucleic acids extracted from human respiratory specimens. These devices are non-multiplexed and intended to be used as an aid in the diagnosis of pulmonary tuberculosis when used in conjunction with clinical and other laboratory findings. These devices do not include devices intended to detect the presence of organism mutations associated with drug resistance. Respiratory specimens may include sputum (induced or expectorated), bronchial specimens (e.g., bronchoalveolar lavage or bronchial aspirate), or tracheal aspirates.

(b) Classification. Class II (special controls). The special control for this device is the FDA document entitled “Class II Special Controls Guideline: Nucleic Acid-Based In Vitro Diagnostic Devices for the Detection of Mycobacterium tuberculosis Complex in Respiratory Specimens.” For availability of the guideline document, see § 866.1(e).

§ 866.3373 Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex (MTB-complex) and the genetic mutations associated with MTB-complex antibiotic resistance in respiratory specimens.

(a) Identification. Nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex (MTB-complex) and the genetic mutations associated with MTB-complex antibiotic resistance in respiratory specimens are qualitative nucleic acid-based devices that detect the presence of MTB-complex-associated nucleic acid sequences in respiratory samples. These devices are intended to aid in the diagnosis of pulmonary tuberculosis and the selection of an initial treatment regimen when used in conjunction with clinical findings and other laboratory results. These devices do not provide confirmation of antibiotic susceptibility since other mechanisms of resistance may exist that may be associated with a lack of clinical response to treatment other than those detected by the device.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The FDA document entitled “Class II Special Controls Guideline: Nucleic Acid-Based In Vitro Diagnostic Devices for the Detection of Mycobacterium tuberculosis Complex and Genetic Mutations Associated with Antibiotic Resistance in Respiratory Specimens,” which addresses the mitigation of risks specific to the detection of MTB-complex. For availability of the document, see § 866.1(e).

(2) The following items, which address the mitigation of risks specific to the detection of the genetic mutations associated with antibiotic resistance of MTB-complex:

(i) The device must include an external positive assay control as appropriate. Acceptable positive assay controls include MTB-complex isolates containing one or more antibiotic-resistance associated target sequences detected by the device.

(ii) The device must include internal controls as appropriate. An acceptable internal control may include human nucleic acid co-extracted with MTB-complex containing nucleic acid sequences associated with antibiotic resistance and primers amplifying human housekeeping genes (e.g., RNaseP, β-actin).

(iii) The device's intended use must include a description of the scope of antibiotic resistance targeted by the assay, i.e., the specific drugs and/or drug classes.

(iv) The specific performance characteristics section of the device's labeling must include information regarding the specificity of the assay oligonucleotides for detecting mutations associated with antibiotic resistance of MTB-complex, and any information indicating the potential for non-specific binding (e.g., BLAST search).

(v) In demonstrating device performance you must perform:

(A) Pre-analytical studies that evaluate:

(1) Frozen samples. If there is use of any frozen samples in the device performance studies, or if there is a device claim for the use of frozen samples for testing, the effect of freezing samples prior to testing and the effect of multiple freeze/thaw cycles on both antibiotic susceptible and antibiotic resistant strains of MTB-complex.

(2) Nucleic acid extraction methods. Extraction methods must parallel those used in devices for the detection of MTB-complex nucleic acid and confirm that the detection of the genetic mutations associated with antibiotic resistance is not affected.

(B) Analytical studies that analyze:

(1) Limit of Detection. Limit of Detection must be determined in the most challenging matrix (e.g., sputum) claimed for use with the device. The Limit of Detection must be determined using both antibiotic susceptible and antibiotic resistant strains of MTB-complex. The antibiotic resistant strains must be those with well characterized genetic mutations associated with antibiotic resistance.

(2) Analytical Reactivity (Inclusivity). Testing must be conducted to evaluate the ability of the device to detect genetic mutations associated with antibiotic resistance in a diversity of MTB-complex strains. Isolates used in testing must be well characterized. Isolate strain characterization must be determined using standardized reference methods recognized by a reputable scientific body and appropriate to the strain lineage.

(3) Within-Laboratory (Repeatability) Precision Testing. Within-laboratory precision studies, if appropriate, must include at least one antibiotic resistant and one antibiotic susceptible strain of MTB-complex.

(4) Between Laboratory Reproducibility Testing. The protocol for the reproducibility study may vary slightly depending on the assay format; however, the panel must include at least one antibiotic resistant and one antibiotic susceptible strain of MTB-complex.

(C) Clinical Studies. Clinical performance of the device must be established by conducting prospective clinical studies that include subjects with culture confirmed active tuberculosis. Studies must attempt to enroll subjects at risk for antibiotic-resistant MTB-complex; however, it may be necessary to include supplemental antibiotic resistant retrospective and contrived samples. Clinical studies must compare device results to both phenotypic drug susceptibility testing and genotypic reference methods. The genotypic reference method must be a polymerase chain reaction based method that uses primers different from those in the experimental device and confirmed by bidirectional sequencing.

§ 866.3375 Mycoplasma spp. serological reagents.

(a) Identification. Mycoplasma spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Mycoplasma spp. in serum. Additionally, some of these reagents consist of Mycoplasma spp. antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Mycoplasma spp. directly from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Mycoplasma and provides epidemiological information on diseases caused by these microorganisms. Mycoplasma spp. are associated with inflammatory conditions of the urinary and respiratory tracts, the genitals, and the mouth. The effects in humans of infection with Mycoplasma pneumoniae range from inapparent infection to mild or severe upper respiratory disease, ear infection, and bronchial pneumonia.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3376 Device to detect and identify fungal nucleic acids directly in respiratory specimens.

(a) Identification. A device to detect and identify fungal nucleic acids directly in respiratory specimens is an in vitro diagnostic device intended for the detection and identification of fungal pathogens in respiratory specimens collected from patients with signs or symptoms and suspicion of fungal infection. The device is intended to aid in the diagnosis of fungal disease in conjunction with clinical signs and symptoms and other laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use must include a detailed description of what the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) and testing location(s) for which the device is intended.

(2) The labeling required under 21 CFR 809.10(b) must include:

(i) A detailed device description, including the parts that make up the device, instrument requirements, ancillary reagents required but not provided, and a detailed explanation of the methodology including all pre-analytical methods for processing of specimens.

(ii) Performance characteristics from analytical studies, including analytical sensitivity (Limit of Detection), inclusivity, reproducibility, interference, cross-reactivity, interfering substances, carryover/cross-contamination, and specimen stability.

(iii) A statement that the device is intended to be used in conjunction with clinical history, signs and symptoms and the results of other diagnostic tests.

(iv) A detailed explanation of the interpretation of test results and acceptance criteria for any quality control testing.

(v) A limiting statement that negative results do not preclude the possibility of infection, and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

(3) Design verification and validation activities must include:

(i) Performance characteristics from clinical studies that include prospective (sequential) samples and, if appropriate, additional characterized samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from comparator methods. Documentation from the clinical studies must include the clinical study protocol (including predefined statistical analysis plan), clinical study report, and results of all statistical analyses.

(ii) A detailed device description of the following:

(A) Overall device design including all parts that make up the device and all control elements incorporated into the testing procedure.

(B) Thorough description of the methodology including, primer/probe sequences, primer/probe design and rationale for target sequence selection.

(C) Computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result, as applicable.

(iii) A detailed documentation for device software, including, software applications and hardware-based devices that incorporate software.

§ 866.3378 Clinical mass spectrometry microorganism identification and differentiation system.

(a) Identification. A clinical mass spectrometry microorganism identification and differentiation system is a qualitative in vitro diagnostic device intended for the identification and differentiation of microorganisms from processed human specimens. The system acquires, processes, and analyzes spectra to generate data specific to a microorganism(s). The device is indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infection.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use statement must include a detailed description of what the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended, when applicable.

(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt with an indication for in vitro diagnostic use.

(3) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed device description, including all device components, control elements incorporated into the test procedure, instrument requirements, ancillary reagents required but not provided, and a detailed explanation of the methodology and all pre-analytical methods for processing of specimens, and algorithm used to generate a final result. This must include a description of validated inactivation procedure(s) that are confirmed through a viability testing protocol, as applicable.

(ii) Performance characteristics for all claimed sample types from clinical studies with clinical specimens that include prospective samples and/or, if appropriate, characterized samples.

(iii) Performance characteristics of the device for all claimed sample types based on analytical studies, including limit of detection, inclusivity, reproducibility, interference, cross-reactivity, interfering substances, carryover/cross-contamination, sample stability, and additional studies regarding processed specimen type and intended use claims, as applicable.

(iv) A detailed explanation of the interpretation of test results for clinical specimens and acceptance criteria for any quality control testing.

(4) The device's labeling must include a prominent hyperlink to the manufacturer's website where the manufacturer must make available their most recent version of the device's labeling required under § 809.10(b) of this chapter, which must reflect any changes in the performance characteristics of the device. FDA must have unrestricted access to this website, or manufacturers must provide this information to FDA through an alternative method that is considered and determined by FDA to be acceptable and appropriate.

(5) Design verification and validation must include:

(i) Any clinical studies must be performed with samples representative of the intended use population and compare the device performance to results obtained from an FDA-accepted reference method and/or FDA-accepted comparator method, as appropriate. Documentation from the clinical studies must include the clinical study protocol (including predefined statistical analysis plan, if applicable), clinical study report, and results of all statistical analyses.

(ii) Performance characteristics for analytical and clinical studies for specific identification processes for the following, as appropriate:

(A) Bacteria,

(B) Yeasts,

(C) Molds,

(D) Mycobacteria,

(E) Nocardia,

(F) Direct sample testing (e.g., blood culture),

(G) Antibiotic resistance markers, and

(H) Select agents (e.g., pathogens of high consequence).

(iii) Documentation that the manufacturer's risk mitigation strategy ensures that their device does not prevent any device(s) with which it is indicated for use, including incorporated device(s), from achieving their intended use (e.g., safety and effectiveness of the functions of the indicated device(s) remain unaffected).

(iv) A detailed device description, including the following:

(A) Overall device design, including all device components and all control elements incorporated into the testing procedure.

(B) Algorithm used to generate a final result from raw data (e.g., how raw signals are converted into a reported result).

(C) A detailed description of device software, including validation activities and outcomes.

(D) Acquisition parameters (e.g., mass range, laser power, laser profile and number of laser shots per profile, raster scan, signal-to-noise threshold) used to generate data specific to a microorganism.

(E) Implementation methodology, construction parameters, and quality assurance protocols, including the standard operating protocol for generation of reference entries for the device.

(F) For each claimed microorganism characteristic, a minimum of five reference entries for each organism (including the type strain for microorganism identification), or, if there are fewer reference entries, a clinical and/or technical justification, determined by FDA to be acceptable and appropriate, for why five reference entries are not needed.

(G) DNA sequence analysis characterizing all type strains and at least 20 percent of the non-type strains of a species detected by the device, or, if there are fewer strain sequences, then a clinical and/or technical justification, determined by FDA to be acceptable and appropriate, must be provided for the reduced number of strains sequenced.

(H) As part of the risk management activities, an appropriate end user device training program, which must be offered as an effort to mitigate the risk of failure from user error.

§ 866.3380 Mumps virus serological reagents.

(a) Identification. Mumps virus serological reagents consist of antigens and antisera used in serological tests to identify antibodies to mumps virus in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used in serological tests to identify mumps viruses from tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of mumps and provides epidemiological information on mumps. Mumps is an acute contagious disease, particularly in children, characterized by an enlargement of one or both of the parotid glands (glands situated near the ear), although other organs may also be involved.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3390 Neisseria spp. direct serological test reagents.

(a) Identification. Neisseria spp. direct serological test reagents are devices that consist of antigens and antisera used in serological tests to identify Neisseria spp. from cultured isolates. Additionally, some of these reagents consist of Neisseria spp. antisera conjugated with a fluorescent dye (immunofluorescent reagents) which may be used to detect the presence of Neisseria spp. directly from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Neisseria, such as epidemic cerebrospinal meningitis, meningococcal disease, and gonorrhea, and also provides epidemiological information on diseases caused by these microorganisms. The device does not include products for the detection of gonorrhea in humans by indirect methods, such as detection of antibodies or of oxidase produced by gonococcal organisms.

(b) Classification. Class II (performance standards).

§ 866.3393 Device to detect nucleic acids from non-viral microorganism(s) causing sexually transmitted infections and associated resistance marker(s).

(a) Identification. A device to detect nucleic acids from non-viral microorganism(s) causing sexually transmitted infections and associated resistance marker(s) is an in vitro diagnostic device intended for the detection and identification of nucleic acids from non-viral microorganism(s) and their associated resistance markers in clinical specimens collected from patients suspected of sexually transmitted infections. The device is intended to aid in the diagnosis of non-viral sexually transmitted infections in conjunction with other clinical and laboratory data. These devices do not provide confirmation of antibiotic susceptibility since mechanisms of resistance may exist that are not detected by the device.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use for the labeling required under § 809.10 of this chapter must include a detailed description of targets the device detects, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.

(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(3) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;

(ii) Detailed discussion of the performance characteristics of the device for all claimed specimen types based on analytical studies, including Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate;

(iii) Detailed descriptions of the test procedure, the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;

(iv) Limiting statements indicating that:

(A) A negative test result does not preclude the possibility of infection;

(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;

(C) Reliable results are dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and

(D) If appropriate (e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer reviewed research), that the clinical performance is inferior in a specific clinical subpopulation or for a specific claimed specimen type; and

(v) If the device is intended to detect antimicrobial resistance markers, limiting statements, as appropriate, indicating that:

(A) Negative results for claimed resistance markers do not indicate susceptibility of detected microorganisms, as resistance markers not measured by the assay or other potential mechanisms of antibiotic resistance may be present;

(B) Detection of resistance markers cannot be definitively linked to specific microorganisms and the source of a detected resistance marker may be an organism not detected by the assay, including colonizing flora;

(C) Detection of antibiotic resistance markers may not correlate with phenotypic gene expression; and

(D) Therapeutic failure or success cannot be determined based on the assay results, since nucleic acid may persist following appropriate antimicrobial therapy.

(4) Design verification and validation must include:

(i) Detailed device description documentation, including methodology from obtaining sample to result, design of primer/probe sequences, rationale for target sequence selection, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).

(ii) Detailed documentation of analytical studies, including, Limit of Detection, inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.

(iii) Detailed documentation and performance results from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from FDA accepted comparator methods. Documentation from the clinical studies must include the clinical study protocol (including a predefined statistical analysis plan) study report, testing results, and results of all statistical analyses.

(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.

§ 866.3395 Norovirus serological reagents.

(a) Identification. Norovirus serological reagents are devices that consist of antigens and antisera used in serological tests to detect the presence of norovirus antigens in fecal samples. These devices aid in the diagnosis of norovirus infection in the setting of an individual patient with symptoms of acute gastroenteritis when the individual patient is epidemiologically linked to other patients with symptoms of acute gastroenteritis and/or aid in the identification of norovirus as the etiology of an outbreak of acute gastroenteritis in the setting of epidemiologically linked patients with symptoms of acute gastroenteritis.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Norovirus Serological Reagents.” See § 866.1(e) for the availability of this guidance document.

§ 866.3400 Parainfluenza virus serological reagents.

(a) Identification. Parainfluenza virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to parainfluenza virus in serum. The identification aids in the diagnosis of parainfluenza virus infections and provides epidemiological information on diseases caused by these viruses. Parainfluenza viruses cause a variety of respiratory illnesses ranging from the common cold to pneumonia.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3402 Plasmodium species antigen detection assays.

(a) Identification. A Plasmodium species antigen detection assay is a device that employs antibodies for the detection of specific malaria parasite antigens, including histidine-rich protein-2 (HRP2) specific antigens, and pan malarial antigens in human whole blood. These devices are used for testing specimens from individuals who have signs and symptoms consistent with malaria infection. The detection of these antigens aids in the clinical laboratory diagnosis of malaria caused by the four malaria species capable of infecting humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae, and aids in the differential diagnosis of Plasmodium falciparum infections from other less virulent Plasmodium species. The device is intended for use in conjunction with other clinical laboratory findings.

(b) Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Plasmodium species Antigen Detection Assays.” See § 866.1(e) for the availability of this guidance document.

§ 866.3405 Poliovirus serological reagents.

(a) Identification. Poliovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to poliovirus in serum. Additionally, some of these reagents consist of poliovirus antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify polioviruses from clinical specimens or from tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of poliomyelitis (polio) and provides epidemiological information on this disease. Poliomyelitis is an acute infectious disease which in its serious form affects the central nervous system resulting in atrophy (wasting away) of groups of muscles, ending in contraction and permanent deformity.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3410 Proteus spp. (Weil-Felix) serological reagents.

(a) Identification. Proteus spp. (Weil-Felix) serological reagents are devices that consist of antigens and antisera, including antisera conjugated with a fluorescent dye (immunofluorescent reagents), derived from the bacterium Proteus vulgaris used in agglutination tests (a specific type of antigen-antibody reaction) for the detection of antibodies to rickettsia (virus-like bacteria) in serum. Test results aid in the diagnosis of diseases caused by bacteria belonging to the genus Rickettsiae and provide epidemiological information on these diseases. Rickettsia are generally transmitted by arthropods (e.g., ticks and mosquitoes) and produce infections in humans characterized by rash and fever (e.g., typhus fever, spotted fever, Q fever, and trench fever).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3415 Pseudomonas spp. serological reagents.

(a) Identification. Pseudomonas spp. serological reagents are devices that consist of antigens and antisera, including antisera conjugated with a fluorescent dye (immunofluorescent reagents), used to identify Pseudomonas spp. from clinical specimens or from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Pseudomonas. Pseudomonas aeruginosa is a major cause of hospital-acquired infections, and has been associated with urinary tract infections, eye infections, burn and wound infections, blood poisoning, abscesses, and meningitis (inflammation of brain membranes). Pseudomonas pseudomallei causes melioidosis, a chronic pneumonia.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3460 Rabiesvirus immunofluorescent reagents.

(a) Identification. Rabiesvirus immunofluorescent reagents are devices that consist of rabiesvirus antisera conjugated with a fluorescent dye used to identify rabiesvirus in specimens taken from suspected rabid animals. The identification aids in the diagnosis of rabies in patients exposed by animal bites and provides epidemiological information on rabies. Rabies is an acute infectious disease of the central nervous system which, if undiagnosed, may be fatal. The disease is commonly transmitted to humans by a bite from a rabid animal.

(b) Classification. Class II (performance standards).

§ 866.3470 Reovirus serological reagents.

(a) Identification. Reovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to reovirus in serum. The identification aids in the diagnosis of reovirus infections and provides epidemiological information on diseases caused by these viruses. Reoviruses are thought to cause only mild respiratory and gastrointestinal illnesses.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3480 Respiratory syncytial virus serological reagents.

(a) Identification. Respiratory syncytial virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to respiratory syncytial virus in serum. Additionally, some of these reagents consist of respiratory syncytial virus antisera conjugated with a fluorescent dye (immunofluorescent reagents) and used to identify respiratory syncytial viruses from clinical specimens or from tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of respiratory syncytial virus infections and provides epidemiological information on diseases caused by these viruses. Respiratory syncytial viruses cause a number of respiratory tract infections, including the common cold, pharyngitis, and infantile bronchopneumonia.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3490 Rhinovirus serological reagents.

(a) Identification. Rhinovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rhinovirus in serum. The identification aids in the diagnosis of rhinovirus infections and provides epidemiological information on diseases caused by these viruses. Rhinoviruses cause common colds.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3500 Rickettsia serological reagents.

(a) Identification. Rickettsia serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rickettsia in serum. Additionally, some of these reagents consist of rickettsial antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify rickettsia directly from clinical specimens. The identification aids in the diagnosis of diseases caused by virus-like bacteria belonging to the genus Rickettsiae and provides epidemiological information on these diseases. Rickettsia are generally transmitted by arthropods (e.g., ticks and mosquitoes) and produce infections in humans characterized by rash and fever (e.g., typhus fever, spotted fever, Q fever, and trench fever).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3510 Rubella virus serological reagents.

(a) Identification. Rubella virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubella virus in serum. The identification aids in the diagnosis of rubella (German measles) or confirmation of a person's immune status from past infections or immunizations and provides epidemiological information on German measles. Newborns infected in the uterus with rubella virus may be born with multiple congenital defects (rubella syndrome).

(b) Classification. Class II. The special controls for this device are:

(1) National Committee for Clinical Laboratory Standards':

(i) 1/LA6 “Detection and Quantitation of Rubella IgG Antibody: Evaluation and Performance Criteria for Multiple Component Test Products, Speciment Handling, and Use of the Test Products in the Clinical Laboratory, October 1997,”

(ii) 1/LA18 “Specifications for Immunological Testing for Infectious Diseases, December 1994,”

(iii) D13 “Agglutination Characteristics, Methodology, Limitations, and Clinical Validation, October 1993,”

(iv) EP5 “Evaluation of Precision Performance of Clinical Chemistry Devices, February 1999,” and

(v) EP10 “Preliminary Evaluation of the Linearity of Quantitive Clinical Laboratory Methods, May 1998,”

(2) Centers for Disease Control's:

(i) Low Titer Rubella Standard,

(ii) Reference Panel of Well Characterized Rubella Sera, and

(3) World Health Organization's International Rubella Standard.

§ 866.3520 Rubeola (measles) virus serological reagents.

(a) Identification. Rubeola (measles) virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubeola virus in serum. The identification aids in the diagnosis of measles and provides epidemiological information on the disease. Measles is an acute, highly infectious disease of the respiratory and reticuloendothelial tissues, particularly in children, characterized by a confluent and blotchy rash.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3550 Salmonella spp. serological reagents.

(a) Identification. Salmonella spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify Salmonella spp. from cultured isolates derived from clinical specimens. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Salmonella spp. directly from clinical specimens or cultured isolates derived from clinical specimens. The identification aids in the diagnosis of salmonellosis caused by bacteria belonging to the genus Salmonella and provides epidemiological information on this disease. Salmonellosis is characterized by high grade fever (“enteric fever”), severe diarrhea, and cramps.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3600 Schistosoma spp. serological reagents.

(a) Identification. Schistosoma spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Schistosoma spp. in serum. The identification aids in the diagnosis of schistosomiasis caused by parasitic flatworms of the genus Schistosoma. Schistosomiasis is characterized by a variety of acute and chronic infections. Acute infection is marked by fever, allergic symptoms, and diarrhea. Chronic effects are usually severe and are caused by fibrous degeneration of tissue around deposited eggs of the parasite in the liver, lungs, and central nervous system. Schistosomes can also cause schistosome dermatitis (e.g., swimmer's itch), a skin disease marked by intense itching.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3630 Serratia spp. serological reagents.

(a) Identification. Serratia spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify Serratia spp. from cultured isolates. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Serratia and provides epidemiological information on these diseases. Serratia spp. are occasionally associated with gastroenteritis (food poisoning) and wound infections.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3660 Shigella spp. serological reagents.

(a) Identification. Shigella spp. serological reagents are devices that consist of antigens and antisera, including antisera conjugated with a fluorescent dye (immunofluorescent reagents), used in serological tests to identify Shigella spp. from cultured isolates. The identification aids in the diagnosis of shigellosis caused by bacteria belonging to the genus Shigella and provides epidemiological information on this disease. Shigellosis is characterized by abdominal pain, cramps, diarrhea, and fever.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3680 Sporothrix schenckii serological reagents.

(a) Identification. Sporothrix schenckii serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Sporothrix schenckii in serum. The identification aids in the diagnosis of sporothrichosis caused by a fungus belonging to the genus Sporothrix and provides epidemiological information on this disease. Sporothrichosis is a chronic tumorlike infection primarily of the skin.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3700 Staphylococcus aureus serological reagents.

(a) Identification. Staphylococcus aureus serological reagents are devices that consist of antigens and antisera used in serological tests to identify enterotoxin (toxin affecting the intestine) producing staphylococci from cultured isolates. The identification aids in the diagnosis of disease caused by this bacterium belonging to the genus Staphylococcus and provides epidemiological information on these diseases. Certain strains of Staphylococcus aureus produce an enterotoxin while growing in meat, dairy, or bakery products. After ingestion, this enterotoxin is absorbed in the gut and causes destruction of the intestinal lining (gastroenteritis).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3720 Streptococcus spp. exoenzyme reagents.

(a) Identification. Streptococcus spp. exoenzyme reagents are devices used to identify antibodies to Streptococcus spp. exoenzyme in serum. The identification aids in the diagnosis of disease caused by bacteria belonging to the genus Streptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.3740 Streptococcus spp. serological reagents.

(a) Identification. Streptococcus spp. serological reagents are devices that consist of antigens and antisera (excluding streptococcal exoenzyme reagents made from enzymes secreted by streptococci) used in serological tests to identify Streptococcus spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genus Streptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3780 Toxoplasma gondii serological reagents.

(a) Identification. Toxoplasma gondii serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Toxoplasma gondii in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identify Toxoplasma gondii from clinical specimens. The identification aids in the diagnosis of toxoplasmosis caused by the parasitic protozoan Toxoplasma gondii and provides epidemiological information on this disease. Congenital toxoplasmosis is characterized by lesions of the central nervous system, which if undetected and untreated may lead to brain defects, blindness, and death of an unborn fetus. The disease is characterized in children by inflammation of the brain and spinal cord.

(b) Classification. Class II (performance standards).

§ 866.3820 Treponema pallidum nontreponemal test reagents.

(a) Identification. Treponema pallidum nontreponemal test reagents are devices that consist of antigens derived from nontreponemal sources (sources not directly associated with treponemal organisms) and control sera (standardized sera with which test results are compared) used in serological tests to identify reagin, an antibody-like agent, which is produced from the reaction of treponema microorganisms with body tissues. The identification aids in the diagnosis of syphilis caused by microorganisms belonging to the genus Treponema and provides epidemiological information on syphilis.

(b) Classification. Class II (performance standards).

§ 866.3830 Treponema pallidum treponemal test reagents.

(a) Identification. Treponema pallidum treponemal test reagents are devices that consist of the antigens, antisera and all control reagents (standardized reagents with which test results are compared) which are derived from treponemal sources and that are used in the fluorescent treponemal antibody absorption test (FTA-ABS), the Treponema pallidum immobilization test (T.P.I.), and other treponemal tests used to identify antibodies to Treponema pallidum directly from infecting treponemal organisms in serum. The identification aids in the diagnosis of syphilis caused by bacteria belonging to the genus Treponema and provides epidemiological information on syphilis.

(b) Classification. Class II (performance standards).

§ 866.3850 Trichinella spiralis serological reagents.

(a) Identification. Trichinella spiralis serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Trichinella spiralis in serum. The identification aids in the diagnosis of trichinosis caused by parasitic roundworms belonging to the genus Trichinella and provides epidemiological information on trichinosis. Trichinosis is caused by ingestion of undercooked, infested meat, especially pork, and characterized by fever, muscle weakness, and diarrhea.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3860 Trichomonas vaginalis nucleic acid assay.

(a) Identification. A Trichomonas vaginalis nucleic acid assay is a device that consists of primers, probes, enzymes, and controls for the amplification and detection of trichomonas nucleic acids in endocervical swabs, vaginal swabs, and female urine specimens, from women symptomatic for vaginitis, cervicitis, or urethritis and/or to aid in the diagnosis of trichomoniasis in asymptomatic women. The detection of trichomonas nucleic acids, in conjunction with other laboratory tests, aids in the clinical laboratory diagnosis of trichomoniasis caused by Trichomonas vaginalis.

(b) Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Nucleic Acid Amplification Assays for the Detection of Trichomonas vaginalis; Guideline for Industry and Food and Drug Administration Staff.” See § 866.1(e) for information on obtaining this document.

§ 866.3870 Trypanosoma spp. serological reagents.

(a) Identification. Trypanosoma spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Trypanosoma spp. in serum. The identification aids in the diagnosis of trypanosomiasis, a disease caused by parasitic protozoans belonging to the genus Trypanosoma. Trypanosomiasis in adults is a chronic disease characterized by fever, chills, headache, and vomiting. Central nervous system involvement produces typical sleeping sickness syndrome: physical exhaustion, inability to eat, tissue wasting, and eventual death. Chagas disease, an acute form of trypanosomiasis in children, most seriously affects the central nervous system and heart muscle.

(b) Classification. Class I (general controls).

§ 866.3900 Varicella-zoster virus serological reagents.

(a) Identification. Varicella-zoster virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to varicella-zoster in serum. The identification aids in the diagnosis of diseases caused by varicella-zoster viruses and provides epidemiological information on these diseases. Varicella (chicken pox) is a mild, highly infectious disease, chiefly of children. Zoster (shingles) is the recurrent form of the disease, occurring in adults who were previously infected with varicella-zoster viruses. Zoster is the response (characterized by a rash) of the partially immune host to a reactivation of varicella viruses present in latent form in the patient's body.

(b) Classification. Class II (performance standards).

§ 866.3920 Assayed quality control material for clinical microbiology assays.

(a) Identification. An assayed quality control material for clinical microbiology assays is a device indicated for use in a test system to estimate test precision or to detect systematic analytical deviations that may arise from reagent or analytical instrument variation. This type of device consists of single or multiple microbiological analytes intended for use with either qualitative or quantitative assays.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include detailed device description documentation and information concerning the composition of the quality control material, including, as appropriate:

(i) Analyte concentration;

(ii) Expected values;

(iii) Analyte source;

(iv) Base matrix;

(v) Added components;

(vi) Safety and handling information; and

(vii) Detailed instructions for use.

(2) Premarket notification submissions must include detailed documentation, including line data as well as detailed study protocols and a statistical analysis plan used to establish performance, including:

(i) Description of the process for value assignment and validation.

(ii) Description of the protocol(s) used to establish stability.

(iii) Line data establishing precision/reproducibility.

(iv) Where applicable, assessment of matrix effects and any significant differences between the quality control material and typical patient samples in terms of conditions known to cause analytical error or affect assay performance.

(v) Where applicable, identify or define traceability or relationship to a domestic or international standard reference material and/or method.

(vi) Where applicable, detailed documentation related to studies for surrogate controls.

(3) Premarket notification submissions must include an adequate mitigation (e.g., real-time stability program) to the risk of false results due to potential modifications to the assays specified in the device's 21 CFR 809.10 compliant labeling.

(4) Your 21 CFR 809.10 compliant labeling must include the following:

(i) The intended use of your 21 CFR 809.10(a)(2) and (b)(2) compliant labeling must include the following:

(A) Assayed control material analyte(s);

(B) Whether the material is intended for quantitative or qualitative assays;

(C) Stating if the material is a surrogate control; and

(D) The system(s), instrument(s), or test(s) for which the quality control material is intended.

(ii) The intended use in your 21 CFR 809.10(a)(2) and (b)(2) compliant labeling must include the following statement: “This product is not intended to replace manufacturer controls provided with the device.”

(iii) A limiting statement that reads “Quality control materials should be used in accordance with local, state, federal regulations, and accreditation requirements.”

§ 866.3930 Vibrio cholerae serological reagents.

(a) Identification. Vibrio cholerae serological reagents are devices that are used in the agglutination (an antigen-antibody clumping reaction) test to identify Vibrio cholerae from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of cholera caused by the bacterium Vibrio cholerae and provides epidemiological information on cholera. Cholera is an acute infectious disease characterized by severe diarrhea with extreme fluid and electrolyte (salts) depletion, and by vomiting, muscle cramps, and prostration. If untreated, the severe dehydration may lead to shock, renal failure, cardiovascular collapse, and death.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.3935 Zika virus serological reagents.

(a) Identification. Zika virus serological reagents are in vitro diagnostic devices that consist of antigens or antibodies for the detection of Zika virus or Zika antibodies in human specimens from individuals who have signs and symptoms consistent with Zika virus infection and/or epidemiological risk factors. The detection aids in the diagnosis of current or recent Zika virus infection or serological status. Negative results obtained with this test do not preclude the possibility of Zika virus infection, past or present. Positive results should be interpreted with consideration of other clinical information and laboratory findings and should not be used as the sole basis for treatment or other patient management decisions.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling required under § 809.10(b) of this chapter must include:

(i) An intended use with a detailed description of what the device detects (Zika IgM antibodies, other Zika antibodies, or Zika antigens), the type of results provided to the user, the specimen type for which testing is indicated (e.g., serum, whole blood), the clinical indications appropriate for test use, and the specific population(s) for which the test is intended.

(ii) Performance characteristics from analytical and clinical studies required under paragraphs (b)(2)(ii) and (iii) of this section.

(iii) A detailed explanation of the interpretation of results and criteria for validity of results (e.g., criteria that internal or external quality controls must meet in order for a test/test run to be valid, minimum signal strength that the sample has to yield to be interpretable as a valid result).

(iv) Limiting statements indicating that:

(A) Results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. The test results should be interpreted in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence.

(B) Device results are intended to be followed up according to the latest professional guidelines (e.g., recommendations from the Centers for Disease Control and Prevention) for the diagnosis of Zika virus infection.

(C) Negative test results do not preclude the possibility of Zika virus infection, past or present.

(D) Specimens can result in false negative results on the device if collected outside of the appropriate response window for specific Zika virus antigens or antibodies, as determined by scientific evidence (e.g., for IgM <7 days post symptom onset (pso) or risk of exposure and if collected past 84 days pso).

(v) Detailed instructions for use that minimize the risk of generating a false positive or false negative result (e.g., co-testing of other matrices).

(2) Design verification and validation must include:

(i) A detailed device description, including all device parts (e.g., Zika antigen target, other flavivirus antigen target, capture antibodies), instrument requirements, ancillary reagents required but not provided, and the technological characteristics, including all pre-analytical methods for specimen processing.

(ii) Detailed documentation and results from analytical performance studies including: characterization of the cut-off(s), analytical sensitivity to a standardized reference material that FDA has determined is appropriate (e.g., World Health Organization reference standard or the Centers for Disease Control and Prevention reference standard), class specificity for human antibodies (e.g., IgM or IgG), analytical specificity (cross reactivity including cross reactivity to other flaviviruses), interference, carryover/cross contamination, specimen stability, hook effect (if applicable), matrix equivalency (if applicable), freeze-thaw studies (if applicable), and reproducibility.

(iii) Detailed documentation and results from clinical studies, including the clinical study protocol (with a description of the testing algorithm and results interpretation table), detailed clinical study report, including line data of the clinical study results, and other appropriate statistical analysis. The samples used in the clinical study must be collected from subjects representative of the full spectrum of the intended use population (e.g., endemic and non-endemic regions if both are indicated).

§ 866.3940 West Nile virus serological reagents.

(a) Identification. West Nile virus serological reagents are devices that consist of antigens and antisera for the detection of anti-West Nile virus IgM antibodies, in human serum, from individuals who have signs and symptoms consistent with viral meningitis/encephalitis. The detection aids in the clinical laboratory diagnosis of viral meningitis/encephalitis caused by West Nile virus.

(b) Classification. Class II (special controls). The special control is FDA's guidance entitled “Class II Special Controls Guidance Document: Serological Reagents for the Laboratory Diagnosis of West Nile Virus.” See § 866.1(e) for the availability of this guidance document.

§ 866.3945 Dengue virus serological reagents.

(a) Identification. Dengue virus serological reagents are devices that consist of antigens and antibodies for the detection of dengue virus and dengue antibodies in individuals who have signs and symptoms of dengue fever or dengue hemorrhagic fever. The detection aids in the clinical laboratory diagnosis of dengue fever or dengue hemorrhagic fever caused by dengue virus.

(b) Classification. Class II (special controls). The special control is FDA's guideline entitled “Class II Special Controls Guideline: Dengue Virus Serological Reagents.” For availability of the guideline document, see § 866.1(e).

§ 866.3946 Dengue virus nucleic acid amplification test reagents.

(a) Identification. Dengue virus nucleic acid amplification test reagents are devices that consist of primers, probes, enzymes, and controls for the amplification and detection of dengue virus serotypes 1, 2, 3, or 4 from viral ribonucleic acid (RNA) in human serum and plasma from individuals who have signs and symptoms consistent with dengue (mild or severe). The identification of dengue virus serotypes 1, 2, 3, or 4 in human serum and plasma (sodium citrate) collected from human patients with dengue provides epidemiologic information for surveillance of circulating dengue viruses.

(b) Classification. Class II (special controls). The special control is FDA's guideline entitled “Class II Special Controls Guideline: Dengue Virus Nucleic Acid Amplification Test Reagents.” For availability of the guideline document, see § 866.1(e).

§ 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

(a) Identification. The in vitro HIV drug resistance genotype assay is a device that consists of nucleic acid reagent primers and probes together with software for predicting drug resistance/susceptibility based on results obtained with these primers and probes. It is intended for use in detecting HIV genomic mutations that confer resistance to specific antiretroviral drugs, as an aid in monitoring and treating HIV infection.

(b) Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: In Vitro HIV Drug Resistance Genotype Assay.” See § 866.1(e) for the availability of this guidance document.

§ 866.3955 Human immunodeficiency virus (HIV) drug resistance genotyping assay using next generation sequencing technology.

(a) Identification. The HIV drug resistance genotyping assay using next generation sequencing (NGS) technology is a prescription in vitro diagnostic device intended for use in detecting HIV genomic mutations that confer resistance to specific antiretroviral drugs. The device is intended to be used as an aid in monitoring and treating HIV infection.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use of the device must:

(i) Specify the analyte (RNA or DNA), the genes in which mutations are detected, the clinical indications appropriate for test use, the sample type, and the specific population(s) for which the device in intended.

(ii) State that the device in not intended for use as an aid in the diagnosis of infection with HIV or to confirm the presence of HIV infection, or for screening donors of blood, plasma, or human cells, tissues, and cellular and tissue-based products.

(2) The labeling must include:

(i) A detailed device description, including but not limited to, all procedures from collection of the patient sample to reporting the final result, all device components, the control elements incorporated into the test procedure, instrument requirements, and reagents required for use but not provided as part of the device.

(ii) Performance characteristics from analytical studies and all intended specimen types.

(iii) A list of specific mutations detected.

(iv) The name and version of the standardized database used for sequence comparison and results derivation.

(v) A detailed explanation of the interpretation of test results, including acceptance criteria for evaluating the validity of a test run.

(vi) A limitation statement that the device is intended to be used in conjunction with clinical history and other laboratory findings. Results of this test are intended to be interpreted by a physician or equivalent.

(vii) A limitation statement that lack of detection of drug resistance mutations does not preclude the possibility of genetic mutation.

(viii) A limitation statement indicating the relevant genetic mutations that are included in the standardized database of HIV genomic sequences used for comparison and results derivation but that are not detected by the test.

(ix) A limitation statement that detection of a genomic drug resistance mutation may not correlate with phenotypic gene expression.

(x) A limitation statement that the test does not detect all genetic mutations associated with antiviral drugs.

(xi) A limitation statement listing the HIV types for which the test is not intended, if any.

(3) Device verification and validation must include:

(i) Design of primer sequences and rationale for sequence selection.

(ii) Computational path from collected raw data to reported result.

(iii) Detailed documentation of analytical studies including, but not limited to, characterization of the cutoff, analytical sensitivity, inclusivity, reproducibility, interference, cross reactivity, instrument and method carryover/cross contamination, sample stability, and handling for all genomic mutations claimed in the intended use.

(iv) Precision studies that include all genomic mutations claimed in the intended use.

(v) Detailed documentation of a multisite clinical study evaluating the sensitivity and specificity of the device. Clinical study subjects must represent the intended use population and device results for all targets claimed in the intended use must be compared to Sanger sequencing or other methods found acceptable by FDA. Drug resistance-associated mutations at or above the 20 percent frequency level must detect the mutations in greater than 90 percent of at least 10 replicates, for each of drug class evaluated.

(vi) Documentation that variant calling is performed at a level of coverage that supports positive detection of all genomic mutations claimed in the intended use.

(vii) Detailed documentation of limit of detection (LoD) studies in which device performance is evaluated by testing a minimum of 100 HIV-positive clinical samples including samples with analyte concentrations near the clinical decision points and near the LoD.

(A) The LoD for the device must be determined using a minimum of 10 HIV-1 group M genotypes if applicable. A detection rate at 1 × LoD greater than or equal to 95 percent must be demonstrated for mutations with a frequency greater than 20 percent.

(B) The LoD of genetic mutations at frequency levels less than 20 percent must be established.

(viii) A predefined HIV genotyping bioinformatics analysis pipeline (BAP). The BAP must adequately describe the bioinformatic analysis of the sequencing data, including but not limited to read alignment, variant calling, assembly, genotyping, quality control, and final result reporting.

(ix) A clear description of the selection and use of the standardized database that is used for sequence comparison and results derivation.

(4) Premarket notification submissions must include the information in paragraphs (b)(3)(i) through (ix) of this section.

§ 866.3956 Human immunodeficiency virus (HIV) serological diagnostic and/or supplemental test.

(a) Identification. Human immunodeficiency virus (HIV) serological diagnostic and supplemental tests are prescription devices for the qualitative detection of HIV antigen(s) and/or detection of antibodies against HIV in human body fluids or tissues. The tests are intended for use as an aid in the diagnosis of infection with HIV and are for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. These tests are not intended to be used for monitoring patient status, or for screening donors of blood or blood products, or human cells, tissues, and cellular and tissue-based products (HCT/Ps).

(b) Classification. Class II (special controls). The special controls for this device are:

(1) For all HIV serological diagnostic and supplemental tests

(i) The labeling must include:

(A) An intended use that states that the device is not intended for use for screening donors of blood or blood products or HCT/Ps.

(B) A detailed explanation of the principles of operation and procedures used for performing the assay.

(C) A detailed explanation of the interpretation of results and recommended actions to take based on results.

(D) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:

(1) The matrices with which the device has been cleared, and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.

(2) The test is not intended to be used to monitor individuals who are undergoing treatment for HIV infection.

(3) A specimen with a reactive result should be investigated further following current guidelines.

(4) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.

(5) A test result that is nonreactive does not exclude the possibility of exposure to or infection with HIV. Nonreactive results in this assay may be due to analyte levels that are below the limit of detection of this assay.

(ii) Device verification and validation must include:

(A) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the methodology. Additional information appropriate to the technology must be included, such as the amino acid sequence of antigen(s) and design of capture antibodies.

(B) For devices with assay calibrators, the design of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.

(C) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of blank, limit of detection, cutoff determination, precision, endogenous and exogenous interferences, cross reactivity, carryover, quality control, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States.

(D) Multisite reproducibility study that includes the testing of three independent production lots.

(E) Analytical sensitivity of the test must be the same as or better than that of other cleared or approved tests. Samples tested must include appropriate numbers and types of samples, including real clinical samples near the lower limit of detection. Analytical specificity of the test must be the same as or better than that of other cleared or approved tests. Samples must include appropriate numbers and types of samples from patients with different underlying illnesses or infections and from patients with potential endogenous interfering substances.

(F) Detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA-cleared or approved comparator. This study must be conducted using patient samples, with an appropriate number of HIV positive and HIV negative samples in applicable risk categories. Additional subgroups or types must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:

(1) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.

(2) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.

(G) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.

(H) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.

(I) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(J) All stability protocols, including acceptance criteria.

(K) Appropriate and acceptable procedure(s) for evaluating customer complaints and other device information that determines when to submit a medical device report.

(L) Premarket notification submissions must include the information contained in paragraph (b)(1)(ii)(A) through (K) of this section.

(iii) Manufacturers must submit a log of all complaints. The log must include the following information regarding each complaint if available: The type of event (e.g., false negative/false nonreactive or false positive/false reactive), lot, date, population, and whether or not the complaint was reported under part 803 of this chapter (Medical Device Reporting). The log must be submitted annually on the anniversary of clearance for 5 years following clearance of a traditional premarket notification.

(2) If the test is intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraph (b)(1) of this section apply:

(i) The PoC labeling must include a statement that the test is intended for PoC use.

(ii) The PoC labeling must include the following information near the statement of the intended use:

(A) That the test is for distribution to clinical laboratories that have an adequate quality assurance program, including planned systematic activities that provide adequate confidence that requirements for quality will be met and where there is assurance that operators will receive and use the instructional materials.

(B) That the test is for use only by an agent of a clinical laboratory.

(C) Instructions for individuals to receive the “Subject Information Notice” prior to specimen collection and appropriate information when test results are provided.

(iii) PoC labeling must include instructions to follow current guidelines for informing the individual of the test result and its interpretation.

(iv) The instructions in the labeling must state that reactive results are considered preliminary and should be confirmed following current guidelines.

(v) Device verification and validation for PoC use must include:

(A) Detailed documentation of performance from a multisite clinical study conducted at appropriate PoC sites. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using patient samples, with appropriate numbers of HIV positive and HIV negative samples in applicable risk categories. Additional subgroup or type claims must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. If the test is intended solely for PoC use, the test must meet only the performance criteria in paragraphs (b)(2)(v)(A)(1) and (2) of this section and not the criteria in paragraph (b)(1)(ii)(F) of this section:

(1) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.

(2) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.

(B) Premarket notification submissions must include the information contained in paragraph (b)(2)(v)(A) of this section.

(3) If the test is intended for supplemental use in addition to use as an aid in initial diagnosis, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, as appropriate, apply:

(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV antibodies or antigens in specimens found to be repeatedly reactive by a diagnostic screening test.

(ii) Device validation and verification for supplemental use must include a clinical study, including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a different confirmatory test. Premarket notification submissions must include this information.

(4) If the test is intended solely as a supplemental test, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, except those in paragraphs (b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:

(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV antibodies or antigens in specimens found to be repeatedly reactive by a diagnostic screening test.

(ii) The labeling must clearly state that the test is not for use for initial diagnosis or is not intended as a first-line test.

(iii) Device validation and verification must include a clinical study including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.

(5) If the test is intended to differentiate different HIV types, the following special controls, in addition to those listed in paragraphs (b)(1) through (4) of this section, as appropriate, apply:

(i) The labeling must include the statement that the test is intended for the confirmation of initial results from a diagnostic test and differentiation of different HIV types.

(ii) The results interpretation in the labeling must include instructions for the user on how to interpret the results, including un-typeable and co-infection results.

(iii) Device validation and verification must include evaluation of analytical and clinical sensitivity and specificity for each of the HIV types, strains, and subtypes of HIV intended to be differentiated. Premarket notification submissions must include this information.

§ 866.3957 Human immunodeficiency virus (HIV) nucleic acid (NAT) diagnostic and/or supplemental test.

(a) Identification. Human immunodeficiency virus (HIV) nucleic acid (NAT) diagnostic and supplemental tests are prescription devices for the qualitative detection of HIV nucleic acid in human body fluids or tissues. The tests are intended for use as an aid in the diagnosis of infection with HIV and are for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. These tests are not intended to be used for monitoring patient status, or for screening donors of blood or blood products, or human cells, tissues, or cellular or tissue-based products (HCT/Ps).

(b) Classification. Class II (special controls). The special controls for this device are:

(1) For all HIV NAT diagnostic and/or supplemental tests

(i) The labeling must include:

(A) An intended use that states that the device is not intended for use for screening donors of blood or blood products, or HCT/Ps.

(B) A detailed explanation of the principles of operation and procedures used for performing the assay.

(C) A detailed explanation of the interpretation of results and recommended actions to take based on results.

(D) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:

(1) The matrices with which the device has been cleared, and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.

(2) The test is not intended to be used to monitor individuals who are undergoing treatment for HIV infection.

(3) A specimen with a reactive result should be investigated further following current guidelines.

(4) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.

(5) A test result that is nonreactive does not exclude the possibility of exposure to or infection with HIV. Nonreactive results in this assay may be due to analyte levels that are below the limit of detection of this assay.

(ii) Device verification and validation must include:

(A) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the methodology. Additional information appropriate to the technology must be included, such as design of primers and probes.

(B) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.

(C) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of blank, limit of detection, cutoff determination, precision, endogenous and exogenous interferences, cross reactivity, carryover, quality control, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States. The effect of each claimed nucleic-acid isolation and purification procedure on detection must be evaluated.

(D) Multisite reproducibility study that includes the testing of three independent production lots.

(E) Analytical sensitivity of the test must be the same as or better than that of other cleared or approved tests. Samples tested must include appropriate numbers and types of samples, including real clinical samples near the lower limit of detection. Analytical specificity of the test must be as the same as or better than that of other cleared or approved tests. Samples must include appropriate numbers and types of samples from patients with different underlying illnesses or infections and from patients with potential endogenous interfering substances.

(F) Detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using appropriate patient samples, with appropriate numbers of HIV positive and negative samples in applicable risk categories. Additional subtype, strain, or types must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:

(1) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.

(2) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.

(G) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.

(H) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.

(I) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(J) All stability protocols, including acceptance criteria.

(K) Appropriate and acceptable procedure(s) for evaluating customer complaints and other device information that determine when to submit a medical device report.

(L) Premarket notification submissions must include the information contained in paragraph (b)(1)(ii)(A) through (K) of this section.

(iii) Manufacturers must submit a log of all complaints. The log must include the following information regarding each complaint, if available: The type of event (e.g., false negative/false nonreactive or false positive/false reactive), lot, date, population, and whether or not the complaint was reported under part 803 of this chapter (Medical Device Reporting). The log must be submitted annually on the anniversary of clearance for 5 years following clearance of a traditional premarket notification.

(2) If the test is intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraph (b)(1) of this section, apply:

(i) The PoC labeling must include a statement that the test is intended for PoC use.

(ii) The PoC labeling must include the following information near the statement of the intended use:

(A) That the test is for distribution to clinical laboratories that have an adequate quality assurance program, including planned systematic activities that provide adequate confidence that requirements for quality will be met and where there is assurance that operators will receive and use the instructional materials.

(B) That the test is for use only by an agent of a clinical laboratory.

(C) Instructions for individuals to receive the “Subject Information Notice” prior to specimen collection and appropriate information when test results are provided.

(iii) PoC labeling must include instructions to follow current guidelines for informing the individual of the test result and its interpretation.

(iv) The instructions in the labeling must state that reactive results are considered preliminary and should be confirmed following current guidelines.

(v) Device verification and validation for PoC use must include:

(A) Detailed documentation from a well-conducted multisite clinical study conducted at appropriate PoC sites. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using patient samples, with appropriate numbers of HIV positive and HIV negative samples in applicable risk categories. Additional subgroup or type claims must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. If the test is intended solely for PoC use, the test must meet only the performance criteria in paragraphs (b)(2)(v)(A)(1) and (2) of this section and not the criteria in paragraph (b)(1)(ii)(F) of this section:

(1) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.

(2) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.

(B) Premarket notification submissions must include the information contained in paragraph (b)(2)(v)(A) of this section.

(3) If the test is intended for supplemental use in addition to use as an aid in initial diagnosis, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, as appropriate, apply:

(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV viral nucleic acid in specimens found to be repeatedly reactive by a diagnostic screening test.

(ii) Device validation and verification for supplemental use must include a clinical study, including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.

(4) If the test is intended solely as a supplemental test, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, except those in paragraphs (b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:

(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV viral nucleic acid in specimens found to be repeatedly reactive by a diagnostic screening test.

(ii) The labeling must clearly state that the test is not for use for initial diagnosis or is not intended as a first-line test.

(iii) Device validation and verification must include a clinical study including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.

(5) If the test is intended to differentiate different HIV types, the following special controls, in addition to those listed in paragraphs (b)(1) through (4) of this section, as appropriate, apply:

(i) The labeling must include the statement that the test is intended for the confirmation of initial results and differentiation of different HIV types.

(ii) The results interpretation in the labeling must include instructions for the user on how to interpret the results, including un-typeable and co-infection results.

(iii) Device validation and verification must include evaluation of analytical and clinical sensitivity and specificity for each of the types, strains, and subtypes of HIV intended to be differentiated. Premarket notification submissions must include this information.

§ 866.3958 Human immunodeficiency virus (HIV) viral load monitoring test.

(a) Identification. A human immunodeficiency virus (HIV) viral load monitoring test is an in vitro diagnostic prescription device for the quantitation of the amount of HIV ribonucleic acid (RNA) in human body fluids. The test is intended for use in the clinical management of individuals living with HIV and is for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. The test is not intended to be used as an aid in diagnosis or for screening donors of blood or blood products or human cells, tissues, or cellular and tissue-based products (HCT/Ps).

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling must include:

(i) An intended use that states that the device is not intended for use as an aid in diagnosis or for use in screening donors of blood or blood products, or HCT/Ps.

(ii) A detailed explanation of the principles of operation and procedures used for assay performance.

(iii) A detailed explanation of the interpretation of results and that recommended actions should be based on current clinical guidelines.

(iv) Limitations, which must be updated to reflect current clinical practice and patient management. The limitations must include, but are not limited to, statements that indicate:

(A) The matrices and sample types with which the device has been cleared and that use of this test with specimen types other than those specifically cleared for this device may cause inaccurate test results.

(B) Mutations in highly conserved regions may affect binding of primers and/or probes resulting in the under-quantitation of virus or failure to detect the presence of virus.

(C) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.

(2) Device verification and validation must include:

(i) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included, such as detailed information on the design of primers and probes.

(ii) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.

(iii) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including but not limited to, limit of blank, limit of detection, limit of quantitation, cutoff determination, precision, linearity, endogenous and exogenous interferences, cross-reactivity, carry-over, quality control, matrix equivalency, sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant genotypes circulating in the United States.

(iv) Multisite reproducibility study that includes the testing of three independent production lots.

(v) Analytical sensitivity of the device must demonstrate acceptable performance at current clinically relevant medical decision points. Samples tested to demonstrate analytical sensitivity must include appropriate numbers and types of samples, including real clinical samples near the lower limit of quantitation and any clinically relevant medical decision points. Analytical specificity of the device must demonstrate acceptable performance. Samples tested to demonstrate analytical specificity must include appropriate numbers and types of samples from patients with different underlying illnesses and infection and from patients with potential interfering substances.

(vi) Detailed documentation of performance from a multisite clinical study or a multisite analytical method comparison study.

(A) For devices evaluated in a multisite clinical study, the study must use specimens from individuals living with HIV being monitored for changes in viral load, and the test results must be compared to the clinical status of the patients.

(B) For tests evaluated in a multisite analytical method comparison study, the performance of the test must be compared to an FDA-cleared or approved comparator. The multisite method comparison study must include appropriate numbers and types of samples with analyte concentrations across the measuring range of the assay, representing clinically relevant genotypes. The multisite method comparison study design, including number of samples tested, must be sufficient to meet the following criteria:

(1) Agreement between the two tests across the measuring range of the assays must have an r2 of greater than or equal to 0.95.

(2) The bias between the test and comparator assay, as determined by difference plots, must be less than or equal to 0.5 log copies/mL.

(vii) Detailed documentation of a single-site analytical method comparison study between the device and an FDA-cleared or approved comparator if a multisite clinical study is performed under paragraph(b)(2)(vi) of this section. The analytical method comparison study must use appropriate numbers and types of samples with analyte concentrations across the measuring range of the assay, representing clinically relevant genotypes. The results must meet the criteria in paragraphs (b)(2)(vi)(B)(1) and (2) of this section.

(viii) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.

(ix) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.

(x) Final release criteria to be used for manufactured device lots with an appropriate justification that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.

(xi) All stability protocols, including acceptance criteria.

(xii) Appropriate and acceptable procedure(s) for addressing complaints and other device information that determines when to submit a medical device report.

(xiii) Premarket notification submissions must include the information contained in paragraphs (b)(2)(i) through (xii) of this section.

§ 866.3960 Nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens.

(a) Identification. A nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens is a qualitative in vitro device intended for the amplification, detection, and identification of microbial-associated nucleic acid sequences from patients with suspected bloodstream infections. This device is intended to aid in the diagnosis of bloodstream infection when used in conjunction with clinical signs and symptoms and other laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.

(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (limit of detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carryover, and cross contamination.

(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.

(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.

(5) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate.

(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.

(7) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate.

(8) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.

§ 866.3966 Device to detect and identify selected microbial agents that cause acute febrile illness.

(a) Identification. A device to detect and identify selected microbial agents that cause acute febrile illness is identified as an in vitro device intended for the detection and identification of microbial agents in human clinical specimens from patients with signs and symptoms of acute febrile illness who are at risk for exposure or who may have been exposed to these agents. It is intended to aid in the diagnosis of acute febrile illness in conjunction with other clinical, epidemiologic, and laboratory data, including patient travel, pathogen endemicity, or other risk factors.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) An intended use that includes a detailed description of targets the device detects and measures, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.

(ii) Limiting statements indicating:

(A) Not all pathogens that cause febrile illness are detected by this test and negative results do not rule out the presence of other infections;

(B) Evaluation of more common causes of acute febrile illness should be considered prior to evaluation with this test;

(C) Test results are to be interpreted in conjunction with other clinical, epidemiologic, and laboratory data available to the clinician; and

(D) When using this test, consider patient travel history and exposure risk, as some pathogens are more common in certain geographical locations.

(iii) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.

(iv) Detailed discussion of the performance characteristics of the device for all claimed specimen types as shown by the analytical and clinical studies required under paragraphs (b)(3)(ii) and (iii) of this section, except specimen stability performance characteristics.

(v) A statement that nationally notifiable results are to be reported to public health authorities in accordance with local, state, and federal law.

(3) Design verification and validation must include:

(i) A detailed device description (e.g., all device parts, control elements incorporated into the test procedure, reagents required but not provided, the principle of device operation and test methodology), and the computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).

(ii) Detailed documentation of analytical studies, including those demonstrating Limit of Detection (LoD), inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.

(iii) Detailed documentation and performance results from a clinical study that includes prospective (sequentially collected) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from FDA-accepted comparator methods. Documentation from the clinical studies must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.

(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.

§ 866.3970 Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.

(a) Identification. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is a qualitative in vitro device intended for the detection and identification of microbial-associated nucleic acid sequences from patients suspected of meningitis or encephalitis. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is intended to aid in the diagnosis of meningitis or encephalitis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.

(2) Premarket notification submissions must include detailed documentation from the following analytical studies: Analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability.

(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted comparator methods.

(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.

(5) The Intended Use statement in the device labeling must include a statement that the device is intended to be used in conjunction with standard of care culture.

(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.

(7) The device labeling must include a limitation stating that the negative results do not preclude the possibility of central nervous system infection.

(8) The device labeling must include a limitation stating that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.

(9) The device labeling must include a limitation stating that positive results do not mean that the organism detected is infectious or is the causative agent for clinical symptoms.

(10) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.

§ 866.3975 Device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis.

(a) Identification. A device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis is a qualitative in vitro diagnostic device intended for the detection of microbial nucleic acid sequences in vaginal specimens collected from patients with signs and symptoms of vaginitis or bacterial vaginosis. This device is intended to aid in the diagnosis of vaginitis or bacterial vaginosis when used in conjunction with clinical signs and symptoms and other laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Design verification and validation must include:

(i) Documentation with a detailed device description of device components; ancillary reagents required but not provided; and explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection.

(ii) Documentation with information that demonstrates the performance characteristics of the device, including:

(A) Limit of Detection;

(B) Precision (reproductivity);

(C) Analytical specificity;

(D) Analytical reactivity (inclusivity);

(E) Specimen stability; and

(F) Effects of interfering substances.

(iii) Detailed documentation from a prospective clinical study. As appropriate to the intended use, the prospective clinical study must be performed on an appropriate study population, including women of various ages and ethnicities. The prospective clinical study must compare the device performance to results obtained from well-accepted comparator methods.

(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed explanation of the interpretation of results and acceptance criteria;

(ii) For devices with an intended use that includes detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, clinical performance stratified by patient demographics such as race, ethnicity, age, and pregnancy status.

(iii) For devices with an intended use that includes detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, a summary of device results in an asymptomatic population with demographic characteristics appropriate to the intended use population.

(iv) For devices with an intended use that includes detection of either Candida species or bacteria associated with bacterial vaginosis, a limitation that Candida species and bacterial compositions associated with bacterial vaginosis can be present as part of normal vaginal flora and results should be considered in conjunction with available clinical information.

§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.

(a) Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:

(1) Influenza A and Influenza B;

(2) Influenza A subtype H1 and Influenza A subtype H3;

(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;

(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;

(5) Human Metapneumovirus;

(6) Rhinovirus; and

(7) Adenovirus.

(b) Classification. Class II (special controls). The special controls are:

(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”

(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and

(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.

§ 866.3981 Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test.

(a) Identification. A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes and targets the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.

(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(3) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;

(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, precision, reproducibility, and clinical studies;

(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;

(iv) A warning statement that viral culture should not be attempted in cases of positive results for SARS-CoV-2 and/or any similar microbial agents unless a facility with an appropriate level of laboratory biosafety (e.g., BSL 3 and BSL 3+, etc.) is available to receive and culture specimens; and

(v) A prominent statement that device performance has not been established for specimens collected from individuals not identified in the intended use population (e.g., when applicable, that device performance has not been established in individuals without signs or symptoms of respiratory infection).

(vi) Limiting statements that indicate that:

(A) A negative test result does not preclude the possibility of infection;

(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;

(C) There is a risk of incorrect results due to the presence of nucleic acid sequence variants in the targeted pathogens;

(D) That positive and negative predictive values are highly dependent on prevalence;

(E) Accurate results are dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and

(F) When applicable (e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer-reviewed literature), that the clinical performance may be affected by testing a specific clinical subpopulation or for a specific claimed specimen type.

(4) Design verification and validation must include:

(i) Detailed documentation, including performance results, from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. The clinical study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator that FDA has determined is appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.

(ii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains (e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately.

(iii) A detailed description of the identity, phylogenetic relationship, and other recognized characterization of the respiratory pathogen(s) that the device is designed to detect. In addition, detailed documentation describing how to interpret the device results and other measures that might be needed for a laboratory diagnosis of respiratory infection.

(iv) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device (e.g., saturation level of hybridization and maximum amplification and detection cycle number, etc.), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable.

(v) A detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.

(vi) For devices intended for the detection and identification of microbial agents for which an FDA recommended reference panel is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference panel of characterized samples. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens, the design verification and validation must include a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. An evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(5) When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device's labeling under § 809.10(b) of this chapter.

(6) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens in addition to detection of SARS-CoV-2 and similar microbial agents, the required labeling under § 809.10(b) of this chapter must include the following:

(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation.

(ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to State or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required followup actions or retesting in the case of an unusual or unexpected device result.

(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated (i.e., H1-2009 and H3), this result requires notification of appropriate local, State, or Federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.

(7) If one of the actions listed at section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those influenza viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate.

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized influenza viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:

(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or

(B) In a section of the device's label or in other labeling that accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's website, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the website containing this information and must allow unrestricted viewing access.

§ 866.3982 Simple point-of-care device to directly detect SARS-CoV-2 viral targets from clinical specimens in near-patient settings.

(a) Identification. A simple point-of-care device to detect SARS-CoV-2 viral targets directly from clinical specimens in near-patient settings is an in vitro diagnostic device for the direct detection of SARS-CoV-2 in clinical specimens and is intended as an aid in the diagnosis of SARS-CoV-2 infections (COVID-19). The device is simple to use and does not involve sample manipulation, transportation of the sample to another functional area (e.g., a central laboratory or other specialized area), or measurement of reagents or analytes that could be affected by conditions such as sample turbidity or cell lysis. The design and procedures of the device are appropriate for use by healthcare professionals in near-patient settings outside a centralized laboratory.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: analytes the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.

(2) The intended use of the device must only include indications for testing of respiratory specimens.

(3) If sample collection devices are used, any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(4) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed and comprehensive device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;

(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: limit of detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, hook-effect, carryover/cross contamination, specimen stability, precision, reproducibility, human factors analysis, flex studies, and clinical studies;

(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;

(iv) A statement in the intended use that positive results do not preclude co-infection with bacteria or other viruses and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions;

(v) Detailed instructions for minimizing the risk of user's exposure to infectious microbial agents that may be present in test specimens and those used as control materials;

(vi) Detailed instructions for minimizing the risk of generating false positive test results due to carry-over contamination from positive test specimens and/or positive control materials, as applicable to the design of the test device;

(vii) A brief reference sheet (Quick Reference Instructions) for the intended user(s) that includes, at a minimum, the name and intended use of the test, easy to follow step-by-step instructions of all control and sample testing procedures for the claimed sample types, including graphic illustrations targeted towards lay users (as applicable), the result(s) interpretation guidance, warnings and limitation statements, toxicology information and safety considerations for any hazardous materials, information for troubleshooting (e.g., Frequently Asked Questions), and technical assistance with the device (e.g., Help-line contact information);

(viii) Limiting statements indicating that:

(A) For those devices intended for testing in symptomatic subjects, a statement that specifies the number of days post symptom onset validated for use of the device and/or a range in which the performance of the test is known;

(B) A negative test result does not preclude the possibility of infection with other bacteria or viruses;

(C) The test results should be interpreted in conjunction with other clinical and laboratory data available to the healthcare provider (as applicable);

(D) There is a risk of erroneous results (i.e., false negatives) due to the presence of novel, emerging respiratory viral variants (e.g., specific strains or isolates);

(E) False positive test results are more likely when prevalence of upper respiratory infection is low in the community;

(F) Accurate results are dependent on adequate specimen collection, transport, storage, and processing (as applicable). Failure to observe proper procedures in any one of these steps can lead to incorrect results;

(G) This test should not be used beyond the expiration date listed on the packaging. Use of expired tests can lead to incorrect results; and

(H) The performance characteristics for that analyte were established when [insert predominant strain, subtype, or variant] was prevalent and that due to the propensity of the virus to mutate, new strains emerge over time which may affect the performance of this device and have serious public health implications. Additional testing with a molecular test and/or sequencing should be considered in situations where a new virus strain or variant is suspected.

(5) Design verification and validation must include:

(i) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including viral target(s), identification of target detection reagents (e.g., primers, antibodies), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design;

(ii) Detailed documentation of data from a prospective multisite clinical study with a design and performance that is appropriate for the intended use of the device, including performance estimates derived from a sufficient number of samples from the intended use population for each claimed specimen type. Results must be obtained from a geographically diverse population, such that the performance of the test device is appropriately representative of all present, circulating strains of the target respiratory virus, at the time of the study and submission. The clinical study must be consistent with and support the intended use population and intended operators (as applicable) and must be conducted in a representative intended use setting. The clinical study must compare the results of the candidate device to results obtained using an FDA accepted molecular comparator method. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses;

(iii) The clinical study designs, including number of samples tested, must be sufficient to meet either of the following criteria:

(A) The lower bound of the two-sided 95 percent confidence interval of the positive percent agreement must be greater than or equal to 80 percent and appropriate risk mitigation measures are established (e.g., presumptive negative results); or

(B) The lower bound of the two-sided 95 percent confidence interval of the positive percent agreement must be greater than or equal to 70 percent and additional and appropriate risk mitigations measures are established (e.g., presumptive negative results and serial testing).

(iv) Detailed documentation of analytical studies, including those demonstrating the limit of detection, inclusivity (including relevant variants), cross-reactivity, microbial interference, interfering substances, competitive inhibition, specimen stability, within-lab precision, hook effect, carryover, cross contamination, and site-to-site reproducibility, as applicable;

(v) Detailed documentation and characterization (e.g., determination of the identity, supplier, purity, and stability) of all critical reagents and protocols for maintaining product integrity throughout its labeled shelf life, i.e., reagent stability studies. Data and protocols, including acceptance criteria, from a multi-lot reagent stability study must include testing of samples with adequately challenging analyte concentration, be provided as part of the regulatory submission and must include in-use/open-kit stability, shipping stability, and freeze-thaw stability (as applicable). The shelf-life stability assessment must include the most challenging sample type identified in the device's intended use and are formulated using whole virus;

(vi) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims;

(vii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis.

(A) This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel isolates or strains (e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). Protocols must include plans to update labeling with additional performance data. All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately;

(B) This must include detailed documentation that demonstrates the effectiveness of risk control measures and device robustness, including the entire testing procedure from sampling to result interpretation, based on results from the following studies, as applicable per the intended use of the test device: human factors engineering (e.g., usability studies and user label comprehension), flex studies, and performance with weakly-reactive samples in the hands of the intended user(s);

(viii) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review; and

(ix) For devices intended for the detection and identification of an analyte for which an FDA recommended reference material is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference material. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(6) If one of the actions listed in section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to one or more of the analytes claimed in the intended use, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to one or more of the analytes claimed in the intended use:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation, the manufacturer must have testing performed on the device with those samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate; and

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation and continuing until 3 years from that date, the results of the emergency analytical reactivity testing, including the detailed information for the samples tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format.

§ 866.3983 SARS-CoV-2 serology test.

(a) Identification. A SARS-CoV-2 serology test is a prescription in vitro diagnostic device for the detection of specific binding antibodies to SARS-CoV-2 in clinical specimens. The detection of SARS-CoV-2 antibodies is intended to aid in identifying individuals with an adaptive immune response to SARS-CoV-2. The test is not intended for the diagnosis of acute SARS-CoV-2 infection, nor screening blood, plasma, cells, or tissue donors.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes the device detects, the specimen types tested, the results provided to the end user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use, as appropriate.

(2) If sample collection devices are used, any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(3) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;

(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies, including the following, as applicable: Assay cutoff or limit of detection expressed in international standard units, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover and cross contamination, matrix equivalency, hook effect, specimen stability, precision, reproducibility, and clinical studies, including the time period in which the clinical performance was established and the variant(s) prevalent in the United States at the time of performance validation;

(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;

(iv) When applicable, performance results of the analytical study testing of a standardized reference material that FDA has determined is appropriate;

(v) Limiting statements that indicate:

(A) A negative test result does not preclude the possibility of infection;

(B) A negative result can occur if the quantity of the anti-SARS-CoV-2 antibodies present in the specimen is below the detection limits of the assay, or the antibodies that are detected are not present during the stage of disease in which a sample is collected;

(C) There is a risk of erroneous results (i.e., negative results) due to the presence of novel emerging viral variants circulating in the intended use population;

(D) The performance characteristics for that analyte were established when [insert predominant strain, subtype, or variant] was prevalent and that due to the propensity of the virus to mutate, new strains emerge over time which may affect the performance of this device and have serious public health implications;

(E) The test results should be interpreted in conjunction with other clinical and laboratory data available to the healthcare provider (as applicable);

(F) Positive and negative predictive values are highly dependent on prevalence;

(G) Accurate results are dependent on adequate specimen collection, transport, storage, and processing (as applicable). Failure to observe proper procedures in any one of these steps can lead to incorrect results;

(H) The test is not intended for donor screening; and

(I) The test is not intended to diagnose acute SARS-CoV-2 infection. An assay that directly detects the virus should be used to evaluate individuals for acute COVID-19, particularly those who have been in contact with the virus.

(vi) For devices intended for the quantitative detection of SARS-CoV-2 antibodies, labeling must include a prominent statement that includes the following: the test calibrators' traceability to a standardized reference material that FDA has determined is appropriate and the limit of blank, limit of detection, and limit of quantitation, with the defined analytical measuring interval.

(4) Design verification and validation must include:

(i) Detailed documentation of performance from a multisite clinical study with an appropriate number of clinical samples (i.e., be appropriately statistically powered) from individuals with recent or prior SARS CoV-2 infection in which the results are compared to results obtained from a comparator that FDA has determined to be appropriate. This study must be conducted in the appropriate laboratory setting to demonstrate clinical performance. For any SARS-CoV-2 serology test intended for use in near-patient settings, a separate clinical study must be conducted in near-patient settings. Documentation from these studies must include study reports with study description, testing results, and all statistical analyses, including an appropriate justification describing how the sample set is representative of the intended use population. These studies must compare the device performance to results obtained from a comparator that FDA has determined to be appropriate. These clinical studies must include testing of unique prospective samples from subjects that are representative of the intended use populations and may, when determined to be acceptable by FDA, include additional characterized clinical samples; or, as an alternative, when determined to be acceptable by FDA, an equivalent sample set;

(ii) For any SARS-CoV-2 antibody test intended for use in near-patient settings, detailed documentation that demonstrates the effectiveness of risk control measures and device robustness, including flex studies, and performance with weakly-reactive samples when used by the intended operators;

(iii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as failure modes effects analysis and hazard analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains (e.g., regular review of published literature and periodic in silico analysis of target amino acid sequence(s) to detect possible mismatches) that may affect detection of antibody. All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA within 48 hours of the request for FDA review, and any results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately to the email address provided in FDA's request;

(iv) Documentation of the specific amino acid sequence of the SARS-CoV-2 target protein(s) that the device utilizes to detect specific antibodies to SARS-CoV-2;

(v) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including protein sequence target(s) for each analyte, design of target detection reagents, internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design;

(vi) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users and patients as part of cybersecurity review;

(vii) For devices intended for the detection of SARS-CoV-2 antibodies for which a standardized reference material (that FDA has determined is appropriate) is available, the performance results of an analytical study testing this standardized reference material. Detailed documentation of that study and its results must be provided, including the study protocol, study report, testing results, and all statistical analyses;

(viii) Detailed documentation of analytical studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including precision, endogenous interferences, cross reactivity, carryover, matrix equivalency, class specificity, hook effect, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare contrived samples for use in analytical studies must be from subjects with clinically relevant circulating antibodies to SARS-CoV-2 in the United States. Cross-reactivity studies must include samples from SARS-CoV-2 antibody negative subjects with antibodies to viruses, high prevalence disease agents, and normal or pathogenic flora. Endogenous interference studies must include SARS-CoV-2 antibody negative and low positive samples with endogenous interference substances, including antibodies present in autoimmune diseases that are reasonably likely to be encountered in clinical specimens under actual use conditions. In addition, for devices intended for the quantitative detection of SARS-CoV-2 antibodies, the information provided must also include the metrological calibration traceability hierarchy to a standardized reference material that FDA has determined is appropriate. As appropriate to the technology and specimen types tested, the information provided to support quantitative tests must also include studies to support the analytical measuring interval, including a limit of blank study, a limit of detection study, an upper and lower limits of quantitation study, a precision study, and a linearity study using clinical samples, and, using a standardized reference material that FDA has determined is appropriate, an accuracy study;

(ix) Detailed documentation of data and protocols, including acceptance criteria, from a real-time reagent stability study must include testing of samples with adequately challenging analyte concentrations and must include shelf-life stability and shipping stability, and, as applicable, in-use and open-kit stability and freeze-thaw stability. The shelf-life stability assessment must include a minimum of three lots;

(x) Detailed documentation of a multisite reproducibility study with testing conducted at a minimum of three sites;

(xi) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims; and

(xii) Lot-to-lot precision studies, as appropriate.

(5) For any SARS-CoV-2 antibody test intended for use in near-patient settings, labeling must also include a brief reference sheet (quick reference instructions) for the intended user(s) that includes, at a minimum, the name and intended use of the test, easy to follow step-by-step instructions of all control and sample testing procedures for the claimed sample types, including graphic illustrations targeted towards lay users (as applicable), the result(s) interpretation guidance, warnings and limitation statements, toxicology information and safety considerations for any hazardous materials, information for troubleshooting (e.g., frequently asked questions), and technical assistance with the device (e.g., helpline contact information).

(6) If one of the actions listed in section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to one or more of the analytes claimed in the intended use, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to one or more of the analytes claimed in the intended use:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation, the manufacturer must have testing performed on the device with those samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate; and

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation and continuing until 3 years from that date, the results of the emergency analytical reactivity testing, including the detailed information for the samples tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format.

§ 866.3984 Over-the-counter test to detect SARS-CoV-2 from clinical specimens.

(a) Identification. An over-the-counter test to detect SARS-CoV-2 from clinical specimens is an in vitro diagnostic device for the detection of SARS-CoV-2 in clinical specimens to aid in the diagnosis of SARS-CoV-2 infection. The device is intended to be used by lay users and without required health care provider intervention in home settings or similar environments in which lay users perform testing.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: analytes the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), and other conditions of use as appropriate.

(2) The intended use of the device must only include indications for testing of respiratory specimens that are appropriate for collection by lay users for which there are performance data that demonstrate lay users can collect specimens without health care provider supervision in home settings or similar environments.

(3) The labeling required under § 809.10(b) of this chapter must include the following:

(i) A statement in the intended use that positive results do not rule out co-infection with other respiratory pathogens;

(ii) Summary instructions and information written in appropriate language for the intended user that includes easy to follow step-by-step instructions for sample testing, explanation of test results, any warnings and precautions relevant to testing, and frequently asked questions (FAQs), as required by paragraph (b)(5)(iii) of this section;

(iii) Limiting statements including the following, as applicable:

(A) For those devices intended for testing in symptomatic subjects, a specification of the number of days post symptom onset validated for use of the device and/or a range in which the performance of the test is known, where applicable;

(B) Statements that a negative test result does not preclude the possibility of infection with other pathogens, and that a positive test result does not preclude the possibility of co-infection with additional pathogens;

(C) A statement that persons with risk factors for severe disease from respiratory pathogens (e.g., chronic lung or heart disease, compromised immune system, diabetes, and other conditions listed by the Centers for Disease Control and Prevention (CDC)) should consult and follow-up with a healthcare provider, who will advise if additional testing or treatment are necessary;

(D) A statement that the test is not a substitute for consultation with a health care provider and should not be used to determine any treatments without provider supervision. A statement that the healthcare provider will consider additional information such as the patient's personal medical history and symptoms, current disease prevalence in the community, and additional test results if applicable, to help determine what steps are best for diagnosis and treatment if needed;

(E) A statement that it is especially important to discuss any test results with a healthcare provider if any of the following occur:

(1) The symptoms persist or worsen;

(2) The patient has high risk for severe illness based on age or medical condition;

(3) The patient has a condition that makes it difficult to use the test (e.g., problems with vision, handling the test components, or understanding test instructions or results); or

(4) The patient is performing this test on behalf of a person who has any of the above conditions;

(F) A statement that accurate results are dependent on adequate product storage and adherence to the specimen collection and testing procedures. A statement that failure to follow test procedures can lead to incorrect results;

(G) A statement that the test must not be used beyond the expiration date listed on the packaging. A statement that use of expired tests can lead to incorrect results;

(H) A statement that false positive test results are more likely when prevalence of SARS-CoV-2 is low in the community; and

(I) A statement that includes all of the following: The performance characteristics for SARS-CoV-2 were established when [insert predominant strain, subtype, or variant and timeframe] was dominant. Test accuracy may change as new SARS-CoV-2 viruses emerge. Additional testing with a lab-based molecular test (e.g., polymerase chain reaction (PCR)) should be considered in situations where a new virus or variant is suspected.

(4) The outer box label required under § 809.10(a) of this chapter must include the following:

(i) A description of who may use the test, including the presence of symptoms, the days post symptom onset and age restrictions (as applicable);

(ii) A list of the components included with the test;

(iii) A list of the components required to run the test, but not provided;

(iv) A statement that persons with risk factors for severe disease from respiratory pathogens should consult and follow-up with a healthcare provider.

(5) The device's labeling must include a prominent hyperlink to the manufacturer's public website where the manufacturer must make the information, identified in this section, publicly and prominently available. The information must include, written in language appropriate for the intended user:

(i) A brief summary of the purpose of the test;

(ii) Instructions that describe how to appropriately perform the test, interpret the results, and, if applicable, perform follow-up testing. The instructions must include the name and intended use of the test, detailed step-by-step instructions of the sample testing procedures, the result(s) interpretation guidance, warnings and limitation statements, information for troubleshooting, and technical assistance with the device (e.g., helpline contact information).

(iii) FAQ: This document must provide technical and educational information (e.g., what does this test do and not do, who should and should not use this test, and directions to resources for further information on the disease and epidemiology).

(iv) Information that demonstrates the performance characteristics established in the studies required under paragraph (b)(6) of this section.

(6) Design verification and validation must include:

(i) A detailed device description, including, but not limited to, device components, and a detailed explanation of the methodology, including viral target(s), identification of target detection reagents (e.g., primers, antibodies), internal controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design;

(ii) Detailed documentation of data from a prospective multisite clinical study with a design and performance that is appropriate for the intended use of the device, including performance estimates derived from a sufficient number of samples from the intended use population for each claimed specimen type. Results must be obtained from geographically diverse locations, such that the performance of the test device is appropriately representative of all present, circulating strains of the claimed viral analyte(s) at the time of the study and submission. Additionally, the clinical study must include participants that are representative of the intended use population and across the clinical range of the claimed viral analyte. The clinical study must be performed in the intended use setting (e.g., at home or a home-like environment). The results obtained with the candidate device must be compared to results obtained using a molecular comparator method that FDA has determined to be appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses;

(iii) The clinical study designs, including number of samples tested, must be sufficient such that the lower bound of the two-sided 95 percent confidence interval of the positive percent agreement with the comparator must be greater than 70 percent and additional and appropriate risk mitigation measures are established (e.g., presumptive negative results, serial testing).

(iv) Detailed documentation of analytical studies, including those demonstrating the limit of detection, inclusivity (including relevant variants), cross-reactivity, microbial interference, interfering substances, competitive inhibition, specimen stability, within-lab precision, hook effect, carryover, and cross-contamination, as applicable;

(v) Detailed documentation and characterization (e.g., determination of the identity, supplier, purity, and stability) of all critical reagents and protocols for maintaining product integrity throughout its labeled shelf-life, i.e., reagent stability studies. Data and protocols, including acceptance criteria, from a multi-lot reagent stability study must include testing of samples with challenging analyte concentration and must include in-use or open-kit stability, shipping stability, and freeze-thaw stability (as applicable); and

(vi) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as failure modes effects analysis and/or hazard analysis.

(A) This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel isolates or strains (e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). Protocols must include plans to update labeling with additional performance data. All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request and any results that are reasonably interpreted to support the conclusion that novel SARS-CoV-2 strains or isolates impact the stated expected performance of the device must be sent to FDA immediately to the email provided in FDA's request;

(B) This must include detailed documentation that demonstrates the effectiveness of risk control measures and device robustness, including the entire testing procedure from sampling to result interpretation, based on results from the following studies, as applicable per the intended use of the test device: usability studies, user label comprehension, and flex studies;

(vii) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users and patients as part of cybersecurity review; and

(viii) For devices intended for the detection of SARS-CoV-2 for which an FDA recommended reference material and/or test panel is available, the performance results of an analytical study testing the FDA recommended reference material. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(7) If one of the actions listed in section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to one or more of the analytes claimed in the intended use, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to SARS-CoV-2:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation, the manufacturer must have testing performed on the device with those samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate; and

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation and continuing until 3 years from that date, the results of the emergency analytical reactivity testing, including the detailed information for the samples tested as described in the certificate of authentication, must be included in a tabular format on the hyperlink the manufacturer's public website as described in paragraph (b)(5) of this section.

§ 866.3985 Device to detect and identify microorganisms and associated resistance marker nucleic acids directly in respiratory specimens.

(a) Identification. A device to detect and identify microorganisms and associated resistance marker nucleic acids directly from respiratory specimens is an in vitro diagnostic device intended for the detection and identification of microorganisms and associated resistance markers in respiratory specimens collected from patients with signs or symptoms of respiratory infection. The device is intended to aid in the diagnosis of respiratory infection in conjunction with clinical signs and symptoms and other laboratory findings. These devices do not provide confirmation of antibiotic susceptibility since mechanisms of resistance may exist other than those detected by the device.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use for the 21 CFR 809.10 labeling must include a detailed description of what the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.

(2) The 21 CFR 809.10(b) labeling must include:

(i) A detailed device description, including all device components, control elements incorporated into the test procedure, instrument requirements, ancillary reagents required but not provided, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.

(ii) Performance characteristics from analytical studies, including, but not limited to, limit of detection, inclusivity, reproducibility, cross reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, and linearity, as applicable.

(iii) A limiting statement that the device is intended to be used in conjunction with clinical history, signs and symptoms, and results of other diagnostic tests, including culture and antimicrobial susceptibility testing.

(iv) A detailed explanation of the interpretation of test results for clinical specimens and acceptance criteria for any quality control testing.

(v) A limiting statement that negative results for microorganisms do not preclude the possibility of infection, and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

(vi) If applicable, a limiting statement that detected microorganisms may not be the cause of lower respiratory tract infection and may be indicative of colonizing or normal respiratory flora.

(vii) If applicable, a limiting statement that detection of resistance markers cannot be definitively linked to specific microorganisms and that the source of a detected resistance marker may be an organism not detected by the assay, including colonizing flora.

(viii) If applicable, a limiting statement that detection of antibiotic resistance markers may not correlate with phenotypic gene expression.

(3) The 21 CFR 809.10(b) labeling and any test report generated by the device must include a limiting statement that negative results for resistance markers do not indicate susceptibility of detected microorganisms.

(4) Design verification and validation must include:

(i) Performance characteristics from clinical studies that include prospective (sequential) samples and, if appropriate, additional characterized samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from an FDA accepted reference method and/or FDA accepted comparator method, as appropriate. Results from the clinical studies must include the clinical study protocol (including predefined statistical analysis plan, if applicable), clinical study report, and results of all statistical analyses.

(ii) A detailed device description including the following:

(A) Thorough description of the assay methodology including, but not limited to, primer/probe sequences, primer/probe design, and rationale for target sequence selection, as applicable.

(B) Algorithm used to generate a final result from raw data (e.g., how raw signals are converted into a reported result).

(iii) A detailed description of device software, including, but not limited to, validation activities and outcomes.

(iv) As part of the risk management activities, an appropriate end user device training program must be offered as an effort to mitigate the risk of failure from user error.

§ 866.3988 Device to detect and identify microorganism nucleic acids and resistance markers from patients with suspected orthopedic infection.

(a) Identification. A device to detect and identify microorganism nucleic acids and resistance markers from patients with suspected orthopedic infection is a qualitative in vitro device intended to simultaneously detect and identify microorganism nucleic acids from human clinical specimens collected from patients with suspected orthopedic infection. The device detects specific nucleic acid sequences for microorganism identification as well as markers for antimicrobial resistance. This device is intended to aid in the diagnosis of orthopedic infections when used in conjunction with other clinical signs and symptoms and other laboratory findings. However, the device does not replace traditional methods for culture and susceptibility testing.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) An intended use that includes a detailed description of targets the device detects and measures, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.

(ii) Limiting statements, when applicable, indicating:

(A) The device is intended to be used in conjunction with clinical history, signs and symptoms, and results of other diagnostic tests, including culture and antimicrobial susceptibility testing;

(B) Detection of resistance markers cannot be definitively linked to specific microorganisms and that the source of a detected resistance marker may be an organism not detected by the assay; and

(C) Antimicrobial resistance can occur via multiple mechanisms. A not detected result for the antimicrobial resistance gene assays does not indicate antimicrobial susceptibility. Culturing and susceptibility testing of isolates is needed to determine antimicrobial susceptibility.

(iii) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.

(iv) Detailed descriptions of the performance characteristics of the device for all claimed specimen types as shown by the analytical and clinical studies required under paragraphs (b)(3)(iii) and (b)(3)(iv) of this section except specimen stability performance characteristics.

(3) Design verification and validation must include:

(i) A detailed device description, including all device parts, control elements incorporated into the test procedure, reagents required but not provided, the principle of device operation and test methodology, and the computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).

(ii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.

(iii) Detailed documentation of analytical studies, including those demonstrating Limit of Detection, inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.

(iv) Detailed documentation and performance results from a clinical study that includes prospective (sequentially collected) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator method that FDA has determined to be appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.

§ 866.3990 Gastrointestinal microorganism multiplex nucleic acid-based assay.

(a) Identification. A gastrointestinal microorganism multiplex nucleic acid-based assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple gastrointestinal microbial nucleic acids extracted from human stool specimens. The device detects specific nucleic acid sequences for organism identification as well as for determining the presence of toxin genes. The detection and identification of a specific gastrointestinal microbial nucleic acid from individuals exhibiting signs and symptoms of gastrointestinal infection aids in the diagnosis of gastrointestinal infection when used in conjunction with clinical evaluation and other laboratory findings. A gastrointestinal microorganism multiplex nucleic acid-based assay also aids in the detection and identification of acute gastroenteritis in the context of outbreaks.

(b) Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Gastrointestinal Microorganism Multiplex Nucleic Acid-Based Assays for Detection and Identification of Microorganisms and Toxin Genes from Human Stool Specimens.” For availability of the guideline document, see § 866.1(e).

§ 866.4001 A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens.

(a) Identification. A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens is identified as an in vitro diagnostic device intended for the qualitative detection and identification of both emerging and common respiratory pathogens from individuals meeting specific emerging respiratory pathogen clinical and/or epidemiological criteria. For example, clinical signs and symptoms associated with infection of the emerging respiratory pathogen, contact with a probable or confirmed emerging respiratory pathogen case, history of travel to geographic locations where cases of the emerging respiratory pathogen were detected, or other epidemiological links for which testing of the emerging respiratory pathogen may be indicated. A device to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens, and in turn to distinguish emerging respiratory pathogen(s) from common respiratory pathogens, is intended to aid in the differential diagnosis of the emerging respiratory pathogen infection, in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidelines provided by the appropriate public health authorities.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The intended use for the labeling required under § 809.10 of this chapter must include a description of what the device detects and measures, the specimen types, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.

(2) The labeling required under § 809.10 of this chapter must include:

(i) A device description, including the parts that make up the device, ancillary reagents required but not provided, and an explanation of the methodology.

(ii) Performance characteristics from analytical studies, including cut-off (if applicable), analytical sensitivity (i.e., limit of detection), inclusivity, reproducibility, interference, cross-reactivity, instrument carryover/cross-contamination (if applicable), and specimen stability.

(iii) Detailed instructions for minimizing the risk of potential users' exposure to the emerging respiratory pathogen(s) that may be present in test specimens and those used as control materials.

(iv) Detailed instructions for minimizing the risk of generating false positive test results due to carry-over contamination from positive test specimens and/or positive control materials.

(v) A warning statement that the interpretation of test results requires experienced healthcare professionals who have training in principles and use of infectious disease diagnostics and reporting of results, in conjunction with the patient's medical history, clinical signs and symptoms, and the results of other diagnostic tests.

(vi) A warning statement that culture should not be attempted in cases of positive results for an emerging respiratory pathogen unless a facility with an appropriate level of laboratory biosafety (e.g., BSL 3 and BSL 3+) is available to receive and culture specimens.

(vii) A warning statement that device positive results for one or more common respiratory pathogens do not rule out bacterial infection, or co-infection with other common respiratory pathogens.

(viii) A warning statement that respiratory pathogen(s) detected may not be the definite cause of disease.

(ix) A warning statement that the use of additional laboratory testing (e.g. bacterial culture, immunofluorescence, x-ray findings) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of a respiratory infection.

(x) A limiting statement that device negative results for the common respiratory pathogens do not preclude infection of a respiratory pathogen and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

(xi) A limiting statement that analyte targets (e.g., pathogen nucleic acid sequences or other molecular signatures) may persist in vivo, independent of organism viability. Detection of analyte target(s) does not imply that the corresponding pathogen(s) is infectious, nor is the causative agent(s) for clinical symptoms.

(xii) A limiting statement that detection of pathogen nucleic acid sequences or other molecular signatures is dependent upon proper specimen collection, handling, transportation, storage and preparation. Failure to observe proper procedures in any one of these steps can lead to incorrect results. There is a risk of false negative values resulting from improperly collected, transported, or handled specimens.

(xiii) A limiting statement that there is a risk of false positive values resulting from cross-contamination by target organisms, their nucleic acids or amplified product, or from non-specific signals in the assay.

(xiv) A limiting statement that there is a risk of false negative results due to the presence of nucleic acid sequence variants in the pathogen targets of the device.

(xv) A limiting statement that device performance was not established in immunocompromised patients.

(xvi) A limiting statement that positive and negative predictive values are highly dependent on prevalence. The device performance was established during one or more specific respiratory seasons. The performance for some respiratory pathogens may vary depending on the prevalence and patient population tested. False positive test results are likely when prevalence of disease due to a particular respiratory pathogen is low or non-existent in a community.

(xvii) In situations where the performance of the device was estimated based largely on testing pre-selected banked retrospective clinical specimens and/or contrived clinical specimen, a limiting statement that the estimated device performance of that specific pathogen or pathogen subtype may not reflect the performance or prevalence in the intended use population.

(xviii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that testing with the device should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected specimens of the emerging respiratory pathogen.

(xix) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that positive results obtained with the device for the emerging respiratory pathogen are for the presumptive identification of that pathogen and that the definitive identification of the emerging respiratory pathogen requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments) for whom reporting is necessary.

(xx) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen, even in the context of device positive results for one or more of the common respiratory pathogens, do not preclude infection with the emerging respiratory pathogen and should not be used as the sole basis for patient management decisions.

(xxi) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen may be due to infection of the emerging respiratory pathogen at a specific respiratory tract location that may not be detected by a particular clinical specimen type. A negative result for the emerging respiratory pathogen in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.

(xxii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that a nationally notifiable Rare Disease of Public Health Significance caused by an emerging respiratory pathogen must be reported, as appropriate, to public health authorities in accordance with local, state, and federal law.

(3) Design verification and validation must include:

(i) Performance results of an appropriate clinical study (e.g., a prospective clinical study) for each specimen type, and, if appropriate, results from additional characterized samples. The clinical study must be performed on a study population consistent with the intended use population and must compare the device performance to results obtained using FDA-accepted comparator methods or to expected negative results if the infection is not generally expected in the intended use population. Clinical specimens evaluated in the study must contain relevant organism concentrations applicable to the specimen type(s) and the targeted analyte(s). Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(ii) For devices with an intended use that includes detection of emerging respiratory pathogen(s) for which an FDA recommended panel is available, design verification and validation must include the performance results of an analytical study testing an FDA recommended reference panel of characterized samples that contain the emerging respiratory pathogen. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(iii) An appropriate risk mitigation strategy, including a detailed description of all procedures and methods, for the post-market identification of genetic mutations and/or novel respiratory pathogen isolates or strains (e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible mismatches. The required documentation for this device must also include all of the results, including any findings, from the application of this post-market mitigation strategy.

(iv) For devices with an intended use that includes detection of multiple common respiratory pathogens, in addition to detecting emerging respiratory pathogen(s) in human clinical specimens, a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the common respiratory pathogens that the device is designed to detect is addressed. Also, address in detail how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory diagnosis of respiratory tract infection. Perform an evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(v) A detailed device description, including the parts that make up the device, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device (e.g., saturation level of hybridization and maximum amplification and detection cycle number), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable and appropriate.

(vi) A detailed description of the device software, including software applications and hardware-based devices that incorporate software.

(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. Perform an evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.

(4) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), the labeling required under § 809.10 of this chapter must include the following:

(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation. When other Influenza A viruses are emerging, performance characteristics may vary.

(ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling required under § 809.10(b)(9) of this chapter must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required follow up actions or retesting in the case of an unusual or unexpected device result.

(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated (e.g., H1-2009 and H3), this result requires notification of appropriate local, state, or federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.

(5) The manufacturer must perform annual analytical reactivity testing of the device with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:

(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.

(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.

(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:

(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or

(B) In the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.

(6) If one of the actions listed at section 564(b)(1)(A)-(D) of the FD&C Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:

(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or

(B) In a section of the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.

Subpart E—Immunology Laboratory Equipment and Reagents

§ 866.4070 RNA Preanalytical Systems.

(a) Identification. RNA Preanalytical Systems are devices intended to collect, store, and transport patient specimens, and stabilize intracellular RNA from the specimens, for subsequent isolation and purification of the intracellular RNA for RT-PCR used in in vitro molecular diagnostic testing.

(b) Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: RNA Preanalytical Systems (RNA Collection, Stabilization and Purification System for RT-PCR Used in Molecular Diagnostic Testing).” See § 866.1(e) for the availability of this guidance document.

§ 866.4100 Complement reagent.

(a) Identification. A complement reagent is a device that consists of complement, a naturally occurring serum protein from any warm-blooded animal such as guinea pigs, that may be included as a component part of serological test kits used in the diagnosis of disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.4500 Immunoelectrophoresis equipment.

(a) Identification. Immunoelectrophoresis equipment for clinical use with its electrical power supply is a device used for separating protein molecules. Immunoelectrophoresis is a procedure in which a complex protein mixture is placed in an agar gel and the various proteins are separated on the basis of their relative mobilities under the influence of an electric current. The separated proteins are then permitted to diffuse through the agar toward a multispecific antiserum, allowing precipitation and visualization of the separate complexes.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.4520 Immunofluorometer equipment.

(a) Identification. Immunofluorometer equipment for clinical use with its electrical power supply is a device used to measure the fluorescence of fluorochrome-labeled antigen-antibody complexes. The concentration of these complexes may be measured by means of reflected light. A beam of light is passed through a solution in which a fluorochrome has been selectively attached to serum protein antibody molecules in suspension. The amount of light emitted by the fluorochrome label is detected by a photodetector, which converts light energy into electrical energy. The amount of electrical energy registers on a readout system such as a digital voltmeter or a recording chart. This electrical readout is called the fluorescence value and is used to measure the concentration of antigen-antibody complexes.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.4540 Immunonephelometer equipment.

(a) Identification. Immunonephelometer equipment for clinical use with its electrical power supply is a device that measures light scattering from antigen-antibody complexes. The concentration of these complexes may be measured by means of reflected light. A beam of light passed through a solution is scattered by the particles in suspension. The amount of light is detected by a photodetector, which converts light energy into electrical energy. The amount of electrical energy registers on a readout system such as a digital voltmeter or a recording chart. This electrical readout is called the light-scattering value and is used to measure the concentration of antigen-antibody complexes. This generic type of device includes devices with various kinds of light sources, such as laser equipment.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.4600 Ouchterlony agar plate.

(a) Identification. An ouchterlony agar plate for clinical use is a device containing an agar gel used to examine antigen-antibody reactions. In immunodiffusion, antibodies and antigens migrate toward each other through gel which originally contained neither of these reagents. As the reagents come in contact with each other, they combine to form a precipitate that is trapped in the gel matrix and is immobilized.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 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 Fluorescence in situ Hybridization (FISH) Enumeration Systems.” See § 866.1(e) for the availability of this guidance document.

§ 866.4750 Automated indirect immunofluorescence microscope and software-assisted system.

(a) Identification. An automated indirect immunofluorescence microscope and software assisted system is a device that acquires, analyzes, stores, and displays digital images of indirect immunofluorescent slides. It is intended to be used as an aid in the determination of antibody status in clinical samples. The device may include a fluorescence microscope with light source, a motorized microscope stage, dedicated instrument controls, a camera, a computer, a sample processor, or other hardware components. The device may use fluorescent signal acquisition and processing software, data storage and transferring mechanisms, or assay specific algorithms to suggest results. A trained operator must confirm results generated with the device.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) The labeling for the device must reference legally marketed assays intended for use with the device.

(2) Premarket notification submissions must include the following information:

(i) A detailed description of the device that includes:

(A) A detailed description of instrumentation and equipment, and illustrations or photographs of non-standard equipment or methods, if applicable;

(B) Detailed documentation of the software, including, but not limited to, stand-alone software applications and hardware-based devices that incorporate software, if applicable;

(C) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the recommended testing procedures;

(D) Detailed description and specifications for sample preparation, processing, and storage, if applicable;

(E) Methodology and protocols for detecting fluorescence and visualizing results; and

(F) Detailed specification of the criteria for test results interpretation and reporting.

(ii) Data demonstrating the performance characteristics of the device, which must include:

(A) A comparison study of the results obtained with the conventional manual method (i.e., reference standard), the device, and the reading of the digital image without aid of the software, using the same set of patient samples for each. The study must use a legally marketed assay intended for use with the device. Patient samples must be from the assay-specific intended use population and differential diagnosis population. Samples must also cover the assay measuring range, if applicable;

(B) Device clinical performance established by comparing device results at multiple U.S. sites to the clinical diagnostic standard used in the United States, using patient samples from the assay-specific intended use population and the differential diagnosis population. For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. Clinical validation must be based on the determination of clinical sensitivity and clinical specificity using the test results (e.g., antibody status based on fluorescence to include pattern and titer, if applicable) compared to the clinical diagnosis of the subject from whom the clinical sample was obtained. The data must be summarized in tabular format comparing the result generated by automated, manual, and digital only interpretation to the disease status;

(C) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-operator, between-instruments, between-site, and total precision for multiple nonconsecutive days (as applicable) using multiple operators, multiple instruments and at multiple sites. A well-characterized panel of patient samples or pools from the associated assay specific intended use population must be used;

(D) Device linearity data generated from patient samples covering the assay measuring range, if applicable;

(E) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable;

(F) Device assay specific cutoff, if applicable;

(G) Device analytical specificity data, including interference by endogenous and exogenous substances, if applicable;

(H) Device instrument carryover data, if applicable;

(I) Device stability data including real-time stability under various storage times and temperatures, if applicable; and

(J) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable.

(iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices, incorporated into the directions for use that mitigate risks associated with testing.

(3) Your 21 CFR 809.10 compliant labeling must include:

(i) A warning statement that reads “The device is for use by a trained operator in a clinical laboratory setting”;

(ii) A warning statement that reads “All software-aided results must be confirmed by the trained operator”;

(iii) A warning statement that reads “This device is only for use with reagents that are indicated for use with the device”; and

(iv) A description of the protocol and performance studies performed in accordance with paragraph (b)(2)(ii) of this section and a summary of the results, if applicable.

§ 866.4800 Radial immunodiffusion plate.

(a) Identification. A radial immunodiffusion plate for clinical use is a device that consists of a plastic plate to which agar gel containing antiserum is added. In radial immunodiffusion, antigens migrate through gel which originally contains specific antibodies. As the reagents come in contact with each other, they combine to form a precipitate that is trapped in the gel matrix and immobilized.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.4830 Rocket immunoelectrophoresis equipment.

(a) Identification. Rocket immunoelectrophoresis equipment for clinical use is a device used to perform a specific test on proteins by using a procedure called rocket immunoelectrophoresis. In this procedure, an electric current causes the protein in solution to migrate through agar gel containing specific antisera. The protein precipitates with the antisera in a rocket-shaped pattern, giving the name to the device. The height of the peak (or the area under the peak) is proportional to the concentration of the protein.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.4900 Support gel.

(a) Identification. A support gel for clinical use is a device that consists of an agar or agarose preparation that is used while measuring various kinds of, or parts of, protein molecules by various immunochemical techniques, such as immunoelectrophoresis, immunodiffusion, or chromatography.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

Subpart F—Immunological Test Systems

§ 866.5040 Albumin immunological test system.

(a) Identification. An albumin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the albumin (a plasma protein) in serum and other body fluids. Measurement of albumin aids in the diagnosis of kidney and intestinal diseases.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5060 Prealbumin immunological test system.

(a) Identification. A prealbumin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the prealbumin (a plasma protein) in serum and other body fluids. Measurement of prealbumin levels in serum may aid in the assessment of the patient's nutritional status.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5065 Human allotypic marker immunological test system.

(a) Identification. A human allotypic marker immunological test system is a device that consists of the reagents used to identify by immunochemical techniques the inherited human protein allotypic markers (such as nGm, nA2 m, and Km allotypes) in serum and other body fluids. The identification may be used while studying population genetics.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5080 Alpha-1-antichymotrypsin immunological test system.

(a) Identification. An alpha-1-antichymotrypsin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques alpha-1-antichymotrypsin (a protein) in serum, other body fluids, and tissues. Alpha-1-antichymotrypsin helps protect tissues against proteolytic (protein-splitting) enzymes released during infection.

(b) Classification. Class II (performance standards).

§ 866.5090 Antimitochondrial antibody immunological test system.

(a) Identification. An antimitochondrial antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the antimitochondrial antibodies in human serum. The measurements aid in the diagnosis of diseases that produce a spectrum of autoantibodies (antibodies produced against the body's own tissue), such as primary biliary cirrhosis (degeneration of liver tissue) and chronic active hepatitis (inflammation of the liver).

(b) Classification. Class II (performance standards).

§ 866.5100 Antinuclear antibody immunological test system.

(a) Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).

(b) Classification. Class II (performance standards).

§ 866.5110 Antiparietal antibody immunological test system.

(a) Identification. An antiparietal antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the specific antibody for gastric parietal cells in serum and other body fluids. Gastric parietal cells are those cells located in the stomach that produce a protein that enables vitamin B12 to be absorbed by the body. The measurements aid in the diagnosis of vitamin B12 deficiency (or pernicious anemia), atrophic gastritis (inflammation of the stomach), and autoimmune connective tissue diseases (diseases resulting when the body produces antibodies against its own tissues).

(b) Classification. Class II (performance standards).

§ 866.5120 Antismooth muscle antibody immunological test system.

(a) Identification. An antismooth muscle antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the antismooth muscle antibodies (antibodies to nonstriated, involuntary muscle) in serum. The measurements aid in the diagnosis of chronic hepatitis (inflammation of the liver) and autoimmune connective tissue diseases (diseases resulting from antibodies produced against the body's own tissues).

(b) Classification Class II (performance standards).

§ 866.5130 Alpha-1-antitrypsin immunological test system.

(a) Identification. An alpha-1-antitrypsin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-1-antitrypsin (a plasma protein) in serum, other body fluids, and tissues. The measurements aid in the diagnosis of several conditions including juvenile and adult cirrhosis of the liver. In addition, alpha-1-antitrypsin deficiency has been associated with pulmonary emphysema.

(b) Classification. Class II (performance standards).

§ 866.5150 Bence-Jones proteins immunological test system.

(a) Identification. A Bence-Jones proteins immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the Bence-Jones proteins in urine and plasma. Immunoglobulin molecules normally consist of pairs of polypeptide chains (subunits) of unequal size (light chains and heavy chains) bound together by several disulfide bridges. In some cancerous conditions, there is a proliferation of one plasma cell (antibody-producing cell) with excess production of light chains of one specific kind (monoclonal light chains). These free homogeneous light chains not associated with an immunoglobulin molecule can be found in urine and plasma, and have been called Bence-Jones proteins. Measurement of Bence-Jones proteins and determination that they are monoclonal aid in the diagnosis of multiple myeloma (malignant proliferation of plasma cells), Waldenstrom's macroglobulinemia (increased production of large immunoglobulins by spleen and bone marrow cells), leukemia (cancer of the blood-forming organs), and lymphoma (cancer of the lymphoid tissue).

(b) Classification. Class II (performance standards).

§ 866.5160 Beta-globulin immunological test system.

(a) Identification. A beta-globulin immunological test system is a device that consists of reagents used to measure by immunochemical techniques beta globulins (serum protein) in serum and other body fluids. Beta-globulin proteins include beta-lipoprotein, transferrin, glycoproteins, and complement, and are rarely associated with specific pathologic disorders.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5170 Breast milk immunological test system.

(a) Identification. A breast milk immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the breast milk proteins.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5180 Fecal calprotectin immunological test system.

(a) Identification. A fecal calprotectin immunological test system is an in vitro diagnostic device that consists of reagents used to quantitatively measure, by immunochemical techniques, fecal calprotectin in human stool specimens. The device is intended forin vitro diagnostic use as an aid in the diagnosis of inflammatory bowel diseases (IBD), specifically Crohn's disease and ulcerative colitis, and as an aid in differentiation of IBD from irritable bowel syndrome.

(b) Classification. Class II (special controls). The special control for these devices is FDA's guidance document entitled “Class II Special Controls Guidance Document: Fecal Calprotectin Immunological Test Systems.” For the availability of this guidance document, see § 866.1(e).

§ 866.5200 Carbonic anhydrase B and C immunological test system.

(a) Identification. A carbonic anhydrase B and C immunological test system is a device that consists of the reagents used to measure by immunochemical techniques specific carbonic anhydrase protein molecules in serum and other body fluids. Measurements of carbonic anhydrase B and C aid in the diagnosis of abnormal hemoglobin metabolism.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5210 Ceruloplasmin immunological test system.

(a) Identification. A ceruloplasmin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the ceruloplasmin (copper-transporting serum protein) in serum, other body fluids, or tissues. Measurements of ceruloplasmin aid in the diagnosis of copper metabolism disorders.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5220 Cohn fraction II immunological test system.

(a) Identification. A Cohn fraction II immunological test system is a device that consists of the reagents that contain or are used to measure that fraction of plasma containing protein gamma globulins, predominantly of the IgG class. The device may be used as a coprecipitant in radioimmunoassay methods, as raw material for the purification of IgG subclasses, and to reduce nonspecific adsorption of plasma proteins in immunoassay techniques. Measurement of these proteins aids in the diagnosis of any disease concerned with abnormal levels of IgG gamma globulins such as agammaglobulinemia or multiple myeloma.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5230 Colostrum immunological test system.

(a) Identification. A colostrum immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the specific proteins in colostrum. Colostrum is a substance excreted by the mammary glands during pregnancy and until production of breast milk begins 1 to 5 days after childbirth.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5240 Complement components immunological test system.

(a) Identification. A complement components immunological test system is a device that consists of the reagents used to measure by immunochemical techniques complement components C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9, in serum, other body fluids, and tissues. Complement is a group of serum proteins which destroy infectious agents. Measurements of these proteins aids in the diagnosis of immunologic disorders, especially those associated with deficiencies of complement components.

(b) Classification. Class II (performance standards).

§ 866.5250 Complement C1 inhibitor (inactivator) immunological test system.

(a) Identification. A complement C1 inhibitor (inactivator) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the C1 component of complement (a group of serum proteins which destroy infectious agents). Measurement of complement C1 inhibitor aids in the diagnosis of hereditary angioneurotic edema (increased blood vessel permeability causing swelling of tissues) and a rare form of angioedema associated with lymphoma (lymph node cancer).

(b) Classification. Class II (performance standards).

§ 866.5260 Complement C3b inactivator immunological test system.

(a) Identification. A complement C3b inactivator immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the complement C3b inactivator (a plasma protein) in serum. Complement is a group of serum proteins that destroy infectious agents. Measurement of complement C3b inactivator aids in the diagnosis of inherited antibody dysfunction.

(b) Classification. Class II (performance standards).

§ 866.5270 C-reactive protein immunological test system.

(a) Identification. A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.

(b) Classification. Class II (performance standards).

§ 866.5320 Properdin factor B immunological test system.

(a) Identification. A properdin factor B immunological test system is a device that consists of the reagents used to measure by immunochemical techniques properdin factor B in serum and other body fluids. The deposition of properdin factor B in body tissues or a corresponding depression in the amount of properdin factor B in serum and other body fluids is evidence of the involvement of the alternative to the classical pathway of activation of complement (a group of plasma proteins which cause the destruction of cells which are foreign to the body). Measurement of properdin factor B aids in the diagnosis of several kidney diseases, e.g., chronic glomerulonephritis (inflammation of the glomeruli of the kidney), lupus nephritis (kidney disease associated with a multisystem autoimmune disease, systemic lupus erythematosus), as well as several skin diseases, e.g., dermititis herpetiformis (presence of vesicles on the skin that burn and itch), and pemphigus vulgaris (large vesicles on the skin). Other diseases in which the alternate pathway of complement activation has been implicated include rheumatoid arthritis, sickle cell anemia, and gram-negative bacteremia.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5330 Factor XIII, A, S, immunological test system.

(a) Identification. A factor XIII, A, S, immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the factor XIII (a bloodclotting factor), in platelets (A) or serum (S). Measurements of factor XIII, A, S, aid in the diagnosis and treatment of certain bleeding disorders resulting from a deficiency of this factor.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9. This exemption does not apply to factor deficiency tests classified under § 864.7290 of this chapter.

§ 866.5340 Ferritin immunological test system.

(a) Identification. A ferritin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the ferritin (an iron-storing protein) in serum and other body fluids. Measurements of ferritin aid in the diagnosis of diseases affecting iron metabolism, such as hemochromatosis (iron overload) and iron deficiency amemia.

(b) Classification. Class II (performance standards).

§ 866.5350 Fibrinopeptide A immunological test system.

(a) Identification. A fibrinopeptide A immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the fibrinopeptide A (a blood-clotting factor) in plasma and other body fluids. Measurement of fibrinopeptide A may aid in the diagnosis and treatment of certain blood-clotting disorders.

(b) Classification. Class II (performance standards).

§ 866.5360 Cohn fraction IV immunological test system.

(a) Identification. A Cohn fraction IV immunological test system is a device that consists of or measures that fraction of plasma proteins, predominantly alpha- and beta- globulins, used as a raw material for the production of pure alpha- or beta- globulins. Measurement of specific alpha- or beta- globulins aids in the diagnosis of many diseases, such as Wilson's disease (an inherited disease affecting the liver and brain), Tangier's disease (absence of alpha-1-lipoprotein), malnutrition, iron deficiency anemia, red blood cell disorders, and kidney disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5370 Cohn fraction V immunological test system.

(a) Identification. A Cohn fraction V immunological test system is a device that consists of or measures that fraction of plasma containing predominantly albumin (a plasma protein). This test aids in the diagnosis of diseases where albumin levels may be depressed, e.g., nephrosis (disease of the kidney), proteinuria (protein in the urine), gastroenteropathy (disease of the stomach and small intestine), rheumatoid arthritis, and viral hepatitis.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5380 Free secretory component immunological test system.

(a) Identification. A free secretory component immunological test system is a device that consists of the reagents used to measure by immunochemical techniques free secretory component (normally a portion of the secretory IgA antibody molecule) in body fluids. Measurement of free secretory component (protein molecules) aids in the diagnosis or repetitive lung infections and other hypogammaglobulinemic conditions (low antibody levels).

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5400 Alpha-globulin immunological test system.

(a) Identification. An alpha-globulin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-globulin (a serum protein) in serum and other body fluids. Measurement of alpha-globulin may aid in the diagnosis of inflammatory lesions, infections, severe burns, and a variety of other conditions.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5420 Alpha-1-glycoproteins immunological test system.

(a) Identification. An alpha-1-glycoproteins immunological test system is a device that consists of the reagents used to measure by immunochemical techniques alpha-1-glycoproteins (a group of plasma proteins found in the alpha-1 group when subjected to electrophoresis) in serum and other body fluids. Measurement of specific alpha-1-glycoproteins may aid in the diagnosis of collagen (connective tissue) disorders, tuberculosis, infections, extensive malignancy, and diabetes.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5425 Alpha-2-glycoproteins immunological test system.

(a) Identification. An alpha-2-glycoproteins immunolgical test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-2-glycoproteins (a group of plasma proteins found in the alpha-2 group when subjected to electrophoresis) in serum and other body fluids. Measurement of alpha-2-glycoproteins aids in the diagnosis of some cancers and genetically inherited deficiencies of these plasma proteins.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5430 Beta-2-glycoprotein I immunological test system.

(a) Identification. A beta-2-glycoprotein I immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the beta-2-glycoprotein I (a serum protein) in serum and other body fluids. Measurement of beta-2-glycoprotein I aids in the diagnosis of an inherited deficiency of this serum protein.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5440 Beta-2-glycoprotein III immunological test system.

(a) Identification. A beta-2-glycoprotein III immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the beta-2-glycoprotein III (a serum protein) in serum and other body fluids. Measurement of beta-2-glycoprotein III aids in the diagnosis of an inherited deficiency of this serum protein and a variety of other conditions.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5460 Haptoglobin immunological test system.

(a) Identification. A haptoglobin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the haptoglobin (a protein that binds hemoglobin, the oxygen-carrying pigment in red blood cells) in serum. Measurement of haptoglobin may aid in the diagnosis of hemolytic diseases (diseases in which the red blood cells rupture and release hemoglobin) related to the formation of hemoglobin-haptoglobin complexes and certain kidney diseases.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5470 Hemoglobin immunological test system.

(a) Indentification. A hemoglobin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the different types of free hemoglobin (the oxygen-carrying pigment in red blood cells) in blood, urine, plasma, or other body fluids. Measurements of free hemoglobin aid in the diagnosis of various hematologic disorders, such as sickle cell anemia, Fanconi's anemia (a rare inherited disease), aplastic anemia (bone marrow does not produce enough blood cells), and leukemia (cancer of the blood-forming organs).

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5490 Hemopexin immunological test system.

(a) Indentification. A hemopexin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the hemopexin (a serum protein that binds heme, a component of hemoglobin) in serum. Measurement of hemopexin aids in the diagnosis of various hematologic disorders, such as hemolytic anemia (anemia due to shortened in vivo survival of mature red blood cells and inability of the bone marrow to compensate for their decreased life span) and sickle cell anemia.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5500 Hypersensitivity pneumonitis immunological test system.

(a) Identification. A hypersensitivity pneumonitis immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the immunoglobulin antibodies in serum which react specifically with organic dust derived from fungal or animal protein sources. When these antibodies react with such dusts in the lung, immune complexes precipitate and trigger an inflammatory reaction (hypersensitivity pneumonitis). Measurement of these immunoglobulin G antibodies aids in the diagnosis of hypersensitivity pneumonitis and other allergic respiratory disorders.

(b) Classification. Class II (performance standards).

§ 866.5510 Immunoglobulins A, G, M, D, and E immunological test system.

(a) Identification. An immunoglobulins A, G, M, D, and E immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the immunoglobulins A, G, M, D, an E (serum antibodies) in serum. Measurement of these immunoglobulins aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

(b) Classification. Class II (performance standards).

§ 866.5520 Immunoglobulin G (Fab fragment specific) immunological test system.

(a) Identification. An immunoglobulin G (Fab fragment specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the Fab antigen-binding fragment resulting from breakdown of immunoglobulin G antibodies in urine, serum, and other body fluids. Measurement of Fab fragments of immunoglobulin G aids in the diagnosis of lymphoproliferative disorders, such as multiple myeloma (tumor of bone marrow cells), Waldenstrom's macroglobulinemia (increased immunoglobulin production by the spleen and bone marrow cells), and lymphoma (tumor of the lymphoid tissues).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5530 Immunoglobulin G (Fc fragment specific) immunological test system.

(a) Identification. An immunoglobulin G (Fc fragment specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the Fc (carbohydrate containing) fragment of immunoglobulin G (resulting from breakdown of immunoglobulin G antibodies) in urine, serum, and other body fluids. Measurement of immunoglobulin G Fc fragments aids in the diagnosis of plasma cell antibody-forming abnormalities, e.g., gamma heavy chain disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5540 Immunoglobulin G (Fd fragment specific) immunological test system.

(a) Identification. An immunoglobulin G (Fd fragment specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the amino terminal (antigen-binding) end (Fd fragment) of the heavy chain (a subunit) of the immunoglobulin antibody molecule in serum. Measurement of immunoglobulin G Fd fragments aids in the diagnosis of plasma antibody-forming cell abnormalities.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5550 Immunoglobulin (light chain specific) immunological test system.

(a) Identification. An immunoglobulin (light chain specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques both kappa and lambda types of light chain portions of immunoglobulin molecules in serum, other body fluids, and tissues. In some disease states, an excess of light chains are produced by the antibody-forming cells. These free light chains, unassociated with gamma globulin molecules, can be found in a patient's body fluids and tissues. Measurement of the various amounts of the different types of light chains aids in the diagnosis of multiple myeloma (cancer of antibody-forming cells), lymphocytic neoplasms (cancer of lymphoid tissue), Waldenstrom's macroglobulinemia (increased production of large immunoglobulins), and connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus.

(b) Classification. Class II (performance standards).

§ 866.5560 Lactic dehydrogenase immunological test system.

(a) Identification. A lactic dehydrogenase immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the activity of the lactic dehydrogenase enzyme in serum. Increased levels of lactic dehydrogenase are found in a variety of conditions, including megaloblastic anemia (decrease in the number of mature red blood cells), myocardial infarction (heart disease), and some forms of leukemia (cancer of the blood-forming organs). However, the diagnostic usefulness of this device is limited because of the many conditions known to cause increased lactic dehydrogenase levels.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5570 Lactoferrin immunological test system.

(a) Identification. A lactoferrin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the lactoferrin (an iron-binding protein with the ability to inhibit the growth of bacteria) in serum, breast milk, other body fluids, and tissues. Measurement of lactoferrin may aid in the diagnosis of an inherited deficiency of this protein.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5580 Alpha-1-lipoprotein immunological test system.

(a) Identification. An alpha-1-lipoprotein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-1-lipoprotein (high-density lipoprotein) in serum and plasma. Measurement of alpha-1-lipoprotein may aid in the diagnosis of Tangier disease (a hereditary disorder of fat metabolism).

(b) Classification. Class II (performance standards).

§ 866.5590 Lipoprotein X immunological test system.

(a) Identification. A lipoprotein X immunological test system is a device that consists of the reagents used to measure by immunochemical techniques lipoprotein X (a high-density lipoprotein) in serum and other body fluids. Measurement of lipoprotein X aids in the diagnosis of obstructive liver disease.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5600 Low-density lipoprotein immunological test system.

(a) Identification. A low-density lipoprotein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the low-density lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein in serum may aid in the diagnosis of disorders of lipid (fat) metabolism and help to identify young persons at risk from cardiovascular diseases.

(b) Classification. Class II (performance standards).

§ 866.5620 Alpha-2-macroglobulin immunological test system.

(a) Identification. An alpha-2-macroglobulin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-2-macroglobulin (a serum protein) in plasma. Measurement of alpha-2-macroglobulin may aid in the diagnosis of blood-clotting or clot lysis disorders.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5630 Beta-2-microglobulin immunological test system.

(a) Identification. A beta-2-microglobulin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques beta-2-microglobulin (a protein molecule) in serum, urine, and other body fluids. Measurement of beta-2-microglobulin aids in the diagnosis of active rheumatoid arthritis and kidney disease.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5640 Infectious mononucleosis immunological test system.

(a) Identification. An infectious mononucleosis immunological test system is a device that consists of the reagents used to measure by immunochemical techniques heterophile antibodies frequently associated with infectious mononucleosis in serum, plasma, and other body fluids. Measurements of these antibodies aid in the diagnosis of infectious mononucleosis.

(b) Classification. Class II (performance standards).

§ 866.5660 Multiple autoantibodies immunological test system.

(a) Identification. A multiple autoantibodies immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when the body's own tissues are injured by autoantibodies).

(b) Classification. Class II (performance standards).

§ 866.5665 Aquaporin-4 autoantibody immunological test system.

(a) Identification. An Aquaporin-4 autoantibody immunological test system is a device that consists of reagents used to measure by immunochemical techniques autoantibodies in human serum samples that react with Aquaporin-4 (AQP4Ab). The measurements aid in the diagnosis of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) in conjunction with other clinical, laboratory, and radiological (e.g., magnetic resonance imaging) findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the following information:

(i) A detailed device description including:

(A) A detailed description of all components including all required ancillary reagents in the test;

(B) If applicable, a detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals;

(C) If applicable, detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software;

(D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the specified testing procedures;

(E) Detailed specifications for sample collection, processing, and storage;

(F) A detailed description of methodology and assay procedure;

(G) A description of how the assay cutoff (the medical decision point between positive and negative) was established and validated as well as supporting data; and

(H) Detailed specification of the criteria for test results interpretation and reporting.

(ii) Detailed information demonstrating the performance characteristics of the device, including:

(A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-site, and total precision for multiple nonconsecutive days, as applicable. A well characterized panel of patient samples or pools from the indicated population that covers the device measuring range must be used.

(B) Device linearity data generated from samples covering the device measuring range, if applicable.

(C) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable.

(D) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable.

(E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions.

(F) Device instrument carryover data, when applicable.

(G) Device stability data, including real-time stability under various storage times and temperatures.

(H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions, where appropriate.

(I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indications of use. A well-characterized panel of patient samples from the indicated population covering the device measuring range must be used.

(J) Specimen matrix comparison data, if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from well-characterized patient samples covering the device measuring range.

(K) Clinical performance must be established by comparing data generated by testing samples from the indicated population and the differential diagnosis or non-target disease groups with the device to the clinical diagnostic standard.

(1) The diagnosis of NMO and NMOSD must be based on clinical findings, laboratory tests (e.g., serological tests), and radiological tests (e.g., magnetic resonance imaging).

(2) The differential diagnosis or non-target disease group must include the applicable diseases or conditions, including but not be limited to the following: Multiple sclerosis, stroke, Lyme disease, shingles, syphilis, human immunodeficiency virus, hepatitis B, tuberculosis, Srgen's syndrome, systemic lupus erythematous, systemic vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease, Type I diabetes, rheumatoid arthritis, Addison's disease, and myasthenia gravis.

(3) Diagnosis of diseases or conditions for the differential or non-target disease groups must be based on established diagnostic criteria and clinical evaluation.

(4) For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided.

(5) The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of NMO and NMOSD.

(6) The data must be summarized in tabular format comparing the interpretation of results to the disease status.

(L) Expected/reference values generated by testing an adequate number of samples from apparently healthy normal individuals.

(iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.

(2) The device's 21 CFR 809.10(b) compliant labeling must include warnings relevant to the device including:

(i) A warning statement that reads “The device is for use by laboratory professionals in a clinical laboratory setting”; and

(ii) A warning statement that reads “The device is not to be used as a stand-alone device but as an adjunct to other clinical information. A diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a single test result. The clinical symptoms, results from physical examination, laboratory tests (e.g., serological tests), and radiological tests (e.g. Magnetic Resonance Imaging), when appropriate, should always be taken into account when considering the diagnosis of NMO and NMOSD.”

(3) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.

§ 866.5670 Zinc transporter 8 autoantibody immunological test system.

(a) Identification. A zinc transporter 8 autoantibody immunological test system is a device that consists of reagents used to measure, by immunochemical techniques, the autoantibodies in human serum samples that react with Zinc Transporter 8 (ZnT8). The measurements aid in the diagnosis of Type 1 diabetes mellitus (autoimmune mediated diabetes) in conjunction with other clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the following information:

(i) A detailed description of the device that includes:

(A) A detailed description of all components in the test system, including a description of the assay components in the kit and all required ancillary reagents;

(B) A detailed description of instrumentation and equipment, and illustrations or photographs of non-standard equipment or methods if applicable;

(C) Detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software where applicable;

(D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the recommended testing procedures;

(E) Detailed specifications for sample collection, processing, and storage;

(F) A detailed description of methodology and assay procedure; and

(G) Detailed specification of the criteria for test results interpretation and reporting.

(ii) Information that demonstrates the performance characteristics of the device, including:

(A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-operator, between-instruments, between-site, and total precision for multiple nonconsecutive days as applicable. A well characterized panel of patient samples or pools from the intended use population that covers the device measuring range must be used;

(B) Device linearity data generated from patient samples covering the assay measuring range if applicable;

(C) Information on traceability to a reference material and description of value assignment of calibrators and controls if applicable;

(D) Device analytical sensitivity data, including limit of blank, limit of detection and limit of quantitation if applicable;

(E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions;

(F) Device instrument carryover data when applicable;

(G) Device stability data including real-time stability under various storage times and temperatures;

(H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions where appropriate;

(I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indication of use. Patient samples from the intended use population covering the device measuring range must be used;

(J) Specimen matrix comparison data if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from patient samples covering the device measuring range;

(K) A description of how the assay cut-off (the medical decision point between positive and negative) was established and validated as well as supporting data;

(L) Clinical performance must be established by comparing data generated by testing samples from the intended use population and the differential diagnosis groups with the device to the clinical diagnostic standard. The diagnosis of Type 1 diabetes mellitus must be based on clinical history, physical examination, and laboratory tests, such as one or more pancreatic or insulin autoantibody test. Because the intended use population for Type 1 diabetes mellitus includes subjects less than 18 years old, samples from representative numbers of these subjects must be included. Representative numbers of samples from all age strata must also be included. The differential diagnosis groups must include, but not be limited to the following: Type 2 diabetes mellitus; metabolic syndrome; latent autoimmune diabetes in adults; other autoimmune diseases such as celiac disease (without a concomitant diagnosis of Type 1 diabetes mellitus), systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto's thyroiditis; infection; renal disease; and testicular cancer. Diseases for the differential groups must be based on established diagnostic criteria and clinical evaluation. For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of Type 1 diabetes mellitus. The data must be summarized in tabular format comparing the interpretation of results to the disease status; and

(M) Expected/reference values generated by testing an adequate number of samples from apparently healthy normal individuals.

(iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.

(2) Your 21 CFR 809.10(a) compliant label and 21 CFR 809.10(b) compliant labeling must include warnings relevant to the assay including:

(i) A warning statement that reads, “The device is for use by laboratory professionals in a clinical laboratory setting”;

(ii) A warning statement that reads, “The test is not a stand-alone test but an adjunct to other clinical information. A diagnosis of Type 1 diabetes mellitus should not be made on a single test result. The clinical symptoms, results on physical examination, and laboratory tests (e.g., serological tests), when appropriate, should always be taken into account when considering the diagnosis of Type 1 diabetes mellitus and Type 2 diabetes mellitus”;

(iii) A warning statement that reads, “Absence of Zinc T8 autoantibody does not rule out a diagnosis of Type 1 diabetes mellitus”; and

(iv) A warning statement that reads, “The assay has not been demonstrated to be effective for monitoring the stage of disease or its response to treatment.”

(3) Your 21 CFR 809.10(b) compliant labeling must include a description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.

§ 866.5680 Myoglobin immunological test system.

(a) Identification. A myoglobin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the myoglobin (an oxygen storage protein found in muscle) in serum and other body fluids. Measurement of myoglobin aids in the rapid diagnosis of heart or renal disease.

(b) Classification. Class II (performance standards).

§ 866.5700 Whole human plasma or serum immunological test system.

(a) Identification. A whole human plasma or serum immunological test system is a device that consists of reagents used to measure by immunochemical techniques the proteins in plasma or serum. Measurements of proteins in plasma or serum aid in the diagnosis of any disease concerned with abnormal levels of plasma or serum proteins, e.g., agammaglobulinemia, allergies, multiple myeloma, rheumatoid vasculitis, or hereditary angioneurotic edema.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.

§ 866.5715 Plasminogen immunological test system.

(a) Identification. A plasminogen immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the plasminogen (an inactive substance from which plasmin, a blood-clotting factor, is formed) in serum, other body fluids, and tissues. Measurement of plasminogen levels may aid in the diagnosis of fibrinolytic (blood-clotting) disorders.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.

§ 866.5735 Prothrombin immunological test system.

(a) Identification. A prothrombin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the prothrombin (clotting factor II) in serum. Measurements of the amount of antigenically competent (ability to react with protein antibodies) prothrombin aid in the diagnosis of blood-clotting disorders.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9. This exemption does not apply to multipurpose systems for in vitro coagulation studies classified under § 864.5425 of this chapter or prothrombin time tests classified under § 864.7750 of this chapter.

§ 866.5750 Radioallergosorbent (RAST) immunological test system.

(a) Identification. A radioallergosorbent immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the allergen antibodies (antibodies which cause an allergic reaction) specific for a given allergen. Measurement of specific allergen antibodies may aid in the diagnosis of asthma, allergies, and other pulmonary disorders.

(b) Classification. Class II (special controls). The device, when intended to detect any of the allergens included in Table 1 in this paragraph, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.